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Unsaturated glycoceramides as molecular carriers for mucosal drug delivery of GLP‐1 analogues
Author(s) -
Welscher Yvonne Maria,
Kaoutzani Lydia,
Lencer Wayne I.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.588.2
Subject(s) - transcytosis , ceramide , endosome , microbiology and biotechnology , epithelial polarity , chemistry , biochemistry , intracellular , cell , endocytosis , biology , apoptosis
The goal is to develop technology using glycosphingolipids for oral or nasal administration of therapeutic peptides. We recently discovered that the structure of the ceramide domain of the ganglioside GM1 dictates intracellular trafficking in epithelial cells. GM1‐ceramides with short or unsaturated fatty acids enter the recycling endosome where they are sorted to multiple destinations including to the basolateral cell surface by transcytosis. GM1‐ceramides with saturated fatty acid chains do not enter these pathways. Here, we test whether GM1 with short‐ or unsaturated chain ceramides can be harnessed as vehicles for transepithelial delivery of bioactive peptides. We linked GM1 to stable versions of the therapeutic hormone glucagon‐like peptide‐1 (GLP‐1). The function of the peptide remained intact in the fusion molecules. The GLP1‐GM1 fusions with short or unsaturated fatty acids were incorporated into apical cell membranes, trafficked into the recycling endosome, and reached the basolateral membrane of polarized epithelial cells. The GLP1‐GM1 fusions with long saturated fatty acid were not sorted into these pathways. Thus, ceramide‐based intra‐cellular trafficking may have clinical utility for delivery of therapeutic cargo by transcytosis across epithelial barriers at mucosal surface. The source of research support is from the NIH/NIDDK R21.