Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells
The polyanionic nature of oligonucleotides and their enzymatic degradation present challenges for the use of siRNA in research and therapy; among the most notable of these is clinically relevant delivery into cells. To address this problem, we designed and synthesized the first members of a new clas...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2012-08, Vol.109 (33), p.13171-13176 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
| container_volume | 109 |
| creator | Geihe, Erika I Cooley, Christina B Simon, Jeff R Kiesewetter, Matthew K Edward, Justin A Hickerson, Robyn P Kaspar, Roger L Hedrick, James L Waymouth, Robert M Wender, Paul A |
| description | The polyanionic nature of oligonucleotides and their enzymatic degradation present challenges for the use of siRNA in research and therapy; among the most notable of these is clinically relevant delivery into cells. To address this problem, we designed and synthesized the first members of a new class of guanidinium-rich amphipathic oligocarbonates that noncovalently complex, deliver, and release siRNA in cells, resulting in robust knockdown of target protein synthesis in vitro as determined using a dual-reporter system. The organocatalytic oligomerization used to synthesize these co-oligomers is step-economical and broadly tunable, affording an exceptionally quick strategy to explore chemical space for optimal siRNA delivery in varied applications. The speed and versatility of this approach and the biodegradability of the designed agents make this an attractive strategy for biological tool development, imaging, diagnostics, and therapeutic applications. |
| doi_str_mv | 10.1073/pnas.1211361109 |
| format | Article |
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To address this problem, we designed and synthesized the first members of a new class of guanidinium-rich amphipathic oligocarbonates that noncovalently complex, deliver, and release siRNA in cells, resulting in robust knockdown of target protein synthesis in vitro as determined using a dual-reporter system. The organocatalytic oligomerization used to synthesize these co-oligomers is step-economical and broadly tunable, affording an exceptionally quick strategy to explore chemical space for optimal siRNA delivery in varied applications. The speed and versatility of this approach and the biodegradability of the designed agents make this an attractive strategy for biological tool development, imaging, diagnostics, and therapeutic applications.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1211361109</identifier><identifier>PMID: 22847412</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>biodegradability ; Biodegradation ; Biological Sciences ; Biological Transport - drug effects ; Carbonates ; Carbonates - chemical synthesis ; Carbonates - chemistry ; Carbonates - toxicity ; Cell Death - drug effects ; Cell membranes ; cell-free protein synthesis ; Cells ; Cells, Cultured ; diagnostic techniques ; Enzymes ; Flow Cytometry ; Fluorescence ; Gene Transfer Techniques ; Genes, Reporter - genetics ; Green Fluorescent Proteins - metabolism ; Guanidine - chemical synthesis ; Guanidine - chemistry ; Guanidine - toxicity ; Humans ; image analysis ; Keratinocytes - cytology ; Keratinocytes - drug effects ; Keratinocytes - metabolism ; Light ; Lipids ; Lycopersicon esculentum - metabolism ; Medical treatment ; Microscopy, Fluorescence ; Monomers ; oligomerization ; Oligomers ; oligonucleotides ; Physical Sciences ; Protein synthesis ; Ribonucleic acid ; RNA ; RNA, Small Interfering - metabolism ; RNA, Small Interfering - toxicity ; Scattering, Radiation ; Small interfering RNA ; Teeth ; therapeutics ; transporters</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2012-08, Vol.109 (33), p.13171-13176</ispartof><rights>copyright © 1993-2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Aug 14, 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c558t-5da9c3c6f1fafb12972b7ca22b88e321bc52eaffa214dbf5f2de7f4e159c6ff83</citedby><cites>FETCH-LOGICAL-c558t-5da9c3c6f1fafb12972b7ca22b88e321bc52eaffa214dbf5f2de7f4e159c6ff83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/109/33.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/41700891$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/41700891$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27922,27923,53789,53791,58015,58248</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22847412$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Geihe, Erika I</creatorcontrib><creatorcontrib>Cooley, Christina B</creatorcontrib><creatorcontrib>Simon, Jeff R</creatorcontrib><creatorcontrib>Kiesewetter, Matthew K</creatorcontrib><creatorcontrib>Edward, Justin A</creatorcontrib><creatorcontrib>Hickerson, Robyn P</creatorcontrib><creatorcontrib>Kaspar, Roger L</creatorcontrib><creatorcontrib>Hedrick, James L</creatorcontrib><creatorcontrib>Waymouth, Robert M</creatorcontrib><creatorcontrib>Wender, Paul A</creatorcontrib><title>Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The polyanionic nature of oligonucleotides and their enzymatic degradation present challenges for the use of siRNA in research and therapy; among the most notable of these is clinically relevant delivery into cells. 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The speed and versatility of this approach and the biodegradability of the designed agents make this an attractive strategy for biological tool development, imaging, diagnostics, and therapeutic applications.