The therapeutic effect of methotrexate-conjugated Pluronic-based polymeric micelles on the folate receptor-rich tumors treatment

Abstract

The therapeutic effect of methotrexate (MTX)-conjugated Pluronic-based polymeric mixed micelles (F127/P105-MTX) on the folate receptor-overexpressing tumors treatment was investigated in this study. Due to its high structural similarity to folic acid and the high expression of folate receptor in most solid tumors, MTX serves as not only a cytotoxic agent but also a homing ligand. Cellular uptake and the endocytic mechanism studies of MTX-conjugated mixed micelles were performed in folate receptor-rich KBv and folate receptor-deficient A-549 cancer cells. Additionally, the efficacy and safety studies of F127/P105-MTX in KBv tumor-bearing mice were evaluated. Results indicate that F127/P105-MTX significantly enhanced the cellular uptake in KBv cells as compared to that of conventional non-MTX-conjugated mixed micelles. Moreover, the results showed that F127/P105-MTX can be internalized by both caveolae- and clathrin-mediated endocytosis in energy-dependent and folate receptor-dependent manners. The in vitro and in vivo antitumor efficacies of F127/P105-MTX were significantly enhanced in comparison with MTX-entrapped mixed micelles. Furthermore, no acute toxicities to hematological system and major organs have been observed after intravenous administration during the regimen. Therefore, our results suggest that F127/P105-MTX could be an effective and safe nano-drug delivery system for cancer therapy, especially for the folate receptor-rich cancer treatment.

Methotrexate Nanoparticles Prepared with Codendrimer from Polyamidoamine (PAMAM) and Oligoethylene Glycols (OEG) Dendrons: Antitumor Efficacy in Vitro and in Vivo

“…Furthermore, liver function markers including alanine aminotransferase, aspartate aminotransferase, and the kidney function markers such as blood urea nitrogen, creatinine were measured to evaluate the safety of drug-loaded nanoparticles ( Supplementary Information, Table S2 ). These results from test groups showed no significant difference when compared with the saline group (p > 0.05), suggesting no obvious hepatic or renal toxicity 43 . All these results of in vivo antitumor studies indicated that MTX/ PGD NPs could improve antitumor efficacy without significant toxicity.…”

Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma

“…Otherwise, it was unclear why the latter, while having higher negative charge than empty liposomes (zeta potential values were ~−53 and −42 mV, respectively; Table 1), bind tumor cells significantly more effectively, as most of the cells express negatively charged (mainly sulfated) proteoglycans on their surface. 27 The sole nanoparticulate drug delivery system exploiting the FR-targeting potential of MTX that was found is the MTX-conjugated pluronic-based micelles reported by Chen et al 28 Interestingly, the A549 cells did not show any increase in binding with the micelles as compared with MTXfree micelles after 60 minutes of incubation. 28 Presumably, in contrast to MTX-DG liposomes, MTX moieties in the micelles are shielded by polyethylene glycol chains, which could decrease the efficacy of targeting.…”

“…27 The sole nanoparticulate drug delivery system exploiting the FR-targeting potential of MTX that was found is the MTX-conjugated pluronic-based micelles reported by Chen et al 28 Interestingly, the A549 cells did not show any increase in binding with the micelles as compared with MTXfree micelles after 60 minutes of incubation. 28 Presumably, in contrast to MTX-DG liposomes, MTX moieties in the micelles are shielded by polyethylene glycol chains, which could decrease the efficacy of targeting.…”

Design of pH-sensitive methotrexate prodrug-targeted curcumin nanoparticles for efficient dual-drug delivery and combination cancer therapy

“…Our group and certain other groups reported that MTX has some affinity for folate receptors because of the structural similarity with folic acid (FA); therefore, MTX could not only serve as an anticancer drug to exert its anticancer effect but also act as a targeting moiety that binds with the folate receptor to exert its targeting function. 8,37,38 In this study, combining the advantages of anticancer drug MTX for active tumor targeting, DSPE-PEG for drug carriers, and imine linkage for acid-triggered intracellular release, a novel targeting DSPE-PEG-Imine-MTX amphiphilic lipopolymer prodrug was synthesized by conjugating the aldehyde group of DSPE-PEG with the aromatic amino group in MTX via Schiff's base reaction ( Figure 1A). Due to the amphiphilicity, DSPE-PEG-Imine-MTX and DSPE-PEG-methoxy (DSPE-MPEG) could be self-assembled into self-targeting and pH-responsive micellar nanoparticles, in which CUR was encapsulated within their hydrophobic core (designated as MTX-Imine-M-CUR; Figure 1B).…”