Disulfide‐Unit Conjugation Enables Ultrafast Cytosolic Internalization of Antisense DNA and siRNA
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 mole...
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| Veröffentlicht in: | Angewandte Chemie International Edition 2019-05, Vol.58 (20), p.6611-6615 |
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| creator | Shu, Zhaoma Tanaka, Iku Ota, Azumi Fushihara, Daichi Abe, Naoko Kawaguchi, Saki Nakamoto, Kosuke Tomoike, Fumiaki Tada, Seiichi Ito, Yoshihiro Kimura, Yasuaki Abe, Hiroshi |
| description | 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 10 minutes 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.
Disulfide conjugation to antisense DNA and siRNA enables efficient and ultrafast cytosolic uptake of these bioactive oligonucleotides without toxicity. This new method solves the long‐standing problems of various oligonucleotide delivery methods and should enhance therapeutic applications of antisense DNA and siRNA. |
| doi_str_mv | 10.1002/anie.201900993 |
| format | Article |
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Disulfide conjugation to antisense DNA and siRNA enables efficient and ultrafast cytosolic uptake of these bioactive oligonucleotides without toxicity. This new method solves the long‐standing problems of various oligonucleotide delivery methods and should enhance therapeutic applications of antisense DNA and siRNA.</description><subject>antisense</subject><subject>Antisense DNA</subject><subject>cellular uptake</subject><subject>Conjugation</subject><subject>Cytoplasm</subject><subject>cytosolic delivery</subject><subject>Deoxyribonucleic acid</subject><subject>disulfide</subject><subject>DNA</subject><subject>Endocytosis</subject><subject>Endosomes</subject><subject>Internalization</subject><subject>Liposomes</subject><subject>Low molecular weights</subject><subject>Molecular weight</subject><subject>Oligonucleotides</subject><subject>siRNA</subject><issn>1433-7851</issn><issn>1521-3773</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNqF0E9LwzAYBvAgipvTq0cpePHSmT9tkxzLNnUwJog7l7RNJCNLZtMi8-RH8DP6SczYnODFU17I733gfQC4RHCIIMS3wmo5xBBxCDknR6CPUoxiQik5DnNCSExZinrgzPtl8IzB7BT0CGQsgQnpg2qsfWeUruXXx-fC6jYaObvsXkSrnY0mVpRG-mhh2kYo4cPvpnXeGV1FU9vKxgqj33fWqSi3rfbSehmN53kkbB15_TTPz8GJEsbLi_07AIu7yfPoIZ493k9H-SyuEpqRWJVIYCJKTOoySyhlGcdUQZYqWnNJuKp5yTitVZZWkJcwLYWEaZUkGSQMU0kG4GaXu27cayd9W6y0r6QxwkrX-QIjniBCOWeBXv-hS9dtrwkKhzoJhwgHNdypqnHeN1IV60avRLMpECy29Rfb-otD_WHhah_blStZH_hP3wHwHXjTRm7-iSvy-XTyG_4NQtWRuw</recordid><startdate>20190513</startdate><enddate>20190513</enddate><creator>Shu, Zhaoma</creator><creator>Tanaka, Iku</creator><creator>Ota, Azumi</creator><creator>Fushihara, Daichi</creator><creator>Abe, Naoko</creator><creator>Kawaguchi, Saki</creator><creator>Nakamoto, Kosuke</creator><creator>Tomoike, Fumiaki</creator><creator>Tada, Seiichi</creator><creator>Ito, Yoshihiro</creator><creator>Kimura, Yasuaki</creator><creator>Abe, Hiroshi</creator><general>Wiley Subscription Services, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-7813-6555</orcidid><orcidid>https://orcid.org/0000-0002-1154-253X</orcidid><orcidid>https://orcid.org/0000-0001-6062-3515</orcidid><orcidid>https://orcid.org/0000-0003-2724-2272</orcidid><orcidid>https://orcid.org/0000-0003-0048-3789</orcidid><orcidid>https://orcid.org/0000-0002-3609-602X</orcidid></search><sort><creationdate>20190513</creationdate><title>Disulfide‐Unit Conjugation Enables Ultrafast Cytosolic Internalization of Antisense DNA and siRNA</title><author>Shu, Zhaoma ; Tanaka, Iku ; Ota, Azumi ; Fushihara, Daichi ; Abe, Naoko ; Kawaguchi, Saki ; Nakamoto, Kosuke ; Tomoike, Fumiaki ; Tada, Seiichi ; Ito, Yoshihiro ; Kimura, Yasuaki ; Abe, Hiroshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4763-fb1a23ab23db647786927f085f7d9e39fd9b897df65c09b05bae05c44603827e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>antisense</topic><topic>Antisense DNA</topic><topic>cellular uptake</topic><topic>Conjugation</topic><topic>Cytoplasm</topic><topic>cytosolic delivery</topic><topic>Deoxyribonucleic acid</topic><topic>disulfide</topic><topic>DNA</topic><topic>Endocytosis</topic><topic>Endosomes</topic><topic>Internalization</topic><topic>Liposomes</topic><topic>Low molecular weights</topic><topic>Molecular weight</topic><topic>Oligonucleotides</topic><topic>siRNA</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shu, Zhaoma</creatorcontrib><creatorcontrib>Tanaka, Iku</creatorcontrib><creatorcontrib>Ota, Azumi</creatorcontrib><creatorcontrib>Fushihara, Daichi</creatorcontrib><creatorcontrib>Abe, Naoko</creatorcontrib><creatorcontrib>Kawaguchi, Saki</creatorcontrib><creatorcontrib>Nakamoto, Kosuke</creatorcontrib><creatorcontrib>Tomoike, Fumiaki</creatorcontrib><creatorcontrib>Tada, Seiichi</creatorcontrib><creatorcontrib>Ito, Yoshihiro</creatorcontrib><creatorcontrib>Kimura, Yasuaki</creatorcontrib><creatorcontrib>Abe, Hiroshi</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Angewandte Chemie International Edition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shu, Zhaoma</au><au>Tanaka, Iku</au><au>Ota, Azumi</au><au>Fushihara, Daichi</au><au>Abe, Naoko</au><au>Kawaguchi, Saki</au><au>Nakamoto, Kosuke</au><au>Tomoike, Fumiaki</au><au>Tada, Seiichi</au><au>Ito, Yoshihiro</au><au>Kimura, Yasuaki</au><au>Abe, Hiroshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Disulfide‐Unit Conjugation Enables Ultrafast Cytosolic Internalization of Antisense DNA and siRNA</atitle><jtitle>Angewandte Chemie International Edition</jtitle><addtitle>Angew Chem Int Ed Engl</addtitle><date>2019-05-13</date><risdate>2019</risdate><volume>58</volume><issue>20</issue><spage>6611</spage><epage>6615</epage><pages>6611-6615</pages><issn>1433-7851</issn><eissn>1521-3773</eissn><abstract>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 10 minutes 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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| subjects | antisense Antisense DNA cellular uptake Conjugation Cytoplasm cytosolic delivery Deoxyribonucleic acid disulfide DNA Endocytosis Endosomes Internalization Liposomes Low molecular weights Molecular weight Oligonucleotides siRNA |
| title | Disulfide‐Unit Conjugation Enables Ultrafast Cytosolic Internalization of Antisense DNA and siRNA |
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