State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China.
State Key Laboratory for Physical Chemistry of Solid Surfaces, Collaborative Innovation Center of Chemistry for Energy Materials, and National & Local Joint Engineering Research Center for Preparation Technology of Nanomaterials, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China.
Theranostics. 2020 May 16;10(14):6384-6398. doi: 10.7150/thno.45558. eCollection 2020.
To circumvent the huge cost, long R&D time and the difficulty to identify the targets of new drugs, repurposing the ones that have been clinically approved has been considered as a viable strategy to treat different diseases. In the current study, we outlined the rationale for repurposing disulfiram (DSF, an old alcohol-aversion drug) to treat primary breast cancer and its metastases. To overcome a few shortcomings of the individual administration of DSF, such as the dependence on copper ions (Cu) and limited capability in selective targeting, we here artificially synthesized the active form of DSF, diethyldithiocarbamate (DTC)-Cu complex (CuET) for cancer therapeutics. To achieve a greater efficacy , smart nanomedicines were devised through a one-step self-assembly of three functional components including a chemically stable and biocompatible phase-change material (PCM), the robust anticancer drug (CuET) and a near-infrared (NIR) dye (DIR), namely CuET/DIR NPs. A number of assays were performed including the photothermal efficacy, light-triggered drug release behavior, nuclear localization, DNA damage and induction of apoptosis of CuET/DIR NPs and molecular mechanisms underlying CuET-induced repression on cancer metastatic behaviors. Meanwhile, the mice bearing 4T1-LG12-drived orthotopic tumors were employed to evaluate biodistribution and anti-tumor effect of CuET/DIR NPs. The intravenous injection model was employed to reflect the changes of the intrinsic metastatic propensity of 4T1-LG12 cells responding to CuET/DIR NPs. The rationally designed nanomedicines have self-traceability for bioimaging, long blood circulation time for enhanced drug accumulation in the tumor site and photo-responsive release of the anticancer drugs. Moreover, our data unearthed that CuET/DIR nanomedicines behave like "Trojan horse" to transport CuET into the cytoplasm, realizing substantial intracellular accumulation. Upon NIR laser irradiation, massive CuET would be triggered to release from the nanomedicines and reach a high local concentration towards the nucleus, where the pro-apoptotic effects were conducted. Importantly, our CuET/DIR nanomedicines revealed a pronounced capability to leash breast cancer metastases through inhibition on EMT. Additionally, these nanomedicines showed great biocompatibility in animals. These combined data unearthed a remarkably enhanced tumor-killing efficacy of our CuET nanomedicines through nuclear targeting. This work may open a new research area of repurposing DSF as innovative therapeutic agents to treat breast cancer and its metastases.
为了规避巨大的成本、漫长的研发时间以及新药靶点难以确定等问题，重新利用已临床批准的药物被认为是治疗不同疾病的可行策略。在本研究中，我们概述了将戒酒硫（DSF，一种旧的戒酒药物）重新用于治疗原发性乳腺癌及其转移的基本原理。为了克服 DSF 单独给药的一些缺点，例如对铜离子（Cu）的依赖性和选择性靶向能力有限，我们在这里人工合成了 DSF 的活性形式，二乙基二硫代氨基甲酸盐（DTC）-Cu 配合物（CuET）用于癌症治疗。为了提高疗效，我们通过一步自组装三种功能成分设计了智能纳米药物，包括化学稳定且生物相容的相变材料（PCM）、强大的抗癌药物（CuET）和近红外（NIR）染料（DIR），即 CuET/DIR NPs。进行了一系列实验，包括光热疗效、光触发药物释放行为、核定位、DNA 损伤和诱导 CuET/DIR NPs 凋亡以及 CuET 诱导的抑制癌症转移行为的分子机制。同时，使用携带 4T1-LG12 驱动的原位肿瘤的小鼠来评估 CuET/DIR NPs 的体内分布和抗肿瘤作用。静脉注射模型用于反映 CuET/DIR NPs 对 4T1-LG12 细胞内在转移倾向的变化。合理设计的纳米药物具有用于生物成像的自追踪性、增强的肿瘤部位药物积累的长血液循环时间和光响应的抗癌药物释放。此外，我们的数据揭示了 CuET/DIR 纳米药物像“特洛伊木马”一样将 CuET 运送到细胞质中，实现了大量的细胞内积累。在近红外激光照射下，大量的 CuET 会从纳米药物中释放出来，并在细胞核处达到高局部浓度，从而发挥促凋亡作用。重要的是，我们的 CuET/DIR 纳米药物通过抑制 EMT 表现出显著抑制乳腺癌转移的能力。此外，这些纳米药物在动物体内表现出很好的生物相容性。这些综合数据揭示了通过核靶向，我们的 CuET 纳米药物具有显著增强的肿瘤杀伤效力。这项工作可能为将 DSF 重新用作治疗乳腺癌及其转移的创新治疗剂开辟一个新的研究领域。
