Nanomedicine-based disulfiram and metal ion co-delivery strategies for cancer treatment

Abstract

Disulfiram (DSF) is a second-line drug for the clinical treatment of alcoholism and has long been proven to be safe for use in clinical practice. In recent years, researchers have discovered the cancer-killing activity of DSF, which is highly dependent on the presence of metal ions, particularly copper ions. Additionally, free DSF is highly unstable and easily degraded within few minutes in blood circulation. Therefore, an ideal DSF formulation should facilitate the co-delivery of metal ions and safeguard the DSF throughout its biological journey before reaching the targeted site. Extensive research have proved that nanotechnology based formulations can effectively realize this goal by strategic encapsulation therapeutic agents within nanoparticle. To be more specific, this is accomplished through precise delivery, coordinated release of metal ions at the tumor site, thereby amplifying its cytotoxic potential. Beyond traditional co-loading techniques, innovative approaches such as DSF-metal complex and metal nanomaterials, have also demonstrated promising results at the animal model stage. This review aims to elucidate the anticancer mechanism associated with DSF and its reliance on metal ions, as well as to provide a comprehensive overview of recent advances in the arena of nanomedicine based co-delivery strategies for DSF and metal ion in the context of cancer therapy.

Keywords: Co-delivery; Disulfiram; Metal ion; Nanomedicine; cancer treatment.

Graphical abstract

Fig. 1

Chemical structure of Disulfiram (DSF), S-methyl-N, N-diethylthiocarbamate (DDC), S-methyl-N, N-diethylthiocarbamate (DTC), and their related metal complexes. Metal is abbreviated as Me.

Fig. 2

The anti-cancer mechanism of DSF in the presence of metal ions. DSF synergizes with metal ions in different ways to produce cytotoxic effects and reduce cancer progression.

Fig. 3

An example of co-administration of DSF and metal ions to reverse the resistance of ALDH positive cells to cisplatin. A) The ability of ovarian cancer cells to form spheroids when exposed to DSF (0.1 μM) and Cu²⁺ (0.1 μM). B) Analysis of ALDH activity in ovarian cancer cells exposed to DSF (10 μM) and Cu²⁺ (1 μM). Cells treated with diethylaminobenzaldehyde (DEAB), a specific ALDH inhibitor, were used as controls. C) Cell viability of ovarian cancer cell lines treated with different concentrations of DSF and cisplatin for 72 h. Reproduced from ref. (Guo et al., 2019) with permission from Elsevier, copyright 2019.

Fig. 4

The co-administration of DSF and copper ions enhances ROS generation and cytotoxicity by activating MAPK signaling pathway. A) The effect of metal ions (copper ions) on gene expression levels in human undifferentiated gastric cancer (HGC-27) cells. B) The mRNA expression levels of eight MAPK related genes (FOS, JUN, GADD45A, CACANA1, DUSP2, HSPA1A, HSPA6, DDIT3) when DSF was co delivered with Cu²⁺ (0.2 μM). C) flow cytometric results of ROS generation in HGC-27 cells and human gastric adenocarcinoma (SGC-7901) cells after drug treatment. Drug dose, Cu²⁺ concentration: 0.2 μM, DSF concentration: 0.24 μM in HGC-27 cells, 0.30 μM in SGC7901 cells. N-acetylcysteine (NAC) was used as a ROS scavenger. D) Expression level of K48 ubiquitination protein in HGC-27 and SGC-7901 cells exposed to various concentrations of Cu²⁺ (0.2 μM) and DSF (0.24 μM in HGC-27 cells, 0.30 μM in SGC7901 cells) for 24 h. Reproduced from ref. (Liu et al., 2022b) with permission from Talor & Francis Group, copyright 2022.

Fig. 5

Nanomedicine-based strategies for co-delivering disulfiram (DSF) and metal ions in cancer treatment. The physicochemical properties and delivery efficiency of drugs can be optimized by effectively incorporating DSF and metal ions into nanoparticles using various strategies. These strategies can be categorized into three groups based on different formulation methods, physical encapsulation of metal ion compounds, formation of metal chelates, and utilization of metal ion-based nanomaterials.

Fig. 6

An example of polymer-modified nanoparticles for enhanced drug delivery efficiency. A) HA PEI nanoparticles (NP-HPD), loaded with DSF and copper ions, were synthesized by conjugating HA and PET through amide bonds. B) The release profiles of DSF and copper ions over a period of 72 h at temperatures of 4 °C, 25 °C, and 37 °C. C) The underlying mechanism involves the targeting of tumor sites via CD44 receptor binding facilitated by HA on the nanoparticles, leading to induction of tumor cell death. D) Cell viability.

Fig. 7

An example of utilizing metal chelation complex for cancer treatment. A) Schematic graph of this design, including the self-assembly of CuET nanoparticles via strong coordination between DTC and Cu2+, as well as the mechanism by which these nanoparticles downregulate the p97-NPL4 pathway and promote cell apoptosis in vivo. B) In vitro drug release curves of CuET@HA NPs at pH 7.4, 5.5, and pH 5.5 with GSH addition. C) Cellular activity assays on two types of cancer cells using different concentrations of DTC, CuET NPs, and CuET@HA. D) Immunoblotting analysis of ubiquitinated proteins under different concentrations of CuET. Reproduced from ref. (Peng et al., 2020) with permission from ACS Publications, copyright 2020.

Fig. 8

An example of example of utilizing SMILE technology for the preparation of DSF metabolite-metal chelation complex (CuET) nanoparticles and their application in cancer treatment via the pyroptosis pathway. A) The preparation of CuET nanoparticles using SMILE technology. B) The impact of stabilizer selection on the formation of nanoparticle systems. C) Drug concentration and drug loading efficiency in nanoparticles prepared using SMILE technology. D) The morphology of analysis of DU145-TXR cells treated with CuET nanoparticles, paclitaxel, and blank PEG-PLA for 24 h. Reproduced from ref. (Chen et al., 2018a) with permission from ACS Publications, copyright 2018.

Fig. 9

An example of the preparation of encapsulated DQ (a DSF prodrug) using nanoscale copper ion MOF to induce ROS generation through a Fenton-like reaction. A) The steps involved in preparing MOF nanoparticles and their mechanism of action, disrupting redox balance in tumor tissue for anti-cancer effects.B) The pH curve of the MPDG system (50 or 100 μg/mL) over time under high glucose concentration conditions. C) The concentration curve of H₂O₂ as the reaction progresses in the system. D) UV–Vis absorption spectra of GSH + DTNB and MP + GSH + DTNB. E) Time-dependent absorption profile of methyl bromide after treatment with methyl bromide and hydrogen peroxide. F) Degradation effect of Glu, MPG + GSH, and MPG + GSH + Glu treatments on MB demonstrated by UV–Vis absorption measurements. G) UV–Vis absorption spectra analysis of MPDG after 6-h treatment with hydrogen peroxide or glutamic acid. Reproduced from ref. (Pan et al., 2022) with permission from Elsevier, copyright 2022.