Inhibition of murine breast cancer growth and metastasis by survivin-targeted siRNA using disulfide cross-linked
Shan Liu1, Wei Huang2, Ming-Ji Jin2
1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China; Department of Pharmaceutics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
Abstract:
Biodegradable disulfide-containing polyethyleneimine (PEI) derivatives showed great potential as siRNA vectors for the treatment of cancer due to the reduction-sensitive property. In this study, we developed and characterized a hyperbranched disulfide cross-linked PEI (lPEI-SS) based on linear PEI (lPEI) by ring-opening reaction of propylene sulfide. We evaluated the efficiency of lPEI-SS as a siRNA vector in vitro with luciferase reporter gene system, and investigated the anti-tumor efficacy of survivin-targeted siRNA (siRNA(sur)) on 4T1 murine breast cancer model using lPEI-SS synthesized here. Results from cytotoxicity and hemolysis assay proved that lPEI-SS showed favorable cell and blood compatibility. lPEI-SS/siRNA polyplexes prepared under the optimized condition were compact spherical particles with the average size of 229.0nm and zeta potential of 42.67mV. Cellular uptake of lPEI-SS/siRNA polyplexes was significantly improved due to the higher branching degree of lPEI-SS over the parent lPEI. lPEI-SS/siRNA(sur) exhibited great anti-proliferation effect on 4T1 cell line, which was found to be caused by the induction of apoptosis. Most importantly, results of tumor volume, tumor weight and histological observation demonstrated that lPEI-SS/siRNA(sur) polyplexes effectively inhibited the tumor growth and metastasis of 4T1 murine breast cancer model.
