Anticancer effectiveness of polymeric drug nanocarriers on colorectal cancer cells

摘要

Doxifluridine, a prodrug of 5-fluorouracil (5-FU), was used as the initiator directly in ring-opening polymerization of ε-caprolactone to form hydrophobic doxifluridine-poly(ε-caprolactone) (doxifluridine-PCL) that was further grafted with hydrophilic chitosan to synthsize amphiphilic doxifluridine-PCL-chitosan copolymer. This amphiphilic copolymer was self-assembled into micellar nanoparticles. After HT-29 colon cancer cells were treated with the polymeric drug nanocarrier, prodrug doxifluridine was converted into 5-fluorouracil by endogenous thymidine phosphorylase (TP) and thereby resulting in cell death. Chemotherapy drug 7-ethyl-10-hydroxy-camptothecin (SN-38), an active water insoluble metabolite of irinoetcan hydrochloride, was further encapsulated in the hydrophobic core of the polymeric drug nanocarriers and treated with HT-29 cells. The anticancer effectiveness of the polymeric drug nanocarriers was extensively enhanced by synergistic anticancer activity of slowly released cytotoxic drugs (i.e., 5-FU and SN-38). HT-29 cells transfected with TP-encoding plasmids were selected by antibiotic G418 to obtain HT-29/TP cells. These cells overexpressed with TP enzyme were challenged with doxifluridine-PCL-chitosan polymeric prodrug micelles. The viability of HT-29/TP cells were dropped significantly after 72-h treatment.