Unsaturated glycoceramides as molecular carriers for mucosal drug delivery of GLP-1
The incretin hormone Glucagon-like peptide 1 (GLP-1) requires delivery by injection for the treatment of Type 2 diabetes mellitus. Here, we test if the properties of glycosphingolipid trafficking in epithelial cells can be applied to convert GLP-1 into a molecule suitable for mucosal absorption. GLP...
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| Veröffentlicht in: | Journal of controlled release 2014-02, Vol.175, p.72-78 |
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| creator | te Welscher, Yvonne M. Chinnapen, Daniel J.-F. Kaoutzani, Lydia Mrsny, Randall J. Lencer, Wayne I. |
| description | The incretin hormone Glucagon-like peptide 1 (GLP-1) requires delivery by injection for the treatment of Type 2 diabetes mellitus. Here, we test if the properties of glycosphingolipid trafficking in epithelial cells can be applied to convert GLP-1 into a molecule suitable for mucosal absorption. GLP-1 was coupled to the extracellular oligosaccharide domain of GM1 species containing ceramides with different fatty acids and with minimal loss of incretin bioactivity. When applied to apical surfaces of polarized epithelial cells in monolayer culture, only GLP-1 coupled to GM1-ceramides with short- or cis-unsaturated fatty acids trafficked efficiently across the cell to the basolateral membrane by transcytosis. In vivo studies showed mucosal absorption after nasal administration. The results substantiate our recently reported dependence on ceramide structure for trafficking the GM1 across polarized epithelial cells and support the idea that specific glycosphingolipids can be harnessed as molecular vehicles for mucosal delivery of therapeutic peptides.
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| doi_str_mv | 10.1016/j.jconrel.2013.12.013 |
| format | Article |
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[Display omitted]</description><identifier>ISSN: 0168-3659</identifier><identifier>EISSN: 1873-4995</identifier><identifier>DOI: 10.1016/j.jconrel.2013.12.013</identifier><identifier>PMID: 24370893</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Amino Acid Sequence ; Animals ; Cell Line ; Ceramides - chemistry ; Ceramides - metabolism ; Diabetes Mellitus, Type 2 - drug therapy ; Drug Carriers - chemistry ; Drug Carriers - metabolism ; Drug delivery ; G(M1) Ganglioside - chemistry ; G(M1) Ganglioside - metabolism ; Glucagon-Like Peptide 1 - administration & dosage ; Glucagon-Like Peptide 1 - chemistry ; GM1 ; HEK293 Cells ; hGLP-1 ; Humans ; Incretins - administration & dosage ; Incretins - chemistry ; Male ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; Molecular Sequence Data ; Transcytosis</subject><ispartof>Journal of controlled release, 2014-02, Vol.175, p.72-78</ispartof><rights>2013 Elsevier B.V.</rights><rights>Copyright © 2013 Elsevier B.V. All rights reserved.</rights><rights>2013 Elsevier B.V. All rights reserved. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c500t-b9cb5098611df42a011c49e7d0aab2140fe1c327f44be7a1c55c20607202db193</citedby><cites>FETCH-LOGICAL-c500t-b9cb5098611df42a011c49e7d0aab2140fe1c327f44be7a1c55c20607202db193</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jconrel.2013.12.013$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24370893$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>te Welscher, Yvonne M.</creatorcontrib><creatorcontrib>Chinnapen, Daniel J.-F.</creatorcontrib><creatorcontrib>Kaoutzani, Lydia</creatorcontrib><creatorcontrib>Mrsny, Randall J.</creatorcontrib><creatorcontrib>Lencer, Wayne I.</creatorcontrib><title>Unsaturated glycoceramides as molecular carriers for mucosal drug delivery of GLP-1</title><title>Journal of controlled release</title><addtitle>J Control Release</addtitle><description>The incretin hormone Glucagon-like peptide 1 (GLP-1) requires delivery by injection for the treatment of Type 2 diabetes mellitus. Here, we test if the properties of glycosphingolipid trafficking in epithelial cells can be applied to convert GLP-1 into a molecule suitable for mucosal absorption. GLP-1 was coupled to the extracellular oligosaccharide domain of GM1 species containing ceramides with different fatty acids and with minimal loss of incretin bioactivity. When applied to apical surfaces of polarized epithelial cells in monolayer culture, only GLP-1 coupled to GM1-ceramides with short- or cis-unsaturated fatty acids trafficked efficiently across the cell to the basolateral membrane by transcytosis. In vivo studies showed mucosal absorption after nasal administration. The results substantiate our recently reported dependence on ceramide structure for trafficking the GM1 across polarized epithelial cells and support the idea that specific glycosphingolipids can be harnessed as molecular vehicles for mucosal delivery of therapeutic peptides.
