Utilization of PLGA nanoparticles in yeast cell wall particle system for oral targeted delivery of exenatide to improve its hypoglycemic efficacy.

Oral delivery of exenatide (EXE), a high-efficiency therapeutic peptide, is urgently needed for long-term treatment of diabetes. In this study, a polylactide-co-glycoside (PLGA) nanoparticles (NPs) in yeast cell wall particle (YCWP) system was built to improve the intestinal absorption of EXE by efficient protection of EXE against gastrointestinal degradation and intestinal phagocytic cell targeted delivery. The EXE-loaded PLGA NPs were prepared by a double emulsion solvent diffusion method and exhibited a uniformly spherical appearance, a nano size (92.4 ± 4.6 nm) and a positive surface charge (+32.3 ± 3.8 mV). And then, the NPs were successfully loaded into the YCWPs by a solvent hydration - lyophilization cycle method to obtain the EXE-PLGA NPs @YCWPs, which was verified by scanning electron microscope and confocal laser scanning microscopy. An obvious sustained drug release and a reduced burst release were achieved by this nano-in-micro carrier. Moreover, the gastrointestinal stability of EXE in PLGA NPs @YCWPs was significantly higher than that in PLGA NPs in the simulated gastrointestinal environment, which were useful in enhancing the intestinal absorption of EXE. In biodistribution study, the EXE-PLGA NPs @YCWPs could quickly reached the root of the villi, and even partly entered the inner of the villi, especially in ileum and Peyer's patches. In vitro cell evaluation demonstrated an efficient β-glucan receptor mediated endocytosis and transport of EXE-PLGA NPs @YCWPs by the macrophage RAW 264.7 cells, suggesting a potential intestinal macrophage targeted absorptive pathway. The in vivo pharmacokinetic study showed a preferred hypoglycemic effect and an increased pharmacological availability (13.7 ± 4.1%) after oral administration of the EXE-PLGA NPs @YCWPs. It is believed that the PLGA nanoparticles in YCWP system could become an efficient strategy to orally deliver therapeutic peptide drugs.