Old wine in new bottles: Advanced drug delivery systems for disulfiram-based cancer therapy.

Disulfiram (DSF) is an FDA-approved drug that has been repurposed for cancer treatment. It showed excellent anticancer efficacy in combination with copper ions (Cu). Several active clinical trials testing the anticancer efficacy of DSF against various cancers are underway. In this review article, we summarized different delivery strategies for DSF-based cancer therapy. In many studies, DSF and Cu were delivered in two separate formulations. DSF and Cu formed copper diethyldithiocarbamate [Cu(DDC)2] complex which was reported as a major active anticancer ingredient for DSF/Cu combination therapy. Various delivery systems for DSF and Cu were developed to enhance their delivery into tumors. The administration of preformed Cu(DDC)2 complex was also explored to achieve better anticancer efficacy. Several studies developed formulations that were capable of delivering Cu(DDC)2 complex in a single formulation. These novel formulations will address drug delivery challenges and have great potential to improve the efficacy of DSF-based cancer therapy. DSF is an off-patent drug molecule. The novel drug formulations of DSF will also serve as a good strategy for developing intellectual properties which will be critical for product development and commercialization.

[1]  Xing Tang,et al.  Disulfiram-loaded mixed nanoparticles with high drug-loading and plasma stability by reducing the core crystallinity for intravenous delivery. , 2018, Journal of colloid and interface science.

[2]  Q. Dou,et al.  An Updated Review on Disulfiram: Molecular Targets and Strategies for Cancer Treatment. , 2019, Current pharmaceutical design.

[3]  R. Mahato,et al.  Paclitaxel- and lapatinib-loaded lipopolymer micelles overcome multidrug resistance in prostate cancer , 2011, Drug Delivery and Translational Research.

[4]  Haotian Zhang,et al.  A Copper-Mediated Disulfiram-Loaded pH-Triggered PEG-Shedding TAT Peptide-Modified Lipid Nanocapsules for Use in Tumor Therapy. , 2015, ACS applied materials & interfaces.

[5]  Zhipeng Wang,et al.  Development and characterisation of disulfiram‐loaded PLGA nanoparticles for the treatment of non‐small cell lung cancer , 2017, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[6]  Yongzhuo Huang,et al.  Smart Cell-Penetrating Peptide-Based Techniques for Intracellular Delivery of Therapeutic Macromolecules. , 2018, Advances in protein chemistry and structural biology.

[7]  Liu Yang,et al.  Membrane Loaded Copper Oleate PEGylated Liposome Combined with Disulfiram for Improving Synergistic Antitumor Effect In Vivo , 2018, Pharmaceutical Research.

[8]  Shuo Yao,et al.  Genetically-engineered protein prodrug-like nanoconjugates for tumor-targeting biomimetic delivery via a SHEATH strategy. , 2019, Nanoscale.

[9]  Timothy X. Witkowski Intellectual property and other legal aspects of drug repurposing , 2011 .

[10]  H. Clevers,et al.  Cancer stem cells revisited , 2017, Nature Medicine.

[11]  A. Ghavamzadeh,et al.  Delivery of disulfiram into breast cancer cells using folate-receptor-targeted PLGA-PEG nanoparticles: in vitro and in vivo investigations , 2016, Journal of Nanobiotechnology.

[12]  Xuesi Chen,et al.  Stable loading and delivery of disulfiram with mPEG-PLGA/PCL mixed nanoparticles for tumor therapy. , 2016, Nanomedicine : nanotechnology, biology, and medicine.

[13]  Feng Li,et al.  Lipid-Drug Conjugate for Enhancing Drug Delivery. , 2017, Molecular pharmaceutics.

[14]  R. Mahato,et al.  Poly(ethylene glycol)-block-poly(2-methyl-2-benzoxycarbonyl-propylene carbonate) micelles for rapamycin delivery: in vitro characterization and biodistribution. , 2011, Journal of pharmaceutical sciences.

[15]  J. Sehouli,et al.  Inhibitory effect on ovarian cancer ALDH+ stem-like cells by Disulfiram and Copper treatment through ALDH and ROS modulation. , 2019, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[16]  P. Ke,et al.  Soft and Condensed Nanoparticles and Nanoformulations for Cancer Drug Delivery and Repurpose , 2020, Advanced therapeutics.

[17]  Jiri Bartek,et al.  Alcohol-abuse drug disulfiram targets cancer via p97 segregase adapter NPL4 , 2017, Nature.

[18]  M. Hanigan Gamma-glutamyl transpeptidase: redox regulation and drug resistance. , 2014, Advances in cancer research.

