Targeted Delivery Of Cisplatin To Prostate Cancer Cells By Aptamer Functionalized Pt(IV) Prodrug-PLGA-PEG Nanoparticles

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology
Article Date: 08 Dec 2008 - 1:00 PDT

email to a friend   printer friendly   opinions  

UroToday.com - In the November 11, 2008 issue of the Proceedings of the National Academy of Sciences, USA, Dr. Shanta Dhar and researchers from MIT and Harvard presented in vitro and in vivo data on delivery of cisplatin to prostate cancer (CaP) cells by nanoparticles (NPs). NPs made from polyethylene glycol (PLGA) can be targeted to an antigen for specific delivery. In this work, prostate specific membrane antigen (PSMA) was bioengineered into the NP, as PSMA is expressed by prostate cancer cells even in the metastatic and castration resistant state. A prodrug approach was used where cisplatin is released from a Pt(IV) precursor, overcoming problems associated with cisplatin encapsulation and allowing a cell-targeting moiety to deliver a lethal dose of cisplatin upon intracellular reduction.

Following PSMA recognition, the NPs are taken into cancer cells by endocytosis. This was tested in LNCaP-expressing PSMA cells and PC3 cells, which do not express PSMA protein on their cell surface. LNCaP cells demonstrated complete internalization of the NPs by receptor-mediated endocytosis while PC3 cells did not.

Complex chemistry methodology was involved in the development of the encapsulated NP, and the controlled release kinetics was determined. An initial burst release during the first 2 hours accounts for only 12% of the total platinum, followed by a dormant period of about 14 hours. Then a period of controlled platinum release occurs, reaching a level of 66% after 24 hours. The entire release period extends over 60 hours. Uptake in LNCaP cells was highly cytotoxic, with an IC50=0.03, micromolar, compared to an IC50=0.13 micromolar for non-targeted particles and 0.18 micromolar for free cisplatin. Thus, the aptamer target NP cisplatin is 80 times more toxic to the cells than free cisplatin.

This technology, while holding significant potential in prostate cancer, can be tailored with other targets and prodrugs for use in other cancers.

Dhar S, Gu FX, Langer R, Farokhzad OC, Lippard SJ
Proc Natl Acad Sci U S A. 2008 Nov 11;105(45):17356-61.
doi:10.1073/pnas.0809154105

Written by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS

UroToday - the only urology website with original content written by global urology key opinion leaders actively engaged in clinical practice.

To access the latest urology news releases from UroToday, go to: www.urotoday.com

Copyright © 2008 - UroToday

• Additional
• References
• Citations