. 2021 Sep 17;8:741316. doi: 10.3389/fmolb.2021.741316

TABLE 3.

Formulation strategies used for delivery of disulfiram for cancer treatment.

Formulation	Components and technique used	Cancer indication	Cell lines/models	Study outcome	Reference
Polymers
DSF encapsulated mixed nanoparticles	mPEG5000-PCL5000, PCL5000, MCT and DSF – High pressure homogenization method	Mouse hepatocellular adenocarcinoma	H22 xenograft tumor model	• Increased Drug loading and stability	Zhuo et al. (2018)
DSF encapsulated mixed nanoparticles		Mouse hepatocellular adenocarcinoma	H22 xenograft tumor model	• Higher degree of tumor necrosis and tumor inhibition in animal models	Zhuo et al. (2018)
DSF encapsulated PLGA nanoparticles	PVA, PLGA, DSF Nanoprecipitation method	Breast Cancer	MCF7 cell lines	• Significantly enhanced stability when compared to free drug in serum solution (10% FBS)	Fasehee et al. (2017)
DSF encapsulated PLGA nanoparticles	PVA, PLGA, DSF Nanoprecipitation method	Breast Cancer	MCF7 cell lines	• Enhanced cytotoxicity compared to free drug	Fasehee et al. (2017)
Folate receptor targeted PLGA-PEG nanoparticles encapsulated with DSF	PLGA, (PEG)-bis amine, PVA, Folate, DSF Nanoprecipitation method	Breast cancer	MCF7 and 4T1 cell lines, BALB/c mice models	• Showed a higher degree of cytotoxicity compared to free drug and non-folate formulations	Fasehee et al. (2016)
		Breast cancer	MCF7 and 4T1 cell lines, BALB/c mice models	• Significant decrease of tumor size in mouse models	Fasehee et al. (2016)
Combination of polyethylene glycol-cisplatin complex and DSF encapsulated nanoparcticles	mPEG-PLGA/PCL, PGA, DSF, Cisplatin	Lung cancer	A549 and A549DDP cell lines. BALB/c mouse model	• synergistically enhanced the cytotoxic effect of cisplatin in vitro	Song et al. (2016)
	mPEG-PLGA/PCL, PGA, DSF, Cisplatin	Lung cancer	A549 and A549DDP cell lines. BALB/c mouse model	• The combination effectively inhibited the tumor growth and displayed excellent safety in mouse models	Song et al. (2016)
PLGA encapsulated DSF Nanoparticles	PVA, PLGA, DSF. emulsion-solvent evaporation method	Lung cancer	A549 cell lines	• enhanced half-life in serum	Najlah et al. (2017)
PLGA encapsulated DSF Nanoparticles	PVA, PLGA, DSF. emulsion-solvent evaporation method	Lung cancer	A549 cell lines	• Higher cytotoxicity compared to free DSF in vitro	Najlah et al. (2017)
Brain tumor-penetrating disulfiram nanoparticles	mPEG, PLGA, DSF. emulsion-solvent evaporation method	Brain cancer	T98G and DAOY cell lines and Female CD-1 mice, female athymic nude (nu/nu) mice, and the triple immune-deficient NCG mice models	• Enhanced delivery of DSF to the brain tumor site and increased stability	Madala et al. (2018)
Brain tumor-penetrating disulfiram nanoparticles	mPEG, PLGA, DSF. emulsion-solvent evaporation method	Brain cancer		• Potent cytotoxic and anti-clonogenic activities	Madala et al. (2018)
Lipid based nanoparticles
Liposome encapsulated formulation of DSF	PC, CHOL, PG Thin film hydration to form multilamellar vesicles subject to size reduction -100–300 nm	Breast Cancer	MCF7, MDA-MB-231, T47D S180 mouse sarcoma models - BALB/c mice. MDA breast cancer models -CD1 Nu/Nu mice	• Selective targeting of cancer cells, induction of apoptosis	(EP2648709B1, 2011; Liu et al., 2014)
				• Enhanced efficacy of conventional anticancer drugs
				• Target cancer stem cells- reduction in CSC markers and clonogenicity
