Abstract
The study aim was to apply murine double minute 2 (MDM2)-siRNA to a biodegradable siRNA delivery vector, ternary complex, for treating colorectal cancer peritoneal dissemination. The ternary complex containing MDM2-siRNA (MDM2-siRNA complex) was constructed by mixing MDM2-siRNA, dendrigraft poly-L-lysine, and γ-polyglutamic acid. Cellular uptake of the ternary complex and suppressive effect on MDM2-mRNA were determined in a mouse colorectal cancer cell line. Tumor-growth inhibition by the MDM2-siRNA complex was evaluated in peritoneal dissemination model mice. The MDM2-siRNA complex, with an approximately 177 nm particle size and -35 mV ζ-potential, prevented degradation of the inner siRNA by RNase. In the in vitro study, the ternary complex was highly taken up by the cells, and 2 μg/mL of the MDM2-siRNA complex significantly decreased MDM2-mRNA to about 30% of control cells. Intraperitoneal administration in colorectal cancer peritoneal dissemination model mice showed little effect of the ternary complex containing scramble-siRNA on cancer growth in the peritoneal cavity. Conversely, the MDM2-siRNA complex significantly reduced peritoneal dissemination to less than 1/1000th of control mice and successfully prolonged survival time. In this study, we found that the biodegradable MDM2-siRNA complex had a suppressive effect on MDM2-mRNA in cancer cells and tumor growth of peritoneal dissemination.