ABSTRACT
Since the discovery of RNA interference (RNAi), there has been an explosion of interest and knowledge in using this technology for clinical applications. Although small molecule inhibitors and monoclonal antibodies have led to many successful therapies for cancer, many important cancer therapy targets are difficult to inhibit using these strategies. Use of short interfering RNA (siRNA) as a method of gene silencing has rapidly become a powerful tool in protein function delineation, gene discovery, and drug development. The promise of specific RNA degradation has also generated much excitement as a possible therapeutic modality, but in vivo siRNA delivery has proven difficult. Moreover, many physiological obstacles stand in the way of successful and efficient delivery. To overcome these limitations, we have developed a number of biocompatible nanoparticle strategies for highly efficient delivery of siRNA. We have used a novel complex of siRNA with a neutral nanoliposome (DOPC) for in vivo siRNA delivery. This delivery platform has shown substantial efficacy with regard to target modulation and anti-tumor effects in many different tumor models, and is now entering clinical trials. To target the tumor microenvironment, we have also developed delivery methods (e.g., chitosan nanoparticles) that allow highly efficient delivery of siRNA into both tumor cells as well as tumor associated endothelial cells. Therefore, the chitosan nanoparticles allow silencing of genes that play a functional role in tumor angiogenesis. In addition, we have also utilized these nanoparticles for targeted delivery by attaching peptides to the nanoparticles, which permits increased delivery into the tumor microenvironment. Collectively, these approaches offer new opportunities for therapeutic gene silencing, especially for otherwise undruggable targets.Read More…