Supramolecular Gelators Derived from Fmoc-Amino Acid Conjugates of Mafenide for Treating Melanoma: Toward Developing Vehicle-Free Drug Delivery

This study presents the development of supramolecular topical gels derived from Fmoc-amino acid conjugates of mafenide, a sulfonamide-containing drug, for plausible vehicle-free drug delivery (VFDD) against melanoma. Four conjugatesFmocV-M, FmocL-M, FmocI-M, and FmocF-Mwere synthesized to balance hydrophobicity and hydrophilicity, promoting gelation via directional hydrogen bonding. These conjugates formed gels in DMSO/water and organic solvents such as methyl salicylate. Biological evaluations using MTT and scratch assays on B16–F10 melanoma cells identified FmocL-M as the most effective, with an IC50 of 25 μg/mL, reducing cell migration speed to 2.8 μm/h (9-fold slower than control’s 25.3 μm/h). FmocL-M induced apoptosis, evidenced by increased early (32.9 vs 8.5% control) and late (8.8 vs 1.4% control) apoptotic cell populations, and caused mitochondrial membrane depolarization (50% green fluorescence vs 25.7% control in flow cytometry and CLSM under various staining conditions). It also disrupted 3D B16–F10 spheroids within 10 days. Rheological studies confirmed rheoreversibility and moldability, which are ideal for topical application. Although the results indicated a plausible VFDD application using the topical gel of FmocL-M, which eliminates the need for a gel matrix, bypassing challenges like cytotoxicity and drug release, it remains to be evaluated the effect of gel itself in treating melanoma.