Smart responsive nanoplatform via in situ forming disulfiram-copper ion chelation complex for cancer combination chemotherapy
Smart responsive nanoplatform via in situ forming disulfiram-copper ion chelation complex for cancer combination chemotherapy
复制标题
通过原位形成双硫仑-铜离子螯合复合物的智能响应纳米平台用于癌症联合化疗
DOI：
10.1016/j.cej.2021.128947
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发表时间：
2021-02-18
影响因子：
15.1
通讯作者：
Wang, Zhifei
中科院分区：
文献类型：
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作者：
Meng, Xiangyu;Jia, Kaiying;Wang, Zhifei
智能反应纳米药物作为载体，可以利用特异性肿瘤微环境（TME）将无毒药物转化为有效的抗癌药物，并在原位释放化疗药物，从而提高对肿瘤的治疗效率，同时不会对周围正常组织/细胞产生脱靶毒性。本文通过将双硫脲（DSF）和多柔比星（DOX）包封在沸石咪唑酸框架-8 （ZIF-8）中，再包覆铜离子(Cu2+)-单宁酸（TA）配合物（表示为DSF/DOX@ZIF-8@Cu-TA），构建ph响应型金属-有机框架纳米颗粒，实现强化联合化疗。弱酸性TME多阶段触发DSF/DOX@ZIF-8@Cu-TA外壳释放Cu2+以及DSF和DOX的协同暴露。DSF（无毒药物）和Cu2+的积累导致DSF和Cu2+螯合反应在原位快速形成高细胞毒性的双（N， N-二乙基二硫代氨基甲酸酯）Cu2+配合物（CuL2），并伴随Cu+基fenton样反应产生ROS。此外，DOX的抗癌作用通过cul2调控的ROSMAPK和NF-KB信号通路增强。构建的DSF/DOX@ZIF-8@Cu-TA在体外和体内均具有显著提高的治疗效果。具有化疗药物成瘾性效应的无毒毒性转变策略为设计新型协同癌症化疗纳米平台提供了一个有希望的范例。
Smart responsive nanomedicines serving as carriers can take advantage of the specific tumor microenvironment (TME) to convert non-toxic drugs into effective anticarcinogens and release chemotherapeutic drugs in situ to improve therapeutic efficiency against tumors without inducing off-target toxicity to surrounding normal tissues/cells. Herein, a pH-responsive metal-organic framework nanoparticle is constructed by encapsulating disulfiram (DSF) and doxorubicin (DOX) into the zeolitic imidazolate framework-8 (ZIF-8) and then coating with copper ion (Cu2+)-tannic acid (TA) complex (denoted as DSF/DOX@ZIF-8@Cu-TA) to achieve enhanced combination chemotherapy. The release of Cu2+ from the outer shell of DSF/DOX@ZIF-8@Cu-TA and the cooperative exposure of DSF and DOX are triggered at multiple stages by mild acidity TME. The accumulation of DSF (non-toxic drugs) and Cu2+ results in the rapid formation of high cytotoxic bis(N, N-diethyl dithiocarbamato)Cu2+ complexes (CuL2) in situ via DSF and Cu2+ chelating reaction, which accompany the production of ROS via Cu+-based Fenton-like reaction. Besides, the anticancer effect of DOX is augmented by CuL2-modulated ROSMAPK and NF-KB signal pathways. The constructed DSF/DOX@ZIF-8@Cu-TA present significantly improved therapeutic efficiency as demonstrated both in vitro and in vivo. The strategy of nontoxicity-to-toxicity transitions with the addictive effect of chemotherapeutics provides a promising paradigm to design novel nanoplatforms for synergistic cancer chemotherapy.