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

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ZrMOF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-MOFBSA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.

Angiogenesis in the tumor microenvironment is the main cause for the insensitivity of tumor cells to chemoradiotherapy.Strategies for increasing the sensitivity of tumor cells to conventional therapies using nanoparticles are limited.In this study,we developed rationally designed microenvironment response nanoparticles with physicochemical and biological features to overcome cisplatin resistance by using decomposition product from Zr-metal-organic framework(MOF)to inhibit the phosphatidylinositol 3-kinase(PI3K)/AKT/mammalian target of rapamycin(mTOR)/vascular endothelial growth factor(VEGF)pathway in chemoradiotherapy.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 remarkably,but also regulates the tumor microenvironment and inhibits the expression of a drug-efflux transporter,namely multidrug resistance-associated protein 1(MRP1),for reversing drug resistance in A549R cells.Thus,CDDP@Zr-MOF causes synergistic cytotoxicity in A549R cells,and high-efficiency eradication of cisplatin-resistant tumor without regrowth by inhibiting angiogenesis in the tumor microenvironment.The microenvironment responsiveness of CDDP@Zr-MOF provides a multipurpose synergistic approach for treating drug-resistant tumors with chemoradiotherapy.