[19]  Chaoliang He,et al.  Combining disulfiram and poly(l-glutamic acid)-cisplatin conjugates for combating cisplatin resistance. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[20]  R. Mahato,et al.  Synthesis and characterization of amphiphilic lipopolymers for micellar drug delivery. , 2010, Biomacromolecules.

[21]  Qianzheng Zhu,et al.  Disulfiram combats cancer via crippling valosin-containing protein/p97 segregase adaptor NPL4. , 2018, Translational cancer research.

[22]  Yongzhuo Huang,et al.  Disulfiram Copper Nanoparticles Prepared with a Stabilized Metal Ion Ligand Complex Method for Treating Drug-Resistant Prostate Cancers. , 2018, ACS applied materials & interfaces.

[23]  Xing Tang,et al.  mPEG5k- b-PLGA2k/PCL3.4k/MCT Mixed Micelles as Carriers of Disulfiram for Improving Plasma Stability and Antitumor Effect in Vivo. , 2018, Molecular pharmaceutics.

[24]  S. Soond,et al.  Albumin Nanovectors in Cancer Therapy and Imaging , 2019, Biomolecules.

[25]  Wenxin Wang,et al.  Anticancer Drug Disulfiram for In Situ RAFT Polymerization: Controlled Polymerization, Multifacet Self-Assembly, and Efficient Drug Delivery. , 2016, ACS macro letters.

[26]  D. Clarke,et al.  Disulfiram metabolites permanently inactivate the human multidrug resistance P-glycoprotein. , 2004, Molecular pharmaceutics.

[27]  R. Mahato,et al.  HPMA polymer-based site-specific delivery of oligonucleotides to hepatic stellate cells. , 2009, Bioconjugate chemistry.

[28]  Yaping Li,et al.  Multi-targeted inhibition of tumor growth and lung metastasis by redox-sensitive shell crosslinked micelles loading disulfiram , 2014, Nanotechnology.

[29]  Weimin Yin,et al.  Dual-targeting biomimetic delivery for anti-glioma activity via remodeling the tumor microenvironment and directing macrophage-mediated immunotherapy , 2018, Chemical science.

[30]  Xinyi Tan,et al.  Synergistic breast tumor cell killing achieved by intracellular co-delivery of doxorubicin and disulfiram via core-shell-corona nanoparticles. , 2018, Biomaterials science.

[31]  Peisheng Xu,et al.  Repurposing disulfiram for cancer therapy via targeted nanotechnology through enhanced tumor mass penetration and disassembly. , 2017, Acta biomaterialia.

[32]  C. Heeschen,et al.  Pancreatic cancer stem cell proliferation is strongly inhibited by diethyldithiocarbamate-copper complex loaded into hyaluronic acid decorated liposomes. , 2019, Biochimica et biophysica acta. General subjects.

[33]  Z. Sauna,et al.  The molecular basis of the action of disulfiram as a modulator of the multidrug resistance-linked ATP binding cassette transporters MDR1 (ABCB1) and MRP1 (ABCC1). , 2004, Molecular pharmacology.

[34]  Wei Deng,et al.  Universal Anticancer Cu(DTC)2 Discriminates between Thiols and Zinc(II) Thiolates Oxidatively. , 2019, Angewandte Chemie.

[35]  M. Bally,et al.  Development and optimization of an injectable formulation of copper diethyldithiocarbamate, an active anticancer agent , 2017, International journal of nanomedicine.

[36]  Jianlin Shi,et al.  Enhanced Tumor-Specific Disulfiram Chemotherapy by In Situ Cu2+ Chelation-Initiated Nontoxicity-to-Toxicity Transition. , 2019, Journal of the American Chemical Society.

[37]  Li Zong,et al.  Integrating the drug, disulfiram into the vitamin E‐TPGS‐modified PEGylated nanostructured lipid carriers to synergize its repurposing for anti‐cancer therapy of solid tumors , 2019, International journal of pharmaceutics.

[38]  Kui Luo,et al.  A dithiocarbamate-based H2O2-responsive prodrug for combinational chemotherapy and oxidative stress amplification therapy. , 2019, Chemical communications.

[39]  Wei He,et al.  Drug‐delivering‐drug approach‐based codelivery of paclitaxel and disulfiram for treating multidrug‐resistant cancer , 2019, International journal of pharmaceutics.

[40]  D. Richardson,et al.  Unraveling the mysteries of serum albumin—more than just a serum protein , 2014, Front. Physiol..

