利用金属有机框架抑制PI3K/AKT/mTOR信号传导通路以克服放化疗中的多重耐药性
Inhibiting PI3K/AKT/mTOR signaling by metal-organic frameworks for overcoming multiple drug resistance in chemoradiotherapy
宋春雨 1关雪 2谢昌明 3姜珊 4洪智文 4吴琼 5曲国蕃 1马腾闯 4崔亚利4
作者信息
- 1. Department of Orthopedics,Harbin Medical University Cancer Hospital,Harbin 150081,China
- 2. Animal Laboratory Center,The Second Affiliated Hospital of Harbin Medical University,Harbin 150081,China
- 3. Department of Thyroid Surgery,Key Laboratory of Hepatosplenic Surgery,Ministry of Education,The First Affiliated Hospital of Harbin Medical University,Harbin 150007,China
- 4. Department of Nuclear Medicine,Harbin Medical University Cancer Hospital,Harbin 150081,China
- 5. Laboratory of Controllable Preparation and Application of Nanomaterials,Key Laboratory of Cryogenics,Technical Institute of Physics and Chemistry,Chinese Academy of Sciences,Beijing 100190,China
- 折叠
摘要
肿瘤微环境中的血管生成是肿瘤细胞对放化疗不敏感的主要原因.在本项研究中,我们设计了一种微环境响应型的纳米颗粒,利用Zr-MOF的分解产物抑制肿瘤细胞中的PI3K/AKT/mTOR/VEGF通路,从而克服A549R细胞对顺铂的耐药性.我们将顺铂包裹在Zr-MOF中,并在表面修饰BSA,形成了CDDP@Zr-MOF-BSA纳米复合体,该复合体在肿瘤微环境中有良好的响应性,有助于在肿瘤区域蓄积,展现出卓越的血管生成抑制能力,并能明显降低药物的外排.此外,CDDP@Zr-MOF-BSA能显著抑制多药耐药相关蛋白1(MRP1)的表达,从而逆转A549R细胞的耐药性.总体而言,CDDP@Zr-MOF-BSA对A549R有细胞毒性,能抑制肿瘤微环境中的血管生成,最终有效提高顺铂耐药肿瘤的治疗效果.CDDP@Zr-MOF-BSA为放化疗治疗耐药肿瘤提供了一种多功能协同的方法.
Abstract
Angiogenesis in the tumor microenvironment is the main cause for the insensitivity of tumor cells to che-moradiotherapy.Strategies for increasing the sensitivity of tumor cells to conventional therapies using nanoparticles are limited.In this study,we developed rationally designed mi-croenvironment response nanoparticles with physicochemical and biological features to overcome cisplatin resistance by using decomposition product from Zr-metal-organic frame-work(MOF)to inhibit the phosphatidylinositol 3-kinase(PI3K)/AKT/mammalian target of rapamycin(mTOR)/vas-cular endothelial growth factor(VEGF)pathway in chemor-adiotherapy.Cisplatin(CDDP)is encapsulated into Zr-MOF and bovine serum albumin(BSA)is modified into the surface of nanoparticles to create CDDP@Zr-MOF-BSA(abbreviated as CDDP@Zr-MOF),which acts as an excellent radiosensitizer and exhibits microenvironment response,preferable tumor accumulation,high-efficiency inhibition of angiogenesis,and obviously reduced efflux on resistant A549 cells.The rate of angiogenesis inhibition in the combined treatment group is 6-fold higher than that in other control groups.Moreover,CDDP@Zr-MOF not only increases the therapeutic effect re-markably,but also regulates the tumor microenvironment and inhibits the expression of a drug-efflux transporter,namely multidrug resistance-associated protein 1(MRP1),for rever-sing drug resistance in A549R cells.Thus,CDDP@Zr-MOF causes synergistic cytotoxicity in A549R cells,and high-effi-ciency eradication of cisplatin-resistant tumor without re-growth by inhibiting angiogenesis in the tumor microenvironment.The microenvironment responsiveness of CDDP@Zr-MOF provides a multipurpose synergistic ap-proach for treating drug-resistant tumors with chemor-adiotherapy.
关键词
angiogenesis/multidrug resistance/radiotherapy/Zr-MOF/microenvironmentKey words
angiogenesis/multidrug resistance/radiotherapy/Zr-MOF/microenvironment引用本文复制引用
基金项目
National Natural Science Foundation of China(82172041)
National Natural Science Foundation of China(81801808)
Harbin Medical University Cancer Hospital Haiyan Foundation(JJZD202101)
Harbin Medical University Cancer Hospital Haiyan Foundation(JJQN2019-02)
Harbin Medical University Cancer Hospital Haiyan Foundation(JJZD2018-02)
Heilongjiang Postdoctoral Fund(LBH-Z18160)
Heilongjiang Postdoctoral Fund(LBH-TZ2018)
Natural Science Foundation of Heilongjiang(YQ2023H023)
Natural Science Foundation of Heilongjiang(LH2020H127)
Heilongjiang Province Youth Innovative Talents Training Program(UNPYSCT-2020162)
出版年
2024
NETL
NSTL
万方数据