</description><subject>biodegradability</subject><subject>Biodegradation</subject><subject>Biological Sciences</subject><subject>Biological Transport - drug effects</subject><subject>Carbonates</subject><subject>Carbonates - chemical synthesis</subject><subject>Carbonates - chemistry</subject><subject>Carbonates - toxicity</subject><subject>Cell Death - drug effects</subject><subject>Cell membranes</subject><subject>cell-free protein synthesis</subject><subject>Cells</subject><subject>Cells, Cultured</subject><subject>diagnostic techniques</subject><subject>Enzymes</subject><subject>Flow Cytometry</subject><subject>Fluorescence</subject><subject>Gene Transfer Techniques</subject><subject>Genes, Reporter - genetics</subject><subject>Green Fluorescent Proteins - metabolism</subject><subject>Guanidine - chemical synthesis</subject><subject>Guanidine - chemistry</subject><subject>Guanidine - toxicity</subject><subject>Humans</subject><subject>image analysis</subject><subject>Keratinocytes - cytology</subject><subject>Keratinocytes - drug effects</subject><subject>Keratinocytes - metabolism</subject><subject>Light</subject><subject>Lipids</subject><subject>Lycopersicon esculentum - metabolism</subject><subject>Medical treatment</subject><subject>Microscopy, Fluorescence</subject><subject>Monomers</subject><subject>oligomerization</subject><subject>Oligomers</subject><subject>oligonucleotides</subject><subject>Physical Sciences</subject><subject>Protein synthesis</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA, Small Interfering - metabolism</subject><subject>RNA, Small Interfering - toxicity</subject><subject>Scattering, Radiation</subject><subject>Small interfering RNA</subject><subject>Teeth</subject><subject>therapeutics</subject><subject>transporters</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1v1DAQxSMEokvhzAmwxJW0Htv58AWpKuVDqkACerYcZ5z1KrFTOyn0vyfRLlu42If5vTdP87LsJdAzoBU_H71OZ8AAeAlA5aNss7yQl0LSx9mGUlbltWDiJHuW0o5SKouaPs1OGKtFJYBtsl8fMLnOY0u6WXvXOu_mIY_ObIkexq0b9bR1hoTedcHo2ASvJyRD6NHMvY5kitqnMcQJYyImDGOPv9-RFnt3h5Fo35KIPeqEJLnvXy-I88Rg36fn2ROr-4QvDv9pdvPx6ufl5_z626cvlxfXuSmKesqLVkvDTWnBatsAkxVrKqMZa-oaOYPGFAy1tZqBaBtbWNZiZQVCIReRrflp9n7vO87NgK1BvyTu1RjdoOO9Ctqp_yfebVUX7hQXy1VlsRi8PRjEcDtjmtQuzNEvmRVQzosSpICFOt9TJoaUItrjBqBqbUqtTamHphbF63-DHfm_1SwAOQCr8sFOKs4VcKjWra_2yC5NIR4ZARWltVznb_Zzq4PSXXRJ3fxgFEpKl1PyQvA_0tWxCA</recordid><startdate>20120814</startdate><enddate>20120814</enddate><creator>Geihe, Erika I</creator><creator>Cooley, Christina B</creator><creator>Simon, Jeff R</creator><creator>Kiesewetter, Matthew K</creator><creator>Edward, Justin A</creator><creator>Hickerson, Robyn P</creator><creator>Kaspar, Roger L</creator><creator>Hedrick, James L</creator><creator>Waymouth, Robert M</creator><creator>Wender, Paul A</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20120814</creationdate><title>Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells</title><author>Geihe, Erika I ; Cooley, Christina B ; Simon, Jeff R ; Kiesewetter, Matthew K ; Edward, Justin A ; Hickerson, Robyn P ; Kaspar, Roger L ; Hedrick, James L ; Waymouth, Robert M ; Wender, Paul A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c558t-5da9c3c6f1fafb12972b7ca22b88e321bc52eaffa214dbf5f2de7f4e159c6ff83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>biodegradability</topic><topic>Biodegradation</topic><topic>Biological Sciences</topic><topic>Biological Transport - 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PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Geihe, Erika I</au><au>Cooley, Christina B</au><au>Simon, Jeff R</au><au>Kiesewetter, Matthew K</au><au>Edward, Justin A</au><au>Hickerson, Robyn P</au><au>Kaspar, Roger L</au><au>Hedrick, James L</au><au>Waymouth, Robert M</au><au>Wender, Paul A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2012-08-14</date><risdate>2012</risdate><volume>109</volume><issue>33</issue><spage>13171</spage><epage>13176</epage><pages>13171-13176</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>The polyanionic nature of oligonucleotides and their enzymatic degradation present challenges for the use of siRNA in research and therapy; among the most notable of these is clinically relevant delivery into cells. 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| identifier | ISSN: 0027-8424 |
| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2012-08, Vol.109 (33), p.13171-13176 |
| issn | 0027-8424 1091-6490 |
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| source | MEDLINE; JSTOR Archive Collection A-Z Listing; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | biodegradability Biodegradation Biological Sciences Biological Transport - drug effects Carbonates Carbonates - chemical synthesis Carbonates - chemistry Carbonates - toxicity Cell Death - drug effects Cell membranes cell-free protein synthesis Cells Cells, Cultured diagnostic techniques Enzymes Flow Cytometry Fluorescence Gene Transfer Techniques Genes, Reporter - genetics Green Fluorescent Proteins - metabolism Guanidine - chemical synthesis Guanidine - chemistry Guanidine - toxicity Humans image analysis Keratinocytes - cytology Keratinocytes - drug effects Keratinocytes - metabolism Light Lipids Lycopersicon esculentum - metabolism Medical treatment Microscopy, Fluorescence Monomers oligomerization Oligomers oligonucleotides Physical Sciences Protein synthesis Ribonucleic acid RNA RNA, Small Interfering - metabolism RNA, Small Interfering - toxicity Scattering, Radiation Small interfering RNA Teeth therapeutics transporters |
| title | Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells |
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