Co-delivery of methotrexate and curcumin with mPEG-PCL polymeric nanoparticles and evaluation of toxicity effect on MCF7 breast cancer cell line

Abstract

Therapeutic strategies used to treat cancer are focused on cytotoxic drugs as the main form of chemotherapy. Recently nanocarrier-based chemotherapy has been widely used to treat cancer. Drugs covalently attached to a polymer chain, known as prodrugs, can significantly enhance drug incorporation efficiency. This study aimed to synthesis a biodegradable mPEG-PCL copolymers for effective and targeted drug delivery of the anticancer compounds curcumin and methotrexate and to investigate their physicochemical properties and effects on breast cancer cells.In this study, mPEG-PCL copolymer was synthesized by polymerization of ὲ-Caprolactone dehydrated monomer in the presence of dry methoxy polyethylene glycol as the initiator and Sn(Oct)2 as catalyst. The mPEG-PCL copolymers were synthesized and their structure was evaluated using Fourier Transform Infrared Spectroscopy (FTIR). Then, methotrexate was conjugated to a copolymer. The methotrexate conjugated mPEG–PCL(MTX–mPEG-PCL) was self-assembled into micelles in the presence of curcumin by nano-precipitation method and the drug loading was assessed. Finally, the cytotoxicity of methotrexate, curcumin and conjugated nanoparticles with methotrexate and curcumin were investigated through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on Michigan Cancer Foundation-7 (MCF-7) cancer cell lines. The size of mPEG-PCL-MTX and mPEG-PCL-MTX-CUR nanoparticles were evaluated by zeta sizer with an average size of 51.89 ± 0.46 nm (PDI = 0.127), and 88.21 ± 0.31 nm (PDI = 0.344), respectively. The zeta potential of nanoparticles was −4.22 mV. FTIR studies showed methotrexate was conjugated to the copolymer. The amount of drug released in nanoparticles at pH = 5.5 was higher than pH = 7.4. By increasing the drug concentration in the drug-carrying nanosystem, cell survival was further reduced. Among the treatment groups, mPEG-PCL-MTX-CUR group demonstrated the greatest impact, while, the MTX group showed the least impact on cancer cell mortality. These findings suggest that micelles conjugated with MTX and loading CUR appear to be promising systems for achieving Enhanced Permeability and Retention (EPR) effect, and pH sensitivity, which could improve the release and accumulation of drugs at tumor sites.