Quality-by-design-based microemulsion of disulfiram for repurposing in melanoma and breast cancer therapy

Abstract

Aim: The current study aims to develop and optimize microemulsions (ME) through Quality-by-Design (QbD) approach to improve the aqueous solubility and dissolution of poorly water-soluble drug disulfiram (DSF) for repurposing in melanoma and breast cancer therapy.

Materials & methods: The ME was formulated using Cinnamon oil & Tween® 80, statistically optimized using a D-optimal mixture design-based QbD approach to develop the best ME with low vesicular size (Zavg) and polydispersity index (PDI).

Results: The DSF-loaded optimized stable ME showed enhanced dissolution, in-vitro cytotoxicity and improved cellular uptake in B16F10 and MCF-7 cell lines compared with their unformulated free DSF.

Conclusion: Our investigations suggested the potential of the statistically designed DSF-loaded optimized ME for repurposing melanoma and breast cancer therapy.

Article Highlights

Formulation & development

The ME of the poorly water-soluble drug DSF was made with Cinnamon oil, Tween^® 80, and water. The selection of suitable oil and surfactant was made using a solubility study.

The influence of the ME composition on the extent of the monophasic isotropic region was explored with the use of pseudo-ternary phase diagrams through the water titration method.

Response surface analysis & optimization of microemulsion

Statistical analysis and optimization were carried out using the D-optimal mixture design-based QbD approach to obtain the optimized ME with low Z_avg and PDI.

Characterizations of microemulsion

The ME was found to have very low viscosity and was transparent, without any sign of precipitation or phase separation.

The RI and %T reflected the isotropic and transparency of the optimized ME.

The robustness to dilution and conductivity measurements represented the o/w type emulsion.

The DLS results displayed the globules with nanometric hydrodynamic size, and the ZP value reflected the existence of a negative charge on the surface of the globules.

The morphological analysis through HRTEM further showed the existence of spherical globules with nanometric size in accordance with DLS results.

The optimized ME reflected excellent accelerated and kinetic stability. The ATR-FTIR results demonstrated the retention of the important peaks of DSF in the ME, reflecting the compatibility of DSF with the formulation excipients.

The developed ME significantly enhanced (p < 0.05) the dissolution of poorly water-soluble drug DSF, which is ascribed to its nanometric globule size, improved effective surface area and solubility.

Anticancer activity evaluation

The optimized ME showed significantly (p < 0.05) enhanced cytotoxicity and cellular uptake against melanoma (B16F10) and breast cancer (MCF-7) cell lines, which is ascribed to the nano size, improved solubility and partitioning into the cellular region.

In addition, the pure DSF and optimized ME demonstrated no cytotoxicity to healthy noncancerous kidney cells (HEK293), reflecting its safety toward normal cells and selected cytotoxicity against cancerous cells.

Our research suggested the potential of the DSF-loaded optimized ME for repurposing melanoma and breast cancer therapy.

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Mohapatra, D., Senapati, P. C., Senapati, S., Pandey, V., Dubey, P. K., Singh, S., & Sahu, A. N. (2024). Quality-by-design-based microemulsion of disulfiram for repurposing in melanoma and breast cancer therapy. Therapeutic Delivery, 1–24. https://doi.org/10.1080/20415990.2024.2363136