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

ACS Appl Mater Interfaces. 2018 Dec 5;10(48):41118-41128. doi: 10.1021/acsami.8b14940. Epub 2018 Nov 16.

Abstract

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.

Keywords: copper diethyldithiocarbamate; disulfiram; drug delivery; drug resistance; nanoparticle; paraptosis; prostate cancer.

MeSH terms

  • Coordination Complexes* / chemistry
  • Coordination Complexes* / pharmacokinetics
  • Coordination Complexes* / pharmacology
  • Copper* / chemistry
  • Copper* / pharmacokinetics
  • Copper* / pharmacology
  • Disulfiram* / chemistry
  • Disulfiram* / pharmacokinetics
  • Disulfiram* / pharmacology
  • Ditiocarb* / chemistry
  • Ditiocarb* / pharmacokinetics
  • Ditiocarb* / pharmacology
  • Drug Resistance, Neoplasm / drug effects*
  • Humans
  • MCF-7 Cells
  • Male
  • Nanoparticles* / chemistry
  • Nanoparticles* / therapeutic use
  • Prostatic Neoplasms* / drug therapy
  • Prostatic Neoplasms* / metabolism
  • Prostatic Neoplasms* / pathology

Substances

  • Coordination Complexes
  • Copper
  • Ditiocarb
  • Disulfiram