Development of both methotrexate and mitomycin C loaded PEGylated chitosan nanoparticles for targeted drug codelivery and synergistic anticancer effect.

Abstract

Codelivery of multiple drugs with one kind of drug carriers provided a promising strategy to suppress the drug resistance and achieve the synergistic therapeutic effect in cancer treatment. In this paper, we successfully developed both methotrexate (MTX) and mitomycin C (MMC) loaded PEGylated chitosan nanoparticles (CS-NPs) as drug delivery systems, in which MTX, as a folic acid analogue, was also employed as a tumor-targeting ligand. The new drug delivery systems can coordinate the early phase targeting effect with the late-phase anticancer effect. The (MTX+MMC)-PEG-CS-NPs possessed nanoscaled particle size, narrow particle size distribution, and appropriate multiple drug loading content and simultaneously sustained drug release. In vitro cell viability tests indicated that the (MTX+MMC)-PEG-CS-NPs exhibited concentration- and time-dependent cytotoxicity. Moreover, in vitro cellular uptake suggested that the (MTX+MMC)-PEG-CS-NPs could be efficiently taken up by cancer cells by FA receptor-mediated endocytosis. On the other hand, the (MTX+MMC)-PEG-CS-NPs can codelivery MTX and MMC to not only achieve the high accumulation at the tumor site but also more efficiently suppress the tumor cells growth than the delivery of either drug alone, indicating a synergistic effect. In fact, the codelivery of two anticancer drugs with distinct functions and different anticancer mechanisms was key to opening the door to their targeted drug delivery and synergistic anticancer effect. Therefore, the (MTX+MMC)-PEG-CS-NPs as targeted drug codelivery systems might have important potential in clinical implications for combination cancer chemotherapy.