Abstract 2887: Nanoconstructs for the efficient delivery of siRNA molecules against Aquaporin-1 for anti-angiogenic therapies

Abstract

Abstract Aquaporins (AQPs) are water-specific, membrane-channel proteins expressed in diverse tissues. In particular, AQP1 has been reported to be specifically and strongly expressed in most tumor microvascular endothelial cells. Angiogenesis and tumor progression have been dramatically impaired, in AQP1-null mice [Saadoun et al. Nature 434:2005]. These findings support the notion that AQP1 could be considered as a specific target for the treatment of various neoplasias. The AQP1 proteins can be specifically blocked by using small interference RNA molecules (siRNAs). However, despite the considerable potential of RNA interference for the treatment of cancer, the proper systemic delivery of exogenous siRNA molecules is still a challenge. The most significant obstacle is ensuring specific and effective delivery of siRNAs to the cytoplasm of the target cell, limiting toxic effects and serum degradation by RNAses. The use of nanoparticles, as intravascular delivery vehicles, has potential in supporting the efficient, effective and safe systemic delivery of siRNAs. Herein, multiple nanotechnological platforms (nanoconstructs) are used to deliver siRNAs against AQP1. The performance of the different nanoconstructs is assessed in vitro using HeLa cells, transfected to express AQP1 molecules. Three nanoconstructs are studied: fullerenes (C60), poly(lactic-co-glycolic acid) (PLGA) nanospheres and hydrogel-template nanoparticles. Positively charged fullerenes are sub-nanometer spheres (diameter ∼ 0.71 nm) that complex with the negatively charged siRNA molecules forming a stable compound under physiological conditions (pH = 7.4). Differently, the PLGA nanospheres and hydrogel-template nanoparticles are loaded with siRNA molecules during their synthesis process. The silencing performance of the three different nanoconstructs is assessed in vitro at multiple time points, over a period of 6 days post incubation. The loading efficiency, the release rate, the cell-entry mechanisms and potential cytotoxic response are analyzed. The performance of the nanoconstructs is compared with traditional delivery systems based on the use of transfection agents (oligofectamine). AQP1 is here used as a model system, and the optimized nanoconstructs could be utilized also for other siRNA therapeutics. 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 2887. doi:1538-7445.AM2012-2887