Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi, 712100, P. R. China.
J Mater Chem B. 2023 Nov 29;11(46):11044-11051. doi: 10.1039/d3tb01564e.
The effectiveness of chemodynamic therapy (CDT) in cancer treatment is limited by insufficient endogenous HO levels in tumor tissue and an increasing ratio of high valence metal ions. To overcome these challenges, a novel nanotherapeutic approach, named GOx-CuCaP-DSF, has been proposed. This approach involves the design of nanotherapeutics that aim to self-supply HO within cancer cells and provide a supplement of low valence metal ions to enhance the performance of CDT. GOx-CuCaP-DSF nanotherapeutics are engineered by incorporating glucose oxidase (GOx) into Ca-doped calcium phosphate (CaP) nanoparticles and loading disulfiram (DSF) through surface adsorption. Under the tumor microenvironment, GOx catalyzes the conversion of tumor-overexpressed glucose (Glu) to liberate HO. The degradation of CaP further lowers the pH, facilitating the release of Cu ions and DSF. The rapid reaction between Cu and DSF leads to the generation of Cu, increasing the Cu/Cu ratio and promoting the Cu-based Fenton reaction, which enhances the efficiency of CDT. Simultaneously, DSF undergoes conversion to diethyldithiocarbamate acid (ET), forming a copper(II) complex (Cu(II)ET) by strong chelation with Cu ions. This Cu(II)ET complex, a potent chemotherapeutic drug, exhibits a synergistic therapeutic effect in combination with CDT. Moreover, the elevated Cu species resulting from DSF reaction promotes the aggregation of toxic mitochondrial proteins, leading to cell cuproptosis. Overall, the strategy of integrating the chemodynamic therapy efficiency of the Fenton reaction with the activation of efficacious cuproptosis using a chemotherapeutic drug presents a promising avenue for enhancing the effectiveness of multi-modal anti-tumor treatments.
化学动力学治疗（CDT）在癌症治疗中的效果受到肿瘤组织中内源性 HO 水平不足和高价金属离子比例增加的限制。为了克服这些挑战，提出了一种新的纳米治疗方法，名为 GOx-CuCaP-DSF。这种方法涉及设计纳米治疗剂，旨在向癌细胞内自供 HO，并提供低化合价金属离子的补充，以增强 CDT 的性能。GOx-CuCaP-DSF 纳米治疗剂是通过将葡萄糖氧化酶（GOx）掺入钙掺杂的磷酸钙（CaP）纳米颗粒中并通过表面吸附负载二硫代氨基甲酸酯（DSF）来设计的。在肿瘤微环境下，GOx 催化肿瘤过表达的葡萄糖（Glu）转化，释放 HO。CaP 的降解进一步降低 pH 值，有利于 Cu 离子和 DSF 的释放。Cu 和 DSF 之间的快速反应导致 Cu 的生成，增加 Cu/Cu 比值并促进基于 Cu 的芬顿反应，从而提高 CDT 的效率。同时，DSF 转化为二乙二硫代氨基甲酸盐酸（ET），通过与 Cu 离子强螯合形成铜（II）配合物（Cu(II)ET）。这种 Cu(II)ET 配合物是一种有效的化疗药物，与 CDT 联合具有协同治疗效果。此外，DSF 反应产生的 Cu 物种促进了毒性线粒体蛋白的聚集，导致细胞铜死亡。总体而言，将 Fenton 反应的化学动力学治疗效率与使用化疗药物激活有效的铜死亡相结合的策略为增强多模态抗肿瘤治疗的效果提供了一种有前途的途径。
