Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
Bioconjug Chem. 2018 Feb 21;29(2):296-305. doi: 10.1021/acs.bioconjchem.7b00622. Epub 2018 Jan 17.
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.
本研究报告了一种通过巯基-二硫键交换反应原位制备 siRNA-聚阳离子缀合物聚合物的简单方法。该缀合物聚合物是使用巯基末端的 siRNA 和 CXCR4 趋化因子受体的生物还原支链聚阳离子抑制剂 (rPAMD) 制备的。与对照常规 rPAMD/siRNA 聚合物相比，rPAMD-SS-siRNA 缀合物聚合物具有更好的胶体稳定性和对肝素、血清和生理盐浓度下解组装的抵抗力。用人血清白蛋白包覆聚合物可以掩盖正表面电荷，并有助于增强体外基因沉默和体内安全性。缀合物聚合物在荷瘤小鼠中静脉注射后显示出改善的体内报告基因沉默。由于缀合物聚合物保留了 rPAMD 抑制 CXCR4 和限制癌细胞侵袭的能力，因此开发的系统有望用于未来癌症的联合抗转移 siRNA 治疗。
