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Disulfiram Copper Nanoparticles Prepared with a Stabilized Metal Ion Ligand Complex Method for Treating Drug-Resistant Prostate Cancers

  • Wu Chen
    Wu Chen
    Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama 36849, United States
    More by Wu Chen
    • , 
  • Wen Yang
    Wen Yang
    Materials Research and Education Center, Materials Engineering, Department of Mechanical Engineering, Auburn University, Auburn, Alabama 36849, United States
    More by Wen Yang
    • , 
  • Pengyu Chen
    Pengyu Chen
    Materials Research and Education Center, Materials Engineering, Department of Mechanical Engineering, Auburn University, Auburn, Alabama 36849, United States
    More by Pengyu Chen
    Orcidhttp://orcid.org/0000-0003-3380-872X
    • , 
  • Yongzhuo Huang*
    Yongzhuo Huang
    State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
    *E-mail: [email protected]. Phone: +86-21-2023-1981 (Y.H.).
    More by Yongzhuo Huang
    Orcidhttp://orcid.org/0000-0001-7067-8915
    • , and 
  • Feng Li*
    Feng Li
    Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama 36849, United States
    *E-mail: [email protected]. Phone: 334-844-7406 (F.L.).
    More by Feng Li
    Orcidhttp://orcid.org/0000-0002-8559-3831
Cite this: ACS Appl. Mater. Interfaces 2018, 10, 48, 41118–41128
Publication Date (Web):November 16, 2018
https://doi.org/10.1021/acsami.8b14940
Copyright © 2018 American Chemical Society
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Abstract

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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-α-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.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.8b14940.

  • Effects of theoretical drug concentration and TPGS concentration on actual Cu(DDC)2 drug concentration and drug-loading efficiency; effects of theoretical drug concentration and DSPE–PEG concentration on actual Cu(DDC)2 drug concentration and drug-loading efficiency; effects of theoretical drug concentration and TPGS concentration on NP particle size and PDI; effects of theoretical drug concentration and DSPE–PEG concentration on NP particle size and PDI; particle size of 2 mg/mL Cu(DDC)2 NPs and corresponding stabilizers without Cu(DDC)2 NPs; TEM of PEG–PLA micelles and PEG–PLA/Cu(DDC)2 NPs; calcein AM/PI staining of DU145-TXR cells treated with Cu(DDC)2 NPs; morphology of DU145-TXR cells treated with Cu(DDC)2 NPs (0.5 μM), paclitaxel (0.5 μM), and blank PEG–PLA for 24 h; morphology of MCF-7 cells treated with 0.5 μM DSPE–PEG/Cu(DDC)2 NPs for 72 h; and morphology of Du145-TXR cells treated with Cu(DDC)2 NPs (0.5 μM) alone and in combination with CHX (20 μM) or CQ (20 μM) for 24 h (PDF)

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Cited By

This article is cited by 15 publications.

