Oral delivery of ferroptosis inducers for effective treatment of hepatic fibrosis  

作　　者：Yinglan Yu Shunlong Zhang Yongfeng Xu Hao Shao Lei Luo 

机构地区：[1]College of Pharmaceutical Sciences,Southwest University,Chongqing 400715,China

出　　处：《Nano Research》2024年第8期7621-7630,共10页纳米研究（英文版）

基　　金：supported by the Fundamental Research Funds for the Central Universities(No.SWU-KQ22024);the NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparation and Excipients(No.PPE2023005);the China Postdoctoral Science Foundation(No.2023M740731);the Chongqing Science and Technology Commission(No.CSTB2022TIAD-KPX0094);National Key Research and Development Program of China(No.2021YFD1800900);National Natural Science Foundation of China(No.82073790).

摘　　要：Liver fibrosis is characterized by the excessive accumulation of extracellular matrix(ECM),which is primarily produced by activated hepatic stellate cells(HSCs).However,effective therapies for hepatic fibrosis are currently lacking.Artesunate is a promising anti-fibrotic drug candidate,but its clinical application is hindered by limited absorption.Here,we present a novel oral delivery platform that enhances the HSCs uptake of artesunate and induces potent ferroptosis.The platform is vitamin Adecorated nanoparticles encapsulated with artesunate.The multifunctional ligand vitamin A interacts with retinol-binding proteins that are highly expressed on the intestinal epithelium to promote transcytosis,highly expressed on the surface of HSCs but lowly expressed in normal hepatocytes.After oral administration,this oral delivery platform enhances transepithelial transport in the intestine,improves drug accumulation in the liver,and continuously increases HSCs uptake of artesunate.Upon drug release in HSCs,artesunate depletes glutathione peroxidase 4 and glutathione,effectively initiating ferroptosis.In vivo experiments demonstrate that this strategy induces pronounced ferroptosis,efficiently relieving liver fibrosis.This work provides a proof-ofconcept demonstration that an oral delivery strategy for ferroptosis inducers may be beneficial for liver fibrosis treatment.

关 键 词：liver fibrosis hepatic stellate cells oral delivery intestinal epithelium ferroptosis 

分 类 号：R575.2[医药卫生—消化系统]