4-S-Cysteaminylphenol-loaded magnetite cationic liposomes for combination therapy of hyperthermia with chemotherapy against malignant melanoma.

Tyrosine analogs are good candidates for developing melanoma chemotherapies because melanogenesis is inherently toxic and expressed uniquely in melanocytic cells. The sulfur homolog of tyrosine, 4-S-cysteaminylphenol (4-S-CAP), was shown to be a substrate of melanoma tyrosinase and can cause selective cytotoxicity of melanocytes and melanoma cells. Previously, in order to improve the adsorption of magnetite nanoparticles to target cell surfaces, and generate heat in an alternating magnetic field (AMF) for cancer hyperthermia, we produced hyperthermia using magnetite cationic liposomes (MCL) that have a positive charge at the liposomal surface. In the present study, we constructed 4-S-CAP-loaded MCL (4-S-CAP/MCL), which act as a novel modality, combining melanoma-specific chemotherapy by 4-S-CAP with intracellular hyperthermia mediated by MCL. The 4-S-CAP/MCL exerted 4-S-CAP-mediated anticancer effects on B16 melanoma cells in vitro and in vivo. Moreover, after intratumoral injection of 4-S-CAP/MCL in vivo, the melanoma nodules were heated to 45 degrees C under an AMF. Significantly higher therapeutic effects were observed in mice treated with the combination therapy mediated by 4-S-CAP/MCL plus AMF irradiation compared with mice treated with 4-S-CAP/MCL alone (without AMF) or mice treated with hyperthermia alone (MCL + AMF irradiation). These results suggest that this novel therapeutic tool is applicable to the treatment of malignant melanoma.