Mitochondria-specific drug release and reactive oxygen species burst induced by polyprodrug nanoreactors can enhance chemotherapy
Mitochondria-specific drug release and reactive oxygen species burst induced by polyprodrug nanoreactors can enhance chemotherapy
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DOI：
10.1038/s41467-019-09566-3
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发表时间：
2019-04-12
影响因子：
16.6
通讯作者：
Xing, Da
中科院分区：
文献类型：
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作者：
Zhang, Wenjia;Hu, Xianglong;Xing, Da
与正常细胞相比，癌细胞表现出轻微升高的活性氧（ROS）水平，大约90%的细胞内ROS是在线粒体中产生的。原位线粒体ROS扩增是一种有前途的策略，以加强癌症治疗。在这里，我们报道了癌细胞和线粒体双靶向多前药物纳米反应器（dt - pn）与高含量的重复喜树碱（CPT）单元共价连接，在内源性线粒体ROS （mtROS）存在下释放初始游离CPT。原位释放的CPT作为细胞呼吸抑制剂，诱导mtROS上调，从而实现随后的CPT释放和mtROS爆发的自我循环。这种mtROS扩增使长期高氧化应激诱导癌细胞凋亡。目前这种内源性激活mtROS扩增增强化学动力治疗的策略克服了ROS的寿命短和作用范围小的缺点，避免了光动力治疗中外源光的穿透限制，在治疗学上具有广阔的应用前景。
Cancer cells exhibit slightly elevated levels of reactive oxygen species (ROS) compared with normal cells, and approximately 90% of intracellular ROS is produced in mitochondria. In situ mitochondrial ROS amplification is a promising strategy to enhance cancer therapy. Here we report cancer cell and mitochondria dual-targeting polyprodrug nanoreactors (DT-PNs) covalently tethered with a high content of repeating camptothecin (CPT) units, which release initial free CPT in the presence of endogenous mitochondrial ROS (mtROS). The in situ released CPT acts as a cellular respiration inhibitor, inducing mtROS upregulation, thus achieving subsequent self-circulation of CPT release and mtROS burst. This mtROS amplification endows long-term high oxidative stress to induce cancer cell apoptosis. This current strategy of endogenously activated mtROS amplification for enhanced chemodynamic therapy overcomes the short lifespan and action range of ROS, avoids the penetration limitation of exogenous light in photodynamic therapy, and is promising for theranostics.