Abstract A38: Nanoreformulation of platinum-based drugs to address disparate cancer treatment outcomes.

Abstract

Abstract Modest responses and systemic toxicities during treatment of advanced cancer limits cancer drug efficacy, especially in African Americans. We determined the utility of cisplatin-loaded biodegradable XPclad nanoparticles coated with folate-conjugated polycaprolactone-polyethylene glycol. XPclad nanoparticles under in vitro conditions exhibited sustained release of the encapsulated cisplatin. Prostate cancer (PCa) cell lines (PC3, LNCaP, PTEN-CaP2, etc.), but not normal prostatic epithelial cells (PrEC and RWPE-1), expressed high levels of folate receptor α (FRα/FR1). Similar to cancer cells, Treg cells but not T helper cells express high affinity folate receptor (FRδ/FR4). Treatment using 20 μM of cisplatin solution resulted in > 90% cell death of PCa cells, PrEC, and RWPE-1 cells as well as purified CD4+CD25HiFoxP3+ T cells (Tregs) and CD4+CD25LoFoxP3- T cells (T helper). However, XPclad nanoparticles, containing cisplatin (equivalent to a 200 nM dose), were taken up and induced the same level of apoptosis in PCa and Treg cells as cisplatin solution, but did not significantly affect PrEC or RWPE-1 cells or T helper cells. Finally, we show that PC3 tumor-bearing mice that received either cisplatin solution (8 mg/kg/week) or cisplatin-encapsulated folate-coated XPclad nanoparticles (equivalent cisplatin dose = 0.08 mg/kg/week) resulted in significant tumor regression. Mice receiving cisplatin solution had significantly higher kidney and liver toxicities than naïve or XPclad nanoparticle-treated mice. Our studies show XPclad nanoparticles enhance tumor therapy efficacy with significantly lower to no toxicity and suggest that FR-targeted nanotherapy modulates the destruction of both tumor cells and Treg cells for increased efficacy. GRANT SUPPORT: G12 RR03034, U54 CA118638 and P60MD00525 Citation Format: James W. Lillard, S. Singh, R. Singh. Nanoreformulation of platinum-based drugs to address disparate cancer treatment outcomes. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A38.