Abstract B17: Inhibition of lung tumor progression in a metastatic mouse model following intravenous delivery of siRNA nanocomplexes

Abstract Exploiting the RNAi pathway offers the potential to advance the treatment of many diseases through highly specific and efficient silencing of gene products. Unfortunately, the requisite safe and efficient delivery of nucleic acids to target cells remains a fundamental problem for the development of RNA and DNA based therapeutics. We have developed a versatile lipopolyamine based delivery system that has been optimized for in vivo delivery by incorporating functional groups onto the core cationic lipopolyamine structure. The direct modification of the core structure (named Staramine) allows for the generation of nanoparticle formulations with a wide range of physicochemical properties and does not require the co-formulation of commercial helper or pegylated lipids. We have previously reported safe, efficient and persistent siRNA mediated transcript knockdown specifically in the lung endothelium using the Starmaine delivery system. Here we extend those observations by administering a siRNA that targets vascular endothelial growth factor receptor 2 (VEGFR-2; KDR/Flk-1) in an animal model of metastatic lung cancer. VEGFR-2, a receptor tyrosine kinase, has been shown to be mainly expressed on endothelial cells and plays a critical role in cell proliferation and differentiation and consequently is also important in angiogenesis associated tumor growth and metastasis. Repeated intravenous administration of nanocomplexes comprised of Staramine formulated VEGFR-2 siRNA (~2 mg/kg/dose) resulted in a significant (40%) reduction of VEGFR-2 transcript levels in isolated tumors from the lungs of mice compared to control injected animals. Similar levels of transcript knockdown were not achieved in tumors when using siRNAs against targets not having the high level of endothelial cell restriction that is seen with VEGFR-2. Immunohistopathology of the lungs of tumor bearing mice administered VEGFR-2 siRNA indicated a significant decrease in vascular density in lung tumors and was consistent with an overall reduction in tumor burden in the mouse lungs. These results support the continued evaluation of using Staramine to deliver siRNAs and other similar molecules as potential therapies for diseases of the lung where the vascular endothelium may be involved. Citation Format: Jason G. Fewell, Khursheed Anwer, Kevin Polach, Majed Matar, Jennifer Rice, Angela Rea-Ramsey, Jeff Sparks, Diane McClure, Casey Pence, Elaine Brunhoeber, Leslie Wilkinson. Inhibition of lung tumor progression in a metastatic mouse model following intravenous delivery of siRNA nanocomplexes [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr B17.