[Display omitted]</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Cell Line</subject><subject>Ceramides - chemistry</subject><subject>Ceramides - metabolism</subject><subject>Diabetes Mellitus, Type 2 - drug therapy</subject><subject>Drug Carriers - chemistry</subject><subject>Drug Carriers - metabolism</subject><subject>Drug delivery</subject><subject>G(M1) Ganglioside - chemistry</subject><subject>G(M1) Ganglioside - metabolism</subject><subject>Glucagon-Like Peptide 1 - administration & dosage</subject><subject>Glucagon-Like Peptide 1 - chemistry</subject><subject>GM1</subject><subject>HEK293 Cells</subject><subject>hGLP-1</subject><subject>Humans</subject><subject>Incretins - administration & dosage</subject><subject>Incretins - chemistry</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Transcytosis</subject><issn>0168-3659</issn><issn>1873-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc2OFCEURonROO3oI2hYuqmSC9QPG42Z6GjSiSY6a0LBrZYOVYxQ1Um_vXS6nehqVt-Ccz8uHEJeA6uBQftuX-9tnBOGmjMQNfC6xBOygb4TlVSqeUo2hesr0TbqirzIec8Ya4TsnpMrLkXHeiU25MfdnM2yJrOgo7twtNFiMpN3mKnJdIoB7RpMotak5DFlOsZEp9XGbAJ1ad1Rh8EfMB1pHOnt9nsFL8mz0YSMry55Te4-f_p586Xafrv9evNxW9mGsaUalB0apvoWwI2SGwZgpcLOMWMGDpKNCFbwbpRywM6AbRrLWcs6zrgbQIlr8v7ce78OEzqL85JM0PfJTyYddTRe_38y-196Fw9aKK6gl6Xg7aUgxd8r5kVPPlsMwcwY16yhactSrBXicVQq3kGpPbU2Z9SmmHPC8WEjYPrkTu_1xZ0-udPAdYky9-bf5zxM_ZVVgA9nAMunHooMna3H2aLzCe2iXfSPXPEH3cmuHg</recordid><startdate>20140210</startdate><enddate>20140210</enddate><creator>te Welscher, Yvonne M.</creator><creator>Chinnapen, Daniel J.-F.</creator><creator>Kaoutzani, Lydia</creator><creator>Mrsny, Randall J.</creator><creator>Lencer, Wayne I.</creator><general>Elsevier B.V</general><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>7X8</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>5PM</scope></search><sort><creationdate>20140210</creationdate><title>Unsaturated glycoceramides as molecular carriers for mucosal drug delivery of GLP-1</title><author>te Welscher, Yvonne M. ; 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Here, we test if the properties of glycosphingolipid trafficking in epithelial cells can be applied to convert GLP-1 into a molecule suitable for mucosal absorption. GLP-1 was coupled to the extracellular oligosaccharide domain of GM1 species containing ceramides with different fatty acids and with minimal loss of incretin bioactivity. When applied to apical surfaces of polarized epithelial cells in monolayer culture, only GLP-1 coupled to GM1-ceramides with short- or cis-unsaturated fatty acids trafficked efficiently across the cell to the basolateral membrane by transcytosis. In vivo studies showed mucosal absorption after nasal administration. The results substantiate our recently reported dependence on ceramide structure for trafficking the GM1 across polarized epithelial cells and support the idea that specific glycosphingolipids can be harnessed as molecular vehicles for mucosal delivery of therapeutic peptides.
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| subjects | Amino Acid Sequence Animals Cell Line Ceramides - chemistry Ceramides - metabolism Diabetes Mellitus, Type 2 - drug therapy Drug Carriers - chemistry Drug Carriers - metabolism Drug delivery G(M1) Ganglioside - chemistry G(M1) Ganglioside - metabolism Glucagon-Like Peptide 1 - administration & dosage Glucagon-Like Peptide 1 - chemistry GM1 HEK293 Cells hGLP-1 Humans Incretins - administration & dosage Incretins - chemistry Male Mice Mice, Inbred C57BL Models, Molecular Molecular Sequence Data Transcytosis |
| title | Unsaturated glycoceramides as molecular carriers for mucosal drug delivery of GLP-1 |
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