Polyacetal polymers, conjugates, particles and uses thereof

This application is a 371 National Phase Entry of International Patent Application No. PCT/US2016/067149 filed on Dec. 16, 2016, which designates the U.S., and which claims benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 62/269,438 filed Dec. 18, 2015, the contents of which are incorporated herein by reference in their entirety.

This invention was made with Government support under Grant No. CA80124-15 awarded by the National Institutes of Health. The Government has certain rights in the invention.

The present invention generally relates to particles, such as nanoparticles, the polymers of which the particles are comprised, as well as to compositions thereof. The present invention also generally relates to methods of using the compositions provided for delivery of agents, such as one or more pharmaceutical agents (e.g., one or more drugs).

Advances in biomedical research have led to the introduction of several novel systemically administered molecular and nanotherapeutic agents in both preclinical and clinical settings (Jones. D. (2007) Nat Rev Drug Discov 6, 174-175; Moghimi, S. M. et al. (2005) Faseb J. 19, 311-330). While these new agents act on unique targets that afford greater specificity to target cells, e.g., tumor cells, or improved pharmacodynamic properties, their effectiveness suffers from limitations in their delivery owing to the properties of the target microenvironment (Jain, R. K. (1998) Nat Med 4, 655-657; Sanhai, W. R. et al. (2008) Nat Nanotechnol 3, 242-244; Chauhan, V et al. (2011) Annu Rev Chem Biomol Eng. 2(1):281-98). Limited approaches are currently available to overcome the delivery barriers for drugs.

Thus, the need exists for identifying new agents and formulations that enhance the delivery, distribution, and/or efficacy of therapeutic agents, including nanotherapeutics (e.g., lipid- or polymeric nanoparticles and viruses), protein and nucleic acid drugs, targeted therapies, immune therapies (e.g., immune checkpoint blockers, vaccines and/or immune cells), and small molecule chemotherapeutic agents.

The present invention discloses, at least in part, pH-sensitive and/or polyacetal polymers and/or linkers; conjugates comprising said polymers and/or linkers, optionally, coupled to one or more agents and/or targeting moieties; and particles (e.g., nanoparticles comprising the aforesaid polymers, linkers and/or conjugates), collectively referred to herein as “compositions,” which can be used to enhance the delivery and/or efficacy of one or more agents in a subject.

Without wishing to be bound by theory, the compositions disclosed herein may improve the efficiency of an agent, e.g., a therapeutic and/or diagnostic agent. In one embodiment, the compositions can result in one or more of: (i) increasing the localization and/or delivery of the agent to a target cell or tissue (e.g., a cancer or a fibrotic cell or tissue; or a liver cell or tissue); (ii) selectively penetrating into a fibrotic tissue (e.g., a desmoplastic tumor or a fibrotic tissue chosen from liver, kidney, lung or bone marrow (e.g., myelofibrotic bone marrow)); (iii) selectively penetrating into a diseased blood vessel (e.g., a leaky tumor vessel); (iv) exhibiting increased pH-sensitivity and/or enhanced agent release in a hypoxic microenvironment, e.g., in a tumor or a fibrotic tissue (e.g., fibrotic or cirrhotic liver, or a tissue having renal fibrosis, pulmonary fibrosis or myelofibrosis); (v) increasing the selective delivery and/or release of the agent to the tumor or fibrotic tissue; or (vi) increasing the half-life of the agent. In some embodiments, by selectively targeting an agent to a cell or tissue in need (e.g., a cancer or a fibrotic tissue), the composition described herein can comprise an agent at a concentration that would otherwise produce an adverse effect when administered systemically as a free form (e.g., not coupled to pH-sensitive and/or polyacetal polymer or particle as described herein).

Certain embodiments disclosed herein provide compositions and methods for treating or preventing a disorder. In some embodiments, the disorder is a fibrotic disorder. In some embodiments, the disorder is a cancer disorder (e.g., a desmoplastic tumor or metastatic lesion). In some embodiments, the disorder is a liver disease or disorder. These embodiments comprise administering to a subject a particle, e.g., a pH-sensitive and/or polyacetal particle described herein, as a single agent or as a combination with one or more therapeutic agents. The compositions disclosed herein can result in a higher amount of released agent at a target site (e.g., in a hypoxic tumor), while having minimal or no effect at other non-target sites (e.g., in intact and/or healthy blood vessels and/or normal or healthy tissues). In one embodiment, the agent delivered or released is a therapeutic and/or diagnostic agent (e.g., an Anti-hypertensive and/or Collagen Modifying Agent (AHCM) (e.g., an angiotensin receptor blocker (ARB) as described herein). Alternatively, or in combination, the agent delivered or released is an anti-cancer therapeutic agent and/or a liver therapeutic agent. Thus, provided herein are compositions and methods for improving the delivery and/or efficacy of a therapy (e.g., a cancer, anti-fibrotic, or a liver therapy), ranging in size from a cell (e.g., an immune cell) or a large nanotherapeutic (e.g., lipid- or polymeric nanoparticles and viruses), protein and nucleic acid drugs, to low molecular weight chemotherapeutics and/or oxygen radicals.

Polymers

In one aspect, the invention features a pH-sensitive polymer, e.g., a polymer comprising a polyacetal polymer (e.g., a polyacetal polymer of Formula (I), Formula (I-a), or Formula (IV) described herein).

In some embodiments, the average molecular weight of the polymer (e.g., a polyacetal polymer as described herein) used in a particle (e.g., a micelle or a nanoparticle as described herein) is from about 2 kDa to about 200 kDa, (e.g., from about 2.5 kDa to about 175 kDa, from about 5 kDa about 150 kDa, from about 10 kDa to about 125 kDa, from about 12.5 kDa to about 100 kDa, from about 15 kDa to about 90 kDa, from about 17.5 kDa to about 80 kDa, from about 20 kDa to about 70 kDa, from about 22.5 kDa to about 60 kDa, or from about 25 kDa to about 50 kDa). In some embodiments, the average molecular weight of the polymer used in a particle (e.g., a micelle or a nanoparticle as described herein) is from about 5 kDa to about 100 kDa (e.g., from about 6 kDa to about 90 kDa, from about 7 kDa to about 95 kDa, from about 8 kDa to about 85 kDa, from about 9 kDa to about 80 kDa, from about 10 kDa to about 75 kDa, from about 11 kDa to about 70 kDa, from about 12 kDa to about 65 kDa, from about 13 kDa to about 60 kDa, from about 14 kDa to about 55 kDa, or from about 15 kDa to about 50 kDa). In some embodiments, the average molecular weight of the polymer used in a particle (e.g., a micelle or a nanoparticle as described herein) is from about 7 kDa to about 100 kDa, (e.g., from about 7 kDa to about 95 kDa, about 7 kDa to about 90 kDa, about 7 kDa to about 80 kDa, about 7 kDa to 75 kDa, about 7 kDa to about 70 kDa, about 7 kDa to about 65 kDa, about 7 kDa to about 60 kDa, about 7 kDa to about 55 kDa, about 7 kDa to about 50 kDa, about 7 kDa to about 45 kDa, about 7 kDa to about 40 kDa, about 7 kDa to about 35 kDa, about 7 kDa to about 30 kDa, about 7 kDa to about 25 kDa, about 7 kDa to about 20 kDa, about 7 kDa to about 15 kDa, or from about 7 kDa to about 75 kDa, about 7.5 kDa to about 75 kDa, about 10 kDa to about 75 kDa, about 12.5 kDa to about 75 kDa, about 15 kDa to about 75 kDa, about 17.5 kDa to about 75 kDa, about 20 kDa to about 75 kDa, about 22.5 kDa to about 75 kDa, about 25 kDa to about 75 kDa, about 27.5 kDa to about 75 kDa, about 30 kDa to about 75 kDa, about 32.5 kDa to about 75 kDa, about 35 kDa to about 75 kDa, about 40 kDa to about 75 kDa, about 42.5 kDa to about 75 kDa, about 45 kDa to about 75 kDa, about 47.5 kDa to about 75 kDa, or about 50 kDa to about 75 kDa). In one embodiment, the average molecular weight of the polymer used in a particle (e.g., a micelle or a nanoparticle as described herein) is from about 5 kDa to about 50 kDa. In another embodiment, the average molecular weight of the polymer used in a particle (e.g., a micelle or a nanoparticle as described herein) is from about 10 kDa to about 50 kDa. In another embodiment, the average molecular weight of the polymer used in a particle (e.g., a micelle or a nanoparticle as described herein) is from about 15 kDa to about 40 kDa. In another embodiment, the average molecular weight of the polymer used in a particle (e.g., a micelle or a nanoparticle as described herein) is from about 15 kDa to about 25 kDa. In another embodiment, the average molecular weight of the polymer used in a particle (e.g., a micelle or a nanoparticle as described herein) is from about 20 kDa to about 40 kDa. In another embodiment, the average molecular weight of the polymer used in a particle (e.g., a micelle or a nanoparticle as described herein) is from about 10 kDa to about 100 kDa. In another embodiment, the average molecular weight of the polymer used in a particle (e.g., a micelle or a nanoparticle as described herein) is from about 10 kDa to about 50 kDa. In some embodiments, the average molecular weight of the polymer used in a particle (e.g., a micelle or a nanoparticle as described herein) is not less than about 10 KDa, about 9 kDa, about 8 kDa, about 7 kDa, about 6 kDa, or about 5 kDa.

In one embodiment, the polymer is sensitive to a pH between about 5.0 and about 7.4, between 5.0 and 7.0, between 5.0 and 6.5, between 5.0 and 5.5, or between 5.9 and 6.2. In one embodiment, the polymer is sensitive to a pH between about 6.0 and about 7.0, between about 6.2 and about 6.9, between about 6.5 and about 6.8, or between about 6.5 and about 6.7. In one embodiment, the polymer is sensitive to a pH between about 5.5 and about 6.5, e.g., between 5.9 and 6.2. In one embodiment, the polymer is sensitive to a hypoxic pH, e.g., a pH about 6.7 to 6.9, e.g., compared to a physiological pH of about 7.4.

In some embodiments, the polymer is sensitive to a pH of no more than 7.4, no more than 7.0, no more than 6.9, no more than 6.8, no more than 6.7, no more than 6.6, no more than 6.5, no more than 6.4, no more than 6.3, no more than 6.2, no more than 6.1, no more than 6.0, no more than 5.5 or lower.

In one embodiment, the polymer is preferentially cleaved or degraded upon exposure to a first pH relative to a second pH. In one embodiment, the polymer is cleaved or degraded at least 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, or 100 times faster upon exposure to a first pH relative to a second pH. In other embodiments, the polymer shows a greater release or degradation rate at a first acidic pH (e.g., pH=6.7) relative to a second more basic pH (e.g., pH=7.4). In one embodiment, ratio of release or degradation rate of the polymer (e.g., when present in a linker, a conjugate (e.g., an agent-polymer conjugate) or a particle (e.g., a nanoparticle)) at pH=6.7 relative to pH=7.4 is greater than 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3 or higher. In one embodiment, ratio of release or degradation rate of the polymer at pH=6.7 relative to pH=7.4 is greater than 2. In one embodiment, the polymer shows increased pH-sensitivity in a hypoxic microenvironment, e.g., in a tumor, or fibrotic tissue.

In some embodiments, the polymer (e.g., the polyacetal polymer) is soluble in water (e.g., hydrophilic). In some embodiments, the polymer (e.g., the polyacetal polymer) is soluble in water, and between about 0.1 to about 5 parts water are required to dissolve 1 part polymer, or between about 1 part to about 5 parts water are required to dissolve 1 part polymer. In some embodiments, the polymer (e.g., the polyacetal polymer) is partially soluble in water. In some embodiments, the polymer (e.g., the polyacetal polymer) is partially soluble in water, and between about 5 to about 50 parts water are required to dissolve 1 part polymer. In some embodiments, the polymer (e.g., the polyacetal polymer) is sparingly soluble in water. In some embodiments, the polymer (e.g., the polyacetal polymer) is sparingly soluble in water, and between about 25 to about 100 parts water is required to dissolve 1 part polymer. In some embodiments, the polymer (e.g., the polyacetal polymer) is slightly soluble in water. In some embodiments, the polymer (e.g., the polyacetal polymer) is slightly soluble in water, and between 100 to about 1,000 parts water are required to dissolve 1 part polymer. In some embodiments, the polymer (e.g., the polyacetal polymer) is very slightly soluble in water. In some embodiments, the polymer (e.g., the polyacetal polymer) is very slightly soluble in water, and between 1,000 to about 10,000 parts water are required to dissolve 1 part polymer. In some embodiments, the polymer (e.g., the polyacetal polymer) is substantially insoluble in water (e.g., hydrophobic). In some embodiments, the polymer (e.g., the polyacetal polymer) is substantially insoluble in water and greater than about 10,000 parts water are required to dissolve 1 part polymer.

In one embodiment, the polymer (e.g., a polyacetal polymer) is amphiphilic. In one embodiment, the polymer (e.g., a polyacetal polymer) comprises a segment that is hydrophobic and a segment that is hydrophilic.

In some embodiments, the polymer (e.g., a polyacetal polymer) is a liquid (e.g., a fluid liquid) at room temperature (e.g., at 25° C.). In some embodiments, the polymer (e.g., a polyacetal polymer) is viscous (e.g., a viscous liquid) at room temperature (e.g., at 25° C.). In some embodiments, the polymer (e.g., a polyacetal polymer) is a gel at room temperature (e.g., at 25° C.). In some embodiments, the polymer (e.g., a polyacetal polymer) is solid (e.g., a crystalline, semi-crystalline, amorphous, glassy, or rubbery solid) at room temperature (e.g., at 25° C.). In some embodiments, the melting temperature (T m ) of the polymer (e.g., a polyacetal polymer) is greater than about 25° C. In some embodiments, the melting temperature (T m ) of the polymer (e.g., a polyacetal polymer) is greater than about 30° C., about 32° C., about 34° C., about 36° C., about 38° C., about 40° C., about 42° C., about 44° C., about 46° C., about 48° C., about 50° C., or higher. In some embodiments, the melting temperature (T m ) of the polymer (e.g., a polyacetal polymer) is between about 30° C. and about 50° C. In some embodiments, the melting temperature (T m ) of the polymer (e.g., a polyacetal polymer) is between about 35° C. and about 45° C.

In some embodiments, the polymer (e.g., the polyacetal polymer) comprises a linear structure. In some embodiments, the polymer (e.g., the polyacetal polymer) comprises a branched structure. In some embodiments, the polymer (e.g., the polyacetal polymer) comprises a branched structure, and each repeating unit in the polymer comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, or at least 8 branch points.

In some embodiments, the polymer (e.g., the polyacetal polymer) comprises a structure according to Formula (I):

wherein:

each of A 1 and A 2 is independently heteroalkylene, heteroalkenylene, heteroalkynylene, heterocyclyl, aryloxy, heteroaryloxy, wherein each heteroalkylene, heteroalkenylene, heteroalkynylene, heterocyclyl, aryloxy, or heteroaryloxy is optionally substituted with 1-5 R 1 ;

each of B 1 and B 2 is independently heteroalkyl, or heterocyclyl, each of which is optionally substituted with 1-6 R 2 ;

each of C 1 and C 2 is independently heteroalkyl, cyclyl, or heterocyclyl, each of which is optionally substituted with 1-6 R 3 , e.g., each of C 1 and C 2 is independently PEG400, PEG1000, or PEG2050;

each of R 1 , R 2 , and R 3 is independently alkyl, alkenyl, alkynyl, hydroxyl, halo, heteroalkyl, keto, alkoxy, ester, cyclyl, heterocyclyl, cycloalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, a linker, an agent, a targeting moiety, a protecting group, or a branching point; and

each of m or n is independently an integer from 1 to 500.

In some embodiments of a polymer of Formula (I), each of A 1 and A 2 is independently heteroalkyl or aryloxy, each of which may be optionally substituted with 1-5 R 1 . In some embodiments, each of A 1 and A 2 is independently heteroalkyl, each of which may be optionally substituted with 1-5 R 1 . In some embodiments, each of A 1 and A 2 is independently C 1 -C 20 heteroalkyl, each of which may be optionally substituted with 1-5 R 1 . In some embodiments, each of A 1 and A 2 is the same C 1 -C 20 heteroalkyl, each of which may be optionally substituted with 1-5 R 1 . In some embodiments, each of A 1 and A 2 is a different C 1 -C 20 heteroalkyl, each of which may be optionally substituted with 1-5 R 1 .

In some embodiments, each of A 1 and A 2 is independently represented by a moiety of Formula (II):

wherein:

X 1 is C 1 -C 12 alkylene, C 2 -C 12 alkenylene, C 2 -C 12 alkynylene, C 1 -C 12 heteroalkylene, C 3 -C 8 cyclyl, or C 3 -C 8 heterocyclyl, wherein each alkylene, alkenylene, alkynylene, heteroalkylene, cyclyl, or heterocyclyl is optionally substituted with 1-6 R 4 ;

each R 4 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, OR 5 , (C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-NR 6 —(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-C(O)NR 6 —(C 1 -C 6 alkylene)-OR 5 , or (C 1 -C 6 alkylene)-NR 6 C(O)—(C 1 -C 6 alkylene)-OR 5 , wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 7 ;

each R 5 is independently hydrogen, C 1 -C 6 alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, a linker, an agent, a targeting moiety, a protecting group, or a branching point, wherein each alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl is optionally substituted with 1-6 R 8 ;

R 6 is hydrogen or C 1 -C 6 alkyl;

each R 7 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, halo, OR 5 , (C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 5 , cyano, cyclyl, heterocyclyl, aryl, or heteroaryl; and

each R 8 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, halo, cyano, cyclyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-6 R 9 ; and

each R 9 is independently C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, cyano, cyclyl, or heterocyclyl.

In some embodiments, X 1 is C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 1 -C 8 cyclyl, or C 1 -C 8 heterocyclyl, wherein each alkylene, heteroalkylene, cyclyl, or heterocyclyl is optionally substituted with 1-6 R 4 . In some embodiments, X 1 is C 1 -C 12 alkylene or C 1 -C 12 heteroalkylene, optionally substituted with 1-6 R 4 . In some embodiments, X 1 is C 1 -C 6 alkylene, optionally substituted with 1-6 R 4 . In some embodiments, X 1 is C 1 -C 12 heteroalkylene, optionally substituted with 1-6 R 4 .

In some embodiments, X 1 is C 3 -C 8 cyclyl or C 3 -C 8 heterocyclyl, wherein each cyclyl or heterocyclyl is optionally substituted with 1-6 R 4 . In some embodiments, X 1 is C 3 -C 6 cyclyl or C 3 -C 6 heterocyclyl, wherein each cyclyl or heterocyclyl is optionally substituted with 1-6 R 4 . In some embodiments, X 1 is C 3 -C 6 cyclyl, optionally substituted with 1-6 R 4 . In some embodiments, X 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1-6 R 4 . In some embodiments, X 1 is cyclopentyl or cyclohexyl, each of which is optionally substituted with 1-6 R 4 . In some embodiments, X 1 is cyclopentyl or cyclohexyl, each of which is optionally substituted with 1-4 R 4 . In some embodiments, X 1 is cyclopentyl or cyclohexyl, each of which is optionally substituted with 1-2 R 4 , and each R 4 is independently C 1 -C 6 alkyl or OR 5 . In some embodiments, X 1 is cyclohexyl substituted with 1 R 4 . In some embodiments, X 1 is cyclohexyl substituted with OR 5 .

In some embodiments, R 5 is hydrogen, C 1 -C 6 alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is arylalkyl or heteroarylalkyl. In some embodiments, R 5 is a linker. In some embodiments, R 5 is an agent (e.g., an ARB). In some embodiments, R 5 is a targeting moiety. In some embodiments, R 5 is a protecting group. In some embodiments, R 5 is a branching point.

In some embodiments, each of A 1 and A 2 does not independently include, or is independently not derived from, tri(methylol)ethane. In some embodiments, each of A 1 and A 2 does not independently include, or is not independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 5 kDa in size. In some embodiments, each of A 1 and A 2 does not independently include, or is not independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 10 kDa in size.

In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane. In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 5 kDa in size. In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 10 kDa in size.

In some embodiments of a polymer of Formula (I), each of A 1 and A 2 is independently hydrophobic. In some embodiments, each of A 1 and A 2 has a partition coefficient (c Log P) value greater than about −2.0. In some embodiments, each of A 1 and A 2 has a c Log P value greater than about −1.5, e.g., about −1.4, about −1.3, about −1.2, about −1.1, about −1.0, about −0.9, about −0.8, about −0.7, about −0.6, about −0.5, about −0.4, about −0.3, about −0.2, about −0.1, about 0, or higher. In some embodiments, each of A 1 and A 2 has a c Log P value between about −2.0 and 2.5. In some embodiments, each of A 1 and A 2 has a c Log P value greater than about −0.5, e.g., about −0.4, about −0.3, about −0.2, about −0.1, about 0, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, or higher. In some embodiments, each of A 1 and A 2 has a c Log P value greater than about 0, e.g., about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, or higher. In some embodiments, each of A 1 and A 2 has a c Log P value between about −2.0 and 4.0.

In some embodiments, each of A 1 and A 2 has a linear structure. In some embodiments, each of A 1 and A 2 has a branched structure. In some embodiments, each of A 1 and A 2 comprises a protected reactive group, e.g., a protected hydroxyl, a protected carboxylic acid, or a protected amine. In some embodiments, each of A 1 and A 2 comprises 1, 2, 3, 4, 5, 6, 7, 8, or more protected reactive groups, e.g., a protected hydroxyl, a protected carboxylic acid, or a protected amine.

In some embodiments, each of A 1 and A 2 is represented by a compound of Formula (II-a):

wherein:

each of X 2 and X 3 is independently C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 12 alkynylene, C 1 -C 12 heteroalkylene, C 3 -C 8 cyclyl, C 3 -C 8 heterocyclyl, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-NR 13 —(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)NR 13 —(C 1 -C 6 alkylene), or (C 1 -C 6 alkylene)-NR 13 C(O)—(C 1 -C 6 alkylene), wherein each alkylene, alkenylene, alkynylene, heteroalkylene, cyclyl, or heterocyclyl is optionally substituted with 1-6 R 12 ;

R 10 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, OR 14 , (C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-NR 13 —(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-C(O)NR 13 —(C 1 -C 6 alkylene)-OR 14 , or (C 1 -C 6 alkylene)-NR 13 C(O)—(C 1 -C 6 alkylene)-OR 14 , wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 15 ;

R 11 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, OR 14 , (C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-NR 13 —(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-C(O)NR 13 —(C 1 -C 6 alkylene)-OR 14 , or (C 1 -C 6 alkylene)-NR 13 C(O)—(C 1 -C 6 alkylene)-OR 14 , wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 15 ;

each R 12 and R 15 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, halo, OR 14 , (C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 14 , cyano, cyclyl, heterocyclyl, aryl, or heteroaryl;

R 13 is hydrogen or C 1 -C 6 alkyl;

R 14 is hydrogen, C 1 -C 6 alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, a linker, a branching point, a protecting group, an agent, or a targeting moiety, wherein each alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl is optionally substituted with 1-6 R 16 , and

each R 16 is independently C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, cyano, cyclyl, or heterocyclyl.

In some embodiments, each of X 2 and X 3 is independently C 1 -C 6 alkylene, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene), wherein each alkyl or alkylene is optionally substituted with 1-6 R 8 . In some embodiments, each of X 1 and X 2 is independently C 1 -C 4 alkyl, (C 1 -C 4 alkylene)-O—(C 1 -C 4 alkylene), (C 1 -C 4 alkylene)-C(O)—(C 1 -C 4 alkylene), (C 1 -C 4 alkylene)-OC(O)—(C 1 -C 4 alkylene), (C 1 -C 4 alkylene)-C(O)O—(C 1 -C 4 alkylene), (C 1 -C 4 alkylene)-OC(O)O—(C 1 -C 4 alkylene), wherein each alkyl or alkylene is optionally substituted with 1-6 R 12 .

In some embodiments, each of X 2 and X 3 is independently C 1 -C 2 alkylene, e.g., CH 2 , CH 2 CH 2 . In some embodiments, each of X 2 and X 3 is independently (C 1 -C 4 alkylene)-O—(C 1 -C 4 alkylene), e.g., CH 2 —O—CH 2 CH 2 , CH 2 CH 2 —O—CH 2 CH 2 . In some embodiments, each of X 1 and X 2 is independently (C 1 -C 4 alkylene)-OC(O)—(C 1 -C 4 alkylene), e.g., CH 2 —OC(O)—CH 2 , CH 2 —OC(O)—CH 2 CH 2 , CH 2 —OC(O)—CH(CH 3 ), CH 2 —OC(O)—CH 2 CH 2 CH 2 , CH 2 CH 2 —OC(O)—CH 2 , CH 2 CH 2 —OC(O)—CH 2 CH 2 , CH 2 CH 2 —OC(O)—CH(CH 3 ). In some embodiments, each of X 2 and X 3 is independently (C 1 -C 4 alkylene)-OC(O)O—(C 1 -C 4 alkylene), e.g., CH 2 —OC(O)O—CH 2 CH 2 ). In some embodiments, each of X 2 and X 3 is the same.

In some embodiments, R 10 is C 1 -C 6 alkyl, (C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-OR 14 , wherein each alkyl or alkylene is optionally substituted with 1-6 R 15 . In some embodiments, R 10 is C 1 -C 6 alkyl, e.g., CH 3 , CH 2 CH 3 . In some embodiments, R 10 is (C 1 -C 6 alkylene)-OR 14 , e.g., CH 2 OR 14 , CH 2 CH 2 OR 14 . In some embodiments, R 10 is (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 14 , In some embodiments, R 10 is (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-OR 14 , e.g., CH 2 —OC(O)—CH 2 , CH 2 —OC(O)—CH 2 CH 2 , CH 2 —OC(O)—CH(CH 3 ), CH 2 —OC(O)—CH 2 CH 2 CH 2 , CH 2 CH 2 —OC(O)—CH 2 , CH 2 CH 2 —OC(O)—CH 2 CH 2 , CH 2 CH 2 —OC(O)—CH(CH 3 ). In some embodiments, R 10 is (C 1 -C 4 alkylene)-OC(O)O—(C 1 -C 4 alkylene), e.g., CH 2 —OC(O)O—CH 2 CH 2 ).

In some embodiments, R 11 is hydrogen or C 1 -C 6 alkyl. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is C 1 -C 6 alkyl. In some embodiments, R 11 is C 1 -C 4 alkyl, e.g., CH 3 , CH 2 CH 3 . In some embodiments. R 11 is (C 1 -C 6 alkylene)-OR 14 , e.g., CH 2 OR 14 , CH 2 CH 2 OR 14 .

In some embodiments, R 14 is hydrogen, C 1 -C 6 alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl. In some embodiments, R 14 is hydrogen. In some embodiments, R 14 is arylalkyl or heteroarylalkyl. In some embodiments, R 14 is a linker. In some embodiments, R 14 is an agent (e.g., an ARB). In some embodiments, R 14 is a targeting moiety. In some embodiments, R 14 is a protecting group. In some embodiments, R 14 is a branching point.

In some embodiments, each of A 1 and A 2 does not independently include, or is not independently derived from, tri(methylol)ethane. In some embodiments, each of A 1 and A 2 does not independently include, or is not independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 5 kDa in size. In some embodiments, each of A 1 and A 2 does not independently include, or is not independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 10 kDa in size.

In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane. In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 5 kDa in size. In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 10 kDa in size.

In some embodiments, the agent is a therapeutic or a diagnostic agent as described herein. In some embodiments, the agent is an AHCM as described herein. In some embodiments, the agent is an ARB as described herein, e.g., losartan, valsartan, telmisartan, candesartan, eprosartan, irbesartan, azilsartan, EXP-3174, olmesartan, or a prodrug or active metabolite thereof, e.g., a compound shown in FIG. 23 .

In some embodiments, the agent is a vitamin D analog or derivative as described herein. In some embodiments, the agent is a vitamin D analog or derivative as described herein, e.g., paricalcitol, doxercalciferol, falecalcitriol, maxacalcitol, tacalcitol, alfacalcidol, eldecalcidol, seocalcitol, lexicalcitol, CD578, inecalcitol, calcipotriol, TX527, 2MD, WY1112, PRI-2205, ILX23-7553, ercalcitriol, EB1089 (seocalcitol), BXL-628 (elocalcitol), MC1288, CB966, BCB 1093, GS1558, SM-10193, EB1072, EB1129, EB1133, EB1155, EB1270, MC1288, EB1213, CB1093, VD2656, VD2668, VD2708, VD2716, VD2728, VD2736, GS1500, GS1558, KH1060, ZK161422, and analogs and derivatives thereof, e.g., as shown in FIG. 24 .

In some embodiments, the agent is a bromodomain and extra-terminal protein inhibitor (i-BET) as described herein. In some embodiments, the agent is a bromodomain and extra-terminal protein inhibitor (i-BET) as described herein, e.g MS436, PFI-1, I-BET 151, OTX-015, JQ1, CPI-203, bromosporine, RVX-208, I-BET 762, I-BET 151, OFXBD02, OFXBD03, XD14, AZD5153, and analogs and derivatives thereof, e.g., as shown in FIGS. 25A and 25B .

In some embodiments, the agent is an IDO inhibitor (i.e., indoleamine 2,3-dioxygenase (IDO) pathway inhibitor) as described herein. In some embodiments, the agent is an IDO inhibitor as described herein, e.g., GDC-0919, indoximod, 1-methyltryptophan (e.g., 1-methyl- L -tryptophan, 1-methyl- D -tryptophan), NLG8189, INCB024360, NLG919, methylthiohydantoin tryptophan, brassinin, annulin B, exiguamine A, INCB023843, or an analog or derivative thereof.

In some embodiments, each of A 1 and A 2 is represented by a compound of Formula (II-b):

wherein:

each of X 2 and X 3 is independently C 1 -C 6 alkylene, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene), or (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene);

R 10 is C 1 -C 6 alkyl, (C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-OR 14 , or (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-OR 14 , wherein each alkylene is optionally substituted with 1-4 (C 1 -C 6 alkylene)-OR 14 ;

R 11 is hydrogen, C 1 -C 6 alkyl, or (C 1 -C 6 alkylene)-OR 14 ; and

R 14 is hydrogen, C 1 -C 6 alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, a linker, an agent, a targeting moiety, a protecting group, or a branching point.

In some embodiments, each of X 2 and X 3 is independently C 1 -C 2 alkylene, e.g., CH 2 , CH 2 CH 2 . In some embodiments, each of X 2 and X 3 is independently (C 1 -C 4 alkylene)-O—(C 1 -C 4 alkylene), e.g., CH 2 —O—CH 2 CH 2 , CH 2 CH 2 —O—CH 2 CH 2 . In some embodiments, each of X 1 and X 2 is independently (C 1 -C 4 alkylene)-OC(O)—(C 1 -C 4 alkylene), e.g., CH 2 —OC(O)—CH 2 , CH 2 —OC(O)—CH 2 CH 2 , CH 2 —OC(O)—CH(CH 3 ), CH 2 —OC(O)—CH 2 CH 2 CH 2 , CH 2 CH 2 —OC(O)—CH 2 , CH 2 CH 2 —OC(O)—CH 2 CH 2 , CH 2 CH 2 —OC(O)—CH(CH 3 ). In some embodiments, each of X 2 and X 3 is independently (C 1 -C 4 alkylene)-OC(O)O—(C 1 -C 4 alkylene), e.g., CH 2 —OC(O)O—CH 2 CH 2 ). In some embodiments, each of X 2 and X 3 is the same.

In some embodiments, R 10 is C 1 -C 6 alkyl, e.g., CH 3 , CH 2 CH 3 . In some embodiments, R 10 is (C 1 -C 6 alkylene)-OR 14 , e.g., CH 2 OR 14 , CH 2 CH 2 OR 14 . In some embodiments, R 10 is (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 14 , In some embodiments, R 10 is (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-OR 14 , e.g., CH 2 —OC(O)—CH 2 , CH 2 —OC(O)—CH 2 CH 2 , CH 2 —OC(O)—CH(CH 3 ), CH 2 —OC(O)—CH 2 CH 2 CH 2 , CH 2 CH 2 —OC(O)—CH 2 , CH 2 CH 2 —OC(O)—CH 2 CH 2 , CH 2 CH 2 —OC(O)—CH(CH 3 ). In some embodiments, R 10 is (C 1 -C 4 alkylene)-OC(O)O—(C 1 -C 4 alkylene), e.g., CH 2 —OC(O)O—CH 2 CH 2 ).

In some embodiments, R 11 is hydrogen or C 1 -C 6 alkyl. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is C 1 -C 6 alkyl. In some embodiments, R 11 is C 1 -C 4 alkyl, e.g., CH 3 , CH 2 CH 3 . In some embodiments, R 11 is (C 1 -C 6 alkylene)-OR 14 , e.g., CH 2 OR 14 , CH 2 CH 2 OR 14 .

In some embodiments, R 14 is hydrogen, C 1 -C 6 alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl. In some embodiments, R 14 is hydrogen. In some embodiments, R 14 is arylalkyl or heteroarylalkyl. In some embodiments, R 14 is a linker. In some embodiments, R 14 is an agent (e.g., an ARB). In some embodiments, R 14 is a targeting moiety. In some embodiments, R 14 is a protecting group. In some embodiments, R 14 is a branching point.

In some embodiments, each of A 1 and A 2 is the same. In some embodiments, each of A 1 and A 2 is the same, e.g., the same compound of Formula (II), Formula (II-a), or Formula (II-b). In some embodiments, each of A 1 and A 2 is different. In some embodiments, each of A 1 and A 2 is the different, e.g., a different compound of Formula (II), Formula (II-a), or Formula (II-b).

In some embodiments, the precursor of each of A 1 and A 2 is independently selected from the following polyols:

In some embodiments, the precursor to each of A 1 and A 2 is independently selected from one of A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A4, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, and A32, e.g., as depicted in FIG. 1B . It is to be understood that when the precursor to A 1 or A 2 is one of the polyols in the above-noted group selected from A1-A32, B 1 or B 2 is connected to one of the oxygen atoms of the hydroxyl groups in said polyols.

In some embodiments, X 1 includes or is derived from a polyol selected from one of A3, A4, A5, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, and A32, e.g., as depicted in FIG. 1B . It is to be understood that when the precursor to A 1 or A 2 is one of the polyols in the above-noted group selected from A1-A32, B 1 or B 2 is connected to one of the oxygen atoms of the hydroxyl groups in said polyols.

In some embodiments, each of A 1 and A 2 is represented by a compound of Formula (II-c):

wherein:

X 1 includes or is derived from any of the polyols shown in FIG. 1B , e.g., a polyol selected from one of A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, and A32, and two of the hydroxyl groups of the polyol are replaced by the oxygen atoms in Formula (II-c).

In some embodiments, X 1 includes or is derived from a polyol selected from one of A3, A4, A5, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, and A32, and two of the hydroxyl groups of the polyol are replaced by the oxygen atoms in Formula (II-c).

In some embodiments, X 1 includes or is derived from A1. In some embodiments, X 1 includes or is derived from A2. In some embodiments, X 1 includes or is derived from A3. In some embodiments, X 1 includes or is derived from A4. In some embodiments, X 1 includes or is derived from A5. In some embodiments, X 1 includes or is derived from A6. In some embodiments, X 1 includes or is derived from A7. In some embodiments, X 1 includes or is derived from A8. In some embodiments, X 1 includes or is derived from A9. In some embodiments, X 1 includes or is derived from A10. In some embodiments, X 1 includes or is derived from A11. In some embodiments, X 1 includes or is derived from A12. In some embodiments, X 1 includes or is derived from A13. In some embodiments, X 1 includes or is derived from A14. In some embodiments, X 1 includes or is derived from A15. In some embodiments, X 1 includes or is derived from A16. In some embodiments, X 1 includes or is derived from A17. In some embodiments, X 1 includes or is derived from A18. In some embodiments, X 1 includes or is derived from A19. In some embodiments, X 1 includes or is derived from A20. In some embodiments, X 1 includes or is derived from A21. In some embodiments, X 1 includes or is derived from A22. In some embodiments, X 1 includes or is derived from A23. In some embodiments, X 1 includes or is derived from A24. In some embodiments, X 1 includes or is derived from A25. In some embodiments, X 1 includes or is derived from A26. In some embodiments, X 1 includes or is derived from A27. In some embodiments, X 1 includes or is derived from A28. In some embodiments, X 1 includes or is derived from A29. In some embodiments, X 1 includes or is derived from A30. In some embodiments, X 1 includes or is derived from A31. In some embodiments, X 1 includes or is derived from A32.

In some embodiments, each of A 1 and A 2 includes or is derived from the same polyol, e.g., a polyol selected from one of A1-A32. In some embodiments, each of A 1 and A 2 includes or is derived from a different polyol, e.g., a polyol selected from one of A1-A32.

In some embodiments, one or both of A 1 and A 2 is represented by a compound of Formula (II-d):

wherein:

X 1 is C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 3 -C 8 cyclyl, or C 3 -C 8 heterocyclyl, wherein each alkylene, heteroalkylene, cyclyl, and heterocyclyl is optionally substituted with 1-6 R 4b ;

R 4a is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, O, (C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-NR 6 —(C 1 -C 6 alkylene)-O—, (C 1 -C 6 alkylene)-C(O)NR 6 —(C 1 -C 6 alkylene)-O, or (C 1 -C 6 alkylene)-NR 6 C(O)—(C 1 -C 6 alkylene)-O, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 7 ;

each R 4b is independently C 1 -C 6 alkyl or (C 1 -C 6 alkylene)-O-L-ARB;

L is a bond or a linker, e.g., a linker as described herein;

ARB is an angiotensin II receptor blocker, e.g., losartan, valsartan, telmisartan, candesartan, eprosartan, irbesartan, azilsartan, EXP-3174, olmesartan, or a prodrug or active metabolite thereof;

R 6 is hydrogen or C 1 -C 6 alkyl; and

each R 7 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, halo, O-L-ARB, (C 1 -C 6 alkylene)-O-L-ARB, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-ARB, cyano, cyclyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, X 1 is C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 1 -C 8 cyclyl, or C 1 -C 8 heterocyclyl. In some embodiments, X 1 is C 1 -C 12 alkylene or C 1 -C 12 heteroalkylene. In some embodiments, X 1 is C 1 -C 6 alkylene. In some embodiments, X 1 is C 1 -C 12 heteroalkylene.

In some embodiments, X 1 is C 3 -C 8 cyclyl or C 3 -C 8 heterocyclyl. In some embodiments, X 1 is C 3 -C 6 cyclyl or C 3 -C 6 heterocyclyl. In some embodiments, X 1 is C 3 -C 6 cyclyl. In some embodiments, X 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, X 1 is cyclopentyl or cyclohexyl. In some embodiments, X 1 is cyclopentyl or cyclohexyl. In some embodiments, X 1 is cyclohexyl.

In some embodiments, R 4a is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, O, (C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O, or (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O, wherein each alkyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 7 . In some embodiments, R 4a is C 1 -C 6 alkyl (e.g., CH 3 or CH 2 CH 3 ). In some embodiments, R 4a is O. In some embodiments, R 4a is (C 1 -C 6 alkylene)-O (e.g., CH 2 O or CH 2 CH 2 O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O (e.g., CH 2 OCH 2 CH 2 O or CH 2 CH 2 OCH 2 CH 2 O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O (e.g., CH 2 OC(O)CH 2 O, CH 2 CH 2 OC(O)CH 2 O, CH 2 OC(O)CH 2 CH 2 O, CH 2 OC(O)CH 2 CH 2 CH 2 O, CH 2 CH 2 OC(O)CH 2 CH 2 O, CH 2 CH 2 OC(O)CH 2 CH 2 CH 2 O, CH 2 OC(O)CH(CH 3 )O, or CH 2 CH 2 OC(O)CH(CH 3 )O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O (e.g., CH 2 OC(O)OCH 2 CH 2 O).

In some embodiments, R 4b is C 1 -C 6 alkyl (e.g., CH 3 , CH 2 CH 3 ). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-ARB, e.g., (CH 2 —O-L-ARB).

In some embodiments, L is a bond. In some embodiments, L is a linker. In some embodiments, L is a linker as described herein, e.g., a polyacetal polymer.

In some embodiments, ARB is losartan, valsartan, telmisartan, candesartan, eprosartan, irbesartan, azilsartan, EXP-3174, olmesartan, or a prodrug or active metabolite thereof. In some embodiments, ARB is losartan. In some embodiments, ARB is valsartan. In some embodiments, ARB is telmisartan. In some embodiments, ARB is candesartan. In some embodiments, ARB is eprosartan. In some embodiments, ARB is azilsartan. In some embodiments, ARB is EXP-3174. In some embodiments, ARB is olmesartan. In some embodiments, ARB is azilsartan medoxomil. In some embodiments, ARB is candesartan cilexetil. In some embodiments, ARB is olmesartan medoxomil. In some embodiments, ARB is a compound shown in FIG. 23 .

In some embodiments, one or both of A 1 and A 2 is represented by a compound of Formula (II-e), Formula (II-f), Formula (II-g), Formula (II-h), or Formula (II-i):

wherein:

X 1 is C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 3 -C 8 cyclyl, or C 3 -C 8 heterocyclyl, wherein each alkylene, heteroalkylene, cyclyl, and heterocyclyl is optionally substituted with 1-6 R 4b ;

R 4a is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, O, (C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-NR 6 —(C 1 -C 6 alkylene)-O—, (C 1 -C 6 alkylene)-C(O)NR 6 —(C 1 -C 6 alkylene)-O, or (C 1 -C 6 alkylene)-NR 6 C(O)—(C 1 -C 6 alkylene)-O, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 7 ;

each R 4b is independently C 1 -C 6 alkyl, (C 1 -C 6 alkylene)-O-L-losartan, (C 1 -C 6 alkylene)-O-L-valsartan, (C 1 -C 6 alkylene)-O-L-telmisartan, (C 1 -C 6 alkylene)-O-L-candesartan, or (C 1 -C 6 alkylene)-O-L-olmesartan;

L is a linker, e.g., a linker as described herein;

R 6 is hydrogen or C 1 -C 6 alkyl; and

each R 7 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, halo, O-L-losartan, O-L-valsartan, O-L-telmisartan, O-L-candesartan, O-L-olmesartan, (C 1 -C 6 alkylene)-O-L-losartan, (C 1 -C 6 alkylene)-O-L-valsartan, (C 1 -C 6 alkylene)-O-L-telmisartan, (C 1 -C 6 alkylene)-O-L-candesartan, (C 1 -C 6 alkylene)-O-L-olmesartan, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-losartan, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-valsartan, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-telmisartan, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-candesartan, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-olmesartan, cyano, cyclyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, X 1 is C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 1 -C 8 cyclyl, or C 1 -C 8 heterocyclyl. In some embodiments, X 1 is C 1 -C 12 alkylene or C 1 -C 12 heteroalkylene. In some embodiments, X 1 is C 1 -C 6 alkylene. In some embodiments, X 1 is C 1 -C 12 heteroalkylene.

In some embodiments, X 1 is C 3 -C 8 cyclyl or C 3 -C 8 heterocyclyl. In some embodiments, X 1 is C 3 -C 6 cyclyl or C 3 -C 6 heterocyclyl. In some embodiments, X 1 is C 3 -C 6 cyclyl. In some embodiments, X 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, X 1 is cyclopentyl or cyclohexyl. In some embodiments, X 1 is cyclopentyl or cyclohexyl. In some embodiments, X 1 is cyclohexyl.

In some embodiments, R 4a is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, O, (C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O, or (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O, wherein each alkyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 7 . In some embodiments, R 4a is C 1 -C 6 alkyl (e.g., CH 3 or CH 2 CH 3 ). In some embodiments, R 4a is O. In some embodiments, R 4a is (C 1 -C 6 alkylene)-O (e.g., CH 2 O or CH 2 CH 2 O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O (e.g., CH 2 OCH 2 CH 2 O or CH 2 CH 2 OCH 2 CH 2 O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O (e.g., CH 2 OC(O)CH 2 O, CH 2 CH 2 OC(O)CH 2 O, CH 2 OC(O)CH 2 CH 2 O, CH 2 OC(O)CH 2 CH 2 CH 2 O, CH 2 CH 2 OC(O)CH 2 CH 2 O, CH 2 CH 2 OC(O)CH 2 CH 2 CH 2 O, CH 2 OC(O)CH(CH 3 )O, or CH 2 CH 2 OC(O)CH(CH 3 )O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O (e.g., CH 2 OC(O)OCH 2 CH 2 O).

In some embodiments, R 4b is C 1 -C 6 alkyl (e.g., CH 3 , CH 2 CH 3 ). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-losartan, e.g., (CH 2 —O-L-losartan). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-valsartan, e.g., (CH 2 —O-L-valsartan). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-telmisartan, e.g., (CH 2 —O-L-telmisartan). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-candesartan, e.g., (CH 2 —O-L-candesartan). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-olmesartan, e.g., (CH 2 —O-L-olmesartan).

In some embodiments, L is a bond. In some embodiments, L is a linker. In some embodiments, L is a linker as described herein, e.g., a polyacetal polymer.

In some embodiments, one or both of A 1 and A 2 is represented by a compound of Formula (II-j):

wherein:

X 1 is C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 3 -C 8 cyclyl, or C 3 -C 8 heterocyclyl, wherein each alkylene, heteroalkylene, cyclyl, and heterocyclyl is optionally substituted with 1-6 R 4b ;

R 4a is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, O, (C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-NR 6 —(C 1 -C 6 alkylene)-O—, (C 1 -C 6 alkylene)-C(O)NR 6 —(C 1 -C 6 alkylene)-O, or (C 1 -C 6 alkylene)-NR 6 C(O)—(C 1 -C 6 alkylene)-O, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 7 ;

each R 4b is independently C 1 -C 6 alkyl, (C 1 -C 6 alkylene)-O-L-T, or (C 1 -C 6 alkylene)-O-L-ARB;

L is a bond or a linker, e.g., a linker as described herein;

T is a targeting moiety, e.g., mannose-6-phosphate;

ARB is an angiotensin II receptor blocker, e.g., losartan, valsartan, telmisartan, candesartan, eprosartan, irbesartan, azilsartan, EXP-3174, olmesartan, or an analog or a derivative thereof (e.g., a prodrug or active metabolite thereof);

R 6 is hydrogen or C 1 -C 6 alkyl, and

each R 7 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, halo, O-L-T, (C 1 -C 6 alkylene)-O-L-T, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-T, O-L-ARB, (C 1 -C 6 alkylene)-O-L-ARB, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-ARB, cyano, cyclyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, X 1 is C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 1 -C 8 cyclyl, or C 1 -C 8 heterocyclyl. In some embodiments, X 1 is C 1 -C 12 alkylene or C 1 -C 12 heteroalkylene. In some embodiments, X 1 is C 1 -C 6 alkylene. In some embodiments, X 1 is C 1 -C 12 heteroalkylene.

In some embodiments, X 1 is C 3 -C 8 cyclyl or C 3 -C 8 heterocyclyl. In some embodiments, X 1 is C 3 -C 6 cyclyl or C 3 -C 6 heterocyclyl. In some embodiments, X 1 is C 3 -C 6 cyclyl. In some embodiments, X 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, X 1 is cyclopentyl or cyclohexyl. In some embodiments, X 1 is cyclopentyl or cyclohexyl. In some embodiments, X 1 is cyclohexyl.

In some embodiments, R 4a is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, O, (C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O, or (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O, wherein each alkyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 7 . In some embodiments, R 4a is C 1 -C 6 alkyl (e.g., CH 3 or CH 2 CH 3 ). In some embodiments, R 4a is O. In some embodiments, R 4a is (C 1 -C 6 alkylene)-O (e.g., CH 2 O or CH 2 CH 2 O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O (e.g., CH 2 OCH 2 CH 2 O or CH 2 CH 2 OCH 2 CH 2 O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O (e.g., CH 2 OC(O)CH 2 O, CH 2 CH 2 OC(O)CH 2 O, CH 2 OC(O)CH 2 CH 2 O, CH 2 OC(O)CH 2 CH 2 CH 2 O, CH 2 CH 2 OC(O)CH 2 CH 2 O, CH 2 CH 2 OC(O)CH 2 CH 2 CH 2 O, CH 2 OC(O)CH(CH 3 )O, or CH 2 CH 2 OC(O)CH(CH 3 )O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O (e.g., CH 2 OC(O)OCH 2 CH 2 O).

In some embodiments, R 4b is C 1 -C 6 alkyl (e.g., CH 3 , CH 2 CH 3 ). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-T, e.g., (CH 2 —O-L-T). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-ARB, e.g., (CH 2 —O-L-ARB).

In some embodiments, L is a bond. In some embodiments, L is a linker. In some embodiments, L is a linker as described herein, e.g., a polyacetal polymer.

In some embodiments, T is a targeting moiety described herein. In some embodiments, T is mannose-6-phosphate.

In some embodiments, ARB is losartan, valsartan, telmisartan, candesartan, eprosartan, irbesartan, azilsartan, EXP-3174, olmesartan, or an analog or a derivative thereof (e.g., a prodrug or active metabolite thereof). In some embodiments, ARB is losartan. In some embodiments, ARB is valsartan. In some embodiments, ARB is telmisartan. In some embodiments, ARB is candesartan. In some embodiments, ARB is eprosartan. In some embodiments, ARB is azilsartan. In some embodiments, ARB is EXP-3174. In some embodiments, ARB is olmesartan. In some embodiments, ARB is azilsartan medoxomil. In some embodiments, ARB is candesartan cilexetil. In some embodiments, ARB is olmesartan medoxomil. In some embodiments, ARB is a compound shown in FIG. 23 .

In some embodiments, each of A 1 and A 2 does not independently include, or is independently not derived from, tri(methylol)ethane. In some embodiments, each of A 1 and A 2 does not independently include, or is not independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 5 kDa in size. In some embodiments, each of A 1 and A 2 does not independently include, or is not independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 10 kDa in size.

In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane. In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 5 kDa in size. In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 10 kDa in size.

In some embodiments of a polymer of Formula (I), each of B 1 and B 2 is independently heteroalkyl or aryloxy, each of which may be optionally substituted with 1-5 R 1 . In some embodiments, each of B 1 and B 2 is independently heteroalkyl, each of which may be optionally substituted with 1-5 R 1 . In some embodiments, each of B 1 and B 2 is independently C 1 -C 20 heteroalkyl, each of which may be optionally substituted with 1-5 R 1 . In some embodiments, each of B 1 and B 2 is the same. In some embodiments, each of B 1 and B 2 is the different.

In some embodiments, each of B 1 and B 2 is independently represented by a moiety of Formula (III):

wherein:

Z 1 is O, C 3 -C 8 cyclyl, C 3 -C 8 heterocyclyl, or C(R 22 )(R 23 ), wherein each of cyclyl and heterocyclyl is optionally substituted with 1-4 R 25 ;

each of X 4 and X 5 is independently C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, C 1 -C 6 heteroalkylene. (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-NR 24 —(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)NR 24 —(C 1 -C 6 alkylene), or (C 1 -C 6 alkylene)-NR 24 C(O)—(C 1 -C 6 alkylene), wherein each alkylene, alkenylene, alkynylene, or heteroalkylene is optionally substituted with 1-6 R 25 ;

each of R 20 and R 21 is independently C 1 -C 6 alkyl, OR 26 , cyclyl, heterocyclyl;

each of R 22 and R 23 is independently hydrogen, C 1 -C 6 alkyl, OR 26 , (C 1 -C 6 alkylene)-OR 26 , halo, cyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkylene, cyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-6 R 27 ;

each R 25 and R 27 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, cyano, cyclyl, or heterocyclyl, and

R 26 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, a linker, an agent, a targeting moiety, a protecting group, or a branching point, wherein each alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl is optionally substituted with 1-6 R 28 ; and

each R 28 is independently C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, cyano, cyclyl, or heterocyclyl.

In some embodiments, Z 1 is O.

In some embodiments, Z 1 is C 3 -C 8 cyclyl or C 3 -C 8 heterocyclyl, each of which is optionally substituted with 1-4 R 25 . In some embodiments, Z 1 is C 3 -C 6 cyclyl or C 3 -C 6 heterocyclyl, each of which is optionally substituted with 1-4 R 25 . In some embodiments, Z 1 is C 3 -C 6 cyclyl, optionally substituted with 1-4 R 25 . In some embodiments, Z 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1-4 R 25 . In some embodiments, Z 1 is cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1-4 R 25 . In some embodiments, Z 1 is cyclohexyl, optionally substituted with 1-4 R 25 . In some embodiments, Z 1 is cyclohexyl.

In some embodiments, Z 1 is C(R 22 )(R 23 ). In some embodiments, Z 1 is C(R 23 )(R 24 ) and each of R 22 and R 23 is independently hydrogen, C 1 -C 6 alkyl, or (C 1 -C 6 alkylene)-OR 26 . In some embodiments, each of R 22 and R 23 is independently hydrogen. In some embodiments, each of R 22 and R 23 is independently hydrogen or C 1 -C 6 alkyl, e.g., CH 3 . In some embodiments, each of R 22 and R 23 is independently hydrogen. In some embodiments, each of R 22 and R 23 is independently C 1 -C 6 alkyl, e.g., CH 3 . In some embodiments, R 22 is hydrogen and R 23 is independently C 1 -C 6 alkyl, e.g., CH 3 . In some embodiments, each of R 22 and R 23 is independently (C 1 -C 6 alkylene)-OR 26 . In some embodiments, each of R 22 and R 23 is independently (C 1 -C 2 alkylene)-OR 26 . In some embodiments, each of R 22 and R 23 is independently (C 1 -C 2 alkylene)-OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point. In some embodiments, R 22 is hydrogen or C 1 -C 6 alkyl (e.g., CH 3 ), R 23 is (C 1 -C 2 alkylene)-OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point. In some embodiments, R 22 is C 1 -C 6 alkyl (e.g., CH 3 ), R 23 is (C 1 -C 2 alkylene)-OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point.

In some embodiments, each of X 4 and X 5 is independently C 1 -C 6 alkylene, wherein alkylene is optionally substituted with 1-6 R 25 . In some embodiments, each of X 4 and X 5 is independently C 1 -C 4 alkylene, wherein alkylene is optionally substituted with 1-6 R 25 . In some embodiments, each of X 4 and X 5 is independently C 1 -C 2 alkylene, wherein alkylene is optionally substituted with 1-6 R 25 . In some embodiments, each of X 4 and X 5 is independently C 1 -C 2 alkylene (e.g., CH 2 , CH 2 CH 2 ).

In some embodiments, each of R 20 and R 21 is independently C 1 -C 6 alkyl or OR 26 . In some embodiments, each of R 20 and R 21 is independently C 1 -C 6 alkyl. In some embodiments, each of R 20 and R 21 is independently C 1 -C 4 alkyl. In some embodiments, each of R 20 and R 21 is independently C 1 -C 2 alkyl, e.g., CH 3 . In some embodiments, each of R 20 and R 21 is independently OR 26 . In some embodiments, each of R 20 and R 21 is independently OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point.

In some embodiments of a polymer of Formula (I), each of B 1 and B 2 is independently hydrophobic. In some embodiments, each of B 1 and B 2 has a partition coefficient (c Log P) value greater than about −2.0. In some embodiments, each of B 1 and B 2 has a c Log P value greater than about −1.5, e.g., about −1.4, about −1.3, about −1.2, about −1.1, about −1.0, about −0.9, about −0.8, about −0.7, about −0.6, about −0.5, about −0.4, about −0.3, about −0.2, about −0.1, about 0, or higher. In some embodiments, each of B 1 and B 2 has a c Log P value between about −2.0 and 4.0. In some embodiments, each of B 1 and B 2 has a c Log P value greater than about −0.5, e.g., about −0.4, about −0.3, about −0.2, about −0.1, about 0, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, or higher. In some embodiments, each of B 1 and B 2 has a c Log P value between about 0 and 4.0. In some embodiments, each of B 1 and B 2 has a c Log P value greater than about 0, e.g., about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, or higher.

In some embodiments, each of B 1 and B 2 has a linear structure. In some embodiments, each of B 1 and B 2 has a branched structure. In some embodiments, each of B 1 and B 2 comprises a protected reactive group, e.g., a protected hydroxyl, a protected carboxylic acid, or a protected amine. In some embodiments, each of B 1 and B 2 comprises 1, 2, 3, 4, 5, 6, 7, 8, or more protected reactive groups, e.g., a protected hydroxyl, a protected carboxylic acid, or a protected amine.

In some embodiments, the agent is a therapeutic or a diagnostic agent as described herein. In some embodiments, the agent is an AHCM as described herein. In some embodiments, the agent is an ARB as described herein, e.g., losartan, valsartan, telmisartan, candesartan, eprosartan, irbesartan, azilsartan, EXP-3174, olmesartan, or an analog or a derivative thereof (e.g., a prodrug or active metabolite thereof), e.g., a compound shown in FIG. 23 .

