Development of cholesteryl peptide micelles for siRNA delivery.

Despite the rapid progress in the siRNA field, developing a safe and efficient delivery system of siRNA remains to be an obstacle in the therapeutical application of siRNA. The purpose of this study is to develop an efficient peptide-based siRNA delivery system for cancer therapy. To this end, cholesterol was conjugated to a series of peptides composed of lysine and histidine residues. The resultant cholesteryl peptides were characterized, and their potential for siRNA delivery was evaluated. Our results indicate that short peptides (11-21 mer) composed of various numbers of lysine and histidine residues alone are not sufficient to mediate efficient siRNA delivery. However, the amphiphilic cholesteryl peptides can self-assemble to form a micelle-like structure in aqueous solutions, which significantly promotes the siRNA condensation capability of the peptides. The cholesteryl peptides form stable complex with siRNA and effectively protect siRNA from degradation in rat serum up to three days. Furthermore, the cholesteryl peptides efficiently transfect siRNA into different cancer cells and trigger potent gene silencing effect, whereas peptides without cholesterol modification cannot deliver siRNA into the cells. In addition, one of the cholesteryl peptides Chol-H3K2s displays comparable cellular uptake and gene silencing effect but less cytotoxicity compared with branched polyethylenimine (bPEI) and Lipofectamine-2000. Our results reveal that the cholesteryl peptides possess great potential as an efficient siRNA delivery system.