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Utility of the 2‐Nitrobenzenesulfonamide Group as a Chemical Linker for Enhanced Extracellular Stability and Cytosolic Cleavage in siRNA‐Conjugated Polymer Systems
Author(s) -
Huang Chih Hao,
Takemoto Hiroyasu,
Nomoto Takahiro,
Tomoda Keishiro,
Matsui Makoto,
Nishiyama Nobuhiro
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600488
Subject(s) - conjugated system , linker , cytosol , cleavage (geology) , chemistry , extracellular , polymer , chemical stability , group (periodic table) , biophysics , biochemistry , organic chemistry , biology , enzyme , computer science , operating system , paleontology , fracture (geology)
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.