PAMAM dendrimers mediate siRNA delivery to target Hsp27 and produce potent antiproliferative effects on prostate cancer cells

Abstract

RNA interference (RNAi) holds great promise for the treatment of inherited and acquired diseases, provided that safe and efficient delivery systems are available. Herein we report that structurally flexible triethanolamine (TEA) core PAMAM dendrimers are able to deliver an Hsp27 siRNA effectively into prostate cancer (PC-3) cells by forming stable nanoparticles with siRNA, protecting the siRNA nanoparticles from enzymatic degradation, and enhancing cellular uptake of siRNA. The Hsp27 siRNA resulted in potent and specific gene silencing of heat-shock protein 27, an attractive therapeutic target in castrate-resistant prostate cancer. Silencing of the hsp27 gene led to induction of caspase-3/7-dependent apoptosis and inhibition of PC-3 cell growth in vitro. In addition, the siRNA-dendrimer complexes are non-cytotoxic under the conditions used for siRNA delivery. Altogether, TEA core PAMAM dendrimer-mediated siRNA delivery, in combination with RNAi that specifically targets Hsp27, may constitute a promising approach for combating castrate-resistant prostate cancer, for which there is no efficacious treatment.