Recently, multidrug resistance (MDR) has become a major clinical chemotherapeutic burden that robustly diminishes the intracellular drug levels through various mechanisms. To overcome the doxorubicin (Dox) resistance in tumor cells, we designed a hierarchical nanohybrid system possessing copper-substituted mesoporous silica nanoparticles (Cu-MSNs). Further, Dox was conjugated to copper metal in the Cu-MSNs framework through a pH-sensitive coordination link, which is acutely sensitive to the tumor acidic environment (pH 5.0–6.0). In the end, the nanocarrier was coated with D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS), a P-gp inhibitor-entrenched compact liposome net for obstructing the drug efflux pump. Copper ions in the framework synergize the antitumor activity of Dox by enhancing the intracellular reactive oxygen species (ROS) levels through a Fenton-like reaction-mediated conversion of hydrogen peroxide. Furthermore, intracellularly generated ROS triggered the apoptosis by reducing the cellular as well as mitochondrial membrane integrity in MDR cells, which was confirmed by the mitochondrial membrane potential (MMP) measurement. The advancement of the design and critical improvement of cytotoxic properties through free radical attack demonstrate that the proposed hierarchical design can devastate the MDR for efficient cancer treatment.

中文翻译：

---

通过分层的pH敏感，产生ROS的纳米反应器的协同作用克服多药耐药性

最近，多药耐药性（MDR）已成为一种主要的临床化学治疗负担，它通过各种机制强烈地降低了细胞内药物的水平。为了克服肿瘤细胞中的阿霉素（Dox）耐药性，我们设计了一种具有铜取代的介孔二氧化硅纳米粒子（Cu-MSNs）的分层纳米混合系统。此外，Dox通过pH敏感的配位键与Cu-MSNs框架中的铜金属结合，该键对肿瘤的酸性环境（pH 5.0-6.0）极为敏感。最后，用D-α-生育酚聚乙二醇1000琥珀酸酯（TPGS）涂覆纳米载体，D-α-生育酚聚乙二醇1000琥珀酸酯（PGS）固定有P-gp抑制剂致密脂质体网，用于阻塞药物外排泵。框架中的铜离子通过Fenton样反应介导的过氧化氢转化增强细胞内活性氧（ROS）水平，从而增强Dox的抗肿瘤活性。此外，细胞内生成的ROS通过降低MDR细胞中的细胞以及线粒体膜完整性来触发细胞凋亡，这一点已通过线粒体膜电位（MMP）测量得到证实。通过自由基攻击的设计进步和细胞毒性特性的关键改善表明，所提出的分层设计可以破坏MDR以进行有效的癌症治疗。细胞内产生的ROS通过降低MDR细胞中的细胞以及线粒体膜完整性来触发细胞凋亡，这一点已通过线粒体膜电位（MMP）测量得到证实。通过自由基攻击的设计进步和细胞毒性特性的关键改善表明，所提出的分层设计可以破坏MDR以进行有效的癌症治疗。细胞内产生的ROS通过降低MDR细胞中的细胞以及线粒体膜完整性来触发细胞凋亡，这一点已通过线粒体膜电位（MMP）测量得到证实。通过自由基攻击的设计进步和细胞毒性特性的关键改善表明，所提出的分层设计可以破坏MDR以进行有效的癌症治疗。