Dual crosslinking of folic acid-modified pectin nanoparticles for enhanced oral insulin delivery

Pectin-based drug delivery systems hold great potential for oral insulin delivery, since they possess excellent gelling property, good mucoadhesion and high stability in the gastrointestinal (GI) tract. However, lack of enterocyte targeting ability and premature drug release in the upper GI tract of the susceptible ionic-crosslinked pectin matrices are two major problems to be solved. To address these issues, we developed folic acid (FA)-modified pectin nanoparticles (INS/DFAN) as insulin delivery vehicles by a dual-crosslinking method using calcium ions and adipic dihydrazide (ADH) as crosslinkers. In vitro studies indicated insulin release behaviors of INS/DFAN depended on -COOH/ADH molar ratio in the dual-crosslinking process. INS/DFAN effectively prevented premature insulin release in simulated GI fluids compared to ionic-crosslinked nanoparticles (INS/FAN). At an optimized -COOH/ADH molar ratio, INS/DFAN with FA graft ratio of 18.2% exhibited a relatively small particle size, high encapsulation efficiency and excellent stability. Cellular uptake of INS/DFAN was FA graft ratio dependent when it was at/below 18.2%. Uptake mechanism and intestinal distribution studies demonstrated the enhanced insulin transepithelial transport by INS/DFAN via FA carrier-mediated transport pathway. In vivo studies revealed that orally-administered INS/DFAN produced a significant reduction in blood glucose levels and further improved insulin bioavailability in type I diabetic rats compared to INS/FAN. Taken together, the combination of dual crosslinking and FA modification is an effective strategy to develop pectin nano-vehicles for enhanced oral insulin delivery.

Automated summary

Pectin-based drug delivery systems have great potential for oral insulin delivery. In this study, we developed folic acid (FA)-modified pectin nanoparticles (INS/DFAN) as insulin delivery vehicles through a dual-crosslinking method. INS/DFAN effectively prevented premature insulin release and enhanced insulin transepithelial transport via the FA carrier-mediated pathway. In vivo studies showed that orally-administered INS/DFAN significantly reduced blood glucose levels and improved insulin bioavailability in type I diabetic rats compared to ionic-crosslinked nanoparticles (INS/FAN). The combination of dual crosslinking and FA modification is an effective strategy for enhanced oral insulin delivery using pectin nano-vehicles.