Methotrexate-conjugated chitosan-grafted pH- and thermo-responsive magnetic nanoparticles for targeted therapy of ovarian cancer

Abstract

Here, methotrexate (MTX)-conjugated multifunctional nanoparticles (NPs) were engineered based on chitosan (CS) for targeted delivery of erlotinib (ETB). First, CS was modified with sodium dodecyl sulfate and maleic anhydride to prepare a polymerizable organo-soluble precursor. N-Isopropylacrylamide (NIPAAm) and itaconic acid (IA) as thermo- and pH-responsive monomers were grafted onto CS by free radical polymerization. Subsequently, magnetic nanoparticles (MNPs) ferrofluid with prepared CS copolymer (CSC) was produced via an inclusion complex between carboxylic acid groups of CSC and MNPs. Finally, MTX was conjugated to amino groups of CS based on the structural similarity of MTX with folic acid as targeting ligand. The prepared MTX-CSC@MNPs were physiochemically characterized by different techniques, including FT-IR, ¹H NMR, DLS, SEM-EDX, and UV-Vis spectroscopy. The mean size of the prepared NPs was around 112 nm with a zeta potential of -28.4 mV. The ETB encapsulation efficiency and NPs loading were about 86% and 17%, respectively. The ETB-loaded NPs showed thermo- and pH-dependent drug release behavior. The ETB-loaded MTX-CSC@MNPs were markedly taken up via folate receptors (FRs) and induced significant toxicity in OVCAR-3 cells. Based on these findings, MTX-CSC@MNPs are proposed as a promising smart nanocarrier for the targeted therapy of FR-positive solid tumors such as ovarian cancer.

Keywords: Cancer therapy; Chitosan; Erlotinib; Targeted drug delivery; Thermo-sensitive; pH-responsive.