title: 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.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Shanta
authors.initials: S
authors.lastname: Dhar
authors.forename: Frank X
authors.initials: FX
authors.lastname: Gu
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.forename: Omid C
authors.initials: OC
authors.lastname: Farokhzad
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lippard
mesh_terms: D052157:Aptamers, Nucleotide / Q000235:genetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use*; D016503:Drug Delivery Systems / Q000379:methods*; D004705:Endocytosis / Q000502:physiology; D005455:Fluorescent Antibody Technique; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D053758:Nanoparticles / Q000627:therapeutic use*; D036103:Nanotechnology / Q000379:methods*; D017671:Platinum Compounds; D011092:Polyethylene Glycols / Q000378:metabolism*; D011098:Polyglactin 910 / Q000378:metabolism*; D011355:Prodrugs / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy*
chemical_list: D052157:Aptamers, Nucleotide; D017671:Platinum Compounds; D011355:Prodrugs; C102418:poly(lactic-glycolic acid)-poly(ethyleneglycol) copolymer; D011098:Polyglactin 910; D011092:Polyethylene Glycols; D002945:Cisplatin