In some embodiments, the agent is a vitamin D analog or derivative as described herein. In some embodiments, the agent is a vitamin D analog or derivative as described herein, e.g., paricalcitol, doxercalciferol, falecalcitriol, maxacalcitol, tacalcitol, alfacalcidol, eldecalcidol, seocalcitol, lexicalcitol, CD578, inecalcitol, calcipotriol, TX527, 2MD, WY1112, PRI-2205, ILX23-7553, ercalcitriol, EB1089 (seocalcitol), BXL-628 (elocalcitol), MC1288, CB966, BCB 1093, GS 1558, SM-10193, EB1072, EB1129, EB1133, EB1155, EB1270, MC1288, EB1213, CB1093, VD2656, VD2668, VD2708, VD2716, VD2728, VD2736, GS1500, GS1558, KH1060, ZK161422, and analogs and derivatives thereof, e.g., as shown in FIG. 24 .

In some embodiments, the agent is a bromodomain and extra-terminal protein inhibitor (i-BET) as described herein. In some embodiments, the agent is a bromodomain and extra-terminal protein inhibitor (i-BET) as described herein, e.g MS436, PFI-1, I-BET 151, OTX-015, JQ1, CPI-203, bromosporine, RVX-208, I-BET 762, I-BET 151, OFXBD02, OFXBD03, XD14, AZD5153, and analogs and derivatives thereof, e.g., as shown in FIGS. 25A and 25B .

In some embodiments, the agent is an IDO inhibitor (i.e., indoleamine 2,3-dioxygenase (IDO) pathway inhibitor) as described herein. In some embodiments, the agent is an IDO inhibitor as described herein, e.g., GDC-0919, indoximod, 1-methyltryptophan (e.g., 1-methyl- L -tryptophan, 1-methyl- D -tryptophan), NLG8189, INCB024360, NLG919, methylthiohydantoin tryptophan, brassinin, annulin B, exiguamine A, INCB023843, or an analog or derivative thereof.

In some embodiments, each of B 1 and B 2 is independently represented by a moiety of Formula (III-a):

wherein:

Z 1 is O, C 3 -C 8 cyclyl, or C(R 22 )(R 23 );

each of X 4 and X 5 is independently C 1 -C 6 alkylene;

each of R 20 and R 21 is independently C 1 -C 6 alkyl or OR 20 ;

each of R 22 and R 23 is independently hydrogen, C 1 -C 6 alkyl, or (C 1 -C 6 alkylene)-OR 26 ; and each R 26 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, a linker, an agent, a targeting moiety, a protecting group, or a branching point.

In some embodiments, Z 1 is O.

In some embodiments, Z 1 is C 3 -C 6 cyclyl. In some embodiments, Z 1 is cyclopentyl, or cyclohexyl. In some embodiments, Z 1 is cyclohexyl.

In some embodiments, Z 1 is C(R 22 )(R 23 ). In some embodiments, Z 1 is C(R 23 )(R 24 ) and each of R 22 and R 23 is independently hydrogen. In some embodiments, each of R 22 and R 23 is independently hydrogen or C 1 -C 6 alkyl, e.g., CH 3 . In some embodiments, each of R 22 and R 23 is independently hydrogen. In some embodiments, each of R 22 and R 23 is independently C 1 -C 6 alkyl, e.g., CH 3 . In some embodiments, R 22 is hydrogen and R 23 is independently C 1 -C 6 alkyl, e.g., CH 3 . In some embodiments, each of R 22 and R 23 is independently (C 1 -C 6 alkylene)-OR 26 . In some embodiments, each of R 22 and R 23 is independently (C 1 -C 2 alkylene)-OR 26 . In some embodiments, each of R 22 and R 23 is independently (C 1 -C 2 alkylene)-OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point. In some embodiments, R 22 is hydrogen or C 1 -C 6 alkyl (e.g., CH 3 ), R 23 is (C 1 -C 2 alkylene)-OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point. In some embodiments, R 22 is C 1 -C 6 alkyl (e.g., CH 3 ), R 23 is (C 1 -C 2 alkylene)-OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point.

In some embodiments, each of X 4 and X 5 is independently C 1 -C 4 alkylene. In some embodiments, each of X 4 and X 5 is independently C 1 -C 2 alkylene. In some embodiments, each of X 4 and X 5 is independently C 1 -C 2 alkylene (e.g., CH 2 , CH 2 CH 2 ).

In some embodiments, each of R 20 and R 21 is independently C 1 -C 6 alkyl. In some embodiments, each of R 20 and R 21 is independently C 1 -C 4 alkyl. In some embodiments, each of R 20 and R 21 is independently C 1 -C 2 alkyl, e.g., CH 3 . In some embodiments, each of R 20 and R 21 is independently OR 26 . In some embodiments, each of R 20 and R 21 is independently OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point.

In some embodiments, the precursor of each of B 1 to B 2 is independently selected from the following vinyl ethers:

In some embodiments, the precursor to each of B 1 and B 2 is independently selected from one of B1, B2, B3, B4, B5, and B6, e.g., as depicted in FIG. 1C . It is to be understood that when the precursor to B 1 or B 2 is one of the vinyl ethers in the above-noted group selected from B1-B6, A 1 or A 2 and C 1 or C 2 is connected at the (CH) group of the vinyl moiety in each of said vinyl ethers.

In some embodiments, each of B 1 and B 2 is independently represented by a moiety of Formula (III-b):

wherein:

Z 2 includes or is derived from any of the vinyl ethers shown in FIG. 1C , e.g., a vinyl ether selected from one of B1, B2, B3, B4, B5, or B6, and two of the hydrogen atoms of the vinyl groups are replaced linkage indicated in Formula (III-b).

In some embodiments, Z 2 includes or is derived from B1. In some embodiments, Z 2 includes or is derived from B2. In some embodiments, Z 2 includes or is derived from B3. In some embodiments, Z 2 includes or is derived from B4. In some embodiments, Z 2 includes or is derived from B5. In some embodiments, Z 2 includes or is derived from B6.

In some embodiments, each of B 1 and B 2 includes or is derived from the same vinyl ether, e.g., a vinyl ether selected from one of B1-B6. In some embodiments, each of B 1 and B 2 includes or is derived from a different vinyl ether, e.g., a vinyl ether selected from one of B1-B6.

In some embodiments of a polymer of Formula (I), each of C 1 and C 2 is heteroalkyl, optionally substituted with 1-6 R 3 . In some embodiments, each of C 1 and C 2 is C 1 -C 20 heteroalkyl, optionally substituted with 1-6 R 3 . In some embodiments, each of C 1 and C 2 is C 1 -C 10 heteroalkyl. In some embodiments, each of C 1 and C 2 is C 1 -C 10 heteroalkyl. In some embodiments, each of C 1 and C 2 is C 1 -C 10 heteroalkyl, e.g., an oxygen-containing C 1 -C 4 heteroalkyl and/or an amine-containing heteroalkyl. In some embodiments, each of C 1 and C 2 comprises a polyethylene glycol (PEG), a polyethylene oxide (PEO), a polypropylene glycol (PPG), a polyglycerol (PG), a poloxamine (POX), a polybutylene oxide (PBO), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polydioxanone (PDO), a polyanhydride, a polyacrylide, a polyvinyl, or a polyorthoester.

In some embodiments, each of C 1 and C 2 comprises a polyethylene glycol (PEG). In some embodiments, each of C 1 and C 2 comprises a polyethylene glycol (PEG) or a polyethylene oxide (PEO). In some embodiments, each of C 1 and C 2 comprises a polyethylene oxide (PEO) or a polypropylene glycol (PPG). In some embodiments, each of C 1 and C 2 comprises a polybutylene oxide (PBO).

In some embodiments, each of C 1 or C 2 has a linear structure, e.g., does not comprise a branching point or cyclic group. In some embodiments, each of C 1 or C 2 has a branched structure, e.g., comprising at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 branching points.

In some embodiments, each of C 1 or C 2 comprises a cyclic structure. In some embodiments, each of C 1 or C 2 comprises a cyclic structure, e.g., a cyclyl or heterocyclyl group. In some embodiments, each of C 1 or C 2 comprises a carbohydrate (e.g., a glucose derivative, galactose derivative, mannose derivative, fucose derivative, sialic acid derivative, or other carbohydrate derivative). In some embodiments, each of C 1 or C 2 comprises a dextran, a cyclodextran, chitosan, or other carbohydrate based moiety.

In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 20,000 Da in size. In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 17,500 Da, from about 200 Da to about 15,000 Da, from about 200 Da to about 12,500 Da, from about 200 Da to about 10,000 Da, from about 200 Da to about 9,000 Da, from about 200 Da to about 8,000 Da, from about 200 Da to about 7,000 Da, from about 200 Da to about 6,000 Da, from about 200 Da to about 5,000 Da, from about 200 Da to about 4,000 Da, from about 200 Da to about 3,000 Da, or from about 200 Da to about 2,000 Da in size. In some embodiments, each of C 1 or C 2 is independently from about 200 Da to about 5,000 Da in size. In some embodiments, each of C 1 or C 2 is independently from about 200 Da to about 2,000 Da in size.

In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 2,000 Da in size. In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 1,750 Da, from about 200 Da to about 1,500 Da, from about 200 to about 1,400 Da, from about 200 to about 1,300 Da, from about 200 to about 1,200, from about 200 to about 1,100, or from about 200 to about 1,000 in size. In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 900 Da, from about 200 Da to about 800, from about 200 to about 700 Da, from about 200 to about 600 Da, from about 200 to about 500 Da, or from about 200 to about 400 Da. each of C 1 or C 2 is independently about 400 Da in size

In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 2,000 Da in size. In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 2,000 Da in size, from about 250 Da to about 1,900 in size, from about 300 Da to about 1,800, from about 350 Da to about 1,700, or from about 400 Da to about 1,600 in size. In some embodiments, each of C 1 or C 2 is independently about 500 Da to about 1,500 in size, from about 600 Da to about 1,500 in size, from about 700 Da to about 1,400, from about 800 Da to about 1,300, or from about 900 Da to about 1,200 in size. In some embodiments, each of C 1 or C 2 is independently about 1,000 Da to about 1,200 Da in size. In some embodiments, each of C 1 or C 2 is independently about 1,000 Da in size.

In some embodiments, each of C 1 and C 2 is the same. In some embodiments, both of C 1 and C 2 is from about 200 Da to about 1200 Da, from about 300 Da to about 1100 Da, or from about 400 Da to about 1000 Da in size. In some embodiments, both of C 1 and C 2 are from about 100 Da to about 500 Da or from about 800 Da to about 1200 Da in size. In some embodiments, both of C 1 and C 2 are 400 Da or 1000 Da in size.

In some embodiments, each of C 1 and C 2 is different. In some embodiments, each of C 1 and C 2 is from about 200 Da to about 1200 Da, from about 300 Da to about 1100 Da, or from about 400 Da to about 1000 Da in size. In some embodiments, one of C 1 and C 2 is from about 100 Da to about 500 Da and the other of C 1 and C 2 is from bout 800 Da to about 1200 Da in size. In some embodiments, one of C 1 and C 2 is about 400 Da in size and the other of C 1 and C 2 is about 1000 Da in size.

In some embodiments of the polymer of Formula (I), the precursor to each of C 1 and C 1 is PEG (e.g., polyethylene glycol). In some embodiments, the PEG comprises PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 800, PEG 1000, PEG 1500, PEG 2000, PEG 2050, PEG 4000, or PEG 6000, also referred to herein as P100, P200, P300, P400, P500, P600, P800, P1000, P1500, P2000, P2050, P4000, and P6000, or any combination thereof. In some embodiments, the PEG comprises P400, P1000, or a combination of P400 and P1000. In some embodiments, the PEG comprises PEG2050.

In some embodiments of a polymer (e.g., a polymer described herein, e.g., a polymer of Formula (I)), each of m and n independently an integer from 2 to 450, from 2 to 400, from 2 to 350, from 2 to 300, from 2 to 250, from 2 to 200, from 2 to 175, from 2 to 150, from 2 to 125, from 2 to 100, from 2 to 90, from 2 to 80, from 2 to 70, from 2 to 60, from 2 to 50, from 2 to 45, from 2 to 40, from 2 to 35, from 2 to 30, from 2 to 25, from 2 to 20, from 2 to 15, from 2 to 10, or from 2 to 5. In some embodiments, each of m and n independently is an integer from 2 to 250. In some embodiments, each of m and n independently is an integer from 2 to 100. In some embodiments, each of m and n independently is an integer from 2 to 50. In some embodiments, each of m and n independently is an integer from 2 to 25. In some embodiments, each of m and n independently is an integer from 2 to 10. In some embodiments, each of m and n independently is an integer from 10 to 500, from 10 to 250, from 10 to 200, from 10 to 150, from 10 to 100, from 10 to 75, from 10 to 50, or from 10 to 25. In some embodiments, each of m and n independently is an integer from 10 to 50.

In an embodiment, m and n taken together are between 10 and 100, 20 and 80, 20 and 60, or 30 and 60.

In some embodiments, the polymer (e.g., the polyacetal polymer) comprises a structure according to Formula (I-a):

wherein:

each of A 1 and A 2 is independently represented by a structure of Formula (II);

each of B 1 and B 2 is independently represented by a structure of Formula (III);

each of C 1 and C 2 is independently heteroalkyl, cyclyl, or heterocyclyl, each of which is optionally substituted with 1-6 R 3 , e.g, each of C 1 and C 2 is independently PEG;

each of R 3 is independently alkyl, alkenyl, alkynyl, hydroxyl, halo, heteroalkyl, keto, alkoxy, ester, cyclyl, heterocyclyl, cycloalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, a linker, an agent, a targeting moiety, or a branching point; and

each of m or n is independently an integer from 1 to 200;

wherein the structure of Formula (II) is represented by:

X 1 is C 1 -C 12 alkylene, C 2 -C 12 alkenylene, C 2 -C 12 alkynylene, C 1 -C 12 heteroalkylene, C 3 -C 8 cyclyl, or C 3 -C 8 heterocyclyl, wherein each alkylene, alkenylene, alkynylene, heteroalkylene, cyclyl, or heterocyclyl is optionally substituted with 1-6 R 4 ;

each R 4 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, OR 5 , (C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-NR 6 —(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-C(O)NR 6 —(C 1 -C 6 alkylene)-OR 5 , or (C 1 -C 6 alkylene)-NR 6 C(O)—(C 1 -C 6 alkylene)-OR 5 , wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 7 ;

each R 5 is independently hydrogen, C 1 -C 6 alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, a linker, a branching point, a protecting group, an agent, or a targeting moiety, wherein each alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl is optionally substituted with 1-6 R 8 ;

R 6 is hydrogen or C 1 -C 6 alkyl;

each R 7 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, halo, OR 5 , (C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 5 , cyano, cyclyl, heterocyclyl, aryl, or heteroaryl; and

each R 8 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, halo, cyano, cyclyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-6 R 9 ; and

each R 9 is independently C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, cyano, cyclyl, or heterocyclyl;

and the structure of Formula (III) is represented by:

wherein:

Z 1 is O, C 3 -C 8 cyclyl, C 3 -C 8 heterocyclyl, or C(R 22 )(R 23 ), wherein each of cyclyl and heterocyclyl is optionally substituted with 1-4 R 25 ;

each of X 4 and X 5 is independently C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, C 1 -C 6 heteroalkylene, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-NR 24 —(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)NR 24 —(C 1 -C 6 alkylene), or (C 1 -C 6 alkylene)-NR 24 C(O)—(C 1 -C 6 alkylene), wherein each alkylene, alkenylene, alkynylene, or heteroalkylene is optionally substituted with 1-6 R 25 ;

each of R 20 and R 21 is independently C 1 -C 6 alkyl, OR 26 , cyclyl, heterocyclyl;

each of R 22 and R 23 is independently hydrogen, C 1 -C 6 alkyl, OR 26 , (C 1 -C 6 alkylene)-OR 26 , halo, cyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkylene, cyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-6 R 27 ;

each R 25 and R 27 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, cyano, cyclyl, or heterocyclyl;

R 26 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, a linker, a branching point, a protecting group, an agent, or a targeting moiety, wherein each alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl is optionally substituted with 1-6 R 28 ; and

each R 28 is independently C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, cyano, cyclyl, or heterocyclyl.

In some embodiments, each of A 1 and A 2 is the same, e.g., the same structure of Formula (II). In some embodiments, each of A 1 and A 2 is different, e.g., a different structure of Formula (II).

In some embodiments, X 1 is C 1 -C 12 alkylene or C 1 -C 12 heteroalkylene, optionally substituted with 1-6 R 4 . In some embodiments, X 1 is C 1 -C 12 heteroalkylene optionally substituted with 1-6 R 4 , e.g., (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene), wherein each alkylene is optionally substituted with 1-6 R 4 . In some embodiments, X 1 is C 3 -C 6 cyclyl, optionally substituted with 1-6 R 4 (e.g., cyclohexyl substituted with OR 5 ).

In some embodiments, each R 4 is independently C 1 -C 6 alkyl, OR 5 , (C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-OR 5 , or (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-OR 5 .

In some embodiments, each R 5 is independently hydrogen, C 1 -C 6 alkyl, a linker, a branching point, a protecting group, an agent, or a targeting moiety.

In some embodiments, the precursor to each of A 1 and A 2 is independently selected from the following polyols:

In some embodiments, the precursor to each of A 1 and A 2 is independently selected from one of A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, and A32, e.g., as depicted in FIG. 1B . It is to be understood that when the precursor to A 1 or A 2 is one of the polyols in the above-noted group selected from A1-A32, B 1 or B 2 is connected to one of the oxygen atoms of the hydroxyl groups in said polyols.

In some embodiments, X 1 includes or is derived from a polyol selected from one of A3, A4, A5, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, and A32, e.g., as depicted in FIG. 1B . It is to be understood that when the precursor to A 1 or A 2 is one of the polyols in the above-noted group selected from A1-A32, B 1 or B 2 is connected to one of the oxygen atoms of the hydroxyl groups in said polyols.

In some embodiments, each of B 1 and B 2 is the same, e.g., the same structure of Formula (II). In some embodiments, each of B 1 and B 2 is different, e.g., a different structure of Formula (II).

In some embodiments, Z 1 is C(R 23 )(R 24 ) and each of R 22 and R 23 is independently hydrogen, C 1 -C 6 alkyl, or (C 1 -C 6 alkylene)-OR 26 . In some embodiments, R 22 is hydrogen and R 23 is independently C 1 -C 6 alkyl, e.g., CH 3 . In some embodiments, R 22 is hydrogen or C 1 -C 6 alkyl (e.g., CH 3 ), R 23 is (C 1 -C 2 alkylene)-OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point. In some embodiments, Z 1 is C 3 -C 6 cyclyl, optionally substituted with 1-4 R 25 (e.g., cyclohexyl).

In some embodiments, each of X 4 and X 5 is independently C 1 -C 6 alkylene (e.g., CH 2 , CH 2 CH 2 ), wherein alkylene is optionally substituted with 1-6 R 25 .

In some embodiments, each of R 20 and R 21 is independently C 1 -C 6 alkyl (e.g., CH 3 ) or OR 26 (e.g., C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point).

In some embodiments, the precursor to each of B 1 and B 2 is independently selected from the following vinyl ethers:

In some embodiments, each of C 1 and C 2 is the same, e.g., the same structure of Formula (II). In some embodiments, each of C 1 and C 2 is different, e.g., a different structure of Formula (II).

In some embodiments, each of C 1 and C 2 is independently heteroalkyl (e.g., an oxygen-containing C 1 -C 4 heteroalkyl and/or an amine-containing heteroalkyl), optionally substituted with 1-6 R 3 .

In some embodiments, each of C 1 and C 2 comprises a polyethylene glycol (PEG), a polyethylene oxide (PEO), a polypropylene glycol (PPG), a polyglycerol (PG), a poloxamine (POX), a polybutylene oxide (PBO), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polydioxanone (PDO), a polyanhydride, a polyacrylide, a polyvinyl, or a polyorthoester.

In some embodiments, each of C 1 and C 2 has a linear structure, e.g., does not comprise a branching point or cyclic group. In some embodiments, each of C 1 and C 2 has a C 1 or C 2 has a branched structure, e.g., comprising at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 branching points.

In some embodiments, each of C 1 and C 2 comprises a cyclic structure, e.g., a cyclyl or heterocyclyl group, e.g., a dextran, a cyclodextran, chitosan, or other carbohydrate based moiety.

In some embodiments, each of C 1 and C 2 is independently 200 to 5000 Da in size.

In some embodiments, each of C 1 and C 2 is a polyethylene glycol (PEG). In some embodiments, each of C 1 and C 2 is independently a polyethylene glycol (PEG) and is between about 200 and 1200 Da in size. In some embodiments, each of C 1 and C 2 is independently PEG 400, PEG 1000, or PEG 2050.

In some embodiments of a polymer (e.g., a polymer described herein, e.g., a polymer of Formula (I)), each of m and n independently an integer from 2 to 450, from 2 to 400, from 2 to 350, from 2 to 300, from 2 to 250, from 2 to 200, from 2 to 175, from 2 to 150, from 2 to 125, from 2 to 100, from 2 to 90, from 2 to 80, from 2 to 70, from 2 to 60, from 2 to 50, from 2 to 45, from 2 to 40, from 2 to 35, from 2 to 30, from 2 to 25, from 2 to 20, from 2 to 15, from 2 to 10, or from 2 to 5. In some embodiments, each of m and n independently is an integer from 2 to 250. In some embodiments, each of m and n independently is an integer from 2 to 100. In some embodiments, each of m and n independently is an integer from 2 to 50. In some embodiments, each of m and n independently is an integer from 2 to 25. In some embodiments, each of m and n independently is an integer from 2 to 10. In some embodiments, each of m and n independently is an integer from 10 to 500, from 10 to 250, from 10 to 200, from 10 to 150, from 10 to 100, from 10 to 75, from 10 to 50, or from 10 to 25. In some embodiments, each of m and n independently is an integer from 10 to 50. In an embodiment, m and n taken together are between 10 and 100, 20 and 80, 20 and 60, or 30 and 60.

In some embodiments, each of m and n independently an integer from 2 to 200, e.g., 5 to 200 or 10 to 200. In some embodiments, each of m and n independently an integer from 5 to 100, e.g., 10 to 50.

In some embodiments, the agent is a therapeutic or a diagnostic agent as described herein. In some embodiments, the agent is an AHCM as described herein. In some embodiments, the agent is an ARB as described herein, e.g., losartan, valsartan, telmisartan, candesartan, eprosartan, irbesartan, azilsartan, EXP-3174, olmesartan, or a prodrug or active metabolite thereof, e.g., a compound shown in FIG. 23 .

In some embodiments, the agent is a vitamin D analog or derivative as described herein. In some embodiments, the agent is a vitamin D analog or derivative as described herein, e.g., paricalcitol, doxercalciferol, falecalcitriol, maxacalcitol, tacalcitol, alfacalcidol, eldecalcidol, seocalcitol, lexicalcitol, CD578, inecalcitol, calcipotriol, TX527, 2MD, WY112, PRI-2205, ILX23-7553, ercalcitriol, EB1089 (seocalcitol), BXL-628 (elocalcitol), MC1288, CB966, BCB 1093, GS 1558, SM-10193, EB1072, EB1129, EB1133, EB1155, EB1270, MC1288, EB1213, CB1093, VD2656, VD2668, VD2708, VD2716, VD2728, VD2736, GS1500, GS1558, KH1060, ZK161422, and analogs and derivatives thereof, e.g., as shown in FIG. 24 .

In some embodiments, the agent is a bromodomain and extra-terminal protein inhibitor (i-BET) as described herein. In some embodiments, the agent is a bromodomain and extra-terminal protein inhibitor (i-BET) as described herein, e.g MS436, PFI-1, I-BET 151, OTX-015, JQ1, CPI-203, bromosporine, RVX-208, I-BET 762, I-BET 151, OFXBD02, OFXBD03, XD14, AZD5153, and analogs and derivatives thereof, e.g., as shown in FIGS. 25A and 25B .

In some embodiments, the agent is an IDO inhibitor (i.e., indoleamine 2,3-dioxygenase (IDO) pathway inhibitor) as described herein. In some embodiments, the agent is an IDO inhibitor as described herein, e.g., GDC-0919, indoximod, 1-methyltryptophan (e.g., 1-methyl- L -tryptophan, 1-methyl- D -tryptophan), NLG8189, INCB024360, NLG919, methylthiohydantoin tryptophan, brassinin, annulin B, exiguamine A, INCB023843, or an analog or derivative thereof.

In some embodiments, the polymer (e.g., the polyacetal polymer) comprises a structure according to Formula (I-b):

wherein:

each of A 1 and A 2 is independently represented by a structure of Formula (II-c);

each of B 1 and B 2 is independently represented by a structure of Formula (III-b);

each of C 1 and C 2 is heteroalkyl, cyclyl, or heterocyclyl, each of which is optionally substituted with 1-6 R 3 ;

each of R 3 is independently alkyl, alkenyl, alkynyl, hydroxyl, halo, heteroalkyl, keto, alkoxy, ester, cyclyl, heterocyclyl, cycloalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, a linker, an agent, a targeting moiety, or a branching point;

and

each of m or n is independently an integer from 1 to 200.

In some embodiments, each of A 1 and A 2 is independently represented by a structure of Formula (II-c), in which X 1 is includes or is derived from any of the polyols shown in FIG. 1B , e.g., a polyol selected from one of A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, and A32, and two of the hydroxyl groups of the polyol are replaced by the oxygen atoms in Formula (II-c).

In some embodiments, each of A 1 and A 2 is independently represented by a structure of Formula (II-c), in which X 1 is includes or is derived from a polyol selected from one of A3, A4, A5, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, and A32, and two of the hydroxyl groups of the polyol are replaced by the oxygen atoms in Formula (II-c).

In some embodiments, each of A 1 and A 2 is includes or is derived from the same polyol, e.g., a polyol selected from one of A1-A32. In some embodiments, each of A 1 and A 2 includes or is derived from a different polyol, e.g., a polyol selected from one of A1-A32.

In some embodiments, X 1 includes or is derived from A1. In some embodiments, X 1 includes or is derived from A2. In some embodiments, X 1 includes or is derived from A3. In some embodiments, X 1 includes or is derived from A4. In some embodiments, X 1 X 1 includes or is derived from A5. In some embodiments, X 1 includes or is derived from A6. In some embodiments, X 1 includes or is derived from A7. In some embodiments, X 1 includes or is derived from A8. In some embodiments, X 1 includes or is derived from A9. In some embodiments, X 1 includes or is derived from A10. In some embodiments, X 1 includes or is derived from A11. In some embodiments, X 1 includes or is derived from A12. In some embodiments, X 1 includes or is derived from A13. In some embodiments, X 1 includes or is derived from A14. In some embodiments, X 1 includes or is derived from A15. In some embodiments, X 1 includes or is derived from A16. In some embodiments, X 1 includes or is derived from A17. In some embodiments, X 1 includes or is derived from A18. In some embodiments, X 1 includes or is derived from A19. In some embodiments, X 1 includes or is derived from A20. In some embodiments, X 1 includes or is derived from A21. In some embodiments, X 1 includes or is derived from A22. In some embodiments, X 1 includes or is derived from A23. In some embodiments, X 1 includes or is derived from A24. In some embodiments, X 1 includes or is derived from A25. In some embodiments, X 1 includes or is derived from A26. In some embodiments, X 1 includes or is derived from A27. In some embodiments, X 1 includes or is derived from A28. In some embodiments, X 1 includes or is derived from A29. In some embodiments, X 1 includes or is derived from A30. In some embodiments, X 1 includes or is derived from A31. In some embodiments, X 1 includes or is derived from A32.

In some embodiments, each of B 1 and B 2 is independently represented by a structure of Formula (III-b), in which Z 2 includes or is derived from any of the vinyl ethers shown in FIG. 1C , e.g., a vinyl ether selected from one of B1, B2, B3, B4, B5, or B6, and two of the hydrogen atoms of the vinyl groups are replaced linkage indicated in Formula (III-b).

In some embodiments, each of B 1 and B 2 includes or is derived from the same vinyl ether, e.g., a vinyl ether selected from one of B1-B6. In some embodiments, each of B 1 and B 2 includes or is derived from a different vinyl ether, e.g., a vinyl ether selected from one of B1-B6.

In some embodiments, Z 2 includes or is derived from B1. In some embodiments, Z 2 includes or is derived from B2. In some embodiments, Z 2 includes or is derived from B3. In some embodiments, Z 2 includes or is derived from B4. In some embodiments, Z 2 includes or is derived from B5. In some embodiments, Z 2 includes or is derived from B6.

In some embodiments, each of C 1 and C 2 is heteroalkyl, optionally substituted with 1-6 R 3 . In some embodiments, each of C 1 and C 2 is C 1 -C 20 heteroalkyl, optionally substituted with 1-6 R 3 . In some embodiments, each of C 1 and C 2 is C 1 -C 10 heteroalkyl. In some embodiments, each of C 1 and C 2 is C 1 -C 10 heteroalkyl. In some embodiments, each of C 1 and C 2 is C 1 -C 10 heteroalkyl, e.g., an oxygen-containing C 1 -C 4 heteroalkyl and/or an amine-containing heteroalkyl. In some embodiments, each of C 1 and C 2 comprises a polyethylene glycol (PEG), a polyethylene oxide (PEO), a polypropylene glycol (PPG), a polyglycerol (PG), a poloxamine (POX), a polybutylene oxide (PBO), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polydioxanone (PDO), a polyanhydride, a polyacrylide, a polyvinyl, or a polyorthoester.

In some embodiments, each of C 1 and C 2 comprises a polyethylene glycol (PEG). In some embodiments, each of C 1 and C 2 comprises a polyethylene glycol (PEG) or a polyethylene oxide (PEO). In some embodiments, each of C 1 and C 2 comprises a polyethylene oxide (PEO) or a polypropylene glycol (PPG). In some embodiments, each of C 1 and C 2 comprises a polybutylene oxide (PBO).

In some embodiments, each of C 1 or C 2 comprises a cyclic structure. In some embodiments, each of C 1 or C 2 comprises a cyclic structure, e.g., a cyclyl or heterocyclyl group. In some embodiments, each of C 1 or C 2 comprises a carbohydrate (e.g., a glucose derivative, galactose derivative, mannose derivative, fucose derivative, sialic acid derivative, or other carbohydrate derivative). In some embodiments, each of C 1 or C 2 comprises a dextran, a cyclodextran, chitosan, or other carbohydrate based moiety.

In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 20,000 Da in size. In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 17,500 Da, from about 200 Da to about 15,000 Da, from about 200 Da to about 12,500 Da, from about 200 Da to about 10,000 Da, from about 200 Da to about 9,000 Da, from about 200 Da to about 8,000 Da, from about 200 Da to about 7,000 Da, from about 200 Da to about 6,000 Da, from about 200 Da to about 5,000 Da, from about 200 Da to about 4,000 Da, from about 200 Da to about 3,000 Da, or from about 200 Da to about 2,000 Da in size. In some embodiments, each of C 1 or C 2 is independently from about 200 Da to about 5,000 Da in size. In some embodiments, each of C 1 or C 2 is independently from about 200 Da to about 2,000 Da in size.

In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 2,000 Da in size. In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 1,750 Da, from about 200 Da to about 1,500 Da, from about 200 to about 1,400 Da, from about 200 to about 1,300 Da, from about 200 to about 1,200, from about 200 to about 1,100, or from about 200 to about 1,000 in size. In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 900 Da, from about 200 Da to about 800, from about 200 to about 700 Da, from about 200 to about 600 Da, from about 200 to about 500 Da, or from about 200 to about 400 Da. each of C 1 or C 2 is independently about 400 Da in size

In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 2,000 Da in size. In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 2,000 Da in size, from about 250 Da to about 1,900 in size, from about 300 Da to about 1,800, from about 350 Da to about 1,700, or from about 400 Da to about 1,600 in size. In some embodiments, each of C 1 or C 2 is independently about 500 Da to about 1,500 in size, from about 600 Da to about 1,500 in size, from about 700 Da to about 1,400, from about 800 Da to about 1,300, or from about 900 Da to about 1,200 in size. In some embodiments, each of C 1 or C 2 is independently about 1,000 Da to about 1,200 Da in size. In some embodiments, each of C 1 or C 2 is independently about 1,000 Da in size.

In some embodiments, each of C 1 and C 2 is the same. In some embodiments, both of C 1 and C 2 is from about 200 Da to about 1200 Da, from about 300 Da to about 1100 Da, or from about 400 Da to about 1000 Da in size. In some embodiments, both of C 1 and C 2 are from about 100 Da to about 500 Da or from about 800 Da to about 1200 Da in size. In some embodiments, both of C 1 and C 2 are 400 Da or 1000 Da in size.

In some embodiments, each of C 1 and C 2 is different. In some embodiments, each of C 1 and C 2 is from about 200 Da to about 1200 Da, from about 300 Da to about 1100 Da, or from about 400 Da to about 1000 Da in size. In some embodiments, one of C 1 and C 2 is from about 100 Da to about 500 Da and the other of C 1 and C 2 is from bout 800 Da to about 1200 Da in size. In some embodiments, one of C 1 and C 2 is about 400 Da in size and the other of C 1 and C 2 is about 1000 Da in size.

In some embodiments of the polymer of Formula (I), the precursor to each of C 1 and C 1 is PEG (e.g., polyethylene glycol). In some embodiments, the PEG comprises PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 800, PEG 1000, PEG 1500, PEG 2000, PEG 2050, PEG 4000, or PEG 6000, also referred to herein as P100, P200, P300, P400, P500, P600, P800, P1000, P1500, P2000, P2050, P4000, and P6000, or any combination thereof. In some embodiments, the PEG comprises P400, P1000, or a combination of P400 and P1000. In some embodiments, the PEG comprises PEG2050.

In some embodiments of a polymer of Formula (I-b), each of m and n independently an integer from 2 to 200, from 2 to 175, from 2 to 150, from 2 to 125, from 2 to 100, from 2 to 90, from 2 to 80, from 2 to 70, from 2 to 60, from 2 to 50, from 2 to 45, from 2 to 40, from 2 to 35, from 2 to 30, from 2 to 25, from 2 to 20, from 2 to 15, from 2 to 10, or from 2 to 5. In some embodiments, each of m and n independently is an integer from 5 to 100, from 5 to 95, from 5 to 85, from 5 to 80, from 5 to 75, from 5 to 70, from 5 to 65, from 5 to 60, from 5 to 55, from 5 to 50, from 5 to 45, from 5 to 40, from 5 to 35, from 5 to 30, from 5 to 25, or from 5 to 20. In some embodiments, each of m and n independently is an integer from 5 to 50. In some embodiments, each of m and n independently is an integer from 10 to 100, from 10 to 95, from 10 to 85, from 10 to 80, from 10 to 75, from 10 to 70, from 10 to 65, from 10 to 60, from 10 to 55, from 10 to 50, from 10 to 45, from 10 to 40, from 10 to 35, from 10 to 30, from 10 to 25, or from 10 to 20. In some embodiments, each of m and n independently is an integer from 10 to 50.

In some embodiments, the agent is a therapeutic or a diagnostic agent as described herein. In some embodiments, the agent is an AHCM as described herein. In some embodiments, the agent is an ARB as described herein, e.g., losartan, valsartan, telmisartan, candesartan, eprosartan, irbesartan, azilsartan, EXP-3174, olmesartan, or a prodrug or active metabolite thereof, e.g., a compound shown in FIG. 23 .

In some embodiments, the agent is a vitamin D analog or derivative as described herein. In some embodiments, the agent is a vitamin D analog or derivative as described herein, e.g., paricalcitol, doxercalciferol, falecalcitriol, maxacalcitol, tacalcitol, alfacalcidol, eldecalcidol, seocalcitol, lexicalcitol, CD578, inecalcitol, calcipotriol, TX527, 2MD, WY1112, PRI-2205, ILX23-7553, ercalcitriol, EB1089 (seocalcitol), BXL-628 (elocalcitol), MC1288, CB966, BCB 1093, GS 1558, SM-10193, EB1072, EB1129, EB1133, EB1155, EB1270, MC1288, EB1213, CB1093, VD2656, VD2668, VD2708, VD2716, VD2728, VD2736, GS1500, GS1558, KH1060, ZK161422, and analogs and derivatives thereof, e.g., as shown in FIG. 24 .

In some embodiments, the agent is a bromodomain and extra-terminal protein inhibitor (i-BET) as described herein. In some embodiments, the agent is a bromodomain and extra-terminal protein inhibitor (i-BET) as described herein, e.g MS436, PFI-1, I-BET 151, OTX-015, JQ1, CPI-203, bromosporine, RVX-208, I-BET 762, I-BET 151, OFXBD02, OFXBD03, XD14, AZD5153, and analogs and derivatives thereof, e.g., as shown in FIGS. 25A and 25B .

In some embodiments, the agent is an IDO inhibitor (i.e., indoleamine 2,3-dioxygenase (IDO) pathway inhibitor) as described herein. In some embodiments, the agent is an IDO inhibitor as described herein, e.g., GDC-0919, indoximod, 1-methyltryptophan (e.g., 1-methyl- L -tryptophan, 1-methyl- D -tryptophan), NLG8189, INCB024360, NLG919, methylthiohydantoin tryptophan, brassinin, annulin B, exiguamine A, INCB023843, or an analog or derivative thereof.

In some embodiments, each of A 1 and A 2 is the same. In some embodiments, each of A 1 and A 2 is different. In some embodiments, the polymer (e.g., a polyacetal polymer as described herein, e.g., a polyacetal polymer of Formula (I), Formula (I-a), or Formula (I-b)), comprises only one of A 1 or A 2 . In some embodiments, the polymer (e.g., a polyacetal polymer as described herein), comprises only one of A 1 or A 2 , and each of m and n is an integer between 2 and 100. In some embodiments, the polymer (e.g., a polyacetal polymer as described herein), comprises only one of A 1 or A 2 , and each of m and n is an integer between 10 and 100. In some embodiments, the polymer (e.g., a polyacetal polymer as described herein), does not comprise A 1 or A 2 , or both A 1 and A 2 .

In some embodiments, each of B 1 and B 2 is the same. In some embodiments, each of B 1 and B 2 is different.

In some embodiments, each of C 1 and C 2 is the same. In some embodiments, each of C 1 and C 2 is different. In some embodiments, the polymer (e.g., a polyacetal polymer as described herein, e.g., a polyacetal polymer of Formula (I), Formula (I-a), or Formula (I-b)), comprises only one of C 1 or C 2 . In some embodiments, the polymer (e.g., a polyacetal polymer as described herein), comprises only one of C 1 or C 2 , and each of m and n is an integer between 2 and 100. In some embodiments, the polymer (e.g., a polyacetal polymer as described herein), comprises only one of C 1 or C 2 , and each of m and n is an integer between 10 and 100. In some embodiments, the polymer (e.g., a polyacetal polymer as described herein), does not comprise C 1 or C 2 , or both C 1 and C 2 .

In any and all embodiments, -represents a linkage to another portion of the polymer (e.g., a polyacetal polymer described herein) or the terminus of the polymer (e.g., a polyacetal polymer described herein). In some embodiments, when represents a terminus of the polymer (e.g., a polyacetal polymer described herein), the terminus may be further modified with hydrogen, a linker (e.g., a linker described herein), an agent (e.g., an agent described herein, e.g., an ARB), or a targeting moiety (e.g., a linker described herein).

In some embodiments, the polymer (e.g., a polyacetal polymer of described herein) comprises a structure according to Formula (I-c):

wherein:

each of A 1 and A 2 is independently represented by a structure of Formula (II-d), Formula (II-e), Formula (II-f), Formula (II-g), Formula (II-h), Formula (II-i), or Formula (II-j);

each of B 1 and B 2 is independently represented by a structure of Formula (III-a);

each of C 1 and C 2 is heteroalkyl, cyclyl, or heterocyclyl, each of which is optionally substituted with 1-6 R 3 ;

each of R 3 is independently alkyl, alkenyl, alkynyl, hydroxyl, halo, heteroalkyl, keto, alkoxy, ester, cyclyl, heterocyclyl, cycloalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, a linker, an agent, a targeting moiety, or a branching point;

each of m or n is independently an integer from 1 to 200; and

wherein the structures of Formula (II-d), Formula (II-e), Formula (II-f), Formula (II-g), Formula (II-h), Formula (II-i), and Formula (II-j) are as described herein; and

the structure of Formula (III-a) is as described herein.

In some embodiments, each of A 1 and A 2 is the same, e.g., the same structure of Formula (II). In some embodiments, each of A 1 and A 2 is different, e.g., a different structure of Formula (II).

In some embodiments, X 1 is C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 1 -C 8 cyclyl, or C 1 -C 8 heterocyclyl. In some embodiments, X 1 is C 1 -C 12 alkylene or C 1 -C 12 heteroalkylene. In some embodiments, X 1 is C 1 -C 6 alkylene. In some embodiments, X 1 is C 1 -C 12 heteroalkylene.

In some embodiments, X 1 is C 3 -C 8 cyclyl or C 3 -C 8 heterocyclyl. In some embodiments, X 1 is C 3 -C 6 cyclyl or C 3 -C 6 heterocyclyl. In some embodiments, X 1 is C 3 -C 6 cyclyl. In some embodiments, X 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, X 1 is cyclopentyl or cyclohexyl. In some embodiments, X 1 is cyclopentyl or cyclohexyl. In some embodiments, X 1 is cyclohexyl.

In some embodiments, R 4a is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, O, (C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O, or (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O, wherein each alkyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 7 . In some embodiments, R 4a is C 1 -C 6 alkyl (e.g., CH 3 or CH 2 CH 3 ). In some embodiments, R 4a is O. In some embodiments, R 4a is (C 1 -C 6 alkylene)-O (e.g., CH 2 O or CH 2 CH 2 O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O (e.g., CH 2 OCH 2 CH 2 O or CH 2 CH 2 OCH 2 CH 2 O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O (e.g., CH 2 OC(O)CH 2 O, CH 2 CH 2 OC(O)CH 2 O, CH 2 OC(O)CH 2 CH 2 O, CH 2 OC(O)CH 2 CH 2 CH 2 O, CH 2 CH 2 OC(O)CH 2 CH 2 O, CH 2 CH 2 OC(O)CH 2 CH 2 CH 2 O, CH 2 OC(O)CH(CH 3 )O, or CH 2 CH 2 OC(O)CH(CH 3 )O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O (e.g., CH 2 OC(O)OCH 2 CH 2 O).

In some embodiments, R 4b is C 1 -C 6 alkyl (e.g., CH 3 , CH 2 CH 3 ). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-losartan, e.g., (CH 2 —O-L-losartan). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-valsartan, e.g., (CH 2 —O-L-valsartan). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-telmisartan, e.g., (CH 2 —O-L-telmisartan). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-candesartan, e.g., (CH 2 —O-L-candesartan). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-olmesartan, e.g., (CH 2 —O-L-olmesartan).

In some embodiments, L is a bond. In some embodiments, L is a linker. In some embodiments, L is a linker as described herein, e.g., a polyacetal polymer.

In some embodiments, ARB is losartan, valsartan, telmisartan, candesartan, or olmesartan. In some embodiments, ARB is losartan or valsartan. In some embodiments, ARB is telmisartan or candesartan. In some embodiments, ARB is losartan. In some embodiments, ARB is valsartan. In some embodiments, ARB is telmisartan. In some embodiments, ARB is candesartan. In some embodiments, ARB is olmesartan.

In some embodiments, T is a targeting moiety described herein. In some embodiments, T is mannose-6-phosphate.

In some embodiments, the precursor to each of A 1 and A 2 is independently selected from the following polyols:

In some embodiments, the precursor to each of A 1 and A 2 is independently selected from one of A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, and A32, e.g., as depicted in FIG. 1B . It is to be understood that when the precursor to A 1 or A 2 is one of the polyols in the above-noted group selected from A1-A32, B 1 or B 2 is connected to one of the oxygen atoms of the hydroxyl groups in said polyols.

In some embodiments, X 1 includes or is derived from a polyol selected from one of A3, A4, A5, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, and A32, e.g., as depicted in FIG. 1B . It is to be understood that when the precursor to A 1 or A 2 is one of the polyols in the above-noted group selected from A1-A32, B 1 or B 2 is connected to one of the oxygen atoms of the hydroxyl groups in said polyols.

In some embodiments, each of B 1 and B 2 is the same, e.g., the same structure of Formula (II). In some embodiments, each of B 1 and B 2 is different, e.g., a different structure of Formula (II).

In some embodiments, Z 1 is C(R 23 )(R 24 ) and each of R 22 and R 23 is independently hydrogen, C 1 -C 6 alkyl, or (C 1 -C 6 alkylene)-OR 26 . In some embodiments, R 22 is hydrogen and R 23 is independently C 1 -C 6 alkyl, e.g., CH 3 . In some embodiments, R 22 is hydrogen or C 1 -C 6 alkyl (e.g., CH 3 ), R 23 is (C 1 -C 2 alkylene)-OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point. In some embodiments, Z 1 is C 3 -C 6 cyclyl, optionally substituted with 1-4 R 25 (e.g., cyclohexyl).

In some embodiments, each of X 4 and X 5 is independently C 1 -C 6 alkylene (e.g., CH 2 , CH 2 CH 2 ), wherein alkylene is optionally substituted with 1-6 R 25 .

In some embodiments, each of R 20 and R 21 is independently C 1 -C 6 alkyl (e.g., CH 3 ) or OR 26 (e.g., C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point).

In some embodiments, the precursor to each of B 1 and B 2 is independently selected from the following vinyl ethers:

In some embodiments, each of C 1 and C 2 is the same, e.g., the same structure of Formula (II). In some embodiments, each of C 1 and C 2 is different, e.g., a different structure of Formula (II).

In some embodiments, each of C 1 and C 2 is independently heteroalkyl (e.g., an oxygen-containing C 1 -C 4 heteroalkyl and/or an amine-containing heteroalkyl), optionally substituted with 1-6 R 3 .

In some embodiments, each of C 1 and C 2 comprises a polyethylene glycol (PEG), a polyethylene oxide (PEO), a polypropylene glycol (PPG), a polyglycerol (PG), a poloxamine (POX), a polybutylene oxide (PBO), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polydioxanone (PDO), a polyanhydride, a polyacrylide, a polyvinyl, or a polyorthoester.

In some embodiments, each of C 1 and C 2 has a linear structure, e.g., does not comprise a branching point or cyclic group. In some embodiments, each of C 1 and C 2 has a C 1 or C 2 has a branched structure, e.g., comprising at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 branching points.

In some embodiments, each of C 1 and C 2 comprises a cyclic structure, e.g., a cyclyl or heterocyclyl group, e.g., a dextran, a cyclodextran, chitosan, or other carbohydrate based moiety.

In some embodiments, each of C 1 and C 2 is independently 200 to 5000 Da in size.

In some embodiments, each of C 1 and C 2 is a polyethylene glycol (PEG). In some embodiments, each of C 1 and C 2 is independently a polyethylene glycol (PEG) and is between about 200 and 1200 Da in size. In some embodiments, each of C 1 and C 2 is independently PEG 400, PEG 1000, or PEG 2050.

In some embodiments of a polymer (e.g., a polymer described herein), each of m and n independently an integer from 2 to 450, from 2 to 400, from 2 to 350, from 2 to 300, from 2 to 250, from 2 to 200, from 2 to 175, from 2 to 150, from 2 to 125, from 2 to 100, from 2 to 90, from 2 to 80, from 2 to 70, from 2 to 60, from 2 to 50, from 2 to 45, from 2 to 40, from 2 to 35, from 2 to 30, from 2 to 25, from 2 to 20, from 2 to 15, from 2 to 10, or from 2 to 5. In some embodiments, each of m and n independently is an integer from 2 to 250. In some embodiments, each of m and n independently is an integer from 2 to 100. In some embodiments, each of m and n independently is an integer from 2 to 50. In some embodiments, each of m and n independently is an integer from 2 to 25. In some embodiments, each of m and n independently is an integer from 2 to 10. In some embodiments, each of m and n independently is an integer from 10 to 500, from 10 to 250, from 10 to 200, from 10 to 150, from 10 to 100, from 10 to 75, from 10 to 50, or from 10 to 25. In some embodiments, each of m and n independently is an integer from 10 to 50. In an embodiment, m and n taken together are between 10 and 100, 20 and 80, 20 and 60, or 30 and 60.

In some embodiments, each of m and n independently an integer from 2 to 200, e.g., 5 to 200 or 10 to 200. In some embodiments, each of m and n independently an integer from 5 to 100, e.g., 10 to 50.

In some embodiments, each of A 1 and A 2 does not independently include, or is independently not derived from, tri(methylol)ethane. In some embodiments, each of A 1 and A 2 does not independently include, or is not independently derived from, tri(methylol)ethane and the polymer of Formula (I-c) is greater than about 5 kDa in size. In some embodiments, each of A 1 and A 2 does not independently include, or is not independently derived from, tri(methylol)ethane and the polymer of Formula (I-c) is greater than about 10 kDa in size.

In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane. In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane and the polymer of Formula (I-c) is greater than about 5 kDa in size. In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane and the polymer of Formula (I-c) is greater than about 10 kDa in size.

In some embodiments, the polymer (e.g., a polyacetal polymer described herein) comprises a structure according to Formula (I-d) or Formula (I-e):

wherein:

each of A 1 or A 2 is independently represented by a structure of Formula (II);

each of B 1 and B 2 is independently represented by a structure of Formula (III);

each of C 1 or C 2 is independently heteroalkyl, cyclyl, or heterocyclyl, each of which is optionally substituted with 1-6 R 3 ;

each of R 3 is independently alkyl, alkenyl, alkynyl, hydroxyl, halo, heteroalkyl, keto, alkoxy, ester, cyclyl, heterocyclyl, cycloalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, a linker, an agent, a targeting moiety, or a branching point; and

each of m and n is an integer between 1 to 200.

wherein the structure of Formula (II) is as described herein;

and the structure of Formula (III) is as described herein.

In some embodiments, each of A 1 and A 2 is the same, e.g., the same structure of Formula (II). In some embodiments, each of A 1 and A 2 is different, e.g., a different structure of Formula (II).

In some embodiments, X 1 is C 1 -C 12 alkylene or C 1 -C 12 heteroalkylene, optionally substituted with 1-6 R 4 . In some embodiments, X 1 is C 1 -C 12 heteroalkylene optionally substituted with 1-6 R 4 , e.g., (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene), wherein each alkylene is optionally substituted with 1-6 R 4 . In some embodiments, X 1 is C 3 -C 6 cyclyl, optionally substituted with 1-6 R 4 (e.g., cyclohexyl substituted with OR 5 ).

In some embodiments, each R 4 is independently C 1 -C 6 alkyl, OR 5 , (C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-OR 5 , or (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-OR 5 .

In some embodiments, each R 5 is independently hydrogen, C 1 -C 6 alkyl, a linker, a branching point, a protecting group, an agent, or a targeting moiety.

In some embodiments, the precursor to each of A 1 and A 2 is independently selected from the following polyols:

In some embodiments, the precursor to each of A 1 and A 2 is independently selected from one of A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, and A32, e.g., as depicted in FIG. 1B . It is to be understood that when the precursor to A 1 or A 2 is one of the polyols in the above-noted group selected from A31, and A32, B 1 or B 2 is connected to one of the oxygen atoms of the hydroxyl groups in said polyols.

In some embodiments, X 1 includes or is derived from a polyol selected from one of A3, A4, A5, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, and A32, e.g., as depicted in FIG. 1B . It is to be understood that when the precursor to A 1 or A 2 is one of the polyols in the above-noted group selected from A1-A32, B 1 or B 2 is connected to one of the oxygen atoms of the hydroxyl groups in said polyols.

In some embodiments, each of B 1 and B 2 is the same, e.g., the same structure of Formula (II). In some embodiments, each of B 1 and B 2 is different, e.g., a different structure of Formula (II).

In some embodiments, Z 1 is C(R 23 )(R 24 ) and each of R 22 and R 23 is independently hydrogen, C 1 -C 6 alkyl, or (C 1 -C 6 alkylene)-OR 26 . In some embodiments, R 22 is hydrogen and R 23 is independently C 1 -C 6 alkyl, e.g., CH 3 . In some embodiments, R 22 is hydrogen or C 1 -C 6 alkyl (e.g., CH 3 ), R 23 is (C 1 -C 2 alkylene)-OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point. In some embodiments, Z 1 is C 3 -C 6 cyclyl, optionally substituted with 1-4 R 25 (e.g., cyclohexyl).

In some embodiments, each of X 4 and X 5 is independently C 1 -C 6 alkylene (e.g., CH 2 , CH 2 CH 2 ), wherein alkylene is optionally substituted with 1-6 R 25 .

In some embodiments, each of R 20 and R 21 is independently C 1 -C 6 alkyl (e.g., CH 3 ) or OR 26 (e.g., C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point).

In some embodiments, the precursor to each of B 1 and B 2 is independently selected from the following vinyl ethers:

In some embodiments, each of C 1 and C 2 is the same, e.g., the same structure of Formula (II). In some embodiments, each of C 1 and C 2 is different, e.g., a different structure of Formula (II).

In some embodiments, each of C 1 and C 2 is independently heteroalkyl (e.g., an oxygen-containing C 1 -C 4 heteroalkyl and/or an amine-containing heteroalkyl), optionally substituted with 1-6 R 3 .

In some embodiments, each of C 1 and C 2 comprises a polyethylene glycol (PEG), a polyethylene oxide (PEO), a polypropylene glycol (PPG), a polyglycerol (PG), a poloxamine (POX), a polybutylene oxide (PBO), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polydioxanone (PDO), a polyanhydride, a polyacrylide, a polyvinyl, or a polyorthoester.

In some embodiments, each of C 1 and C 2 has a linear structure, e.g., does not comprise a branching point or cyclic group. In some embodiments, each of C 1 and C 2 has a C 1 or C 2 has a branched structure, e.g., comprising at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 branching points.

In some embodiments, each of C 1 and C 2 comprises a cyclic structure, e.g., a cyclyl or heterocyclyl group, e.g., a dextran, a cyclodextran, chitosan, or other carbohydrate based moiety.

In some embodiments, each of C 1 and C 2 is independently 200 to 5000 Da in size.

In some embodiments, each of C 1 and C 2 is a polyethylene glycol (PEG). In some embodiments, each of C 1 and C 2 is independently a polyethylene glycol (PEG) and is between about 200 and 1200 Da in size. In some embodiments, each of C 1 and C 2 is independently PEG 400, PEG 1000, or PEG 2050.

In some embodiments of a polymer (e.g., a polymer described herein, e.g., a polymer of Formula (I)), each of m and n independently an integer from 2 to 450, from 2 to 400, from 2 to 350, from 2 to 300, from 2 to 250, from 2 to 200, from 2 to 175, from 2 to 150, from 2 to 125, from 2 to 100, from 2 to 90, from 2 to 80, from 2 to 70, from 2 to 60, from 2 to 50, from 2 to 45, from 2 to 40, from 2 to 35, from 2 to 30, from 2 to 25, from 2 to 20, from 2 to 15, from 2 to 10, or from 2 to 5. In some embodiments, each of m and n independently is an integer from 2 to 250. In some embodiments, each of m and n independently is an integer from 2 to 100. In some embodiments, each of m and n independently is an integer from 2 to 50. In some embodiments, each of m and n independently is an integer from 2 to 25. In some embodiments, each of m and n independently is an integer from 2 to 10. In some embodiments, each of m and n independently is an integer from 10 to 500, from 10 to 250, from 10 to 200, from 10 to 150, from 10 to 100, from 10 to 75, from 10 to 50, or from 10 to 25. In some embodiments, each of m and n independently is an integer from 10 to 50. In an embodiment, m and n taken together are between 10 and 100, 20 and 80, 20 and 60, or 30 and 60.

In some embodiments, each of m and n independently an integer from 2 to 200, e.g., 5 to 200 or 10 to 200. In some embodiments, each of m and n independently an integer from 5 to 100, e.g., 10 to 50.

In some embodiments, each of A 1 and A 2 does not independently include, or is independently not derived from, tri(methylol)ethane. In some embodiments, each of A 1 and A 2 does not independently include, or is not independently derived from, tri(methylol)ethane and the polymer of Formula (I-d) or Formula (I-e) is greater than about 5 kDa in size. In some embodiments, each of A 1 and A 2 does not independently include, or is not independently derived from, tri(methylol)ethane and the polymer of Formula (I-d) or Formula (I-e) is greater than about 10 kDa in size.

In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane. In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane and the polymer of Formula (I-d) or Formula (I-e) is greater than about 5 kDa in size. In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane and the polymer of Formula (I-d) or Formula (I-e) is greater than about 10 kDa in size.

In some embodiments, the polymer (e.g., the polyacetal polymer) comprises a structure according to Formula (IV):

wherein:

X 1 is C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 3 -C 8 cyclyl, or C 3 -C 8 heterocyclyl, wherein each alkylene, heteroalkylene, cyclyl, or heterocyclyl is optionally substituted with 1-6 R 4 ;

each of X 4 and X 5 is independently C 1 -C 6 alkylene, optionally substituted with 1-6 R 4 ;

Z 1 is O, C 3 -C 8 cyclyl, or C(R 22 )(R 23 );

each of C 1 and C 2 is heteroalkyl, cyclyl, or heterocyclyl, each of which is optionally substituted with 1-6 R 3 ;

each of R 3 is independently alkyl, hydroxyl, halo, heteroalkyl, keto, alkoxy, ester, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, a linker, an agent, a targeting moiety, a protecting group, or a branching point;

each R 4 is independently C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, OR 5 , (C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-OR 5 , or (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-OR 5 , wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 7 ;

each R 5 is independently hydrogen, C 1 -C 6 alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, a linker, an agent, a targeting moiety, a protecting group, or a branching point, wherein each alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl is optionally substituted with 1-6 R 8 ;

each R 7 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, halo, OR 5 , (C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 5 , cyano, cyclyl, heterocyclyl, aryl, or heteroaryl; and

each R 8 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, halo, cyano, cyclyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-6 R 9 ;

each R 9 is independently C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, cyano, cyclyl, or heterocyclyl;

each of R 20 and R 21 is independently C 1 -C 6 alkyl or OR 26 ;

each of R 22 and R 23 is independently hydrogen, C 1 -C 6 alkyl, or (C 1 -C 6 alkylene)-OR 26 ; and each R 26 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, a linker, an agent, a targeting moiety, a protecting group, or a branching point;

each of p and x is independently 0 or 1;

and one of p or x is 1; and

m or n is independently an integer from 5 to 200.

