Synthesis and in vitro antitumor activity of galactosamine–docetaxel conjugates

Abstract

AbstractDocetaxel (DTX) is a semi‐synthetic analogue of paclitaxel which has attracted extensive attention in the treatment of cancer. However, the current clinically used DTX formulations display low tumor targeting ability, leading to unsatisfactory therapeutic outcomes with adverse effects, which poses significant challenges to the clinical application. In this study, three galactosamine (Gal) and docetaxel conjugates with different linkers were synthesized, namely DTX‐(suc‐Gal)2, DTX‐(DTDPA‐Gal)2, and DTX‐(DSeDPA‐Gal)2. These three conjugates were characterized by 1H NMR, FT‐IR and HRMS. The in vitro drug release study shows that DTX‐(DTDPA‐Gal)2 and DTX‐(DSeDPA‐Gal)2 exhibit glutathione (GSH)‐responsive drug release and DTX‐(DSeDPA‐Gal)2 displays higher GSH‐responsiveness. The in vitro antitumor activity study shows that DTX‐(DTDPA‐Gal)2 and DTX‐(DSeDPA‐Gal)2 exhibit enhanced cytotoxicity, cell apoptosis rate and G2/M phase arrest against HepG2 cells as compared to DTX‐(suc‐Gal)2, DTX‐(DSeDPA‐Gal)2 displays the highest cytotoxicity, cell apoptosis rate and G2/M phase arrest among these three conjugates. In addition, DTX‐(DSeDPA‐Gal)2 exhibits higher selectivity to HepG2 cells as compared to free DTX. The DTX‐(DSeDPA‐Gal)2 developed in this study has been proven to be an effective DTX conjugate for selective killing hepatoma cells.