Mimicking natural cholesterol assimilation to elevate the oral delivery of liraglutide for type II diabetes therapy

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are a series of polypeptides broadly applied in the long-term treatment of type II diabetes. However, administration of GLP-RA is mainly through repetitive subcutaneous injection, which may seriously decrease the compliance and safety. Herein, a bio-inspired oral delivery system was designed to enhance the oral absorption of liraglutide (Lira), a kind of GLP-1 RA, by mimicking the natural cholesterol assimilation. 25-hydroxycholesterol (25HC), a cholesterol derivative, was modified on the surfaced of Lira-loaded PLGA nanoparticles (Lira 25HC NPs) and functioned as a top-down actuator to facilitate unidirectional transcytosis across the intestinal epithelium. After oral delivery, Lira 25HC NPs displayed improved therapeutic effect as compared with oral free Lira on type II diabetes db/db mice, as evidenced by multiple relieved diabetic symptoms including the enhanced glucose tolerance, repressed weight growth, improved liver glucose metabolism, decreased fasting blood glucose, HbA(1c), serum lipid, and increased beta cells activity. Surprisingly, the fasting blood glucose, liver glucose metabolism, and HbAlc of oral Lira-loaded 25HC NPs were comparable to subcutaneous injection of free Lira. Further mechanisms revealed that 25HC ligand could mediate the nanoparticles to mimic natural cholesterol absorption by exerting high affinity towards apical Niemann-Pick C1 Like 1 (NPC1L1) and then basolateral ATP binding cassette transporter A1 (ABCA1) overexpressed on the opposite side of intestinal epithelium. This cholesterol assimilation-mimicking strategy achieve the unidirectional transport across the intestinal epithelium, thus improving the oral absorption of liraglutide. In general, this study established a cholesterol simulated platform and provide promising insight for the oral delivery of GLP-1 RA. (C) 2022 Published by Elsevier B.V. on behalf of Shenyang Pharmaceutical University.

Automated summary

GLP-1 RA are commonly used peptides for the treatment of type II diabetes, but their repetitive subcutaneous administration can reduce compliance and safety. A bio-inspired oral delivery system using 25HC-modified PLGA nanoparticles was designed to enhance the oral absorption of Lira, leading to improved therapeutic effects on diabetic mice. The system mimics natural cholesterol assimilation to achieve unidirectional transport across the intestinal epithelium, providing promising insights for oral delivery of GLP-1 RA.