Abstract 5650: Targeting siRNA to tumors and their stroma as a dual anticancer and anti-angiogenic therapy

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 8_Supplement; p. 5650
• Main Authors: Ofek, Paula, Fischer, Wiebke, Calderon, Marcelo, Haag, Rainer, Satchi-Fainaro, Ronit
• Format: Journal Article
• Language: English
• Published: 15.04.2012
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-5650

Abstract New targets for RNA interference (RNAi)-based cancer therapy are constantly emerging from the increasing knowledge on the molecular pathways involved in carcinogenesis. Nevertheless, in vivo delivery of small interfering RNA (siRNA) remains a crucial challenge for its therapeutic success. SiRNAs on their own are not taken-up by most mammalian cells in a way that preserves their activity. In order to circumvent these limitations, we developed a cationic carrier system, which can strongly improve its stability, intracellular trafficking and silencing efficacy. We have recently developed a polyglycerol (PG)-Amine, a water-soluble polyglycerol-based dendrimer that accumulates in the tumor environment due to the enhanced permeability and retention (EPR) effect, and therefore, represents an ideal delivery vehicle for antitumor biological agents. PG-Amine entrapment of siRNA neutralized its negative charge in a dose-dependent manner and significantly improved its cellular uptake. The luciferase gene, ectopically overexpressed in U87 human glioblastoma cell line was used as a model system and its silencing efficacy was extensively evaluated both in vitro and in vivo. Following encouraging results obtained from several cancer cell lines, the silencing efficiency of the nanocarrier luciferase-siRNA polyplexes was followed-up in vivo by non-invasive intravital bioluminescence imaging. A significant gene silencing effect was accomplished in vivo in both human glioblastoma and murine mammary adenocarcinoma mouse models following intravenous administration of our polyplexes. We further characterized the effect of silencing a few selected key proteins (e.g. Notch1) in vitro and achieved significant effects on the proliferation and migration of glioblastoma and neuroblastoma cell lines. In conclusion, we predict that specific delivery of siRNA to tumor epithelial and endothelial cells in vivo, and silencing of an important cell growth and angiogenesis regulator will warrant this approach as a successful anticancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5650. doi:1538-7445.AM2012-5650