期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 58, 期 20, 页码 6611-6615出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201900993
关键词
antisense; cellular uptake; cytosolic delivery; disulfide; siRNA
资金
- CREST, Japan Agency of Science and Technology (JST) [JPMJCR18S1]
- Japan Society for the Promotion of Science (JSPS) [16KT0052, 25282240]
- Scientific Research on Innovative Areas 2707 Middle Molecular Strategy from MEXT [18H04398]
- Grants-in-Aid for Scientific Research [16KT0052, 18H04398, 25282240] Funding Source: KAKEN
Development of intracellular delivery methods for antisense DNA and siRNA is important. Previously reported methods using liposomes or receptor-ligands take several hours or more to deliver oligonucleotides to the cytoplasm due to their retention in endosomes. Oligonucleotides modified with low molecular weight disulfide units at a terminus reach the cytoplasm 10minutes after administration to cultured cells. This rapid cytoplasmic internalization of disulfide-modified oligonucleotides suggests the existence of an uptake pathway other than endocytosis. Mechanistic analysis revealed that the modified oligonucleotides are efficiently internalized into the cytoplasm through disulfide exchange reactions with the thiol groups on the cellular surface. This approach solves several critical problems with the currently available methods for enhancing cellular uptake of oligonucleotides and may be an effective approach in the medicinal application of antisense DNA and siRNA.
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