Disulfiram Copper Nanoparticles Prepared with a Stabilized Metal Ion Ligand Complex Method for Treating Drug-Resistant Prostate Cancers
Disulfiram Copper Nanoparticles Prepared with a Stabilized Metal Ion Ligand Complex Method for Treating Drug-Resistant Prostate Cancers
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DOI：
10.1021/acsami.8b14940
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发表时间：
2018-12-05
影响因子：
9.5
通讯作者：
Li, Feng
中科院分区：
文献类型：
--
作者：
Chen, Wu;Yang, Wen;Li, Feng
双硫兰(DSF)是一种酒精厌恶药物，已被探索用于癌症治疗。DSF与铜离子形成的二乙基二硫代氨基甲酸铜(Cu(DDC)(2))络合物是其抗癌活性的主要活性成分。直接给予铜(DDC)(2)是一种很有前途的增强DSF抗癌效果的策略。然而，有效的药物输送仍然是铜(DDC)(2)的一个重大挑战，并阻碍了其临床应用。在本研究中，我们开发了一种简便的稳定金属离子配体络合物(SMILE)的方法来制备铜(DDC)(2)纳米颗粒(NPs)。SMILE法可以用不同类型的稳定剂，包括1，2-distearoyl-sn-glycerol-3-phosphoethanolamine聚乙二醇2000、D-生育酚聚乙二醇1000琥珀酸酯、甲氧基聚乙二醇5000-b-聚(L-丙交酯)5000和其他公认的美国食品和药物管理局批准的安全辅料来制备纳米铜(DDC)(2)。优化后的处方显示出优异的载药率(接近100%)、高的药物浓度(与传统的胶束制剂相比，药物浓度提高了200倍以上)以及最佳的粒径在100 nm以下。铜(DDC)(2)纳米粒在血清中具有良好的稳定性，可在72h内保存，也可在室温下保存至少一个月。通过3-(4，5-二甲基-噻唑-2-基)-2，5-二苯基四氮唑溴化法、集落形成实验、钙黄素-AM/碘化丙啶染色等多种方法检测了铜(DDC)(2)纳米粒制剂的抗癌作用。铜(DDC)(2)纳米粒子对耐药的前列腺癌和其他癌细胞表现出良好的活性，半数抑制浓度(IC50)约为100 nM。我们的研究还表明，纳米铜通过细胞凋亡诱导耐药的前列腺癌DU145-TXR细胞死亡，这是一种非凋亡性的细胞死亡。据我们所知，SILE方法首次提供了一种简单而有效的方法来制备具有高药物浓度、优异的负载效率和理想的物理化学性能的纳米铜(DDC)(2)。这种方法可能解决DSF/铜为基础的化疗的药物输送挑战，并促进其临床翻译。
Disulfiram (DSF), an alcohol-aversion drug, has been explored for cancer treatment. Copper diethyldithiocarbamate (Cu(DDC)(2)) complex formed by DSF and copper ions is a major active ingredient for its anticancer activity. Direct administration of Cu(DDC)(2) is a promising strategy to enhance the anticancer efficacy of DSF. However, efficient drug delivery remains a significant challenge for Cu(DDC)(2) and hinders its clinical use. In this study, we developed a facile stabilized metal ion ligand complex (SMILE) method to prepare Cu(DDC)(2) nanoparticles (NPs). The SMILE method could prepare Cu(DDC)(2) NPs with different types of stabilizers including 1,2-distearoyl-sn-glycerol-3-phosphoethanolamine poly(ethylene glycol) (PEG) 2000, D-alpha-tocopherol PEG 1000 succinate, methoxy PEG 5000-b-poly(L-lactide) 5000, and other generally recognized as safe excipients approved by the US Food and Drug Administration. The optimized formulations demonstrated excellent drug-loading efficiency (close to 100%), high drug concentrations (increased drug concentration by over 200-fold compared to the traditional micelle formulation), and an optimal particle size in the sub-100 nm range. Cu(DDC)(2) NPs exhibited outstanding stability in serum for 72 h and can also be stored at room temperature for at least 1 month. The anticancer effects of Cu(DDC)(2) NP formulations were determined by multiple assays including 3-(4,5-dimethyl-thiazol-2-yl)2,5-diphenyl tetrazolium bromide assay, colony-forming assay, calcein-AM/propidium iodide staining, and others. Cu(DDC)(2) NPs showed excellent activity against drug-resistant prostate cancer cells and other cancer cells with a half-maximal inhibitory concentration (IC50) of around 100 nM. Our study also demonstrated that Cu(DDC)(2) NPs induced cell death in drug-resistant prostate cancer cells (DU145-TXR) through paraptosis, which is a nonapoptotic cell death. To our best knowledge, the SMILE method provides, for the first time, a simple yet efficient process for generating Cu(DDC)(2) NPs with high drug concentration, excellent loading efficiency, and desirable physicochemical properties. This method could potentially address drug delivery challenges of DSF/copper-based chemotherapy and facilitate its clinical translation.