Itraconazole for Topical Treatment of Skin Carcinogenesis: Efficacy Enhancement by Lipid Nanocapsule Formulations.

Itraconazole (ITC), an antifungal drug with anticancer activity, shows potential for oral treatment of skin cancer. There is clinical need for topical ITC for treating low-risk skin carcinogenesis. Our objective was to develop ITC nanoformulations with enhanced anticancer efficacy. Lipid nanocapsules (LNC), either unmodified (ITC/LNC) or modified with the amphiphiles miltefosine (ITC/MF-LNC) or the lipopeptide biosurfactant surfactin (ITC/SF-LNC) as bioactive additives were developed. LNC formulations showed high ITC entrapment efficiency (>98%), small diameter (42-45 nm) and sustained ITC release. Cytotoxicity studies using malignant SCC 9 cells and normal human fibroblasts (NHF) demonstrated significant enhancement of ITC anticancer activity and selectivity for cancer cells by the LNC formulations and a synergistic ITC-amphiphile interaction improving the combination performance. Treatment of intradermal tumor-bearing mice with the ITC nanoformulation gels compared with ITC and 5-FU gels achieved significant tumor growth inhibition that was remarkably enhanced by ITC/MF-LNC and ITC/SF-LNC as well as recovery of skin architecture. Molecularly, tumoral expression of Ki-67 and cytokeratin proliferative proteins was significantly suppressed by LNC formulations, the suppressive effect on cytokeratins was superior to that of 5-FU. These findings provide new evidence for effective topical treatment of low-risk skin carcinogenesis utilizing multiple approaches that involve drug repurposing, nanotechnology, and bioactive amphiphiles as formulation enhancing additives.