Targeted structure-specific particulate delivery systems
Provided are targeted structure-specific particulate-based delivery systems comprising: a nanoparticle; a PEG polymer coating on the surface of the nanoparticle; a targeting moiety conjugated on a surface of the nanoparticle and configured to promote specific binding to a cell surface molecule expressed by a target cell; and a biologically active agent in or on the nanoparticle, wherein the biologically active agent is selected to enhance a desired response in a target cell intracellularly or extracellularly. Methods of treating a disease or disorder administering the delivery system are contemplated.
1. A drug delivery nanoparticle, comprising:
(a) a nanoparticle having a hydrodynamic diameter of between 110 nm and 115 nm;
(b) a coating of polyethylene glycol with a surface density of about at least about 0.1 polyethylene glycol molecules per nm 2 ;
(c) an anti-Fn14 antibody that specifically binds to the cell surface of a tumor cell, wherein the anti-Fn14 antibody is present on the surface of the nanoparticle at a density of between about 11 anti-Fn14 antibody molecules per nanoparticle to about 56 anti-Fn14 antibody molecules per nanoparticle; and
(d) a therapeutic agent, wherein the nanoparticle penetrates extracellular matrix, wherein the nanoparticle has minimal non-specific binding to extracellular matrix.
2. The drug delivery nanoparticle of claim 1 , wherein the target tumor cell is selected from the group consisting of a bladder, brain, breast, cervical, colorectal, esophageal, liver, lung, skin, ovarian, pancreatic, prostate, renal, testicular, bone, liver, and lymph node cell.
3. The drug delivery nanoparticle of claim 1 , wherein the tumor cell is a glioblastoma cell.
4. The drug delivery nanoparticle of claim 1 , wherein the nanoparticle is formed from a biodegradable polymer selected from the group consisting of poly-D-L-lactide-co-glycolide (PLGA); polylactic acid (PLA); poly-ε-caprolactone (PCL); chitosan, gelatin, albumin, and poly-alkyl-cyano-acrylates (PAC).
5. The drug delivery nanoparticle of claim 1 , wherein the Fn14-binding antibody is an Fn14 monoclonal antibody or fragment thereof.
6. The drug delivery nanoparticle of claim 5 , wherein the anti-Fn14 antibody is selected from the group consisting of ITEM4, ITEM-4-SH, ITEM4 scFv, and ITEM4 Fab.
7. The drug delivery nanoparticle of claim 1 , wherein the therapeutic agent is selected from the group consisting of cisiplatin, doxorubicin, etoposide, and paclitaxel.
8. The drug delivery nanoparticle of claim 1 , wherein the nanoparticle releases an effective amount of the biologically active agent over a period of at least four hours.
9. A pharmaceutical composition, comprising a pharmaceutically acceptable vehicle and a drug delivery nanoparticle of claim 1 .
10. A kit comprising the pharmaceutical composition of claim 9 .
11. A method for treating a tumor of the brain, lung, or breast, the method comprising administering to a patient in need thereof an effective amount of the drug delivery nanoparticle of claim 1 .
12. The method of claim 11 , wherein the nanoparticle is administered locally to the brain.
13. The method of claim 11 , wherein the nanoparticle is administered systemically and the nanoparticle penetrates the brain by passing through the blood-brain-barrier and then extracellular matrix.
14. The method of claim 11 , wherein the tumor is glioblastoma.