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.