title: Unsaturated glycoceramides as molecular carriers for mucosal drug delivery of GLP-1.
abstract: 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.
authors.affiliation: Division of Gastroenterology, Boston Children's Hospital, 300 Longwood Avenue, Boston 02115, USA; Harvard Medical School, 25 Shattuck St, Boston 02115, USA.
authors.forename: Yvonne M
authors.initials: YM
authors.lastname: te Welscher
authors.affiliation: Division of Gastroenterology, Boston Children's Hospital, 300 Longwood Avenue, Boston 02115, USA; Harvard Medical School, 25 Shattuck St, Boston 02115, USA.
authors.forename: Daniel J-F
authors.initials: DJ
authors.lastname: Chinnapen
authors.affiliation: Division of Gastroenterology, Boston Children's Hospital, 300 Longwood Avenue, Boston 02115, USA.
authors.forename: Lydia
authors.initials: L
authors.lastname: Kaoutzani
authors.affiliation: Bath University, Department of Pharmacy and Pharmacology, Claverton Down, Bath, BA2 7AY England, UK.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Mrsny
authors.affiliation: Division of Gastroenterology, Boston Children's Hospital, 300 Longwood Avenue, Boston 02115, USA; Harvard Medical School, 25 Shattuck St, Boston 02115, USA; Harvard Digestive Diseases Center, 300 Longwood Avenue, Boston 02115, USA. Electronic address: wayne.lencer@childrens.harvard.edu.
authors.forename: Wayne I
authors.initials: WI
authors.lastname: Lencer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002518:Ceramides / Q000737:chemistry* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D005677:G(M1) Ganglioside / Q000737:chemistry* / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage* / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D054795:Incretins / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D057900:Transcytosis
chemical_list: D002518:Ceramides; D004337:Drug Carriers; D054795:Incretins; D005677:G(M1) Ganglioside; D052216:Glucagon-Like Peptide 1
keywords: Drug delivery; GM1; Transcytosis; hGLP-1