Dendrimer-Derived Mimics of Host Defense Peptides Selectively Disrupt Cancer Cell Membranes for Melanoma Therapy

Background: Melanoma is one of the most common malignancies, posing a significant health threat to patients, particularly in advanced stages due to its high aggressiveness. Chemotherapy agents with biocompatibility and low susceptibility to induce resistance are required for systematic management. Methods: Dendrimer-derived mimics (DMs) of host defense peptides (HDPs), which were constructed by a dendrimer core and optimized ratios of the hydrophobic arm, were used to treat A375 cells and HaCaT cells as the control. Live/dead staining, flow cytometry, and scanning electron microscopy (SEM) were conducted to analyze the anticancer mechanism. Mice with subcutaneous tumors were used to test the antitumor activity and toxicity in vivo. Results: DMs exhibited enhanced activity against A375 cells with remarkable selectivity, which mimics the action of natural HDPs and can cause damage to cell membranes. DMs can effectively inhibit solid tumor growth with minimal systemic toxicity and no adverse effects on healthy tissues. Conclusion: All the findings highlight DMs as promising anticancer candidates with significant potential for systemic melanoma therapy.