Oral nano-formulation improves pancreatic islets dysfunction via lymphatic transport for antidiabetic treatment  

作　　者：Lin Hou Xueyuan Peng Ruiting Wang Yifei Wang Hong Li Huijuan Zhang Yun Zhang Zhenzhong Zhang 

机构地区：[1]School of Pharmaceutical Sciences,Zhengzhou University,Zhengzhou 450001,China [2]Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases,Zhengzhou University,Zhengzhou 450001,China [3]Collaborative Innovation Center of New Drug Research and Safety Evaluation,Zhengzhou University,Zhengzhou 450001,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第7期3137-3152,共16页药学学报（英文版）

基　　金：supported by National Natural Science Foundation of China(Nos.81972893,and 82172719);Excellent Youth Science Foundation of Henan province(212300410071,China);Training program for young key teachers in Henan Province(2020GGJS019,China)。

摘　　要：Type 2 diabetes mellitus(T2DM)therapy is facing the challenges of long-term medication and gradual destruction of pancreatic isletβ-cells.Therefore,it is timely to develop oral prolonged action formulations to improve compliance,while restoringβ-cells survival and function.Herein,we designed a simple nanoparticle with enhanced oral absorption and pancreas accumulation property,which combined apical sodiumdependent bile acid transporter-mediated intestinal uptake and lymphatic transportation.In this system,taurocholic acid(TCA)modified poly(lactic-co-glycolic acid)(PLGA)was employed to achieve pancreas location,hydroxychloroquine(HCQ)was loaded to execute therapeutic efficacy,and 1,2-dilauroyl-sn-glycero-3-phosphocholine(DLPC)was introduced as stabilizer together with synergist(PLGA-TCA/DLPC/HCQ).In vitro and in vivo results have proven that PLGA-TCA/DLPC/HCQ reversed the pancreatic islets damage and dysfunction,thus impeding hyperglycemia progression and restoring systemic glucose homeostasis via only once administration every day.In terms of mechanism PLGA-TCA/DLPC/HCQ ameliorated oxidative stress,remodeled the inflammatory pancreas microenvironment,and activated PI3K/AKT signaling pathway without obvious toxicity.This strategy not only provides an oral delivery platform for increasing absorption and pancreas targetability but also opens a new avenue for thorough T2DM treatment.

关 键 词：Type 2 diabetes mellitus Oral drug delivery PLGA nanoparticles Pancreatic isletβ-cells Lymphatic transportation Taurocholic acid HYDROXYCHLOROQUINE Pancreas microenvironment 

分 类 号：R587.1[医药卫生—内分泌]