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This study reports on a simple method to prepare siRNA-polycation conjugate polyplexes by in situ thiol-disulfide exchange reaction. The conjugate polyplexes are prepared using thiol-terminated siRNA and a bioreducible branched polycationic inhibitor of the CXCR4 chemokine receptor (rPAMD). The rPAMD-SS-siRNA conjugate polyplexes exhibit improved colloidal stability and resistance against disassembly with heparin, serum, and physiological salt concentrations when compared with control conventional rPAMD/siRNA polyplexes. Coating the polyplexes with human serum albumin masks the positive surface charge and contributes to the enhanced in vitro gene silencing and improved safety in vivo. The conjugate polyplexes display improved in vivo reporter gene silencing following intravenous injection in tumor-bearing mice. Because the conjugate polyplexes retained the ability of rPAMD to inhibit CXCR4 and restrict cancer cell invasion, the developed systems show promise for future combination anti-metastatic siRNA therapies of cancer.

Conjugate Polyplexes with Anti-Invasive Properties and Improved siRNA Delivery In Vivo