The role of disulfide-bridge on the activities of H-shape gemini-like cationic lipid based siRNA delivery

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• 作者：Xiao-Fei Ma¹ ; Jing Sun¹ ; Chong Qiu¹ ; Yi-Fan Wu ; Yi Zheng ; Min-Zhi Yu ; Xi-Wei Pei ; Lin Wei ; Yu-Jie Niu ; Wen-Hao Pang ; Zhen-Jun Yang ; ^{yangzj@bjmu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Jian-Cheng Wang ; ^{wang-jc@bjmu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Qiang Zhang
• 关键词：siRNA delivery ; Gemini-like lipid ; Disulfide bond ; Biodegradation ; Nanocarrier
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：10 August 2016
• 年：2016
• 卷：235
• 期：Complete
• 页码：99-111
• 全文大小：2557 K

文摘

In our previous study, a H-shape gemini-like cationic lipid (ssGLCL, formerly named as CLD), composed of two hydrophilic lysine heads and two hydrophobic oleyl alcohol tails with a bridge of the redox-active disulfide-bond, had been synthesized and used as a nanocarrier for delivering small interfering RNAs (siRNAs) into cells. In order to further elucidate the role of disulfide (―S―S―) bridge on the activity of ssGLCL based siRNA delivery, a comparable ccGLCL bridged with a non-reducible carbon–carbon bond was synthesized and used as control in this study. Both two H-shape GLCL molecules could individually self-assemble into cationic nanoparticles in water phase and complex with negatively-charged siRNA into nanoplexes with particle size of ~ 200 nm and zeta potential of ~ + 30 mV, and exhibit effective siRNA delivery both in vitro and in vivo. Investigation of internalization pathway displayed that both ssGLCL/siRNA and ccGLCL/siRNA nanoplexes were predominantly internalized into MCF-7 cells by the clathrin-mediated endocytosis pattern. Although a lower cellular uptake of siRNA was found in the human breast cancer MCF-7 cells, the ssGLCL/siRNA nanoplexes could exhibit similar or even stronger down-regulation effects on the targeted EGFR mRNA and protein in MCF-7 cells when compared to the ccGLCL/siRNA nanoplexes. Furthermore, mechanistic study showed that the enhanced down-regulation effects of ssGLCL/siRNA nanoplexes on targeted mRNA and protein were probably attributed to the increased release of siRNA from lysosomes to cytoplasm following the cleavage of redox-active disulfide-bridge in ssGLCL. Therefore, we believed that the redox-active H-shape ssGLCL could be a potential nanocarrier towards improving siRNA delivery.