Magnetic Graphene Oxide for Dual Targeted Delivery of Doxorubicin and Photothermal Therapy

Abstract

To develop a pH-sensitive dual targeting magnetic nanocarrier for chemo-phototherapy in cancer treatment, we prepared magnetic graphene oxide (MGO) by depositing Fe3O4 magnetic nanoparticles on graphene oxide (GO) through chemical co-precipitation. MGO was modified with polyethylene glycol (PEG) and cetuximab (CET, an epidermal growth factor receptor (EGFR) monoclonal antibody) to obtain MGO-PEG-CET. Since EGFR was highly expressed on the tumor cell surface, MGO-PEG-CET was used for dual targeted delivery an anticancer drug doxorubicin (DOX). The physico-chemical properties of MGO-PEG-CET were fully characterized by dynamic light scattering, transmission electron microscopy, X-ray diffraction, Fourier transform Infrared spectroscopy, thermogravimetric analysis, and superconducting quantum interference device. Drug loading experiments revealed that DOX adsorption followed the Langmuir isotherm with a maximal drug loading capacity of 6.35 mg/mg, while DOX release was pH-dependent with more DOX released at pH 5.5 than pH 7.4. Using quantum-dots labeled nanocarriers and confocal microscopy, intracellular uptakes of MGO-PEG-CET by high EGFR-expressing CT-26 murine colorectal cells was confirmed to be more efficient than MGO. This cellular uptake could be inhibited by pre-incubation with CET, which confirmed the receptor-mediated endocytosis of MGO-PEG-CET. Magnetic targeted killing of CT-26 was demonstrated in vitro through magnetic guidance of MGO-PEG-CET/DOX, while the photothermal effect could be confirmed in vivo and in vitro after exposure of MGO-PEG-CET to near-infrared (NIR) laser light. In addition, the biocompatibility tests indicated MGO-PEG-CET showed no cytotoxicity toward fibroblasts and elicited minimum hemolysis. In vitro cytotoxicity tests showed the half maximal inhibitory concentration (IC50) value of MGO-PEG-CET/DOX toward CT-26 cells was 1.48 µg/mL, which was lower than that of MGO-PEG/DOX (2.64 µg/mL). The IC50 value could be further reduced to 1.17 µg/mL after combining with photothermal therapy by NIR laser light exposure. Using subcutaneously implanted CT-26 cells in BALB/c mice, in vivo anti-tumor studies indicated the relative tumor volumes at day 14 were 12.1 for control (normal saline), 10.1 for DOX, 9.5 for MGO-PEG-CET/DOX, 5.8 for MGO-PEG-CET/DOX + magnet, and 0.42 for MGO-PEG-CET/DOX + magnet + laser. Therefore, the dual targeting MGO-PEG-CET/DOX could be suggested as an effective drug delivery system for anticancer therapy, which showed a 29-fold increase in therapeutic efficacy compared with control by combining chemotherapy with photothermal therapy.

Optimization of the Preparation of Magnetic Liposomes for the Combined Use of Magnetic Hyperthermia and Photothermia in Dual Magneto-Photothermal Cancer Therapy

“…For CMNPs and MLs, six diffraction peaks were observed at 2 θ = 30.3°, 35.5°,43.4°, 53.5°, 57.2°, and 62.6°, which could be indexed to the (220), (311), (400), (422), (511), and (440) planes of a cubic cell. The crystalline structure was affirmed to be comparable with that of magnetite (JCPDS card number 19-0629), which indicates pure Fe 3 O 4 associated with the spinal structure of magnetite in CMNPs [ 15 , 32 , 40 ]. The absence of the six diffraction peaks in the patterns shown for blank liposomes, which were prepared similarly to MLs but without CMNPs, further supports the encapsulation of CMNPs in MLs.…”

“…Iron oxide MNPs are trending in clinical use for treatment of cancers by direct infusion of MNPs to solid tumors for MH treatment of glioblastoma and prostate carcinoma [ 13 ]. Furthermore, since MNPs can be driven to a precise targeted site with an external magnetic field, MNPs alone [ 14 ] or nanocomposites containing MNPs [ 15 ] are widely exploited for targeted drug and gene delivery. Endeavors are also being made to upgrade the heating proficiency of iron oxide MNPs for tumor ablation.…”

Current trends and challenges in cancer management and therapy using designer nanomaterials

“…Recently, nanographene oxide complexed with upconverting nanoparticles were used for tumor imaging and photothermal therapy, signifying the potential of multifunctional graphene for clinical antitumor treatments [213]. The combination of chemotherapy with photothermal therapy has proved to be efficient when magnetic graphene oxide modified with PEG and cetuximab was used against CT-26 murine colorectal cells [214]. The active targeting was achieved using cetuximab, an epidermal growth factor receptor (EGFR) monoclonal antibody, since epidermal growth factor receptor is highly expressed on the tumor surface of colorectal cancer cells.…”

Injectable Thermo-Sensitive Chitosan Hydrogel Containing CPT-11-Loaded EGFR-Targeted Graphene Oxide and SLP2 shRNA for Localized Drug/Gene Delivery in Glioblastoma Therapy

“…Nanocarriers tend to undergo rapid elimination from the reticuloendothelial system due to their small size, in addition to lacking a “smart” selectivity for tumor tissues [ 9 ]. Therefore, the targeted delivery of anti-tumor drugs for cancer therapy is considered to be more effective than traditional chemotherapy [ 10 ]. Indeed, an active targeting strategy could increase the ability of nanocarriers to be specifically recognized by tumor cells through modifying the carrier surface with a ligand, such as a monoclonal antibody [ 11 ].…”