Long-acting inhalable chitosan-coated poly(lactic-co-glycolic acid) nanoparticles containing hydrophobically modified exendin-4 for treating type 2 diabetes

• Published in: International journal of nanomedicine 2013-01, Vol.8 (1), p.2975-2983
• Main Authors: Lee, Changkyu, Choi, Ji Su, Kim, Insoo, Oh, Kyung Taek, Lee, Eun Seong, Park, Eun-Seok, Lee, Kang Choon, Youn, Yu Seok
• Format: Article
• Language: English
• Subjects: Administration, Inhalation; Adsorption; Analysis of Variance; Animals; Blood Glucose - drug effects; Cell Line; Cell Survival - drug effects; Chitin; Chitosan - chemistry; chitosan-coating; Diabetes; Diabetes Mellitus, Type 2; Drug Carriers - chemistry; Drug delivery systems; Drug therapy; Drugs; Exenatide; exendin-4; Glucose; Health aspects; Humans; Hydrophobic and Hydrophilic Interactions; inhalation; Lactic Acid - chemistry; Male; Mice; Mice, Inbred C57BL; Nanoparticles; Nanoparticles - chemistry; Original Research; Peptides - administration & dosage; Peptides - chemistry; Peptides - pharmacokinetics; Peptides - pharmacology; PLGA nanoparticles; Polyglycolic Acid - chemistry; Surface Properties; Type 2 diabetes; Vehicles; Venoms - administration & dosage; Venoms - chemistry; Venoms - pharmacokinetics; Venoms - pharmacology
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S48197

Inhalable glycol chitosan-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing palmitic acid-modified exendin-4 (Pal-Ex4) (chitosan Pal-Ex4 PLGA NPs) were prepared and characterized. The surface morphology, particle size, and zeta potential of chitosan Pal-Ex4 PLGA NPs were investigated, and the adsorption and cytotoxicity of chitosan Pal-Ex4 PLGA NPs were evaluated in human lung epithelial cells (A549). Finally, the lung deposition characteristics and hypoglycemia caused by chitosan Pal-Ex4 PLGA NPs were evaluated after pulmonary administration in imprinting control region (ICR) and type 2 diabetic db/db mice. Results showed that chitosan Pal-Ex4 PLGA NPs were spherical, compact and had a diameter of ~700 nm and a positive surface charge of +28.5 mV Chitosan-coated PLGA NPs were adsorbed onto A549 cells much more so than non-coated PLGA NPs. Pal-Ex4 release from chitosan-coated PLGA NPs was delayed by as much as 1.5 days as compared with chitosan-coated Ex4 PLGA NPs. In addition, chitosan-coated PLGA NPs remained in the lungs for ~72 hours after pulmonary administration, whereas most non-coated PLGA NPs were lost at 8 hours after administration. Furthermore, the hypoglycemic efficacy of inhaled chitosan Pal-Ex4 PLGA NPs was 3.1-fold greater than that of chitosan Ex4 PLGA NPs in db/db mice. The authors believe chitosan Pal-Ex4 PLGA NPs have considerable potential as a long-acting inhalation delivery system for the treatment of type 2 diabetes.