Abstract：
Both chemodynamic therapy and photodynamic therapy, based on the production of reactive oxygen (ROS), have excellent potential in cancer therapy. However, the abnormal redox homeostasis in tumor cells, especially the overexpressed glutathione (GSH) could scavenge ROS and reduce the anti-tumor efficiency. Therefore, it is essential to develop a simple and effective tumor-specific drug delivery system for modulating the tumor microenvironment (TME) and achieving synergistic therapy at the tumor site. In this study, self-assembled nanoparticles (named CDZP NPs) were developed using copper ion (Cu2+), doxorubicin (Dox), zinc phthalocyanine (ZnPc) and a trace amount of poly(2-(di-methylamino)ethylmethacrylate)-poly[(R)-3-hydroxybutyrate]-poly(2-(dimethylamino)ethylmethacrylate) (PDMAEMA-PHB-PDMAEMA) through chelation, π-π stacking and hydrophobic interaction. These triple factor-responsive (pH, laser and GSH) nanoparticles demonstrated unique advantages through the synergistic effect. Highly controllable drug release ensured its effectiveness at the tumor site, Dox-induced chemotherapy and ZnPc-mediated fluorescence (FL) imaging exhibited the distribution of nanoparticles. Meanwhile, Cu2+-mediated GSH-consumption not only reduced the intracellular ROS elimination but also produced Cu+ to catalyze hydrogen peroxide (H2O2) and generated hydroxyl radicals (˙OH), thereby enhancing the chemodynamic and photodynamic therapy. Herein, this study provides a green and relatively simple method for preparing multifunctional nanoparticles that can effectively modulate the TME and improve synergetic cancer therapy.
摘要：
化学动力疗法和光动力疗法，基于活性氧（ROS）的产生，在癌症治疗中具有极好的潜力。然而,肿瘤细胞中异常的氧化还原稳态，特别是过表达的谷胱甘肽（GSH）可以清除ROS并降低抗肿瘤效率。因此,开发一种简单有效的肿瘤特异性药物递送系统以调节肿瘤微环境（TME）并在肿瘤部位实现协同治疗是至关重要的。在这项研究中,使用铜离子(Cu2+)开发了自组装纳米粒子(名为CDZPNPs)，多柔比星（Dox），酞菁锌（ZnPc）和痕量的聚（甲基丙烯酸2-（二甲基氨基）乙酯）-聚[（R）-3-羟基丁酸酯]-聚（甲基丙烯酸2-（二甲基氨基）乙酯）（PDMAEMA-PHB-PDMAEMA）通过螯合，π-π堆积和疏水相互作用。这些三重因子响应性(pH，激光和GSH)纳米粒子通过协同效应表现出独特的优势。高度可控的药物释放确保了其在肿瘤部位的有效性，Dox诱导的化疗和ZnPc介导的荧光（FL）成像显示纳米颗粒的分布。同时,Cu2介导的GSH消耗不仅减少了细胞内ROS的消除，而且还产生了Cu以催化过氧化氢（H2O2）并产生羟基自由基（•OH），从而增强化学动力和光动力疗法。在这里，本研究提供了一种绿色且相对简单的制备多功能纳米颗粒的方法，该方法可以有效调节TME并改善癌症的协同治疗。