In some embodiments, X 1 is C 1 -C 12 alkylene or C 1 -C 12 heteroalkylene, optionally substituted with 1-6 R 4 . In some embodiments, X 1 is C 1 -C 6 alkylene, optionally substituted with 1-6 R 4 . In some embodiments, X 1 is C 1 -C 12 heteroalkylene, optionally substituted with 1-6 R 4 .

In some embodiments, X 1 is C 3 -C 6 cyclyl or C 3 -C 6 heterocyclyl, wherein each cyclyl or heterocyclyl is optionally substituted with 1-6 R 4 . In some embodiments, X 1 is C 3 -C 6 cyclyl, optionally substituted with 1-6 R 4 . In some embodiments, X 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1-6 R 4 . In some embodiments, X 1 is cyclopentyl or cyclohexyl, each of which is optionally substituted with 1-6 R 4 . In some embodiments, X 1 is cyclopentyl or cyclohexyl, each of which is optionally substituted with 1-4 R 4 . In some embodiments, X 1 is cyclopentyl or cyclohexyl, each of which is optionally substituted with 1-2 R 4 , and each R 4 is independently C 1 -C 6 alkyl or OR 5 . In some embodiments, X 1 is cyclohexyl substituted with 1 R 4 . In some embodiments, X 1 is cyclohexyl substituted with OR 5 .

In some embodiments, R 5 is hydrogen, C 1 -C 6 alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is arylalkyl or heteroarylalkyl. In some embodiments, R 5 is a linker. In some embodiments, R 5 is an agent (e.g., an ARB). In some embodiments, R 5 is a targeting moiety. In some embodiments, R 5 is a protecting group. In some embodiments, R 5 is a branching point.

In some embodiments, Z 1 is O.

In some embodiments, Z 1 is C 3 -C 8 cyclyl or C 3 -C 8 heterocyclyl, each of which is optionally substituted with 1-4 R 25 . In some embodiments, Z 1 is C 1 -C 6 cyclyl or C 1 -C 6 heterocyclyl, each of which is optionally substituted with 1-4 R 25 . In some embodiments, Z 1 is C 3 -C 6 cyclyl, optionally substituted with 1-4 R 25 . In some embodiments, Z 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1-4 R 25 . In some embodiments, Z 1 is cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1-4 R 25 . In some embodiments, Z 1 is cyclohexyl, optionally substituted with 1-4 R 25 . In some embodiments, Z 1 is cyclohexyl.

In some embodiments, Z 1 is C(R 22 )(R 23 ). In some embodiments, Z 1 is C(R 23 )(R 24 ) and each of R 22 and R 23 is independently hydrogen, C 1 -C 6 alkyl, or (C 1 -C 6 alkylene)-OR 26 . In some embodiments, each of R 22 and R 23 is independently hydrogen. In some embodiments, each of R 22 and R 23 is independently hydrogen or C 1 -C 6 alkyl, e.g., CH 3 . In some embodiments, each of R 22 and R 23 is independently hydrogen. In some embodiments, each of R 22 and R 23 is independently C 1 -C 6 alkyl, e.g., CH 3 . In some embodiments, R 22 is hydrogen and R 23 is independently C 1 -C 6 alkyl, e.g., CH 3 . In some embodiments, each of R 22 and R 23 is independently (C 1 -C 6 alkylene)-OR 26 . In some embodiments, each of R 22 and R 23 is independently (C 1 -C 2 alkylene)-OR 26 . In some embodiments, each of R 22 and R 23 is independently (C 1 -C 2 alkylene)-OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point. In some embodiments, R 22 is hydrogen or C 1 -C 6 alkyl (e.g., CH 3 ), R 23 is (C 1 -C 2 alkylene)-OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point. In some embodiments, R 22 is C 1 -C 6 alkyl (e.g., CH 3 ), R 23 is (C 1 -C 2 alkylene)-OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point.

In some embodiments, each of X 4 and X 5 is independently C 1 -C 6 alkylene, wherein alkylene is optionally substituted with 1-6 R 25 . In some embodiments, each of X 4 and X 5 is independently C 1 -C 4 alkylene, wherein alkylene is optionally substituted with 1-6 R 25 . In some embodiments, each of X 4 and X 5 is independently C 1 -C 2 alkylene, wherein alkylene is optionally substituted with 1-6 R 25 . In some embodiments, each of X 4 and X 5 is independently C 1 -C 2 alkylene (e.g., CH 2 , CH 2 CH 2 ).

In some embodiments, each of R 20 and R 21 is independently C 1 -C 6 alkyl or OR 20 . In some embodiments, each of R 20 and R 21 is independently C 1 -C 6 alkyl. In some embodiments, each of R 20 and R 21 is independently C 1 -C 4 alkyl. In some embodiments, each of R 20 and R 21 is independently C 1 -C 2 alkyl, e.g., CH 3 . In some embodiments, each of R 20 and R 21 is independently OR 26 . In some embodiments, each of R 20 and R 21 is independently OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point.

In some embodiments, each of C 1 and C 2 is C 1 -C 10 heteroalkyl, e.g., an oxygen-containing C 1 -C 4 heteroalkyl and/or an amine-containing heteroalkyl. In some embodiments, each of C 1 and C 2 comprises a polyethylene glycol (PEG), a polyethylene oxide (PEO), a polypropylene glycol (PPG), a polyglycerol (PG), a poloxamine (POX), a polybutylene oxide (PBO), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polydioxanone (PDO), a polyanhydride, a polyacrylide, a polyvinyl, or a polyorthoester.

In some embodiments, each of C 1 and C 2 comprises a polyethylene glycol (PEG). In some embodiments, each of C 1 and C 2 comprises a polyethylene glycol (PEG) or a polyethylene oxide (PEO). In some embodiments, each of C 1 and C 2 comprises a polyethylene oxide (PEO) or a polypropylene glycol (PPG). In some embodiments, each of C 1 and C 2 comprises a polybutylene oxide (PBO).

In some embodiments, each of C 1 or C 2 comprises a cyclic structure. In some embodiments, each of C 1 or C 2 comprises a cyclic structure, e.g., a cyclyl or heterocyclyl group. In some embodiments, each of C 1 or C 2 comprises a carbohydrate (e.g., a glucose derivative, galactose derivative, mannose derivative, fucose derivative, sialic acid derivative, or other carbohydrate derivative). In some embodiments, each of C 1 or C 2 comprises a dextran, a cyclodextran, chitosan, or other carbohydrate based moiety.

In some embodiments, the precursor to C 1 is PEG (e.g., polyethylene glycol). In some embodiments, the PEG comprises PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 800, PEG 1000, PEG 1500, PEG 2000, PEG 2050, PEG 4000, or PEG 6000, also referred to herein as P100, P200, P300, P400, P500, P600, P800, P1000, P1500, P2000, P2050, P4000, and P6000, or any combination thereof. In some embodiments, the PEG comprises P400, P1000, or a combination of P400 and P1000. In some embodiments, the PEG comprises PEG 2050.

In some embodiments, m is integer from 5 to 175, from 5 to 150, from 5 to 125, from 5 to 100. In some embodiments, m is integer from 5 to 100, from 5 to 95, from 5 to 85, from 5 to 80, from 5 to 75, from 5 to 70, from 5 to 65, from 5 to 60, from 5 to 55, from 5 to 50, from 5 to 45, from 5 to 40, from 5 to 35, from 5 to 30, from 5 to 25, or from 5 to 20. In some embodiments, m is an integer from 5 to 50. In some embodiments, m is an integer from 10 to 100, from 10 to 95, from 10 to 85, from 10 to 80, from 10 to 75, from 10 to 70, from 10 to 65, from 10 to 60, from 10 to 55, from 10 to 50, from 10 to 45, from 10 to 40, from 10 to 35, from 10 to 30, from 10 to 25, or from 10 to 20. In some embodiments, m is an integer from 10 to 50.

In some embodiments, the polymer (e.g., a polyacetal polymer described herein) is derived from or comprises a compound of Formula (II) (e.g., a polyol) selected from one or more of A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, and A32; a compound of Formula (III) (e.g., a vinyl ether) selected from one or more of B1, B2, B3, B4, B5 and B6; and a compound of C 1 or C 2 (e.g., a PEG). In one embodiment, the polymer is derived from or comprises A1 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A2 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A3 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A4 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A5 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A6 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A7 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A8 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A9 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A10 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A11 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A12 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A13 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A14 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A15 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A16 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A17 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A18 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A19 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A20 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A21 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A22 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A23 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A24 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A25 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A26 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A27 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A28 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A29 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A30 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A31 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). In one embodiment, the polymer is derived from or comprises A32 and a vinyl ether chosen from one or more of B1, B2, B3, B4, B5, and B6, and may or may not comprise a PEG moiety (e.g., P400, P1000, or P2050). Each of the foregoing polyol and vinyl ethers are shown in FIGS. 1B and 1C .

In one embodiment, the polymer (e.g., a polyacetal polymer described herein) is derived from or comprises a polyol and a vinyl ether depicted in FIGS. 1B and 1C . In one embodiment, the polymer (e.g., a polyacetal polymer, e.g., of Formula (I), Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d), Formula (I-e), or Formula (IV)) is derived from or comprises a polyol and a vinyl ether depicted in FIGS. 1B and 1C and has a ratio of release or degradation rate of the polymer at a first pH (e.g., a first more acidic pH such as pH=6.7) relative to a second pH (e.g., a second less acidic pH such as pH=7.4) is greater than 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3 or higher. In one embodiment, the ratio of release or degradation rate of the polymer at pH=6.7 relative to pH=7.4 is greater than 2. In these embodiments, the polymer is pH-sensitive such that it can degrade or release an agent attached thereto selectively at a target site, which has a different pH from a non-target-site. The release or degradation rate of the polymer can be measured at a temperature of about 37° C.

In one embodiment, the polymer (e.g., a polyacetal polymer described herein) is derived from or comprises a polyol and a vinyl ether depicted in FIGS. 1B and 1C and is hydrophobic (e.g., insoluble in water). In one embodiment, the polymer (e.g., a polyacetal polymer described herein) is derived from or comprises a polyol and a vinyl ether depicted in FIGS. 1B and 1C and is sparingly soluble in water. In one embodiment, the polymer (e.g., a polyacetal polymer described herein) is derived from or comprises a polyol and a vinyl ether depicted in FIGS. 1B and 1C and is slightly soluble in water. In one embodiment, the polymer (e.g., a polyacetal polymer described herein) is derived from or comprises a polyol and a vinyl ether depicted in FIGS. 1B and 1C and is partially soluble in water.

In one embodiment, the polymer (e.g., a polyacetal polymer described herein) is derived from or comprises a polyol and a vinyl ether depicted in FIGS. 1B and 1C and is amphiphilic. In one embodiment, the polymer (e.g., a polyacetal polymer described herein) is derived from or comprises a polyol and a vinyl ether depicted in FIGS. 1B and 1C and comprises one segment that is hydrophobic and one segment that is hydrophilic.

In some embodiments, the polymer (e.g., a polymer as described herein) is present in (e.g., is part or all of) a linker, e.g., pH-sensitive linker as described herein.

In some embodiments, the polymer (e.g., a polymer as described herein) is present in a conjugate (e.g., an agent-polymer conjugate, a targeting moiety-polymer conjugate, or an agent-polymer-targeting moiety conjugate, as described herein). In one embodiment, the agent and/or targeting moiety are directly coupled (e.g., covalently coupled) to the polyacetal polymer. In another embodiment, an acetal monomer or a polyacetal polymer couples or links (e.g., covalently couples or links) the agent and/or targeting moiety to a second polymer (e.g., a polymer other than a polyacetal polymer). In one embodiment, the agent is a therapeutic or a diagnostic agent as described herein. In one embodiment, the agent is an AHCM as described herein.

In some embodiments, the polymer (e.g., a polymer as described herein) when present in a particle is associated (e.g., covalently or non-covalently) to an agent. In one embodiment, the agent is a therapeutic or a diagnostic agent as described herein. In one embodiment, the agent is an AHCM as described herein.

In some embodiments, the polymer is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% made of polyacetal polymers (e.g., a polyacetal polymer according to Formula (I)). In certain embodiments, the polymer can further comprise one or more hydrophobic or hydrophilic polymers to enhance a desired property. In certain embodiments, the polymer comprises (e.g., is linked to) a water-soluble monomer or polymer (e.g., polyethylene glycol (PEG) monomer or polymer), e.g., to increase one or more of amphiphilicity, hydrophilicity, water-solubility, pH sensitivity or stability. In other embodiments, the polymer comprises one or more of a polyacetal monomer or polymer with or without PEG, and one or more of: dextran (e.g., with a molecular weight of about 50 kDa or above), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polydioxanone (PDO), polyanhydrides, polyorthoesters, cyclodextrin, or chitosan, or a pegylated form thereof. In other embodiments, the polymer comprises one or more of a polyol monomer (e.g., a monomer according to Formula (II), Formula (II-a), Formula (II-b), or Formula (II-c), or a polyol as shown in FIG. 1B , with or without a compound of C 1 or C 2 , e.g., a PEG and one or more of: a polyethylene oxide (PEO), a polypropylene glycol (PPG), a polyglycerol (PG), a poloxamine (POX), a polybutylene oxide (PBO), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polydioxanone (PDO), a polyanhydride, a polyacrylide, a polyvinyl, or a polyorthoester. In some embodiments, the polymer comprises a plurality of a PLA, dextran, or a polyacetal polymer described herein. In one embodiment, the dextran has a molecular weight of at least about 200 kDa. In one embodiment, the dextran has a molecular weight of at least about 500 kDa. Exemplary polymers that can be combined with the polyacetal polymers are described herein, e.g., in the section entitled “Polymers.”

In one embodiment, the polyacetal monomer or polymer (with or without an agent, e.g., an AHCM, and/or a targeting moiety) is coupled (e.g., covalently coupled) to a second polymer, e.g., one or more of: dextran, polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polydioxanone (PDO), polyanhydrides, polyorthoesters, cyclodextrin, or chitosan, or a pegylated form thereof (e.g., poly(lactic acid)-b-poly(ethylene glycol) (PLA-PEG), poly(lactic acid)-b-poly(ethylene glycol) (PLGA-PEG), or (cyclodextrin)-co-poly(ethylene glycol) (CDP)).

Linkers

In another aspect, the invention features a linker, e.g., a pH-sensitive linker. In one embodiment, the linker couples (e.g., covalently links) a first moiety to a second moiety. In one embodiment, the linker comprises, or consists of, a polyacetal polymer as described herein.

In some embodiments, the first moiety is an agent (e.g., a therapeutic agent as described herein) and/or a targeting moiety, and the second moiety is a polymer (e.g., a polyacetal polymer). In some embodiments, the polyacetal is a polymer described herein (e.g., a polymer of Formula (I), Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d), Formula (I-e), or Formula (IV)).

In other embodiments, the first moiety is an agent (e.g., a therapeutic agent as described herein) and/or a targeting moiety, and the second moiety is a polymer other than a polyacetal monomer (e.g., a second polymer, e.g., one or more of: polyethylene glycol (PEG), a polyethylene oxide (PEO), a polypropylene glycol (PPG), a polyglycerol (PG), a poloxamine (POX), a polybutylene oxide (PBO), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polydioxanone (PDO), a polyanhydride, a polyacrylide, a polyvinyl, a polyorthoester, a dextran, a cyclodextran, chitosan, or other carbohydrate based polymer as described herein).

In some embodiments, the first moiety is an agent, and the second moiety comprises a targeting moiety (optionally in combination with a polymer other than a polyacetal polymer described herein).

In some embodiments, the linker (e.g., a linker comprising a polyacetal polymer described herein, e.g., a structure of Formula (I), Formula (I-a), Formula (I-b), or Formula (IV)) is pH-sensitive. In certain embodiments, the linker is sensitive to a pH between about 5.0 and about 7.4, between 5.0 and 7.0, between 5.0 and 6.5, between 5.0 and 5.5, or between 5.9 and 6.2. In one embodiment, the linker is sensitive to a pH between about 5.5 and about 6.5, e.g., between 5.9 and 6.2.

In some embodiments, the linker is sensitive to a pH of no more than 7.4, no more than 7.0, no more than 6.9, no more than 6.8, no more than 6.7, no more than 6.6, no more than 6.5, no more than 6.4, no more than 6.3, no more than 6.2, no more than 6.1, no more than 6.0, no more than 5.5 or lower.

In one embodiment, the linker is sensitive to a hypoxic pH, e.g., a pH about 6.7 to 6.9, e.g., compared to a physiological pH of about 7.4.

In one embodiment, the linker is preferentially cleaved or degraded upon exposure to a first pH relative to a second pH. In one embodiment, the linker is cleaved or degraded at least 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, or 100 times faster upon exposure to a first pH relative to a second pH. In other embodiments, the linker shows a greater release or degradation rate at a first acidic pH (e.g., pH=6.7) relative to a second more basic pH (e.g., pH=7.4). In one embodiment, ratio of release or degradation rate of the linker at pH=6.7 relative to pH=7.4 is greater than 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3 or higher. In one embodiment, ratio of release or degradation rate of the linker at pH=6.7 relative to pH=7.4 is greater than 2. In one embodiment, the linker shows increased pH-sensitivity in a hypoxic microenvironment, e.g., in a tumor or fibrotic tissue.

In some embodiments, the average molecular weight of the linker (e.g., a polyacetal polymer as described herein) is from about 2 kDa to about 200 kDa, (e.g., from about 2.5 kDa to about 175 kDa, from about 5 kDa about 150 kDa, from about 10 kDa to about 125 kDa, from about 12.5 kDa to about 100 kDa, from about 15 kDa to about 90 kDa, from about 17.5 kDa to about 80 kDa, from about 20 kDa to about 70 kDa, from about 22.5 kDa to about 60 kDa, or from about 25 kDa to about 50 kDa). In some embodiments, the average molecular weight of the linker (e.g., a polyacetal polymer as described herein) is from about 5 kDa to about 100 kDa (e.g., from about 6 kDa to about 90 kDa, from about 7 kDa to about 95 kDa, from about 8 kDa to about 85 kDa, from about 9 kDa to about 80 kDa, from about 10 kDa to about 75 kDa, from about 11 kDa to about 70 kDa, from about 12 kDa to about 65 kDa, from about 13 kDa to about 60 kDa, from about 14 kDa to about 55 kDa, or from about 15 kDa to about 50 kDa). In some embodiments, the average molecular weight of the polymer used in a linker (e.g., a polyacetal polymer as described herein) is from about 7 kDa to about 100 kDa, (e.g., from about 7 kDa to about 95 kDa, about 7 kDa to about 90 kDa, about 7 kDa to about 80 kDa, about 7 kDa to 75 kDa, about 7 kDa to about 70 kDa, about 7 kDa to about 65 kDa, about 7 kDa to about 60 kDa, about 7 kDa to about 55 kDa, about 7 kDa to about 50 kDa, about 7 kDa to about 45 kDa, about 7 kDa to about 40 kDa, about 7 kDa to about 35 kDa, about 7 kDa to about 30 kDa, about 7 kDa to about 25 kDa, about 7 kDa to about 20 kDa, about 7 kDa to about 15 kDa, or from about 7 kDa to about 75 kDa, about 7.5 kDa to about 75 kDa, about 10 kDa to about 75 kDa, about 12.5 kDa to about 75 kDa, about 15 kDa to about 75 kDa, about 17.5 kDa to about 75 kDa, about 20 kDa to about 75 kDa, about 22.5 kDa to about 75 kDa, about 25 kDa to about 75 kDa, about 27.5 kDa to about 75 kDa, about 30 kDa to about 75 kDa, about 32.5 kDa to about 75 kDa, about 35 kDa to about 75 kDa, about 40 kDa to about 75 kDa, about 42.5 kDa to about 75 kDa, about 45 kDa to about 75 kDa, about 47.5 kDa to about 75 kDa, or about 50 kDa to about 75 kDa). In one embodiment, the average molecular weight of the linker is from about 5 kDa to about 50 kDa. In another embodiment, the average molecular weight of the linker is from about 10 kDa to about 50 kDa. In another embodiment, the average molecular weight of the linker is from about 15 kDa to about 40 kDa. In another embodiment, the average molecular weight of the linker is from about 15 kDa to about 25 kDa. In another embodiment, the average molecular weight of the linker is from about 20 kDa to about 40 kDa. In some embodiments, the average molecular weight of the linker is not less than about 10 KDa, about 9 kDa, about 8 kDa, about 7 kDa, about 6 kDa, or about 5 kDa.

In some embodiments, the linker (e.g., a polyacetal polymer described herein) is soluble in water (e.g., hydrophilic). In some embodiments, the linker (e.g., a polyacetal polymer described herein) is soluble in water, and between about 0.1 to about 5 parts water are required to dissolve 1 part linker, or between about 1 part to about 5 parts water are required to dissolve 1 part polymer. In some embodiments, the linker (e.g., a polyacetal polymer described herein) is partially soluble in water. In some embodiments, the linker (e.g., a polyacetal polymer described herein) is partially soluble in water, and between about 5 to about 50 parts water are required to dissolve 1 part linker. In some embodiments, the linker (e.g., a polyacetal polymer described herein) is sparingly soluble in water. In some embodiments the linker (e.g., a polyacetal polymer described herein) is sparingly soluble in water, and between about 25 to about 100 parts water is required to dissolve 1 part linker. In some embodiments, the linker (e.g., a polyacetal polymer described herein) is slightly soluble in water. In some embodiments, the linker (e.g., a polyacetal polymer described herein) is slightly soluble in water, and between 100 to about 1,000 parts water are required to dissolve 1 part linker. In some embodiments, the linker (e.g., a polyacetal polymer described herein) is very slightly soluble in water. In some embodiments, the linker (e.g., a polyacetal polymer described herein) is very slightly soluble in water, and between 1,000 to about 10,000 parts water are required to dissolve 1 part linker. In some embodiments, the linker (e.g., a polyacetal polymer described herein) is substantially insoluble in water (e.g., hydrophobic). In some embodiments, the linker (e.g., a polyacetal polymer described herein) is substantially insoluble in water and greater than about 10,000 parts water are required to dissolve 1 part linker.

In one embodiment, the linker (e.g., a polyacetal polymer described herein) is amphiphilic. In one embodiment, the linker (e.g., a polyacetal polymer described herein) comprises a segment that is hydrophobic and a segment that is hydrophilic.

In some embodiments, the polymer (e.g., a polyacetal polymer) is a liquid (e.g., a fluid liquid) at room temperature (e.g., at 25° C.). In some embodiments, the linker (e.g., a polyacetal polymer described herein) is viscous (e.g., a viscous liquid) at room temperature (e.g., at 25° C.). In some embodiments, the linker (e.g., a polyacetal polymer described herein) comprises a gel at room temperature (e.g., at 25° C.). In some embodiments, the linker (e.g., a polyacetal polymer described herein) is solid (e.g., a crystalline, semi-crystalline, amorphous, glassy, or rubbery solid) at room temperature (e.g., at 25° C.). In some embodiments, the melting temperature (T m ) of the linker (e.g., a polyacetal polymer) is greater than about 25° C. In some embodiments, the melting temperature (T m ) of the linker (e.g., a polyacetal polymer described herein) is greater than about 30° C., about 32° C., about 34° C., about 36° C., about 38° C., about 40° C., about 42° C., about 44° C., about 46° C., about 48° C., about 50° C., or higher. In some embodiments, the melting temperature (T m ) of the linker (e.g., a polyacetal polymer described herein) is between about 30° C. and about 50° C. In some embodiments, the melting temperature (T m ) of the linker (e.g., a polyacetal polymer described herein) is between about 35° C. and about 45° C.

In some embodiments, the linker (e.g., a polyacetal polymer described herein) comprises a linear structure. In some embodiments, the linker (e.g., a polyacetal polymer described herein) comprises a branched structure. In some embodiments, the linker (e.g., a polyacetal polymer described herein) comprises a branched structure, and each repeating unit in the linker comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, or at least 8 branch points.

In one embodiment, the linker is chosen from one or more of an acetal group, a ketal group, an anhydride group, an ester group, a hydrazone group, a silyl ether group, a combination of acetal or ketal with ester group, an oligo-acetal or oligo-ketal group, a combination of the oligo-ketal and silyl ether group, or a combination of the oligo-ketal and vinyl ether group. In other embodiments, the linker is chosen from a combination of acetal or ketal with cis-aconityl, hydrazine, oxime, imidazole or trityl groups. Any of the aforesaid groups or combination of groups can modified to enhance the pH sensitivity of the linker, e.g., as described herein.

In some embodiments, the linker is a cleavable moiety. In some embodiments, the linker is degraded or hydrolyzed at physiological conditions. In some embodiments, the linker is pH sensitive. In some embodiments, the linker is degraded or hydrolyzed through the action of an enzyme (e.g., a protease or esterase).

In some embodiments, the linker is a peptide. In some embodiments, the linker is a peptide, and the peptide sequence is comprised of naturally occurring amino acids. In some embodiments, the linker is a peptide, and the peptide sequence comprises at least one synthetically derived amino acids, e.g., at least 2, at least 3, at least 4, at least 5, at least 8, at least 10, at least 15, at least 20, or more synthetically derived amino acids. In some embodiments, the peptide has a linear structure. In some embodiments, the peptide has a branched structure. In some embodiments, the peptide has a branched structure with, e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, or at least 8 branching points. In some embodiments, the peptide has a cyclic structure.

In some embodiments, the linker is a peptide, and the peptide sequence comprises at least 2 amino acid residues. In some embodiments, the peptide sequence comprises at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 amino acid residues. In some embodiments, the peptide sequence is from about 1 to about 10 amino acid residues. In some embodiments, the peptide sequence is from about 1 to about 15, about 20, about 25, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 amino acid residues. In some embodiments, the peptide sequence is from about 10 to about 100 amino acid residues. In some embodiments, the peptide sequence is from about 25 to about 100 amino acid residues. In some embodiments, the peptide sequence is from about 50 to about 100 amino acid residues.

In some embodiments, the linker comprises a substrate peptide that is cleaved, e.g., activated, by a matrix metalloprotease (MMP) selected from a sequence disclosed in U.S. Patent Application No. 2015/0087810. In some embodiments, the substrate peptide comprises a protease substrate comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 353-363, 372-375, 376-378, 395-401, 411-419, 426-433, 437-449, 454-456, 459-469, 475-482, 487-495, 318-323, 325-327, 330-335, 341-347, 14-33, and 159, e.g., as described in U.S. Patent Application No. 2015/0087810. In some embodiments, the linker comprises a substrate peptide derived from a sequence disclosed in U.S. Pat. No. 8,541,203, e.g., a substrate peptide chosen from an enzyme selected from the group consisting of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-14, plasmin, PSA, PSMA, CATHEPSIN D, CATHEPSIN K, CATHEPSIN S, ADAM10, ADAM12, ADAMTS, Caspase-1, Caspase-2, Caspase-3, Caspase-4, Caspase-5, Caspase-6, Caspase-7, Caspase-8, Caspase-9, Caspase-10, Caspase-11, Caspase-12, Caspase-13, Caspase-14, and TACE. In some embodiments, the linker comprises a sequence disclosed in U.S. Pat. No. 8,513,390. In some embodiments, the linker comprises a sequence disclosed in International Patent Publication No. WO2003/079972. In some embodiments, the linker comprises a sequence disclosed in U.S. Pat. No. 7,495,099. In some embodiments, the linker comprises a sequence disclosed in U.S. Pat. No. 8,580,244. In some embodiments, the linker comprises a sequence disclosed in one of the following articles: van Kempen, et al. Eur Cancer (2006) 42:728-734; Desnoyers, L. R. et al. Sci Transl Med (2013) 5:207ra144; Rice, J. J. et al. Protein Sci (2006) 15:825-836; Boulware, K. T. and Daugherty, P. S. Proc Natl Acad Sci USA (2006) 103:7583-7588; Deperthes, D. Biol Chem (2002) 383:1107-1112; Harris, J. L. Proc Natl Acad Sci USA (2000) 97:7754-7759; Salmaso S. and Caliceti, P. J Drug Deliv (2013) 2013:1-19; and Eckhard, U et al Matrix Biol (2015) doi: 10.1016/j.matbio.2015.09.003 (epub ahead of print). The contents of any of the publications referenced herein are hereby expressly incorporated by reference.

In some embodiments, the linker comprises a substrate peptide that is cleaved, e.g., activated, by a protease, e.g., a protease present in a tumor or fibrotic microenvironment (e.g, a matrix metalloprotease (MMP), e.g., as described by Desnoyers, L. R. et al. Sci Transl Med (2013) 5:207ra144; Eckhard, U et al Matrix Biol (2015) doi: 10.1016/j.matbio.2015.09.003 (epub ahead of print); and van Kempen, et al. Eur Cancer (2006) 42:728-734. In one embodiment, the linker includes the amino acid sequence of a substrate for uPA, e.g., comprises the amino acid sequence LSGRSDNH (SEQ ID NO: 1), e.g., as described in U.S. Pat. No. 8,513,390. In some embodiment, the linker sequence further includes a Gly-Ser-containing peptide linker, at either end, or both ends to the substrate peptide. Additional exemplary proteases that may be upregulated in a tumor microenvironment include, but are not limited to, urokinase-type plasminogen activator (uPA), which is upregulated in human carcinomas (S. Ulisse, et al. Curr. Cancer Drug Targets 9, 32-71 (2009)), membrane-type serine protease 1 (MT-SP1/matriptase) (K. Uhland Cell. Mol. Life Sci. 63, 2968-2978 (2006); A. M. LeBeau, et al. Proc. Natl. Acad. Sci . U.S.A. 110, 93-98 (2013)), and legumain, a lysosomal protease found to be released and active in the acidic extracellular tumor microenvironment (C. Liu, et al. Cancer Res. 63, 2957-2964 (2003)). In some embodiments, the protease is produced by an inflammatory cell, e.g., a tumor infiltrating leukocyte (e.g., a leukocyte-derived MMP), e.g., as described by van Kempen, et al. Eur Cancer (2006) 42:728-734. In other embodiments, the MMP is chosen from MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP12, MMP13 or MMP14, e.g., as described by Eckhard, U et al. supra.

In some embodiments, the substrate peptide is derived from a CLiPS library (as described in, e.g., K. T. Boulware, P. S. Daugherty, Proc. Natl. Acad. Sci . U.S.A. 103, 7583-7588 (2006)). In other embodiments, the substrate peptide specificity is evaluated using combinatorial fluorogenic substrate libraries, e.g., as described by Harris, J. L. Proc Natl Acad Sci USA (2000) 97:7754-7759. In other embodiments, the substrate peptide is derived from a phage display library (e.g., it is a phase display substrate), e.g., as described by Deperthes, D. Biol Chem (2002) 383:1107-1112. For example, a phage display substrate is exposed to a plurality of proteases; peptides released through specific cleavage can be amplified in an expression system. In other embodiments, the substrate peptide is derived from a bacterial display library, e.g., as described by Rice, J. J. et al. Protein Sci (2006) 15:825-836.

In some embodiments, the linker comprises a compound of Formula (VI):

wherein:

R 31 is an agent, e.g., a therapeutic agent or diagnostic agent (e.g., an AHCM), or a targeting moiety (e.g., as described herein);

X is O or S;

R 32 is H or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, cycloalkyl, or heterocyclyl;

Y is C, CH, N, O or S;

R 33 is C(O)OR a , or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R 34 is absent, H, —C(O)OR a , or C 1 -C 6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R a is H or C 1 -C 6 alkyl; and

wherein when Y is CH, N, O, or S, represents a single bond.

In some embodiments, X is O. In some embodiments, X is S.

In some embodiments, R 32 is H. In some embodiments, R 32 is alkyl. In some embodiments, R 32 is methyl or ethyl.

In some embodiments, Y is C. In some embodiments, Y is CH. In some embodiments, Y is N, O, or S.

In some embodiments, R 33 is C(O)OR a , wherein R a is H or alkyl. In some embodiments, when Y is C or CH, R 23 is —C(O)OR a . In some embodiments, when Y is C or CH, R 33 is —C(O)OR a , wherein R a is H or alkyl. In some embodiments, when Y is N, O, or S, R 33 is alkyl, C 2 -C 6 alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, when Y is N, O, or S, R 33 is alkyl. In some embodiments, when Y is N, O, or S, R 33 is methyl or ethyl.

In some embodiments, when Y is CH, O, or S, R 34 is absent. In some embodiments, when Y is C or N, R 34 is alkyl. In some embodiments, when Y is C or N, R 34 is alkyl. In some embodiments, when Y is C, R 34 is alkyl.

In some embodiments, when Y is C, represents a double bond. In some embodiments, when Y is CH, N, O, or S, represents a single bond.

In some embodiments, the linker is a compound of Formula (VII):

wherein:

R 41 is an agent, e.g., a therapeutic agent or diagnostic agent (e.g., an AHCM), or a targeting moiety (e.g., as described herein);

Z is C or Si;

each of R 42 or R 43 is independently alkyl, cycloalkyl, or heterocyclyl, or one of R 42 or R 43 is H; or R 42 and R 43 taken together with the Z atom they are attached to form a 4- to 8-membered cycloalkyl or heterocyclyl;

R 44 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or —C(O)NR c R d , —NR c C(O)R e —, —NR c C(O)OR f —, or R 44 taken together with the carbon atom it is attached to form a 5- to 8-membered ring with R 42 that encompasses O and Z; and

each of R c , R d , R e , or R f is independently H, or alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, Z is C. In some embodiments, Z is Si.

In some embodiments, each of R 42 or R 43 is independently alkyl. In some embodiments, each of R 42 or R 43 is independently methyl, ethyl, or isopropyl. In some embodiments, R 42 and R 43 are taken together with the Z atom to which they are attached to form a 4- to 8-membered cycloalkyl or heterocyclyl.

In some embodiments, R 44 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R 44 is alkyl, or cycloalkyl. In some embodiments, R 44 is alkyl, e.g., methyl or ethyl. In some embodiments, R 44 is cycloalkyl, e.g., cyclohexyl. In some embodiments, R 44 is —C(O)NR c R d , —NR c C(O)R e —, —NR c C(O)OR f —. In some embodiments, R 44 is —C(O)NR c R d , —NR c C(O)R e —, —NR c C(O)OR f —, wherein R c , R d , or R f is each independently H or alkyl and R e is alkyl. In some embodiments, R 44 is —NR c C(O)R e —, wherein R c is H or alkyl and R e is alkyl. In some embodiments, R 44 taken together with the carbon atom it is attached to forms a 5- to 8-membered ring with R 42 that encompasses O and Z (wherein e.g., Z is C).

In other embodiments, the linker is a monomer or polymer, e.g., a polyacetal polymer, as disclosed herein, optionally coupled to an agent. In one embodiment, the linker comprises the polymer of Formula (I), e.g., the polymer of Formula (I) as described herein. In other embodiments, the linker comprises the polymer of Formula (I) as described herein, wherein each of m and n is independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the sum of m and n is greater than 0. In one embodiment, the linker comprises the polymer of Formula (I-a), e.g., the polymer of Formula (I-a) as described herein. In other embodiments, the linker comprises the polymer of Formula (I-a) as described herein, wherein each of m and n is independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the sum of m and n is greater than 0. In one embodiment, the linker comprises the polymer of Formula (I-b), e.g., the polymer of Formula (I-b) as described herein. In other embodiments, the linker comprises the polymer of Formula (I-b) as described herein, wherein each of m and n is independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the sum of m and n is greater than 0. In one embodiment, the linker comprises the polymer of Formula (I-c), e.g., the polymer of Formula (I-c) as described herein. In other embodiments, the linker comprises the polymer of Formula (I-c) as described herein, wherein each of m and n is independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the sum of m and n is greater than 0. In one embodiment, the linker comprises the polymer of Formula (I-d), e.g., the polymer of Formula (I-d) as described herein. In other embodiments, the linker comprises the polymer of Formula (I-d) as described herein, wherein each of m and n is independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the sum of m and n is greater than 0. In one embodiment, the linker comprises the polymer of Formula (I-e), e.g., the polymer of Formula (I-e) as described herein. In other embodiments, the linker comprises the polymer of Formula (I-e) as described herein, wherein each of m and n is independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the sum of m and n is greater than 0. In one embodiment, the linker comprises the polymer of Formula (IV), e.g., the polymer of Formula (IV) as described herein. In other embodiments, the linker comprises the polymer of Formula (IV) as described herein, wherein each of m and n is independently chosen from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

In some embodiments, the linker, e.g., the pH sensitive linker, is selected from the group consisting of:

wherein R is an agent (e.g., an agent described herein) and is linked to the polymer or R is the polymer (e.g., a polyacetal polymer described herein) and is linked to an agent (e.g., an agent described herein). In some embodiments, R is an agent (e.g., an agent described herein) and is linked to the polymer (e.g., a polyacetal polymer described herein).

In some embodiments, the linker, e.g., the pH sensitive linker, is derived from one or more of:

wherein R is an agent (e.g., an agent described herein) or R is the polymer (e.g., a polyacetal polymer described herein). In some embodiments, R is an agent (e.g., an agent described herein). In some embodiments, R is the polymer (e.g., a polyacetal polymer described herein).

In other embodiments, the linker, e.g., the pH sensitive linker, is chosen from L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, or L12, as shown in FIG. 4 .

In certain embodiments, the linker, e.g., the pH sensitive linker, is coupled, e.g., covalently coupled, to an agent and/or a targeting moiety, e.g., as described herein. In one embodiment, the agent is a therapeutic agent or a diagnostic agent, e.g., a therapeutic or a diagnostic agent as described herein. In one embodiment, the agent is an AHCM as described herein.

In certain embodiments, the linker, e.g., the pH sensitive linker, is coupled, e.g., covalently coupled, to a polymer (e.g., any polymer described herein). In one embodiment, the polymer is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% made of polyacetal polymers (e.g., a polymer according to Formula (I), Formula (I-a), Formula (I-b), or Formula (IV)). In certain embodiments, the linker is coupled to one or more hydrophobic or hydrophilic polymers to enhance a desired property. In certain embodiments, the linker can comprise, or be linked to a water-soluble monomer or polymer (e.g., polyethylene glycol (PEG) monomer or polymer), e.g., to increase one or more of amphiphilicity, hydrophilicity, water-solubility, pH sensitivity or stability.

In other embodiments, the linker is coupled, e.g., covalently coupled, to a plurality (e.g., one or more) of: a polyethylene oxide (PEO), a polypropylene glycol (PPG), a polyglycerol (PG), a poloxamine (POX), a polybutylene oxide (PBO), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polydioxanone (PDO), a polyanhydride, a polyacrylide, a polyvinyl, a polyorthoester, a dextran, a cyclodextran, chitosan, or other carbohydrate based polymer as described herein. In other embodiments, the linker is coupled, e.g., covalently coupled, to a plurality (e.g., one or more) of: a polyethylene oxide (PEO), a polypropylene glycol (PPG), a polyglycerol (PG), a poloxamine (POX), a polybutylene oxide (PBO), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polydioxanone (PDO), a polyanhydride, a polyacrylide, a polyvinyl, a polyorthoester, a dextran, a cyclodextran, chitosan, or other carbohydrate based polymer as described herein. In some embodiments, the polymer comprises a plurality of (e.g., 2, 3, 4, 5, or more of) a PLA-PEG, dextran, or a polyacetal polymer described herein. Exemplary polymers that can be combined with the polyacetal polymers are described herein, e.g., in the section entitled “Polymers” below.

In one embodiment, the linker (with or without an agent, e.g., an AHCM and/or a targeting moiety) is coupled (e.g., covalently coupled) to a second polymer, e.g., one or more of: a polyethylene oxide (PEO), a polypropylene glycol (PPG), a polyglycerol (PG), a poloxamine (POX), a polybutylene oxide (PBO), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polydioxanone (PDO), a polyanhydride, a polyacrylide, a polyvinyl, a polyorthoester, a dextran, a cyclodextran, chitosan, or other carbohydrate based polymer as described herein.

In one embodiment, the linker is a bond. In one embodiment, the first moiety is an agent (e.g., a therapeutic agent as described herein) and/or a targeting moiety, and the second moiety is a polymer (e.g., a polyacetal polymer), and the first moiety and the second moiety are directly connected to each other through a bond.

Conjugates and Particles

In another aspect, the invention features a conjugate comprising a polyacetal polymer, e.g., one or more polyacetal polymers as described herein. In one embodiment, the particle comprises a conjugate, e.g., one or more conjugates as described herein.

In some embodiments, the conjugate includes:

a polymer, e.g., polyacetal polymer as described herein;

an agent (e.g., one or more therapeutic and/or or diagnostic agents (e.g., an AHCM, a microenvironment modulator, an other stromal modulator, and/or an anti-cancer agent or liver therapy) as described herein), and

(optionally) a targeting moiety (e.g., a cell-targeting agent);

(optionally) wherein the polymer, the agent and/or a targeting moiety, are coupled (e.g., covalently coupled, via a linker, e.g., a pH-sensitive linker as described herein).

In another aspect, the invention features a particle (e.g., a nanoparticle, e.g., a particle having a hydrodynamic diameter of greater than about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, or 200 nm). In embodiments, the particle includes:

a polymer, e.g., polyacetal polymer as described herein;

an agent (e.g., one or more therapeutic and/or or diagnostic agents (e.g., an AHCM, a microenvironment modulator, an other stromal modulator, and/or an anti-cancer agent or liver therapy) as described herein), and

(optionally) a targeting moiety (e.g., a cell-targeting agent);

(optionally) wherein the polymer, the agent and/or a targeting moiety, are coupled (e.g., covalently coupled, via a linker, e.g., a pH-sensitive linker as described herein).

In some embodiments, the conjugate or particle has a hydrodynamic diameter of less than about 100 nm (e.g., about 10 nm to 50 nm) and has one, two, three or all of the following properties:

(i) shows a ratio of release or degradation rate at pH=6.7 relative to pH=7.4 that is greater than 1.5 (e.g., 2);

(ii) shows increased pH-sensitivity in a hypoxic microenvironment, e.g., is sensitive to a hypoxic pH e.g., a pH about 6.7 to 6.9, e.g., compared to a physiological pH of about 7.4;

(iii) is slightly soluble (e.g., between about 100 to about 1000 parts water is required to dissolve 1 part polymer) or very slightly soluble (e.g., between about 1,000 to about 10,000 parts water are required to dissolve 1 part polymer) in water; or

(iv) the polymer, e.g., the polyacetal polymer, has a melting temperature (T m ) of about 35° C. or greater.

In some embodiments, the conjugate or particle is essentially or close to neutrally-charged. In some embodiments, the conjugate or particle is positively-charged. In some embodiments, the conjugate or particle is negatively-charged.

In one embodiment, the conjugate or particle comprises a polymer (e.g., any polymer disclosed herein, including a polyacetal polymer (e.g., a polymer comprised of Formula (I), Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d), Formula (I-e), or Formula (IV)), a pH-sensitive linker (e.g., a pH-sensitive linker as described herein) and an agent (e.g., a therapeutic and/or diagnostic agent (e.g., an AHCM, e.g., an ARB, e.g., losartan, valsartan, telmisartan, candesartan, eprosartan, irbesartan, azilsartan, EXP-3174, olmesartan, or a prodrug or active metabolite thereof), as described herein) and/or the targeting moiety (e.g., a liver targeting moiety, e.g., M6P).

In one embodiment, the conjugate or particle comprises a pH-sensitive and/or polyacetal polymer as disclosed herein, and an agent and/or targeting moiety (e.g., an agent-polymer conjugate, a targeting moiety-polymer conjugate, or an agent-polymer-targeting moiety conjugate), any of which can be as described herein.

In another embodiment, the conjugate or particle comprises a polymer (e.g., any polymer disclosed herein, including a pH-sensitive and/or polyacetal polymer), a linker (e.g., a pH-sensitive linker as described herein) and an agent and/or targeting moiety, any of which can be as described herein. In one embodiment, the polymer, the linker, the agent and/or targeting moiety in the conjugate or particle are coupled, e.g., covalently coupled, directly or indirectly (e.g., with or without a linker). In one embodiment, the polymer (e.g., a polymer comprised of a polyol of Formula (II), a vinyl ether of Formula (III), and a PEG), the agent (e.g., an ARB, e.g., losartan, valsartan, telmisartan, candesartan, eprosartan, irbesartan, azilsartan, EXP-3174, olmesartan, or a prodrug or active metabolite thereof) and/or the targeting moiety (e.g., a liver targeting moiety, e.g., M6P) in the conjugate or particle are covalently coupled (each of the components can be covalently coupled with or without a linker).

In other embodiments, the conjugate or particle comprises a polymer (e.g., a polymer comprised of a polyol of Formula (II), a vinyl ether of Formula (III), and a PEG), and (optionally) a linker, which is noncovalently coupled, e.g., through ionic or hydrophobic interactions to one or more of the agent (e.g., an ARB, e.g., losartan, valsartan, telmisartan, candesartan, eprosartan, irbesartan, azilsartan, EXP-3174, olmesartan, or an analogue or derivative thereof (e.g., a prodrug or active metabolite thereof)) and/or the targeting moiety (e.g., a liver targeting moiety, e.g., M6P). In one embodiment, the polymer and the agent are covalently coupled (with or without a linker), and the targeting moiety is noncovalently coupled. In one embodiment, the polymer and the agent are noncovalently coupled. In one embodiment, the polymer and the agent and/or the targeting moiety are noncovalently coupled.

In other embodiments, the conjugate or particle comprises a mixture of covalently coupled components (e.g., the polymer and the agent and/or the targeting moiety) and noncovalently coupled components (e.g., the polymer and the agent and/or the targeting moiety). The mixture can have a different ratio of covalently and noncovalently coupled components. In one embodiment, the conjugate comprises: (i) the polymer covalently coupled to about 50% of the agent and/or about 50% of the targeting moiety (with or without a linker); (ii) the polymer noncovalently coupled to about 500 of the agent and/or about 500 of the targeting moiety (with or without a linker); or (iii) a mixture of (i) and (ii). In another embodiment, the conjugate comprises: (i) the polymer covalently coupled to about 75% of the agent and/or about 75% of the targeting moiety (with or without a linker); (ii) the polymer noncovalently coupled to about 25% of the agent and/or about 25% of the targeting moiety (with or without a linker); or (iii) a mixture of (i) and (ii). In another embodiment, the conjugate comprises: (i) the polymer covalently coupled to about 25% of the agent and/or about 25% of the targeting moiety (with or without a linker); (ii) the polymer noncovalently coupled to about 75% of the agent and/or about 75% of the targeting moiety (with or without a linker); or (iii) a mixture of (i) and (ii). In another embodiment, the conjugate or particle comprises: (i) the polymer covalently coupled to about 90% of the agent and/or about 90% of the targeting moiety (with or without a linker); (ii) the polymer noncovalently coupled to about 10% of the agent and/or about 10% of the targeting moiety (with or without a linker); or (iii) a mixture of (i) and (ii). In another embodiment, the conjugate or particle comprises: (i) the polymer covalently coupled to about 10% of the agent and/or about 10% of the targeting moiety (with or without a linker); (ii) the polymer noncovalently coupled to about 90% of the agent and/or about 90% of the targeting moiety (with or without a linker); or (iii) a mixture of (i) and (ii). In another embodiment, the conjugate or particle comprises: (i) the polymer covalently coupled to about 95% of the agent and/or about 95% of the targeting moiety (with or without a linker); (ii) the polymer noncovalently coupled to about 5% of the agent and/or about 5% of the targeting moiety (with or without a linker); or (iii) a mixture of (i) and (ii). In another embodiment, the conjugate or particle comprises: (i) the polymer covalently coupled to about 5% of the agent and/or about 5% of the targeting moiety (with or without a linker); (ii) the polymer noncovalently coupled to about 95% of the agent and/or about 95% of the targeting moiety (with or without a linker); or (iii) a mixture of (i) and (ii). In another embodiment, the conjugate or particle comprises: (i) the polymer covalently coupled to about 99% or higher of the agent and/or about 99% or higher of the targeting moiety (with or without a linker); (ii) the polymer noncovalently coupled to about 1% or less of the agent and/or about 1% or less of the targeting moiety (with or without a linker); or (iii) a mixture of (i) and (ii). In another embodiment, the conjugate or particle comprises: (i) the polymer covalently coupled to about 1% or less of the agent and/or about 1% or less of the targeting moiety (with or without a linker); (ii) the polymer noncovalently coupled to about 99%, or higher of the agent and/or about 99% or higher of the targeting moiety (with or without a linker); or (iii) a mixture of (i) and (ii).

In other embodiments, the polymer, the agent, and about 50% of the targeting moiety in the conjugate or particle are covalently coupled. In other embodiments, the polymer, the agent, and about 50% of the targeting moiety in the conjugate or particle are noncovalently coupled. In one embodiment, the polymer, the agent, and about 75% of the targeting moiety in the conjugate are covalently coupled. In one embodiment, the polymer, the agent, and about 75% of the targeting moiety in the conjugate or particle are noncovalently coupled. In one embodiment, the polymer, the agent, and about 90% of the targeting moiety in the conjugate or particle are covalently coupled. In one embodiment, the polymer, the agent, and about 90% of the targeting moiety in the conjugate or particle are noncovalently coupled. In one embodiment, the polymer, the agent, and about 95% or more of the targeting moiety in the conjugate or particle are covalently coupled. In one embodiment, the polymer, the agent, and about 95% or more of the targeting moiety in the conjugate or particle are noncovalently coupled. In one embodiment, the polymer, the agent, and about 99% or more of the targeting moiety in the conjugate or particle are covalently coupled. In one embodiment, the polymer, the agent, and about 99% or more of the targeting moiety in the conjugate or particle are noncovalently coupled.

In one embodiment, the conjugate or particle comprises an agent and/or a targeting moiety (e.g., as described herein), wherein one or both are directly coupled (e.g., covalently coupled) to a polyacetal polymer (e.g., a polymer comprised of a polyol of Formula (II), a vinyl ether of Formula (III), and a PEG). In one embodiment, the conjugate or particle comprises an agent and/or a targeting moiety (e.g., as described herein), wherein one or both are noncovalently coupled to a polyacetal polymer (e.g., a polymer comprised of a polyol of Formula (II), a vinyl ether of Formula (III), and a PEG).

In another embodiment, the conjugate or particle comprises an agent and/or targeting moiety (e.g., as described herein) coupled (e.g., covalently coupled), via pH-sensitive linker (e.g., as described herein; an acetal monomer or a polyacetal polymer) to a second polymer (e.g., a polymer other than a polyacetal polymer, e.g., but not limited to dextran, PEG, PLGA, PLA or combinations thereof).

In some embodiments, the agent is a therapeutic or a diagnostic agent as described herein. In some embodiments, the agent is an AHCM as described herein. In some embodiments, the agent is an ARB as described herein, e.g., losartan, valsartan, telmisartan, candesartan, eprosartan, irbesartan, azilsartan, EXP-3174, olmesartan, or an analogue or derivative thereof (e.g., a prodrug or active metabolite thereof), e.g., a compound shown in FIG. 23 .

In some embodiments, the agent is a vitamin D analog or derivative as described herein. In some embodiments, the agent is a vitamin D analog or derivative as described herein, e.g., paricalcitol, doxercalciferol, falecalcitriol, maxacalcitol, tacalcitol, alfacalcidol, eldecalcidol, seocalcitol, lexicalcitol, CD578, inecalcitol, calcipotriol, TX527, 2MD, WY1112, PRI-2205, ILX23-7553, ercalcitriol, EB1089 (seocalcitol), BXL-628 (elocalcitol), MC1288, CB966, BCB 1093, GS 1558, SM-10193, EB1072, EB1129, EB1133, EB1155, EB1270, MC1288, EB1213, CB1093, VD2656, VD2668, VD2708, VD2716, VD2728, VD2736, GS1500, GS1558, KH1060, ZK161422, and analogs and derivatives thereof, e.g., as shown in FIG. 24 . Additional vitamin D analogs and derivatives are described, e.g. in Leyssens, C. et al, Front Physiol (2014) dx.doi.org/10.3389/fphys.2014.00122, which is incorporated herein by reference in its entirety.

In some embodiments, the agent is a bromodomain and extra-terminal protein inhibitor (i-BET) as described herein. In some embodiments, the agent is a bromodomain and extra-terminal protein inhibitor (i-BET) as described herein, e.g MS436, PFI-1, I-BET 151, OTX-015, JQ1. CPI-203, bromosporine, RVX-208, I-BET 762, I-BET 151, OFXBD02, OFXBD03, XD14, AZD5153, and analogs and derivatives thereof, e.g., as shown in FIGS. 25A and 25B . Additional bromodomain and extra-terminal protein inhibitors (i-BET) are described e.g., in Haas, M. J. et al SciBX (2014) 7(15); ACS Chem Biol (2015) 10:22-39 ; Expert Opin Ther Pat (2014) 24:185-199 ; Clin Cancer Res (2015) 21:1628-1638 ; Oncotarget (2015) 6:17698-17712 ; Bioorg Med Chem Lett (2015) 25:1842-1848 ; Cancer Res (2013) 73:3336-3346 ; Am. J Cardiovasc Drugs (2015) September 18 [epub ahead of print]; and J Med Chem (2013) 56:9251-9264, each of which is incorporated by reference herein in its entirety.

In some embodiments, the agent is a bromodomain and extra-terminal protein inhibitor (i-BET) as described herein, e.g., in FIGS. 25A and 25B , and may be covalently coupled to the polymer, e.g., a polymer described herein, via a hydroxyl group, a sulfonamide, a carboxylic acid, a carboxamide, an amine, or a benzimidazolone. In some embodiments, the agent is OTX-2015 (5), RVX-208 (7), OXFBD02 (9), OXFBD03 (10), XD14 (18), or dinaciclib (19), e.g., as shown in FIGS. 25A and/or 25B , and may be covalently coupled to the polymer, e.g., a polymer described herein, via a hydroxyl group. In some embodiments, the agent is (12), PFI-1 (14), (15), MS436 (16), TG101348 (22), TG101209 (23), or bromosporine, e.g., as shown in FIGS. 25A and/or 25B , and may be covalently coupled to the polymer, e.g., a polymer described herein, via a sulfonamide. In some embodiments, the agent is I-BET726 (12), CPI-203 (6), or B12536 (21), e.g., as shown in FIGS. 25A and/or 25B , and may be covalently coupled to the polymer, e.g., a polymer described herein, via a carboxylic acid or a carboxamide. In some embodiments, the agent is I-BET151 (11) or B12536 (21), e.g., as shown in FIGS. 25A and/or 25B , and may be covalently coupled to the polymer, e.g., a polymer described herein, via a benzimidazolone or pyrimidine amine.

In some embodiments, the agent is an IDO inhibitor (i.e., indoleamine 2,3-dioxygenase (IDO) pathway inhibitor) as described herein, and may be covalently coupled to the polymer, e.g., a polymer described herein, via a hydroxyl group, a sulfonamide, a carboxylic acid, a carboxamide, an amine, or a benzimidazolone. Exemplary IDO inhibitors include, but are not limited to, GDC-0919, indoximod, 1-methyltryptophan (e.g., 1-methyl- L -tryptophan, 1-methyl- D -tryptophan), NLG8189, INCB024360, NLG919, methylthiohydantoin tryptophan, brassinin, annulin B, exiguamine A, INCB023843, or an analog or derivative thereof. Additional IDO inhibitors are described e.g., in Lob, S. et al Nat Rev Cancer (2009) 9:445-452; Rohrig, U. F. et al J Med Chem (2015) 58:9421-9437; and U.S. patent application Ser. No. 14/919,184, each of which is incorporated by reference herein in its entirety.

In one embodiment, the conjugate or particle (e.g., a conjugate or particle comprising a polymer comprised of a polyol of Formula (II), a vinyl ether of Formula (III), and a PEG, and/or a pH sensitive linker) is sensitive to a pH between about 5.0 and about 7.4, between 5.0 and 7.0, between 5.0 and 6.5, between 5.0 and 5.5, between 5.9 and 6.2. In one embodiment, the conjugate is sensitive to a pH between about 5.5 and about 6.5, e.g., between 5.9 and 6.2. In one embodiment, the conjugate or particle is preferentially cleaved or degraded upon exposure to a first pH relative to a second pH). In one embodiment, the conjugate or particle is sensitive to a hypoxic pH, e.g., a pH about 6.7 to 6.9, e.g., compared to a physiological pH of about 7.4.

