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 ~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 ~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.
College of Pharmacy, Pusan National University, Jangjeon-dong, Geumjeong-gu, Busan 609-735, Republic of Korea.
Juho
J
Lee
Changkyu
C
Lee
Tae Hyung
TH
Kim
Eun Seong
ES
Lee
Beom Soo
BS
Shin
Sang-Cheol
SC
Chi
Eun-Seok
ES
Park
Kang Choon
KC
Lee
Yu Seok
YS
Youn
D000215:Acylation; D000280:Administration, Inhalation; D000818:Animals; D048271:Chitosan / Q000008:administration & dosage / Q000737:chemistry; D003900:Desoxycorticosterone / Q000008:administration & dosage / Q000737:chemistry; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry; D000077270:Exenatide; D005782:Gels; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000737:chemistry; D008168:Lung / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry; D019308:Palmitic Acid / Q000008:administration & dosage / Q000737:chemistry; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry; D014688:Venoms / Q000008:administration & dosage* / Q000737:chemistry
D004337:Drug Carriers; D005782:Gels; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; C118638:glycol-chitosan; D019308:Palmitic Acid; D003900:Desoxycorticosterone; D048271:Chitosan; D000077270:Exenatide