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.

Inclusion of a pH-responsive amino acid-based amphiphile in methotrexate-loaded chitosan nanoparticles as a delivery strategy in cancer therapy

“…Moreover, the formation process is solely based on the electrostatic interaction of oppositely charged compounds and, thus, it is not necessary any chemical modification. CS-based NPs containing MTX were already reported in the literature, but most of them with drawback of using a cross-linked agent (Chen et al 2014;Jia et al 2014;Wu et al 2009). Likewise, there is considerable progress already achieved regarding the mechanisms underlying drug release from the nanostructures, being most of the current release methods based on reactions that commonly occur in response to environmental factors, 4 i.e.…”

Folic Acid Decorated Chitosan Nanoparticles and its Derivatives for the Delivery of Drugs and Genes to Cancer Cells

“…Furthermore, in vitro cellular uptake recommended that (MTX + MMC)-PEG-CS-NPs could be proficiently taken up by cancer cells via FA receptor-mediated endocytosis. In contrast, (MTX + MMC)-PEG-CS-NPs can co-deliver MTX and MMC to not only attain the highest accumulation at tumour site but also powerfully reduce the growth of tumour cells compared with the delivery of a single drug 63 . The derivatives of N-succinyl-chitosan were loaded with MMC and the conjugate is soluble in water when the MMC content is less than 12%, due to the hydrophilic property of N-succinyl-chitosan.…”

The Position of Combination Chemotherapy with Mitomycin C and Methotrexate in the Treatment of Metastatic Breast Cancer - Especially Triple Negative Breast Cancer

“…Recently, several studies on drug delivery systems have focused on the combination of MMC and MTX [39,40]. These studies, in which MTX/MMC-PEG(polyethylene glycol)ylated chitosan nanoparticles and MMC/MTX-loaded DSPE (1,2-Distearoyl-sn-glycero-3-phosphoetaholamine)-PE G micelles were developed and administered to model mice, demonstrated a synergistic effect of MMC and MTX.…”