Abstract 5517: Targeting anticancer therapeutics: A role for reconstituted high density lipoprotein (rHDL)

Abstract

Abstract BACKGROUND: RNA interference (RNAi) holds great potential as a therapeutic strategy. However, efficient and biocompatible methods are needed for systemic delivery of siRNA. In order to develop a biologically safe delivery system, we utilized rHDL nanoparticles for systemic delivery of siRNA. METHODS: We used fluorescently (Alexa-555) tagged siRNA to test the extent of siRNA delivery. For proof-of-concept studies, we targeted FAK and STAT3, which are considered critical targets in many solid tumors. Several orthotopic mouse models of ovarian carcinoma (HeyA8, SKOV3ip1, and HeyA8-MDR) and colon cancer (HCT116) were utilized. Following treatment, effects on tumor weight, angiogenesis (CD31), cell proliferation (Ki-67), and apoptosis (TUNEL) were assessed. RESULTS: The rHDL nanoparticles delivered siRNA in a scavenger receptor (SR-B1) -specific fashion to ∼80% of a given tumor following a single intravenous injection. FAK or STAT3 targeted siRNA-rHDL effectively silenced FAK or STAT3 expression in vivo for over 4 days. In the HeyA8 orthotopic ovarian cancer model, FAK siRNA-rHDL or docetaxel monotherapy resulted in 62 to 74% reduction in tumor weight (p<0.01, 0.005, respectively) and the combination treatment resulted in the greatest reduction in tumor weight (by 96%; p<0.002), and the number of tumor nodules (by 74%; p<0.015). Additionally, STAT3 siRNA-rHDL alone demonstrated 62 to 76% reduction in tumor weight in several orthotopic ovarian cancer models (HeyA8, SKOV3ip1, and HeyA8-MDR; P<0.04, 0.04, and 0.01, respectively) compared to control treatment. Docetaxel treatment alone resulted in a 62 to 77% decrease in tumor growth in the HeyA8 and SKOV3ip1 models (P<0.01, and <0.03, respectively). Combination of docetaxel and STAT3 siRNA-rHDL resulted in 84 to 96% reduction in tumor growth (HeyA8; P<0.003, SKOV3ip1; P<0.009) compared to either treatment alone. Additionally, in the HeyA8-MDR model, the addition of STAT3 silencing to docetaxel treatment reduced tumor growth by 89% compared to docetaxel monotherapy (P<0.001). In the metastatic mouse model of colon cancer (HCT116), STAT3 siRNA-rHDL or oxaliplatin alone resulted in 79% and 55% reduction in tumor weight (respectively; P<0.01, both) while combination of STAT3 siRNA-rHDL and oxaliplatin resulted in 96% reduction in tumor weight and 86% reduction in number of metastatic tumor nodules (P<0.01, both). Furthermore, the combination of STAT3 siRNA/rHDL and docetaxel significantly reduced cell proliferation (by 48%; P<0.001), MVD (by 88%; P<0.001) and cell survival (by 30-folds; P<0.001) compared to control siRNA/rHDL. H&E staining of organs following therapy experiments revealed no significant changes compared to the control group. CONCLUSION: rHDL is a novel nanocarrier that is safe and highly effective for delivery of therapeutic payloads. These findings have profound clinical implications for cancer treatment in humans. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5517.