Targeted delivery system

The invention relates to targeted delivery technology. More particularly, the invention relates to a delivery system targeting sigma receptors over-expressed cells.

Anti-cancer drugs presently in clinical use have low therapeutic windows, resulting in serious side effects. Therefore, a targeted delivery system for delivering those toxic drugs to target cells is needed.

Nanoparticle delivery systems, such as liposomes, polymer-based delivery systems, or emulsions, are unable to target to specific cells. Therefore, targeted ligands that can modify the nanoparticle delivery systems are required for developing targeted delivery systems. However, antibodies, the most common used ligands in targeted drug delivery may cause serious immune response after systemic injection and this would be a potential problem.

Small molecule ligands with no immunogeneicity and ease for scale up production are more desirable for modifying delivery systems, thus are more potential for targeted delivery systems development compared to antibodies.

Accordingly, an embodiment of the invention provides a targeted delivery system comprising a carrier for a drug; and a targeted ligand modifying the carrier to target the encapsulated drug to a sigma receptor (SR) over-expressed cell.

Also provided is a target delivery system comprising a drug and a targeted ligand conjugated therewith to targeted deliver the drug to a sigma receptor over-expressed cell.

The invention can be more fully understood and further advantages become apparent when reference is made to the following description of the invention and the accompanying drawings in which:

FIG. 1 illustrates the synthesis of ligand and its conjugation with lipid.

FIG. 2A-2D show the cellular uptake study results for head and neck cancer cells treated with FITC-oligonucleotide containing LPDII or LPDII-AA by fluorescence microscope. FIG. 2A , 22 B cells treated with LPDII; FIG. 2B , HONE-1 cells treated with LPDII; FIG. 2C , 22 B cells treated with LPDII-AA; and FIG. 2D , HONE-1 cells treated with LPDII-AA. FIG. 2A˜2D : 200×

FIG. 3A˜3B illustrate the delivery efficiencies of formula LPDII and LPDII-AA to head and neck cancer cells HONE-1 ( FIG. 3A) and 22B ( FIG. 3B ).

FIG. 4 illustrates the delivery efficiencies of formula LPDII and LPDII-AA to head and neck cancer cell, 22 B, or cervical cancer cell, Hela, in the respective presence and absence of HP (haloperidol).

FIG. 5A˜5B show cell proliferation inhibition of head and neck cancer cell, HONE-1 ( FIG. 5A) and 22B ( FIG. 5B ), respectively untreated and treated with free AS, LPDII or LPDII-AA.

FIG. 6A˜6B show EGFR down-regulation of head and neck cancer cell, HONE-1 ( FIG. 6A) and 22B ( FIG. 6B ), respectively untreated and treated with free AS, LPDII, or LPDII-AA.

FIG. 7 shows tumor growth inhibition in SCID mice respectively treated with LPDII and LPDII-AA.

A variety of human tumors over-express SR, membrane-bound proteins that possess high affinity for haloperidol, various neuroleptics, and benzamide derivatives. Recently, researchers have synthesized a variety of benzamide derivatives and applied those new compounds for the treatment of cancers or as imaging agents for tissues which over-express SR.

The invention is based on the discovery of a targeted ligand, a benzamide derivative, anisamide (AA), originally used as an imaging agent in research for prostate cancer which over-express SR. We have conjugated AA ligands onto antisense oligonucleotide (AS-ODN) containing carriers and showed that these targeted carriers could specifically deliver AS-ODN into SR over-expressed cells.

The targeted delivery system of an embodiment of the invention, first of all, is an active targeting delivery system utilizing a molecule such as a ligand to recognize a specific receptor on the surface of a target cell for selective delivery of the drug into the target cell. When the ligands recognize the cell surface receptors, mechanism of receptor-mediated endocytosis is triggered and drugs containing carriers are uptaken by cells. SR is a cell surface receptor that can trigger endocytosis after binding with SR ligands.

Second, Benzamide derivatives, first proposed as small molecule compounds possessing high affinity for SR, have to date only been applied in tumor imaging, but firstly applied here as a targeted ligand for targeted delivery of drugs.

The targeting delivery system comprises a carrier for a drug and a sigma ligand modifying the carrier to target the encapsulated drug to a sigma receptor over-expressed cell.

Another target delivery system comprises a drug and a sigma ligand conjugated therewith to target delivery to a sigma receptor over-expressed cell.

The “targeted ligand” used herein comprises benzamide derivatives, preferably anisamide. Anisamide links to a lipid by chemical synthesis to form, for example, DSPE-PEG-SP2-AA (distearoylglycerolphosphatidylethanolamine-polyethyleneglycol(3400)-ω-[2-(4′-methoxybenzamido)]ethylamine). The modification of the carriers can thus be achieved.

The “carrier” used herein comprises nanoparticles. The nanoparticle comprises, but is not limited to, a liposome, a polymer based nanoparticle, or an emulsion; preferably a liposome.

The “drug” used herein comprises an organic compound, a peptide, a protein, an oligonucleotide, or DNA. When the carrier is a liposome, the drug can be an oligonucleotide, preferably an antisense oligonucleotide.

The “sigma receptor over-expressed cell” comprises a tumor cell. The tumor cell can be, but is not limited to, breast cancer, head and neck cancer, lung cancer, liver cancer, brain cancer, or prostate cancer. When the tumor cell is a head and neck cancer cell, the drug can be an antisense oligonucleotide of epidermal growth factor receptor (EGFR).

Practical examples are described herein.