[41]  Duane D. Miller,et al.  Synthesis, formulation and in vitro evaluation of a novel microtubule destabilizer, SMART-100. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[42]  Ji Young Kim,et al.  Disulfiram targets cancer stem-like properties and the HER2/Akt signaling pathway in HER2-positive breast cancer. , 2016, Cancer letters.

[43]  W. Geldenhuys,et al.  Disulfiram-based disulfides as narrow-spectrum antibacterial agents. , 2018, Bioorganic & medicinal chemistry letters.

[44]  Q. Dou,et al.  Repurposing Disulfiram as an Anti-Cancer Agent: Updated Review on Literature and Patents. , 2019, Recent patents on anti-cancer drug discovery.

[45]  Qin Xu,et al.  Intein-mediated site-specific synthesis of tumor-targeting protein delivery system: Turning PEG dilemma into prodrug-like feature. , 2017, Biomaterials.

[46]  Wei He,et al.  A Smart Paclitaxel-Disulfiram Nanococrystals for Efficient MDR Reversal and Enhanced Apoptosis , 2018, Pharmaceutical Research.

[47]  Y. Liu,et al.  Poly lactic-co-glycolic acid controlled delivery of disulfiram to target liver cancer stem-like cells , 2017, Nanomedicine : nanotechnology, biology, and medicine.

[48]  Shizhi Qian,et al.  Biomimetic metal-organic nanoparticles prepared with a 3D-printed microfluidic device as a novel formulation for disulfiram-based therapy against breast cancer. , 2020, Applied materials today.

[49]  Dual‐Targeting to Cancer Cells and M2 Macrophages via Biomimetic Delivery of Mannosylated Albumin Nanoparticles for Drug‐Resistant Cancer Therapy , 2017 .

[50]  Dongkai Wang,et al.  In vitro and in vivo evaluation of biotin-mediated PEGylated nanostructured lipid as carrier of disulfiram coupled with copper ion , 2019, Journal of Drug Delivery Science and Technology.

[51]  Jianhua Zhu,et al.  pH-triggered surface charge-switchable polymer micelles for the co-delivery of paclitaxel/disulfiram and overcoming multidrug resistance in cancer , 2017, International journal of nanomedicine.

[52]  Duane D. Miller,et al.  Micellar Delivery of Bicalutamide and Embelin for Treating Prostate Cancer , 2009, Pharmaceutical Research.

[53]  B. Johansson A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites , 1992, Acta psychiatrica Scandinavica. Supplementum.

[54]  Marilyn D. Saulsbury,et al.  Preparation and Characterization of Lipophilic Doxorubicin Pro-drug Micelles. , 2016, Journal of visualized experiments : JoVE.

[55]  M. Bally,et al.  PRCosomes: pretty reactive complexes formed in liposomes , 2016, Journal of drug targeting.

[56]  Q Ping Dou,et al.  Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. , 2006, Cancer research.

[57]  S. Britland,et al.  Liposome encapsulated Disulfiram inhibits NFκB pathway and targets breast cancer stem cells in vitro and in vivo , 2014, Oncotarget.

[58]  Rolf Larsson,et al.  Inhibition of proteasome activity, nuclear factor‐KB translocation and cell survival by the antialcoholism drug disulfiram , 2006 .

[59]  A. Armesilla,et al.  Disulfiram targets cancer stem-like cells and reverses resistance and cross-resistance in acquired paclitaxel-resistant triple-negative breast cancer cells , 2013, British Journal of Cancer.

[60]  K. Edwards,et al.  Nanoscale Reaction Vessels Designed for Synthesis of Copper-Drug Complexes Suitable for Preclinical Development , 2016, PloS one.

[61]  Weiguang Wang,et al.  Hot melt extruded and injection moulded disulfiram-loaded PLGA millirods for the treatment of glioblastoma multiforme via stereotactic injection. , 2015, International journal of pharmaceutics.

[62]  K. Srivenugopal,et al.  Brain- and brain tumor-penetrating disulfiram nanoparticles: Sequence of cytotoxic events and efficacy in human glioma cell lines and intracranial xenografts , 2017, Oncotarget.

[63]  D. George,et al.  Leveraging γ-Glutamyl Transferase To Direct Cytotoxicity of Copper Dithiocarbamates against Prostate Cancer Cells. , 2018, Angewandte Chemie.

[64]  X. Bian,et al.  Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells , 2012, British Journal of Cancer.

[65]  R. Mahato,et al.  Doxorubicin and lapatinib combination nanomedicine for treating resistant breast cancer. , 2014, Molecular pharmaceutics.

[66]  Shirui Mao,et al.  Smart pH-sensitive and temporal-controlled polymeric micelles for effective combination therapy of doxorubicin and disulfiram. , 2013, ACS nano.