双硫仑抗癌机理启发构建pH/H2O2双级响应纳米药物用于癌症的联合治疗

Copper(II) diethyldithiocarbamate (Cu(DTC)2), which can be generated by the reaction of disulfiram (DSF) and Cu(II), is the main reason for the superb in vitro anticancer activity of DSF. However, DSF’s in vivo antitumor efficacy is still not satisfactory due to its rapid metabolism in blood. Polymers have been utilized to prolong the half-life of DSF in blood by physical encapsulation. Nevertheless, this strategy is limited by low DSF loading contents and potential drug leakage during the delivery. What’s worse, DSF alone shows poor antitumor efficacy if only tumorous low-concentration Cu(II) is available. In our previous study, Cu(DTC)2 that was generated by the in situ reaction of DSF and Cu(II) could be efficiently loaded and delivered by polymeric carriers in a coordination manner. However, the as-prepared nanomedicine showed poor tumor selectivity to normal tissues. Herein, we propose a polymeric nanomedicine co-loading DTC and Cu(II) by tumor microenviroment-sensitive covalent bonds and coordination bonds, respectively. The nanomedicine is expected to not only improve the safety and stability in drug delivery but also achieve tumor-specific inhibition and enable a combination therapy of chemotherapy and oxidative stress amplification by generation of Cu(DTC)2 in cancer cells. Our project is aimed to optimize the delivering strategy of DSF/Cu(II) and enhance its in vivo antitumor efficacy and tumor selectivity, providing a new idea for the anticancer application of DSF/Cu(II).

双硫仑(DSF)能与Cu(II)反应生成二乙基二硫代氨基甲酸铜(Cu(DTC)2)使其具有优异的体外抗癌活性，但DSF体内代谢过快导致其体内抗肿瘤疗效欠佳。高分子通过物理包裹可延长DSF在血液中半衰期，但载药量低、易泄露，并且仅靠肿瘤组织低浓度的Cu(II)不足以实现理想的抗肿瘤疗效。我们前期研究发现，高分子载体通过配位作用可高效负载与递送DSF与Cu(II)原位生成的Cu(DTC)2，但该纳米药物对癌细胞的选择性并不理想。本项目在此基础上，设计通过肿瘤微环境敏感共价键和配位键分别负载DTC和Cu(II)的高分子纳米药物，在提高纳米药物在递送过程中安全性与稳定性的同时，在肿瘤细胞内生成Cu(DTC)2，提高对肿瘤的选择性，实现化疗与氧化应激放大的联合治疗。本项目通过优化DSF/Cu(II)的递送策略，提高其体内抑瘤效果与肿瘤选择性，为DSF/Cu(II)抗癌应用提供新的思路。

双硫仑（DSF）作为一种临床上使用七十年的戒酒药物，近年来被发现可“老药新用”于抗肿瘤治疗。其抑瘤功效主要取决于其与铜离子形成的小分子复合物Cu(DTC)2的超强抑癌活性，但受限于体内严格的铜稳态调节，肿瘤细胞内可利用的Cu2+浓度非常有限，因此如何实现DSF/Cu的有效肿瘤递送对于提高其体内抗肿瘤疗效至关重要。基于上述背景，本项目构建了系列DSF/Cu药物递送系统，提出了多种药物递送策略（小分子前药、递送Cu(DTC)2、分别递送DSF/Cu以及共递送DSF/Cu），提高了在乳腺癌、非小细胞肺癌和黑色素瘤等实体瘤中的抗肿瘤疗效。以白蛋白为载体构建了一种原位成药与可控负载的铜基化疗-光热纳米药物，可在无有机溶剂条件下大剂量、重复制备铜纳米药物，探明了Cu(DTC)2和CuS两种药物不同比例条件下的光热转化和抑癌机理，体内外实验结果表明有很好的黑色素瘤抑制效果。利用葡萄糖氧化酶催化肿瘤细胞内高浓度葡萄糖实现自催化供给H2O2，产生的H2O2可激活小分子前药DQ释放出DTC，DTC与铜MOF中的Cu2+结合原位生成抗癌药物Cu(DTC)2；此外，H2O2还可与Cu2+发生类芬顿反应，产生高细胞毒性的∙OH，实现化学动力学治疗；该体系在小鼠皮下乳腺癌模型中抑瘤率达86.2%。制备了白蛋白Cu(DTC)2纳米粒，载药量高达27.5%，通过电化学和荧光实验证明Cu(DTC)2的GSH反应惰性，且可有效逆转顺铂耐药非小细胞肺癌。总之，本项目丰富了铜基药物递送体系，为金属配合物药物递送系统开发提供了思路。圆满完成了项目计划任务书的内容，实现了预期研究目标。

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