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

• DOI: 10.1073/pnas.0809154105
• Publication Date: 2008-11-01T00:46:03Z
• Authors: Shanta Dhar; Frank X. Gu; Robert Langer; Omid C. Farokhzad; Stephen J. Lippard
• Keywords: PLGA; Aptamer; Nanocarriers

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