In one embodiment, the conjugate or particle is cleaved or degraded at least 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, or 100 times faster upon exposure to a first pH relative to a second pH. In other embodiments, the conjugate or particle shows a greater release or degradation rate of the pH-sensitive polymer and/or linker at a first acidic pH (e.g., pH=6.7) relative to a second more basic pH (e.g., pH=7.4). In one embodiment, ratio of release or degradation rate of the pH-sensitive polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4 or higher. In one embodiment, the ratio of release or degradation rate of the conjugate (e.g., via degradation of pH-sensitive polymer and/or linker) at pH=6.7 relative to pH=7.4 is greater than 2. In one embodiment, the conjugate or particle shows increased pH-sensitivity in a hypoxic microenvironment, e.g., in a tumor, or fibrotic tissue.

In some embodiments, the conjugate or particle comprises a polymer, e.g., a polyacetal polymer, as disclosed herein. In one embodiment, the conjugate or particle comprises the polymer of Formula (I), e.g., the polymer of Formula (I) as described herein, wherein each of m and n is an integer from 2 to 450, from 2 to 400, from 2 to 350, from 2 to 300, from 2 to 250, from 2 to 200, from 2 to 175, from 2 to 150, from 2 to 125, from 2 to 100, from 2 to 90, from 2 to 80, from 2 to 70, from 2 to 60, from 2 to 50, from 2 to 45, from 2 to 40, from 2 to 35, from 2 to 30, from 2 to 25, from 2 to 20, from 2 to 15, from 2 to 10, or from 2 to 5. In some embodiments, each of m and n independently is an integer from 2 to 250. In some embodiments, each of m and n independently is an integer from 2 to 100. In some embodiments, each of m and n independently is an integer from 2 to 50. In some embodiments, each of m and n independently is an integer from 2 to 25. In some embodiments, each of m and n independently is an integer from 2 to 10. In some embodiments, each of m and n independently is an integer from 10 to 500, from 10 to 250, from 10 to 200, from 10 to 150, from 10 to 100, from 10 to 75, from 10 to 50, or from 10 to 25. In some embodiments, each of m and n independently is an integer from 10 to 50. In an embodiment, m and n taken together are between 10 and 100, 20 and 80, 20 and 60, or 30 and 60.

In one embodiment, the conjugate or particle comprises the polymer of Formula (I-a), e.g., the polymer of Formula (I-a) as described herein, wherein each of m and n is an integer from 2 to 450, from 2 to 400, from 2 to 350, from 2 to 300, from 2 to 250, from 2 to 200, from 2 to 175, from 2 to 150, from 2 to 125, from 2 to 100, from 2 to 90, from 2 to 80, from 2 to 70, from 2 to 60, from 2 to 50, from 2 to 45, from 2 to 40, from 2 to 35, from 2 to 30, from 2 to 25, from 2 to 20, from 2 to 15, from 2 to 10, or from 2 to 5. In some embodiments, each of m and n independently is an integer from 2 to 250. In some embodiments, each of m and n independently is an integer from 2 to 100. In some embodiments, each of m and n independently is an integer from 2 to 50. In some embodiments, each of m and n independently is an integer from 2 to 25. In some embodiments, each of m and n independently is an integer from 2 to 10. In some embodiments, each of m and n independently is an integer from 10 to 500, from 10 to 250, from 10 to 200, from 10 to 150, from 10 to 100, from 10 to 75, from 10 to 50, or from 10 to 25. In some embodiments, each of m and n independently is an integer from 10 to 50. In an embodiment, m and n taken together are between 10 and 100, 20 and 80, 20 and 60, or 30 and 60.

In one embodiment, the conjugate or particle comprises the polymer of Formula (I-b), e.g., the polymer of Formula (I-b) as described herein, wherein each of m and n is an integer from 2 to 450, from 2 to 400, from 2 to 350, from 2 to 300, from 2 to 250, from 2 to 200, from 2 to 175, from 2 to 150, from 2 to 125, from 2 to 100, from 2 to 90, from 2 to 80, from 2 to 70, from 2 to 60, from 2 to 50, from 2 to 45, from 2 to 40, from 2 to 35, from 2 to 30, from 2 to 25, from 2 to 20, from 2 to 15, from 2 to 10, or from 2 to 5. In some embodiments, each of m and n independently is an integer from 2 to 250. In some embodiments, each of m and n independently is an integer from 2 to 100. In some embodiments, each of m and n independently is an integer from 2 to 50. In some embodiments, each of m and n independently is an integer from 2 to 25. In some embodiments, each of m and n independently is an integer from 2 to 10. In some embodiments, each of m and n independently is an integer from 10 to 500, from 10 to 250, from 10 to 200, from 10 to 150, from 10 to 100, from 10 to 75, from 10 to 50, or from 10 to 25. In some embodiments, each of m and n independently is an integer from 10 to 50. In an embodiment, m and n taken together are between 10 and 100, 20 and 80, 20 and 60, or 30 and 60.

In one embodiment, the conjugate or particle comprises the polymer of Formula (I-c), e.g., the polymer of Formula (I-c) as described herein, wherein each of m and n is an integer from 2 to 450, from 2 to 400, from 2 to 350, from 2 to 300, from 2 to 250, from 2 to 200, from 2 to 175, from 2 to 150, from 2 to 125, from 2 to 100, from 2 to 90, from 2 to 80, from 2 to 70, from 2 to 60, from 2 to 50, from 2 to 45, from 2 to 40, from 2 to 35, from 2 to 30, from 2 to 25, from 2 to 20, from 2 to 15, from 2 to 10, or from 2 to 5. In some embodiments, each of m and n independently is an integer from 2 to 250. In some embodiments, each of m and n independently is an integer from 2 to 100. In some embodiments, each of m and n independently is an integer from 2 to 50. In some embodiments, each of m and n independently is an integer from 2 to 25. In some embodiments, each of m and n independently is an integer from 2 to 10. In some embodiments, each of m and n independently is an integer from 10 to 500, from 10 to 250, from 10 to 200, from 10 to 150, from 10 to 100, from 10 to 75, from 10 to 50, or from 10 to 25. In some embodiments, each of m and n independently is an integer from 10 to 50. In an embodiment, m and n taken together are between 10 and 100, 20 and 80, 20 and 60, or 30 and 60.

In some embodiments, the conjugate or particle comprises a polymer, e.g., a polyacetal polymer, as disclosed herein. In one embodiment, the conjugate or particle comprises the polymer of Formula (I-d), e.g., the polymer of Formula (I-d) as described herein, wherein each of m and n is an integer from 2 to 450, from 2 to 400, from 2 to 350, from 2 to 300, from 2 to 250, from 2 to 200, from 2 to 175, from 2 to 150, from 2 to 125, from 2 to 100, from 2 to 90, from 2 to 80, from 2 to 70, from 2 to 60, from 2 to 50, from 2 to 45, from 2 to 40, from 2 to 35, from 2 to 30, from 2 to 25, from 2 to 20, from 2 to 15, from 2 to 10, or from 2 to 5. In some embodiments, each of m and n independently is an integer from 2 to 250. In some embodiments, each of m and n independently is an integer from 2 to 100. In some embodiments, each of m and n independently is an integer from 2 to 50. In some embodiments, each of m and n independently is an integer from 2 to 25. In some embodiments, each of m and n independently is an integer from 2 to 10. In some embodiments, each of m and n independently is an integer from 10 to 500, from 10 to 250, from 10 to 200, from 10 to 150, from 10 to 100, from 10 to 75, from 10 to 50, or from 10 to 25. In some embodiments, each of m and n independently is an integer from 10 to 50. In an embodiment, m and n taken together are between 10 and 100, 20 and 80, 20 and 60, or 30 and 60.

In one embodiment, the conjugate or particle comprises the polymer of Formula (I-e), e.g., the polymer of Formula (I-e) as described herein, wherein each of m and n is an integer from 2 to 450, from 2 to 400, from 2 to 350, from 2 to 300, from 2 to 250, from 2 to 200, from 2 to 175, from 2 to 150, from 2 to 125, from 2 to 100, from 2 to 90, from 2 to 80, from 2 to 70, from 2 to 60, from 2 to 50, from 2 to 45, from 2 to 40, from 2 to 35, from 2 to 30, from 2 to 25, from 2 to 20, from 2 to 15, from 2 to 10, or from 2 to 5. In some embodiments, each of m and n independently is an integer from 2 to 250. In some embodiments, each of m and n independently is an integer from 2 to 100. In some embodiments, each of m and n independently is an integer from 2 to 50. In some embodiments, each of m and n independently is an integer from 2 to 25. In some embodiments, each of m and n independently is an integer from 2 to 10. In some embodiments, each of m and n independently is an integer from 10 to 500, from 10 to 250, from 10 to 200, from 10 to 150, from 10 to 100, from 10 to 75, from 10 to 50, or from 10 to 25. In some embodiments, each of m and n independently is an integer from 10 to 50. In an embodiment, m and n taken together are between 10 and 100, 20 and 80, 20 and 60, or 30 and 60.

In one embodiment, the conjugate or particle comprises the polymer of Formula (IV), e.g., the polymer of Formula (IV) as described herein, wherein each of m and n is an integer from 2 to 450, from 2 to 400, from 2 to 350, from 2 to 300, from 2 to 250, from 2 to 200, from 2 to 175, from 2 to 150, from 2 to 125, from 2 to 100, from 2 to 90, from 2 to 80, from 2 to 70, from 2 to 60, from 2 to 50, from 2 to 45, from 2 to 40, from 2 to 35, from 2 to 30, from 2 to 25, from 2 to 20, from 2 to 15, from 2 to 10, or from 2 to 5. In some embodiments, each of m and n independently is an integer from 2 to 250. In some embodiments, each of m and n independently is an integer from 2 to 100. In some embodiments, each of m and n independently is an integer from 2 to 50. In some embodiments, each of m and n independently is an integer from 2 to 25. In some embodiments, each of m and n independently is an integer from 2 to 10. In some embodiments, each of m and n independently is an integer from 10 to 500, from 10 to 250, from 10 to 200, from 10 to 150, from 10 to 100, from 10 to 75, from 10 to 50, or from 10 to 25. In some embodiments, each of m and n independently is an integer from 10 to 50. In an embodiment, m and n taken together are between 10 and 100, 20 and 80, 20 and 60, or 30 and 60.

In certain embodiments, the conjugate or particle comprises a polymer that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% made of polyacetal polymers (e.g., a polymer acceding to Formula (I), Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d), Formula (I-e), or Formula (IV)). Alternatively, or in combination, the conjugate or particle can comprise one or more hydrophobic or hydrophilic polymers to enhance a desired property. In certain embodiments, the conjugate or particle can comprise, or be linked to a water-soluble monomer or polymer (e.g., a PEG monomer or polymer), e.g., to increase one or more of amphiphilicity, hydrophilicity, water-solubility, pH sensitivity or stability.

In other embodiments, the conjugate or particle can comprise a polymer other than a polyacetal polymer, e.g., a polymer comprising one or more of: dextran, polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polydioxanone (PDO), polyanhydrides, polyorthoesters, cyclodextrin, or chitosan, or a pegylated form thereof. In other embodiments, the conjugate comprises (e.g., is coupled, e.g., covalently coupled), to one or more of: poly(lactic acid)-b-poly(ethylene glycol) (PLA-PEG), poly(lactic acid)-b-poly(ethylene glycol) (PLGA-PEG), or (cyclodextrin)-co-poly(ethylene glycol) (CDP). In some embodiments, the polymer comprises a PLA-PEG, dextran, or a polyacetal polymer described herein, or any combination thereof. Exemplary polymers that can be combined with the polyacetal polymers are described herein, e.g., in the section entitled “Polymers”.

In one embodiment, the conjugate or particle comprises a linker (with or without an agent, e.g., an AHCM) coupled (e.g., covalently coupled) to a second polymer, e.g., one or more of: dextran, polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polydioxanone (PDO), polyanhydrides, polyorthoesters, cyclodextrin, or chitosan, or a pegylated form thereof (e.g., poly(lactic acid)-b-poly(ethylene glycol) (PLA-PEG), poly(lactic acid)-b-poly(ethylene glycol) (PLGA-PEG), or (cyclodextrin)-co-poly(ethylene glycol) (CDP)).

In one embodiment, the conjugate or particle comprises a linker chosen from one or more of an acetal group, a ketal group, an anhydride group, a silyl ether group, a combination of acetal or ketal with ester group, an oligo-acetal or oligo-ketal group, a combination of the oligo-ketal and silyl ether group, or a combination of the oligo-ketal and vinyl ether group. In other embodiments, the conjugate is chosen from a combination of acetal or ketal with cis-aconityl, hydrazine, oxime, imidazole or trityl groups. Any of the aforesaid groups or combination of groups can be modified to enhance the pH sensitivity of the conjugate, e.g., as described herein.

In one embodiment, the conjugate or particle comprises a linker having the polymer of Formula (I) as described herein, wherein each of m and n is independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the sum of m and n is greater than 0. In one embodiment, the conjugate or particle comprises a linker having the polymer of Formula (I-a) as described herein, wherein each of m and n is independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the sum of m and n is greater than 0. In one embodiment, the conjugate or particle comprises a linker having the polymer of Formula (I-b) as described herein, wherein each of m and n is independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the sum of m and n is greater than 0. In one embodiment, the conjugate or particle comprises a linker having the polymer of Formula (I-c) as described herein, wherein each of m and n is independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the sum of m and n is greater than 0. In one embodiment, the conjugate or particle comprises a linker having the polymer of Formula (I-d) as described herein, wherein each of m and n is independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the sum of m and n is greater than 0. In one embodiment, the conjugate or particle comprises a linker having the polymer of Formula (I-e) as described herein, wherein each of m and n is independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the sum of m and n is greater than 0. In one embodiment, the conjugate or particle comprises a linker having the polymer of Formula (IV) as described herein, wherein m is independently chosen from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

In some embodiments, the conjugate or particle comprises a linker, e.g., the pH sensitive linker, chosen from a compound of Formula (VI) or Formula (VII). In some embodiments, R 31 or R 41 of Formula (VI) or Formula (VII) includes the agent and/or targeting moiety described herein.

In some embodiments, the conjugate or particle, e.g., the pH sensitive conjugate or particle, comprises a linker selected from the group consisting of:

wherein R can be the agent (e.g., an agent described herein) and is linked to the polymer or R can be the polymer and is linked to the agent (e.g., an agent described herein). In some embodiments, R is the agent and is linked to the polymer.

In some embodiments, the conjugate or particle comprises a linker selected from the group consisting of:

In other embodiments, the conjugate or particle comprises a linker, e.g., a pH sensitive linker, chosen from L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, or L12, e.g., as shown in FIG. 4 .

In some embodiments, the conjugate or particle comprises a single agent (e.g., one or more of the same agent) and/or targeting moiety (e.g., one or more of the same agent and/or targeting moiety as described herein). In some embodiments, the conjugate or particle comprises multiple agents and/or targeting moieties (e.g., 2, 3, 4, 5, 6 or more different agents and/or targeting moieties). In some embodiments, the agents are attached directly to a polymer (e.g., any polymer described herein) or a linker as described herein. In other embodiments, the agent(s) and/or targeting moiety(ies) are attached to the polymer (e.g., any polymer described herein) via a linker (e.g., any linker including a pH-sensitive linker as described herein). In some embodiments, the agents are the same agent. In some embodiments, the agents are different agents.

In one embodiment, conjugate or particle comprises an agent and/or targeting moiety attached at one end of the polymer, e.g., surface exposed end of the polymer. In other embodiments, the conjugate or particle comprises an agent and/or targeting moiety in the middle of the polymer. In one embodiment, the conjugate or particle comprises an agent and/or targeting moiety attached to at least two polymers such that the agent and/or targeting moiety is present between the two polymers.

In some embodiments, the agent and/or targeting moiety contains a reactive functional group for conjugation to the linker or polymer (e.g., the pH sensitive linker or polymer as described herein). In some embodiments, the functional group is chosen from a hydroxyl group, amino group (e.g., a primary or secondary amino group), thiol group, carboxylic acid group, aldehyde group, ketone group, hydrazino group, azido group, vinyl ether group, alkenyl group, isothiocyanate group, or acrylate group. In other embodiments, the agent and/or targeting moiety can be activated for conjugation to the linker or polymer (e.g., the pH sensitive linker or polymer as described herein) through the use of an activating agent. In some embodiments, the activating agent is, e.g., succinic anhydride, thiophosgene, 4-nitrophenyl chloroformate, or ethylenediamine. In other embodiments, the agent and/or targeting moiety can be activated for conjugation to a polymer (e.g., a polyacetal polymer described herein) or another moiety or polymer (e.g., PEG, PLA, PLGA, PDO, cyclodextrin) through the use of an activating agent, e.g., succinic anhydride, thiophosgene, 4-nitrophenyl chloroformate, ethylenediamine, or cis-acotinic anhydride. In other embodiments, the agent and/or targeting moiety is coupled to a polymer (e.g., the polyacetal polymer) and then activated for conjugation to another moiety or polymer (e.g., PEG, PLA, PLGA, PDO, cyclodextrin) through the use of an activating agent, e.g., succinic anhydride, thiophosgene, 4-nitrophenyl chloroformate, ethylenediamine, or cis-acotinic anhydride. In still other embodiments, the agent and/or targeting moiety is coupled to a moiety (e.g., PEG, PLA, PLGA, PDO, cyclodextrin) and then activated for conjugation to a polymer (e.g., the polyacetal polymer) through the use of an activation agent, e.g., succinic anhydride, thiophosgene, 4-nitrophenyl chloroformate, ethylenediamine, or cis-acotinic anhydride.

In some embodiments, the conjugate or particle is amphiphilic.

In some embodiments, the particle can be formed from the conjugates described herein, e.g., by precipitation and/or self-assembly.

In some embodiments, the conjugate is not precipitated from solution and/or self-assembled.

In another embodiment, the particle comprises a polyacetal polymer, e.g., a pH sensitive polyacetal polymer as described herein, a linker (e.g., a pH-sensitive linker as described herein) and an agent (e.g., a therapeutic and/or diagnostic agent (e.g., an AHCM), as described herein) and/or the targeting moiety. In one embodiment, the polymer, the linker, the agent and/or the targeting moiety in the particle are coupled, e.g., covalently coupled, directly or indirectly. In one embodiment, the polymer, the linker, the agent and/or the targeting moiety in the particle are coupled, e.g., noncovalently coupled, e.g., through ionic or hydrophobic interactions.

In another embodiment, the particle is modified in the surface or portion thereof to prevent, e.g., reduce, opsonin interactions and/or phagocyte clearance, e.g., as described in Salmaso S. and Caliceti, P. J Drug Deliv (2013) 2013:1-19. In some embodiments, the particle comprises a polymer that increases the flexibility and/or hydrophilicity of the particle surface. Exemplary polymers that can be used include, but are not limited to, natural and semisynthetic polysaccharides or synthetic polymers. For example, dextran (Dex), polysialicacid (PSA), hyaluronic acid (HA), chitosan (CH), and heparin are frequently used natural polysaccharides. Synthetic polymers include polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyacrylamide (Pam), poly(ethylene glycol) (PEG), and PEG-based copolymers such as poloxamers, poloxamines, and polysorbates, e.g., as described in Salmaso S. and Caliceti, supra.

In other embodiments, the particle comprises a water-soluble derivative of camptothecins, e.g., as described in U.S. Pat. No. 7,495,099. In some embodiments, the particle comprises a water-soluble high-molecular weight derivative of camptothecins, which is obtained by ester-bonding a carboxylic acid group of a polyethylene glycol-polycarboxylic acid polymer to a phenolic hydroxyl group of phenolic camptothecins.

In other embodiments, the particle comprises a cyclodextrin-based polymer, e.g., as described in U.S. Pat. No. 8,580,244.

In one embodiment, the particle comprises an agent and/or a targeting moiety (e.g., as described herein), wherein one or both are directly coupled (e.g., covalently coupled) to the polyacetal polymer (e.g., a polymer that comprises the compound of Formula (I), Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d), Formula (I-e), or Formula (IV)). In another embodiment, the particle comprises an agent and/or targeting moiety (e.g., as described herein) coupled (e.g., covalently coupled), via pH-sensitive linker (e.g., as described herein; an acetal monomer or a polyacetal polymer) to a second polymer (e.g., a polymer other than a polyacetal polymer).

In one embodiment, the particle is not selectively delivered or targeted to a target site, e.g., the particle does not include a targeting moiety (e.g., a cell- or liver-targeting agent as described herein).

In another embodiment, the particle is selectively delivered or targeted to a target site. In some embodiments, selective delivery can occur without targeting. In one embodiment, the particle is delivered to a target site via a targeting moiety (e.g., a cell- or liver-targeting agent). In one embodiment, the targeting moiety is chosen from one or more of a ligand, e.g., a cell surface receptor, a glycoprotein, a vitamin, cholesterol, an antibody or fragment thereof, a peptide, a protein, a lectin, an aptamer, a nucleic acid, a lipoprotein, a hormone, a charged molecule, a mono-, olio-, and polysaccharide, or low molecular weight ligands such as sugars, folic acids, and peptides. Exemplary targeting moieties are further described in detail herein, e.g., in the sections entitled “Targeting Moieties.”

Any of the particles disclosed herein, including any of the particles described in the section entitled “Particles” in the Detailed Description, including liposomal, polymeric and other particles. Such particles can include the agents disclosed herein, or in combination with the agents disclosed herein (e.g., in free or particle form).

Size of the Particles

In one embodiment, the particle, e.g., a particle as described herein, including a pH-sensitive and/or polyacetal polymer has a size to include any of the agents described herein, e.g., the AHCM, the microenvironment modulator, the other stromal modulator, the small molecule therapeutic or protein, e.g., an antibody.

In one embodiment, the particle includes one or more agents (e.g., therapeutic and/or diagnostic agent described herein). In one embodiment, the particle includes the same agent. In one embodiment, the particle includes different agents. The agent(s) can be coupled to the particle (e.g., as a conjugate as described herein) and/or contained non-covalently inside the particle.

In one embodiment, the particle is substantially or completely size-excluded from reaching arteriole smooth muscle, which is protected by non-leaky vessels. In other embodiments, the particle selectively penetrates a leaky vessel, e.g., a leaky vessel of a tumor or liver.

In some embodiments, the particle, e.g., a particle as described herein, has hydrodynamic diameter of greater than about 1, 5, 10, 15, 20, 25, 30, 35, 45, 50, 75, 100, 150, 200 nm, but less than 300 nm, e.g., as a nanoparticle. In one embodiment, the particle, e.g., a particle as described herein, has a hydrodynamic diameter of less than 100 nm, less than 90 nm, less than 80 nm, less than 70 nm, less than 60 nm, less than 50 nm, less than 40 nm, less than 30 nm, less than 20 nm, less than 15 nm, less than 14 nm, less than 13 nm, less than 12 nm, less than 11 nm, less than 10 nm, less than 5 nm, or less than 1 nm. In other embodiments, the particle, e.g., a particle described herein, has a hydrodynamic diameter between about 5 to 50 nm, 10 to 40 nm, 10 to 30 nm, or 10 to 20 nm.

In an embodiment, the AHCM, the microenvironment modulator and/or the other stromal modulator: is a small molecule therapeutic; is a protein, e.g., an antibody or an antibody fragment thereof or conjugate thereof (e.g., an antibody drug conjugate); or is provided in a particle. In one embodiment, the AHCM is chosen from one or more of: an angiotensin II receptor blocker (AT 1 blocker or ARB), an antagonist of RAAS antagonist, an ACE inhibitor, a TSP-1 inhibitor, a TGF-β1 inhibitor, a CTGF inhibitor, an SDF-1a inhibitor; an ERA; an AT 2 agonist; a VDR agonist; or a combination of two, three or more of the above.

In an embodiment, the anti-cancer agent, the anti-fibrotic therapeutic agent, the liver therapeutic agent, or second therapeutic agent: is a small molecule therapeutic with a hydrodynamic diameter of 1 nm or less; is a protein, e.g., an antibody or an antibody fragment thereof or conjugate thereof (e.g., an antibody drug conjugate); or is provided in a particle.

In an embodiment, the therapy is a cancer therapeutic (also referred to herein as “an anti-cancer agent”), anti-fibrotic agent, a liver therapeutic agent, or second therapeutic agent (e.g., but not limited to an immunomodulator or an anti-angiogenic agent) is administered as an entity having a hydrodynamic diameter of greater than about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, or 500 nm. For example, the second therapeutic agent (e.g., the anti-cancer agent or liver therapeutic agent) can be a protein, e.g., an antibody or an antibody fragment or conjugate thereof (e.g., an antibody drug conjugate). The second therapeutic agent (e.g., the anti-cancer agent or liver therapeutic agent) can also be administered as a particle, e.g., a polymeric nanoparticle (e.g., a pH-sensitive particle as described herein) or a liposome, that includes the agent as a small molecule therapeutic (i.e., a molecule having a hydrodynamic diameter of about 1 nm or less) or a protein, e.g., an antibody.

In an embodiment, an AHCM, microenvironment modulator and/or other stromal modulator is administered as an entity having a hydrodynamic diameter of greater than about 1 nm (e.g., greater than about 1, 5, 10, 15, 20, 25. 30, 50, 75, 90, 100, 150, 200, or 500) and a second therapeutic agent (e.g., an anti-cancer agent and/or liver therapeutic agent) is administered as an entity having a hydrodynamic diameter of about 1 nm or less. In one embodiment, the AHCM is present in the entity without a second therapeutic agent (e.g., a chemotherapeutic agent). The AHCM can be formulated for extended release, e.g., in an extended release formulation for substantially continuous release for hours, days, weeks, months or years, for example, using pH-sensitive polymer and/or linker of different degradation rates.

In an embodiment, an AHCM, microenvironment modulator and/or other stromal modulator is administered as an entity having a hydrodynamic diameter of about 1 nm, or less, and a second therapeutic agent (e.g., an anti-cancer agent and/or liver therapeutic agent) is administered as an entity having a hydrodynamic diameter of about 1 nm or greater (e.g., greater than about 1, 5, 10, 20, 50, 75, 100, 150, 200, 500, or 1,000 nm).

In an embodiment, an AHCM, microenvironment modulator and/or other stromal modulator is administered as an entity having a hydrodynamic diameter of less than, or equal to, about 1 nm and a second therapeutic agent (e.g., an anti-cancer agent) is administered as an entity having a hydrodynamic diameter of less than about 1 nm.

In an embodiment, an AHCM, microenvironment modulator and/or other stromal modulator is administered as an entity having a hydrodynamic diameter of greater than about 1 nm (e.g., greater than about 1, 5, 10, 20, 50, 75, 100, 150, 200, 500, or 1,000 nm), and a second therapeutic agent (e.g., an anti-cancer agent) is administered as an entity having a hydrodynamic diameter of greater than about 1 nm (e.g., greater than about 1, 5, 10, 20, 50, 75, 100, 150, 200, 500, or 1,000 nm).

The AHCM, microenvironment modulator and/or other stromal modulator and the second therapeutic agent (e.g., the anti-cancer agent or liver therapeutic) can be in separate or the same entity. For example, if provided as separate entities the AHCM can be provided as a first particle (e.g., a pH sensitive and/or polyacetal particle as disclosed herein; a particle (e.g., pH-sensitive and/or polyacetal particle comprising AHCM, microenvironment modulator and/or other stromal modulator)) and the second therapeutic agent (e.g., the anti-cancer agent and/or anti-fibrotic or liver therapeutic agent) provided as a second particle (e.g., where the second particle has a structural property (e.g., size or composition) or a functional property (e.g., release kinetics or a pharmacodynamic property) that differs from the first particle). Alternatively, an AHCM, microenvironment modulator and/or other stromal modulator and a second therapeutic agent (e.g., an anti-cancer agent and/or liver therapeutic agent) can be provided on the same entity, e.g., in the same nanoparticle.

In an embodiment, the AHCM, microenvironment modulator and/or other stromal modulator is selected from a therapeutic entity having a hydrodynamic diameter: equal to or less than 1 or 2 nm; between 2-20, 10-25, 20-40, 40, 50-150 nm; between 10, 15, 20, 25, 35, 40, 45, 50-100 nm; between 10, 15, 20, 25, 35, 40, 45, 50-200 nm; between 10, 15, 20, 25, 35, 40, 45, 50, 75, 100, 150, 200, 300-500 nm; and between 10, 15, 20, 25, 35, 40, 45, 50, 75, 100, 150, 200, 300, 1000 nm; or 10, 15, 20, 25, 35, 45, 50, 75, 100, 150 or 200 nm.

In an embodiment, the anti-cancer agent, liver therapeutic agent, or second therapeutic agent is selected from a therapeutic entity having a hydrodynamic diameter: equal to or less than 1 or 2 nm; between 2-20, 10-25, 20-40, 40, 50-150 nm; between 10, 15, 20, 25, 35, 40, 45, 50-100 nm; between 10, 15, 20, 25, 35, 40, 45, 50-200 nm; between 10, 15, 20, 25, 35, 40, 45, 50, 75, 100, 150, 200, 300-500 nm; and between 10, 15, 20, 25, 35, 40, 45, 50, 75, 100, 150, 200, 300-1000 nm; or 10, 15, 20, 25, 35, 45, 50, 75, 100, 150 or 200 nm.

In an embodiment, the AHCM, microenvironment modulator and/or other stromal modulator, anti-cancer agent, liver therapeutic agent, or the second therapeutic agent (e.g., but not limited to an immunomodulator or an anti-angiogenic agent), each independently, can be provided as an entity having the following size ranges (in nm): a hydrodynamic diameter of less than or equal to 1, or between 0.1 and 1.0 nm, e.g., that of a typical small molecule; a hydrodynamic diameter of between 5 and 20, or 5 and 15 nm, e.g., that of a protein, e.g., an antibody; or a hydrodynamic diameter of 10-5,000, 20-1,000, 10-500, 10-200, 10-150, or 10-100, 10-25, 20-40, 40, 50-150 nm; between 10, 15, 20, 25, 35, 40, 45, 50-100 nm; between 10, 15, 20, 25, 35, 40, 45, 50-200 nm; between 10, 15, 20, 25, 35, 40, 45, 50, 75, 100, 150, 200, 300-500 nm; and between 10, 15, 20, 25, 35, 40, 45, 50, 75, 100, 150, 200, 300-1000 nm; or 10, 15, 20, 25, 35, 45, 50, 75, 100, 150 or 200 nm, e.g., a range of typical nanoparticles.

Particle Dosage and Drug Loading

In some embodiments, the percentage of the polymer monomers that are conjugated to an agent (e.g., a therapeutic or diagnostic agent) is between 1-100% (e.g., as many as 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100%). In some embodiments, the percentage of polymer monomers that are conjugated to an agent is less than 10%, e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3%. In some embodiments, the percentage of polymer monomers that are conjugated to an agent is between, or inclusive of 2% to 10%, 3% to 9%, or 4% to 60%. In some embodiments, the percentage of polymer monomers that are conjugated to an agent is between 10-90%. In some embodiments, the percentage of polymer monomers that are conjugated to an agent is between 15-75%. In the some embodiments, the percentage of polymer monomers that are conjugated to an agent is between 20-60%. In the some embodiments, the percentage of polymer monomers that are conjugated to an agent is between 35-50%.

Without being bound by theory, the particles disclosed herein may improve the efficiency of an agent (e.g., a therapeutic and/or diagnostic agent) by one or more of increasing the localization and/or release (e.g., preferential release) of the agent to a target cell (e.g., a cancer or a fibrotic cell; a cell associated with a hypoxic environment), or increasing the half life of the agent, thus resulting in a significantly higher amount of a released agent at a target site (e.g., a tumor or liver (e.g., cirrhotic cell). According, the conjugates and particles disclosed herein can be more effective therapeutically than the free agent (e.g., due to enhanced drug uptake in the target tissue) and/or allow for a lower therapeutic dose of the agent, e.g., without substantially compromising the resulting drug concentration at a target tissue. In some embodiments, the conjugates and particles disclosed herein can reduce the adverse effect associated with systemic administration of an agent in free form (e.g., not coupled to a polymer, conjugate or particle described herein).

In other embodiments, the agent-containing particle (e.g., a particle containing an AHCM) has a dose or amount of the agent that is less than the dose or amount of said agent in free form to have a desired effect (e.g., a desired therapeutic effect). In one embodiment, the agent-containing particle has a dose or amount of the agent that is less than the standard of care dose of the agent for a desired therapy (e.g., a dose that is less than 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, that of the standard of care dose of the agent). In one embodiment, where the agent is an AHCM, the dose is less than the anti-hypertensive or anti-heart failure dose for AT 1 inhibitors or ARBs such as losartan, candesartan, eprosartan, irbesartan, olmesartan, telmisartin, and valsartan.

In some embodiments, the agent is incorporated into a particle at a dose equivalent to the dose or amount of said agent in free form to have a desired effect (e.g., a desired therapeutic effect), e.g., the standard of care dose for the intended use of the free agent. In these embodiments, the particle produces a greater therapeutic effect and/or a less adverse effect than the free agent. In certain embodiments, the particle increases the amount of the agent delivered to a tissue or cell in need thereof and reduces the amount of the agent exposed to a non-target tissue or cell, as compared to the free agent.

In some embodiments, the agent is incorporated into a particle at a dose higher than the dose or amount of said agent in free form to have a desired effect (e.g., a desired therapeutic effect), e.g., the standard of care dose for the intended use of the free agent. In some embodiments, the agent is incorporated into a particle at a dose higher than the dose or amount of said agent in free form that would produce an adverse effect by systemic administration (e.g., a reduction in blood pressure). Since the particle described herein releases the agent at a target site based on pH microenvironment, other non-target sites (e.g., blood vessels) with different pH would be less likely to be exposed to the agent.

Exemplary Conjugates

In one embodiment, the conjugate comprises a polyacetal polymer (e.g., as described herein) and an agent (e.g., an agent as described herein, e.g., an ARB).

In another embodiment, the conjugate comprises a polyacetal-losartan conjugate. In another embodiments, the conjugate comprises a losartan-linked polyol derivative, e.g., as described in Formula (II-e). In one embodiment, the polyacetal-losartan conjugate has a ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4 or higher. In one embodiment, ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 2.

In one embodiment, the conjugate comprises a valsartan-linked polyol derivative, e.g., as shown in FIG. 2B . In one embodiment, the conjugate comprises a valsartan-linked polyol derivative, e.g., as described in Formula (II-f). In one embodiment, the polyacetal-valsartan conjugate has a ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4 or higher. In one embodiment, ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 2.

In another embodiment, the conjugate comprises a polyacetal-telmisartan conjugate. In another embodiments, the conjugate comprises a telmisartan-linked polyol derivative, e.g., as described in Formula (II-g). In one embodiment, the polyacetal-telmisartan conjugate has a ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4 or higher. In one embodiment, ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 2.

In another embodiment, the conjugate comprises a polyacetal-candesartan conjugate.

In another embodiments, the conjugate comprises a candesartan-linked polyol derivative, e.g., as described in Formula (II-h). In one embodiment, the polyacetal-candesartan conjugate has a ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4 or higher. In one embodiment, ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 2.

In another embodiment, the conjugate comprises a polyacetal-olmesartan conjugate. In another embodiments, the conjugate comprises an olmesartan-linked polyol derivative, e.g., as described in Formula (II-i). In one embodiment, the polyacetal-olmesartan conjugate has a ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4 or higher. In one embodiment, ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 2.

In another embodiment, the conjugate comprises an agent (e.g., an agent as described herein), a linker (e.g., a linker as described herein), and a polyacetal polymer (e.g., as described herein). In another embodiment, the conjugate comprises an agent (e.g., an agent as described herein), a linker (e.g., a linker as described herein, e.g, in FIG. 3 or FIG. 4 ), and a polyacetal polymer (e.g., as described herein). In another embodiment, the conjugate described herein is a polyacetal polymer comprising one or more of gemcitabine, 5-fluorouracil or irinotecan. In one embodiment, the conjugate comprises a linker as shown in FIG. 3 or FIG. 4 .

In another embodiment, the conjugate comprises an agent (e.g., an agent as described herein, e.g., an ARB), a linker (e.g., a linker as described herein, e.g., as shown in FIGS. 5A-5D ), and a polyacetal polymer (e.g., as described herein). In another embodiment, the conjugate comprises a linker selected from succinic acid or ethylene diamine, e.g., as shown in FIGS. 5A-5D .

In other embodiments, the conjugate comprises an agent (e.g., an agent as described herein, e.g., an ARB), a linker (e.g., a linker as described herein, e.g., as shown in FIGS. 5A-5D ), a polyacetal polymer (e.g., as described herein), and a targeting moiety (e.g., a targeting moiety as described herein). In one embodiment, the targeting moiety is a mannose-6-phosphate (M6P). Exemplary conjugates of losartan, a polymer (with or without a linker), and M6P as a targeting moiety are depicted in FIGS. 5A-5D . In one embodiment, the conjugate has the structure depicted in FIG. 5A . In one embodiment, the conjugate has the structure depicted in FIG. 5B . In one embodiment, the conjugate has the structure depicted in FIG. 5C . In one embodiment, the conjugate has the structure depicted in FIG. 5D .

In one embodiment, the conjugates described herein are present in a particle, e.g., a nanoparticle, from about 10 to 100 nm, about 20 to 90 nm, about 30 to 60 nm, about 30 to 45 nm, in size.

In one embodiment, the particle has a polymer polydispersity index of less than about 1 (e.g., less than about 0.5, less than about 0.25, less than or equal to about 0.15, or less than or equal to about 0.1).

In some embodiments, the conjugate is soluble in water (e.g., hydrophilic). In some embodiments, the conjugate is soluble in water, and between about 0.1 to about 5 parts water are required to dissolve 1 part conjugate, or between about 1 part to about 5 parts water are required to dissolve 1 part conjugate. In some embodiments, the conjugate is partially soluble in water. In some embodiments, the conjugate is partially soluble in water, and between about 5 to about 50 parts water are required to dissolve 1 part conjugate. In some embodiments, the conjugate is sparingly soluble in water. In some embodiments, the conjugate is sparingly soluble in water, and between about 25 to about 100 parts water is required to dissolve 1 part conjugate. In some embodiments, the conjugate is slightly soluble in water. In some embodiments, the conjugate is slightly soluble in water, and between 100 to about 1,000 parts water are required to dissolve 1 part conjugate. In some embodiments, the conjugate is very slightly soluble in water. In some embodiments, the conjugate is very slightly soluble in water, and between 1,000 to about 10,000 parts water are required to dissolve 1 part conjugate. In some embodiments, the conjugate is substantially insoluble in water (e.g., hydrophobic). In some embodiments, the conjugate is substantially insoluble in water and greater than about 10,000 parts water are required to dissolve 1 part conjugate.

Exemplary Particles

In one embodiment, the particle comprises a polyacetal polymer (e.g., as described herein) and an agent (e.g., an agent as described herein, e.g., an ARB).

In another embodiment, the particle comprises a polyacetal-losartan conjugate. In another embodiments, the particle comprises a losartan-linked polyol derivative, e.g., as described in Formula (II-e). In one embodiment, the polyacetal-losartan conjugate has a ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4 or higher. In one embodiment, ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 2.

In one embodiment, the particle comprises a polyacetal-valsartan conjugate, e.g., a polyacetal-valsartan conjugate as shown in FIG. 2B . In one embodiment, the particle comprises a valsartan-linked polyol derivative, e.g., as described in Formula (II-f). In one embodiment, the polyacetal-valsartan conjugate has a ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4 or higher. In one embodiment, ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 2.

In another embodiment, the particle comprises a polyacetal-telmisartan conjugate. In another embodiments, the particle comprises a telmisartan-linked polyol derivative, e.g., as described in Formula (II-g). In one embodiment, the polyacetal-telmisartan conjugate has a ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4 or higher. In one embodiment, ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 2.

In another embodiment, the particle comprises a polyacetal-candesartan conjugate. In another embodiments, the particle comprises a candesartan-linked polyol derivative, e.g., as described in Formula (II-h). In one embodiment, the polyacetal-candesartan conjugate has a ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4 or higher. In one embodiment, ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 2.

In another embodiment, the particle comprises a polyacetal-olmesartan conjugate. In another embodiments, the particle comprises an olmesartan-linked polyol derivative, e.g., as described in Formula (II-i). In one embodiment, the polyacetal-olmesartan conjugate has a ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4 or higher. In one embodiment, ratio of release or degradation rate of the polyacetal polymer and/or linker at pH=6.7 relative to pH=7.4 is greater than 2.

In another embodiment, the particle comprises an agent (e.g., an agent as described herein), a linker (e.g., a linker as described herein), and a polyacetal polymer (e.g., as described herein). In another embodiment, the particle comprises an agent (e.g., an agent as described herein), a linker (e.g., a linker as described herein, e.g, in FIG. 3 or FIG. 4 ), and a polyacetal polymer (e.g., as described herein). In another embodiment, the particle described herein comprises a polyacetal polymer comprising one or more of gemcitabine, 5-fluorouracil or irinotecan. In one embodiment, the particle comprises a linker as shown in FIG. 3 or FIG. 4 .

In another embodiment, the particle comprises an agent (e.g., an agent as described herein, e.g., an ARB), a linker (e.g., a linker as described herein, e.g., as shown in FIGS. 5A-5D ), and a polyacetal polymer (e.g., as described herein). In another embodiment, the particle comprises a linker selected from succinic acid or ethylene diamine, e.g., as shown in FIGS. 5A-5D .

In other embodiments, the particle comprises an agent (e.g., an agent as described herein, e.g., an ARB), a linker (e.g., a linker as described herein, e.g., as shown in FIGS. 5A-5D ), a polyacetal polymer (e.g., as described herein), and a targeting moiety (e.g., a targeting moiety as described herein). In one embodiment, the targeting moiety is a mannose-6-phosphate (M6P). Exemplary particle comprising conjugates of losartan, a polymer (with or without a linker), and M6P as a targeting moiety are depicted in FIGS. 5A-5D . In one embodiment, the particle comprises a conjugate with the structure depicted in FIG. 5A . In one embodiment, the particle comprises a conjugate with the structure depicted in FIG. 5B . In one embodiment, the particle comprises a conjugate with the structure depicted in FIG. 5C . In one embodiment, the particle comprises a conjugate with the structure depicted in FIG. 5D .

In one embodiment, the particle has a polymer polydispersity index of less than about 1 (e.g., less than about 0.5, less than about 0.25, less than or equal to about 0.15, or less than or equal to about 0.1).

Method of Making the Compositions

Methods of Making Polymers

In some embodiments, the polymer described herein (e.g., polyacetal polymer, e.g., of Formula (I), Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d), Formula (I-e), or Formula (V)) are synthesized through self- or cross-polyaddition of vinyl ethers with polyols in a stepwise manner. In one embodiment, the polymerization reaction includes the polyaddition of polyols with vinyl ethers catalyzed by a Bronsted (e.g., protic) or Lewis acid catalyst (e.g., p-toluene sulfonic acid (pTSA), camphor sulfonic acid, benzene sulfonic acid, or boron trifluoride). Examples of solvents that can be used for such polyaddition reaction to synthesize polymers include, but are not limited to, toluene, chloroform, tetrahydrofuran (THF), dioxane, 2-methyltetrahydrofuran, dichloromethane (DCM), dimethylformamide (DMF), dimethylsulfoxide (DMSO), or any combinations thereof. In some embodiments, the polymerization reaction is carried out in a mixture of THF and toluene. In some embodiments, the solvent is freshly distilled prior to the reaction. In some embodiments, the solvent is anhydrous. In some embodiments, the polymerization reaction is carried out in the presence of a base (e.g., trimethylamine (TEA), or 4-dimethylaminopyridine (DMAP)).

In some embodiments, the polymerization is carried out in a dry container (e.g., glassware) in a nitrogen or argon atmosphere. In some embodiments, the reaction temperature is 0° C., room temperature, or 40-60° C. In some embodiments, the reaction temperature is 50° C. In some embodiments, the reaction temperature is 60-80° C.

In some embodiments, the individual monomer units in the polymerization reaction are of high purity. In some embodiments, the individual monomer units in the polymerization reaction are at least 90%, at least 92%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 99.9% pure. In some embodiments, the individual monomer units in the polymerization reaction are vacuum dried prior to use in the reaction. In some embodiments, the individual monomer units in the polymerization reaction are freshly distilled (e.g., with CaH 2 or K 2 CO 3 ), purified, recrystallized, or dried prior to use in the reaction. In some embodiments, the individual monomer units in the polymerization reaction are synthesized prior to use. In some embodiments, the individual monomer units in the polymerization reaction are commercially available.

In some embodiments, the individual monomer units in the polymerization reaction comprise a polyol (e.g., a compound represented by Formula (II), Formula (II-a), Formula (II-b), Formula (II-c), Formula (II-d), Formula (II-e), Formula (II-f), Formula (II-g), Formula (II-h), Formula (II-i), Formula (II-j), or as depicted in FIG. 1B ), and a vinyl ether (e.g., a compound represented by Formula (III), Formula (III-a), Formula (III-b), or depicted in FIG. 1C ). In some embodiments, the ratio of the polyol to the vinyl ether is from about 10:1 to about 1:10. In some embodiments, the ratio of the polyol to the vinyl ether is from about 5:1 to about 1:5. In some embodiments, the ratio of the polyol to the vinyl ether is from about 3:1 to about 1:3. In some embodiments, the ratio of the polyol to the vinyl ether is from about 2.5:1 to about 1:2.5, from about 2.25:1 to about 1:2.25, from about 2:1 to about 1:2, from about 1.9:1 to about 1:1.9, from about 1.8:1 to about 1:1.8, from about 1.7:1 to about 1:1.7, from about 1.6:1 to about 1:1.6, or from about 1.5:1 to about 1:1.5. In some embodiments, the ratio of the polyol to the vinyl ether is about 1.5:1 to about 1:1. In some embodiments, the ratio of the polyol to the vinyl ether is from about 1.4:1 to about 1:1, from about 1.3:1 to about 1:1, from about 1.2:1 to about 1:1, or from about 1.1:1 to about 1:1. In some embodiments, the ratio of the polyol to the vinyl ether is about 1:1.

In some embodiments, the ratio of the polyol to the vinyl ether is from about 1.2:1.0 to about 1.0:1.2. In some embodiments, the ratio of the polyol to the vinyl ether is from about 1.1:1 to about 1:1.1. In some embodiments, the ratio of the polyol to the vinyl ether is about 1.01:1, about 1.02:1, about 1.03:1, about 1.04:1, about 1.05:1, about 1.06:1, about 1.07:1, about 1.08:1, or about 1.09:1. In some embodiments, the ratio of the polyol to the vinyl ether is about 1:1.01, about 1:1.02, about 1:1.03, about 1:1.04, about 1:1.05, about 1:1.06, about 1:1.07, about 1:1.08, or about 1:1.09. In some embodiments, the ratio of the polyol to the vinyl ether is from about 1.05:1 to about 1:1.05.

In some embodiments, the individual monomer units in the polymerization reaction comprise a vinyl ether (e.g., a compound represented by Formula (III), Formula (III-a), Formula (III-b), or depicted in FIG. 1C ), and a PEG (e.g., as described by C 1 or C 2 in Formula (I), Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d), Formula (I-e), or Formula (IV)). In some embodiments, only one PEG is used in the polymerization reaction. In some embodiments, one of PEG 400 and PEG 1000 is used in the polymerization reaction. In some embodiments, more than one PEG is used in the polymerization reaction. In some embodiments, each of PEG 400 and PEG 1000 is used in the polymerization reaction. In some embodiments, the ratio of PEG 400 to PEG 1000 used in the polymerization reaction is between about 0.25:1 to about 1:0.25, from about 0.3:1 to about 1:0.3, from about 0.5:1 to about 1:0.5, from about 0.6:1 to about 1:0.6, or from about 0.75:1 to about 1:0.75. In some embodiments, the ratio of PEG 400 to PEG 1000 is 1:1. In some embodiments, PEG 2050 is used in the polymerization reaction.

In some embodiments, the individual monomer units in the polymerization reaction comprise a polyol (e.g., a compound represented by Formula (II), Formula (II-a), Formula (II-b), Formula (II-c), Formula (II-d), Formula (II-e), Formula (II-f), Formula (II-g), Formula (II-h), Formula (II-i), Formula (II-j), or as depicted in FIG. 1B ), a vinyl ether (e.g., a compound represented by Formula (III), Formula (III-a), Formula (III-b), or depicted in FIG. 1C ), and a PEG (e.g., as described by C 1 or C 2 in Formula (I), Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d), Formula (I-e), or Formula (IV)).

In some embodiments, the reaction time ranges from about 1 hour to about 48 hours. In some embodiments, the reaction time ranges from about 1 hour to about 36 hours, to about 24 hours, to about 18 hours, to about 16 hours, to about 14 hours, to about 12 hours, to about 10 hours, to about 8 hours, to about 6 hours, to about 4 hours, to about 2 hours. In some embodiments, the reaction time ranges from about 1 hour to about 24 hours. In some embodiments, the reaction time ranges from about 1 hour to about 16 hours, or from about 1 hour to about 8 hours, or from about 1 hour to about 4 hours.

In some embodiments, an excess of a polyol (e.g., a compound represented by Formula (II), Formula (II-a), Formula (II-b), Formula (II-c), Formula (II-d), Formula (II-e), Formula (II-f), Formula (II-g), Formula (II-h), Formula (II-i), Formula (II-j), or as depicted in FIG. 1B ) is added to the polymerization reaction in order to quench or substantially stop the polymerization process. In some embodiments, an excess of about 1.5, about 2.0, about 5.0, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 250, about 500, about 1000, or more of a polyol (e.g., a polyol described herein) is added to the polymerization reaction relative to the starting amount of said polyol in order to quench or substantially stop the polymerization process.

In some embodiments, the reaction is quenched through the addition of base (e.g., including, but not limited to, triethylamine or ammoniacal methanol). In some embodiments, the polymer mixture is purified by extraction, vacuum drying, trituration, or chromatography (e.g., silica gel chromatography, HPLC).

Methods of Making Conjugates

In some embodiments, the conjugation of an agent (e.g., an agent described herein, e.g., an ARB), a targeting moiety (e.g., M6P), or a linker (e.g., a linker described herein) to the polymers described herein can occur via a reactive group, e.g., a free hydroxyl group, on the polymers. In some embodiments, it is more desirable that the agents (e.g., an ARB) have at least one or more carboxylic acids and/or hydroxyl groups. By way of example only, in one embodiment, the agent valsartan with a carboxylic acid group or the agent losartan with a hydroxyl group can be conjugated to the polymer described herein via ester bond formation. Exemplary coupling agents used for conjugation include, but are not limited to, EDC, DIC, DCC, HOAt, HOBt, and PyBOP. In some embodiments, the conjugation reaction further comprises a base (e.g., TEA, pyridine). In some embodiments, the conjugation reaction further comprises a catalyst (e.g., DMAP). In some embodiments, conjugation of an agent to a polymer occurs through a linker (e.g., a linker described herein, in the section entitled “Linkers”). In some embodiments, conjugation of a linker to the polyacetal polymer occurs prior to conjugation of an agent or a targeting moiety to the polyacetal polymer.

In some embodiments, a free hydroxyl group on a polymer (e.g., a polyacetal polymer described herein) must be exposed through removal of a hydroxyl protecting group (e.g., a benzyl ether, a t-butyl ether, a benzoic acid ester, an acetic acid ester, or an allyl ether). In some embodiments, the polymer (e.g., a polymer described herein) comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 15, at least 20, at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 200, or more protected hydroxyl groups (e.g., one or more of a benzyl ether, a t-butyl ether, a benzoic acid ester, an acetic acid ester, or an allyl ether). Methods for removal of said hydroxyl protecting groups are known in the art. In some embodiments, removal of a hydroxyl protecting group is carried out prior to conjugation of an agent to a polymer (e.g., a polyacetal polymer described herein).

In some embodiments, the number of equivalents of an agent (e.g., an agent described herein, e.g., an ARB), a targeting moiety (e.g., M6P), or a linker (e.g., a linker described herein) in the conjugation reaction is greater than the number of equivalents of the polyacetal polymer (e.g., a polyacetal polymer described herein). In some embodiments, the conjugation reaction comprises an excess of an amount of an agent (e.g., an agent described herein, e.g., an ARB), a targeting moiety (e.g., M6P), or a linker (e.g., a linker described herein) compared with the polyacetal polymer (e.g., a polyacetal polymer described herein). In some embodiments, the conjugation reaction comprises a sub-stoichiometric amount of an agent (e.g., an agent described herein, e.g., an ARB), a targeting moiety (e.g., M6P), or a linker (e.g., a linker described herein) compared with the polyacetal polymer (e.g., a polyacetal polymer described herein). In some embodiments, the ratio of an agent (e.g., an agent described herein, e.g., an ARB), a targeting moiety (e.g., M6P), or a linker (e.g., a linker described herein) to the polyacetal polymer (e.g., a polyacetal polymer described herein) is about 1000:1, about 750:1, about 500:1, about 250:1, 100:1, about 75:1, about 50:1, about 25:1, about 15:1, about 10:1, about 8:1, about 5:1, about 3:1, or about 2:1. In some embodiments, the ratio of an agent (e.g., an agent described herein, e.g., an ARB), a targeting moiety (e.g., M6P), or a linker (e.g., a linker described herein) to the polyacetal polymer (e.g., a polyacetal polymer described herein) is 1:1. In some embodiments, the ratio of the polyacetal polymer (e.g., a polyacetal polymer described herein) to an agent (e.g., an agent described herein, e.g., an ARB), a targeting moiety (e.g., M6P), or a linker (e.g., a linker described herein) is about 1:0.9, about 1:0.8, about 1:0.7, about 1:0.6, about 1:0.5, about 1:0.4, about 1:0.3, about 1:0.2, about 1:0.1, about 1:0.05, about 1:0.01, about 1:0.05, about 1:0.01, or less.

In some embodiments, the agents (e.g., drugs) lack one or more carboxylic acids and/or hydroxyl groups. In one exemplary embodiment, losartan does not have a free carboxylic acid group for conjugation to the polymer. In this exemplary embodiment, it may be desirable to convert a hydroxyl group on the polymer side chain into a carboxylic acid through the use of a modification agent. Exemplary modification agents include, e.g., succinic anhydride (e.g., as shown in FIG. 5A ). An esterification reaction may then be carried out between the modified polymer and an agent (e.g., losartan) to conjugate the agent (e.g., losartan) to the polymer (e.g., as shown in FIG. 5B ). In some embodiments, a sub-stoichiometric amount of the agent can be used in the esterification reaction in order to prevent full saturation of the modified polymer (e.g., the polymer modified with carboxylic acid groups). In some embodiments, a sub-stoichiometric amount of the agent can be used to provide about 50%, about 60%, about 70%, about 80, about 90%, about 95%, or about 99% or more saturation of the modified polymer (e.g., the polymer modified with carboxylic acid groups). In some embodiments, the modified polymer contains free, unreacted modifications (e.g., carboxylic acid groups) after conjugation of the agent (e.g., losartan). In some embodiments, the modified polymer contains about 50%, about 40%, about 30%, about 20%, about 10%, about 5%, or about 1% or less free, unreacted modifications (e.g., carboxylic acid groups). In some embodiments, the free, unreacted modifications on the polymer may be reacted with a second modification agent (e.g, an amine, e.g., ethylenediamine, as shown in FIG. 5C )).

In some embodiments, the conjugation of a targeting moiety to a polymer described herein (e.g., a polyacetal polymer) can involve the formation of a covalent linkage. In some embodiments, the conjugation of a targeting moiety (e.g., M6P) can involve reaction of the targeting moiety (e.g., M6P) with the modified polymer (e.g., the polymer modified with amine groups, or the losartan-polymer modified with amine groups). In some embodiments, the targeting moiety (e.g., M6P) must first be activated for conjugation to the modified polymer (e.g., the polymer modified with amine groups, or the losartan-polymer modified with amine groups). By way of example, in an embodiment, the targeting moiety M6P (e.g., α-4-nitrophenyl M6P) may be activated to yield an M6P-isothiocyanate. In some embodiments, the activation of the targeting moiety requires at least two steps (e.g., synthesis of α-4-nitrophenyl M6P followed by formation of M6P-isothiocyanate). In some embodiments, the activated targeting moiety (e.g., M6P-isothiocyanate) can be conjugated to the modified polymer (e.g., the polymer modified with amine groups, or the losartan-polymer modified with amine groups).

In some embodiments, the conjugation of a targeting moiety to a polymer described herein (e.g., a polyacetal polymer) can involve the formation of a noncovalent linkage, e.g., an ionic interaction or hydrophobic interaction. In some embodiments, the conjugation of a targeting moiety (e.g., M6P) can involve reaction of the targeting moiety (e.g., M6P) with the modified polymer (e.g., the polymer modified with amine groups, or the losartan-polymer modified with amine groups). In some embodiments, the targeting moiety (e.g., M6P) is not activated prior to conjugation to or association with the modified polymer (e.g., the polymer modified with amine groups, or the losartan-polymer modified with amine groups). By way of example, in an embodiment, the targeting moiety M6P (e.g., α-4-nitrophenyl M6P) is incubated with the modified polymer (e.g., the polymer modified with amine groups, or the losartan-polymer modified with amine groups) to yield an M6P-nanoARB (e.g., a polymer modified with both M6P and an ARB, e.g, losartan, e.g., as shown in FIG. 5D ).

In some embodiments, the reaction time ranges from about 1 hour to about 48 hours. In some embodiments, the reaction time ranges from about 1 hour to about 36 hours, to about 24 hours, to about 18 hours, to about 16 hours, to about 14 hours, to about 12 hours, to about 10 hours, to about 8 hours, to about 6 hours, to about 4 hours, to about 2 hours. In some embodiments, the reaction time ranges from about 1 hour to about 24 hours. In some embodiments, the reaction time ranges from about 1 hour to about 16 hours, or from about 1 hour to about 8 hours, or from about 1 hour to about 4 hours.

