Utility of the 2-Nitrobenzenesulfonamide Group as a Chemical Linker for Enhanced Extracellular Stability and Cytosolic Cleavage in siRNA-Conjugated Polymer Systems

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• 作者：Chih Hao Huang ; Dr. Hiroyasu Takemoto ; Dr. Takahiro Nomoto ; Dr. Keishiro Tomoda ; Dr. Makoto Matsui and Prof. Dr. Nobuhiro Nishiyama
• 刊名：ChemMedChem
• 出版年：2017
• 出版时间：January 5, 2017
• 年：2017
• 卷：12
• 期：1
• 页码：19-22
• 全文大小：922K
• ISSN：1860-7187

文摘

Herein we report the 2-nitrobenzenesulfonamide group as a new chemical linker that responds to the difference in redox potential across the cellular membrane, toward the construction of siRNA–polymer conjugates. PEG-conjugated to siRNA via the 2-nitrobenzenesulfonamide group (PEG–sul–siRNA) exhibited highly selective siRNA release under intracellular conditions due to the exclusive presence of the GSH/GST combination in the cell. In addition, siRNA release from PEG–sul–siRNA under extracellular reductive conditions was dramatically suppressed relative to PEG–siRNA conjugates containing a conventional redox-sensitive disulfide linkage (PEG–disulfide–siRNA), indicating the enhanced extracellular stability of the 2-nitrobenzenesulfonamide group. The enhanced gene-silencing effect of PEG–sul–siRNA for cultured cells relative to PEG–siRNA, containing a non-cleavable carboxylic amide linkage (PEG–car–siRNA), confirmed the intracellular release of siRNA via the PEG–sul–siRNA system. These results suggest that the 2-nitrobenzenesulfonamide group could be a suitable chemical linker alternative to the conventional disulfide group.