Magnetic graphene oxide nanosheets with amidoamine dendronized crosslinks for dual pH and redox-sensitive doxorubicin delivery

Abstract

Delivering anticancer drugs to the appropriate site within the body poses a critical challenge in cancer treatment with chemotherapeutic agents like doxorubicin (DOX). Magnetic graphene oxide (GO) nanosheets with generation 1 (G1) amidoamine-dendronized crosslinks were developed by coupling cystamine-functionalized GO nanosheets with Fe3O4 nanoparticles modified with primary amine and methyl acrylate. These magnetic GO nanosheets were loaded with DOX to create a dual pH- and redox-responsive delivery system for cancer chemotherapy. The prepared magnetic nanosheets underwent characterization using FTIR, XRD, DLS, VSM, FE-SEM, and TEM. Physical DOX adsorption was evaluated using various isotherms, including Langmuir, Freundlich, Temkin, and Dubinin-Radushkevich. The in-vitro release profiles of DOX from the magnetic nanosheets were studied under different pH conditions, with and without glutathione (GSH), and the drug release data were fitted with various kinetic models. Additionally, an MTT assay was employed to assess the compatibility and antitumor activity of DOX-loaded magnetic nanosheets in the HepG2 cell line. The results showed that the maximum drug loading was 13.1% (w/w) at a drug/carrier ratio of 1. Without GSH addition, the maximum drug release after 10 days was only 17.9% and 24.1% at pH 7.4 and 5.3, respectively. However, in the presence of GSH, the maximum drug release reached 51.7% and 64.8% at pH 7.4 and 5.3, respectively. Finally, the research findings suggest that the magnetic nanosheets exhibited pH- and redox-stimuli drug release, high biocompatibility, and superior antitumor activity compared to free DOX.

Keywords: Doxorubicin; Drug release kinetic; Fe3O4; Graphene oxide; Redox; Stimuli-responsive; Superparamagnetic nanoparticle.

Fig. 1

Schematic presentation of the synthesis of GO-Cys (upper panel), Fe₃O₄-NH₂, Fe₃O₄- β-amino acid methyl ester, and Fe₃O₄@GO-Cys (lower panel)

Fig. 2

(A) FT-IR spectra and (B) vibrating sample magnetometer (VSM) curves of GO, GO-Cys, Fe₃O₄, Fe₃O₄-NH₂, Fe₃O₄-β-amino acid methyl ester and Fe₃O₄@GO-Cys

Fig. 3

XRD patterns of GO, GO-Cys, and Fe₃O₄@GO-Cys

Fig. 4

FE-SEM images of (A) GO, (B) GO-Cys, (C) Fe₃O₄-β-amino acid methyl ester, and (D) Fe₃O₄@GO-Cys

Fig. 5

TEM image of Fe₃O₄@ GO-Cys

Fig. 6

(A) loading efficiency (LE) and drug loading (DL) of DOX into Fe₃O₄@GO-Cys NPs, (B) Langmuir, (C) Temkin, (D) Freundlich, and (E) Dubinin-Radushkevich adsorption isotherms

Fig. 7

DOX release from Fe₃O₄@GO-Cys NPs fitted on (A) zero-order, (B) first-order, (C) Higuchi, and (D) Korsmeyer-Peppas equations

Fig. 8

Schematic presentation of DOX loading and release from Fe₃O₄@GO-Cys

Fig. 9

MTT assay of HepG2 cell viability after 72 h exposure to different concentrations of DOX, Fe₃O₄@GO-Cys, and DOX-loaded Fe₃O₄@GO-Cys