In some embodiments, the reaction is quenched through the addition of base (e.g., including, but not limited to, triethylamine or ammoniacal methanol). In some embodiments, the polymer mixture is purified by extraction, vacuum drying, trituration, or chromatography (e.g., silica gel chromatography, HPLC).

Methods of Making Particles

In some embodiments, particles are prepared from the conjugates and/or polymers described herein. In some embodiments, preparation of particles is carried out through precipitation, emulsion (e.g., single emulsion or double emulsion), and/or salting out of the conjugates from an aqueous solution. In some embodiments, emulsions are formed in which an emulsion (water/oil or oil/water) is dispersed in a continuous phase (water or oil, respectively) to produce water/oil/water or oil/water/oil. In some embodiments, preparation of particles is carried out through precipitation of the conjugates from an organic solvent. In some embodiments, preparation of particles is carried out by dissolving the conjugates and/or polymers described herein in an organic solvent, e.g., THF, acetonitrile, or DMF. In some embodiments, the organic solvent comprising the conjugates and/or polymers is added drop-wise to a volume of water to form the particles. In some embodiments, the organic solvent comprising the conjugates and/or polymers is added drop-wise to a volume of water at a steady rate (e.g., 0.1 mL/min, 0.5 mL/min, 1 mL/min, 1.5 mL/min, 2 mL/min, 5 mL/min, 7.5 mL/min, 10 mL/min, 15 mL/min, 20 mL/min) to form the particles. In some embodiments, the organic solvent (e.g., THF, acetonitrile, or DMF) is removed by evaporation to provide a dried film. In some embodiments, an aqueous solution (e.g., water or a buffer, e.g., PBS) solution is used to wash the dried film, e.g., once, twice, three times, or more. In some embodiments, the mixture is then sonicated or mixed in a cold water bath (e.g., at a temperature less than 25° C., less than 20° C., less than 15° C., less than 10° C., less than 5° C., less than 0° C.) to form the precipitated particles. In some embodiments, the resulting particles are then filtered and characterized to determine the average diameter, polydispersity, and molecular weight.

Formulations and Pharmaceutical Compositions

Any of the compositions (e.g., polymer, linker, conjugate or particles) disclosed herein can be formulated in an acceptable carrier, e.g., for therapeutic or diagnostic use, or for storage.

In one embodiment, combinations of one or more particles as described herein can be administered to a subject as a single composition or two or more compositions. The compositions can be administered via the same or different route.

In one embodiment, the particle, e.g., a nanoparticle, is stored in solid form under suitable condition for storage. In one embodiment, the formulation comprises a protectant agent, for example, for freeze drying and/or reconstitution. The protectant agent can be chosen from one or more of dextran, sucrose, α or β or γ-cyclodextrin or serum albumin (e.g., bovine serum albumin). In one embodiment, the protectant agent is bovine serum albumin.

The particle(s) can be sterilized by γ-irradiation of the lyophilized formulation, or sterile filtration of liquid formulation. Other sterilization technique including ultraviolet irradiation or ethanol sterilization can also be used. See, e.g., J Pharm Sci. 2011 February; 100(2):646-54 for additional sterilization method that can be used to sterilize the particle described herein.

Uses

In another aspect, the invention features a method of treating or preventing a disorder or condition, in a subject, or of improving the delivery and/or efficacy of a therapy (e.g., a cancer therapy, or an anti-fibrotic or anti-inflammatory therapy) in a subject. The method includes:

administering a conjugate or a particle (e.g., one or more pH sensitive and/or polyacetal conjugates or particles as described herein), as a single agent or in combination with a therapy (e.g., against cancer, a fibrotic disorder, or an inflammatory disorder), to the subject;

optionally, administering the therapy (e.g., a cancer therapy, or an anti-fibrotic or anti-inflammatory therapy),

under conditions sufficient to treat or prevent the disorder or condition in the subject, or to improve the delivery and/or efficacy of the therapy provided to the subject. In one embodiment, the disorder or condition is a hyperproliferative and/or fibrotic disorder (e.g., a cancer or a fibrotic or inflammatory disorder as described herein). In some embodiments, the therapy comprises a low-dose anti-angiogenic agent. In some embodiments, the therapy comprises an immunomodulator and/or a chemotherapeutic agent.

In another aspect, the invention features a combination or composition for use in treating a disorder, e.g., a cancer, or a fibrotic or inflammatory disorder, or improving the delivery and/or efficacy of a therapy (e.g., a cancer therapy, or an anti-fibrotic or anti-inflammatory therapy). In embodiments, the composition for use includes (e.g., one or more conjugate or a particle (e.g., one or more pH sensitive and/or polyacetal conjugates or particles as described herein). In one embodiment, the composition includes one, two or more of:

(i) an AHCM (e.g., an ARB);

(ii) a microenvironment modulator (e.g., an anti-angiogenic inhibitor, e.g., a low-dose anti-angiogenic inhibitor) and/or other stromal modulators;

(iii) an immunomodulator (e.g., anti-inflammatory agent (e.g., a cytokine inhibitor) or an inhibitor of an immune checkpoint molecule, and

optionally, a therapy (e.g., a cancer therapy, or an anti-fibrotic or anti-inflammatory therapy).

In another aspect, the invention features a method for treating or preventing a liver disorder or condition in a subject. The method includes administering to the subject one or both of a metformin agent or an AHCM, and a vascular/stromal normalizing dose (e.g., a sub-anti-angiogenic dose) of a second agent chosen from one or more of: anti-angiogenic agent, sorafenib or an inhibitor of the angiopoietin-Tie-2 pathway (e.g., an Ang-1 or an Ang-2 inhibitor), thereby treating or preventing the liver disorder or condition.

In one embodiment, the particle administered (e.g., one or more particles as described herein), comprises:

a polymer, e.g., a pH-sensitive polymer as described herein;

an agent (e.g., one or more therapeutic and/or or diagnostic agents (e.g., an AHCM, microenvironment modulator, other stromal modulator, and/or a cancer, anti-fibrotic, or anti-inflammatory therapy));

(optionally) a targeting moiety (e.g., a cell- or a liver-targeting agent); and

(optionally) one or more pegylated moieties or polymers,

(optionally) wherein the polymer, the agent and/or a targeting moiety, are coupled (e.g., covalently or noncovalently coupled via a linker, e.g., a pH-sensitive linker as described herein).

In some embodiments, the particle(s) or polymer-AHCM conjugate(s) can be used or disposed in implants or devices for local or systemic drug delivery. In some embodiments, the particle(s) or polymer-AHCM conjugate(s) can be embedded in hydrogels, e.g., for local or systemic drug delivery.

In any of the methods and uses described herein, the method or use further includes identifying the subject as being in need of improved delivery and/or efficacy of the therapy (e.g., the cancer therapy, or the anti-fibrotic or anti-inflammatory therapy). In some embodiments, the method includes identifying the subject as having a desmoplastic disorder (e.g., a cancer, or a fibrotic or inflammatory disorder). In some embodiments, the method includes identifying the subject as being overweight or obese, e.g., as having a BMI greater than 25. In yet other embodiments, the method further includes identifying the subject as having a metabolic disorder, e.g., a systemic metabolic disorder. In embodiments, responsive to said identification, administering one, two, or more of: (i) an AHCM (e.g., an ARB); (ii) a microenvironment modulator (e.g., an anti-angiogenic inhibitor) and/or other stromal modulators; or (iii) an immunomodulator. In one embodiment, the subject is a patient with a metastatic cancer, e.g., a metastatic form of a cancer disclosed herein (one or more of pancreatic (e.g., pancreatic adenocarcinoma), breast, colorectal, lung (e.g., small or non-small cell lung cancer), skin, ovarian, or liver cancer.

In one embodiment, the subject is a patient having treatment-resistant cancer or hyperproliferative disorder.

In one embodiment, the subject is, or is identified as being, overweight or obese. Assessment of overweight and obesity can be determined by the classification of body mass index (BMI) as defined by “Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults” from the National Institutes of Health. Body mass index is obtained by dividing a subject's weight, e.g., in kilograms (kg) by the square of the subject's height, e.g., in meters (m). Subjects with a BMI 18.5 to 24.9 are typically classified as normal weight, while subjects with a BMI 25.0 to 29.9 are classified as overweight. Subjects with a BMI 30.0 or greater are classified as obese, and can be subdivided into three classes: Class I (BMI=30.0 to 34.9; Class II (BMI=35.0 to 39.9); and Class III (BMI is greater or equal to 40).

In one embodiment, the subject is overweight, e.g., the subject has a BMI of greater than or equal to 25.0 but less than or equal to 29.9.

In another embodiment, the subject is, or is identified as being, obese, e.g., the subject has a BMI of greater than or equal to 30, e.g., greater than 30, greater than 35, greater than 40, greater than 45, or greater than 50.

Obesity can also be associated with one or more of: desmoplasia, e.g., in adipose tissues and the pancreas; dysfunctional adipocytes, e.g., hypertrophied adipocytes; increased hypoxia; fibrosis; accumulation of fat, e.g., steatosis; increased angiotensin II (AngII) type-1 receptor (AT1) signaling; and/or increased expression, production, and/or secretion of pro-inflammatory cytokines, e.g., interleukin-1beta (IL-1 beta).

In an embodiment, the subject is, or is identified as being, overweight or obese, and has a fibrotic or a hyperproliferative cancerous condition described herein. In an embodiment, the subject is, or is identified as being, overweight or obese and has a fibrotic disorder described herein. In an embodiment, the subject is, or is identified as being, overweight or obese and has a liver disorder or condition described herein.

In some embodiments, responsive to a determination of a weight/metabolic-related parameter indicative of normal or underweight (e.g., BMI value less than 25), performing one, two, three or more of:

(i) identifying the subject as being less likely to respond to the therapy, e.g., AHCM, microenvironment modulator, or other stromal therapy;

(ii) stratifying the subject, or a patient populations (e.g., stratifying the subject) as being less likely to respond (e.g., responders vs. non-responders) to the therapy, e.g., the metformin therapy and/or the AHCM therapy;

(iii) more effectively monitor the therapy, e.g., the metformin therapy and/or the AHCM therapy; or

(iv) discontinuing or not administering the metformin agent, alone or in combination with, one, two, three or more of: (i) an AHCM (e.g., an ARB); (ii) a microenvironment modulator (e.g., an anti-angiogenic inhibitor, e.g., a low-dose anti-angiogenic inhibitor) and/or other stromal modulators; (iii) an anti-inflammatory agent (e.g., a cytokine inhibitor); or (iv) an inhibitor of an immune checkpoint molecule.

Exemplary Particle Polymers and Linkers for Use in the Methods

In one embodiment, the particle administered comprises a polymer (e.g., any polymer disclosed herein, including a pH-sensitive polymer), a pH-sensitive linker (e.g., a pH-sensitive linker as described herein) and an agent (e.g., a therapeutic and/or diagnostic agent (e.g., an AHCM)) and/or the targeting moiety, e.g., each as described herein. In one embodiment, the polymer, the linker, the agent and/or the targeting moiety in the particle are coupled, e.g., covalently coupled, directly or indirectly.

In another embodiment, the particle administered comprises a pH-sensitive polymer, e.g., a pH sensitive polyacetal polymer as described herein, a linker (e.g., a pH-sensitive linker as described herein) and an agent (e.g., a therapeutic and/or diagnostic agent (e.g., an AHCM)) and/or the targeting moiety, as described herein. In one embodiment, the polymer, the linker, the agent and/or the targeting moiety in the particle are coupled, e.g., covalently coupled, directly or indirectly.

In one embodiment, the particle administered comprises an agent and/or a targeting moiety (e.g., as described herein), wherein one or both are directly coupled (e.g., covalently coupled) to the polyacetal polymer (e.g., a polymer that comprises the compound of Formula (I), Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d), Formula (I-e), or Formula (IV)). In another embodiment, the particle administered comprises an agent and/or a targeting moiety (e.g., as described herein), wherein one or both are noncovalently coupled (e.g., through an ionic or hydrophobic interaction) to the polyacetal polymer (e.g., a polymer that comprises the compound of Formula (I), Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d), Formula (I-e), or Formula (IV)). In yet another embodiment, the particle comprises an agent and/or targeting moiety (e.g., as described herein) coupled (e.g., covalently coupled or noncovalently coupled), via pH-sensitive linker (e.g., as described herein; an acetal monomer or a polyacetal polymer) to a second polymer (e.g., a polymer other than a polyacetal polymer).

In one embodiment, the particle administered does not include a targeting moiety (e.g., a cell- or a liver-targeting agent).

In another embodiment, the particle administered is selectively targeted or delivered to a target site. In one embodiment, the particle is delivered to a target site, e.g., via a targeting moiety (e.g., a cell- or liver-targeting agent). In one embodiment, the targeting moiety is chosen from one or more of a ligand, e.g., a cell surface receptor, a glycoprotein, a vitamin, cholesterol, an antibody or fragment thereof, a peptide, a protein, a lectin, an aptamer, a lipoprotein, a hormone, a charged molecule, a mono-, olio-, and polysaccharide, or low molecular weight ligands such as sugars, folic acids, and peptides. Exemplary targeting moieties are further described in detail herein, e.g., in the sections entitled “Targeting Moieties” and “Liver Targeting Moieties.”

In one embodiment, the method includes administering one, two, or all of AHCM, the microenvironment modulator, or the therapy (e.g., the cancer, fibrotic, immunomodulatory, or liver therapy), or any combination thereof, as a particle (e.g., any of the particles disclosed herein) having a hydrodynamic diameter of greater than about 1, 5, 10, 15, 20, 25, 30, 35, 45, 50, 75, 100, 150, 200 nm, but less than 300 nm, e.g., as a nanoparticle.

Additional features and embodiments of the compositions (e.g., conjugates and particles described herein) and methods disclosed herein include one or more of the following:

Agents

In certain embodiments, the compositions (e.g., conjugate or particles) and methods disclosed herein comprises at least one (including, e.g., at least two, at least three) agent(s), e.g., a therapeutic agent and/or a diagnostic agent, e.g., as described herein. The agent(s) can be coupled to the particle (e.g., as a conjugate as described herein). In other embodiments, the agent(s) can be contained non-covalently inside the particle. In some embodiments, a first agent can be coupled to the particle (e.g., as a conjugate as described herein), and a second agent can be contained non-covalently inside the particle.

In one embodiment, the agent is protein (e.g., an antibody molecule or fusion protein), a peptide, a nucleic acid molecule (e.g., an antisense or inhibitory double stranded RNA molecule), a small molecule, a chemotherapeutic agent or drug, among others. Any of the agents disclosed herein, including those listed in the section entitled “Agents” can be used in the conjugates, particles and other compositions and methods disclosed herein.

Exemplary embodiments of the agents that can be used in the conjugates, particles, other compositions and methods disclosed herein include one or more of the following:

Exemplary AHCMs for the Compositions and Methods Disclosed

In certain embodiments, the agent used in the compositions (e.g., conjugates and particles described herein) of the invention is an AHCM. The AHCM can be used a therapeutic or diagnostic agent. In some embodiments, the agent, e.g., the therapeutic and/or diagnostic agent, administered as a particle, conjugate, or as a free agent is an AHCM, e.g., an AHCM as described herein.

In one embodiment, the AHCM is chosen from one or more of:

an angiotensin II receptor type 1 blocker (AT 1 blocker or ARB),

an renin antagonist;

an antagonist of renin angiotensin aldosterone system (“RAAS antagonist”),

an angiotensin converting enzyme (ACE) inhibitor,

a thrombospondin 1 (TSP-1) inhibitor, e.g., a TSP-1 pathway inhibitor,

a transforming growth factor beta 1 (TGF-β1) inhibitor, e.g., a TGF-β1 pathway inhibitor,

a connective tissue growth factor (CTGF) inhibitor, e.g., a CTGF pathway inhibitor,

a stromal cell-derived growth factor 1 alpha (SDF-1a) inhibitor, e.g., an SDF-1a pathway inhibitor,

an endothelin receptor antagonist (ERA);

an agonist of angiotensin II receptor type 2 (AT 2 );

a vitamin D receptor (VDR) agonist; or

a combination of two or more of the above.

Unless the context describes otherwise, the term “AHCM” may refer to one or more agents as described herein.

The compositions and methods disclosed herein can include one, two, three or more AHCMs, alone or in combination with one or more therapies, e.g., cancer therapies or liver therapies disclosed herein.

In another embodiment, the AHCM is an AT 1 inhibitor. In an embodiment, the AT 1 blocker is chosen from one or more of: losartan (COZAAR®), candesartan (ATACAND®), eprosartan mesylate (TEVETEN®), EXP 3174, irbesartan (AVAPRO®), L158,809, olmesartan (BENICAR®), saralasin, telmisartin (MICARDIS®), valsartan (DIOVAN®), or an analogue or derivative thereof (e.g., a prodrug or a metabolite thereof), e.g., as shown in FIG. 23 .

In another embodiment, the AHCM is a vitamin D receptor (VDR) agonist.

Exemplary VDR agonists include, but are not limited to, paricalcitol, doxercalciferol, falecalcitriol, maxacalcitol, tacalcitol, alfacalcidol, eldecalcidol, seocalcitol, lexicalcitol, CD578, inecalcitol, calcipotriol, TX527, 2MD, WY1112, PRI-2205, ILX23-7553, ercalcitriol, EB1089 (seocalcitol), BXL-628 (elocalcitol), MC1288, CB966, BCB 1093, GS 1558, SM-10193, EB1072, EB1129, EB1133, EB1155, EB1270, MC1288, EB1213, CB1093, VD2656, VD2668, VD2708, VD2716, VD2728, VD2736, GS1500, GS1558, KH1060, ZK61422, and analogs and derivatives thereof, e.g., as shown in FIG. 24 , or molecules as described by Scolletta et al. (2013) Mediators of Inflammation 2013, Article ID 876319; and Adorini (2005) Cellular Immunology 233: 115-124.

The exemplary AHCMs are described herein are not limiting, e.g, derivatives of AHCMs described herein can be used in the methods described herein.

In an embodiment, an AHCM can modulate the microenvironment. Exemplary AHCMs that can modulate the microenvironment, e.g., by modulating collagen levels and/or changing the differentiation state of fibroblasts or stellate cells, include, but are not limited to, ARBs, VDR agonists, ERAs, and combinations thereof. In one embodiment, the AHCM (alone or in combination) enhances the efficacy, delivery and/or diffusion of a therapy.

Any of the AHCMs described herein can be prepared and used as a single agent (e.g., in free form, as a conjugate, or as a particle as described herein), or in combination, e.g., in combination with any of the agents described herein (e.g., a microenvironment modulator, other stromal modulator and/or any of therapies disclosed herein, each of which may be in free form, as a conjugate, or as a particle as described herein).

Additional description of the AHCMs is provided throughout, including the sections below entitled “Agents” and “AHCMs.” Any of the AHCMs disclosed herein, including those listed in the section entitled “Agents” and “AHCMs” can be used in the conjugates, particles, other compositions and methods disclosed herein.

Exemplary Microenvironment Modulators for the Compositions and Methods Disclosed

In other embodiments, the agent used in the compositions (e.g., conjugates and particles described herein) and methods of the invention is a microenvironment modulator. In another embodiment, the agent administered as a particle, conjugate, or as a free agent is a microenvironment modulator.

In an embodiment, a microenvironment modulator can alter the microenvironment by one or more of: modifying the level and/or production collagen, procollagen or extracellular matrix components; by modulating the crosslinking of matrix molecules; by altering the differentiation of fibroblast or stellate cells; and/or by having an anti-fibrotic effect. In one embodiment, the microenvironment modulator (alone or in combination) enhances the efficacy, delivery and/or diffusion of a therapy.

In one embodiment, the microenvironment modulator is chosen from one or more of an anti-angiogenic therapy, an agent that decreases the level or production of hyaluronic acid, an inhibitor of the hedgehog pathway, an agent that improves drug penetration in tumors (e.g., a disulfide-based cyclic RGD peptide (iRGD) or an analogue thereof), a taxane therapy, an agent that modulates (e.g, inhibits) a hypoxia inducible factor (HIF) (e.g., HIF-1α and HIF-2α), an agent that decreases the level or production of collagen or procollagen, an agent that modulates the crosslinking of matrix molecules, an agent that depletes or changes the differentiation state of fibroblasts or stellate cells, an anti-fibrotic agent (e.g., a pirfenidone (PFD, 5-methyl-1-phenyl-2-(1H)-pyridone); or a combination of two or more of the above.

In one embodiment, the microenvironment modulator is an anti-angiogenic agent. In one embodiment, the anti-angiogenic agent is chosen from a VEGF-inhibitor, an inhibitor of the angiopoietin-Tie-2 pathway (e.g., an Ang-1 or an Ang-2 inhibitor), or sorafenib. Examples of anti-angiopoietin/Tie-2 pathway agents (or inhibitors of the angiopoietin-Tie-2 pathway) include, but are not limited to, AMG 386, CVX-060, CVX-241, MEDI-3617, REGN910, AMG-780, CEP-1198, ARRY-614, MGCD265, Regorafenib, and combinations thereof. In one embodiment, the anti-angiogenic agent can be an inhibitor of tyrosine or Serine/Threonin kinases such as VEGFR, PDGFR, c-kit receptors, b-Raf, or combinations thereof. Additional examples of anti-angiogenic agents include, but are not limited to, agents that inhibit oncogene activation (e.g., anti-EGFR such as gefitinib; anti-HER2 such as Trastuzumab; anti-Pl3K-AKT-mTOR such as NVPBEZ235, Pl-103, Palomid-529, Nelfinavir; anti-Ras such as FTIs); agents that target androgens (e.g., Castration or endocrine therapy); agents that inhibits inflammatory cytokine-induced VEGF activation; anti-PlGF agents; anti-integrin agents (e.g., Cilengitide); agents that targets PHD2/HIF pathway; anti-Rgs5 agents; Ang-1 agonistic agents; SEMA3A/NRP-1 agonistic agents; PDGF-B agonistic agents; eNOS agonistic agents; PDGF-C agonistic agents; PDGF-D agonistic agents, IFN-β agonistic agents; TSP-1 agonistic agents; anti-TNFα/TNFR agents; anti-TGFβ/TGFR agents; anti-VE-PTP agents; anti-MMP agents (e.g., anti-MMP-2; anti-MMP-9; anti-MMP-14); WNT agonistic agents; extracellular matrix-inducing agents (e.g., fibronectin; laminin; netrin-1; thrombospondin 1, etc.); Notch1 agonistic agents; Frizzled agonistic agents; and a combination of two or more thereof.

Any of the microenvironment modulators described herein can be used as a single agent (e.g., in free form, as a conjugate, or as a particle as described herein), or in combination, e.g., in combination with any of the agents described herein (e.g., an AHCM, other stromal modulator and/or any of the therapies disclosed herein, each of which may be in free form, as a conjugate, or as a particle as described herein).

Additional description of the microenvironment modulators is provided throughout, including the section below entitled “Microenvironment Modulators.” Any of the microenvironment modulators disclosed herein, including those listed in the section entitled “Microenvironment Modulators” can be used in the conjugates, particles, other compositions and methods disclosed herein.

Exemplary Other Stromal Modulators for the Compositions and Methods Disclosed

In other embodiments, the agent used in the compositions (e.g., conjugates and particles described herein) and methods of the invention is a stromal modulator (other than a microenvironment modulator as described herein, referred to herein as “other stromal modulator”). In one embodiment, the other stromal modulator modulates healing and/or the matrix/stromal cell microenvironment. In some embodiments, the agent, e.g., the therapeutic and/or diagnostic agent, administered as a particle, conjugate, or as a free agent is the other stromal modulator.

In one embodiment, the other stromal modulator is chosen from an inhibitor of a receptor for a VEGF ligand (e.g., a Flt-1, -2, and/or -3 receptor), an inhibitor of an FGF receptor, a c-Met/HGF receptor inhibitor, a TNFR inhibitor, a cytokine/cytokine receptor inhibitor, a JAK/STAT3 inhibitor, an Osteopontin (SPP1) modulator, a Bone morphogenic protein (BMPs) inhibitor, an inhibitor of FAK, a CSF-1R inhibitor, a c-Kit inhibitor, DDR1 inhibitor, a metabolic inhibitor, and/or a mitochondrial inhibitor.

Any of the other stromal modulators disclosed herein, including those listed in the section entitled “Other Stromal Modulator,” can be used in the conjugates, particles, other compositions and methods disclosed herein. Any of the other stromal modulators described herein can be used as a single agent (e.g., in free form, as a conjugate, or as a particle as described herein), or in combination, e.g., in combination with any of the agents described herein (e.g., an AHCM, a microenvironment modulator, and/or any of the therapies disclosed herein, each of which may be in free form, as a conjugate, or as a particle as described herein).

Anti-Cancer Agents

In other embodiments, the agent used in the compositions (e.g., conjugates and particles described herein) and methods of the invention is a small molecule (e.g., a kinase inhibitor). In some embodiments, the agent, e.g., therapeutic agent, administered as a particle, conjugate, or as a free agent is an anti-cancer agent.

In some embodiments, the agent, e.g., the therapeutic agent, in the conjugate is an anti-cancer agent. In some embodiments, the anti-cancer agent is a small molecule, a kinase inhibitor, an alkylating agent, a vascular disrupting agent, a microtubule targeting agent, a mitotic inhibitor, a topoisomerase inhibitor, an anti-angiogenic agent, or an anti-metabolite. In one embodiment, the agent, e.g., the therapeutic agent, is a taxane (e.g., paclitaxel, docetaxel, larotaxel or cabazitaxel). In some embodiments, the anti-cancer agent is an anthracycline (e.g., doxorubicin). In some embodiments, the anti-cancer agent is a platinum-based agent (e.g., cisplatin or oxaliplatin). In some embodiments, the anti-cancer agent is a pyrimidine analog (e.g., gemcitabine). In some embodiments, the anti-cancer agent is chosen from camptothecin, irinotecan, rapamycin, FK506, 5-FU, leucovorin, or a combination thereof. In other embodiments, the anti-cancer agent is a protein biologic (e.g., an antibody molecule), or a nucleic acid therapy (e.g., an antisense or inhibitory double stranded RNA molecule).

Additional examples of anti-cancer agents are disclosed herein, see e.g., the section entitled “Agents.” Any of the anti-cancer agents disclosed herein, including those listed in the section entitled “Agents” can be used in the conjugates, particles and other compositions disclosed herein.

Immunomodulators

In some embodiments, the agent, e.g., therapeutic agent, administered as a particle or as a free agent is an immune modulator (e.g., one or more of: an activator of a costimulatory molecule, an inhibitor of an immune checkpoint molecule, or an anti-inflammatory agent).

In certain embodiments, the immunomodulator is an inhibitor of an immune checkpoint molecule (e.g., an inhibitor of PD-1, PD-L1, LAG-3, TIM-3 or CTLA4, or any combination thereof).

In some embodiments, the immunomodulator is a cancer vaccine.

In some embodiments, the immunomodulator is an anti-inflammatory agent, e.g., an anti-inflammatory agent as described herein.

In certain embodiments, the immunomodulator administered as a particle, conjugate, or as a free agent is an activator of a costimulatory molecule. In one embodiment, the agonist of the costimulatory molecule is chosen from an agonist (e.g., an agonistic antibody or antigen-binding fragment thereof, or a soluble fusion) of OX40, OX40L, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, GITRL, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD73, CD160, B7-H3 or CD83 ligand.

In certain embodiments, the immunomodulator administered as a particle or as a free agent is an inhibitor of an immune checkpoint molecule. In one embodiment, the immunomodulator is an inhibitor of PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD73, CD160, 2B4 and/or TGFR beta. In one embodiment, the inhibitor of an immune checkpoint molecule inhibits PD-1, PD-L1, LAG-3, TIM-3 or CTLA4, or any combination thereof. Inhibition of an inhibitory molecule can be performed at the DNA, RNA or protein level. In some embodiments, an inhibitory nucleic acid (e.g., a dsRNA, siRNA or shRNA), can be used to inhibit expression of an inhibitory molecule. In other embodiments, the inhibitor of an inhibitory signal is, a polypeptide e.g., a soluble ligand (e.g., PD-1-Ig or CTLA-4 Ig), or an antibody or antigen-binding fragment thereof, that binds to the inhibitory molecule; e.g., an antibody or fragment thereof that binds to PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD73, CD160, 2B4 and/or TGFR beta, or a combination thereof.

In certain embodiments, the immunomodulator administered as a particle or as a free agent is an anti-inflammatory agent.

In one embodiment, the anti-inflammatory agent is an agent that blocks, inhibits, or reduces inflammation or signaling from an inflammatory signaling pathway. In one embodiment, the anti-inflammatory agent inhibits or reduces the activity of one or more of any of the following: IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-18, IL-23, interferons (IFNs), e.g., IFNα, IFNβ, IFNγ, IFN-γ inducing factor (IGIF), transforming growth factor-β (TGF-β), transforming growth factor-α (TGF-α), tumor necrosis factors TNF-α, TNF-β, TNF-RI, TNF-RII, CD23, CD30, CD40L, EGF, G-CSF, GDNF, PDGF-BB, RANTES/CCL5, IKK, NF-kB, TLR2, TLR3, TLR4, TL5, TLR6, TLR7, TLR8, TLR8, TLR9, and/or any cognate receptors thereof.

In one embodiment, the anti-inflammatory agent is an IL-1 or IL-1 receptor antagonist, such as anakinra (KINERET®), rilonacept, or canakinumab.

In one embodiment, the anti-inflammatory agent is an IL-6 or 1-6 receptor antagonist, e.g., an anti-IL-6 antibody or an anti-IL-6 receptor antibody, such as tocilizumab (ACTEMRA®), olokizumab, clazakizumab, sarilumab, sirukumab, siltuximab, or ALX-0061.

In one embodiment, the anti-inflammatory agent is a TNF-α antagonist, e.g., an anti-TNFα antibody, such as infliximab (REMICADE®), golimumab (SIMPONI®), adalimumab (HUMIRA®), certolizumab pegol (CIMZIA®) or etanercept.

In one embodiment, the anti-inflammatory agent is a corticosteroid, e.g., as described herein.

In some embodiments, the immunomodulator can be covalently conjugated to the AHCM, and/or polymer-AHCM conjugate(s). In some embodiments, the immunomodulator can be covalently conjugated to the surface of a particle described herein comprising AHCM. In some embodiments, the immunomodulator can be linked to AHCM, polymer-AHCM conjugate(s) or AHCM particle(s) via one or more physical or chemical bondage(s), such as covalent bond, hydrogen bond, van der Waals interaction, hydrophobic interaction, electron donor-electron recipient interaction, host-guest interaction (e.g., but not limited to, biotin to avidin, or interaction between nucleobases).

Targeting Moieties for the Compositions and Methods Disclosed

In certain embodiments, any of the particles and conjugates disclosed herein, including pH-sensitive and/or polyacetal particles and conjugates, comprise a targeting moiety, e.g., a targeting moiety that is specific to a cell type. To target a specific cell, a targeting moiety or ligand can be coupled, e.g., covalently or non-covalently, to a component of a particle or a conjugate, e.g., a particle or conjugate as described herein. The targeting moiety or ligand specifically can bind to a receptor or surface molecule at the surface membrane of the targeted cell, and thus deliver the particle or conjugated to the targeted cell. In some embodiments, the targeting moiety or ligand can impart therapeutic activity by transferring said polymer, conjugate, or particle (e.g., a polymer, conjugate, or particle as described herein) across cellular membranes, altering the pharmacokinetics, and/or modulating the localization of the polymer, conjugate, or particle (e.g., a polymer, conjugate, or particle as described herein).

In one embodiment, the targeting moiety is a hydrophilic polymer, e.g., PEG.

In other embodiments, the targeting moiety is chosen from one or more of a ligand, e.g., a cell surface receptor, a glycoprotein, a vitamin, cholesterol, an antibody or fragment thereof, a peptide, a protein, a lectin, an aptamer, a lipoprotein, a hormone, a nucleic acid, a charged molecule, a mono-, olio-, and polysaccharide, or low molecular weight ligands such as sugars, folic acids, and peptides. In some embodiments, the targeting moiety is a sugar, e.g., mannose, mannosamine, mannuronic acid, galactose, galactosamine, galactosuronic acid, glucose, glucosamine, glucuronic acid, fucose, fucosamine, or sialic acid. In some embodiments, the targeting moiety is a polymer comprising several sugars, e.g., a disaccharide, trisaccharide, oligosaccharide, or polysaccharide. In some embodiments, the sugar or polymer of sugars comprises a derivatized or modified sugar, e.g., a phosphorylated sugar, e.g., mannose-6-phosphate or glucosamine 1-phosphate. Exemplary targeting moieties are further described in detail herein, e.g., in the sections entitled “Targeting Moieties” and “Liver Targeting Moieties.”

Exemplary Disorders and Conditions

In certain embodiments, the disorder treated with the compositions and methods disclosed herein is chosen from one or more of a hyperproliferative disorder, a cancer (e.g., a solid or fibrotic cancer), a fibrotic disorder or condition, an inflammatory disorder or condition, or an autoimmune disorder.

In one embodiment, the disorder, e.g., a cancer, treated is an epithelial, a mesenchymal or a hematologic malignancy. In an embodiment, the cancer treated is a solid tumor (e.g., carcinoid, carcinoma or sarcoma), a soft tissue tumor (e.g., a heme malignancy), and a metastatic lesion, e.g., a metastatic lesion of any of the cancers disclosed herein.

In one embodiment, the cancer treated is a fibrotic or desmoplastic solid tumor, e.g., a tumor having one or more of: limited tumor perfusion, compressed blood vessels, high interstitial fluid pressure (IFPs), or fibrotic tumor interstitium.

In one embodiment, the solid tumor is chosen from one or more of pancreatic (e.g., pancreatic adenocarcinoma (e.g., pancreatic ductal adenocarcinoma (PDA or PDAC)), breast, gastric, colorectal, lung (e.g., small or non-small cell lung cancer), skin, ovarian, prostate, or liver cancer. Additional examples of cancers treated are described herein below.

In certain embodiments, the cancer treated contains (e.g., has elevated levels of) extracellular matrix components, such as fibers (e.g., collagen, procollagen) and/or polysaccharides (e.g., glycosaminoglycans such as hyaluronan or hyaluronic acid). The levels of the extracellular matrix components in the cancer can vary depending on the particular cancer type, the stage of malignancy, and/or in response to cancer therapy. For example, certain cancer may show elevated levels of extracellular matrix components in response to chemotherapy and/or radiation. In such cancers, the AHCM alone, or in combination with the microenvironment modulator, can be administered (as a particle or free agent) at any time before, during or after the cancer therapy.

In one embodiment, the cancer or tumor treated is a solid, fibrotic tumor chosen from one or more of pancreatic (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), breast, colorectal, colon, lung (e.g., small or non-small cell lung cancer), skin, ovarian, prostate, cervix, gastrointestinal (e.g., carcinoid or stromal), stomach, head and neck, kidney, brain cancer or liver cancer (e.g. HCC), or a metastatic lesion thereof. Additional examples of cancers treated are described herein below.

In one embodiment, the disorder is fibrotic or desmoplastic solid tumor, e.g., a tumor having one or more of: limited tumor perfusion, compressed blood vessels, high interstitial fluid pressure (IFPs), or fibrotic tumor interstitium. In certain embodiments, the subject has a tumor having (e.g., elevated levels of) extracellular matrix components, such as fibers (e.g., collagen, procollagen) and/or polysaccharides (e.g., glycosaminoglycans such as hyaluronan or hyaluronic acid). The levels of the extracellular matrix components in the tumor can vary depending on the particular cancer type, the stage of malignancy, and/or in response to cancer therapy. For example, certain tumors may show elevated levels of extracellular matrix components in response to chemotherapy and/or radiation. In such cancers, the AHCM alone or in combination with the microenvironment modulator can be administered at any time before, during or after the cancer therapy.

In certain embodiments, the disorder is chosen from one or more of a hyperproliferative disorder, a cancer, a fibrotic disorder or condition, an inflammatory disorder or condition, or an autoimmune disorder.

In one embodiment, the disorder is a hyperproliferative disorder, e.g., a hyperproliferative connective tissue disorder (e.g., a hyperproliferative fibrotic disease). In one embodiment, the fibrotic (e.g., hyperproliferative fibrotic) disease is multisystemic or organ-specific. Exemplary fibrotic diseases include, but are not limited to, multisystemic (e.g., systemic sclerosis, multifocal fibrosclerosis, sclerodermatous graft-versus-host disease in bone marrow transplant recipients, nephrogenic systemic fibrosis, scleroderma), and organ-specific disorders (e.g., fibrosis of the lung, liver, heart, kidney, pancreas, skin and other organs). In other embodiments, the fibrotic disease is chosen from liver fibrosis (e.g., liver cirrhosis. NASH, and other conditions described herein), pulmonary fibrosis, renal fibrosis, fibrosis of the bone marrow (e.g., myelofibrosis), and the like.

In other embodiments, the disorder is a fibrotic condition or disorder as described herein in the sections entitled “Treatment of Fibrotic Conditions or Disorder” in the Summary and Detailed Description below.

In other embodiment, the disorder is a hyperproliferative genetic disorder, e.g., a hyperproliferative genetic disorder chosen from Marfan's syndrome or Loeys-Dietz syndrome.

In other embodiments, the hyperproliferative disorder (e.g., the hyperproliferative fibrotic disorder) is chosen from one or more of chronic obstructive pulmonary disease, asthma, aortic aneurysm, radiation-induced fibrosis, skeletal-muscle myopathy, diabetic nephropathy, and/or arthritis.

In other embodiments, the disorder is a liver condition or disorder as described in the sections entitled “Treatment of Liver Conditions or Disorder” in the Summary and Detailed Description below.

In one embodiment, disorder is an inflammatory condition or disorder, e.g., as described herein. In one embodiment, the inflammatory disorder is osteomyelitis, e.g., chronic osteomyelitis.

Additional examples of disorders, therapies and combination therapies that can be used in the compositions and methods of the invention are provided throughout, including the sections entitled “Therapeutic Methods,” “Disorders,” “Combination Therapies,” “Cancer Therapies,” Treatment of Liver Disorders” and “Combination Therapies for Treatment of Liver Disorders” in the Summary and Detailed Description provided herein below.

Treatment of Fibrotic or Liver Conditions or Disorders

In other embodiments, the disorder or condition treated using the methods and compositions disclosed herein is a fibrotic or liver disorder or condition. In one embodiment, the fibrotic disorder is a liver disorder. In one embodiment, two or more of an AHCM, the microenvironment modulator, other stromal modulator, and/or a fibrotic or liver disorder therapy (e.g., as described herein) are administered to a subject.

In one embodiment, at least one, two, three or all of the AHCM, the microenvironment modulator, other stromal modulator or a therapy is administered as a particle (e.g., a pH-sensitive particle disclosed herein). In one embodiment, one, two, three or more of the AHCM, microenvironment modulator, other stromal modulator or therapy is provided in a non-targeted particle or a liver-targeted particle. Any particle disclosed herein can be used in these methods including a polymeric particle or a lipid particle.

In one embodiment, the polymeric particle administered comprises a polymer chosen from one or more of: (i) polysaccharides, polypeptides, polyacetals, polyketals, polyanhydrides, polyhydroxybutyric acid, polyorthoesters, polysiloxanes, polycaprolactone, poly(lactic-co-glycolic acid), poly(lactic acid), poly(glycolic acid), and copolymers or block polymers prepared from the monomers of these polymers; or (ii) a pH-sensitive polymer or monomer as described herein; or (iii) any combinations of (i) and (ii).

In one embodiment, the polymeric particle administered comprises a polymer chosen from one or more of: poly(lactic acid)-b-poly(ethylene glycol) (PLA-PEG), poly(lactic acid)-b-poly(ethylene glycol) (PLGA-PEG), dextran, (cyclodextrin)-co-poly(ethylene glycol) (CDP), or a pH-sensitive polymer or monomer as described herein; or any combination thereof.

In one embodiment, the AHCM is provided in a particle, e.g., a targeted (e.g., liver) targeted or a particle without a specific targeting moiety, or a non-targeted particle (e.g., any particle disclosed herein). In one embodiment, the particle is a pH-sensitive and/or polyacetal particle, e.g., comprises a pH-sensitive and/or polyacetal polymer and/or a linker as described herein. In other embodiments, the particle comprises a poly-acetal-agent and a targeting moiety (e.g., a targeting moiety as described herein).

In one embodiment, the targeting moiety is a mannose-6-phosphate (M6P). Exemplary conjugates include losartan, a polymer (with or without a linker) and M6P as a targeting moiety (e.g., as depicted in FIGS. 5A-5D ). In one embodiment, the conjugate has the structure depicted in FIG. 5B . In other embodiments, the conjugate has the structure depicted in FIG. 5C and/or FIG. 5D . In such embodiments, the microenvironment modulator and/or a liver disorder therapy can be administered as a free agent.

In one embodiment, the microenvironment modulator, other stromal modulator and/or a fibrotic or liver disorder therapy is provided in a particle, e.g., a liver targeted or non-targeted particle (e.g., any particle disclosed herein). In one embodiment, the particle is a pH-sensitive and/or polyacetal particle, e.g., comprises a pH-sensitive and/or polyacetal polymer and/or linker as described herein. In such embodiments, the AHCM is provided as a free agent.

In certain embodiments, the combination of two or all of the AHCM, microenvironment modulator, or a liver disorder therapy is administered in an amount to cause one or more of: increase hepatic perfusion; increase vascular or sinusoidal diameter; increase hepatic vasculature; decrease the level or production of extracellular matrix proteins (e.g., area or deposition of ECM components); decrease the level or production of collagen; decrease hypoxia in the liver; decrease portal pressure; decrease hepatic inflammation (e.g., decrease ALT production or level); increase hepatic synthesis (e.g., albumin production or level), thereby enhancing the penetration and/or distribution of the liver disorder therapy.

Vascular/Stromal Normalizing Doses

In another aspect the invention features a method for treating or preventing a fibrotic or a liver disorder or condition in a subject. The method includes administering to the subject an AHCM (e.g., an AHCM as disclosed herein) and a vascular/stromal normalizing dose (e.g., a sub-anti-angiogenic dose) of a second agent, e.g., a second agent chosen from one or more of: a microenvironment modulator, an other stromal modulator, an anti-angiogenic agent, sorafenib, a sorafenib similarly-targeted pathway modulator, or an inhibitor of the angiopoietin-Tie-2 pathway (e.g., an Ang-1 or an Ang-2 inhibitor), thereby treating or preventing the liver disorder or condition.

In one embodiment, one, two, or more of the AHCM, or the second agent is provided in a particle, e.g., a liver targeted or non-targeted particle (e.g., any particle disclosed herein).

In one embodiment, the AHCM is provided in a particle, e.g., a liver targeted or non-targeted particle (e.g., any particle disclosed herein), and the second agent is administered as a free agent (e.g., non-conjugated soluble agent). In one embodiment, the particle is a pH-sensitive particle, e.g., comprises a pH-sensitive and/or polyacetal polymer and/or a linker as described herein.

In one embodiment, the second agent is chosen from one or more of: anti-angiogenic agent, sorafenib, an inhibitor of the angiopoietin-Tie-2 pathway (e.g., an Ang-1 or an Ang-2 inhibitor), a microenvironment modulator, or an other stromal modulator, or a combination thereof. In one embodiment, the second agent is provided in free form, as a conjugate, or as a particle as described herein (e.g., a liver targeted or non-targeted particle (e.g., any particle disclosed herein)). In one embodiment, the particle is a pH-sensitive and/or polyacetal particle, e.g., comprises a pH-sensitive and/or polyacetal polymer and/or linker as described herein. In one embodiment, said second agent is administered at a dose or dosage formulation that is less than 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, that of the standard of care dose.

In one embodiment, the second agent is chosen from an inhibitor of tyrosine or Ser/Thr kinase chosen from VEGFR, PDGFR, c-kit receptors, or b-Raf In one embodiment, the second agent is provided in free form, as a conjugate, or as a particle as described herein (e.g., a liver targeted or non-targeted particle (e.g., any particle disclosed herein)). In one embodiment, the particle is a pH-sensitive and/or polyacetal particle, e.g., comprises a pH-sensitive and/or polyacetal polymer and/or linker as described herein. In one embodiment, said second agent is administered at a dose or dosage formulation that is less than 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, that of the standard of care dose.

In one embodiment, the administration of the AHCM and the second agent is provided in an amount sufficient to result in one, two, three, four, five, six, seven, eight, nine, ten, eleven or more of: (i) inhibition of the hepatic renin angiotensin system; (ii) reduction in fibrosis and/or collagen deposition; (iii) increase in hepatic vascular function; (iv) repair of hepatic blood vessels; (v) increase in vascular normalization; (vi) reduction in pore size; (vii) reduction in hypoxic tissue; (viii) increase in perfusion of the diseased liver tissue; (ix) increase in agent delivery; (x) improvement of stromal signaling; (xi) improvement of or normalization of angiocrine signaling; or (xii) reduction of hepatic inflammation (e.g., as detected by plasma ALT levels), in the diseased (e.g., cirrhotic) liver.

In one embodiment, the second agent is administered at a vascular/stromal normalizing dose. A vascular/stromal normalizing dose can have an angiogenic effect. In one embodiment, the vascular/stromal normalizing dose of the second agent results in one or more of: (i) increase in hepatic vascular function; (ii) repair of hepatic blood vessels; (iii) increase in vascular normalization; (iv) reduction in pore size; (v) reduction in hypoxic tissue; (vi) increase in perfusion of the diseased liver tissue; (vii) restoration of agent delivery; (viii) improved stromal signaling; or (ix) improved or normalized angiocrine signaling. In one embodiment, the effect of the “vascular/stromal normalizing” is detected by one or more of: angiography imaging, immunostaining of level of hypoxia (e.g., using pimonidazol-FITC), increased sinusoidal perfusion, or increased stromal/angiocrine signaling, e.g., as shown in the appended Examples.

In an embodiment, the liver disorder is a fibrotic disorder or connective tissue disorder affecting the function or physiology of the liver. In one embodiment, the fibrotic disorder or connective tissue disorder can be systemic (affecting the whole body), multi-organ, or organ-specific (e.g., liver-specific). Examples of fibrotic liver disorders include, but are not limited to, liver fibrosis (hepatic fibrosis), liver cirrhosis, and any disorder associated with accumulation of extracellular matrix proteins, e.g., collagen, in the liver, liver scarring, and/or abnormal hepatic vasculature. In one embodiment, the liver disorder is liver cirrhosis. Liver cirrhosis is considered to be an end stage of liver fibrosis, involving regenerative nodules (as a result of repair processes), and is typically accompanied with the distortion of the hepatic vasculature.

In other embodiments, the liver disorder is a liver cancer. Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (HCC), primary liver cell carcinoma, hepatoma, fibrolamellar carcinoma, focal nodular hyperplasia, cholangiosarcoma, intrahepatic bile duct cancer, angiosarcoma or hemangiosarcoma, hepatic adenoma, hepatic hemangiomas, hepatic hamartoma, hepatoblastoma, infantile hemangioendothelialoma, mixed tumors of the liver, tumors of mesenchymal tissue, and sarcoma of the liver. Liver cancers can also be associated with metastasis of non-liver cancers, such as breast cancer, colorectal cancer, esophageal cancer, kidney or renal cancer, lung cancer, ovarian cancer, pancreatic cancer, rectal cancer, skin cancer (e.g., melanoma), gastric or stomach cancer (including gastrointestinal cancer), and uterine cancer. In one embodiment, the liver disorder is HCC.

In certain embodiments, the liver disorder or condition is caused by one or more insults including, but not limited to, liver inflammation or damage; viral (e.g., chronic viral) infection (e.g., hepatitis B, hepatitis C virus, hepatitis A virus, hepatitis D virus (hepatitis delta virus), hepatitis E virus, Epstein-Barr adenovirus, or cytomegalovirus; or parasitic infection, such as schistosomiasis); alcoholism; fatty liver disease; metabolic disorders (e.g., hemachromatosis, diabetes, obesity, hypertension, dyslipidemia, galactosemia, or glycogen storage disease); autoimmune disorders (e.g., autoimmune hepatitis (AIH), autoimmune liver disease, lupoid hepatitis, systemic lupus erythematosus, primary biliary cirrhosis (PBC), scleroderma, or systemic scerlosis); inflammatory liver disorders (e.g., steatohepatitis, primary sclerosing cholangitis (PSC), ulcerative colitis, Crohn's disease, inflammatory bowel disease); inherited or congenital liver disease (e.g., Wilson's disease, Gilbert's disease, Byler syndrome, Greenland-Eskimo familial cholestasis, Zellweger's syndrome, Alagilles syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), alpha 1-antitrypsin deficiency, cystic fibrosis, Indian childhood cirrhosis, or hereditary hemochromatosis); and liver injury (e.g., drug toxicity, alcoholism, ischemia, malnutrition, or physical trauma).

In one embodiment, the liver disorder is fatty liver (or FLD), alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, simple steatosis, Reye's syndrome, and any disorder associated with abnormal retention of lipids in liver cells.

Additional examples of liver disorders that can be treated by the methods and compositions of the invention are provided throughout, including the section entitled “Treatment of Liver Conditions or Disorders.”

Treatment of Fibrotic Conditions or Disorders

In another aspect, the invention features a method of treating or preventing a fibrotic condition or disorder in a subject. The method includes administering a composition described herein (e.g., one or more of: a particle or conjugate as described; an AHCM and/or microenvironment modulator in free form or as a conjugate or particle), as a single agent or in combination with another agent or therapeutic modality, to a subject in need thereof, in an amount sufficient to decrease or inhibit the fibrotic condition in the subject.

In certain embodiments, reducing fibrosis, or treatment of a fibrotic condition, includes reducing or inhibiting one or more of: formation or deposition of tissue fibrosis; reducing the size, cellularity (e.g., fibroblast or immune cell numbers), composition; or cellular content, of a fibrotic lesion; reducing the collagen or hydroxyproline content, of a fibrotic lesion; reducing expression or activity of a fibrogenic protein; reducing fibrosis associated with an inflammatory response; decreasing weight loss associated with fibrosis; or increasing survival.

In certain embodiments, the fibrotic condition is primary fibrosis. In one embodiment, the fibrotic condition is idiopathic. In other embodiments, the fibrotic condition is associated with (e.g., is secondary to) a disease (e.g., an infectious disease, an inflammatory disease, an autoimmune disease, a malignant or cancerous disease, and/or a connective disease); a toxin; an insult (e.g., an environmental hazard (e.g., asbestos, coal dust, polycyclic aromatic hydrocarbons), cigarette smoking, a wound); a medical treatment (e.g., surgical incision, chemotherapy or radiation), or a combination thereof.

In certain embodiments, the fibrotic condition is a fibrotic condition of the lung, a fibrotic condition of the liver (e.g., as described herein), a fibrotic condition of the heart or vasculature, a fibrotic condition of the kidney, a fibrotic condition of the skin, a fibrotic condition of the gastrointestinal tract, a fibrotic condition of the bone marrow or a hematopoietic tissue, a fibrotic condition of the nervous system, a fibrotic condition of the eye, an inflammatory fibrotic condition, or a combination thereof.

Additional examples of fibrotic disorders or conditions that can be treated with the compositions and methods described herein are provided herein in the section entitled “Treatment of Fibrotic Conditions or Disorders.”

Subjects

The compositions and methods described herein can be used to treat subjects having characteristics or needs defined herein. In some embodiments a subject, or a treatment for a subject, is selected on the basis of a characteristic described herein. In one embodiment, the methods described herein allow optimized selection of patients and therapies. In some embodiments, subjects can be selected or identified prior to subjecting them to any aspects of the methods described herein.

In one embodiment, the subject is selected, or is identified, as being in need of receiving the AHCM and/or the microenvironment modulator on the basis of optimizing a therapy, e.g., the need for improved delivery and/or efficacy of the therapy (e.g., the cancer or liver therapy).

In one embodiment, the subject does not have hypertension, or is not being treated for hypertension, at the time of initiation of the AHCM treatment, or at the time of selection of the patient for AHCM administration.

In an embodiment, the subject, e.g., patient, has not been administered a dose of an AHCM, e.g., an AHCM named herein, or any AHCM, within 5, 10, 30, 60 or 100 days of, the diagnosis of the disorder, e.g., the cancer or liver disorder, or the initiation of the AHCM dosing.

In an embodiment, the subject, e.g., a subject with normal or low blood pressure, is selected or is identified on the basis of being in need of an AHCM and/or the microenvironment modulator, e.g., is selected or is identified as being in need of receiving the AHCM and/or the microenvironment modulator on the basis of optimizing a therapy, e.g., the need for improved delivery and/or efficacy of the therapy (e.g., the cancer therapy).

In some embodiments, subjects who are in need of receiving the AHCM and/or the microenvironment modulator on the basis of the need for improved delivery or efficacy of the cancer therapy, or optimizing the therapy, are the subjects who partially respond or do not respond to the cancer therapy alone.

In an embodiment, an AHCM and/or the microenvironment modulator is selected for treating a subject, on the basis of its ability to optimize a treatment, e.g., a cancer treatment, e.g., improving delivery and/or efficacy of the therapy, e.g., the cancer therapy.

In one embodiment, the subject is in need of cancer or liver therapy. In another embodiment, the subject is in need of, or being considered for, anti-cancer or liver therapy (e.g., treatment with any of the anti-cancer or liver therapeutics described herein). In certain embodiments, the method includes the step of determining if the subject has a cancer or a liver disorder, and, responsive to said determination, administering the AHCM and/or the microenvironment modulator, and the agent (e.g., an anti-fibrotic therapy).

In other embodiments, the subject is at risk of developing, or having a recurrence of, a cancer, e.g., a subject with pre-neoplasia or a genetic pre-disposition for cancer (e.g., a subject having a BRCA1 mutation; or a breast cancer patient treated with in an adjuvant setting (e.g., with tamoxifen).

In other embodiments, the subject has early-cancer, or more progressive (e.g., moderate), or metastatic cancer.

In one embodiment, the subject has a solid, fibrotic tumor chosen from one or more of pancreatic (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), breast, colorectal, colon, lung (e.g., small or non-small cell lung cancer), skin, ovarian, prostate, cervix, gastrointestinal (e.g., carcinoid or stromal), stomach, head and neck, kidney, or liver cancer, or a metastatic lesion thereof. Additional examples of cancers treated are described herein below.

In one embodiment, the subject has a fibrotic or desmoplastic solid tumor, e.g., a tumor having one or more of: limited tumor perfusion, compressed blood vessels, high interstitial fluid pressure (IFPs), increased hypoxia, or fibrotic tumor interstitium. In certain embodiments, the subject has a tumor having (e.g., elevated levels of) extracellular matrix components, such as fibers (e.g., collagen, procollagen) and/or polysaccharides (e.g., glycosaminoglycans such as hyaluronan or hyaluronic acid). The levels of the extracellular matrix components in the tumor can vary depending on the particular cancer type, the stage of malignancy, and/or in response to cancer therapy. For example, certain tumors may show elevated levels of extracellular matrix components in response to chemotherapy and/or radiation. In such cancers, the AHCM alone or in combination with the microenvironment modulator can be administered at any time before, during or after the cancer therapy. In an embodiment, the fibrotic or desmoplastic solid tumor is PDAC.

In other embodiments, the subject has a hyperproliferative cancerous condition (e.g., a benign, pre-malignant or malignant condition). The subject can be one at risk of having the disorder, e.g., a subject having a relative afflicted with the disorder, or a subject having a genetic trait associated with risk for the disorder. In one embodiment, the subject can be symptomatic or asymptomatic. In an embodiment, the subject harbors an alteration in an oncogenic gene or gene product. In an embodiment, the subject is a patient who is undergoing cancer therapy (e.g., the same or other anti-cancer agents, surgery and/or radiation). In an embodiment, the subject is a patient who has undergone cancer therapy (e.g., other anti-cancer agents, surgery and/or radiation). In one embodiment, the subject has not been treated with the cancer therapy.

In one embodiment, the subject is a patient with a metastatic cancer, e.g., a metastatic form of a cancer disclosed herein (one or more of pancreatic (e.g., pancreatic adenocarcinoma), breast, colorectal, lung (e.g., small or non-small cell lung cancer), skin, ovarian, or liver cancer.

In one embodiment, the subject is a patient having treatment-resistant cancer or hyperproliferative disorder.

In one embodiment, the subject is, or is identified as being, overweight or obese.

In one embodiment, the subject is normal weight, e.g., the subject has a BMI of greater than or equal to 18.5 but less than or equal to 24.9.

In one embodiment, the subject is overweight, e.g., the subject has a BMI of greater than or equal to 25.0 but less than or equal to 29.9.

In another embodiment, the subject is, or is identified as being, obese, e.g., the subject has a BMI of greater than or equal to 30, e.g., greater than 30, greater than 35, greater than 40, greater than 45, or greater than 50. Obesity can also be associated with one or more of: desmoplasia, e.g., in adipose tissues and the pancreas; dysfunctional adipocytes, e.g., hypertrophied adipocytes; increased hypoxia; fibrosis; accumulation of fat, e.g., steatosis; increased angiotensin II (AngII) type-1 receptor (AT1) signaling; and/or increased expression, production, and/or secretion of pro-inflammatory cytokines, e.g., interleukin-1β (IL-1β).

