Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation
Many systemically effective drugs such as cyclosporin A are ineffective topically because of their poor penetration into skin. To surmount this problem, we conjugated a heptamer of arginine to cyclosporin A through a pH-sensitive linker to produce R7-CsA. In contrast to unmodified cyclosporin A, whi...
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| Veröffentlicht in: | Nature medicine 2000-11, Vol.6 (11), p.1253-1257 |
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| creator | Rothbard, Jonathan B Khavari, Paul A Garlington, Sarah Lin, Qun Kirschberg, Thorsten Kreider, Erik McGrane, P. Leo Wender, Paul A |
| description | Many systemically effective drugs such as cyclosporin A are ineffective topically because of their poor penetration into skin. To surmount this problem, we conjugated a heptamer of arginine to cyclosporin A through a pH-sensitive linker to produce R7-CsA. In contrast to unmodified cyclosporin A, which fails to penetrate skin, topically applied R7-CsA was efficiently transported into cells in mouse and human skin. R7-CsA reached dermal T lymphocytes and inhibited cutaneous inflammation. These data establish a general strategy for enhancing delivery of poorly absorbed drugs across tissue barriers and provide a new topical approach to the treatment of inflammatory skin disorders. |
| doi_str_mv | 10.1038/81359 |
| format | Article |
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Leo ; Wender, Paul A</creator><creatorcontrib>Rothbard, Jonathan B ; Khavari, Paul A ; Garlington, Sarah ; Lin, Qun ; Kirschberg, Thorsten ; Kreider, Erik ; McGrane, P. Leo ; Wender, Paul A</creatorcontrib><description>Many systemically effective drugs such as cyclosporin A are ineffective topically because of their poor penetration into skin. To surmount this problem, we conjugated a heptamer of arginine to cyclosporin A through a pH-sensitive linker to produce R7-CsA. In contrast to unmodified cyclosporin A, which fails to penetrate skin, topically applied R7-CsA was efficiently transported into cells in mouse and human skin. R7-CsA reached dermal T lymphocytes and inhibited cutaneous inflammation. These data establish a general strategy for enhancing delivery of poorly absorbed drugs across tissue barriers and provide a new topical approach to the treatment of inflammatory skin disorders.</description><identifier>ISSN: 1078-8956</identifier><identifier>EISSN: 1546-170X</identifier><identifier>DOI: 10.1038/81359</identifier><identifier>PMID: 11062537</identifier><language>eng</language><publisher>United States: Nature Publishing Group</publisher><subject>Administration, Topical ; Animals ; arginine ; Arginine - analogs & derivatives ; Arginine - chemical synthesis ; Arginine - pharmacokinetics ; Arginine - therapeutic use ; Biological Transport ; Biotinylation ; cyclosporin A ; Cyclosporine - administration & dosage ; Cyclosporine - chemistry ; Cyclosporins - administration & dosage ; Cyclosporins - chemical synthesis ; Cyclosporins - pharmacokinetics ; Cyclosporins - therapeutic use ; Drugs ; Humans ; Inflammation ; Inflammation - prevention & control ; Interleukin-2 - biosynthesis ; Ionomycin - pharmacology ; Jurkat Cells ; Lymphocytes ; Medicine ; Mice ; Mice, Inbred BALB C ; Molecular Structure ; Peptides ; Prodrugs - chemical synthesis ; Prodrugs - pharmacokinetics ; Prodrugs - therapeutic use ; Skin - cytology ; Skin - metabolism ; Skin Absorption ; Skin diseases ; Tetradecanoylphorbol Acetate - pharmacology</subject><ispartof>Nature medicine, 2000-11, Vol.6 (11), p.1253-1257</ispartof><rights>COPYRIGHT 2000 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Nov 2000</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c599t-4030c95e873f598e746c0829fff048567a486a36171d5d24c7015c839b9b99ae3</citedby><cites>FETCH-LOGICAL-c599t-4030c95e873f598e746c0829fff048567a486a36171d5d24c7015c839b9b99ae3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,2729,27931,27932</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11062537$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rothbard, Jonathan B</creatorcontrib><creatorcontrib>Khavari, Paul A</creatorcontrib><creatorcontrib>Garlington, Sarah</creatorcontrib><creatorcontrib>Lin, Qun</creatorcontrib><creatorcontrib>Kirschberg, Thorsten</creatorcontrib><creatorcontrib>Kreider, Erik</creatorcontrib><creatorcontrib>McGrane, P. Leo</creatorcontrib><creatorcontrib>Wender, Paul A</creatorcontrib><title>Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation</title><title>Nature medicine</title><addtitle>Nat Med</addtitle><description>Many systemically effective drugs such as cyclosporin A are ineffective topically because of their poor penetration into skin. To surmount this problem, we conjugated a heptamer of arginine to cyclosporin A through a pH-sensitive linker to produce R7-CsA. In contrast to unmodified cyclosporin A, which fails to penetrate skin, topically applied R7-CsA was efficiently transported into cells in mouse and human skin. R7-CsA reached dermal T lymphocytes and inhibited cutaneous inflammation. These data establish a general strategy for enhancing delivery of poorly absorbed drugs across tissue barriers and provide a new topical approach to the treatment of inflammatory skin disorders.