Next-generation topical antifungal therapy: Biocompatible voriconazole nanostructured lipid carriers with enhanced skin penetration for cutaneous candidiasis

Fungal infections caused by Candida albicans represent a growing global health concern. The increasing resistance to conventional antifungals and limitations of current topical formulations highlights the urgent need for more effective and targeted therapies. The main objectives of this work were to develop and evaluate voriconazole-loaded nanostructured lipid carriers (VCZ-NLCs) for treating cutaneous candidiasis. In this sense, four formulations (A-D) were prepared by the high shear homogenization and ultrasonication technique, differing mainly in polysorbate 80 concentration, phospholipid type and cholesterol presence. All the obtained VCZ-NLCs were spherical, small (< 150 nm), relatively homogeneous (polydispersity indexes: 0.22-0.57), neutral or slightly negative charged and showed good entrapment efficiencies (> 70 %). The Peppas-Shalin model exhibited the best fit to the release profiles, suggestive of a predominantly non-Fickian behavior. Formulation A, with the highest concentration of polysorbate 80 and cholesterol, gave rise to the most stable particles with the smallest mean diameter and polydispersity index values, and the highest entrapment efficiency, but exhibited a weak cytotoxicity and lower skin penetration than the other formulations (A: 0.94 % accumulated in the receptor compartment vs. B: 2.28 %, C: 2.25 % and D: 1.37 %). In contrast, formulations C and D, lacking cholesterol and with reduced concentration of polysorbate 80, were more biocompatible and showed deeper skin penetration, with 50 % of VCZ accumulated in 1 g of skin (epidermis and dermis). Antifungal susceptibility tests of C. albicans to VCZ resulted in an MIC 50 value between 15 and 30 ng/mL. No significant differences were observed among formulations in antifungal activity. Overall, our findings suggest that VCZ-NLCs represent a promising strategy for the topical treatment of more invasive cutaneous candidiasis, with formulations C and D showing the greatest potential.