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Long acting hyaluronate – exendin 4 conjugate for the treatment of type 2 diabetes

Paper ID Volume ID Publish Year Pages File Format Full-Text
9120 617 2010 8 PDF Available
Title
Long acting hyaluronate – exendin 4 conjugate for the treatment of type 2 diabetes
Abstract

Despite clinical exploitation of exendin 4 for the treatment of type 2 diabetes, the significantly short half-life requiring twice a day injection has limited the wide applications. In this work, a protocol for the synthesis of long acting hyaluronate (HA) – exendin 4 conjugate was successfully developed using Michael addition chemistry between vinyl sulfone modified HA (HA-VS) and thiolated exendin 4. The exendin 4 content could be controlled in the range of 5–30 molecules per single HA chain with a bioconjugation efficiency higher than 90%. The conjugation of exendin 4 with HA resulted in about 20 times improved in vitro serum stability maintaining the hypoglycemic and gluco-regulatory bioactivities of exendin 4. HA – exendin 4 conjugates showed excellent glucose-lowering capabilities in type 2 db/db mice demonstrating protracted hypoglycemic effect up to 3 days after a single subcutaneous injection. Furthermore, insulin immunohistochemical analysis of islets in db/db mice confirmed the improved insulinotropic activity of HA – exendin 4 conjugates. The HA – exendin 4 conjugates will be investigated further as a twice a week injection dosage form for clinical applications.

Keywords
Hyaluronic acid; Exendin-4; Conjugation; Drug delivery; Type 2 diabetes
First Page Preview
Long acting hyaluronate – exendin 4 conjugate for the treatment of type 2 diabetes
Publisher
Database: Elsevier - ScienceDirect
Journal: Biomaterials - Volume 31, Issue 14, May 2010, Pages 4121–4128
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering