Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA-PEG nanoparticles.

Abstract

Cisplatin is used to treat a variety of tumors, but dose limiting toxicities or intrinsic and acquired resistance limit its application in many types of cancer including prostate. We report a unique strategy to deliver cisplatin to prostate cancer cells by constructing Pt(IV)-encapsulated prostate-specific membrane antigen (PSMA) targeted nanoparticles (NPs) of poly(D,L-lactic-co-glycolic acid) (PLGA)-poly(ethylene glycol) (PEG)-functionalized controlled release polymers. By using PLGA-b-PEG nanoparticles with PSMA targeting aptamers (Apt) on the surface as a vehicle for the platinum(IV) compound c,t,c-[Pt(NH(3))(2)(O(2)CCH(2)CH(2)CH(2)CH(2)CH(3))(2)Cl(2)] (1), a lethal dose of cisplatin was delivered specifically to prostate cancer cells. PSMA aptamer targeted delivery of Pt(IV) cargos to PSMA(+) LNCaP prostate cancer cells by endocytosis of the nanoparticle vehicles was demonstrated using fluorescence microscopy by colocalization of green fluorescent labeled cholesterol-encapsulated NPs and early endosome marker EEA-1. The choice of linear hexyl chains in 1 was the result of a systematic study to optimize encapsulation and controlled release from the polymer without compromising either feature. Release of cisplatin from the polymeric nanoparticles after reduction of 1 and formation of cisplatin 1,2-intrastrand d(GpG) cross-links on nuclear DNA was confirmed by using a monoclonal antibody for the adduct. A comparison between the cytotoxic activities of Pt(IV)-encapsulated PLGA-b-PEG NPs with the PSMA aptamer on the surface (Pt-NP-Apt), cisplatin, and the nontargeted Pt(IV)-encapsulated NPs (Pt-NP) against human prostate PSMA-overexpressing LNCaP and PSMA(-) PC3 cancer cells revealed significant differences. The effectiveness of PSMA targeted Pt-NP-Apt nanoparticles against the PSMA(+) LNCaP cells is approximately an order of magnitude greater than that of free cisplatin.

• Authors: Shanta Dhar, Frank X Gu, Robert Langer, Omid C Farokhzad, Stephen J Lippard
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 45 Pg. 17356-61 (Nov 11 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18978032 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Aptamers, Nucleotide
• Platinum Compounds
• Prodrugs
• poly(lactic-glycolic acid)-poly(ethyleneglycol) copolymer
• Polyglactin 910
• Polyethylene Glycols
• Cisplatin

Topics

• Aptamers, Nucleotide (genetics, therapeutic use)
• Cell Line, Tumor
• Cisplatin (administration & dosage, therapeutic use)
• Drug Delivery Systems (methods)
• Endocytosis (physiology)
• Fluorescent Antibody Technique
• Humans
• Male
• Microscopy, Fluorescence
• Molecular Structure
• Nanoparticles (therapeutic use)
• Nanotechnology (methods)
• Platinum Compounds
• Polyethylene Glycols (metabolism)
• Polyglactin 910 (metabolism)
• Prodrugs (therapeutic use)
• Prostatic Neoplasms (drug therapy)