</description><subject>Administration, Topical</subject><subject>Animals</subject><subject>arginine</subject><subject>Arginine - analogs & derivatives</subject><subject>Arginine - chemical synthesis</subject><subject>Arginine - pharmacokinetics</subject><subject>Arginine - therapeutic use</subject><subject>Biological Transport</subject><subject>Biotinylation</subject><subject>cyclosporin A</subject><subject>Cyclosporine - administration & dosage</subject><subject>Cyclosporine - chemistry</subject><subject>Cyclosporins - administration & dosage</subject><subject>Cyclosporins - chemical synthesis</subject><subject>Cyclosporins - pharmacokinetics</subject><subject>Cyclosporins - therapeutic use</subject><subject>Drugs</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Inflammation - prevention & control</subject><subject>Interleukin-2 - biosynthesis</subject><subject>Ionomycin - pharmacology</subject><subject>Jurkat Cells</subject><subject>Lymphocytes</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Molecular Structure</subject><subject>Peptides</subject><subject>Prodrugs - chemical synthesis</subject><subject>Prodrugs - pharmacokinetics</subject><subject>Prodrugs - therapeutic use</subject><subject>Skin - cytology</subject><subject>Skin - metabolism</subject><subject>Skin Absorption</subject><subject>Skin diseases</subject><subject>Tetradecanoylphorbol Acetate - pharmacology</subject><issn>1078-8956</issn><issn>1546-170X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqN0ltrHCEUAOChtDRpmr9QbKGBPkyq4zjq47L0EggEeqNvg-scZw2ObtUp3X9fN7u9bMlD8UHRz-NRT1WdE3xJMBWvBaFMPqhOCWu7mnD89WEZYy5qIVl3Uj1J6RZjTDGTj6sTQnDXMMpPK78M_nYeVbbBo2CQiqP11gMKzo5hgphQDkhvtQtpE6L1aIGM0tbZrDLsFjdWK4cGcPY7xC1SfkDWr-3K_gppvXFqmu6OeFo9MsolOD_0Z9Xnt28-Ld_X1zfvrpaL61ozKXPdlkS1ZCA4NUwK4G2nsWikMQa3gnVctaJTtCOcDGxoWs0xYVpQuSpNKqBn1cU-7iaGbzOk3E82aXBOeQhz6gnnTYelLPDFP_A2zNGX3PqmoaQhLcUF1Xs0Kgd9uU_IUekRPETlggdjy_SCyJawklFb_OU9vrQBJqvv3fDqaEMxGX7kUc0p9VcfP_y_vflybC_-smtQLq9TcPPuK9IxfLmHOoaUIph-E-2k4rYnuN_VV39XX8U9OzzXvJpg-KMOBVXA8z3wKs8RfgM_FVJCFUR_ApiV0Uw</recordid><startdate>20001101</startdate><enddate>20001101</enddate><creator>Rothbard, Jonathan B</creator><creator>Khavari, Paul A</creator><creator>Garlington, Sarah</creator><creator>Lin, Qun</creator><creator>Kirschberg, Thorsten</creator><creator>Kreider, Erik</creator><creator>McGrane, P. 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Leo</au><au>Wender, Paul A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation</atitle><jtitle>Nature medicine</jtitle><addtitle>Nat Med</addtitle><date>2000-11-01</date><risdate>2000</risdate><volume>6</volume><issue>11</issue><spage>1253</spage><epage>1257</epage><pages>1253-1257</pages><issn>1078-8956</issn><eissn>1546-170X</eissn><abstract>Many systemically effective drugs such as cyclosporin A are ineffective topically because of their poor penetration into skin. To surmount this problem, we conjugated a heptamer of arginine to cyclosporin A through a pH-sensitive linker to produce R7-CsA. In contrast to unmodified cyclosporin A, which fails to penetrate skin, topically applied R7-CsA was efficiently transported into cells in mouse and human skin. R7-CsA reached dermal T lymphocytes and inhibited cutaneous inflammation. These data establish a general strategy for enhancing delivery of poorly absorbed drugs across tissue barriers and provide a new topical approach to the treatment of inflammatory skin disorders.</abstract><cop>United States</cop><pub>Nature Publishing Group</pub><pmid>11062537</pmid><doi>10.1038/81359</doi><tpages>5</tpages></addata></record> |
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| subjects | Administration, Topical Animals arginine Arginine - analogs & derivatives Arginine - chemical synthesis Arginine - pharmacokinetics Arginine - therapeutic use Biological Transport Biotinylation cyclosporin A Cyclosporine - administration & dosage Cyclosporine - chemistry Cyclosporins - administration & dosage Cyclosporins - chemical synthesis Cyclosporins - pharmacokinetics Cyclosporins - therapeutic use Drugs Humans Inflammation Inflammation - prevention & control Interleukin-2 - biosynthesis Ionomycin - pharmacology Jurkat Cells Lymphocytes Medicine Mice Mice, Inbred BALB C Molecular Structure Peptides Prodrugs - chemical synthesis Prodrugs - pharmacokinetics Prodrugs - therapeutic use Skin - cytology Skin - metabolism Skin Absorption Skin diseases Tetradecanoylphorbol Acetate - pharmacology |
| title | Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation |
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