Abstract
PURPOSE: Melanoma, which is initiated from melanocytes, is the most fatal type of skin cancer. Melanoma-initiating cells significantly contribute to the initiation, metastasis, and recurrence of melanoma, and CD20 is a marker of melanoma-initiating cells. All-trans retinoic acid (ATRA) has been demonstrated to induce differentiation, inhibit proliferation, and promote the apoptosis of cancer cells and cancer-initiating cells (CICs). However, there has been no report on ATRA activity against melanoma-initiating cells. In this study, we examined the activity of ATRA against melanoma-initiating cells and developed ATRA-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles, which were conjugated with a CD20 antibody (ATRA-PNP-CD20) for targeted delivery of ATRA to CD20(+) melanoma-initiating cells. MATERIALS AND METHODS: The effects of ATRA and ATRA-PNP-CD20 against melanoma-initiating cells were investigated using a cytotoxicity assay, tumorsphere formation assay, and flow cytometry. RESULTS: ATRA-PNP-CD20 had a size of 126.9 nm and a negative zeta potential. The drug-loading capacity of ATRA-PNP-CD20 was 8.7%, and ATRA-PNP-CD20 displayed a sustained release of ATRA for 144 hours. The results showed that ATRA-PNP-CD20 could effectively and specifically deliver ATRA to CD20(+) melanoma-initiating cells, achieving superior inhibitory effects against CD20(+) melanoma-initiating cells compared with those of free ATRA and nontargeted nanoparticles. To the best of our knowledge, we report for the first time a potent activity of ATRA against CD20(+) melanoma-initiating cells, targeted drug delivery of ATRA via nanoparticles to melanoma-initiating cells, and the achievement of a superior inhibitory effect against melanoma-initiating cells by using a CD20 antibody. CONCLUSION: ATRA-PNP-CD20 represents a promising tool for eliminating melanoma-initiating cells and shows a potential for the therapy of melanoma.