Disulfide-Unit Conjugation Enables Ultrafast Cytosolic Internalization of Antisense DNA and siRNA

被引：73

作者：

Shu, Zhaoma ^{[1
]}

Tanaka, Iku ^{[1
]}

Ota, Azumi ^{[1
]}

Fushihara, Daichi ^{[1
]}

Abe, Naoko ^{[1
]}

Kawaguchi, Saki ^{[1
]}

Nakamoto, Kosuke ^{[1
]}

Tomoike, Fumiaki ^{[2
]}

Tada, Seiichi ^{[3
]}

Ito, Yoshihiro ^{[3
]}

Kimura, Yasuaki ^{[1
]}

Abe, Hiroshi ^{[1
,3
,4
]}

机构：

[1] Nagoya Univ, Chem Dept, Chikusa Ku, Furo Cho, Nagoya, Aichi 4648602, Japan

[2] Nagoya Univ, Res Ctr Mat Sci, Chikusa Ku, Furo Cho, Nagoya, Aichi 4648602, Japan

[3] RIKEN, Emergent Bioengn Mat Res Team, Ctr Emergent Matter Sci, 2-1 Hirosawa, Wako, Saitama 3510198, Japan

[4] CREST Japan Sci & Technol Agcy, Tokyo 1020076, Japan

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2019年 / 58卷 / 20期

基金：

日本学术振兴会;

关键词：

antisense; cellular uptake; cytosolic delivery; disulfide; siRNA; CELL-PENETRATING PEPTIDES; TAT-DEPENDENT TRANSACTIVATION; LIPOSOME COMPLEXES; SURFACE THIOLS; IN-VIVO; DELIVERY; GENE; THERAPEUTICS; INHIBITION; MECHANISMS;

D O I：

10.1002/anie.201900993

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页码：6611 / 6615

页数：5

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