Giuseppina Salzano
Northeastern University, USA
Title: Multifunctional polymeric micelles for the simultaneous delivery of siRNA and chemotherapeutic agents: A promising strategy to reverse the drug resistance in the treatment of cancer
Biography
Biography: Giuseppina Salzano
Abstract
Since its discovery small interfering RNAs (siRNA) have quickly crept into the biopharmaceutical research as a powerful tool for the treatment of different human diseases based on altered gene-expression. Despite promising data from pre-clinical studies, concrete hurdles still need to be overcome to bring therapeutic siRNAs in clinic. With this in mind, we have reversibly modified siRNA with a phosphothioethanol (PE) portion via a reducible disulfide bond and incorporated the resulting siRNA-S-S-PE conjugate into nanosized polyethyelene glycol 2000-phosphatidyl ethanolamine (PEG2000-PE)-based polymeric micelles (PM). Then, we successfully co-incorporated in the same PM an anti-survivin siRNA-S-S-PE conjugate and chemotherapeutic agents, such as paclitaxel (PXL) for combined therapy. The developed nanopreparation showed high colloidal stability, high incorporation efficiency of both active agents, and small particle sizes compatible for parenteral administration. In an animal model of cancer, the micelles accumulate in distal tumors and delivered anti–survivin siRNA and PXL in sufficiently high amounts to mediate a potent and specific survivin downregulation and to improve anticancer activity as compared with single agents. In addition, survivin downregulation by anti–survivin siRNA/PXL PM mediated the sensitization of a resistant ovarian tumor to non-effective doses of PXL. Compared to conventional systems for siRNA delivery, we suggested a new type of platform that can respond to local stimuli, such as high levels of reductase in cancer cells, and release the siRNA free and active at the desired site. Moreover, the developed PM are suitable to incorporate different type of active agents for combined therapy.