可生物降解纳米药物通过重塑肿瘤微环境和调节能量代谢高效治疗结直肠癌

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中文摘要：顺铂(CDDP)是治疗结直肠癌的常用化疗药物,但其存在清除快、耐药和靶向性差等问题.同时,缺氧、高水平谷胱甘肽和快速能量代谢等复杂的肿瘤微环境,也是导致化疗疗效不理想的原因之一.本文首先在沸石咪唑框架上负载CDDP,而后在表面包裹二氧化锰外壳,最后以透明质酸(HA)作为靶向分子进行修饰,成功构建了一种肿瘤微环境响应型纳米平台(ZIF-90@CDDP@MnO2@HA),实现了化疗、化学动力学疗法和饥饿疗法的联合治疗.肿瘤微环境响应性药物释放大大提高了化疗的疗效.MnO2外壳一方面会消耗谷胱甘肽(GSH)以抑制CDDP解毒和活性氧(ROS)清除,同时,释放的Mn2+可实现化学动力治疗.另一方面,MnO2通过原位氧气生成下调低氧诱导转录因子1α的表达,不仅能提高化疗耐受性,还能通过下调己糖激酶2和葡萄糖转运蛋白1的表达,抑制有氧糖酵解,进一步促进饥饿疗法.此外,ZIF-90释放的Zn2+会造成线粒体损伤,进一步抑制三磷酸腺苷(ATP)的产生,从而加强饥饿疗法.这种协同治疗策略在体外和体内均表现出良好的抗肿瘤效果,为结直肠癌联合治疗开辟了一条新途径.

外文标题：A biodegradable nanodrug with highly efficient treatment effect by remodeling tumor microenvironment and manipulating energy metabolism against colorectal cancer

外文摘要：Cisplatin(CDDP),a widely used chemotherapy drug for colorectal cancer,suffers from rapid clearance,re-sistance,and nonspecific delivery.Meanwhile,the sophisti-cated tumor microenvironments(TME),such as hypoxia,elevated glutathione(GSH)level,and rapid energy metabo-lism,result in an unsatisfactory treatment effectiveness of chemotherapy.Herein,a TME-responsive nanoplatform was constructed by loading CDDP and coating with a manganese dioxide(MnO2)shell on the zeolitic imidazolate framework,and finally modified with hyaluronic acid(HA)as a targeting molecule(ZIF-90@CDDP@MnO2@HA)for the combined chemotherapy/chemodynamic therapy(CDT)/starvation therapy of colorectal cancer.The TME-responsive drug release significantly improves the therapeutic efficacy of chemother-apy.On the one hand,the MnO2 shell depletes GSH to inhibit CDDP detoxification and reactive oxygen species clearance,and the released Mn2+could achieve CDT.On the other hand,the downregulating expression of hypoxia-inducible tran-scription factor 1α by oxygen generation not only reverses chemotherapy resistance but also inhibits aerobic glycolysis by downregulating expression of hexokinase 2 and glucose transportase-1,further contributing to starvation therapy.In addition,Zn2+released from ZIF-90 causes mitochondrial damage,further inhibiting adenosine triphosphate produc-tion in concert with glycolysis inhibition to enhance starvation therapy.This synergistic treatment strategy exhibits an ex-cellent antitumor effect in vitro and in vivo,which opens a new way to enhance the antitumor efficacy of CDDP-based che-motherapy for colorectal cancer.

外文关键词：

colorectal cancercisplatinstarvation therapyche-modynamic therapybiodegradable

作者：

张绍鹏、张昊、宋沛哲、曹悦、李伟、王大广、王樱蕙、张洪杰

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作者单位：

Department of Gastrocolorectal 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(CIAC)

Chinese Academy of Sciences(CAS),Changchun 130022,China

Department of Neurosurgery,The First Hospital of Jilin University,Changchun 130021,China

Department of Chemistry,Tsinghua University,Beijing 100084,China

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关键词：

colorectal cancer cisplatin starvation therapy che-modynamic therapy biodegradable

基金：

National Natural Science Foundation of ChinaProgram of Science and Technology Development Plan of Jilin Province of China

项目编号：

5207214220230508071RC

出版年：

2024

DOI：

10.1007/s40843-023-2693-7

中国科学:材料科学(英文)

CSTPCD

ISSN：

年,卷(期)：2024.67(1)

参考文献量43