Abstract 3663: Prostate specific membrane antigen (PSMA) targeting nano-EGCG for prostate cancer prevention and treatment.

Abstract

Abstract We recently employed the use of nanotechnology to improve the outcome of bioactive food components for cancer chemoprevention and termed the concept as ‘nanochemoprevention’ (Cancer Res. 2009;69(5):1712-6). To demonstrate the proof-of-principle we encapsulated green tea polyphenol epigallocatechin-3-gallate (EGCG) in polylactic acid-polyethylene glycol (PLA-PEG) nanoparticles and showed that this formulation demonstrates greater than ten-fold dose advantage over non-encapsulated EGCG in human prostate cancer (PCa) cells both in vitro and in vivo settings. Emerging data suggest that EGCG possess cancer preventive as well as chemotherapeutic potential against PCa. More recently, we also proposed targeted nanoparticles as novel prototypes for the delivery of EGCG (J Med Chem. 2011;54:1321-32) for prevention and therapy of PCa. Here, we extended the work and developed polymeric EGCG-encapsulated nanoparticles targeted with small molecular entities able to bind to prostate specific membrane antigen (PSMA), a transmembrane protein that is overexpressed on PCa cells, and evaluated their efficacy in several in vitro assays using PCa cell lines of differential PSMA expression status. Biocompatible polymer PLGA-PEG-COOH was synthesized and used as base to conjugate a urea-based inhibitor (DCL) or a glutamate-containing molecule (Asp-Glu) to obtain PLGA-PEG-DCL and PLGA-PEG-Asp-Glu nanoparticles suitable for targeted delivery to the prostate. Next, to investigate the impact of DCL- and Asp-Glu-PEGylation on ligand binding, a comparative docking study on the PSMA active site was performed, and crucial protein-ligand interactions were analyzed. Prepared nanoparticles were characterized in terms of morphology, size and zeta potential, encapsulation efficiency, and in vitro release kinetics. Nanoparticles derived from these three polymer systems were spherical in shape with a unimodal size distribution, showing mean diameter ranging from 130 to 250 nm with a zeta potential of around -30 mV. Cellular binding and uptake of the fluorescent nanosystems were detected in PC-3, DU-145 and LNCaP cell lines at two time points and PSMA specific internalization and accumulation was observed. The antiproliferative efficacy of nano-EGCG, compared to EGCG alone, was assessed 72 h post treatment using MTT assay. Both PSMA specific EGCG polymeric nanoparticles lead to an increased antiproliferative and pro-apoptotic activity in PSMA positive LNCaP cells as compared to PSMA negative DU145 and PC3 cells. These data suggest that encapsulated EGCG retains its biological effectiveness, with prostate specific targeting, for exerting its pro-apoptotic properties, critically important determinant of chemopreventive and chemotherapeutic effects of EGCG. Citation Format: Imtiaz A. Siddiqui, Vanna Sanna, Vaqar M. Adhami, Sameh M. Shabana, Mario Sechi, Hasan Mukhtar. Prostate specific membrane antigen (PSMA) targeting nano-EGCG for prostate cancer prevention and treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3663. doi:10.1158/1538-7445.AM2013-3663