Modified monobenzone supercarriers as targeted therapies for metastatic melanoma.

Abstract

e21530 Background: Melanoma is the deadliest form of skin cancer, with a five-year survival rate of ~35% once metastasis occurs. Despite advances in targeted and immunotherapeutic approaches, metastatic melanoma remains difficult to fully eradicate. Targeting the melanogenic pathway offers a complementary and selective strategy, as melanin biosynthesis occurs exclusively in melanocytes and melanoma cells via oxidation of L-tyrosine by tyrosinase and TRP-1 within melanosomes. Monobenzyl ether of hydroquinone (MBEH) is a phenolic compound used as a topical depigmenting agent that causes melanocyte destruction via tyrosinase-mediated toxic quinone generation inducing necrotic cell death and subsequent immune activation. MBEH has demonstrated anti-tumor effects in vivo when applied topically to tumors, yet the drug is not suited for systemic application to attack metastatic tumors. Methods: To reduce MBEH toxicity and improve solubility and selectivity, we developed a modified derivative formulated into ~100–150 nm liposomal nanoparticles (TOnc-LNP). Melanoma cells were treated in vitro with TOnc-LNP for 24 hours, and viability was assessed by IncuCyte imaging and LDH assays. In vivo , NSG and C57BL/6 mice received systemic TOnc-LNP every three days for two weeks, followed by lung, serum, and spleen collection for tumor burden and immunophenotypic analyses. Results: Treatment with TOnc-LNP resulted in pronounced, concentration-dependent killing of B16-F10 murine cutaneous melanoma cells and primary human uveal melanoma cells in vitro, reducing viable cell populations by more than 90% within 24 hours. In contrast, unencapsulated MBEH exerted only growth-inhibitory effects. Time-resolved live-cell imaging revealed extensive nanoparticle-induced membrane disruption, culminating in widespread cell death and lysis. In a murine pulmonary metastasis model using immunodeficient mice, systemic administration of TOnc-LNPs markedly reduced metastatic burden, with treated animals exhibiting over 50% fewer grossly visible lung metastases and more than a 40% reduction in gp100-positive tumor coverage relative to control mice, indicating substantial decreases in both metastatic nodule number and tumor-occupied lung area. Consistent with these findings, in an immunocompetent murine pulmonary metastasis model, TOnc-LNP treatment resulted in a greater than 70% reduction in metastatic lung nodules compared with controls. Conclusions: These results demonstrate that nanoparticle-mediated delivery significantly enhances the therapeutic efficacy of our lead candidate, achieving potent suppression of metastatic melanoma. Collectively, these findings support the further development of TOnc-LNP as a promising systemic strategy for melanoma therapy, with potential translational relevance for improving clinical outcomes in patients with metastatic disease.