A depot-forming glucagon-like peptide-1 fusion protein reduces blood glucose for five days with a single injection.
Peptide drugs are an exciting class of pharmaceuticals for the treatment of a variety of diseases; however, their short half-life dictates multiple and frequent injections causing undesirable side effects. Herein, we describe a novel peptide delivery system that seeks to combine the attractive features of prolonged circulation time with a prolonged release formulation. This system consists of glucagon-like peptide-1, a type-2 diabetes drug fused to a thermally responsive, elastin-like-polypeptide (ELP) that undergoes a soluble-insoluble phase transition between room temperature and body temperature, thereby forming an injectable depot. We synthesized a set of GLP-1-ELP fusions and verified their proteolytic stability and potency in vitro. Significantly, a single injection of depot forming GLP-1-ELP fusions reduced blood glucose levels in mice for up to 5 days, 120 times longer than an injection of the native peptide. These findings demonstrate the unique advantages of using ELPs to release peptide-ELP fusions from a depot combined with enhanced systemic circulation to create a tunable peptide delivery system.
Department of Biomedical Engineering, Duke University, Durham 27708, USA.
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Amiram
Department of Biomedical Engineering, Duke University, Durham 27708, USA.
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Luginbuhl
Department of Biomedical Engineering, Duke University, Durham 27708, USA.
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Li
Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham 27710, USA.
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Feinglos
Department of Biomedical Engineering, Duke University, Durham 27708, USA. Electronic address: chilkoti@duke.edu.
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Chilkoti
D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004549:Elastin / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D007267:Injections; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D044367:Phase Transition; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology
D001786:Blood Glucose; D003692:Delayed-Action Preparations; D007004:Hypoglycemic Agents; D011993:Recombinant Fusion Proteins; D052216:Glucagon-Like Peptide 1; D004549:Elastin
Drug delivery; Elastin-like polypeptide; Glucagon-like peptide-1; Peptide; Subcutaneous depot