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

Asian Journal of Pharmaceutical Sciences 2022年第5期17卷 653-665页

作者： Ruinan Wu Zhanghan Wu Liyun Xing Xi Liu Lei Wu Zhou Zhou Lian Li Yuan Huang Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China

Glucagon-like peptide-1 receptor agonists(GLP-1 RA)are a series of polypeptides broadly applied in the long-term treatment of typeⅡdiabetes.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 typeⅡdiabetes 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 increasedβcells activity.Surprisingly,the fasting blood glucose,liver glucose metabolism,and hba1c 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.

关键词： Glucagon-like peptide-1 Oral delivery cholesterol assimilation Liraglutide TypeⅡdiabetes hba 1c

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