Solubility prediction and cytotoxicity of lipidic microemulsion: HSPiP modeling and synergism with ciclopirox olamine

Cutaneous cancer is a constantly progressive health challenge as life-threatening in men and women around the world. This study addressed repurposed ciclopirox olamine (COA) through the utilization of different essential oils limonene (LIM), eugenol (EU), and olive oil (OLO) as natural lipids possessing innate anticancer potential. HSPiP software provided preliminary screening of oils and solvents based on the theoretical solubility of COA. Placebo microemulsions (ME1-ME3) were prepared after optimizing S_mix at varied ratios (surfactant to co-surfactant ratio) and evaluated for size, zeta potential, and polydispersity index (PDI). EU, LIM, and OLO (as microemulsions) were used to assess anticancer potential against A431, A375, and B16-F10 cell lines. Moreover, HSF (human fibroblast cells) was used to assess the safety of these excipients at the same concentrations. It was required to carry out concentration-dependent cytotoxic potential of EU and LIM against A431 and B16-F10 as compared to COA. Finally, an apoptosis study was conducted to understand the mechanistic perspective of EU and LIM against A431 and B16-F10. Results showed an excellent correlation (r² = 0.97) of the predicted theoretical solubility of COA in the explored excipients to the experimental solubility data. UV scanning of the COA-solubilized oils negated any chemical interactions. ME1-ME3 showed tween-80 (10.9-21.6%) dependent size reduction (510-339 nm) and PDI values (0.28-0.31). In the cytotoxicity study, EU, LIM, and OLO elicited concentration-dependent cellular killing. LIM was found to be relatively sensitive to A431 and B16-F10 compared to EU. Notably, LIM resulted in dramatically aggressive induced early and late apoptosis in both cell lines at the explored IC₅₀. Thus, the topical nanoformulations of COA containing anticancer essential oils can offer a promising approach for treating cutaneous melanoma.