Self-assembled glycol chitosan nanogels containing palmityl-acylated exendin-4 peptide as a long-acting anti-diabetic inhalation system

Inhalable deoxycholic acid-modified glycol chitosan (DOCA-GC) nanogels containing palmityl acylated exendin-4 (Ex4-C16) were prepared by self-assembly and characterized physicochemically. The lung deposition of DOCA-GC nanogels was monitored using an infrared imaging system, and the hypoglycemia caused by Ex4-C16-loaded DOCA-GC nanogels was evaluated after pulmonary administration in type 2 diabetic db/db mice. The cytotoxicities and lung histologies induced by DOCA-GC nanogels were examined in human lung epithelial cells (A549 and Calu-3) and db/db mice, respectively. Results showed that the DOCA-GC nanogels prepared were spherical and compact and had a diameter of similar to 220 nm. Although the incorporation of Ex4-C16 (50.9 +/- 7.8%) into DOCA-GC nanogels was significantly lower than that of Ex4 (81.4 +/- 4.9%), the Ex4-C16 release from DOCA-GC nanogels was greatly delayed vs. Ex4. DOCA-GC nanogels were deposited rapidly after pulmonary administration and remained in the lungs for similar to 72 h. Furthermore, the hypoglycemic duration of inhaled Ex4-C16 nanogels was much greater than that of Ex4 nanogels in db/db mice. Cytotoxicity results of DOCA-GC nanogels were considered acceptable, and the tissue histologies of mouse lungs administered nanogels did not show any significant difference vs. control lungs. The authors believe that Ex4-C16 DOCA-GC nanogels offer a long-acting inhalation delivery system for treating type 2 diabetes. (c) 2012 Elsevier B.V. All rights reserved.