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To improve the oral efficiency of exenatide, we prepared polyethylene glycol-poly(lactic-co-glycolic acid) (PEG-PLGA) NPs modified with Fc (NPs-Fc) for exenatide oral delivery. Exenatide was encapsulated into the NPs by the w/o/w emulsion-solvent evaporation method. The particle size of the NPs-Fc was approximately 30 nm larger than that of the unmodified NPs with polydispersity indices in a narrow range (PDIs; PDI < 0.3) as detected by DLS, and the highest encapsulation efficiency of exenatide in the NPs was greater than 80%. Fc-conjugated NPs permeated Caco-2 cells faster and to a greater extent compared to unmodified NPs, as verified by CLSM and flow cytometry. Hypoglycemic effect studies demonstrated that oral administration of exenatide-loaded PEG-PLGA NPs modified by an Fc group extended the hypoglycemic effects compared with s.c. injection of the exenatide solution. Fluorescence-labeled NPs were used to investigate the effects of Fc targeting, and the results demonstrated that the NPs-Fc stayed in the gastrointestinal tract for a longer time in comparison with the unmodified NPs, as shown by the whole-body fluorescence images and fluorescence images of the dissected organs detected by in vivo imaging in live mice. Therefore, Fc-targeted nano-delivery systems show great promise for oral peptide/protein drug delivery.

As a result of an error during figure assembly in Figure 3, the image for NPs at 1 h shows blue channel image for NPs-Fc at 1 h. Graph: Figure 3Confocal microscopy images of fluorescently labeled NPs and NPs-Fc incubation with Caco-2 cell for 0.5, 1, 2, and 4 h. [Extracted from the article]

Although oral delivery of exenatide has significant advantages, its poor permeability through intestinal epithelial membranes and rapid digestion by pepsin and ereptase in the gastrointestinal tract make effective oral delivery of exenatide a formidable challenge. In this study, we constructed a zinc ion (Zn 2+ ) and exenatide complex functionalized nanoparticle (NP) oral delivery system to overcome the above-mentioned issue. Polyethylene glycol-poly(lactic-co-glycolic acid) (PEG-PLGA) was used as a drug carrier to escape enzymatic degradation in the gastrointestinal tract, and low molecular weight protamine (LMWP) was used as a functional group to increase penetration of NPs into the intestinal epithelium. The functionalized NPs exhibited significantly improved penetration across the intestinal epithelium, as shown by cell uptake and transmembrane transport experiments. Moreover, a significant hypoglycemic effect was observed in diabetic rats. The relative bioavailability of the orally administered functionalized NPs vs. subcutaneous injection was 7.44%, 29-fold that of the exenatide-Zn 2+ solution group. These findings indicate that our modification could effectively improve exenatide treatment. [ABSTRACT FROM AUTHOR]