Utility of the 2-nitrobenzenesulfonamide group as a chemical linker for enhanced extracellular stability and cytosolic cleavage in siRNA-conjugated polymer systems
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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2-硝基苯磺酰胺基团作为化学接头的用途，用于增强 siRNA 缀合聚合物系统中的细胞外稳定性和胞质裂解
DOI：
10.1002/cmdc.201600488
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发表时间：
2017
期刊：
影响因子：
3.4
通讯作者：
N. Nishiyama
中科院分区：
文献类型：
--
作者：
C. H. Huang;H. Takemoto;T. Nomoto;K. Tomoda;M. Matsui;N. Nishiyama
在本文中，我们报告了2-硝基苯磺酰胺基团作为一种新的化学接头，其响应于跨细胞膜的氧化还原电位差，用于构建siRNA-聚合物缀合物。通过2-硝基苯磺酰胺基团与siRNA缀合的PEG（PEG-sul-siRNA）在细胞内条件下表现出高度选择性的siRNA释放，这是由于GSH/GST组合在细胞中的排他性存在。此外，相对于含有常规氧化还原敏感性二硫键的PEG-siRNA缀合物（PEG-二硫键-siRNA），在细胞外还原条件下从PEG-sul-siRNA释放siRNA被显著抑制，表明2-硝基苯磺酰胺基团的细胞外稳定性增强。相对于含有不可裂解的羧酰胺键的PEG-siRNA（PEG-car-siRNA），PEG-sul-siRNA对培养细胞的增强的基因沉默作用证实了siRNA通过PEG-sul-siRNA系统的细胞内释放。这些结果表明，2-硝基苯磺酰胺基团可以是替代常规二硫化物基团的合适的化学连接基。
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.