In an embodiment, the subject is, or is identified as being, overweight or obese, and has a fibrotic or a hyperproliferative cancerous condition described herein. In an embodiment, the subject is, or is identified as being, overweight or obese and has a fibrotic disorder described herein. In an embodiment, the subject is, or is identified as being, overweight or obese and has a liver disorder or condition described herein.

In one embodiment, the subject is, or is identified as being, overweight or obese, and has a fibrotic or desmoplastic tumor, e.g., a tumor having one or more of: limited tumor perfusion, compressed blood vessels, high interstitial fluid pressure (IFPs), increased hypoxia, or fibrotic tumor interstitium. In certain embodiments, the subject is overweight or obese, and has a tumor having (e.g., elevated levels of) extracellular matrix components, such as fibers (e.g., collagen, procollagen), fibroblasts (e.g., elevated levels of cancer associated fibroblasts (CAFs) or increased activity of CAFs) and/or polysaccharides (e.g., glycosaminoglycans such as hyaluronan or hyaluronic acid).

In one embodiment, the subject is overweight or obese, and has pancreatic ductal adenocarcinoma (PDAC).

In other embodiments, the subject is, or is identified as being, overweight or obese, has a fibrotic or a hyperproliferative cancerous condition described herein, and exhibits one, two, three, four or more of: increased angiogenesis; increased inflammatory cell infiltration, e.g., in adipose tissues; shows enhanced tumor progression and/or metastatis; shows increased recruitment of tumor-associated macrophages (TAM); or shows increased activation of an angiogenic pathway, e.g., VEGFR-1 pathway.

In one embodiment, the subject is overweight or obese, and has breast cancer.

In other embodiments, the subject (e.g., an overweight or obese subject having a cancer or a fibrotic condition described herein (e.g., a breast or pancreatic cancer, desmoplastic tumor)) is treated with an AHCM (e.g., a composition comprising an AHCM as described herein) in combination with an anti-angiogenic agent, e.g., a VEGF/VEGFR inhibitor, an anti-diabetic drug, e.g., metformin, or a combination of the anti-angiogenic agent and the anti-diabetic drug. Accordingly, a method for treating an overweight or obese subject having a cancer or a fibrotic condition as described herein (e.g., a breast or pancreatic cancer, a desmoplastic tumor)). The method includes: administering to the subject an AHCM (e.g., a composition comprising an AHCM as described herein) in combination with an anti-angiogenic agent, e.g., a VEGF/VEGFR inhibitor, an anti-diabetic drug, e.g., metformin, or a combination of the anti-angiogenic agent and the anti-diabetic drug, in an amount sufficient to treat the cancer or the fibrotic conditions. In one embodiment, the administration reduces one, two, three, four or more of: fibrosis; angiogenesis; inflammatory cell infiltration, e.g., in adipose tissues; tumor progression and/or metastatis; recruitment of tumor-associated macrophages (TAM); or activation of an angiogenic pathway, e.g., VEGFR-1 pathway. The AHCM (e.g., a composition comprising an AHCM as described herein) can be administered prior to, concurrently with, or after the anti-angiogenic agent and/or anti-diabetic drug.

In such embodiments where the subject is, or is identified as being, overweight or obese, and has a hyperproliferative cancerous condition as described herein, e.g., a fibrotic or desmoplastic tumor, the AHCM is administered in combination with an anti-cancer therapy, e.g., a chemotherapeutic. In other embodiments, the AHCM is administered in combination with an anti-angiogenic agent, e.g., a VEGF/VEGFR inhibitor, an anti-diabetic drug, e.g., metformin, or a combination of both. In an embodiment, administration of the AHCM is initiated prior to the initiation of administration of the anti-cancer, anti-angiogenic, or anti-diabetic therapy (one or more of which are referred to herein as “the therapy”). In an embodiment, administration of the AHCM is concurrent with the administration of the therapy. In an embodiment, therapy with the AHCM continues during the entire therapy schedule. In yet other embodiments, administration of the AHCM is discontinued prior to cessation of the therapy. In other embodiments, administration of the AHCM is continued after cessation of the therapy. Administration of an AHCM with other therapies is further described herein in the section entitled “Combination Therapies.”

In other embodiments where the subject is, or is identified as being, overweight or obese, and has a fibrotic condition, or a hyperproliferative cancerous condition as described herein, e.g., a fibrotic or desmoplastic tumor, any of the AHCM, alone or in combination with any of the anti-angiogenic therapy, the anti-diabetic therapy, the anti-cancer therapy, or a combination thereof, can be administered as a particle or conjugate as described herein. The particles or conjugates can include a single agent or combination of agents. In an embodiment, the particle or agent comprises an agent (e.g., an ARB, a chemotherapeutic, an anti-diabetic drug, and/or an inhibitor of the VEGF pathway). In an embodiment, administration of the ARB-containing particle is concurrent with the administration of an anti-diabetic drug, e.g., metformin, a chemotherapeutic, and/or an inhibitor of the VEGF pathway.

In any of the aforesaid embodiments, the AHCM can be administered as a free agent or as a composition (e.g., as a conjugate or a particle as described herein) comprising the AHCM). In certain embodiments, at least one, two or all of the AHCM, the anti-angiogenic agent, the anti-cancer agent, or the anti-diabetic therapy is administered as a particle (e.g., a pH-sensitive particle disclosed herein).

In one embodiment, the AHCM is provided in a particle, e.g., a targeted or non-targeted particle (e.g., any particle disclosed herein). In one embodiment, the particle is a pH-sensitive particle, e.g., comprises a polyacetal polymer and/or a linker as described herein. In such embodiments, the anti-angiogenic agent, the anti-cancer agent, and/or the anti-diabetic therapy can be administered as a free agent.

In one embodiment, the anti-angiogenic agent, the anti-cancer agent, and/or the anti-diabetic therapy is provided in a particle, e.g., a targeted or non-targeted particle (e.g., any particle disclosed herein). In one embodiment, the particle is a pH-sensitive particle, e.g., comprises a pH-sensitive polymer and/or linker as described herein. In such embodiments, the AHCM is provided as a free agent.

In other embodiments, the subject being selected for subjecting to the methods or pharmaceutical compositions herein does not have a renal disease or a disease associated with kidneys.

In one embodiment, the subject treated is a mammal, e.g., a primate, typically a human (e.g., a patient having, or at risk of, a cancer or tumor as described herein).

In certain embodiments, the subject treated has a disorder chosen from one or more of a hyperproliferative disorder, a cancer, a fibrotic disorder, an inflammatory disorder or an autoimmune disorder.

In one embodiment, the subject treated has a hyperproliferative disorder, e.g., a hyperproliferative connective tissue disorder (e.g., a hyperproliferative fibrotic disease). In one embodiment, the hyperproliferative fibrotic disease is multisystemic or organ-specific. Exemplary hyperproliferative fibrotic diseases include, but are not limited to, multisystemic (e.g., systemic sclerosis, multifocal fibrosclerosis, sclerodermatous graft-versus-host disease in bone marrow transplant recipients, nephrogenic systemic fibrosis, scleroderma), and organ-specific disorders (e.g., fibrosis of the lung, liver, heart, kidney, pancreas, skin and other organs).

In other embodiment, the subject treated has a hyperproliferative genetic disorder, e.g., a hyperproliferative genetic disorder chosen from Marfan's syndrome or Loeys-Dietz syndrome.

In other embodiments, the hyperproliferative disorder (e.g., the hyperproliferative fibrotic disorder) is chosen from one or more of chronic obstructive pulmonary disease, asthma, aortic aneurysm, radiation-induced fibrosis, skeletal-muscle myopathy, diabetic nephropathy, and/or arthritis.

Headings, sub-headings or numbered or lettered elements, e.g., (a), (b), (i) etc, are presented merely for ease of reading. The use of headings or numbered or lettered elements in this document does not require the steps or elements be performed in alphabetical order or that the steps or elements are necessarily discrete from one another.

All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

FIGS. 1A, 1B, and 1C show the synthesis of an exemplary polyacetal polymer. FIG. 1A shows a scheme of the modular polymerization reaction comprising polyol and vinyl ether monomers into polyacetals. In some case, the polyacetal polymer may further comprise a PEG component, wherein the size of the PEG (shown as x in FIG. 1A ) may range from 200 to 5000. FIG. 1B shows exemplary polyol monomers that may be incorporated into the polyacetal polymers, e.g., A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, and A32. FIG. 1C shown exemplary vinyl ether monomers that may be incorporated into the polyacetal polymers, e.g., B1, B2, B3, B4, B5, and B6.

FIGS. 2A and 2B show the synthesis of exemplary polyacetal polymers conjugated to an ARB. FIG. 2A shows the conjugation of a generic ARB to a free hydroxyl group in a polyacetal polymer to yield an ARB-linked polyacetal polymer. FIG. 2B shows the synthesis of an exemplary polyacetal polymer, namely a polyacetal polymer conjugated to the ARB valsartan. The carboxylic acid on the valsartan is activated by DIC in the presence of TEA and results in attachment of valsartan to the polyacetal polymer, yielding a valsartan-linked polymer.

FIGS. 3A, 3B, and 3C show the synthesis and characterization of conjugates containing drugs for treating pancreatic cancer and pH-sensitive polymers. FIG. 3A shows three drugs commonly used for treating pancreatic cancer. FIG. 3B shows different pH-sensitive linkers for screening for the most sensitive pH linker to link the drugs from FIG. 3A to the polymer. FIG. 3C shows reverse phase HPLC profiles (UV=350) of irinotecan and purified irinotecan-aconitic acid for the pH sensitive linker study.

FIGS. 4A, 4B, and 4C show the selection of pH-sensitive linkers for conjugates for irinotecan and gemcitabine. FIG. 4A shows the different pH sensitive linkers. FIGS. 4B and 4C show the release profiles of irinotecan conjugates with the indicated pH-sensitive linkers as labeled in FIG. 4A when in buffers at pH 6.7 or 7.4.

FIGS. 5A, 5B, 5C, and 5D show a schematic representation of the synthesis of an exemplary conjugate comprising a polyacetal polymer linked to the ARB losartan and a targeting moiety, mannose-6-phosphate. FIG. 5A shows the activation of free hydroxyl groups on a polyacetal polymer with excess succinic anhydride to yield reactive carboxylic acid groups. FIG. 5B shows the conjugation of losartan to the succinylated polyacetal polymer. In this reaction, a sub-stoichiometric quantity of losartan is used in order to prevent full saturation of the free carboxylic acid groups. FIG. 5C shows the modification of the remaining free carboxylic acid groups on the polymer with ethylenediamine to yield a reactive amino group. FIG. 5D outlines the conjugation of M6P-isothiocyanate to the losartan-linked polyacetal polymer to produce a polyacetal polymer conjugated to both M6P and losartan.

FIG. 6 shows the structure of the metformin agents metformin, phenformin, bisguanidine, and buformin.

FIGS. 7A, 7B, 7C, 7D, 7E, and 7F show that obesity promotes tumor initiation and progression. FIG. 7A shows that high-fat (60%) versus low-fat (10%) diets generated a difference in body weight (BW) in C57BL/6, FVB and the spontaneous PDAC (KPC and iKRAS) models. Diet started at six weeks of age, continued for ten weeks (C57BL/6 and FVB), at which time tumors were implanted, and then continued until the end of experiments. In the spontaneous tumor models, diets were administered until tumor collection. Mice genetically deficient for leptin (ob/ob) on a standard chow for seven weeks gained weight compared to age matched WT mice (n=8-10/group for C57Bl/6, FVB and ob/ob, 4-10/group for KPC, 7-21/group for iKRAS). Left bars represent mice fed a low-fat diet, right bars represent mice fed a high fat diet for all groups except C57/B6 on the far right of the graph, in which the right bar represents the ob/ob mice. FIG. 7B shows the time to develop tumors of about 1 g in iKRAS mice fed low (left bars) or high-fat diet (right bars). FIG. 7C shows the effect of obesity on tumor growth. PAN02 and AK4.4 syngeneic tumors were orthotopically implanted in C57BL/6 and FVB mice respectively at ten weeks of diet (lean diet, left bars; and obese diet or ob/ob mice, right bars); ob/ob mice were implanted with PAN02 tumors at seven weeks of age. Tumors were collected 21 days later. Obese animals presented with higher tumor weights than lean counterparts in all models (n=8-10/group). FIG. 7D is representative images of mesenteric peritoneal dissemination in lean and obese mice implanted with PAN02 tumors. Mesenteries collected at the same time as tumors in FIG. 7C . FIG. 7E is a graph showing the quantification of mesenteric peritoneal metastasis in the PAN02 model. FIG. 7F is a graph showing the quantification of retro-peritoneal metastasis in the AK4.4 model. Data are shown as mean±standard error of the mean (SEM). P values were determined by the Student t-test. *, P<0.05; **, P<0.01; ***, P<0.001.

FIGS. 8A, 8B, 8C, 8D, 8E, 8F, 8G, 8H, 8J, 8I, 8J, and 8K show that obesity aggravates tumor desmoplasia. FIG. 8A is images showing adipocyte enlargement and fibrosis in visceral adipose tissue and tumors from obese mice. Masson's Trichrome staining denotes fibrosis in blue. Arrows: Adipocytes. Scale bars: 200 μm. Quantification of adipocyte count ( FIG. 8B ) and size ( FIG. 8C ) in PAN02 and AK4.4 tumors indicates an enrichment for enlarged adipocytes in the tumor microenvironment in lean (left bars) and obese mice (right bars) (n=3 tumors/group, 8 ROIs/tumor). FIG. 8D shows representative pictures of the adipose tissue-tumor interaction, revealing increased expression of fibrosis where tumors invade the adjacent adipose tissue. On the far right, tumor epithelium is observed in close proximity to fibrotic adipose tissue and normal pancreas. Tumor sections were stained for Masson's Trichrome. Scale bars: 100 μm (PAN02, left panel), 200 μm (AK4.4, middle panel), 500 μm (Ak4.4 right panel). FIG. 8E is representative pictures of collagen-I staining (immunofluorescence) in tumors. Scale bars: 1 mm. FIG. 8F is representative pictures of fibrillar collagen in tumors using second harmonic generation (SHG). Scale bars: 100 μm. FIG. 8G is a graph showing the quantification of collagen expression normalized to lean animals. Tumors from obese mice presented with increased collagen-I expression in three different tumor models. FIG. 8H is a graph showing the quantification of fibrillary collagen normalized to lean animals. Tumors from obese mice presented with increased expression of fibrillar collagen in PAN02 and AK4.4 orthotopic PDACs. (n=3-6/group). In FIGS. 8G and 8 H, left bars represent lean mice, right bars represent obese mice. FIG. 8I is representative pictures of αSMA expression in AK4.4, PAN02 and KPC tumors by immunofluorescence. FIG. 8J is a graph showing the quantification of αSMA expression by immunofluorescence was performed as a % of αSMA expression in DAPI+ viable tumor area ( FIG. 8J ), as well as a % of double positive αSMA/Col-I expression in DAPI+ viable tumor area ( FIG. 8K ) (n=3-6/group). In FIGS. 8J and 8K , left bars represent lean mice, right bars represent obese mice. Representative pictures of αSMA/Col-I double staining in PAN02 and AK4.4 tumors are in FIGS. 16D and 16E . Data are shown as mean±SEM. P values were determined by the Student t-test. *, P<0.05; **, P<0.01.

FIGS. 9A, 9B, 9C, 9D, and 9E show that obesity-aggravated desmoplasia impairs drug delivery. FIG. 9A is representative pictures of CD31(+) vessels and lectin in PAN02 tumors. Scale bars: 200 μm. FIG. 9B is a graph showing the quantification of the total (CD31+) and lectin-positive (CD31/lectin+) vessel area in PAN02 tumors. Obese mice (right bars) presented with decreased perfusion (n=3-6 tumors/group) compared to lean mice (left bars). FIG. 9C shows the protein expression of hypoxia markers in PAN02 tumors. Obese mice presented with increased hypoxia in tumors. FIG. 9D shows the effect of obesity on the delivery of chemotherapy to tumors. 5-FU quantified via high performance liquid chromatography (HPLC). Obesity decreased delivery of the chemotherapeutic agent (n=4 tumors/group). FIG. 9E shows the effect of obesity on response to chemotherapy. PAN02 tumors were orthotopically implanted at ten weeks of diet, treatments were initiated at day seven post-implantation and tumors resected at day 19. 5-FU was less effective in preventing PAN02 tumor growth in obese animals than in lean (two-way ANOVA, n=8-10/group). Data are shown as mean±SEM. P values were determined by the Student t-test unless otherwise stated. *, P<0.05; **, P<0.01

FIGS. 10A, 10B, 10C, 10D, 10E, 10F, 10G, 10H, 10I, 10J, 10K, and 10L show that blockade of AT1 reverses the obesity-aggravated desmoplasia and improves response to chemotherapy. FIGS. 10A and 10B shows the effect of obesity on target genes of AT1 signaling. Expression of genes associated with AT-1 pathway activation and fibrosis/desmoplasia is increased in PAN02 ( FIG. 10A ) and AK4.4 ( FIG. 10B ) tumors from obese mice (right bars) in comparison to lean mice (left bars). Depicted genes where a 2-fold change in mRNA expression was observed in either tumor model. Data normalized to lean group. 3-4 samples per group pooled in one single PCR array fibrosis gene set plate. FIG. 10C shows that losartan reduced tumor αSMA protein expression more dramatically in the obese setting in AK4.4 tumors. FIG. 10D shows the quantification of protein expression was normalized to tubulin. FIG. 10E shows that losartan reduced tumor fibrillar collagen (top panels) as well as collagen-1 expression (bottom panels) in AK4.4 tumors from obese mice. Scale bars: 100 μm (SHG) and 1 mm (Col-1) FIGS. 10F-H shows the quantification of collagen was performed as a % of a region of interest (ROI) for SHG (n=4 tumors/group, 8 ROIs per tumor) ( FIG. 10F ) and as a % of viable tumor area in the whole tumor for collagen-1 immunofluorescence (n=4-6 tumors/group) (AK4.4 in FIG. 10G and PAN02 in FIG. 10H ). FIG. 10I shows the protein expression by western blotting of AK4.4 tumors revealed that losartan normalized the obesity-augmented expression of several AT1 signaling and desmoplasia-related markers, i.e. AT1, TGFB, SMAD2, vimentin, snail, MMP9, and phospho-p38. Of note, similar to αSMA, the changes of AT1, as well as other desmoplasia related markers, were relatively mild in the lean setting. FIG. 10J shows the quantification of protein expression was normalized to tubulin (far left bars represent lean mice; middle left bars represent obese mice; middle right bars represent lean mice treated with losartan; and far right bars represent obese mice treated with losartan.) (Depicted are significant differences between control and losartan treatment). FIG. 10K shows that in the PAN02 model, losartan and AT1 genetic deficiency (Agtr1a−/− mice) improved response to chemotherapy in obese, but not in lean animals. FIG. 10L shows that in the AK4.4 model, losartan improved response to chemotherapy in both lean and obese settings but with higher magnitude in obese setting ( FIGS. 10K and 10L : Two-way ANOVA with Bonferroni correction for multiple comparisons, n=4-8 tumors/group. Depicted are significant differences of treatment groups compared to control or 5-FU groups). Data are shown as mean±SEM with the exception of FIGS. 10A and 10B . P values were determined by the Student t-test unless otherwise stated. *, P<0.05; **, P<0.01, ***p<0.001.

FIG. 11A, 11B, 11C, 11D, 11E, 11F, 11G, 11H, 11I, AND 11J show that tumor-associated neutrophils mediate obesity-induced tumor progression and aggravated desmoplasia. FIG. 11A shows the effect of obesity on immune cell infiltration in PDACs. Obesity promoted infiltration of myeloid Gr-1(+)F4/80(−) cell population in PAN02 tumors in obese mice. FIG. 11B is a quantification normalized by total viable cells (i) or total CD45 leucocytes (ii) (n=4-6 tumors/group). FIG. 11C is representative FACS scatter plots of CD45(+)CD11b(+)Ly6G(+) tumor associated neutrophils (TANs), CD8(+) cytotoxic lymphocytes and CD4(+)CD25(+) regulatory T cells in PAN02 tumors in lean and obese setting. FIGS. 11D and 11E shows quantification normalized by total viable cells ( FIG. 11D ) or total CD4 cells ( FIG. 11E ) (n=3-6 tumors/group). Obese promoted an increase in TANs and a decrease in CD8 cells in PAN02 tumors. A strong tendency for increased Tregs was also observed. FIG. 11F shows the effect of TAN depletion (TAN-D) on PDAC growth in obese mice. TAN depletion from day 1 using anti-Ly6G specific pharmacological inhibitory antibody in obese mice significantly reverted the obesity-increased tumor weight in PAN02 and AK4.4 models (n=4-6 tumors/group). FIG. 11G shows the preferential accumulation of TANs in areas with activated PSCs. Scale bars: 1 mm (whole tumors) and 100 μm (caption). FIG. 11I shows TAN depletion reduced AT1 expression, collagen production and MMP9 expression in PAN02 tumors in obese animals. FIG. 11J shows TAN depletion led to increasing in perfusion in PAN02 tumors in obese animals. % of CD31(+), lectin(+) or double positive vessel density in the viable area of whole tumors. (n=4-6 tumors/group). For bar graphs in FIGS. 11A, 11B, 11D, and 11E , left bars represent lean mice, and right bars represent obese mice. For the bar graph in FIG. 11J , left bars represent obese mice, and right bars represent obese mice with TAN depletion. Data are shown as mean±SEM. P values were determined by the Student t-test, or one-way ANOVA for panels C and E. *, P<0.05; **, P<0.01, ***p<0.001.

FIGS. 12A, 12B, 12C, 12D, 12E, 12F, 12G, 12H, 12I, 12J, and 12K show the adipose microenvironment promotes TAN infiltration and fibrosis via IL-1ß. FIG. 12A shows an effect of obesity on cytokine expression in PAN02 tumors. Multiplex protein revealed that PAN02 tumors from obese mice (right bars) had increased expression of IL-1ß (n=4-6 tumors/group) in comparison to lean mice (left bars). FIG. 12B shows that IL-1ß was abundantly expressed by adipocytes and PSCs in the adipocyte-rich areas where PSCs predominate in PAN02 tumors. Scale bars: 200 μm (upper panels), 30 μm (lower panels). FIG. 12C shows the effect of IL-1ß blockade on immune cell profile. An anti-IL1ß neutralizing antibody decreased CD45(+)CD11b(+)Ly6G(+) TAN infiltration while recovering CD4+ and CD8+Tcells ( FIGS. 12C and 12D ) and decreasing Tregs ( FIG. 12E ) (one-way ANOVA, n=3-6 tumors/group). In FIG. 12D , left bars represent lean mice, middle bars represent obese mice, and right bars represent obese mice with IL-1B inhibition. FIG. 12E shows that IL-1ß blockade normalized obesity-aggravated tumor growth. (one-way ANOVA, n=3-6 tumors/group). FIG. 12G is a western blot showing that IL-1ß inhibition decreased obesity-induced αSMA and AT1 expression (bands are part of a larger WB. Lean control group is depicted in FIG. 3E ). FIG. 12H shows IL-1ß expression in TANs. Immunofluorescence for PAN02 tumor sections denoting co-localization. Scale bar: 30 μm. FIG. 12I shows TAN depletion using Ly6G specific antibody abolished obesity-induce IL1-ß expression in PAN02 tumors. (one-way ANOVA, n=4-6 tumors/group). FIGS. 12J and 12H shows the effect of AT1 blockade on immune cell profile. In tumors implanted in AT1-KO (PAN02), TANs were decreased. This was associated with increased CD8 cells and reduced Tregs (n=3-6 tumors/group). In FIGS. 12J and 12K , the far left bars represent lean mice; the middle left bars represent obese mice; the middle right bars represent lean AT1-KO mice; and the far right bars represent obese AT1-KO mice. Data in FIGS. 12C, 12D, 12E, 12J and 12K were parts of the same experiment. Data are shown as mean: SEM. P values were determined by the Student t-test unless otherwise stated. *, P<0.05; **, P<0.01.

FIGS. 13A, 13B, 13C, 13D, and 13E show that PDACs from obese patients recapitulate the findings in preclinical models. FIG. 13A is representative pictures of adipocytes in human PDAC from patients with normal weight [Body mass index (BMI)<25] and obesity (BMI>30). Scale bars: 100 μm. FIG. 13B shows the quantification of adipocyte size in human PDACs. Tumors from obese patients presented with hypertrophied adipocytes (n=8 tumors/group). FIG. 13C is representative pictures of Collagen-I and HA in human PDAC from patients with normal weight (BMI<25) and obesity (BMI>30). Scale bars: 1 mm. FIG. 13D shows the quantification of Collagen-I and HA in human PDACs (n=8 tumors/group); left bars represent patients with BMI<25 and right bars represent patients with BMI>30. Data are shown as mean±SEM. P values were determined by the Student t-test. *, P<0.05; **, P<0.01. FIG. 13E is a graphical summary of the key findings in this study. PDACs in obese hosts present with increased fatty stroma, inflammation, and desmoplasia. The amplified crosstalk between CAAs, TANs and PSCs that occurs in obesity leads to an aggravation of desmoplasia, increased tumor progression and reduced response to chemotherapy.

FIG. 14 shows the effect of obesity on KPC tumor initiation. Time to develop tumors of about 1 g in KPC mice fed low (lean mice, left bars) or high-fat diet (obese mice, right bars). Data are shown as mean±SEM. P value was determined by the Student t-test.

FIGS. 15A and 15B show the adipose tissue-tumor interaction. FIG. 15A is representative pictures of PAN02, AK4.4 and iKRAS tumors invading visceral adipose tissue in obese mice. FIG. 15B is additional pictures depicting an association of fibrosis with adipocytes in AK4.4 tumors from obese mice. Masson's trichrome staining in tumors revealed a predominance of fibrosis content in areas rich in adipocytes or adjacent to adipose tissue. Scale bars: 500 μm (upper panels, lower left panel), 250 μm (lower right panel).

FIGS. 16A, 16B, 16C, 16D, 16E, and 16F show the co-expression of collagen-I and hyaluronan in PSCs, and impact of obesity on tumor hyaluronan levels. FIG. 16A is representative pictures and FIG. 16B shows the quantification of hyaluronan (HA) binding protein (HABP, which detects HA) in AK4.4 tumors from lean and obese mice. Scale bars: 1 mm (n=3-6/group). FIG. 16C shows the quantification of HA (ELISA) in PAN02 tumors from lean and obese mice (n=3-6/group). FIG. 16D shows immunofluorescence demonstrating that αSMA-expressing PSCs associate with collagen-1 expression in PAN02 tumors. Whole tumor staining depicted on the left picture; caption of an area where the two markers overlap in the center picture; amplification of the center figure on the right. Scale bars: 1 mm (far left panel), 200 μm (center panel), 50 μm (caption). FIG. 16E is a representative picture of co-expression of αSMA with collagen-I and hyaluronan in AK4.4 tumors. Scale bar: 200 μm. FIG. 16F is a western blot denoting the effect of obesity on PSC marker αSMA expression in PAN02 tumors. Data in FIGS. 16B and 16C are shown as mean±SEM. P values were determined by the Student t-test.

FIGS. 17A, 17B, 17C, and 17D show that obesity-aggravated desmoplasia reduces perfusion and efficacy of chemotherapy in AK4.4 tumors. FIG. 17A shows the effect of obesity on AK4.4 tumor perfusion. Quantification of total and lectin-positive vessel area in AK4.4 tumors. Obese mice (right bars) presented with decreased perfusion (n=5-12 tumors/group) compared to lean mice (left bars). FIG. 17B shows the effect of obesity on protein expression of hypoxia markers in AK4.4 tumors. Obese mice presented with increased expression of the hypoxia marker Hif-1α in tumors. FIG. 17C shows the effect of obesity on the delivery of doxorubicin to PAN02 tumors. Doxorubicin quantified via immunofluorescence (n=4 tumors/group). FIG. 17D shows the effect of obesity on response to chemotherapy. AK4.4 syngeneic tumors were orthotopically implanted at ten weeks of diet; treatments were initiated at day 7 post-implantation and tumors resected at day 19. 5-FU was less effective in preventing tumor growth in obese animals (two-way ANOVA, n=6-8/group). Data in FIGS. 17A, 17C and 17D , are shown as mean±SEM. P values were determined by the Student t-test unless otherwise stated. *, P<0.05.

FIGS. 18A, 18B, 18C, 18D, 18E, 18F, and 18G show the additional effects of AT-1 inhibition on obesity-aggravated desmoplasia, perfusion and drug delivery. FIG. 18A shows the double immunofluorescence for αSMA and AT receptor in two orthotopic PDACs. ˜70% of activated PSCs expressed AT1 receptor in PAN02 and ˜35% in AK4.4. Scale bar: 30 μm (left panels), 500 μm (right panel). FIG. 18B shows the protein expression of the signaling molecules downstream of AT1 in PAN02 and AK4.4 tumors, revealing increased activity in obese mice. FIG. 18C shows the effect of losartan on the expression of fibrosis/desmoplasia-related markers in AK4.4 tumors. mRNA expression of markers of tumor fibrosis/desmoplasia was increased in tumors in obese mice and was reverted by losartan. Losartan did not alter these markers in lean mice (3-4 samples per group were pooled for the PCR array analysis). FIG. 18D shows the effect of losartan on αSMA expression in PAN02 tumors. Losartan induced a tendency for reduced tumor αSMA protein expression in obese but not lean setting (Two-way ANOVA, n=3-6/group). FIG. 18E is a western blot showing a decrease in αSMA expression in PAN02 tumors implanted in obese AT1 KO mice compared with obese WT mice (bands are part of a larger WB. Lean control group is depicted in FIG. 18F ). FIGS. 18F and 18G shows that losartan tended to improve perfusion ( FIG. 18F ) and increase chemotherapy delivery ( FIG. 18G ) in PAN02 (left panels) and AK4.4 (right panels) tumors from obese but not lean mice (Two-way ANOVA with Bonferroni correction for multiple comparisons, n=4-8 tumors per group). Data in FIGS. 18D, 18F and 18G are shown as mean±SEM. In FIGS. 18C and 18F , far left bars represent lean mice, middle left bars represent lean mice treated with losartan, middle right bars represent obese mice, and far left bars represent obese mice treated with losartan.

FIGS. 19A and 19B show the effect of obesity on immune cell infiltration and cytokine profile in AK4.4 tumors. FIG. 19A shows that obesity promoted infiltration of myeloid Gr-1(+)F4/80(−) cell population in AK4.4 tumors in obese mice. Quantification normalized by total CD45 leucocytes (n=4 tumors/group). FIG. 19B shows that obesity associated with increased levels of IL-1ß in AK4.4 tumors in obese mice (n=4 tumors/group). Data are shown as mean±SEM. P values were determined by the Student t-test. *, P<0.05. In FIGS. 19A and 19B , left bars represent lean mice, and right bars represent obese mice.

FIGS. 20A, 20B, 20C, and 20D show the effects of TAN depletion on vessel perfusion and cytokine expression in obese mice. FIG. 20A is a representative FACS scatter plots of CD45(+)CD11b(+)Ly6G(+) tumor-associated neutrophils (TANs) in control and TAN-depleted obese mice. Ly6G specific inhibition led to a significant reduction (˜90%) of the Ly6G(+) cell population in PAN02 tumors from obese mice. FIG. 20B shows the effect of TAN depletion on vessel perfusion in AK4.4 tumors in obese animals. % of CD31(+), lectin(+) or double positive vessel density in the viable area of whole AK4.4 tumors. FIG. 20C shows the % of CD31 expression that co-stains with lectin in PAN02 and AK4.4 tumors (n=4-6 tumors/group). FIG. 20D shows that TAN depletion reduced the expression of CXCL-1 (IL-8, KC), and tended to reduce the expression of TNFα and IL-12 in PAN02 tumors from obese mice. Data in FIGS. 20B, 20C, and 20D are shown as mean±SEM. P values were determined by the Student t-test. *, P<0.05. In FIGS. 20B, 20C, and 20D , left bars represent obese mice and right bars represent TAN-depleted obese mice.

FIGS. 21A, 21B, and 21C show the effect of losartan on the immune tumor microenvironment. FIG. 21A shows the effect of losartan on cytokine expression in PAN02 and AK4.4 tumors in obese mice. Multiplex protein revealed that losartan reduced the expression of multiple cytokines including IL-1 in PDACs (n=4-7 tumors/group). FIGS. 21B and 21C show that within the CD45 population, losartan treatment tended to decrease the enrichment for GR(+)F480(−) cells ( FIG. 21B ), and within CD4 cells, the enrichment for T regulatory cells ( FIG. 21C ) (n=4 tumors/group). Error bars represent standard error of the mean. P values were determined by the Student t-test in A. *, P<0.05, **, P<0.01, ***, P<0.001.

FIG. 22 is a representative picture of AT1 expression in cancer-associated adipocytes in PAN02 tumors. Cancer-associated adipocytes (arrows), similar to normal adipocytes, express AT1. Scale bar: 100 μm.

FIG. 23 shows representative ARBs, e.g., losartan, valsartan, telmisartan, candesartan, eprosartan, irbesartan, azilsartan, EXP-3174, olmesartan, or prodrugs or active metabolites thereof.

FIG. 24 shows representative vitamin D analogs, e.g., paricalcitol, doxercalciferol, falecalcitriol, maxacalcitol, tacalcitol, alfacalcidol, eldecalcidol, seocalcitol, lexicalcitol, CD578, inecalcitol, calcipotriol, TX527, 2MD, WY1112, PRI-2205, ILX23-7553, and analogs and derivatives thereof.

FIGS. 25A and 25B show representative bromodomain and extra-terminal protein inhibitors (i-BET), e.g., MS436, PFI-1, I-BET 151, OTX-015, JQ1, CPI-203, bromosporine, RVX-208, I-BET 762, I-BET 151, OFXBD02, OFXBD03, XD14, AZD5153, and analogs and derivatives thereof.

FIGS. 26A, 26B, and 26C show the results of a single dose pharmacokinetic study of Can-DPC in whole blood ( FIG. 26A ), tumor ( FIG. 26B ), and liver ( FIG. 26C ) as measured by LC/MS/MS as described in Example 13.

The mildly acidic pH in tumor tissues (pH˜6.5-7.2), inflammatory tissues, as well as in the endosomal intracellular compartments (pH˜4.5-6.5) may trigger drug release from pH sensitive delivery vehicles upon their arrival at the targeted disease sites. The release of contents of the delivery vehicles can be retarded or hindered if the vehicles are not sensitive enough to outer pH stimuli. Certain embodiments of the nanoparticles disclosed herein exhibit the sensitivity to the pH environment change. Further, the nanoparticles disclosed herein can keep integrity in the bloodstream pH, but release their contents when exposed to extracellular tumor microenvironment. In certain embodiments, the nanoparticles disclosed herein rapidly release the contents inside hypoxic cells (e.g., tumor cells or liver cells).

Accordingly, the present invention provides, at least in part, pH-sensitive and/or polyacetal polymers and/or linkers; conjugates comprising said polymers and/or linkers, optionally, coupled to one or more agents and/or targeting moieties; and particles (e.g., nanoparticles comprising the aforesaid polymers, linkers and/or conjugates), collectively referred to herein as “compositions,” which can be used to enhance the delivery and/or efficacy of one or more agents in a subject. In one embodiment, the polymer is capable of forming micelles or self-assembling into nano-structures. In some embodiments, the pH-sensitive and/or polyacetal polymer disclosed herein is capable of forming micelles or self-assembling into nano-structures with diameters over about 12 nm.

Without being bound by theory, the compositions disclosed herein may improve the efficiency of an agent, e.g., a therapeutic and/or diagnostic agent, e.g., by one or more of: (i) increasing the localization and/or delivery of the agent to a target cell (e.g., a cancer or a liver cell); (ii) selectively penetrating into a fibrotic tissue (e.g., a desmoplastic tumor or fibrotic liver); (iii) selectively penetrating into a diseased blood vessel (e.g., a leaky tumor vessel); (iv) exhibiting increased pH-sensitivity and/or enhanced agent release in a hypoxic microenvironment, e.g., in a tumor or a fibrotic tissue (e.g., fibrotic or cirrhotic liver); (v) increasing the selective delivery and/or release of the agent to the tumor or fibrotic tissue; or (vi) increasing the half-life of the agent.

Certain embodiments disclosed herein provide compositions and methods for treating or preventing a disorder (e.g., a cancer (e.g., a desmoplastic tumor) or a liver disorder), by administering to a subject a particle, e.g., a pH-sensitive and/or polyacetal particle described herein, as a single agent or as a combination with one or more therapeutic agents. The pH-sensitive and/or polyacetal compositions disclosed herein can result in a significantly higher amount of released agent at a target site (e.g., a hypoxic tumor or liver).

Thus, provided herein are compositions and methods for improving the delivery and/or efficacy of a therapy (e.g., a cancer, a fibrotic or immunomodulary or liver therapy), ranging in size from a cell (e.g., an immune cell) or a large nanotherapeutic (e.g., lipid- or polymeric nanoparticles and viruses), protein and nucleic acid drugs, to low molecular weight chemotherapeutics and/or oxygen radicals.

Additional embodiments that can be combined with the compositions and methods of the invention are disclosed in WO 2012/068531 and WO 2013/169739, both of which are entitled “Novel Compositions and Uses of Anti-Hypertension Agents for Cancer Therapy,” which are hereby expressly incorporated by reference in their entirety.

Certain terms are defined throughout the specification and in the section entitled “Selected Definitions” set forth below.

Polymers

A “polymer,” as used herein, is given its ordinary meaning as used in the art, i.e., a molecular structure comprising one or more repeat units (monomers), connected by covalent bonds. The repeat units may all be identical, or in some cases, there may be more than one type of repeat unit present within the polymer. In one embodiment, the polymer has at least 2 repeat units. In other embodiments, the polymer has at least 4 repeat units, at least 7 repeat units, at least 12 repeat units, at least 17 repeat units, at least 44 repeat units, or at least 100 repeat units.

If more than one type of repeat unit is present within the polymer, then the polymer is said to be a “copolymer.” It is to be understood that in any embodiment employing a polymer, the polymer being employed can be a copolymer in some cases. The repeat units forming the copolymer may be arranged in any fashion. For example, the repeat units may be arranged in a random order, in an alternating order, or as a “block” copolymer, i.e., comprising one or more regions each comprising a first repeat unit (e.g., a first block) and one or more regions each comprising a second repeat unit (e.g., a second block), etc. Block copolymers may have two (a diblock copolymer), three (a triblock copolymer) or more numbers of distinct blocks. The term “homopolymer” is a polymer incorporating a single species of monomer units. The polymer can be natural or synthetically derived. In some embodiments, the polymer is not biodegradable. In some other embodiments, the polymer is biodegradable. In some embodiments, the polymer is biocompatible.

Suitable polymers include polymers, copolymers, and block polymers based on monomers containing ionizable groups or polymerizable double bonds. Exemplary monomers include, but are not limited to, acrylic acid, methyl methacrylate, methyl acrylic acid, ethyl acrylate, vinyl sulfonic acid, styrene, styrene sulfonic acid (e.g., p-styrene sulfonic acid), maleic acid, butenoic acid, vinyl phosphate, vinyl phosphonate, ethylene, propylene, styrene, vinyl methyl ether, vinyl acetate, vinyl alcohol, acrylonitrile, acrylamide, N—(C 1 -C 6 alkyl) acrylamide (such as N-isopropylacrylamide, N-t-butylacrylamide), and the like. Polymer matrices are made by homopolymerizing or copolymerizing any of the foregoing monomers. Other suitable polymers can include alginate, chitosan, collagen, gelatin, hyaluronate, fibrin, agarose, and derivatives thereof. In some embodiments the polymer can be a polysaccharide, for example, but not limited to, dextran. In some embodiments the polymer can be a polypeptide. In some embodiments, the polymer can be an antibody.

In some embodiments, the polymer can be selected from the group consisting of polysaccharides, polypeptides, polyacetals, polyketals, polyanhydrides, polyhydroxybutyric acid, polyorthoesters, polysiloxanes, polycaprolactone, poly(lactic-co-glycolic acid), poly(lactic acid), poly(glycolic acid), and copolymers or block polymers prepared from the monomers of these polymers. Some exemplary polymers which can be used in the present invention include but are not limited to one or a mixture of polymers selected from the group consisting of glycosaminoglycan, silk, fibrin, MATRIGEL®, poly-ethyleneglycol (PEG), polyhydroxy ethyl methacrylate, polyvinyl alcohol, polyacrylamide, poly (N-vinyl pyrolidone), poly glycolic acid (PGA), poly lactic-co-glycolic acid (PLGA), polylactic acid, poly e-caprolactone (PCL), polyethylene oxide, poly propylene fumarate (PPF), poly acrylic acid (PAA), hydrolysed polyacrylonitrile, polymethacrylic acid, polyethylene amine, alginic acid, pectinic acid, carboxy methyl cellulose, hyaluronic acid, heparin, heparin sulfate, chitosan, carboxymethyl chitosan, chitin, pullulan, gellan, xanthan, collagen, gelatin, carboxymethyl starch, carboxymethyl dextran, chondroitin sulfate, cationic guar, cationic starch, and any combinations thereof, as well as salts and esters thereof.

In some embodiments the polymer can be poly(lactic acid)-b-poly(ethylene glycol) (PLA-PEG), poly(lactic acid)-b-poly(ethylene glycol) (PLGA-PEG), or (cyclodextrin)-co-poly(ethylene glycol) (CDP). In some preferred embodiments, polymer is PLA-PEG, dextran, or a polyacetal polymer described herein.

In some embodiments of the various aspects disclosed herein, the polymer (e.g., the pH-sensitive or polyacetal polymer) comprises a compound according to Formula (I):

wherein:

each of A 1 and A 2 is independently heteroalkylene, heteroalkenylene, heteroalkynylene, heterocyclyl, aryloxy, heteroaryloxy, wherein each heteroalkylene, heteroalkenylene, heteroalkynylene, heterocyclyl, aryloxy, or heteroaryloxy is optionally substituted with 1-5 R 1 ;

each of B 1 and B 2 is independently heteroalkyl, heterocyclyl, each of which is optionally substituted with 1-6 R 2 ;

each of C 1 and C 2 is independently heteroalkyl, cyclyl, or heterocyclyl, each of which is optionally substituted with 1-6 R 3 , e.g., each of C 1 and C 2 is independently PEG400, PEG000, or PEG2050;

each of R 1 , R 2 , and R 3 is independently alkyl, alkenyl, alkynyl, hydroxyl, halo, heteroalkyl, keto, alkoxy, ester, cyclyl, heterocyclyl, cycloalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, a linker, an agent, a targeting moiety, a protecting group, or a branching point, and

each of m or n is independently an integer from 1 to 500.

In some embodiments of a polymer of Formula (I), each of A 1 and A 2 is independently heteroalkyl or aryloxy, each of which may be optionally substituted with 1-5 R 1 . In some embodiments, each of A 1 and A 2 is independently heteroalkyl, each of which may be optionally substituted with 1-5 R 1 . In some embodiments, each of A 1 and A 2 is independently C 1 -C 20 heteroalkyl, each of which may be optionally substituted with 1-5 R 1 . In some embodiments, each of A 1 and A 2 is the same C 1 -C 20 heteroalkyl, each of which may be optionally substituted with 1-5 R 1 . In some embodiments, each of A 1 and A 2 is a different C 1 -C 20 heteroalkyl, each of which may be optionally substituted with 1-5 R 1 .

In some embodiments, each of A 1 and A 2 is independently represented by a moiety of Formula (II):

wherein:

X 1 is C 1 -C 12 alkylene, C 2 -C 12 alkenylene, C 2 -C 12 alkynylene, C 1 -C 12 heteroalkylene, C 3 -C 8 cyclyl, or C 3 -C 8 heterocyclyl, wherein each alkylene, alkenylene, alkynylene, heteroalkylene, cyclyl, or heterocyclyl is optionally substituted with 1-6 R 4 ;

each R 4 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, OR 5 , (C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-NR 6 —(C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-C(O)NR 6 —(C 1 -C 6 alkylene)-OR 5 , or (C 1 -C 6 alkylene)-NR 6 C(O)—(C 1 -C 6 alkylene)-OR 5 , wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 7 ;

each R 5 is independently hydrogen, C 1 -C 6 alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, a linker, an agent, a targeting moiety, a protecting group, or a branching point, wherein each alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl is optionally substituted with 1-6 R 8 ;

R 6 is hydrogen or C 1 -C 6 alkyl;

each R 7 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, halo, OR 5 , (C 1 -C 6 alkylene)-OR 5 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 5 , cyano, cyclyl, heterocyclyl, aryl, or heteroaryl; and

each R 8 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, halo, cyano, cyclyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-6 R 9 ; and

each R 9 is independently C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, cyano, cyclyl, or heterocyclyl.

In some embodiments, X 1 is C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 1 -C 8 cyclyl, or C 1 -C 8 heterocyclyl, wherein each alkylene, heteroalkylene, cyclyl, or heterocyclyl is optionally substituted with 1-6 R 4 . In some embodiments, X 1 is C 1 -C 12 alkylene or C 1 -C 12 heteroalkylene, optionally substituted with 1-6 R 4 . In some embodiments, X 1 is C 1 -C 6 alkylene, optionally substituted with 1-6 R 4 . In some embodiments, X 1 is C 1 -C 12 heteroalkylene, optionally substituted with 1-6 R 4 .

In some embodiments, X 1 is C 3 -C 8 cyclyl or C 3 -C 8 heterocyclyl, wherein each cyclyl or heterocyclyl is optionally substituted with 1-6 R 4 . In some embodiments, X 1 is C 3 -C 6 cyclyl or C 3 -C 6 heterocyclyl, wherein each cyclyl or heterocyclyl is optionally substituted with 1-6 R 4 . In some embodiments, X 1 is C 3 -C 6 cyclyl, optionally substituted with 1-6 R 4 . In some embodiments, X 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1-6 R 4 . In some embodiments, X 1 is cyclopentyl or cyclohexyl, each of which is optionally substituted with 1-6 R 4 . In some embodiments, X 1 is cyclopentyl or cyclohexyl, each of which is optionally substituted with 1-4 R 4 . In some embodiments, X 1 is cyclopentyl or cyclohexyl, each of which is optionally substituted with 1-2 R 4 , and each R 4 is independently C 1 -C 6 alkyl or OR 5 . In some embodiments, X 1 is cyclohexyl substituted with 1 R 4 . In some embodiments, X 1 is cyclohexyl substituted with OR 5 .

In some embodiments, R 5 is hydrogen, C 1 -C 6 alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is arylalkyl or heteroarylalkyl. In some embodiments, R 5 is a linker. In some embodiments, R 5 is an agent (e.g., an ARB). In some embodiments, R 5 is a targeting moiety. In some embodiments, R 5 is a protecting group. In some embodiments, R 5 is a branching point.

In some embodiments, each of A 1 and A 2 does not independently include, or is independently not derived from, tri(methylol)ethane. In some embodiments, each of A 1 and A 2 does not independently include, or is not independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 5 kDa in size. In some embodiments, each of A 1 and A 2 does not independently include, or is not independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 10 kDa in size.

In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane. In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 5 kDa in size. In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 10 kDa in size.

In some embodiments of a polymer of Formula (I), each of A 1 and A 2 is independently hydrophobic. In some embodiments, each of A 1 and A 2 has a partition coefficient (c Log P) value greater than about −2.0. In some embodiments, each of A 1 and A 2 has a c Log P value greater than about −1.5, e.g., about −1.4, about −1.3, about −1.2, about −1.1, about −1.0, about −0.9, about −0.8, about −0.7, about −0.6, about −0.5, about −0.4, about −0.3, about −0.2, about −0.1, about 0, or higher. In some embodiments, each of A 1 and A 2 has a c Log P value between about −2.0 and 2.5. In some embodiments, each of A 1 and A 2 has a c Log P value greater than about −0.5, e.g., about −0.4, about −0.3, about −0.2, about −0.1, about 0, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, or higher. In some embodiments, each of A 1 and A 2 has a c Log P value greater than about 0, e.g., about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, or higher. In some embodiments, each of A 1 and A 2 has a c Log P value between about −2.0 and 4.0.

In some embodiments, each of A 1 and A 2 has a linear structure. In some embodiments, each of A 1 and A 2 has a branched structure. In some embodiments, each of A 1 and A 2 comprises a protected reactive group, e.g., a protected hydroxyl, a protected carboxylic acid, or a protected amine. In some embodiments, each of A 1 and A 2 comprises 1, 2, 3, 4, 5, 6, 7, 8, or more protected reactive groups, e.g., a protected hydroxyl, a protected carboxylic acid, or a protected amine.

In some embodiments, each of A 1 and A 2 is represented by a compound of Formula (II-a):

wherein:

each of X 2 and X 3 is independently C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 12 alkynylene, C 1 -C 12 heteroalkylene, C 3 -C 8 cyclyl, C 3 -C 8 heterocyclyl, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-NR 13 —(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)NR 13 —(C 1 -C 6 alkylene), or (C 1 -C 6 alkylene)-NR 13 C(O)—(C 1 -C 6 alkylene), wherein each alkylene, alkenylene, alkynylene, heteroalkylene, cyclyl, or heterocyclyl is optionally substituted with 1-6 R 12 ;

R 10 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, OR 14 , (C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-NR 13 —(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-C(O)NR 13 —(C 1 -C 6 alkylene)-OR 14 , or (C 1 -C 6 alkylene)-NR 13 C(O)—(C 1 -C 6 alkylene)-OR 14 , wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 15 ;

R 11 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, OR 14 , (C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-NR 13 —(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-C(O)NR 13 —(C 1 -C 6 alkylene)-OR 14 , or (C 1 -C 6 alkylene)-NR 13 C(O)—(C 1 -C 6 alkylene)-OR 14 , wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 15 ;

each R 12 and R 13 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, halo, OR 14 , (C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 14 , cyano, cyclyl, heterocyclyl, aryl, or heteroaryl;

R 13 is hydrogen or C 1 -C 6 alkyl:

R 14 is hydrogen, C 1 -C 6 alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, a linker, a branching point, a protecting group, an agent, or a targeting moiety, wherein each alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl is optionally substituted with 1-6 R 16 ; and

each R 16 is independently C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, cyano, cyclyl, or heterocyclyl.

In some embodiments, each of X 2 and X 3 is independently C 1 -C 6 alkylene, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene), wherein each alkyl or alkylene is optionally substituted with 1-6 R 8 . In some embodiments, each of X 1 and X 2 is independently C 1 -C 4 alkyl, (C 1 -C 4 alkylene)-O—(C 1 -C 4 alkylene), (C 1 -C 4 alkylene)-C(O)—(C 1 -C 4 alkylene), (C 1 -C 4 alkylene)-OC(O)—(C 1 -C 4 alkylene), (C 1 -C 4 alkylene)-C(O)O—(C 1 -C 4 alkylene), (C 1 -C 4 alkylene)-OC(O)O—(C 1 -C 4 alkylene), wherein each alkyl or alkylene is optionally substituted with 1-6 R 12 .

In some embodiments, each of X 2 and X 3 is independently C 1 -C 2 alkylene, e.g., CH 2 , CH 2 CH 2 . In some embodiments, each of X 2 and X 3 is independently (C 1 -C 4 alkylene)-O—(C 1 -C 4 alkylene), e.g., CH 2 —O—CH 2 CH 2 , CH 2 CH 2 —O—CH 2 CH 2 . In some embodiments, each of X 1 and X 2 is independently (C 1 -C 4 alkylene)-OC(O)—(C 1 -C 4 alkylene), e.g., CH 2 —OC(O)—CH 2 , CH 2 —OC(O)—CH 2 CH 2 , CH 2 —OC(O)—CH(CH 3 ), CH 2 —OC(O)—CH 2 CH 2 CH 2 , CH 2 CH 2 —OC(O)—CH 2 , CH 2 CH 2 —OC(O)—CH 2 CH 2 , CH 2 CH 2 —OC(O)—CH(CH 3 ). In some embodiments, each of X 2 and X 3 is independently (C 1 -C 4 alkylene)-OC(O)O—(C 1 -C 4 alkylene), e.g., CH 2 —OC(O)O—CH 2 CH 2 ). In some embodiments, each of X 2 and X 3 is the same.

In some embodiments, R 10 is C 1 -C 6 alkyl, (C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-OR 14 , wherein each alkyl or alkylene is optionally substituted with 1-6 R 15 . In some embodiments, R 10 is C 1 -C 6 alkyl, e.g., CH 3 , CH 2 CH 3 . In some embodiments, R 10 is (C 1 -C 6 alkylene)-OR 14 , e.g., CH 2 OR 14 , CH 2 CH 2 OR 14 . In some embodiments, R 10 is (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 14 , In some embodiments, R 10 is (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-OR 14 , e.g., CH 2 —OC(O)—CH 2 , CH 2 —OC(O)—CH 2 CH 2 , CH 2 —OC(O)—CH(CH 3 ), CH 2 —OC(O)—CH 2 CH 2 CH 2 , CH 2 CH 2 —OC(O)—CH 2 , CH 2 CH 2 —OC(O)—CH 2 CH 2 , CH 2 CH 2 —OC(O)—CH(CH 3 ). In some embodiments, R 10 is (C 1 -C 4 alkylene)-OC(O)O—(C 1 -C 4 alkylene), e.g., CH 2 —OC(O)O—CH 2 CH 2 ).

In some embodiments, R 11 is hydrogen or C 1 -C 6 alkyl. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is C 1 -C 6 alkyl. In some embodiments, R 11 is C 1 -C 4 alkyl, e.g., CH 3 , CH 2 CH 3 . In some embodiments, R 11 is (C 1 -C 6 alkylene)-OR 14 , e.g., CH 2 OR 14 , CH 2 CH 2 OR 14 .

In some embodiments, R 14 is hydrogen, C 1 -C 6 alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl. In some embodiments, R 14 is hydrogen. In some embodiments, R 14 is arylalkyl or heteroarylalkyl. In some embodiments, R 14 is a linker. In some embodiments, R 14 is an agent (e.g., an ARB). In some embodiments, R 14 is a targeting moiety. In some embodiments, R 14 is a protecting group. In some embodiments, R 14 is a branching point.

In some embodiments, each of A 1 and A 2 does not independently include, or is not independently derived from, tri(methylol)ethane. In some embodiments, each of A 1 and A 2 does not independently include, or is not independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 5 kDa in size. In some embodiments, each of A 1 and A 2 does not independently include, or is not independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 10 kDa in size.

In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane. In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 5 kDa in size. In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 10 kDa in size.

In some embodiments, each of A 1 and A 2 is represented by a compound of Formula (II-b):

wherein:

each of X 2 and X 3 is independently C 1 -C 6 alkylene, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene), or (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene);

R 10 is C 1 -C 6 alkyl, (C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 14 , (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-OR 14 , or (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-OR 14 , wherein each alkylene is optionally substituted with 1-4 (C 1 -C 6 alkylene)-OR 14 ;

R 11 is hydrogen, C 1 -C 6 alkyl, or (C 1 -C 6 alkylene)-OR 14 ; and

R 14 is hydrogen, C 1 -C 6 alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, a linker, an agent, a targeting moiety, a protecting group, or a branching point.

In some embodiments, each of X 2 and X 3 is independently C 1 -C 2 alkylene, e.g., CH 2 , CH 2 CH 2 . In some embodiments, each of X 2 and X 3 is independently (C 1 -C 4 alkylene)-O—(C 1 -C 4 alkylene), e.g., CH 2 —O—CH 2 CH 2 , CH 2 CH 2 —O—CH 2 CH 2 . In some embodiments, each of X 1 and X 2 is independently (C 1 -C 4 alkylene)-OC(O)—(C 1 -C 4 alkylene), e.g., CH 2 —OC(O)—CH 2 , CH 2 —OC(O)—CH 2 CH 2 , CH 2 —OC(O)—CH(CH 3 ), CH 2 —OC(O)—CH 2 CH 2 CH 2 , CH 2 CH 2 —OC(O)—CH 2 , CH 2 CH 2 —OC(O)—CH 2 CH 2 , CH 2 CH 2 —OC(O)—CH(CH 3 ). In some embodiments, each of X 2 and X 3 is independently (C 1 -C 4 alkylene)-OC(O)O—(C 1 -C 4 alkylene), e.g., CH 2 —OC(O)O—CH 2 CH 2 ). In some embodiments, each of X 2 and X 3 is the same.

In some embodiments, R 10 is C 1 -C 6 alkyl, e.g., CH 3 , CH 2 CH 3 . In some embodiments, R 10 is (C 1 -C 6 alkylene)-OR 14 , e.g., CH 2 OR 14 , CH 2 CH 2 OR 14 . In some embodiments, R 10 is (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-OR 14 , In some embodiments, R 10 is (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-OR 14 , e.g., CH 2 —OC(O)—CH 2 , CH 2 —OC(O)—CH 2 CH 2 , CH 2 —OC(O)—CH(CH 3 ), CH 2 —OC(O)—CH 2 CH 2 CH 2 , CH 2 CH 2 —OC(O)—CH 2 , CH 2 CH 2 —OC(O)—CH 2 CH 2 , CH 2 CH 2 —OC(O)—CH(CH 3 ). In some embodiments, R 10 is (C 1 -C 4 alkylene)-OC(O)O—(C 1 -C 4 alkylene), e.g., CH 2 —OC(O)O—CH 2 CH 2 ).

