Abstract 5535: Delivery of siRNA via functionalized lipopolyamine systems

Abstract

Abstract The efficient delivery of siRNA molecules to target cells is critical for the application of RNAi to the treatment of human cancers. To this end, we have developed novel cationic lipopolyamime structures that can be used to complex or encapsulate siRNA into nanoparticles for efficient in vitro or in vivo delivery. Unlike conventional cationic delivery systems, these lipopolyamines are chemically flexible which allow for covalent attachment of functional moieties which can modulate their biological activity. For example, modification of these systems with serum stabilizing agents allows for modulation of physical parameters important for biological properties such as toxicity and biodistribution. Intravenous (iv) injection of these functionalized nanoparticles showed preferential distribution to the lungs and corresponding depletion of targeted mRNA transcripts from lung tissue. We have investigated these systems for use in delivering siRNA targeting VEGF in mice with advanced disseminated ovarian cancer through intraperitoneal (ip) injection of siRNA-lipopolyamine nanoparticles. This model was established by injecting animals (ip) with 2.5×106 ID8 cells (malignant transformed ovarian surface epithelial cells that have been further modified to overexpress VEGF protein). Delivery of serum stabilized complexes to the peritoneal cavity of mice with disseminated ovarian cancer resulted in significant target gene knockdown in cells obtained from the malignant ascites fluid of these animals with modest knockdown in the peritoneal tumors themselves. A further modification of the core lipopolyamine structure incorporated attachment of a targeting peptide ligand through a linker molecule. Physico-chemical characterization of this targeted system and in vitro assays with ID8 cancer cells demonstrated specific delivery of siRNAs dependent on the presence of the targeting ligand on the liposome and the targeted receptor on the cell surface. These results have prompted in vivo testing using the targeted delivery systems to assess siRNA distribution as a function of delivered dose. Additional studies are underway that will establish the optimized delivery conditions for use in tumor bearing animals. 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 5535.