DOI: 10.6084/m9.figshare.27050794
title: Quality-by-design-based microemulsion of disulfiram for repurposing in melanoma and breast cancer therapy

description: <b>Aim:</b> 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. <b>Materials & methods:</b> The ME was formulated using Cinnamon oil & Tween<sup>®</sup> 80, statistically optimized using a D-optimal mixture design-based QbD approach to develop the best ME with low vesicular size (Z<sub>avg</sub>) and polydispersity index (PDI). <b>Results:</b> The DSF-loaded optimized stable ME showed enhanced dissolution, <i>in-vitro</i> cytotoxicity and improved cellular uptake in B16F10 and MCF-7 cell lines compared with their unformulated free DSF. <b>Conclusion:</b> Our investigations suggested the potential of the statistically designed DSF-loaded optimized ME for repurposing melanoma and breast cancer therapy. Identifying new medicinal uses of an existing marketed drug can save both money and time in the process of drug development. From many of the recently reported literature, disulfiram (a drug used for alcoholism) has shown its activity against various cancers, including breast and skin cancer. However, it possesses poor water solubility and absorption, leading to low medicinal activity. The current study aims to develop a novel microemulsion dosage form through a statistical design approach to enhance the solubility, dissolution and anticancer activity for repurposing in melanoma and breast cancer treatment. The novel microemulsion was prepared, statistically analyzed and optimized. The optimized microemulsion was found to be stable and showed improved medicinal activity against breast and skin cancer compared with the pure drug. Our research showed the potential of the developed microemulsion of the disulfiram for its new therapeutic use in skin cancer and breast cancer. Quality-by-Design (QbD)-based development, characterizations and anticancer activity evaluation of disulfiram loaded microemulsion for repurposing in melanoma and breast cancer therapy. The ME of the poorly water-soluble drug DSF was made with Cinnamon oil, Tween<sup>®</sup> 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. Statistical analysis and optimization were carried out using the D-optimal mixture design-based QbD approach to obtain the optimized ME with low Z<sub>avg</sub> and PDI. 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 (<i>p</i> &lt; 0.05) the dissolution of poorly water-soluble drug DSF, which is ascribed to its nanometric globule size, improved effective surface area and solubility. The optimized ME showed significantly (<i>p</i> &lt; 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.