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

Shanta Dhar, Frank X. Gu, Robert Langer, Omid C. Farokhza, Stephen J. Lippard

Research output: Contribution to journalArticle

689 Citations (Scopus)

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(NH3)2(O 2CCH2CH2CH2CH2CH 3)2Cl2] (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.

Original languageEnglish (US)
Pages (from-to)17356-17361
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number45
DOIs
StatePublished - Nov 11 2008
Externally publishedYes

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Ethylene Glycol
Prodrugs
Nanoparticles
Cisplatin
Prostatic Neoplasms
Polymers
polylactic acid-polyglycolic acid copolymer
Platinum Compounds
human glutamate carboxypeptidase II
Endosomes
Endocytosis
Fluorescence Microscopy
Prostate
Neoplasms
Cholesterol
Monoclonal Antibodies

Keywords

  • Controlled release
  • DNA cross-link
  • Metals in medicine
  • PSMA

ASJC Scopus subject areas

  • General

Cite this

Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA - PEG nanoparticles. / Dhar, Shanta; Gu, Frank X.; Langer, Robert; Farokhza, Omid C.; Lippard, Stephen J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 45, 11.11.2008, p. 17356-17361.

Research output: Contribution to journalArticle

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