Development of siRNA Delivery Strategy by Active Control of Tumor Microenvironment

Abstract

Efficient systemic siRNA delivery to cells in the target tissue is a current critical challenge in the drug delivery field. Several studies have demonstrated that nanoparticles such as polyethylene glycol (PEG)-coated siRNA-lipoplexes may enhance the systemic delivery of siRNA to tumor. However, the disordered tumor microenvironment still poses a potential impediment with respect to the efficient delivery of PEG-coated siRNA-lipoplexes. We recently showed that metronomic S-1 dosing (daily oral administration) enhanced the accumulation of PEG-coated liposome containing anticancer drug in solid tumor tissue and thereby increased therapeutic efficacy in tumor-bearing mouse model. To extend this work, we tried to investigate the effect of metronomic S-1 dosing on the intratumoral accumulation of PEG-coated siRNA-lipoplex and, thereby, their therapeutic efficacy in solid tumor-bearing mouse model. Results showed that metronomic S-1 dosing improved systemic delivery of intravenously injected PEG-coated siRNA-lipoplexes into solid tumor tissue. In addition, the combined therapy of S-1 and PEG-coated siRNA-lipoplexes showed potent tumor growth suppressive effect. Our proposed strategy may pose a promising therapeutic one to conquer cancer progression with siRNA.