Lenvatinib-zinc phthalocyanine conjugates as potential agents for enhancing synergistic therapy of multidrug-resistant cancer by glutathione depletion
Lenvatinib-zinc phthalocyanine conjugates as potential agents for enhancing synergistic therapy of multidrug-resistant cancer by glutathione depletion
复制标题
Lenvatinib-锌酞菁结合物作为潜在药物，通过谷胱甘肽消耗增强多重耐药癌症的协同治疗
DOI：
10.1016/j.ejmech.2019.02.065
复制
发表时间：
2019
影响因子：
6.7
通讯作者：
Chunshun Zhao
中科院分区：
文献类型：
--
作者：
Gaofei Wei;Liangfeng Huang;Yali Jiang;Yifeng Shen;Zeqian Huang;Yanjuan Huang;Xiaoqi Sun;Chunshun Zhao
由于GSH水平升高，多药耐药(MDR)严重阻碍了靶向治疗的疗效。因此，降低细胞内GSH水平对于靶向治疗药物逆转肿瘤耐药是非常必要的。在本研究中，我们合成了一种光敏的多功能偶联物，将VEGFR抑制剂Lenvatinib通过烷基链连接到光敏剂ZnPc上，从而实现光动力治疗逆转多药耐药和增强抗肿瘤治疗。照射后，ZnPc-C8-LEN可产生ROS耗竭细胞内GSH。GSH的降低可能通过Bcl2/caspase3途径促进细胞死亡，减少P gp的表达，从而逆转对Lenvatinib的耐药性。此外，通过聚乙二醇2000-PLA2000的包裹，锌碳纳米粒显著增强了肿瘤的蓄积，并显示了良好的抗肿瘤活性。而ZnPc-C8-LEN的荧光特性可以实时监测体内纳米粒子的变化，指导后续的治疗时间和地点。结果表明，结合物ZnPc-C8-LEN对谷胱甘肽耗竭的多药耐药肿瘤具有显著的协同治疗作用。该方法为结合靶向治疗和光动力治疗逆转靶向耐药和增强协同治疗提供了一种很有前景的策略。
The therapeutic efficacy of targeted therapy is dramatically hindered by multidrug resistance (MDR) because of elevated GSH levels. Thus, depletion of intracellular GSH level is highly desirable for targeted-therapeutic agents to reverse tumor drug resistance. In this study, a photosensitive multifunctional conjugate ZnPc-C8-Len, in which lenvatinib (a VEGFR inhibitor) is linked to a photosensitizer ZnPc through an alkyl chains, was synthesized to realize photodynamic therapy to reverse multidrug resistance and enhanced antitumor therapy. Upon the irradiation, ZnPc-C8-Len could generate ROS to deplete intracellular GSH. The decreased GSH would enhance apoptotic cell death by Bcl-2/caspase 3 pathway and reduce expression of P-gp to reverse lenvatinib resistance. Moreover, through PEG2000-PLA2000encapsulation, ZnPc-C8-Len NPs displayed significantly enhanced tumor accumulation and excellentin vivoantitumor activity. And the fluorescence characteristics of ZnPc-C8-Len could monitor the changes of nanoparticlesin vivoin real time to guide when and where to conduct the subsequent therapy. As a result, conjugate ZnPc-C8-Len had an outstanding capability to enhance synergistic therapy of multidrug-resistant cancer by glutathione depletion. And the approach reported here provide a promising strategy in development of conjugate integrated targeted therapy with photodynamic therapy to reverse targeted drug multidrug resistance and enhance synergistic therapy.