Co-delivery of Dacarbazine and All-Trans Retinoic Acid (ATRA) Using Lipid Nanoformulations for Synergistic Antitumor Efficacy Against Malignant Melanoma

Abstract

Malignant melanoma is a highly aggressive skin cancer responsible for 80% of mortality, and the overall median survival in patients with metastatic melanoma is only 6-9 months. Combination treatment through the simultaneous administration of dual drugs in a single nanocarrier has been demonstrated to be elegant and effective in combatting cancer. Herein, we employ a combination therapy based on dacarbazine (DBZ), FDA approved drug for melanoma and all-trans retinoic acid (ATRA), promising anticancer agents loaded on lipid nanoformulations (RD-LNF) as a new treatment strategy for malignant melanoma. We have successfully encapsulated both the drugs in lipid nanoformulations and showed a controlled release of payload over time. We demonstrated that the simultaneous delivery of DBZ and ATRA could effectively reduce cell proliferation in a concentration-dependent manner. The combinational nanoparticles significantly reduced the colony formation ability of B16F10 melanoma cells. Flow cytometer analysis showed that RD-LNF induced a greater proportion of apoptosis cells with significant inhibition of cell cycle progression and cell migration. These results suggest the promising potential of RD-LNF in the treatment of malignant melanoma with high efficacy.

In Vitro Anticancer Effects of All-trans Retinoic Acid in Combination with Dacarbazine against CD117+ Melanoma Cells

“…They showed that the simultaneous delivery of ATRA and dacarbazine resulted in significant inhibition of colony formation and cell proliferation in B16F10 melanoma cells. Similar to our study, they showed that the combination of ATRA and dacarbazine inhibited the melanoma cells at the sub-G0 phase [24].…”

Retinoic Acid Inhibits Tumor-Associated Mesenchymal Stromal Cell Transformation in Melanoma

“…However, the application of ATRA in solid tumors remains to be explored. RA can inhibit tumor cell proliferation in melanoma ( Edward and MacKie, 1989 ; Zhang and Rosdahl, 2005 ; Li and Han, 2020 ) and promote immune surveillance in breast cancer, colorectal cancer, and melanoma by influencing the metabolism of MDSCs, upregulating genes related to immune response, and supporting the survival of tumor-specific CD8 + T cells ( Guo et al, 2012 ; Paroni et al, 2020 ; Sun et al, 2020 ). Conversely, RA treatment was also reported to benefits tumor progression in sarcoma and chronic lymphocytic leukemia (CLL) by promoting the pro-tumoral differentiation of intertumoral monocytes in sarcoma and increasing CD38 expression in CLL cells ( Chen et al, 2018 ; Devalaraja et al, 2020 ).…”

Novel N-Substituted Amino Acid Hydrazone-Isatin Derivatives: Synthesis, Antioxidant Activity, and Anticancer Activity in 2D and 3D Models In Vitro

“…The combination strategy is one of the possible solutions that can overcome the resistance of melanoma cells to conventional therapy. Li and Han [54] have shown that a combination of dacarbazine and all-trans retinoic acid, loaded in lipid nanoformulations, is able to reduce B16F10's colony formation ability, whereas dacarbazine alone shows a limited ability to inhibit colony formation. In several studies, the colony-forming effect of kinase inhibitors was assessed by clonogenic assay.…”