一种兼具程序性缓释双氢青蒿素和Fe^(2+)自供应能力的智能纳米药物用于肿瘤协同治疗  

Smart nanoplatform with programmed release of dihydroartemisinin and Fe^(2+)self-supply for synergistic cancer therapy

作　　者：赵莹 王樱蕙 曹悦 周仕杰 刘洋 牛瑞 徐博 张松涛 王大广 宋术岩 张洪杰 Ying Zhao;Yinghui Wang;Yue Cao;Shijie Zhou;Yang Liu;Rui Niu;Bo Xu;Songtao Zhang;Daguang Wang;Shuyan Song;Hongjie Zhang(Department of Gastric and Colorectal Surgery,General Surgery Center,The First Hospital of Jilin University,Changchun 130021,China;State Key Laboratory of Rare Earth Resource Utilization,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun 130022,China;School of Pharmacy,Henan University of Chinese Medicine,Zhengzhou 450046,China;Department of Chemistry,Tsinghua University,Beijing 100084,China)

机构地区：[1]Department of Gastric and Colorectal Surgery,General Surgery Center,The First Hospital of Jilin University,Changchun 130021,China [2]State Key Laboratory of Rare Earth Resource Utilization,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun 130022,China [3]School of Pharmacy,Henan University of Chinese Medicine,Zhengzhou 450046,China [4]Department of Chemistry,Tsinghua University,Beijing 100084,China

出　　处：《Science China Materials》2023年第10期4071-4078,共8页中国科学（材料科学（英文版）

基　　金：supported by the National Key Research and Development Program of China(2020YFA0712102);the National Natural Science Foundation of China(52022094,22020102003,and 52072142);the Program of Science and Technology Development Plan of Jilin Province of China(20210101111JC and 20230508071RC);the Youth Innovation Promotion Association of Chinese Academy of Sciences(2019232)。

摘　　要：双氢青蒿素(DHA)作为一种新型的抗癌药物引起了全世界的广泛关注.然而,DHA的固有缺陷降低了其在血液系统中的运输效率,而肿瘤细胞中铁含量不足进一步导致疗效不佳.因此,构建一个可同时负载DHA和Fe^(3+)并在肿瘤微环境中特异性释放出DHA/Fe的纳米药物具有重大意义.本文报道了一种智能纳米药物CaCO_(3)@DHA@Fe^(3+)-TA@PEG(CDFP NPs)用于肿瘤协同治疗.Fe^(3+)-TA壳层的包覆赋予CDFP NPs良好的光热性能.此外,CDFP NPs在酸性的肿瘤微环境中可以快速降解并释放出TA,Fe^(3+),DHA和Ca^(2+).Fe^(3+)与TA反应生成Fe^(2+),Fe^(2+)与DHA相互作用生成高毒性的自由基.此外,在氧化应激状态下,Ca^(2+)过载导致线粒体功能紊乱,最终诱导肿瘤细胞死亡.在光热治疗,活性氧,Ca^(2+)过载的协同作用下,CDFP NPs在体内外均表现出良好的治疗效果.Dihydroartemisinin(DHA)has caught worldwide attention as an innovative antitumor drug.However,the inherent defects of DHA reduce its transport efficiency in the bloodstream,and insufficient iron content in the tumor cells further leads to poor therapeutic efficacy.Therefore,it is highly desirable to exploit a DHA/Fe-loaded nanoplatform which releases its payload responding to the tumor microenvironment(TME).Herein,we reported the smart nanodrugs CaCO_(3)@DHA@Fe^(3+)-tannic acid(TA)@polyethylene glycol(PEG)(CDFP)nanoparticles(NPs)that specifically release DHA and self-supply Fe^(2+)ions at the tumor site for synergistic cancer therapy.Fe^(3+)-TA shell with good photothermal performance makes CDFP NPs suitable photothermal agents for photothermal therapy(PTT).Once CDFP NPs were internalized by tumor cells,TA,Fe^(3+),DHA,and Ca^(2+)could be released in the acidic TME.And TA can reduce Fe^(3+)to Fe^(2+),followed by Fe^(2+)-DHA mediated chemodynamic reaction to yield reactive oxygen species(ROS).Meanwhile,intracellular overloaded Ca^(2+)ions lead to the mitochondrial dysfunction,which increases ROS production and further induces tumor cell apoptosis.Such CDFP NPs with PTT,Fe^(2+)-DHA mediated ROS,and Ca^(2+)overloading show excellent antitumor effects in vitro and in vivo,certifying their great potential in further clinical application.

关 键 词：DIHYDROARTEMISININ self-supply Fe^(2+) Ca^(2+)overloading synergistic therapy 

分 类 号：TQ460.1[化学工程—制药化工] TB383.1[一般工业技术—材料科学与工程] R730.5[医药卫生—肿瘤]