In some embodiments, R 11 is hydrogen or C 1 -C 6 alkyl. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is C 1 -C 6 alkyl. In some embodiments, R 11 is C 1 -C 4 alkyl, e.g., CH 3 , CH 2 CH 3 . In some embodiments, R 11 is (C 1 -C 6 alkylene)-OR 14 , e.g., CH 2 OR 14 , CH 2 CH 2 OR 14 .

In some embodiments, R 14 is hydrogen, C 1 -C 6 alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl. In some embodiments, R 14 is hydrogen. In some embodiments, R 14 is arylalkyl or heteroarylalkyl. In some embodiments, R 14 is a linker. In some embodiments, R 14 is an agent (e.g., an ARB). In some embodiments, R 14 is a targeting moiety. In some embodiments, R 14 is a protecting group. In some embodiments, R 14 is a branching point.

In some embodiments, each of A 1 and A 2 is the same. In some embodiments, each of A 1 and A 2 is the same, e.g., the same compound of Formula (II), Formula (II-a), or Formula (II-b). In some embodiments, each of A 1 and A 2 is different. In some embodiments, each of A 1 and A 2 is the different, e.g., a different compound of Formula (II), Formula (II-a), or Formula (II-b).

In some embodiments, the precursor of each of A 1 and A 2 is independently selected from the following polyols:

In some embodiments, the precursor to each of A 1 and A 2 is independently selected from one of A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A4, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, and A32, e.g., as depicted in FIG. 1B . It is to be understood that when the precursor to A 1 or A 2 is one of the polyols in the above-noted group selected from A1-A32, B 1 or B 2 is connected to one of the oxygen atoms of the hydroxyl groups in said polyols.

In some embodiments, X 1 includes or is derived from a polyol selected from one of A3, A4, A5, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, and A32, e.g., as depicted in FIG. 1B . It is to be understood that when the precursor to A 1 or A 2 is one of the polyols in the above-noted group selected from A1-A32, B 1 or B 2 is connected to one of the oxygen atoms of the hydroxyl groups in said polyols.

In some embodiments, each of A 1 and A 2 is represented by a compound of Formula (II-c):

wherein:

X 1 includes or is derived from any of the polyols shown in FIG. 1B , e.g., a polyol selected from one of A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, and A32, and two of the hydroxyl groups of the polyol are replaced by the oxygen atoms in Formula (II-c).

In some embodiments, X 1 includes or is derived from any of the polyols shown in FIG. 1B , e.g., a polyol selected from one of A3, A4, A5, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, and A32, and two of the hydroxyl groups of the polyol are replaced by the oxygen atoms in Formula (II-c).

In some embodiments, X 1 includes or is derived from A1. In some embodiments, X 1 includes or is derived from A2. In some embodiments, X 1 includes or is derived from A3. In some embodiments, X 1 includes or is derived from A4. In some embodiments, X 1 includes or is derived from A5. In some embodiments, X 1 includes or is derived from A6. In some embodiments, X 1 includes or is derived from A7. In some embodiments, X 1 includes or is derived from A8. In some embodiments, X 1 includes or is derived from A9. In some embodiments, X 1 includes or is derived from A10. In some embodiments, X 1 includes or is derived from A11. In some embodiments, X 1 includes or is derived from A12. In some embodiments, X 1 includes or is derived from A13. In some embodiments, X 1 includes or is derived from A14. In some embodiments, X 1 includes or is derived from A15. In some embodiments, X 1 includes or is derived from A16. In some embodiments, X 1 includes or is derived from A17. In some embodiments, X 1 includes or is derived from A18. In some embodiments, X 1 includes or is derived from A19. In some embodiments, X 1 includes or is derived from A20. In some embodiments, X 1 includes or is derived from A21. In some embodiments, X 1 includes or is derived from A22. In some embodiments, X 1 includes or is derived from A23. In some embodiments, X 1 includes or is derived from A24. In some embodiments, X 1 includes or is derived from A25. In some embodiments, X 1 includes or is derived from A26. In some embodiments, X 1 includes or is derived from A27. In some embodiments, X 1 includes or is derived from A28. In some embodiments, X 1 includes or is derived from A29. In some embodiments, X 1 includes or is derived from A30. In some embodiments, X 1 includes or is derived from A31. In some embodiments, X 1 includes or is derived from A32.

In some embodiments, each of A 1 and A 2 includes or is derived from the same polyol, e.g., a polyol selected from one of A1-A32. In some embodiments, each of A 1 and A 2 includes or is derived from a different polyol, e.g., a polyol selected from one of A1-A32.

In some embodiments, one or both of A 1 and A 2 is represented by a compound of Formula (II-d):

wherein:

X 1 is C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 3 -C 8 cyclyl, or C 3 -C 8 heterocyclyl, wherein each alkylene, heteroalkylene, cyclyl, and heterocyclyl is optionally substituted with 1-6 R 4b ;

R 4a is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, O, (C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-NR 6 —(C 1 -C 6 alkylene)-O—, (C 1 -C 6 alkylene)-C(O)NR 6 —(C 1 -C 6 alkylene)-O, or (C 1 -C 6 alkylene)-NR 6 C(O)—(C 1 -C 6 alkylene)-O, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 7 ;

each R 4b is independently C 1 -C 6 alkyl or (C 1 -C 6 alkylene)-O-L-ARB;

L is a bond or a linker, e.g., a linker as described herein;

ARB is an angiotensin II receptor blocker, e.g., losartan, valsartan, telmisartan, candesartan, eprosartan, irbesartan, azilsartan, EXP-3174, olmesartan, or a prodrug or active metabolite thereof;

R 6 is hydrogen or C 1 -C 6 alkyl; and

each R 7 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, halo, O-L-ARB, (C 1 -C 6 alkylene)-O-L-ARB, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-ARB, cyano, cyclyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, X 1 is C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 1 -C 8 cyclyl, or C 1 -C 8 heterocyclyl. In some embodiments, X 1 is C 1 -C 12 alkylene or C 1 -C 12 heteroalkylene. In some embodiments, X 1 is C 1 -C 6 alkylene. In some embodiments, X 1 is C 1 -C 12 heteroalkylene.

In some embodiments, X 1 is C 3 -C 8 cyclyl or C 3 -C 8 heterocyclyl. In some embodiments, X 1 is C 3 -C 6 cyclyl or C 3 -C 6 heterocyclyl. In some embodiments, X 1 is C 3 -C 6 cyclyl. In some embodiments, X 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, X 1 is cyclopentyl or cyclohexyl. In some embodiments, X 1 is cyclopentyl or cyclohexyl. In some embodiments, X 1 is cyclohexyl.

In some embodiments, R 4a is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, O, (C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O, or (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O, wherein each alkyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 7 . In some embodiments, R 4a is C 1 -C 6 alkyl (e.g., CH 3 or CH 2 CH 3 ). In some embodiments, R 4a is O. In some embodiments, R 4a is (C 1 -C 6 alkylene)-O (e.g., CH 2 O or CH 2 CH 2 O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O (e.g., CH 2 OCH 2 CH 2 O or CH 2 CH 2 OCH 2 CH 2 O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O (e.g., CH 2 OC(O)CH 2 O, CH 2 CH 2 OC(O)CH 2 O, CH 2 OC(O)CH 2 CH 2 O, CH 2 OC(O)CH 2 CH 2 CH 2 O, CH 2 CH 2 OC(O)CH 2 CH 2 O, CH 2 CH 2 OC(O)CH 2 CH 2 CH 2 O, CH 2 OC(O)CH(CH 3 )O, or CH 2 CH 2 OC(O)CH(CH 3 )O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O (e.g., CH 2 OC(O)OCH 2 CH 2 O).

In some embodiments, R 4b is C 1 -C 6 alkyl (e.g., CH 3 , CH 2 CH 3 ). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-ARB, e.g., (CH 2 —O-L-ARB).

In some embodiments, L is a bond. In some embodiments, L is a linker. In some embodiments, L is a linker as described herein, e.g., a polyacetal polymer.

In some embodiments, ARB is losartan, valsartan, telmisartan, candesartan, eprosartan, irbesartan, azilsartan, EXP-3174, olmesartan, or a prodrug or active metabolite thereof. In some embodiments, ARB is losartan. In some embodiments, ARB is valsartan. In some embodiments, ARB is telmisartan. In some embodiments, ARB is candesartan. In some embodiments, ARB is eprosartan. In some embodiments, ARB is azilsartan. In some embodiments, ARB is EXP-3174. In some embodiments, ARB is olmesartan. In some embodiments, ARB is azilsartan medoxomil. In some embodiments, ARB is candesartan cilexetil. In some embodiments, ARB is olmesartan medoxomil. In some embodiments, ARB is a compound shown in FIG. 23 .

In some embodiments, one or both of A 1 and A 2 is represented by a compound of Formula (II-e), Formula (II-f), Formula (II-g), Formula (II-h), or Formula (II-i):

wherein:

X 1 is C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 3 -C 8 cyclyl, or C 3 -C 8 heterocyclyl, wherein each alkylene, heteroalkylene, cyclyl, and heterocyclyl is optionally substituted with 1-6 R 4b ;

R 4a is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, O, (C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-NR 6 —(C 1 -C 6 alkylene)-O—, (C 1 -C 6 alkylene)-C(O)NR 6 —(C 1 -C 6 alkylene)-O, or (C 1 -C 6 alkylene)-NR 6 C(O)—(C 1 -C 6 alkylene)-O, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 7 ;

each R 4b is independently C 1 -C 6 alkyl, (C 1 -C 6 alkylene)-O-L-losartan, (C 1 -C 6 alkylene)-O-L-valsartan, (C 1 -C 6 alkylene)-O-L-telmisartan, (C 1 -C 6 alkylene)-O-L-candesartan, or (C 1 -C 6 alkylene)-O-L-olmesartan;

L is a linker, e.g., a linker as described herein;

R 6 is hydrogen or C 1 -C 6 alkyl; and

each R 7 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, halo, O-L-losartan, O-L-valsartan, O-L-telmisartan, O-L-candesartan, O-L-olmesartan, (C 1 -C 6 alkylene)-O-L-losartan, (C 1 -C 6 alkylene)-O-L-valsartan, (C 1 -C 6 alkylene)-O-L-telmisartan, (C 1 -C 6 alkylene)-O-L-candesartan, (C 1 -C 6 alkylene)-O-L-olmesartan, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-losartan, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-valsartan, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-telmisartan, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-candesartan, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-olmesartan, cyano, cyclyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, X 1 is C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 1 -C 8 cyclyl, or C 1 -C 8 heterocyclyl. In some embodiments, X 1 is C 1 -C 12 alkylene or C 1 -C 12 heteroalkylene. In some embodiments, X 1 is C 1 -C 6 alkylene. In some embodiments, X 1 is C 1 -C 12 heteroalkylene.

In some embodiments, X 1 is C 3 -C 8 cyclyl or C 3 -C 8 heterocyclyl. In some embodiments, X 1 is C 3 -C 6 cyclyl or C 3 -C 6 heterocyclyl. In some embodiments, X 1 is C 3 -C 6 cyclyl. In some embodiments, X 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, X 1 is cyclopentyl or cyclohexyl. In some embodiments, X 1 is cyclopentyl or cyclohexyl. In some embodiments, X 1 is cyclohexyl.

In some embodiments, R 4a is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, O, (C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O, or (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O, wherein each alkyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 7 . In some embodiments, R 4a is C 1 -C 6 alkyl (e.g., CH 3 or CH 2 CH 3 ). In some embodiments, R 4a is O. In some embodiments, R 4a is (C 1 -C 6 alkylene)-O (e.g., CH 2 O or CH 2 CH 2 O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O (e.g., CH 2 OCH 2 CH 2 O or CH 2 CH 2 OCH 2 CH 2 O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O (e.g., CH 2 OC(O)CH 2 O, CH 2 CH 2 OC(O)CH 2 O, CH 2 OC(O)CH 2 CH 2 O, CH 2 OC(O)CH 2 CH 2 CH 2 O, CH 2 CH 2 OC(O)CH 2 CH 2 O, CH 2 CH 2 OC(O)CH 2 CH 2 CH 2 O, CH 2 OC(O)CH(CH 3 )O, or CH 2 CH 2 OC(O)CH(CH 3 )O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O (e.g., CH 2 OC(O)OCH 2 CH 2 O).

In some embodiments, R 4b is C 1 -C 6 alkyl (e.g., CH 3 , CH 2 CH 3 ). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-losartan, e.g., (CH 2 —O-L-losartan). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-valsartan, e.g., (CH 2 —O-L-valsartan). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-telmisartan, e.g., (CH 2 —O-L-telmisartan). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-candesartan, e.g., (CH 2 —O-L-candesartan). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-olmesartan, e.g., (CH 2 —O-L-olmesartan).

In some embodiments, L is a bond. In some embodiments, L is a linker. In some embodiments, L is a linker as described herein, e.g., a polyacetal polymer.

In some embodiments, one or both of A 1 and A 2 is represented by a compound of Formula (II-j):

wherein:

X 1 is C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 3 -C 8 cyclyl, or C 3 -C 8 heterocyclyl, wherein each alkylene, heteroalkylene, cyclyl, and heterocyclyl is optionally substituted with 1-6 R 4b ;

R 4a is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, O, (C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-NR 6 —(C 1 -C 6 alkylene)-O—, (C 1 -C 6 alkylene)-C(O)NR 6 —(C 1 -C 6 alkylene)-O, or (C 1 -C 6 alkylene)-NR 6 C(O)—(C 1 -C 6 alkylene)-O, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 7 ;

each R 4b is independently C 1 -C 6 alkyl, (C 1 -C 6 alkylene)-O-L-T, or (C 1 -C 6 alkylene)-O-L-ARB;

L is a bond or a linker, e.g., a linker as described herein;

T is a targeting moiety, e.g., mannose-6-phosphate;

ARB is an angiotensin II receptor blocker, e.g., losartan, valsartan, telmisartan, candesartan, eprosartan, irbesartan, azilsartan, EXP-3174, olmesartan, or a prodrug or active metabolite thereof;

R 6 is hydrogen or C 1 -C 6 alkyl; and

each R 7 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, halo, O-L-T, (C 1 -C 6 alkylene)-O-L-T, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-T, O-L-ARB, (C 1 -C 6 alkylene)-O-L-ARB, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-ARB, cyano, cyclyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, X 1 is C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 1 -C 8 cyclyl, or C 1 -C 8 heterocyclyl. In some embodiments, X 1 is C 1 -C 12 alkylene or C 1 -C 12 heteroalkylene. In some embodiments, X 1 is C 1 -C 6 alkylene. In some embodiments, X 1 is C 1 -C 12 heteroalkylene.

In some embodiments, X 1 is C 3 -C 8 cyclyl or C 3 -C 8 heterocyclyl. In some embodiments, X 1 is C 3 -C 6 cyclyl or C 3 -C 6 heterocyclyl. In some embodiments, X 1 is C 3 -C 6 cyclyl. In some embodiments, X 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, X 1 is cyclopentyl or cyclohexyl. In some embodiments, X 1 is cyclopentyl or cyclohexyl. In some embodiments, X 1 is cyclohexyl.

In some embodiments, R 4a is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, O, (C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O, or (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O, wherein each alkyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 7 . In some embodiments, R 4a is C 1 -C 6 alkyl (e.g., CH 3 or CH 2 CH 3 ). In some embodiments, R 4a is O. In some embodiments, R 4a is (C 1 -C 6 alkylene)-O (e.g., CH 2 O or CH 2 CH 2 O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O (e.g., CH 2 OCH 2 CH 2 O or CH 2 CH 2 OCH 2 CH 2 O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O (e.g., CH 2 OC(O)CH 2 O, CH 2 CH 2 OC(O)CH 2 O, CH 2 OC(O)CH 2 CH 2 O, CH 2 OC(O)CH 2 CH 2 CH 2 O, CH 2 CH 2 OC(O)CH 2 CH 2 O, CH 2 CH 2 OC(O)CH 2 CH 2 CH 2 O, CH 2 OC(O)CH(CH 3 )O, or CH 2 CH 2 OC(O)CH(CH 3 )O). In some embodiments, R 4a is (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O (e.g., CH 2 OC(O)OCH 2 CH 2 O).

In some embodiments, R 4b is C 1 -C 6 alkyl (e.g., CH 3 , CH 2 CH 3 ). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-T, e.g., (CH 2 —O-L-T). In some embodiments, R 4b is (C 1 -C 6 alkylene)-O-L-ARB, e.g., (CH 2 —O-L-ARB).

In some embodiments, L is a bond. In some embodiments, L is a linker. In some embodiments, L is a linker as described herein, e.g., a polyacetal polymer.

In some embodiments, T is a targeting moiety described herein. In some embodiments, T is mannose-6-phosphate.

In some embodiments, ARB is losartan, valsartan, telmisartan, candesartan, eprosartan, irbesartan, azilsartan, EXP-3174, olmesartan, or an analogue or derivative thereof (e.g., a prodrug or active metabolite thereof). In some embodiments, ARB is losartan. In some embodiments, ARB is valsartan. In some embodiments, ARB is telmisartan. In some embodiments, ARB is candesartan. In some embodiments, ARB is eprosartan. In some embodiments, ARB is azilsartan. In some embodiments, ARB is EXP-3174. In some embodiments, ARB is olmesartan. In some embodiments, ARB is azilsartan medoxomil. In some embodiments, ARB is candesartan cilexetil. In some embodiments, ARB is olmesartan medoxomil. In some embodiments, ARB is a compound shown in FIG. 23 .

In some embodiments, each of A 1 and A 2 does not independently include, or is independently not derived from, tri(methylol)ethane. In some embodiments, each of A 1 and A 2 does not independently include, or is not independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 5 kDa in size. In some embodiments, each of A 1 and A 2 does not independently include, or is not independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 10 kDa in size.

In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane. In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 5 kDa in size. In some embodiments, each of A 1 and A 2 independently includes, or is independently derived from, tri(methylol)ethane and the polymer of Formula (I) is greater than about 10 kDa in size.

In some embodiments of a polymer of Formula (I), each of B 1 and B 2 is independently heteroalkyl or aryloxy, each of which may be optionally substituted with 1-5 R 1 . In some embodiments, each of B 1 and B 2 is independently heteroalkyl, each of which may be optionally substituted with 1-5 R 1 . In some embodiments, each of B 1 and B 2 is independently C 1 -C 20 heteroalkyl, each of which may be optionally substituted with 1-5 R 1 . In some embodiments, each of B 1 and B 2 is the same. In some embodiments, each of B 1 and B 2 is the different.

In some embodiments, each of B 1 and B 2 is independently represented by a moiety of Formula (III):

wherein:

Z 1 is O, C 3 -C 8 cyclyl, C 3 -C 8 heterocyclyl, or C(R 22 )(R 23 ), wherein each of cyclyl and heterocyclyl is optionally substituted with 1-4 R 25 ;

each of X 4 and X 5 is independently C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, C 1 -C 6 heteroalkylene, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-NR 24 —(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-C(O)NR 24 —(C 1 -C 6 alkylene), or (C 1 -C 6 alkylene)-NR 24 C(O)—(C 1 -C 6 alkylene), wherein each alkylene, alkenylene, alkynylene, or heteroalkylene is optionally substituted with 1-6 R 25 ;

each of R 20 and R 21 is independently C 1 -C 6 alkyl, OR 26 , cyclyl, heterocyclyl;

each of R 22 and R 23 is independently hydrogen, C 1 -C 6 alkyl, OR 26 , (C 1 -C 6 alkylene)-OR 26 , halo, cyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkylene, cyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-6 R 27 ;

each R 25 and R 27 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, cyano, cyclyl, or heterocyclyl, and

R 26 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, a linker, an agent, a targeting moiety, a protecting group, or a branching point, wherein each alkyl, cyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl is optionally substituted with 1-6 R 28 ; and

each R 28 is independently C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, cyano, cyclyl, or heterocyclyl.

In some embodiments, Z 1 is O.

In some embodiments, Z 1 is C 3 -C 8 cyclyl or C 3 -C 8 heterocyclyl, each of which is optionally substituted with 1-4 R 25 . In some embodiments, Z 1 is C 3 -C 6 cyclyl or C 3 -C 6 heterocyclyl, each of which is optionally substituted with 1-4 R 25 . In some embodiments, Z 1 is C 3 -C 6 cyclyl, optionally substituted with 1-4 R 25 . In some embodiments, Z 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1-4 R 25 . In some embodiments, Z 1 is cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1-4 R 25 . In some embodiments, Z 1 is cyclohexyl, optionally substituted with 1-4 R 25 . In some embodiments, Z 1 is cyclohexyl.

In some embodiments, Z 1 is C(R 22 )(R 23 ). In some embodiments, Z 1 is C(R 23 )(R 24 ) and each of R 22 and R 23 is independently hydrogen, C 1 -C 6 alkyl, or (C 1 -C 6 alkylene)-OR 26 . In some embodiments, each of R 22 and R 23 is independently hydrogen. In some embodiments, each of R 22 and R 23 is independently hydrogen or C 1 -C 6 alkyl, e.g., CH 3 . In some embodiments, each of R 22 and R 23 is independently hydrogen. In some embodiments, each of R 22 and R 23 is independently C 1 -C 6 alkyl, e.g., CH 3 . In some embodiments, R 22 is hydrogen and R 23 is independently C 1 -C 6 alkyl, e.g., CH 3 . In some embodiments, each of R 22 and R 23 is independently (C 1 -C 6 alkylene)-OR 26 . In some embodiments, each of R 22 and R 23 is independently (C 1 -C 2 alkylene)-OR 26 . In some embodiments, each of R 22 and R 23 is independently (C 1 -C 2 alkylene)-OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point. In some embodiments, R 22 is hydrogen or C 1 -C 6 alkyl (e.g., CH 3 ), R 23 is (C 1 -C 2 alkylene)-OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point. In some embodiments, R 22 is C 1 -C 6 alkyl (e.g., CH 3 ), R 23 is (C 1 -C 2 alkylene)-OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point.

In some embodiments, each of X 4 and X 5 is independently C 1 -C 6 alkylene, wherein alkylene is optionally substituted with 1-6 R 25 . In some embodiments, each of X 4 and X 5 is independently C 1 -C 4 alkylene, wherein alkylene is optionally substituted with 1-6 R 25 . In some embodiments, each of X 4 and X 5 is independently C 1 -C 2 alkylene, wherein alkylene is optionally substituted with 1-6 R 25 . In some embodiments, each of X 4 and X 5 is independently C 1 -C 2 alkylene (e.g., CH 2 , CH 2 CH 2 ).

In some embodiments, each of R 20 and R 21 is independently C 1 -C 6 alkyl or OR 26 . In some embodiments, each of R 20 and R 21 is independently C 1 -C 6 alkyl. In some embodiments, each of R 20 and R 21 is independently C 1 -C 4 alkyl. In some embodiments, each of R 20 and R 21 is independently C 1 -C 2 alkyl, e.g., CH 3 . In some embodiments, each of R 20 and R 21 is independently OR 26 . In some embodiments, each of R 20 and R 21 is independently OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point.

In some embodiments of a polymer of Formula (I), each of B 1 and B 2 is independently hydrophobic. In some embodiments, each of B 1 and B 2 has a partition coefficient (c Log P) value greater than about −2.0. In some embodiments, each of B 1 and B 2 has a c Log P value greater than about −1.5, e.g., about −1.4, about −1.3, about −1.2, about −1.1, about −1.0, about −0.9, about −0.8, about −0.7, about −0.6, about −0.5, about −0.4, about −0.3, about −0.2, about −0.1, about 0, or higher. In some embodiments, each of B 1 and B 2 has a c Log P value between about −1.5 and 2.5. In some embodiments, each of B 1 and B 2 has a c Log P value greater than about −0.5, e.g., about −0.4, about −0.3, about −0.2, about −0.1, about 0, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, or higher. In some embodiments, each of B 1 and B 2 has a c Log P value greater than about 0, e.g., about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, or higher.

In some embodiments, each of B 1 and B 2 has a linear structure. In some embodiments, each of B 1 and B 2 has a branched structure. In some embodiments, each of B 1 and B 2 comprises a protected reactive group, e.g., a protected hydroxyl, a protected carboxylic acid, or a protected amine. In some embodiments, each of B 1 and B 2 comprises 1, 2, 3, 4, 5, 6, 7, 8, or more protected reactive groups, e.g., a protected hydroxyl, a protected carboxylic acid, or a protected amine.

In some embodiments, each of B 1 and B 2 is independently represented by a moiety of Formula (III-a):

wherein:

Z 1 is O, C 3 -C 8 cyclyl, or C(R 22 )(R 23 );

each of X 4 and X 5 is independently C 1 -C 6 alkylene;

each of R 20 and R 21 is independently C 1 -C 6 alkyl or OR 20 ;

each of R 22 and R 23 is independently hydrogen, C 1 -C 6 alkyl, or (C 1 -C 6 alkylene)-OR 26 ; and each R 26 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, a linker, an agent, a targeting moiety, a protecting group, or a branching point.

In some embodiments, Z 1 is O.

In some embodiments, Z 1 is C 3 -C 6 cyclyl. In some embodiments, Z 1 is cyclopentyl, or cyclohexyl. In some embodiments, Z 1 is cyclohexyl.

In some embodiments, Z 1 is C(R 22 )(R 23 ). In some embodiments, Z 1 is C(R 23 )(R 24 ) and each of R 22 and R 23 is independently hydrogen. In some embodiments, each of R 22 and R 23 is independently hydrogen or C 1 -C 6 alkyl, e.g., CH 3 . In some embodiments, each of R 22 and R 23 is independently hydrogen. In some embodiments, each of R 22 and R 23 is independently C 1 -C 6 alkyl, e.g., CH 3 . In some embodiments, R 22 is hydrogen and R 23 is independently C 1 -C 6 alkyl, e.g., CH 3 . In some embodiments, each of R 22 and R 23 is independently (C 1 -C 6 alkylene)-OR 26 . In some embodiments, each of R 2 and R 23 is independently (C 1 -C 2 alkylene)-OR 26 . In some embodiments, each of R 22 and R 23 is independently (C 1 -C 2 alkylene)-OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point. In some embodiments, R 22 is hydrogen or C 1 -C 6 alkyl (e.g., CH 3 ), R 23 is (C 1 -C 2 alkylene)-OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point. In some embodiments, R 22 is C 1 -C 6 alkyl (e.g., CH 3 ), R 23 is (C 1 -C 2 alkylene)-OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point.

In some embodiments, each of X 4 and X 5 is independently C 1 -C 4 alkylene. In some embodiments, each of X 4 and X 5 is independently C 1 -C 2 alkylene. In some embodiments, each of X 4 and X 5 is independently C 1 -C 2 alkylene (e.g., CH 2 , CH 2 CH 2 ).

In some embodiments, each of R 20 and R 21 is independently C 1 -C 6 alkyl. In some embodiments, each of R 2 and R 21 is independently C 1 -C 4 alkyl. In some embodiments, each of R 20 and R 21 is independently C 1 -C 2 alkyl, e.g., CH 3 . In some embodiments, each of R 2 and R 21 is independently OR 26 . In some embodiments, each of R 20 and R 21 is independently OR 26 , and R 26 is C 2 -C 6 alkenyl (e.g., CH═CH 2 ) or a branching point.

In some embodiments, the precursor of each of B 1 to B 2 is independently selected from the following vinyl ethers:

In some embodiments, the precursor to each of B 1 and B 2 is independently selected from one of B1, B2, B3, B4, B5, and B6, e.g., as depicted in FIG. 1C . It is to be understood that when the precursor to B 1 or B 2 is one of the vinyl ethers in the above-noted group selected from B1-B6, A 1 or A 2 and C 1 or C 2 is connected at the (CH) group of the vinyl moiety in each of said vinyl ethers.

In some embodiments, each of B 1 and B 2 is independently represented by a moiety of Formula (III-b):

wherein:

Z 2 includes or is derived from any of the vinyl ethers shown in FIG. 1C , e.g., a vinyl ether selected from one of B1, B2, B3, B4, B5, or B6, and two of the hydrogen atoms of the vinyl groups are replaced linkage indicated in Formula (III-b).

In some embodiments, Z 2 includes or is derived from B1. In some embodiments, Z 2 includes or is derived from B2. In some embodiments, Z 2 includes or is derived from B3. In some embodiments, Z 2 includes or is derived from B4. In some embodiments, Z 2 includes or is derived from B5. In some embodiments, Z 2 includes or is derived from B6.

In some embodiments, each of B 1 and B 2 includes or is derived from the same vinyl ether, e.g., a vinyl ether selected from one of B1-B6. In some embodiments, each of B 1 and B 2 includes or is derived from a different vinyl ether, e.g., a vinyl ether selected from one of B1-B6.

In some embodiments of a polymer of Formula (I), each of C 1 and C 2 is heteroalkyl, optionally substituted with 1-6 R 3 . In some embodiments, each of C 1 and C 2 is C 1 -C 20 heteroalkyl, optionally substituted with 1-6 R 3 . In some embodiments, each of C 1 and C 2 is C 1 -C 10 heteroalkyl. In some embodiments, each of C1 and C 2 is C 1 -C 10 heteroalkyl. In some embodiments, each of C 1 and C 2 is C 1 -C 10 heteroalkyl, e.g., an oxygen-containing C 1 -C 4 heteroalkyl and/or an amine-containing heteroalkyl. In some embodiments, each of C 1 and C 2 comprises a polyethylene glycol (PEG), a polyethylene oxide (PEO), a polypropylene glycol (PPG), a polyglycerol (PG), a poloxamine (POX), a polybutylene oxide (PBO), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polydioxanone (PDO), a polyanhydride, a polyacrylide, a polyvinyl, or a polyorthoester.

In some embodiments, each of C 1 and C 2 comprises a polyethylene glycol (PEG). In some embodiments, each of C 1 and C 2 comprises a polyethylene glycol (PEG) or a polyethylene oxide (PEO). In some embodiments, each of C 1 and C 2 comprises a polyethylene oxide (PEO) or a polypropylene glycol (PPG). In some embodiments, each of C 1 and C 2 comprises a polybutylene oxide (PBO).

In some embodiments, each of C 1 or C 2 has a linear structure, e.g., does not comprise a branching point or cyclic group. In some embodiments, each of C 1 or C 2 has a branched structure, e.g., comprising at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 branching points.

In some embodiments, each of C 1 or C 2 comprises a cyclic structure. In some embodiments, each of C 1 or C 2 comprises a cyclic structure, e.g., a cyclyl or heterocyclyl group. In some embodiments, each of C 1 or C 2 comprises a carbohydrate (e.g., a glucose derivative, galactose derivative, mannose derivative, fucose derivative, sialic acid derivative, or other carbohydrate derivative). In some embodiments, each of C 1 or C 2 comprises a dextran, a cyclodextran, chitosan, or other carbohydrate based moiety.

In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 20,000 Da in size. In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 17,500 Da, from about 200 Da to about 15,000 Da, from about 200 Da to about 12,500 Da, from about 200 Da to about 10,000 Da, from about 200 Da to about 9,000 Da, from about 200 Da to about 8,000 Da, from about 200 Da to about 7,000 Da, from about 200 Da to about 6,000 Da, from about 200 Da to about 5,000 Da, from about 200 Da to about 4,000 Da, from about 200 Da to about 3,000 Da, or from about 200 Da to about 2,000 Da in size. In some embodiments, each of C 1 or C 2 is independently from about 200 Da to about 5,000 Da in size. In some embodiments, each of C 1 or C 2 is independently from about 200 Da to about 2,000 Da in size.

In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 2,000 Da in size. In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 1,750 Da, from about 200 Da to about 1,500 Da, from about 200 to about 1,400 Da, from about 200 to about 1,300 Da, from about 200 to about 1,200, from about 200 to about 1,100, or from about 200 to about 1,000 in size. In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 900 Da, from about 200 Da to about 800, from about 200 to about 700 Da, from about 200 to about 600 Da, from about 200 to about 500 Da, or from about 200 to about 400 Da. each of C 1 or C 2 is independently about 400 Da in size

In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 2,000 Da in size. In some embodiments, each of C 1 or C 2 is independently about 200 Da to about 2,000 Da in size, from about 250 Da to about 1,900 in size, from about 300 Da to about 1,800, from about 350 Da to about 1,700, or from about 400 Da to about 1,600 in size. In some embodiments, each of C 1 or C 2 is independently about 500 Da to about 1,500 in size, from about 600 Da to about 1,500 in size, from about 700 Da to about 1,400, from about 800 Da to about 1,300, or from about 900 Da to about 1,200 in size. In some embodiments, each of C 1 or C 2 is independently about 1,000 Da to about 1,200 Da in size. In some embodiments, each of C 1 or C 2 is independently about 1,000 Da in size.

In some embodiments, each of C 1 and C 2 is the same. In some embodiments, both of C 1 and C 2 is from about 200 Da to about 1200 Da, from about 300 Da to about 1100 Da, or from about 400 Da to about 1000 Da in size. In some embodiments, both of C 1 and C 2 are from about 100 Da to about 500 Da or from about 800 Da to about 1200 Da in size. In some embodiments, both of C 1 and C 2 are 400 Da or 1000 Da in size.

In some embodiments, each of C 1 and C 2 is different. In some embodiments, each of C 1 and C 2 is from about 200 Da to about 1200 Da, from about 300 Da to about 1100 Da, or from about 400 Da to about 1000 Da in size. In some embodiments, one of C 1 and C 2 is from about 100 Da to about 500 Da and the other of C 1 and C 2 is from bout 800 Da to about 1200 Da in size. In some embodiments, one of C 1 and C 2 is about 400 Da in size and the other of C 1 and C 2 is about 1000 Da in size.

In some embodiments of the polymer of Formula (I), the precursor to each of C 1 and C 1 is PEG (e.g., polyethylene glycol). In some embodiments, the PEG comprises PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 800, PEG 1000, PEG 1500, PEG 2000, PEG 2050, PEG 4000, or PEG 6000, also referred to herein as P100, P200, P300, P400, P500, P600, P800, P1000, P1500, P2000, P2050, P4000, and P6000, or any combination thereof. In some embodiments, the PEG comprises P400, P1000, or a combination of P400 and P1000. In some embodiments, the PEG comprises P2050.

In some embodiments of a polymer (e.g., a polymer described herein, e.g., a polymer of Formula (I)), each of m and n independently an integer from 2 to 450, from 2 to 400, from 2 to 350, from 2 to 300, from 2 to 250, from 2 to 200, from 2 to 175, from 2 to 150, from 2 to 125, from 2 to 100, from 2 to 90, from 2 to 80, from 2 to 70, from 2 to 60, from 2 to 50, from 2 to 45, from 2 to 40, from 2 to 35, from 2 to 30, from 2 to 25, from 2 to 20, from 2 to 15, from 2 to 10, or from 2 to 5. In some embodiments, each of m and n independently is an integer from 2 to 250. In some embodiments, each of m and n independently is an integer from 2 to 100. In some embodiments, each of m and n independently is an integer from 2 to 50. In some embodiments, each of m and n independently is an integer from 2 to 25. In some embodiments, each of m and n independently is an integer from 2 to 10. In some embodiments, each of m and n independently is an integer from 10 to 500, from 10 to 250, from 10 to 200, from 10 to 150, from 10 to 100, from 10 to 75, from 10 to 50, or from 10 to 25. In some embodiments, each of m and n independently is an integer from 10 to 50.

In an embodiment, m and n taken together are between 10 and 100, 20 and 80, 20 and 60, or 30 and 60.

In one embodiment, the polymer, e.g., the polyacetal polymer, disclosed herein is pH sensitive. As used herein, the term “pH sensitive” in reference to the polyacetal polymers means that the polymer is sufficiently stable at a first pH but is cleaved or degraded at a second pH. In some embodiment, the polymer is cleaved at least 10 times or more, preferably at least 100 times faster at a second pH relative to the first pH. In some embodiments, the polymer degrades at an increased rate at a pH lower than 7.5 relative to degradation at pH 7.5 or higher. In some embodiments, the first pH can be pH about 7.5 or higher. In some embodiments, the second pH can be in the range of about between about 5.0 and about 7.4; pH between about 5.0 and about 7.0; pH between about 5.0 and 6.5; pH between about 5.0 and 6.0. In some embodiments, the second pH can be between about 5.9 and 6.2. In some embodiments, the second pH can be between about 5.5 and 6.5.

In the various aspects disclosed herein, the polyacetal polymers can be conjugated with a polyethylene glycol (PEG).

Linkers

As used herein, the term “pH sensitive linker” means a linker which is sufficiently stable at a first pH, but which is cleaved at a second pH to release the two parts the linker is holding together. In one embodiment, the pH sensitive linker is cleaved at least 10 times or more, preferably at least 100 times faster at a second pH relative to the first pH. In some embodiments, the first pH can be pH about 7.5 or higher. In some embodiments, the second pH is in the range of about between about 5.0 and about 7.4; pH between about 5.0 and about 7.0; pH between about 5.0 and 6.5; pH between about 5.0 and 6.0. In some embodiments, the second pH can be between about 5.9 and 6.2. In some embodiments, the second pH can be between about 5.5 and 6.5.

The pH sensitive linker can be selected via high-throughput strategy. The sensitivity can be tuned based on the variation of chemical structures. For example, in some embodiments, the linker is sensitive to pH between about 5.0 and about 7.4. In some embodiments, the linker is sensitive to pH between about 5.0 and about 7.0. In some embodiments, the linker is sensitive to pH between about 5.0 and 6.5. In some embodiments, the linker is sensitive to pH between about 5.0 and 5.5. In some embodiments, the linker is sensitive to pH between about 5.9 and 6.2. In some embodiments, the linker is sensitive to pH between about 5.5 and 6.5.

In some embodiments, the linker is sensitive to a pH of no more than 7.4, no more than 7.0, no more than 6.9, no more than 6.8, no more than 6.7, no more than 6.6, no more than 6.5, no more than 6.4, no more than 6.3, no more than 6.2, no more than 6.1, no more than 6.0, no more than 5.5 or lower.

In some embodiments of the various aspects disclosed herein, the pH sensitive linker can be an acetal or ketal group, anhydride group, a silyl ether group, a combination of acetal or ketal with ester group, an oligo-acetal or oligo-ketal group, a combination of the oligo-ketal and silyl ether group, a combination of the oligo-ketal and vinyl ether group. The pH sensitive linker can be also a combination of acetal or ketal with cis-aconityl, hydrazine, oxime, imidazole or trityl groups in order to fine tune the pH sensitivity.

In some embodiments, the linker comprises a compound of Formula (VI):

wherein:

R 31 is an agent, e.g., a therapeutic agent or diagnostic agent (e.g., an AHCM), or a targeting moiety (e.g., as described herein);

X is O or S;

R 32 is H or optionally substituted alkyl, C 2 -C 6 alkenyl, cycloalkyl, or heterocyclyl;

Y is C, CH, N, O or S;

R 33 is —C(O)OR a , or optionally substituted alkyl, C 2 -C 6 alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R a is H or optionally substituted alkyl;

n is an integer between 1 and 20;

wherein when Y is CH, N, O, or S, represents a single bond;

when represents a double bond, it may exist in either the E or Z configuration; and

when Y is O or S, R 33 is absent.

In some embodiments, X is O. In some embodiments, X is S.

In some embodiments, R 32 is H. In some embodiments, R 32 is alkyl. In some embodiments, R 32 is methyl or ethyl.

In some embodiments, Y is C. In some embodiments, Y is CH. In some embodiments, Y is N, O, or S.

In some embodiments, R 33 is —C(O)OR a , wherein R a is H or alkyl. In some embodiments, when Y is C or CH, R 33 is —C(O)OR a . In some embodiments, when Y is C or CH, R 33 is —C(O)OR a , wherein R a is H or alkyl. In some embodiments, when Y is N, O, or S, R 33 is alkyl, C 2 -C 6 alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, when Y is N, O, or S, R 33 is alkyl. In some embodiments, when Y is N, O, or S, R 33 is methyl or ethyl. In some embodiments, when Y is CH, O, or S, R 33 is absent. In some embodiments, when Y is C, represents a double bond. In some embodiments, when represents a double bond, it may exist in either the E or Z configuration. In some embodiments, when Y is CH, N, O, or S, represents a single bond.

In some embodiments, the linker is a compound of Formula (VII):

wherein:

R 41 is an agent, e.g., a therapeutic agent or diagnostic agent (e.g., an AHCM), or a targeting moiety (e.g., as described herein);

Z is C or Si;

each of R 42 or R 43 is independently alkyl, cycloalkyl, or heterocyclyl, or one of R 42 or R 43 is H; or R 42 and R 43 taken together with the Z atom they are attached to form a 4- to 8-membered cycloalkyl or heterocyclyl;

R 44 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or —C(O)NR c R d , —NR c C(O)R e —, —NR c C(O)OR f —, or R 44 taken together with the carbon atom it is attached to form a 5- to 8-membered ring with R 42 that encompasses O and Z; and

each of R c , R d , R e , or R f is independently H, or alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, Z is C. In some embodiments, Z is Si.

In some embodiments, each of R 42 or R 43 is independently alkyl. In some embodiments, each of R 42 or R 43 is independently methyl, ethyl, or isopropyl. In some embodiments, R 42 and R 43 are taken together with the Z atom to which they are attached to form a 4- to 8-membered cycloalkyl or heterocyclyl.

In some embodiments, R 44 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R 44 is alkyl, or cycloalkyl. In some embodiments, R 44 is alkyl, e.g., methyl or ethyl. In some embodiments, R 44 is cycloalkyl, e.g., cyclohexyl. In some embodiments, R 44 is —C(O)NR c R d , —NR c C(O)R e —, —NR c C(O)OR f —. In some embodiments, R 44 is —C(O)NR c R d , —NR c C(O)R e —, —NR c C(O)OR f —, wherein R c , R d , or R f is each independently H or alkyl and R e is alkyl. In some embodiments, R 44 is —NR c C(O)R e —, wherein R c is H or alkyl and R e is alkyl. In some embodiments, R 44 taken together with the carbon atom it is attached to forms a 5- to 8-membered ring with R 42 that encompasses O and Z (wherein e.g., Z is C).

Particles

As used herein, the term “nanoparticle” refers to particle having a particle size of about 0.1 nm to about 1000 nm. Generally, the nanoparticle can be of any shape or form, e.g., spherical, rod, elliptical, cylindrical, capsule, or disc; and these nanoparticles can be part of a network or an aggregate. Generally, the particles disclosed herein have an average size of from about 1 nm to about 500 nm. In some embodiments, the particles have an average size of from about 5 nm to about 100 nm. In some embodiments, the particles have an average size of from about 7.5 nm to about 50 nm. In one embodiment, the nanoparticles have an average size of about 7.5 nm to about 37.5 nm.

As used herein, the term “hydrodynamic diameter” refers to the diameter of the particles in the solution, which includes the actual size and the hydrodynamic water layer.

It will be understood by one of ordinary skill in the art that particles usually exhibit a distribution of particle sizes around the indicated “size.” Unless otherwise stated, the term “particle size” as used herein refers to the mode of a size distribution of particles, i.e., the value that occurs most frequently in the size distribution. Methods for measuring the particle size are known to a skilled artisan, e.g., by dynamic light scattering (such as photocorrelation spectroscopy, laser diffraction, low-angle laser light scattering (LALLS), and medium-angle laser light scattering (MALLS)), light obscuration methods (such as Coulter analysis method), or other techniques (such as rheology, and light or electron microscopy).

In some embodiments, the particles can be substantially spherical. What is meant by “substantially spherical” is that the ratio of the lengths of the longest to the shortest perpendicular axes of the particle cross section is less than or equal to about 1.5. Substantially spherical does not require a line of symmetry. Further, the particles can have surface texturing, such as lines or indentations or protuberances that are small in scale when compared to the overall size of the particle and still be substantially spherical. In some embodiments, the ratio of lengths between the longest and shortest axes of the particle is less than or equal to about 1.5, less than or equal to about 1.45, less than or equal to about 1.4, less than or equal to about 1.35, less than or equal to about 1.30, less than or equal to about 1.25, less than or equal to about 1.20, less than or equal to about 1.15 less than or equal to about 1.1. Without wishing to be bound by a theory, surface contact is minimized in particles that are substantially spherical, which minimizes the undesirable agglomeration of the particles upon storage. Many crystals or flakes have flat surfaces that can allow large surface contact areas where agglomeration can occur by ionic or non-ionic interactions. A sphere permits contact over a much smaller area.

The particles can be, e.g., monodisperse or polydisperse and the variation in diameter of the particles of a given dispersion can vary. In some embodiments, the particles have substantially the same particle size. Particles having a broad size distribution where there are both relatively big and small particles allow for the smaller particles to fill in the gaps between the larger particles, thereby creating new contact surfaces. A broad size distribution can result in larger spheres by creating many contact opportunities for binding agglomeration. The particles described herein are within a narrow size distribution, thereby minimizing opportunities for contact agglomeration. What is meant by a “narrow size distribution” is a particle size distribution that has a ratio of the volume diameter of the 90th percentile of the small spherical particles to the volume diameter of the 10th percentile less than or equal to 5. In some embodiments, the volume diameter of the 90th percentile of the small spherical particles to the volume diameter of the 10th percentile is less than or equal to 4.5, less than or equal to 4, less than or equal to 3.5, less than or equal to 3, less than or equal to 2.5, less than or equal to 2, less than or equal to 1.5, less than or equal to 1.45, less than or equal to 1.40, less than or equal to 1.35, less than or equal to 1.3, less than or equal to 1.25, less than or equal to 1.20, less than or equal to 1.15, or less than or equal to 1.1. In some embodiments, the volume diameter of the 90th percentile of the small spherical particles to the volume diameter of the 10th percentile is about 2.1 to about 2.5.

A “narrow size distribution” can also mean that the hydrodynamic diameter distribution has a ratio of the volume diameter of the 90th percentile of the small spherical particles to the volume diameter of the 10th percentile less than or equal to 5. In some embodiments, the volume diameter of the 90th percentile of the small spherical particles to the volume diameter of the 10th percentile is less than or equal to 4.5, less than or equal to 4, less than or equal to 3.5, less than or equal to 3, less than or equal to 2.5, less than or equal to 2, less than or equal to 1.5, less than or equal to 1.45, less than or equal to 1.40, less than or equal to 1.35, less than or equal to 1.3, less than or equal to 1.25, less than or equal to 1.20, less than or equal to 1.15, or less than or equal to 1.1. In some embodiments, the volume diameter of the 90th percentile of the small spherical particles to the volume diameter of the 10th percentile is about 2.1 to about 2.5.

Geometric Standard Deviation (GSD) can also be used to indicate the narrow size distribution. GSD calculations involved determining the effective cutoff diameter (ECD) at the cumulative less than percentages of 15.9% and 84.1%. GSD is equal to the square root of the ratio of the ECD less than 84.17% to ECD less than 15.9%. The GSD has a narrow size distribution when GSD<2.5. In some embodiments, GSD is less than 2, less than 1.75, or less than 1.5. In one embodiment, GSD is less than 1.8.

In some embodiments, the particle is soluble in water (e.g., hydrophilic). In some embodiments, the particle is soluble in water, and between about 0.1 to about 5 parts water are required to dissolve 1 part particle, or between about 1 part to about 5 parts water are required to dissolve 1 part particle. In some embodiments, the particle is partially soluble in water. In some embodiments, the particle is partially soluble in water, and between about 5 to about 50 parts water are required to dissolve 1 part particle. In some embodiments, the particle is sparingly soluble in water. In some embodiments, the particle is sparingly soluble in water, and between about 25 to about 100 parts water is required to dissolve 1 part particle. In some embodiments, the particle is slightly soluble in water. In some embodiments, the particle is slightly soluble in water, and between 100 to about 1,000 parts water are required to dissolve 1 part particle. In some embodiments, the particle is very slightly soluble in water. In some embodiments, the particle is very slightly soluble in water, and between 1,000 to about 10,000 parts water are required to dissolve 1 part particle. In some embodiments, the particle is substantially insoluble in water (e.g., hydrophobic). In some embodiments, the particle is substantially insoluble in water and greater than about 10,000 parts water are required to dissolve 1 part particle.

The polymers for use in forming the nanoparticles can have a molecular weight of from about 20 kDa to about 1,000 kDa. In some embodiments, the average molecular weight of the polymer used in forming the nanoparticles (e.g., the nanoparticles as described herein) is from about 5 kDa to about 1,000 kDa, (e.g., from about 5 kDa to about 750 kDa, from about 6 kDa about 500 kDa, from about 7 kDa to about 400 kDa, from about 8 kDa to about 300 kDa, from about 9 kDa to about 200 kDa, from about 10 kDa to about 100 kDa, from about 12.5 kDa to about 75 kDa, from about 15 kDa to about 50 kDa). In some embodiments the average molecular weight of the polymer used in forming the nanoparticles (e.g., the nanoparticles as described herein) is from about 20 kDa to about 1,000 kDa, (e.g., from about 30 kDa to about 900 kDa, from about 40 kDa to about 800 kDa, from about 50 kDa to about 750 kDa, from about 80 kDa to about 600 kDa, from about 100 kDa to about 550 kDa, or about 100 kDa, about 200 kDa, about 300 kDa, about 400 kDa, about 500 kDa, about 550 kDa, or about 600 kDa. In some embodiments the average molecular weight of the polymer used in forming the nanoparticles (e.g., the nanoparticles as described herein) is from about 5 kDa to about 100 kDa, (e.g., from about 6 kDa to about 90 kDa, from about 7 kDa about 80 kDa, from about 8 kDa to about 70 kDa, from about 9 kDa to about 60 kDa, from about 10 kDa to about 65 kDa, from about 11 kDa to about 50 kDa, from about 12 kDa to about 45 kDa, from about 13 kDa to about 40 kDa, from about 14 kDa to about 35 kDa, from about 15 kDa to about 30 kDa, from about 15 kDa to about 25 kDa, from about 15 kDa to about 20 kDa). In some embodiments, the average molecular weight of the polymer used in forming the nanoparticles (e.g., the nanoparticles as described herein) is from about 5 kDa to about 50 kDa, (e.g., from about 6 kDa to about 45 kDa, from about 7 kDa about 40 kDa, from about 8 kDa to about 35 kDa, from about 9 kDa to about 30 kDa, from about 10 kDa to about 25 kDa, from about 10 kDa to about 20 kDa, from about 10 kDa to about 15 kDa). In some embodiments, the average molecular weight of the polymer used in forming the nanoparticles (e.g., the nanoparticles as described herein) is from about 5 kDa to about 25 kDa, (e.g., from about 5 kDa to about 20 kDa, from about 5 kDa to about 15 kDa, from about 5 kDa to about 10 kDa, or about 5 kDa, about 6 kDa, about 7 kDa, about 8 kDa, about 9 kDa, about 10 kDa, about 11 kDa, about 12 kDa, about 13 kDa, about 14 kDa, about 15 kDa, about 16 kDa, about 17 kDa, about 18 kDa, about 19 kDa, about 20 kDa, about 21 kDa, about 22 kDa, about 23 kDa, about 24 kDa, about 25 kDa). In one embodiment, the average molecular weight of the polymer used in a particle (e.g., a micelle or a nanoparticle as described herein) is from about 5 kDa to about 10 kDa. In another embodiment, the average molecular weight of the polymer used in a particle (e.g., a micelle or a nanoparticle as described herein) is from about 10 kDa to about 15 kDa. In another embodiment, the average molecular weight of the polymer used in a particle (e.g., a micelle or a nanoparticle as described herein) is from about 15 kDa to about 25 kDa. In another embodiment, the average molecular weight of the polymer used in a particle (e.g., a micelle or a nanoparticle as described herein) is from about 15 kDa to about 20 kDa.

In some embodiments, nanoparticles can have a molecular weight of about 100 kDa to about 550 kDa. Without limitations, the molecular weight can be the peak average molecular weight (Mp), the number average molecular weight (Mn), or the weight average molecular weight (Mw).

In some embodiments, the nanoparticle disclosed herein further comprises a therapeutic agent, which is not covalently linked to the polymer forming the nanoparticle. In other words, the nanoparticle further comprises a therapeutic agent encapsulated in therein. In some embodiments, the particle encapsulates the therapeutic agent at an efficiency of at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99%. In some embodiments, the particle encapsulates the therapeutic agent at an efficiency of less than 10%, e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3%. In some embodiments, the particle encapsulates the therapeutic agent at an efficiency of between, or inclusive of 2% to 10%, 3% to 9%, or 4% to 6%.

In some embodiments, the net charge of the particle is neutral. In some embodiments, the net charge of the particle is more positive (or less negative) at an endosomal pH or at the pH at the site of a tumor than at physiological pH. In some embodiments, the net charge of the particle is more positive (or less negative) at a pH in the range of 4-6.5 than at a pH in the range of 7-8. In other embodiments, the net charge of the particle is more positive (or less negative) at a pH of 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4 or 6.5 than at a pH of 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 or 8. In still some other embodiments, the particle is neutral or is negatively charged at physiological pH and is positively charged at an endosomal pH or at the pH at the site of a tumor. In some embodiments, the particle is more positively charged (or less negatively charged) at an endosomal pH or at the pH at the site of a tumor than at physiological pH.

The charge of the particle can be determined at pH in the range of pH 3-pH 9. In some embodiments, the pH is 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5 or 9. In some embodiments, the pH is an endosomal pH or the pH at the site of a tumor. In some embodiments, the pH is in the range of 4-6.5. In other embodiments, the pH is 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4 or 6.5. In other embodiments, the pH is physiological pH. In some embodiments, the pH is in the range of 7-8. In other embodiments, the pH is 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 or 8.

In certain embodiments, the AHCM agents, the microenvironment modulators, the therapy, or any combination thereof, can be packaged in any nanoparticle delivery platform. Alternatively, or in combination, the AHCM agents and/or microenvironment modulators (or nanoparticles comprising the same) can be used (e.g., administered) in combination with any nanoparticle known in the art.

In one embodiment, a pH-sensitive particle disclosed herein can be used in combination with any nanoparticle delivery platform, e.g., any platform as disclosed herein.

Lipid- or oil-based nanoparticles, such as liposomes and solid lipid nanoparticles can be used to deliver agents described herein. DOXIL® is an example of a liposomic nanoparticle. Solid lipid nanoparticles for the delivery on anti-cancer agents are described in Serpe et al. (2004) Eur. J. Pharm. Bioparm. 58:673-680 and Lu et al. (20060 Eur. J. Pharm. Sci. 28: 86-95. Polymer-based nanoparticles, e.g., PLGA-based nanoparticles can be used to deliver agents described herein. These tend to rely on biodegradable backbone with the therapeutic agent intercalated (with or without covalent linkage to the polymer) in a matrix of polymer. PLGA is a widely used in polymeric nanoparticles, see Hu et al. (2009) J. Control. Release 134:55-61; Cheng et al. (2007) Biomaterials 28:869-876, and Chan et al. (2009) Biomaterials 30:1627-1634. PEGylated PLGA-based nanoparticles can also be used to deliver anti-cancer agents, see, e.g., Danhhier et al., (2009) J. Control. Release 133:11-17, Gryparis et al (2007) Eur. J. Pharm. Biopharm. 67:1-8. Metal-based, e.g., gold-based nanoparticles can also be used to deliver anti-cancer agents. Protein-based, e.g., albumin-based nanoparticles can be used to deliver agents described herein. E.g., an agent can be bound to nanoparticles of human albumin. An exemplary anti-cancer agent/protein nanoparticle is Abraxane®, in which paclitaxel is pund to nanoparticles of albumin.

Nanoparticles can employ active targeting, passive targeting or both. Active targeting can rely on inclusion of a ligand that binds with a target at or near a preselected site, e.g., a solid tumor. Passive targeting nanoparticles can diffuse and accumulate at sites of interest, e.g., sites characterized by excessively leaky microvasculature, e.g., as seen in tumors and sites of inflammation.

A broad range of nanoparticles are known in the art. Exemplary approaches include those described in WO2010/005726, WO2010/005723, WO2010/005721, WO2010/121949, WO2010/0075072, WO2010/068866, WO2010/005740, WO2006/014626, U.S. Pat. Nos. 7,820,788, 7,780,984, the contents of which are incorporated herein in reference by their entirety.

Exemplary nanoparticle delivery platforms that can be used to package the AHCM agent and/or microenvironment modulator, the therapy, or any combination thereof, include non-targeted and targeted nanoparticles. These platforms can be classified into the following categories: liposomes, nanoparticle albumin-bound technology, polymeric nanoparticles, dendrimers, metal nanoparticles, and molecular targeted nanoparticles (reviewed in e.g., Wang, A. Z. et al. (2012) Annu. Rev. Med. 63:185-98, incorporated herein by reference). Examples of these nanoparticle delivery platforms are discussed in more detail below.

Liposomes

Lipid- or oil-based nanoparticles, such as liposomes can be used to, deliver the agents described herein, or can be used in combination with the agents described herein. Coating liposomes with polymers such as PEG can improve their stability and half-life in the blood. Typically, liposomal drug formulations enhance the biodistribution and pharmacokinetic profile of a drug.

