Abstract 5517: Targeting anticancer therapeutics: A role for reconstituted high density lipoprotein (rHDL)
Authors: Mian M. Shahzad, Ligegowda S. Mangala, Jeong W. Lee, Koji Matsuo, Maya P. Nair, Hee D. Han, Edna M. Mora, Chunhua Lu, Puja Gaur, Shyon B. Haghpeykar, Amy R. Carroll, Rebeca L. Stone, Gabriel Lopez-Berestein, Andras G. Lacko, Anil K. Sood
Journal: Cancer Research (2010)

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&amp;lt;0.01, 0.005, respectively) and the combination treatment resulted in the greatest reduction in tumor weight (by 96%; p&amp;lt;0.002), and the number of tumor nodules (by 74%; p&amp;lt;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&amp;lt;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&amp;lt;0.01, and &amp;lt;0.03, respectively). Combination of docetaxel and STAT3 siRNA-rHDL resulted in 84 to 96% reduction in tumor growth (HeyA8; P&amp;lt;0.003, SKOV3ip1; P&amp;lt;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&amp;lt;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&amp;lt;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&amp;lt;0.01, both). Furthermore, the combination of STAT3 siRNA/rHDL and docetaxel significantly reduced cell proliferation (by 48%; P&amp;lt;0.001), MVD (by 88%; P&amp;lt;0.001) and cell survival (by 30-folds; P&amp;lt;0.001) compared to control siRNA/rHDL. H&amp;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.