Journal
BIOMATERIALS
Volume 30, Issue 12, Pages 2329-2339Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2008.12.066
Keywords
Nanoparticle; Toxicity; Efficacy; Insulin; Tight junction
Funding
- National Science Council, Taiwan, Republic of China. [NSC 97-2120-M-007-001]
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A variety of approaches have been studied in the past to overcome the problems encountered with the oral delivery of insulin, but with little success. In this study, self-assembled nanoparticles (NPs) with a pH-sensitive characteristic were prepared by mixing the anionic poly-gamma-glutamic acid solution with the cationic chitosan solution in the presence of MgSO4 and sodium tripolyphosphate. The in vitro results found that the transport of insulin across Caco-2 cell monolayers by NPs appeared to be pH-dependent; with increasing pH, the amount of insulin transported decreased significantly. An in vivo toxicity study was performed to establish the safety of the prepared NPs after oral administration. Additionally, the impact of orally administered NPs on the pharmacodynamics; (PD) and pharmacokinetics (PK) of insulin was evaluated in a diabetic rat model. The in vivo results indicated that the prepared NPs could effectively adhere on the mucosal surface and their constituted components were able to infiltrate into the mucosal cell membrane. The toxicity study indicated that the NPs were well tolerated even at a dose 18 times higher than that used in the PD/PK study. Oral administration of insulin-loaded NPs demonstrated a significant hypoglycemic action for at least 10 h in diabetic rats and the corresponding relative bioavailability of insulin was found to be 15.1 +/- 0.9%. These findings suggest that the NPs prepared in the study are a promising vehicle for oral delivery of insulin. (C) 2008 Elsevier Ltd. All rights reserved.
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