title: Utility of the 2-Nitrobenzenesulfonamide Group as a Chemical Linker for Enhanced Extracellular Stability and Cytosolic Cleavage in siRNA-Conjugated Polymer Systems.
abstract: 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.
authors.affiliation: Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, R1-11, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa, 226-8503, Japan.
authors.forename: Chih Hao
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, R1-11, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa, 226-8503, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Takemoto
authors.affiliation: Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, R1-11, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa, 226-8503, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nomoto
authors.affiliation: Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, R1-11, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa, 226-8503, Japan.
authors.forename: Keishiro
authors.initials: K
authors.lastname: Tomoda
authors.affiliation: Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, R1-11, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa, 226-8503, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Matsui
authors.affiliation: Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, R1-11, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa, 226-8503, Japan.
authors.forename: Nobuhiro
authors.identifier: 0000-0002-6886-9357
authors.initials: N
authors.lastname: Nishiyama
mesh_terms: D006801:Humans; D011108:Polymers / Q000737:chemistry* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000378:metabolism*; D013449:Sulfonamides / Q000737:chemistry*
chemical_list: D011108:Polymers; D034741:RNA, Small Interfering; D013449:Sulfonamides
keywords: chemical linkers; polymers; prodrugs; redox chemistry; small interfering RNA (siRNA)