One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer.

Autor:	Luginbuhl KM; Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA., Schaal JL; Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA., Umstead B; PhaseBio Pharmaceuticals, Inc., Malvern, Pennsylvania 19355, USA., Mastria EM; Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA., Li X; Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA., Banskota S; Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA., Arnold S; PhaseBio Pharmaceuticals, Inc., Malvern, Pennsylvania 19355, USA., Feinglos M; Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, North Carolina 27710, USA., D'Alessio D; Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, North Carolina 27710, USA., Chilkoti A; Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA.
Jazyk:	angličtina
Zdroj:	Nature biomedical engineering [Nat Biomed Eng] 2017; Vol. 1. Date of Electronic Publication: 2017 Jun 05.
DOI:	10.1038/s41551-017-0078
Abstrakt:	Stimulation of the glucagon-like peptide-1 (GLP1) receptor is a useful treatment strategy for type 2 diabetes because of pleiotropic effects, including the regulation of islet hormones and the induction of satiety. However, the native ligand for the GLP1 receptor has a short half-live owing to enzymatic inactivation and rapid clearance. Here, we show that a subcutaneous depot formed after a single injection of GLP1 recombinantly fused to a thermosensitive elastin-like polypeptide results in zero-order release kinetics and circulation times of up to 10 days in mice and 17 days in monkeys. The optimized pharmacokinetics leads to 10 days of glycemic control in three different mouse models of diabetes, as well as to the reduction of glycosylated hemoglobin levels and weight gain in ob/ob mice treated once weekly for 8 weeks. Our results suggest that the optimized GLP1 formulation could enhance therapeutic outcomes by eliminating peak-and-valley pharmacokinetics and improving overall safety and tolerability. The design principles that we established should be broadly applicable for improving the pharmacological performance of other peptide and protein therapeutics.
Databáze:	MEDLINE
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