Sulfobetaine modification of poly (D, L-lactide-co-glycolic acid) nanoparticles enhances mucus permeability and improves bioavailability of orally delivered liraglutide

The glucagon-like peptide-1 (GLP-1) analogue used to treat diabetes is an increasingly popular polypeptide protein therapeutic, commonly marketed as an injection. However, the effective oral administration of peptide drugs remains challenging because of their extremely low bioavailability. In recent years, a number of delivery systems that have been shown to be effective in improving the therapeutic efficacy of oral drugs. Herein, liraglutide was employed as a model drug and amphoteric sulfobetaine (SB12) was selected for the surface modification of poly (D, L-lactide-co-glycolic acid) (PLGA) nanoparticles (NPs) to obtain hydrophilic and electroneutral SB12-NPs. The functional SB12-NPs were first screened to identify the optimal prescription process and obtained from the final prescription were evaluated. The particle size, zeta potential, encapsulation efficiency (EE%) and drug-loading (DL%) of SB12-NPs were 87.25 ± 0.77 nm, −3.91 ± 1.88 mV, 77.45% ± 1.62%, and 10.46% ± 0.21%, respectively. The cellular uptake of Lira-SB12 NPs was significantly better than that of free liraglutide, and verified that it was transported mainly through endocytosis mediated by clathrin- and lipid raft–mediated. The trans-mucous permeability (2.86-fold) and intestinal permeability (1.79-fold) of SB12-NPs were significantly higher than those of free liraglutide. Single and multiple doses of SB12-NPs showed that the blood sugar level of diabetic mice could be lower to about 70% of the initial value. The SB12-NPs demonstrated a higher relative bioavailability of 9.59% compared with that of oral pure liraglutide (5.13%). Thus, SB12-modified PLGA NPs with hydrophilic and electroneutral surface properties can significantly improve mucus permeability and oral bioavailability, and have the potential to be applied for oral delivery of peptides and proteins.