In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 5517-5517
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 & lt;0.01, 0.005, respectively) and the combination treatment resulted in the greatest reduction in tumor weight (by 96%; p & lt;0.002), and the number of tumor nodules (by 74%; p & 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 & 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 & lt;0.01, and & lt;0.03, respectively). Combination of docetaxel and STAT3 siRNA-rHDL resulted in 84 to 96% reduction in tumor growth (HeyA8; P & lt;0.003, SKOV3ip1; P & 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 & 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 & 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 & lt;0.01, both). Furthermore, the combination of STAT3 siRNA/rHDL and docetaxel significantly reduced cell proliferation (by 48%; P & lt;0.001), MVD (by 88%; P & lt;0.001) and cell survival (by 30-folds; P & lt;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.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-5517
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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