Decanoic acid-modified glycol chitosan hydrogels containing tightly adsorbed palmityl-acylated exendin-4 as a long-acting sustained-release anti-diabetic system

作者：Lee Changkyu; Choi Ji Su; Kim Insoo; Byeon Hyeong Jun; Kim Tae Hyung; Oh Kyung Taek; Lee Eun Seong; Lee Kang Choon; Youn Yu Seok^*

来源：Acta Biomaterialia, 2014, 10(2): 812-820.

DOI：10.1016/j.actbio.2013.10.009

• Chitosan hydrogels
• Decanoic acid
• Fatty acid modification
• Exendin-4
• Type 2 diabetes

Decanoic acid-modified glycol chitosan (DA-GC) hydrogels containing tightly adsorbed palmitic acid-modified exendin-4 (Ex4-C16) were prepared, and their pharmaceutical abilities as a long-acting sustained-release exendin-4 system for the treatment of diabetes were evaluated. Glycol chitosan (GC) was conjugated with N-hydroxysuccinimide-activated decanoic acid (DA) in anhydrous 0.4% dimethylaminopyridine/dimethylsulfoxide at different feed ratios. DA-GC hydrogels formed by physical self-assembly during dialysis vs. deionized water, and their inner network structures, swelling or gel-forming abilities and release properties were examined. The hypoglycemia caused by Ex4-C16-loaded DA-GC hydrogels was evaluated by subcutaneous administration in type 2 diabetic db/db mice. The results obtained showed that GC prepared at a DA: GC feed ratio of 1:100 had optimal properties with respect to hydrogel swelling, stiffness and Ex4-C16 incorporation, whereas DA-GC hydrogels prepared at a feed ratio of greater than 1:100 formed gels that were too stiff. The in vitro and in vivo release of Ex4-C16 from DA-GC hydrogels was dramatically delayed compared with native Ex4 probably due to strong hydrophobic interactions. In particular, Ex4-C16 in DA-GC hydrogels was found to be present around the injection site up to 10 days after subcutaneous administration, whereas Ex4 in DA-GC hydrogels was cleared from injection sites in similar to 2 days in ICR mice. Finally, the hypoglycemia induced by Ex4-C16 DA-GC hydrogels was maintained for %26gt;7 days. Our findings demonstrate that Ex4-C16 DA-GC hydrogels offer a potential delivery system for the long-term treatment of type 2 diabetes.

• 出版日期2014-2