机构地区:[1]Department of Gastrocolorectal 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(CIAC),Chinese Academy of Sciences(CAS),Changchun 130022,China [3]Department of Neurosurgery,The First Hospital of Jilin University,Changchun 130021,China [4]Department of Chemistry,Tsinghua University,Beijing 100084,China
出 处:《Science China Materials》2024年第1期331-342,共12页中国科学(材料科学)(英文版)
基 金:supported by the National Natural Science Foundation of China (52072142);the Program of Science and Technology Development Plan of Jilin Province of China (20230508071RC)。
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@MnO_(2)@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.MnO_(2)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,MnO_(2)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.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(MnO_(2))shell on the zeolitic imidazolate framework,and finally modified with hyaluronic acid(HA)as a targeting molecule(ZIF-90@CDDP@MnO_(2)@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 MnO_(2) 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 1αby 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.
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