Liposomal formulations of anthracycline drugs have been approved for clinical use. Examples include, but are not limited to, liposomal daunorubicin (e.g., DaunoXome®: Gilead Sciences, approved for treatment of Kaposi's sarcoma); liposomal doxorubicin (e.g., Myocet (D-99)® Elan Pharmaceuticals, approved for treatment of breast cancer); PEGylated liposomal doxorubicin (e.g., Doxil®, Ortho Biotech Products (US), Caelyx: Schering-Plough (international), approved for treatment of breast cancer, ovarian cancer, or Kaposi's sarcoma).

Other liposomal formulations, include, but are not limited to, PEGylated liposomal topoisomerase inhibitor (e.g., Compound name S-CKD602, developed by Johnson & Johnson/Alza Corporation, which is in Phase II clinical trial for treatment of various malignancies); liposomal irinotecan metabolite (e.g., LE-SN38, developed by NeoPharm, which is in Phase I-II clinical trial for treatment of neoplasms and colorectal cancer; or a polymeric micelle of SN-38 (e.g., NK012 developed by Nippon Kayaku, Co.); lipid nanoparticle formulation of siRNA directed toward vascular endothelial growth factor and kinesin spindle protein (e.g., ALN-VSP), developed by Alnylam, which is in Phase I clinical trials for treatment of advanced solid tumors with liver involvement; liposomal thymidylate synthase inhibitor (e.g., OSI-7904L) and liposomal lurtotecan (e.g., OSI-211), both of which were developed by OSI Pharmaceuticals, which are in Phase II clinical trials. Additional examples of liposomal mixtures of drugs and nanoparticle delivery systems include, but are not limited to, liposomal irinotecan and floxuridine (e.g., CPX-1 in Phase II clinical trial for colorectal cancer); liposomal cytarabine and daunorubicin (e.g., CPX-351 in Phase III clinical trial for acute myeloid leukemia); and the CPX-8 nanoparticle delivery system, all of which are being developed by Celator Pharmaceuticals. Further examples include a glycoprotein micelle (e.g., SP1049C containing doxorubicin developed by Supratek Pharma Inc. to treat various cancers).

Additional examples of liposomal and lipid mixtures of drugs for intravenous delivery or injection, include, but are not limited to, liposomal cytarabine (e.g., DepoCyt which is commercially available for treating lymphomatous meningitis and leukemia); a lipid:drug suspension of two phospholipids (DMPC and DMPG) (e.g., Abelcet, which is a complex with amphotericin B to treat fungal infections), both of which are available from Sigma Tau Pharmaceuticals.

Other exemplary formulations include the lipid nanoparticle (LNP) technology developed by Tekmira described, e.g., in U.S. Pat. No. 7,244,448 entitled “Liposomal Antineoplastic Drugs and Uses Thereof;” U.S. Pat. No. 7,811,602 entitled “Liposomal Formulations comprising Dihydrosphingomyelin and Methods of Use Thereof;” U.S. Pat. No. 8,722,082 entitled “Lipids and Compositions for the Delivery of Therapeutics;” and Semple, S. C., et al. Rational design of cationic lipids for siRNA delivery (2010) Nature Biotechnology, 28:172-176, all of which are incorporated herein by reference. In some embodiments, lipid micelles/nanoparticle formulations (primarily cationic lipids) that encapsulate RNA molecules (e.g., RNAi, siRNA, or mRNA) can be used to allow for efficient transport through the bloodstream to target tissues. Exemplary nanoparticle formulations for RNA delivery include, e.g., LNP containing RNAi targeted toward polo-like kinase 1 (PLK1) (e.g., TKM-PLK1, which is in Phase I/II trials for gastrointestinal neuroendocrine tumors, adrenocortical carcinoma, and hepatocellular carcinoma).

Additional exemplary formulations include lipid nanoparticles comprising multiple lipid layers (multilamellar), in which the individual layers are chemically “stapled” together using dithiol crosslinkers, as described in, e.g., U.S. Pat. No. 8,747,869, entitled “Lipid Vesicle Compositions and Methods of Use;” and Moon, J J; Suh, H; et al. “Interbilayer-crosslinked multilamellar vesicles as synthetic vaccines for potent humoral and cellular immune responses” (2011) Nature Materials, 10:243-251, both of which are incorporated herein by reference. Such layered structure provides the particles with enhanced stability relative to liposomes. This technology, which is also termed “Interbilayer Crosslinked Multilamellar Vesicles (ICMVs)” is being developed by Vedranta Pharmaceuticals.

Liposomal formulations described herein can include a targeting agent, e.g., an antibody or antibody fragment (e.g., a human antibody fragment (GAH) targeting liposomal doxorubicin (e.g., MCC-465)), or a ligand, e.g., transferrin (e.g., transferring-targeted liposomal oxaliplatin (e.g., MBP-426 developed by Mebiopharm Co., Ltd to treat cancer); or transferrin targeted liposome with p53 gene (e.g., SGT53-01 developed by SynerGene Therapeutics to treat solid tumors).

Albumin-Bound (Nab) Nanoparticle

In other embodiments, albumin can be used as a carrier for the AHCM and/or microenvironment modulator, the therapy, or any combination thereof. For example, albumin can be complexed to the AHCM, microenvironment modulator, the agent (e.g., a chemotherapeutic drug) through noncovalent, reversible interactions. Alternatively, or in combination, the AHCM and/or microenvironment modulator (or a nanoparticle containing the same) can be used in combination with albumin-drug coated nanoparticles, e.g., a nanoparticle coated with albumin and paclitaxel (e.g., Abraxane® developed by Celgene, which is approved for treating breast cancer, non-small cell lung cancer, and pancreatic cancer).

Polymeric Nanoparticles

In yet other embodiments, the AHCM, the microenvironment modulator, the therapy, or any combination thereof can be packaged in a polymeric nanoparticle. Alternatively, or in combination, the AHCM (or a nanoparticle containing the AHCM) can be used in combination with one or more art-known polymeric nanoparticles. A common class of nanoparticles contains an inner core loaded with a drug and an outer shell for protection and/or immune shielding, with or without a targeting agent.

Examples of non-targeted polymeric nanoparticles include, but are not limited to, a polymeric-micelle composed of PEG and polylactic acid (PLA) (e.g., Cynviloq® which encapsulates paclitaxel (developed by Sorrento Therapeutics)); a polymeric PEG-polyamino acid (e.g., NC-6004, which encapsulates cisplatin (developed by NanoCarrier Co.)); a polymeric PEG-polyaspartate (e.g., NK105, which encapsulates paclitaxel (developed by Nippon Kayaku Co.); a polymeric PEG-polyaspartate (e.g., NK911, which encapsulates doxorubicin (developed by Nippon Kayaku Co.); a cyclodextrin polymeric nanoparticle (CDP) as described in, e.g., U.S. Pat. Nos. 8,389,499, 8,314,230, 8,603,454, 8,404,799, all of which are incorporated herein by reference. Exemplary cyclodextin-PEG polymers comprising various chemotherapeutic drugs include CDPs bound to camptothecin (e.g., CRLX101 developed by Cerulean Pharma to treat relapsed renal cell carcinoma, ovarian cancer, rectal cancer), and CDPs bound to docetaxel (e.g., CRLX301 also developed by Cerulean Pharma).

Polymeric nanoparticles described herein can include a targeting agent, e.g., an antibody or antibody fragment, or a ligand, e.g., transferrin or other receptor ligand. Examples of targeted polymeric nanoparticles include, but are not limited to, polylactic co-glycolic acid (PLGA) nanoparticles encapsulating a reverse micelle, in which the interior is hydrophilic and the exterior is hydrophobic. Either part of the micelle may be loaded with therapeutics. The PLGA matrix is coated with PEG for immune shielding, and a targeting ligand (e.g., one or more of an antibody, an antibody fragment, or a ligand (e.g., a receptor ligand)); the ligand is linked to a PEG molecule to direct the particles within the body. These targeted nanoparticles are described in, e.g., U.S. Pat. Nos. 8,193,334, 7,534,449, and Hrkach, J. et al. Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. (2012) Science Translational Medicine 4:1-12, all of which are incorporated herein by reference. Exemplary PLGA nanoparticle containing a docetaxel payload interior and a prostate-specific membrane antigen (PSMA)-targeting ligand ACUPA (a PSMA substrate analog) on the surface is BIND-014, which is used to treat solid tumors (developed by BIND Bioscience).

Additional examples of targeted polymeric nanoparticles include, but are not limited to, transferring-targeted polymeric (e.g., cyclodextrin) nanoparticles (e.g., CALAA-01, which includes a siRNA and was developed by Calando Pharmaceuticals to treat solid tumors).

Metal/Carbon-Based Nanoparticles

In other embodiments, the AHCM, the microenvironment modulator, the therapy, or all can be packaged in a metal/carbon-based nanoparticle. Alternatively, or in combination, the AHCM and/or the microenvironment modulator (or a nanoparticle containing the same) can be used in combination with one or more art-known metal/carbon-based nanoparticles. These nanoparticles can contain a metal (gold, titanium) or carbon-based inner shell, surrounded by, e.g., an AHCM, a cytotoxic drug and/or a polymer, such as PEG, for immune shielding and/or targeted delivery.

Exemplary metal/carbon-based nanoparticle include a colloidal gold nanoparticle (e.g., 30-50 nm) coated with PEG-thiol as described in, e.g., U.S. Pat. Nos. 7,229,841, 7,387,900 and 6,274,552, incorporated herein by reference. Specific products of the Aurimune platform being developed by CytImmune include CYT-6091, which is a first generation Aurimune nanoparticle bearing tumor necrosis factor (TNF) on the surface; CYT-21000, which is a second generation Aurimune nanoparticle bearing TNF and Taxol on the surface, and CYT-61000 (particle bearing interferon) and CYT-71000 (particle bearing gemcitabine).

Synthetic Vaccine Particles (SVPs)

In other embodiments, the AHCM, the microenvironment modulator, the therapy, or any combination thereof, can be packaged in an SVP. Alternatively, or in combination, the AHCM and/or the microenvironment modulator (or a nanoparticle containing the same) can be used in combination with one or more SVPs. This platform involves a nanoparticle polymer embedded with B cell antigens; the nanoparticle encapsulates either T-cell antigens (e.g., disease-specific epitopes or protein antigens) or immunomodulators (e.g., TLR agonists or checkpoint inhibitors), as described in, e.g., US 20130028941, US 20140199340 and US 20120301498. Exemplary products developed by Selecta Biosciences include SEL-212 and SEL-068.

Light-Activated Drug Delivery

In other embodiments, the AHCM, the microenvironment modulator, the therapy, or any combination thereof, can be packaged in a light-activated drug delivery. Alternatively, or in combination, the AHCM and/or the microenvironment modulator (or a nanoparticle containing the same) can be used in combination with one or more light-activated nanoparticles. Fluorescent, porous silica nanoparticles filled with various chemotherapeutics (e.g. camptothecin) or nucleic acids. The pores in the particles are capped with “nanovalves” to prevent leakage. Upon exposure to exogenous two-photon radiation (laser light), the nanovalves open and release drug cargo. Typically, the nanoparticles treat tumors within 4 cm of skin surface due to ability of laser to penetrate skin, and fluorescent labels allow for tracking of nanoparticles through the body. The technology is described, e.g., in US 20120207795, US 20100310465, and Croissant, J., et al. Two-photon-triggered drug delivery via fluorescent nanovalves. (2014) Small. 10:1752-1755, all of which are incorporated herein by reference.

Nanodiamonds

In other embodiments, the AHCM, the microenvironment modulator, the therapy, or any combination thereof, can be packaged in one or more nanodiamonds. Alternatively, or in combination, the AHCM and/or the microenvironment modulator (or a nanoparticle containing the same) can be used in combination with one or more nanodiamonds. Nanodiamonds, carbon-based particles about, e.g., 4-5 nm in diameter, can be bound to a broad range of drug compounds. Binding seems to be through hydrophobic interactions between particle surface and drug molecules. Current uses include doxorubin linked nanodiamonds and daunorubicin-linked nanodiamonds for leukemia.

Other particles, e.g., encapsulated and/or carrier-targeted particles are within the scope of the invention.

Agents

As used herein, the term “agent” means a molecule, group of molecules, complex or substance administered to an organism for diagnostic, therapeutic, preventative medical, or veterinary purposes. As used herein, the term “therapeutic agent” includes a “drug” or a “vaccine.” This term include externally and internally administered topical, localized and systemic human and animal pharmaceuticals, treatments, remedies, nutraceuticals, cosmeceuticals, biologicals, devices, diagnostics and contraceptives, including preparations useful in clinical and veterinary screening, prevention, prophylaxis, healing, wellness, detection, imaging, diagnosis, therapy, surgery, monitoring, cosmetics, prosthetics, forensics and the like. This term can also be used in reference to agriceutical, workplace, military, industrial and environmental therapeutics or remedies comprising selected molecules or selected nucleic acid sequences capable of recognizing cellular receptors, membrane receptors, hormone receptors, therapeutic receptors, microbes, viruses or selected targets comprising or capable of contacting plants, animals and/or humans. This term can also specifically include nucleic acids and compounds comprising nucleic acids that produce a therapeutic effect, for example deoxyribonucleic acid (DNA), ribonucleic acid (RNA), or mixtures or combinations thereof.

The term “agent” also includes an agent that is capable of providing a local or systemic biological, physiological, or therapeutic effect in the biological system to which it is applied. For example, a therapeutic agent can act to control infection or inflammation, enhance cell growth and tissue regeneration, control tumor growth, act as an analgesic, promote anti-cell attachment, and enhance bone growth, among other functions. Other suitable therapeutic agents can include anti-viral agents, hormones, antibodies, or therapeutic proteins. Other therapeutic agents include prodrugs, which are agents that are not biologically active when administered but, upon administration to a subject are converted to biologically active agents through metabolism or some other mechanism. Additionally, a silk-based drug delivery composition can contain combinations of two or more therapeutic agents.

An agent, e.g., a therapeutic agent, can include a wide variety of different compounds, including chemical compounds and mixtures of chemical compounds, e.g., small organic or inorganic molecules; saccharines; oligosaccharides; polysaccharides; biological macromolecules, e.g., peptides, proteins, and peptide analogs and derivatives; peptidomimetics; antibodies and antigen binding fragments thereof; nucleic acids; nucleic acid analogs and derivatives; an extract made from biological materials such as bacteria, plants, fungi, or animal cells; animal tissues; naturally occurring or synthetic compositions; and any combinations thereof.

In some embodiments, the agent, e.g., a therapeutic agent, is a small molecule. As used herein, the term “small molecule” can refer to compounds that are “natural product-like.” However, the term “small molecule” is not limited to “natural product-like” compounds. Rather, a small molecule is typically characterized in that it contains several carbon-carbon bonds, and has a molecular weight of less than 5000 Daltons (5 kDa), preferably less than 3 kDa, still more preferably less than 2 kDa, and most preferably less than 1 kDa. In some cases it is preferred that a small molecule have a molecular weight equal to or less than 700 Daltons.

Exemplary agents, e.g., a therapeutic agents, include, but are not limited to, those found in Harrison's Principles of Internal Medicine, 13th Edition, Eds. T. R. Harrison et al. McGraw-Hill N.Y., N.Y.; Physicians' Desk Reference, 50th Edition, 1997, Oradell New Jersey, Medical Economics Co.; Pharmacological Basis of Therapeutics, 8th Edition, Goodman and Gilman, 1990; United States Pharmacopeia, The National Formulary, USP XII NF XVII, 1990; current edition of Goodman and Oilman's The Pharmacological Basis of Therapeutics ; and current edition of The Merck Index , the complete contents of all of which are incorporated herein by reference

Agents, e.g., therapeutic agents, include the herein disclosed categories and specific examples. It is not intended that the category be limited by the specific examples. Those of ordinary skill in the art will recognize also numerous other compounds that fall within the categories and that are useful according to the present disclosure. Examples include an angiotensin receptor blocker, a CXCR4 inhibitor, a chemotherapeutic agent, a radiosensitizer, a steroid, a xanthine, a beta-2-agonist bronchodilator, an anti-inflammatory agent, an analgesic agent, a calcium antagonist, an angiotensin-converting enzyme inhibitors, a beta-blocker, a centrally active alpha-agonist, an alpha-1-antagonist, an anticholinergic/antispasmodic agent, a vasopressin analogue, an antiarrhythmic agent, an antiparkinsonian agent, an antiangina/antihypertensive agent, an anticoagulant agent, an antiplatelet agent, a sedative, an ansiolytic agent, a peptidic agent, a biopolymeric agent, an antineoplastic agent, a laxative, an antidiarrheal agent, an antimicrobial agent, an antifungal agent, a vaccine, a protein, an antibody or a nucleic acid.

Non-limiting examples of suitable agents, e.g., therapeutic agents, include, but are not limited to, antimicrobial agents, analgesics, antinflammatory agents, counterirritants, coagulation modifying agents, diuretics, sympathomimetics, anorexics, antacids and other gastrointestinal agents; antiparasitics, antidepressants, antihypertensives, anticholinergics, stimulants, antihormones, central and respiratory stimulants, drug antagonists, lipid-regulating agents, uricosurics, cardiac glycosides, electrolytes, ergot and derivatives thereof, expectorants, hypnotics and sedatives, antidiabetic agents, dopaminergic agents, antiemetics, muscle relaxants, para-sympathomimetics, anticonvulsants, antihistamines, beta-blockers, purgatives, antiarrhythmics, contrast materials, radiopharmaceuticals, antiallergic agents, tranquilizers, vasodilators, antiviral agents, and antineoplastic or cytostatic agents or other agents with anticancer properties, or a combination thereof. Other suitable medicaments may be selected from contraceptives and vitamins as well as micro- and macronutrients. Still other examples include antiinfectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; antiheimintics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; antidiuretic agents; antidiarrleals; antihistamines, antiinflammatory agents; antimigraine preparations; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics, antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including calcium channel blockers and beta-blockers such as pindolol and antiarrhythmics; antihypertensives; diuretics; vasodilators including general coronary, peripheral and cerebral; central nervous system stimulants; cough and cold preparations, including decongestants; hormones such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressives; muscle relaxants; parasympatholytics; psychostimulants; sedatives; and tranquilizers; and naturally derived or genetically engineered proteins, polysaccharides, glycoproteins, or lipoproteins.

Some specific non-limiting examples of agents, e.g., therapeutic agents, include doxorubicin, mitomycin, cisplatin, daunorubicin, bleomycin, actinomycin D, neocarzinostatin, carboplatin, stratoplatin, Ara-C. Other examples include Capoten, Monopril, Pravachol, Avapro, Plavix, Cefzil, Duricef/Ultracef. Azactam, Videx, Zerit, Maxipime, VePesid, Paraplatin, Platinol, Taxol, UFT, Buspar, Serzone, Stadol NS, Estrace, Glucophage (Bristol-Myers Squibb); Ceclor, Lorabid. Dynabac, Prozac, Darvon, Permax, Zyprexa, Humalog, Axid, Gemzar, Evista (Eli Lily); VasotecNaseretic, Mevacor, Zocor, Prinivil/Prinizide, Plendil, Cozaar/Hyzaar, Pepcid, Prilosec, Primaxin, Noroxin, Recombivax HB, Varivax, Timoptic/XE, Trusopt, Proscar, Fosamax, Sinemet, Crixivan, Propecia, Vioxx, Singulair, Maxalt, Ivermectin (Merck & Co.); Diflucan, Unasyn, Sulperazon, Zithromax, Trovan, Procardia XL, Cardura, Norvasc, Dofetilide, Feldene, Zoloft, Zeldox, Glucotrol XL, Zyrtec, Eletriptan, Viagra, Droloxifene, Aricept, Lipitor (Pfizer); Vantin, Rescriptor, Vistide, Genotropin, Micronase/Glyn./Glyb., Fragmin, Total Medrol, Xanax/alprazolam, Sermion, Halcion/triazolam, Freedox, Dostinex, Edronax, Mirapex, Pharmorubicin, Adriamycin, Camptosar, Remisar, Depo-Provera, Caverject, Detrusitol, Estring, Healon, Xalatan, Rogaine (Pharmacia & Upjohn); Lopid, Accrupil, Dilantin, Cognex, Neurontin, Loestrin, Dilzem, Fempatch, Estrostep, Rezulin, Lipitor, Omnicef, FemHRT, Suramin, or Clinafloxacin (Warner Lambert).

In some embodiments, the agent, e.g., therapeutic agent, can be an anti-cancer drug such as 20-epi-1,25 dihydroxyvitamin D3, 4-ipomeanol, 5-ethynyluracil, 9-dihydrotaxol, abiraterone, acivicin, aclarubicin, acodazole hydrochloride, acronine, acylfulvene, adecypenol, adozelesin, aldesleukin, all-tk antagonists, altretamine, ambamustine, ambomycin, ametantrone acetate, amidox, amifostine, aminoglutethimide, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitors, antagonist D, antagonist G, antarelix, anthramycin, anti-dorsalizing morphogenetic protein-1, antiestrogen, antineoplaston, antisense oligonucleotides, aphidicolin glycinate, apoptosis gene modulators, apoptosis regulators, apurinic acid, ARA-CDP-DL-PTBA, arginine deaminase, asparaginase, asperlin, asulacrine, atamestane, atrimustine, axinastatin 1, axinastatin 2, axinastatin 3, azacitidine, azasetron, azatoxin, azatyrosine, azetepa, azotomycin, baccatin III derivatives, balanol, batimastat, benzochlorins, benzodepa, benzoylstaurosporine, beta lactam derivatives, beta-alethine, betaclamycin B, betulinic acid, BFGF inhibitor, bicalutamide, bisantrene, bisantrene hydrochloride, bisaziridinylspermine, bisnafide, bisnafide dimesylate, bistratene A, bizelesin, bleomycin, bleomycin sulfate, BRC/ABL antagonists, breflate, brequinar sodium, bropirimine, budotitane, busulfan, buthionine sulfoximine, cactinomycin, calcipotriol, calphostin C, calusterone, camptothecin derivatives, canarypox IL-2, capecitabine, caracemide, carbetimer, carboplatin, carboxamide-amino-triazole, carboxyamidotriazole, carest M3, carmustine, cam 700, cartilage derived inhibitor, carubicin hydrochloride, carzelesin, casein kinase inhibitors, castanospermine, cecropin B, cedefingol, cetrorelix, chlorambucil, chlorins, chloroquinoxaline sulfonamide, cicaprost, cirolemycin, cisplatin, cis-porphyrin, cladribine, clomifene analogs, clotrimazole, collismycin A, collismycin B, combretastatin A4, combretastatin analog, conagenin, crambescidin 816, crisnatol, crisnatol mesylate, cryptophycin 8, cryptophycin A derivatives, curacin A, cyclopentanthraquinones, cyclophosphamide, cycloplatam, cypemycin, cytarabine, cytarabine ocfosfate, cytolytic factor, cytostatin, dacarbazine, dacliximab, dactinomycin, daunorubicin hydrochloride, decitabine, dehydrodidemnin B, deslorelin, dexifosfamide, dexormaplatin, dexrazoxane, dexverapamil, dezaguanine, dezaguanine mesylate, diaziquone, didemnin B, didox, diethylnorspermine, dihydro-5-azacytidine, dioxamycin, diphenyl spiromustine, docetaxel, docosanol, dolasetron, doxifluridine, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, dronabinol, duazomycin, duocarmycin SA, ebselen, ecomustine, edatrexate, edelfosine, edrecolomab, eflornithine, eflornithine hydrochloride, elemene, elsamitrucin, emitefur, enloplatin, enpromate, epipropidine, epirubicin, epirubicin hydrochloride, epristeride, erbulozole, erythrocyte gene therapy vector system, esorubicin hydrochloride, estramustine, estramustine analog, estramustine phosphate sodium, estrogen agonists, estrogen antagonists, etanidazole, etoposide, etoposide phosphate, etoprine, exemestane, fadrozole, fadrozole hydrochloride, fazarabine, fenretinide, filgrastim, finasteride, flavopiridol, flezelastine, floxuridine, fluasterone, fludarabine, fludarabine phosphate, fluorodaunorunicin hydrochloride, fluorouracil, flurocitabine, forfenimex, formestane, fosquidone, fostriecin, fostriecin sodium, fotemustine, gadolinium texaphyrin, gallium nitrate, galocitabine, ganirelix, gelatinase inhibitors, gemcitabine, gemcitabine hydrochloride, glutathione inhibitors, hepsulfam, heregulin, hexamethylene bisacetamide, hydroxyurea, hypericin, ibandronic acid, idarubicin, idarubicin hydrochloride, idoxifene, idramantone, ifosfamide, ilmofosine, ilomastat, imidazoacridones, imiquimod, immunostimulant peptides, insulin-like growth factor-1 receptor inhibitor, interferon agonists, interferon alpha-2A, interferon alpha-2B, interferon alpha-N1, interferon alpha-N3, interferon beta-IA, interferon gamma-IB, interferons, interleukins, iobenguane, iododoxorubicin, iproplatin, irinotecan, irinotecan hydrochloride, iroplact, irsogladine, isobengazole, isohomohalicondrin B, itasetron, jasplakinolide, kahalalide F, lamellarin-N triacetate, lanreotide, lanreotide acetate, leinamycin, lenograstim, lentinan sulfate, leptolstatin, letrozole, leukemia inhibiting factor, leukocyte alpha interferon, leuprolide acetate, leuprolide/estrogen/progesterone, leuprorelin, levamisole, liarozole, liarozole hydrochloride, linear polyamine analog, lipophilic disaccharide peptide, lipophilic platinum compounds, lissoclinamide 7, lobaplatin, lombricine, lometrexol, lometrexol sodium, lomustine, lonidamine, losoxantrone, losoxantrone hydrochloride, lovastatin, loxoribine, lurtotecan, lutetium texaphyrin, lysofylline, lytic peptides, maitansine, mannostatin A, marimastat, masoprocol, maspin, matrilysin inhibitors, matrix metalloproteinase inhibitors, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, merbarone, mercaptopurine, meterelin, methioninase, methotrexate, methotrexate sodium, metoclopramide, metoprine, meturedepa, microalgal protein kinase C inhibitors, MIF inhibitor, mifepristone, miltefosine, mirimostim, mismatched double stranded RNA, mitindomide, mitocarcin, mitocromin, mitogillin, mitoguazone, mitolactol, mitomalcin, mitomycin, mitomycin analogs, mitonafide, mitosper, mitotane, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mitoxantrone hydrochloride, mofarotene, molgramostim, monoclonal antibody, human chorionic gonadotrophin, monophosphoryl lipid a/myobacterium cell wall SK, mopidamol, multiple drug resistance gene inhibitor, multiple tumor suppressor 1-based therapy, mustard anticancer agent, mycaperoxide B, mycobacterial cell wall extract, mycophenolic acid, myriaporone, n-acetyldinaline, nafarelin, nagrestip, naloxone/pentazocine, napavin, naphterpin, nartograstim, nedaplatin, nemorubicin, neridronic acid, neutral endopeptidase, nilutamide, nisamycin, nitric oxide modulators, nitroxide antioxidant, nitrullyn, nocodazole, nogalamycin, n-substituted benzamides, O6-benzylguanine, octreotide, okicenone, oligonucleotides, onapristone, ondansetron, oracin, oral cytokine inducer, ormaplatin, osaterone, oxaliplatin, oxaunomycin, oxisuran, paclitaxel, paclitaxel analogs, paclitaxel derivatives, palauamine, palmitoylrhizoxin, pamidronic acid, panaxytriol, panomifene, parabactin, pazelliptine, pegaspargase, peldesine, peliomycin, pentamustine, pentosan polysulfate sodium, pentostatin, pentrozole, peplomycin sulfate, perflubron, perfosfamide, perillyl alcohol, phenazinomycin, phenylacetate, phosphatase inhibitors, picibanil, pilocarpine hydrochloride, pipobroman, piposulfan, pirarubicin, piritrexim, piroxantrone hydrochloride, placetin A, placetin B, plasminogen activator inhibitor, platinum complex, platinum compounds, platinum-triamine complex, plicamycin, plomestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, propyl bis-acridone, prostaglandin J2, prostatic carcinoma antiandrogen, proteasome inhibitors, protein A-based immune modulator, protein kinase C inhibitor, protein tyrosine phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, puromycin, puromycin hydrochloride, purpurins, pyrazofurin, pyrazoloacridine, pyridoxylated hemoglobin polyoxyethylene conjugate, RAF antagonists, raltitrexed, ramosetron, RAS farnesyl protein transferase inhibitors, RAS inhibitors, RAS-GAP inhibitor, retelliptine demethylated, rhenium RE 186 etidronate, rhizoxin, riboprine, ribozymes, RII retinamide, RNAi, rogletimide, rohitukine, romurtide, roquinimex, rubiginone B1, ruboxyl, safingol, safingol hydrochloride, saintopin, sarcnu, sarcophytol A, sargramostim, SDI 1 mimetics, semustine, senescence derived inhibitor 1, sense oligonucleotides, siRNA, signal transduction inhibitors, signal transduction modulators, simtrazene, single chain antigen binding protein, sizofiran, sobuzoxane, sodium borocaptate, sodium phenylacetate, solverol, somatomedin binding protein, sonermin, sparfosate sodium, sparfosic acid, sparsomycin, spicamycin D, spirogermanium hydrochloride, spiromustine, spiroplatin, splenopentin, spongistatin 1, squalamine, stem cell inhibitor, stem-cell division inhibitors, stipiamide, streptonigrin, streptozocin, stromelysin inhibitors, sulfinosine, sulofenur, superactive vasoactive intestinal peptide antagonist, suradista, suramin, swainsonine, synthetic glycosaminoglycans, talisomycin, tallimustine, tamoxifen methiodide, tauromustine, tazarotene, tecogalan sodium, tegafur, tellurapyrylium, telomerase inhibitors, teloxantrone hydrochloride, temoporfin, temozolomide, teniposide, teroxirone, testolactone, tetrachlorodecaoxide, tetrazomine, thaliblastine, thalidomide, thiamiprine, thiocoraline, thioguanine, thiotepa, thrombopoietin, thrombopoietin mimetic, thymalfasin, thymopoietin receptor agonist, thymotrinan, thyroid stimulating hormone, tiazofurin, tin ethyl etiopurpurin, tirapazamine, titanocene dichloride, topotecan hydrochloride, topsentin, toremifene, toremifene citrate, totipotent stem cell factor, translation inhibitors, trestolone acetate, tretinoin, triacetyluridine, triciribine, triciribine phosphate, trimetrexate, trimetrexate glucuronate, triptorelin, tropisetron, tubulozole hydrochloride, turosteride, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, uracil mustard, uredepa, urogenital sinus-derived growth inhibitory factor, urokinase receptor antagonists, vapreotide, variolin B, velaresol, veramine, verdins, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinepidine sulfate, vinglycinate sulfate, vinleurosine sulfate, vinorelbine, vinorelbine tartrate, vinrosidine sulfate, vinxaltine, vinzolidine sulfate, vitaxin, vorozole, zanoterone, zeniplatin, zilascorb, zinostatin, zinostatin stimalamer, or zorubicin hydrochloride.

In some embodiments, the agent, e.g., therapeutic agent, can be an anti-infective such as Difloxacin Hydrochloride; Lauryl Isoquinolinium Bromide; Moxalactam Disodium; Ornidazole; Pentisomicin; Sarafloxacin Hydrochloride; Protease inhibitors of HIV and other retroviruses; Integrase Inhibitors of HIV and other retroviruses; Cefaclor (Ceclor); Acyclovir (Zovirax); Norfloxacin (Noroxin); Cefoxitin (Mefoxin); Cefuroxime axetil (Ceftin); or Ciprofloxacin (Cipro).

In some embodiments, the agent, e.g., therapeutic agent, can be an anti-inflammatory agent such as Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac, Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone; Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate; Diflumidone Sodium; Diflunisal; Difluprednate; Diftalone; Dimethyl Sulfoxide; Drocinonide; Endrysone; Enlimomab; Enolicam Sodium; Epirizole; Etodolac; Etofenamate; Felbinac; Fenamole; Fenbufen; Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone; Fluazacort; Flufenamic Acid; Flumizole; Flunisolide Acetate; Flunixin; Flunixin Meglumine; Fluocortin Butyl; Fluorometholone Acetate; Fluquazone; Flurbiprofen; Fluretofen; Fluticasone Propionate; Furaprofen; Furobufen; Halcinonide; Halobetasol Propionate; Halopredone Acetate; Ibufenac; Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen; Indoxole; Intrazole; Isoflupredone Acetate; Isoxepac; Isoxicam; Ketoprofen; Lofemizole Hydrochloride; Lornoxicam; Loteprednol Etabonate; Meclofenamate Sodium; Meclofenamic Acid; Meclorisone Dibutyrate; Mefenamic Acid; Mesalamine; Meseclazone; Methylprednisolone Suleptanate; Morniflumate; Nabumetone; Naproxen, Naproxen Sodium; Naproxol; Nimazone; Olsalazine Sodium; Orgotein; Orpanoxin; Oxaprozin; Oxyphenbutazone; Paranyline Hydrochloride; Pentosan Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pirfenidone; Piroxicam; Piroxicam Cinnamate; Piroxicam Olamine; Pirprofen; Prednazate; Prifelone; Prodolic Acid; Proquazone; Proxazole; Proxazole Citrate; Rimexolone; Romazarit; Salcolex; Salnacedin; Salsalate; Sanguinarium Chloride; Seclazone; Sermetacin; Sudoxicam; Sulindac; Suprofen; Talmetacin; Talniflumate; Talosalate; Tebufelone; Tenidap; Tenidap Sodium; Tenoxicam; Tesicam; Tesimide; Tetrydamine; Tiopinac; Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide; Triflumidate; Zidometacin or Zomepirac Sodium.

In some embodiments, the agent, e.g., therapeutic agent, can one for treating cardiovascular disease. Such drugs include anti-thrombotic and/or fibrinolytic agents, such as plasminogen; Streptokinase; Urokinase: Anisoylated Plasminogen-Streptokinase Activator Complex; Pro-Urokinase; (Pro-UK); rTPA (alteplase or activase; “r” denotes recombinant); rPro-UK; Abbokinase; Eminase; Sreptase Anagrelide Hydrochloride; Bivalirudin; Dalteparin Sodium; Danaparoid Sodium; Dazoxiben Hydrochloride; Efegatran Sulfate; Enoxaparin Sodium; Ifetroban; Ifetroban Sodium; Tinzaparin Sodium; Retaplase; Trifenagrel; Warfarin; and Dextrans. Such drugs also include anti-platelet agents such as Clopridogrel; Sulfinpyrazone; Aspirin; Dipyridamole; Clofibrate; Pyridinol Carbamate; PGE; Glucagon; Antiserotonin drugs; Caffeine; Theophyllin Pentoxifyllin; Ticlopidine; and Anagrelide. Such drugs also include lipid reducing agents such as gemfibrozil, cholystyramine, colestipol, nicotinic acid, probucol lovastatin, fluvastatin, simvastatin, atorvastatin, pravastatin, and cirivastatin. Such drugs include direct thrombin inhibitors such as hirudin, hirugen, hirulog, agatroban, PPACK, and thrombin aptamers. Such drugs also include calcium channel blockers such as dihydropyridines, such as nifedipine, the phenyl alkyl amines, such as verapamil, and the benzothiazepines, such as diltiazem. Other calcium channel blockers include amrinone, amlodipine, bencyclane, felodipine, fendiline, flunarizine, isradipine, nicardipine, nimodipine, perhexilene, gallopamil, tiapamil and tiapamil analogues (such as 1993RO-11-2933), phenytoin, barbiturates, and the peptides dynorphin, omega-conotoxin, and omega-agatoxin. Such drugs also include beta-adrenergic receptor blocking agents such as atenolol, acebutolol, alprenolol, befunolol, betaxolol, bunitrolol, carteolol, celiprolol, hedroxalol, indenolol, labetalol, levobunolol, mepindolol, methypranol, metindol, metoprolol, metrizoranolol, oxprenolol, pindolol, propranolol, practolol, sotalolnadolol, tiprenolol, tomalolol, timolol, bupranolol, penbutolol, trimepranol, 2-(3-(1,1-dimethylethyl)-amino-2-hydroxypropoxy)-3-pyridenecarbonitrilHCI, 1-butylamino-3-(2,5-dichlorophenoxy)-2-propanol, 1-isopropylamino-3-(4-(2-cyclopropylmethoxyethyl)phenoxy)-2-propanol, 3-isopropylamino-1-(7-methylindan-4-yloxy)-2-butanol, 2-(3-t-butylamino-2-hydroxy-propylthio)-4-(5-carbamoyl-2-thienyl)thiazol, 7-(2-hydroxy-3-t-butylaminpropoxy)phthalide. Such drugs also include anticoagulant agents such as Ancrod; Anticoagulant Citrate Dextrose Solution; Anticoagulant Citrate Phosphate Dextrose Adenine Solution; Anticoagulant Citrate Phosphate Dextrose Solution; Anticoagulant Heparin Solution; Anticoagulant Sodium Citrate Solution; Ardeparin Sodium; Bivalirudin; Bromindione; Dalteparin Sodium; Desirudin; Dicumarol; Heparin Calcium; Heparin Sodium; Lyapolate Sodium; Nafamostat Mesylate; Phenprocoumon; Tinzaparin Sodium; and Warfarin Sodium.

In some embodiments, the therapeutic agent can for treating a neurological disease. Such drugs include, but are not limited to, Diazepam, Valium, Clonazepam, Methamphetamine, Adderall, Neurontin, K-Dur, Gabapentin, Klonopin, Methylphenidate, Provigil, Ritalin, Lamictal, Modafinil, Abilify, Aripiprazole, Azmacort, Concerta, Depakote, Dilantin, Divalproex sodium, Klor-Con, Lamotrigine, Lithium, Natalizumab, Phenergan, Phenytoin, Prednisone, Promethazine, Risperdal, Risperidone, Temazepam, Topamax, Topiramate, Triamcinolone, Tysabri and Verapamil.

Some specific non-limiting examples of agents, e.g., therapeutic agents, that can be included in a particle disclosed herein include acebutolol, acetaminophen, acetohydoxamic acid, acetophenazine, acyclovir, adrenocorticoids, allopurinol, alprazolam, aluminum hydroxide, amantadine, ambenonium, amiloride, aminobenzoate potassium, amobarbital, amoxicillin, amphetamine, ampicillin, androgens, anesthetics, anticoagulants, anticonvulsants-dione type, antithyroid medicine, appetite suppressants, aspirin, atenolol, atropine, azatadine, bacampicillin, baclofen, beclomethasone, belladonna, bendroflumethiazide, benzoyl peroxide, benzthiazide, benztropine, betamethasone, betha nechol, biperiden, bisacodyl, bromocriptine, bromodiphenhydramine, brompheniramine, buclizine, bumetanide, busulfan, butabarbital, butaperazine, caffeine, calcium carbonate, captopril, carbamazepine, carbenicillin, carbidopa & levodopa, carbinoxamine inhibitors, carbonic anhydsase, carisoprodol, carphenazine, cascara, cefaclor, cefadroxil, cephalexin, cephradine, chlophedianol, chloral hydrate, chlorambucil, chloramphenicol, chlordiazepoxide, chloroquine, chlorothiazide, chlorotrianisene, chlorpheniramine, 6× chlorpromazine, chlorpropamide, chlorprothixene, chlorthalidone, chlorzoxazone, cholestyramine, cimetidine, cinoxacin, clemastine, clidinium, clindamycin, clofibrate, clomiphere, clonidine, clorazepate, cloxacillin, colochicine, coloestipol, conjugated estrogen, contraceptives, cortisone, cromolyn, cyclacillin, cyclandelate, cyclizine, cyclobenzaprine, cyclophosphamide, cyclothiazide, cycrimine, cyproheptadine, danazol, danthron, dantrolene, dapsone, dextroamphetamine, dexamethasone, dexchlorpheniramine, dextromethorphan, diazepan, dicloxacillin, dicyclomine, diethylstilbestrol, diflunisal, digitalis, diltiazen, dimenhydrinate, dimethindene, diphenhydramine, diphenidol, diphenoxylate & atrophive, diphenylopyraline, dipyradamole, disopyramide, disulfiram, divalporex, docusate calcium, docusate potassium, docusate sodium, doxyloamine, dronabinol ephedrine, epinephrine, ergoloidmesylates, ergonovine, ergotamine, erythromycins, esterified estrogens, estradiol, estrogen, estrone, estropipute, etharynic acid, ethchlorvynol, ethinyl estradiol, ethopropazine, ethosaximide, ethotoin, fenoprofen, ferrous fumarate, ferrous gluconate, ferrous sulfate, flavoxate, flecainide, fluphenazine, fluprednisolone, flurazepam, folic acid, furosemide, gemfibrozil, glipizide, glyburide, glycopyrrolate, gold compounds, griseofiwin, guaifenesin, guanabenz, guanadrel, guanethidine, halazepam, haloperidol, hetacillin, hexobarbital, hydralazine, hydrochlorothiazide, hydrocortisone (cortisol), hydroflunethiazide, hydroxychloroquine, hydroxyzine, hyoscyamine, ibuprofen, indapamide, indomethacin, insulin, iofoquinol, iron-polysaccharide, isoetharine, isoniazid, isopropamide isoproterenol, isotretinoin, isoxsuprine, kaolin & pectin, ketoconazole, lactulose, levodopa, lincomycin liothyronine, liotrix, lithium, loperamide, lorazepam, magnesium hydroxide, magnesium sulfate, magnesium trisilicate, maprotiline, meclizine, meclofenamate, medroxyproyesterone, melenamic acid, melphalan, mephenytoin, mephobarbital, meprobamate, mercaptopurine, mesoridazine, metaproterenol, metaxalone, methamphetamine, methaqualone, metharbital, methenamine, methicillin, methocarbamol, methotrexate, methsuximide, methyclothinzide, methylcellulos, methyidopa, methylergonovine, methylphenidate, methylprednisolone, methysergide, metoclopramide, matolazone, metoprolol, metronidazole, minoxidil, mitotane, monamine oxidase inhibitors, nadolol, nafcillin, nalidixic acid, naproxen, narcotic analgesics, neomycin, neostigmine, niacin, nicotine, nifedipine, nitrates, nitrofurantoin, nomifensine, norethindrone, norethindrone acetate, norgestrel, nylidrin, nystafin, orphenadrine, oxacillin, oxazepam, oxprenolol, oxymetazoline, oxyphenbutazone, pancrelipase, pantothenic acid, papaverine, para-aminosalicylic acid, paramethasone, paregoric, pemoline, penicillamine, penicillin, penicillin-v, pentobarbital, perphenazine, phenacetin, phenazopyridine, pheniramine, phenobarbital, phenolphthalein, phenprocoumon, phensuximide, phenylbutazone, phenylephrine, phenylpropanolamine, phenyl toloxamine, phenytoin, pilocarpine, pindolol, piper acetazine, piroxicam, poloxamer, polycarbophil calcium, polythiazide, potassium supplements, pruzepam, prazosin, prednisolone, prednisone, primidone, probenecid, probucol, procainamide, procarbazine, prochlorperazine, procyclidine, promazine, promethazine, propantheline, propranolol, pseudoephedrine, psoralens, syllium, pyridostigmine, pyrodoxine, pyrilamine, pyrvinium, quinestrol, quinethazone, uinidine, quinine, ranitidine, rauwolfia alkaloids, riboflavin, rifampin, ritodrine, alicylates, scopolamine, secobarbital, senna, sannosides a & b, simethicone, sodium bicarbonate, sodium phosphate, sodium fluoride, spironolactone, sucrulfate, sulfacytine, sulfamethoxazole, sulfasalazine, sulfinpyrazone, sulfisoxazole, sulindac, talbutal, tamazepam, terbutaline, terfenadine, terphinhydrate, teracyclines, thiabendazole, thiamine, thioridazine, thiothixene, thyroblobulin, thyroid, thyroxine, ticarcillin, timolol, tocainide, tolazamide, tolbutamide, tolmetin trozodone, tretinoin, triamcinolone, trianterene, triazolam, trichlormethiazide, tricyclic antidepressants, tridhexethyl, trifluoperazine, triflupromazine, trihexyphenidyl, trimeprazine, trimethobenzamine, trimethoprim, tripclennamine, triprolidine, valproic acid, verapamil, vitamin A, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, xanthine, and the like.

In some embodiments, the agent can be a diagnostic agent. For example, the diagnostic agent can be a fluorescent molecule; a gas; a metal; a commercially available imaging agents used in positron emissions tomography (PET), computer assisted tomography (CAT), single photon emission computerized tomography, x-ray, fluoroscopy, and magnetic resonance imaging (MRI); or a contrast agents. Non-limiting examples of suitable materials for use as contrast agents in MRI include gadolinium chelates, as well as iron, magnesium, manganese, copper, and chromium. Examples of materials useful for CAT and x-ray imaging include, but are not limited to, iodine-based materials.

In some embodiments, the agent can be a radionuclide, e.g., for use as a therapeutic, diagnostic, or prognostic agents. Among the radionuclides used, gamma-emitters, positron-emitters, and X-ray emitters are suitable for diagnostic and/or therapy, while beta emitters and alpha-emitters may also be used for therapy. Suitable radionuclides for forming use with various embodiments of the present invention include, but are not limited to, 123 I, 125 I, 130 I, 131 I, 133 I, 135 I, 47 Sc, 72 As, 72 Sc, 90 Y, 88 Y, 97 Ru, 100 Pd, 101m Rh, 119 Sb, 128 Ba, 197 Hg, 211 At, 212 Bi, 212 Pb, 109 Pd, 111 In, 67 Ga, 68 Ga, 67 Cu, 75 Br, 77 Br, 99m Tc, 14 C, 13 N, 15 O, 32 P, 33 P, or 18 F.

In some embodiments, the agent, e.g., therapeutic agent, can be angiotensin receptor blocker (ARB), a CXCR-4 antagonist, or a chemotherapeutic drug.

In some embodiments, the agent, e.g., therapeutic agent, can be selected from the group consisting of losartan, valsartan, telmisartan, olmesartan, AMD3100, paclitaxel, docetaxel, doxorubicin, camptothecin, irinotecan, rapamycin, FK506, 5-FU, gemcitabine, oxaliplatin, cisplatin, leucovorin, and combinations thereof.

Many drugs have dose-limiting side effects that reduce the systemic administration in free drug formulation at high dose for patients; while the high dose is usually expected to achieve significant therapeutic efficacy. For example, the inventors recently demonstrated that the clinically approved angiotensin receptor blocker (ARB) losartan can reduce desmoplasia in PDAC. Losartan can enhance vascular perfusion by decompressing vessels, leading to improved drug delivery and chemotherapy effectiveness. Similarly, the CXCR4 inhibitor, AMD3100, can reduce fibrosis. Unfortunately, both drugs have dose-limiting side effects that limit their utility in patients: ARBs are primarily anti-hypertensive drugs and can at the higher doses induce severe hypotension; AMD3100 can potentially cause hematologic side effects as this pathway is critical in hematopoietic stem/progenitor cell trafficking. The particles described herein can limit the free drug release in blood circulation and promote rapid drug release intratumorally to enhance therapeutic efficacy, avoiding side effects caused by free drugs in circulation. In some embodiments, the therapeutic agent is an therapeutic agent that usually cannot be systemic administration at high dose due to the side effects, and thus requires formulations for selective release in a desired tissue or location. Accordingly, in some embodiments, the therapeutic agent(s) for use in the present disclosure include, but are not limited to, those having dose limiting side effects.

In some embodiments the drugs can be polypeptide. In some embodiments, the therapeutic agent can be an antibody. In some embodiments, the therapeutic agent can be an oligonucleotide.

For conjugation with the polymer, the agent can comprise a reactive group. The term “reactive group” refers to a functional group that is capable of reacting with another functional group. Exemplary reactive functional groups include, but are not limited to, hydroxyls, amines, thiols, thials, sulfinos, carboxylic acids, amides, and the like. The reactive functional group on the polymer and the agent can be the same or different. In some embodiments, the therapeutic agent comprises at least one the below groups for conjugation to pH sensitive linkers or polymers: hydroxyl group, amine group (primary or secondary amine group), carboxylic acid groups, aldehyde group, ketone group, hydrazine group, azide group, vinyl ether group, alkene group and acrylate group.

Anti-Hypertensive and or Collagen Modifying Agents (AHCM Agents)

The methods provided herein are directed to administration of an AHCM, in free or particle form, e.g., for treating or preventing a disease or disorder described herein, e.g., a cancer or a fibrotic disorder described herein. The method can include one, two, three or more AHCM agents, alone or in combination with one or more therapeutic agents described herein (e.g., a microenvironment modulator, and/or other stromal modulator, and/or an additional therapy, e.g., a anti-cancer, an immunomodulatory or anti-fibrotic therapy).

In certain embodiments, the AHCM agent used in the methods and compositions of the invention can be chosen from one or more of: an antagonist of renin angiotensin aldosterone system (“RAAS antagonist”), an renin antagonist, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (AT 1 blocker), a thrombospondin 1 (TSP-1) inhibitor, a transforming growth factor beta 1 (TGF-β1) inhibitor, and a connective tissue growth factor (CTGF) inhibitor. The method can include one, two, three or more AHCM agents, alone or in combination with one or more cancer therapeutics.

In one embodiment, the AHCM is a RAAS antagonist. In an embodiment, the RAAS antagonist is chosen from one or more of: aliskiren (TEKTURNA®, RASILEZ®), remikiren (Ro 42-5892), enalkiren (A-64662), SPP635, or a derivative thereof.

In yet another embodiment, the AHCM is an ACE inhibitor. In an embodiment, the ACE inhibitor is chosen from one or more of: benazepril (LOTENSIN®), captopril (CAPOTEN®), enalapril (VASOTEC®), fosinopril (MONOPRIL®), lisinopril (PRINIVIL®, ZESTRIL®), moexipril (UNIVASC®), perindopril (ACEON®), quinapril (ACCUPRIL®), ramipril (ALTACE®), trandolapril (MAVIK®), or a derivative thereof. Exemplary angiotensin II receptor blockers (AT 1 blockers) include, but are not limited to, losartan (COZAAR®), candesartan (ATACAND®), eprosartan mesylate (TEVETEN®), EXP 3174, irbesartan (AVAPRO®), L158,809, olmesartan (BENICAR®), saralasin, telmisartin (MICARDIS®), valsartan (DIOVAN®), and prodrugs, metabolites, and derivatives thereof, e.g., as shown in FIG. 23 .

In one embodiment, the AT 1 blocker is losartan, or a derivative thereof. Losartan is an anti-hypertensive agent with minimal safety risks (Johnston C I (1995) Lancet 346:1403-1407). Furthermore, in addition to its antihypertensive properties, losartan is also an antifibrotic agent that has been shown to reduce the incidence of cardiac and renal fibrosis (Habashi J P, et al. (2006) Science 312:117-121; and. Cohn R D, et al. (2007) Nat Med 13:204-210). The antifibrotic effects of losartan are caused, in part, by the suppression of active transforming growth factor-β1 (TGF-β1) levels via an angiotensin II type I receptor (AGTR1) mediated down-regulation of TGF-β1 activators like thrombospondin-1 (TSP-1) (Habashi J P, et al. (2006) Science 312:117-121; Cohn R D, et al. (2007) Nat Med 13:204-210; Lavoie P, et al. (2005) J Hypertens 23:1895-1903; Chamberlain J S (2007) Nat Med 13:125-126; and Dietz H C (2010) J Clin Invest 120:403-407).

In yet another embodiment, the AHCM is a thrombospondin 1 (TSP-1) inhibitor. In an embodiment, the TSP-1 inhibitor is chosen from one or more of: ABT-510, CVX-045, LSKL, or a derivative thereof.

In one embodiment, the AHCM is a transforming growth factor beta 1 (TGF-β1) inhibitor (e.g., an anti-TGF-β1 antibody, a TGF-β1 peptide inhibitor, or an inhibitor of a TGF-β1 receptor). In certain embodiment, the TGF-β1 inhibitor is chosen from one or more of: CAT-192, fresolimumab (GC1008), LY 2157299, Peptide 144 (P144), SB-431542, SD-208, compounds described in U.S. Pat. No. 7,846,908 and U.S. Patent Application Publication No. 2011/0008364, or a derivative thereof.

In yet another embodiment, the AHCM is a connective tissue growth factor (CTGF) inhibitor. In certain embodiment, the CTGF inhibitor is chosen from one or more of: DN-9693, FG-3019, and compounds described in European Patent Application Publication No. 1839655, U.S. Pat. No. 7,622,454, or a derivative thereof.

In yet another embodiment, the AHCM is an agonist of AT2 receptor. Exemplary AT2 agonists include, but are not limited to CGP 42112A, Compound 21 or C21 (e.g., as described by Steckelings, U M et al. (2012) Curr Opin Nephrol Hypertens. 21(2): 142-6; Steckelings, U M et al. (2011) Curr Opin Pharmacol. 11(2):187-192).

Exemplary beta-blockers include, but are not limited to, atenolol (TENORMIN®), betaxolol (KERLONE®), bisoprolol (ZEBETA®), metoprolol (LOPRESSOR®), metoprolol extended release (TOPROL XI®), nadolol (CORGARD®), propranolol (INDERAL®), propranolo long-acting (INDERAL LA®), timolol (BLOCADREN®), acebutolol (SECTRAL®), penbutolol (LEVATOL®), pindolol, carvedilol (COREG®), labetalol (NORMODYNE®, TRANDATE®), and derivatives thereof.

In one embodiment, the AHCM agent is a TGF-β1 inhibitor, e.g., an anti-TGF-β1 antibody, a TGF-β1 peptide inhibitor. In certain embodiment, the TGF-β1 inhibitor is chosen from one or more of: CAT-192, fresolimumab (GC1008), LY 2157299, Peptide 144 (P144), SB-431542, SD-208, compounds described in U.S. Pat. No. 7,846,908 and U.S. Patent Application Publication No. 2011/0008364, or a derivative thereof.

In yet another embodiment, the AHCM is an inhibitor of stromal cell-derived growth factor 1 alpha (SDF-1a/CXCL12a). In certain embodiments, the SDF-1a inhibitor is an anti-SDF1a antibody or fragment thereof. In other embodiments, the SDF-1a inhibitor is an inhibitor of an SDF-1a receptor (e.g., a CXCR4 inhibitor), for example the small molecule inhibitor Plerixafor (AMD-3100) or the peptide antagonist LY2510924.

In another embodiment, the AHCM is an endothelin receptor antagonist (ERA). Exemplary ERAs include, but are not limited to, selective ETA receptor antagonists (including, e.g., but not limited to, sitaxentan, ambrisentan, atrasentan, BQ-123, zibotentan), which affect endothelin A receptors; dual antagonists (including, e.g., but not limited to, bosentan, macitentan, tezosentan), which affect both endothelin A and B receptors; and selective ETB receptor antagonists (including, e.g., not limited to, BQ-788 and A192621) which affect endothelin B.

Suitable doses for administration of the AHCM agent can be evaluated based on the standard of care anti-hypertensive doses of the AHCM agents are available in the art.

Exemplary standard of care anti-hypertensive and anti-heart failure doses and dosage formulations for AT 1 inhibitors in humans are as follows: 25-100 mg day −1 of losartan (available in a dosage form for oral administration containing 12.5 mg, 25 mg, 50 mg or 100 mg of losartan); 4 to 32 mg day −1 of candesartan (ATACAND®) (e.g., available in a dosage form for oral administration containing 4 mg, 8 mg, 16 mg, or 32 mg of candesartan); 400 to 800 mg day −1 of eprosartan mesylate (TEVETEN®) (e.g., available in a dosage form for oral administration containing 400 or 600 mg of eprosartan); 150 to 300 mg day −1 of irbesartan (AVAPRO®) (e.g., available in a dosage form for oral administration containing 150 or 300 mg of irbesartan); 20 to 40 mg day −1 of olmesartan (BENICAR®) (available in a dosage form for oral administration containing 5 mg, 20 mg, or 40 mg of olmesartan); 20 to 80 mg day −1 of telmisartin (MICARDIS®) (e.g., available in a dosage form for oral administration containing of 20 mg, 40 mg or 80 mg of telmisartin); and 80 to 320 mg day −1 of valsartan (DIOVAN®) (e.g., available in a dosage form for oral administration containing 40 mg, 80 mg, 160 mg or 320 mg of valsartan).

Exemplary standard of care anti-hypertensive and anti-heart failure doses and dosage formulations for ACE inhibitors in humans are as follows: 10 to 40 mg day −1 of benazepril (LOTENSIN®) (Lotensin (benazepril) is supplied as tablets containing 5 mg, 10 mg, 20 mg, or 40 mg of benazepril hydrochloride for oral administration); 25 to 100 mg day −1 of captopril (CAPOTEN®) (available in a dosage form for oral administration containing 12.5 mg, 25 mg, 50 mg or 100 mg of captopril); 5 to 40 mg day −1 of enalapril (VASOTEC®) (available in a dosage form for oral administration containing 2.5 mg, 5 mg, 10 mg or 20 mg of enalapril; 10 to 40 mg day −1 of fosinopril (MONOPRIL®) (available in a dosage form for oral administration containing 10 mg, 20 mg, or 40 mg of fosinopril); 10 to 40 mg day −1 of lisinopril (PRINIVIL®, ZESTRIL®) (available in a dosage form for oral administration containing 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg or 40 mg of lisinopril); 7.5 to 30 mg day −1 of moexipril (UNIVASC®) (available in a dosage form for oral administration containing 7.5 mg or 15 mg of Moexipril); 4 to 8 mg day −1 of perindopril (ACEON®) (availab