Abstract
Exenatide is an FDA-approved glucose-lowering peptide drug for the treatment of type 2 diabetes by subcutaneous injection. To address the issues on the inconvenience for patient use and the difficulty of oral administration of peptide drugs, chemical cross-linking of two pH-responsive biomaterials, alginate and hyaluronate, was carried out to prepare a new material for the encapsulation of exenatide as a form of microspheres. The exenatide-loaded microspheres exhibited spherical structures with excellent loading and release behaviors in the simulated gastrointestinal tract environments. After oral administration of the microspheres in db/db mice, maximum plasma concentration of exenatide appeared at 4 hours, and blood glucose was effectively reduced to a normal level within 2 hours and maintained for another 4 hours. The bioavailability of the exenatide-loaded microspheres, relative to subcutaneous injection of exenatide, reached 10.2%. Collectively, the present study demonstrated the feasibility of orally delivering exenatide with the new cross-linked biomaterial and formulation, and showed therapeutic potential for clinical applications.
Highlights
Exendin-4 containing 39 amino acid residues was originally isolated from Helodermatidae venom
Given that exendin-4 can compete with glucagon-like peptide-1 (GLP-1) for the same binding site in mammalian cells with higher affinity and stronger resistance to the degradation by dipeptidyl peptidase IV (DPP-IV), exendin-4 exhibits obvious advantages to be developed as a glucose-lowering agent with similar functions as GLP-1 [1,2,3]
The results indicated that the exenatide-loaded microspheres could effectively deliver the drug to lower plasma glucose level after oral administration
Summary
Exendin-4 containing 39 amino acid residues was originally isolated from Helodermatidae venom. This peptide shares 53% sequence homology with glucagon-like peptide-1 (GLP-1) [1]. Exenatide, the synthetic version of exendin-4, was approved by the FDA in 2005 as adjunctive therapy to improve glucose homeostasis in type 2 diabetic patients [4]. It is favorable for exenatide to mimic physiological route of GLP-1 from intestine to circulation to avoid potential side effects [6]. The development of a non-injective route for exenatide delivery has drawn great interests by both industry and academia, and oral administration is an ultimate choice based on the easy acceptance by diabetic patients [7]
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