Abstract 1312: PSMA antibody functionalized docetaxel-loaded magnetic nanoparticles for prostate cancer therapy

Abstract

Abstract Objectives: Prostate cancer (PrCa) is the second most leading cause of cancer-related death in men in the United States. Chemotherapy (Docetaxel, Dox) is currently the most common first-line therapeutic option. However, adverse side effects and chemo-resistance of docetaxel limit its clinical use. Improving docetaxel targeted delivery and its activity at the tumor site using a targeted nanoparticle system could be an attractive strategy for PrCa therapy. Prostate Specific Membrane Antigen (PSMA) is highly overexpressed in PrCa cells, thus is a highly attractive molecular target for PrCa therapy. In this study, we developed and determined anti-cancer efficacy of a novel docetaxel loaded, PSMA targeted magnetic nanoparticle (PSMA-MNP-Dox) formulation for PrCa therapy. Methods: Docetaxel loaded magnetic nanoparticle (MNP-Dox) formulation is composed of an iron oxide core coated with cyclodextrin (for drug loading) and F127 polymer (for particle stability and chemosensitization). Therapeutic efficacy of this unique nanoparticle formulation was evaluated using clinically relevant cell line models (C4-2, PC-3, and DU-145) through cell proliferation and colony formation assays. Molecular effects of this formulation on apoptosis, anti-apotosis, and drug resistance associated proteins were evaluated using immunoblotting assays. Contrast imaging property of MNP-Dox formulation was examined using Phantom Gel MR imaging model. For active targeting, PSMA antibody conjugation to this formulation was achieved through N-hydroxysuccinimide group containing PEG polymer. Active targeting potential of this formulation was evaluated in PSMA+ (C4-2) and PSMA- (PC-3) cell lines, C4-2 generated tumor xenografts. Results: MNP-Dox formulation showed optimal particle size and zeta potential which can efficiently internalized in PrCa cells. Our formulation showed anti-cancer efficacy in prostate cancer cell lines. Additionally, it induces the expression of apoptosis associated proteins, Bax and Bad, cleaved PARP, and caspase 3, and downregulated the expression of anti-apoptotic proteins, Bcl-2 and Bcl-xL. Moreover, it also inhibited the expression of chemoresistance associated proteins (PSMA and MDR1). Our PSMA antibody targeted MNPs-Dox formulation exhibited a profound uptake pattern in PSMA+ cells (C4-2) compared to PSMA null (PC-3)- cells, suggesting its targeting potential. A similar targeting potential was also observed in ex-vivo studies while using C4-2 tumor xenografts, however, no intense targeting was observed in normal tissues due to lack of PSMA expression. Conclusion: PSMA antibody functionalized MNP-Dox formulation can efficiently target PSMA + PrCa cells and deliver docetaxel into prostate tumors. This targeted drug delivery system could reduce the dose of docetaxel required to kill cancer cells, thus minimizing long-term docetaxel associated systemic toxicity and drug-resistance. Citation Format: Prashanth Kumar Bhusetty Nagesh, Nia Johnson, Vijaya K.N. Boya, Pallabita Chowdhury, Aditya Ganju, Bilal Hafeez, Sheema Khan, Meena Jaggi, Subhash C. Chauhan, Murali M. Yallapu. PSMA antibody functionalized docetaxel-loaded magnetic nanoparticles for prostate cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1312.