ROS-Responsive Mitochondria-Targeting Blended Nanoparticles: Chemo- and Photodynamic Synergistic Therapy for Lung Cancer with On-Demand Drug Release upon Irradiation with a Single Light Source.
ROS-Responsive Mitochondria-Targeting Blended Nanoparticles: Chemo- and Photodynamic Synergistic Therapy for Lung Cancer with On-Demand Drug Release upon Irradiation with a Single Light Source.
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作者：
Yue C;Yang Y;Zhang C;Alfranca G;Cheng S;Ma L;Liu Y;Zhi X;Ni J;Jiang W;Song J;de la Fuente JM;Cui D
癌细胞中的线粒体比正常细胞保持更负的膜电位。线粒体是细胞活性氧（ROS）的主要来源，这是光动力疗法所必需的。因此，靶向线粒体的策略可以最大限度地提高癌症的光动力治疗效率。在这里，我们首次报道了一种新的线粒体靶向药物递送系统 ZnPc/CPT-TPPNP 的合成。为了合成这种新型化合物，聚乙二醇用硫缩酮连接基修饰的喜树碱 (TL-CPT) 和三苯基鏻进行官能化，形成嵌段共聚物 TL-CPT-PEG1K-TPP。通过将嵌段共聚物 TL-CPT-PEG1K-TPP 与 1, 2-二硬脂酰基-sn-甘油-3-磷酸乙醇胺-N-[甲氧基（聚乙二醇）] (DSPE-PEG) 混合，构建了 ZnPc/CPT-TPPNP，用于传递光敏剂锌酞菁 (ZnPc)。三苯基膦可以在线粒体内选择性积累数百倍。硫缩酮接头具有 ROS 响应性，CPT 可以在 ROS 裂解时释放。我们还表明，ZnPc/CPT-TPPNP 中负载的 ZnPc 吸收 633 nm 激光产生 ROS，其既可用于光动力疗法，也可用于裂解硫缩酮接头，从而释放喜树碱用于化疗。因此，靶向线粒体的纳米颗粒可以提高光动力治疗效果。我们的结果表明，用三苯基膦阳离子对纳米粒子进行表面修饰有助于光敏剂向线粒体的有效亚细胞递送。该纳米颗粒具有良好的ROS响应作用，可释放CPT，作为拓扑异构酶Ⅰ抑制剂，可转移至细胞核并干扰DNA复制。因此，混合纳米粒子提供了一种新的有前景的方法，作为一种单光源靶向线粒体的ROS激活化疗和光动力疗法，用于肺癌治疗。
Mitochondria in cancer cells maintain a more negative membrane potential than normal cells. Mitochondria are the primary source of cellular reactive oxygen species (ROS), which are necessary for photodynamic therapy. Thus, the strategy of targeting mitochondria can maximize the photodynamic therapeutic efficiency for cancer. Here we report, for the first time, synthesis of a new mitochondria-targeting drug delivery system, ZnPc/CPT-TPPNPs. To synthesize this novel compound, polyethylene glycol was functionalized with thioketal linker-modified camptothecin (TL-CPT) and triphenylphosphonium to form the block copolymer, TL-CPT-PEG1K-TPP. The ZnPc/CPT-TPPNPs was constructed for delivery of the photosensitizer Zinc phthalocyanine (ZnPc) by blending the block copolymer TL-CPT-PEG1K-TPP with 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)] (DSPE-PEG).Triphenylphosphine can accumulate selectively several hundred-fold within mitochondria. The thioketal linker is ROS-responsive and CPT can be released upon ROS cleavage. We also show that the ZnPc loaded in ZnPc/CPT-TPPNPs absorbed the 633 nm laser to produce ROS, which could be utilized both in photodynamic therapy and to cleave the thioketal linker thereby releasing camptothecin for chemotherapy. Thus, the mitochondria-targeting nanoparticles could elevate photodynamic therapeutic efficacy. Our results showed that surface modification of the nanoparticles with triphenylphosphine cations facilitated efficient subcellular delivery of the photosensitizer to mitochondria. The nanoparticles had a good ROS-responsive effect to release CPT, which could transfer to the nucleus and interfere with DNA replication as a topoisomeraseⅠinhibitor. Thus, the blended nanoparticles provide a new promising approach as a mitochondria-targeting ROS-activated chemo- and photodynamic therapy with a single light source for lung cancer.
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