				• Protection of thiol group in vivo, react with Cu to exert anticancer activity in mouse models of sarcoma and breast cancer
Co-encapsulated liposomal formulation of Doxorubicin and DSF	DSPC, CHOL, mPEG2000-DSPE. Thin film hydration method	Breast cancer	MCF7, MDA-MB-231	• Decrease in Pgp expression and reversal of Pgp mediated drug resistance	Rolle et al. (2020)
	DSPC, CHOL, mPEG2000-DSPE. Thin film hydration method	Breast cancer	MCF7, MDA-MB-231	• Enhanced efficacy of DOX	Rolle et al. (2020)
DSF entrapped vitamin E-TPGS-modified PEGylated nanostructured lipid carriers	Lecithin, Precirol^® ATO, Labrafac Lipophile WL134, DSF. Emulsification ultrasonication method	Breast cancer	MCF7, 4T1, BALB/C mouse models	• Enhanced long term stability	Banerjee et al. (2019)
				• Higher toxicity compared to free drug in vitro
				• Significant increase in tumor inhibition with no toxicity in vivo
PEGylated Liposome Encapsulating DSF	HSPC, DPPC, CHOL, DSPE-PEG2000, DSF. Ethanol-based proliposome technology	Colorectal cancer	H630-WT and H630-R10	• Significantly improved serum stability	Najlah et al. (2019)
PEGylated Liposome Encapsulating DSF		Colorectal cancer	H630-WT and H630-R10	• Cytotoxic to colorectal cancer cell lines in presence of copper in vitro	Najlah et al. (2019)
Micelle based nanoparticles
pH triggered polymeric micelles for the co-delivery of paclitaxel/disulfiram	Methoxy PEG-b-PLL, DMA, PTX and DSF. Nanoprecipitation method	Breast Cancer	MCF7 and MAF7/ADR	• Enhanced internalization of nanoparticles into tumor cells	Huo et al. (2017)
		Breast Cancer	MCF7 and MAF7/ADR	• Inhibition of Pgp transport function	Huo et al. (2017)
DSF encapsulated micelles	mPEG5k-b-PLGA2k/PCL3.4 k/MCT, DSF solvent diffusion method	Liver cancer	H22 xenograft mouse model	• Increased stability and bioavailability in plasma	Miao et al. (2018)
DSF encapsulated micelles	mPEG5k-b-PLGA2k/PCL3.4 k/MCT, DSF solvent diffusion method	Liver cancer	H22 xenograft mouse model	• Enhanced tumor inhibition in mouse model	Miao et al. (2018)
DSF loaded redox-sensitive shell crosslinked micelles	SMA micelles were crosslinked by adding cystamine dihydrochloride and sodium bicarbonate	Breast cancer	4T1	• Significant tumour inhibition	Duan et al. (2014)
DSF loaded redox-sensitive shell crosslinked micelles		Breast cancer	4T1	• Increased Stability	Duan et al. (2014)
Other Nanoparticle delivery systems
DSF- loaded magnetic mesoporous silica nanoparticles	PEI-FA, Fe3O4@mSiO2 Np’s, DSF Thermal decomposition and Sol gel reaction method	Breast Cancer	MCF7	• Exhibited selective toxicity to tumor cells	Solak et al. (2021)
DSF- loaded magnetic mesoporous silica nanoparticles		Breast Cancer	MCF7	• Highly cytotoxic in the presence of copper	Solak et al. (2021)
Cu(DDC)2 and regorafenib encapsulated BSA nanoparticles	Denaturing of BSA by urea to induce nanoparticle formulation	Glioma	H22	• Improved stability and increased efficacy against resistant xenografted tumors	Zhao et al. (2018)
DSF loaded gold nanorods	Seed solution preparation and surface PEG modification	Breast Cancer	MCF-7	• Improved circulation time, increased tumor accumulation, tumor shrinkage in vivo	Xu et al. (2020a)
Cyclodextrin Cu(DDC)2	SBE-CD and HP-CD were the cyclodextrins used	Breast cancer	MDA-MB231	• Stability for 28 days, retained anti-cancer properties of Cu(DDC)2	Said Suliman et al. (2021)