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Targeting of Pancreatic β‐Cells With High Specificity Using a Heterobivalent GLP‐1/Glibenclamide Ligand
Author(s) -
Hart Nathaniel,
Vagner Josef,
Chung Woo Jin,
Weber Craig,
Limesand Sean W,
De Silva Channa R,
Lynch Ronald M
Publication year - 2010
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.24.1_supplement.816.9
Subject(s) - receptor , glibenclamide , cell , endocytosis , chemistry , in vivo , enteroendocrine cell , glucagon like peptide 1 receptor , cell culture , microbiology and biotechnology , ligand (biochemistry) , endocrinology , medicine , biology , pharmacology , biochemistry , diabetes mellitus , endocrine system , genetics , hormone , agonist
Pancreatic β‐cell dysfunction, and subsequent loss of β‐cell mass underlies the development of Diabetes Mellitus. The ability to monitor β‐cell mass in vivo is limited because the endocrine pancreas comprises less than 5% of the total pancreatic mass requiring highly specific β‐cell targeting agents; new targeting agents will require at least 100X higher specificity than previously tested agents. We previously demonstrated that multivalent ligands (MVL) composed of two different receptor binding moieties that crosslink multiple receptors, increase the specificity of binding to cells that express only the complimentary receptor pair. To test this approach for use in β‐cell specific targeting, we synthesized a ligand composed of Glucagon‐like Peptide 1 and Glibenclamide (Glb, Sulfonylurea Receptor 1ligand). Using rt‐PCR, expression of these surface receptors was demonstrated in a β‐cell line βTC3, while the ductal cell line PANC1 was shown to express only SUR1. The divalent GLP‐1/Glb binds βTC3 cells at concentrations at least 50 fold lower than required for binding to PANC1cells. The MVL rapidly is internalized from the cell surface (within 2–3 min) after binding via endocytosis. Our findings indicate that the GLP‐1/Glb MVL has increased affinity and specificity for β‐cells, and therefore provides a basis for developing high specificity targeting agents to monitor β‐cell mass. Supported by: Juvenile Diabetes Research Foundation, and the Arizona Biomedical Research Commission