Combination and Co-delivery of Methotrexate and Curcumin: Preparation and In Vitro Cytotoxic Investigation on Glioma Cells

Abstract

Nanoformulations for co-delivery of multiple therapeutics and combinational therapies are expected to provide improved pharmacokinetics, reduced drug toxicities, and avert drug resistance. Methotrexate (MTX) and curcumin (CUR) were chosen as model drugs for this study primarily due to their anticancer activities in different phases of the cell cycle. The nanoprecipitation technique was used to prepare CUR-, MTX-, and CUR/MTX-co-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles. Encapsulation and drug loading efficiencies were 87.9% and 8.0% for CUR-loaded PLGA nanoparticles and 81.4% and 13.5% for MTX-loaded PLGA nanoparticles, respectively. In addition, drug co-encapsulation and co-loading efficiencies were 77.2% and 6.5% for CUR and 86.1% and 15.5% for MTX, respectively. The results of cell cycle analysis indicated that CUR- and MTX-loaded PLGA nanoparticles additively complemented each other in the S and sub-G1 phases. The obtained combinational index (CI) also exhibited that CUR- and MTX-loaded PLGA nanoparticles produce additive cytotoxicity at Fa = 0.5 on U87MG glioma cells. In addition, necrosis dominates cell death in nanomediated monotherapy whereas apoptosis dominates co-delivery treatment. The highest amount of LDH released was related to co-delivery as well. Nano-assisted combinational therapy and co-delivery can be used to obtain efficacies of drugs at lower concentrations, thus potentially increasing the therapeutic window of the drugs.