Microtubule binding agents such as
paclitaxel and
vincristine have activity in metastatic
melanoma. However, even responsive
tumors develop resistance, highlighting the need to investigate new
drug molecules. Here, we showed that a new compound, CH-2-102, developed by our group, has high anti-
tumor efficacy in human and murine
melanoma cells. We confirmed that CH-2-102 robustly suppresses the microtubule polymerization process by directly interacting with the
colchicine binding site. Our results unveil that CH-2-102 suppresses microtubule polymerization and subsequently induces G2 phase cell arrest as one of the possible mechanisms. Notably, CH-2-102 maintains its efficacy even in the
paclitaxel resistance
melanoma cells due to different binding sites and a non-Pgp substrate. We developed a pH-responsive
drug-
polymer Schiff bases linker for high
drug loading into nanoparticles (NPs). Our CH-2-102 conjugated NPs induced
tumor regression more effectively than Abraxane® (
Nab-paclitaxel, N-PTX), free
drug, and non-sensitive NPs in B16-F10 cell-derived lung
metastasis mouse model. Furthermore, our results suggest that the formulation has a high impact on the in vivo efficacy of the
drug and warrants further investigation in other
cancers, particularly
taxane resistant. In conclusion, the microtubule polymerization inhibitor CH-2-102 conjugated pH-responsive NPs induce
tumor regression in lung
metastasis melanoma mice, suggesting it may be an effective strategy for treating metastatic
melanoma.