Chen Meixu, Huang Zeqian, Xia Meng, Ding Yaqing, Shan Ting, Guan Zilin, Dai Xiuling, Xu Xiaoyu, Huang Yanjuan, Huang Min, Zhao Chunshun
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
J Control Release. 2022 Jan;341:351-363. doi: 10.1016/j.jconrel.2021.11.041. Epub 2021 Nov 29.
Disulfiram (DSF), a familiar FDA-approved drug used for alcohol withdrawal, has recently been verified with potent antitumor therapeutic effect by generating Cu(DTC), which is the complex of its metabolite diethyldithiocarbamate (DTC) and copper. However, its poor tumor selectivity and insufficient endogenous Cu concentration within tumor site largely hinders the application of DSF-based antitumor therapy. Therefore, a GSH-responsive coordination nanoparticles (Cu-IXZ@DSF) was established as a copper carrier to achieve synchronous but separate delivery of Cu and DSF without antitumor ability, further to realize selectively triggered tumor in situ Cu(DTC) generation for antitumor therapy. A widely-used proteasome inhibitor ixazomib (IXZ) was chosen as ligands and Cu was used as coordination nodes to form nanosized Cu-IXZ@DSF. The DSF encapsulated in Cu-IXZ@DSF could be reduced to DTC by intracellular GSH, which could contend for Cu and realize in situ high toxic Cu(DTC) generation. Meanwhile, the chelation could lead to the disassembly of Cu-IXZ@DSF and release of IXZ to eventually achieve tumor specific "transformation from low toxicity to high toxicity" chemotherapy. The results of in vitro and in vivo experiments demonstrated that the as-prepared nanoplatform Cu-IXZ@DSF showed good biosafety and excellent antitumor effect via endoplasmic reticulum stress (ERS) as well as reactive oxygen species (ROS) generation pathway. Therefore, this nanocarrier provides an inspiring strategy with specific-triggered antitumor Cu(DTC) generation for DSF-based chemotherapy with high therapeutic effect and biosafety and showing great potential of treating cancer.
双硫仑（DSF）是一种经美国食品药品监督管理局（FDA）批准的用于戒酒的常见药物，最近已被证实通过生成其代谢物二乙二硫代氨基甲酸盐（DTC）与铜的络合物Cu（DTC）具有强大的抗肿瘤治疗效果。然而，其较差的肿瘤选择性以及肿瘤部位内源性铜浓度不足在很大程度上阻碍了基于DSF的抗肿瘤治疗的应用。因此，构建了一种谷胱甘肽响应性配位纳米颗粒（Cu-IXZ@DSF）作为铜载体，以实现铜和无抗肿瘤能力的DSF的同步但分离递送，进而实现选择性触发肿瘤原位生成Cu（DTC）用于抗肿瘤治疗。选择一种广泛使用的蛋白酶体抑制剂伊沙佐米（IXZ）作为配体，铜作为配位节点，形成纳米尺寸的Cu-IXZ@DSF。包裹在Cu-IXZ@DSF中的DSF可被细胞内谷胱甘肽还原为DTC，后者可争夺铜并实现原位生成高毒性的Cu（DTC）。同时，螯合作用可导致Cu-IXZ@DSF解体并释放IXZ，最终实现肿瘤特异性的“从低毒到高毒”化疗。体外和体内实验结果表明，所制备的纳米平台Cu-IXZ@DSF通过内质网应激（ERS）以及活性氧（ROS）生成途径显示出良好的生物安全性和优异的抗肿瘤效果。因此，这种纳米载体为基于DSF的化疗提供了一种具有特异性触发抗肿瘤Cu（DTC）生成的鼓舞人心的策略，具有高治疗效果和生物安全性，在癌症治疗中显示出巨大潜力。