  1. Xiao Li, Ke Du, Jian Sun, Fude Feng. Apoferritin as a Carrier of Cu(II) Diethyldithiocarbamate and Biomedical Application for Glutathione-Responsive Combination Chemotherapy. ACS Applied Bio Materials 2020, 3 (1) , 654-663. https://doi.org/10.1021/acsabm.9b01014
  2. Chung-Hui HuangPengyu Chen X. Michael LiuFeng Li. Metal–Organic Nanomaterials for Drug Delivery. 2020,,, 79-95. https://doi.org/10.1021/bk-2020-1350.ch007
  3. Xinyu Peng, Qingqing Pan, Boya Zhang, Shiyu Wan, Sai Li, Kui Luo, Yuji Pu, Bin He. Highly Stable, Coordinated Polymeric Nanoparticles Loading Copper(II) Diethyldithiocarbamate for Combinational Chemo/Chemodynamic Therapy of Cancer. Biomacromolecules 2019, 20 (6) , 2372-2383. https://doi.org/10.1021/acs.biomac.9b00367
  4. Han-Xiao Tang, Yuan-Yuan Cai, Chen-Guang Liu, Jian-Ting Zhang, Ranjith Kumar Kankala, Shi-Bin Wang, Ai-Zheng Chen. Sub-micronization of disulfiram and disulfiram-copper complexes by Rapid expansion of supercritical solution toward augmented anticancer effect. Journal of CO2 Utilization 2020, 39 , 101187. https://doi.org/10.1016/j.jcou.2020.101187
  5. Yin Zhong, Rui Sun, Yu Geng, Quan Zhou, Ying Piao, Tao Xie, Ruhong Zhou, Youqing Shen. N -Oxide polymer–cupric ion nanogels potentiate disulfiram for cancer therapy. Biomaterials Science 2020, 8 (6) , 1726-1733. https://doi.org/10.1039/C9BM01841G
  6. Anne McMahon, Wu Chen, Feng Li. Old wine in new bottles: Advanced drug delivery systems for disulfiram-based cancer therapy. Journal of Controlled Release 2020, 319 , 352-359. https://doi.org/10.1016/j.jconrel.2020.01.001
  7. Ya Chang, Jizong Jiang, Wu Chen, Wen Yang, Lili Chen, Pengyu Chen, Jianzhong Shen, Shizhi Qian, Teng Zhou, Linfeng Wu, Liang Hong, Yongzhuo Huang, Feng Li. Biomimetic metal-organic nanoparticles prepared with a 3D-printed microfluidic device as a novel formulation for disulfiram-based therapy against breast cancer. Applied Materials Today 2020, 18 , 100492. https://doi.org/10.1016/j.apmt.2019.100492
  8. Wen Yang, Hanitrarimalala Veroniaina, Xiaole Qi, Pengyu Chen, Feng Li, Pu Chun Ke. Soft and Condensed Nanoparticles and Nanoformulations for Cancer Drug Delivery and Repurpose. Advanced Therapeutics 2020, 3 (1) , 1900102. https://doi.org/10.1002/adtp.201900102
  9. Yuexiang Niu, Engong Tang, Qingan Zhang. Cytotoxic effect of silica nanoparticles against hepatocellular carcinoma cells through necroptosis induction. Toxicology Research 2019, 8 (6) , 1042-1049. https://doi.org/10.1039/C9TX00240E
  10. Yuexiang Niu, Engong Tang, Qingan Zhang. Cytotoxic effect of silica nanoparticles against hepatocellular carcinoma cells through necroptosis induction. Toxicology Research 2019, 8 (6) , 1042-1049. https://doi.org/10.1039/C9TX00240E
  11. Yuexiang Niu, Engong Tang, Qingan Zhang. Cytotoxic effect of silica nanoparticles against hepatocellular carcinoma cells through necroptosis induction. Toxicology Research 2019, 8 (6) , 1042-1049. https://doi.org/10.1039/C9TX00240E
  12. Qingqing Pan, Boya Zhang, Xinyu Peng, Shiyu Wan, Kui Luo, Wenxia Gao, Yuji Pu, Bin He. A dithiocarbamate-based H 2 O 2 -responsive prodrug for combinational chemotherapy and oxidative stress amplification therapy. Chemical Communications 2019, 55 (92) , 13896-13899. https://doi.org/10.1039/C9CC05438C
  13. Qingzhu Yang, Yao Yao, Kai Li, Lin Jiao, Jiazhen Zhu, Cheng Ni, Mengmeng Li, Q. Ping Dou, Huanjie Yang. An Updated Review of Disulfiram: Molecular Targets and Strategies for Cancer Treatment. Current Pharmaceutical Design 2019, 25 (30) , 3248-3256. https://doi.org/10.2174/1381612825666190816233755
  14. Zdenek Skrott, Dusana Majera, Jan Gursky, Tereza Buchtova, Marian Hajduch, Martin Mistrik, Jiri Bartek. Disulfiram’s anti-cancer activity reflects targeting NPL4, not inhibition of aldehyde dehydrogenase. Oncogene 2019, 38 (40) , 6711-6722. https://doi.org/10.1038/s41388-019-0915-2
  15. Elmira Ekinci, Sagar Rohondia, Raheel Khan, Qingping P. Dou. Repurposing Disulfiram as An Anti-Cancer Agent: Updated Review on Literature and Patents. Recent Patents on Anti-Cancer Drug Discovery 2019, 14 (2) , 113-132. https://doi.org/10.2174/1574892814666190514104035

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