Abstract 4916: Efficiacy of NU7441-encapsulated PLGA nanoparticles in radiation sensitization of prostate cancer cells

Abstract

Abstract Introduction: Prostate cancer remains the leading cause of cancer-related mortality in men with an estimated 241,740 new cases and 28,170 deaths expected by end of 2012. Conventional cancer treatments such as radiation therapy can be ineffective due to radiation resistance of prostate cancer cells. This resistance arises due to their increased DNA double strand break (DSB) repair ability, especially through Non-Homologous End Joining (NHEJ). In this study, we have developed biodegradable and biocompatible poly lactic-co-glycolic acid (PLGA)-based nanoparticles containing the potent radio-sensitizer NU7441 (8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one) for radiation sensitization of prostate cancer cells by inhibiting DNA-dependent protein kinase, which regulates NHEJ. Methods: PLGA nanoparticles encapsulating NU7441 and iron oxide as an imaging and targeting agent were prepared by a standard double emulsion technique and characterized for size and surface charge. R11 peptide was surface conjugated onto the nanoparticles for prostate cancer-specific targeting. Stability studies in de-ionized (DI) water and serum were conducted over 5 days followed by drug release studies in DI water at 37oC. Further, in vitro studies were done to study cytocompatibility with prostate epithelial cells (PZ-HPV7) and cellular uptake by prostate cancer cells (PC3). DSB repair kinetics of prostate cancer cells following nanoparticle uptake was studied using a DSB repair assay. Results: Our nanoparticles had an average size of 274.13+ 79.96 nm and showed good stability in water and serum for 5 days. The nanoparticles also showed bi-phasic NU7441 release within 21 days at 37oC and >80% PZ-HPV7 cell viability up to 2000 µg/ml nanoparticle concentration. Further, the particles were selectively uptake by PC3 cells in a dose and magnetic field-dependent manner and showed effective radiation sensitization of these cells in vitro. Conclusions: Our results thus demonstrate that R11-conjugated PLGA-iron oxide nanoparticles containing NU7441 are biocompatible and can be potentially used to radio-sensitize prostate cancer cells in vivo. Citation Format: Jyothi U. Menon, Vasu Tumati, Jer-Tsong Hsieh, Kytai T. Nguyen, Debabrata Saha. Efficiacy of NU7441-encapsulated PLGA nanoparticles in radiation sensitization of prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4916. doi:10.1158/1538-7445.AM2014-4916