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.
Highlights
Claiming the lives of 8.8 million people in 2015 alone, cancer is always a serious leading cause of death worldwide [1]
We focus on using magnetic graphene oxide (MGO) by chemical co-precipitation of Fe3O4 magnetic nanoparticles on GO nano-platelets [32], which was further modified with polyethylene (PEG) and CET (MGO-polyethylene glycol (PEG)-CET), for magnetic and the receptor-mediated dual targeted delivery of DOX
Modification using ClCH2COOH introduced abundant –COOH groups on MGO surface, which reacted with the –NH2 groups of avidin through carbodiimide-mediated amide bond formation catalyzed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS)
Summary
Claiming the lives of 8.8 million people in 2015 alone, cancer is always a serious leading cause of death worldwide [1]. There are several different treatment techniques, including surgery, radiation, chemotherapy, targeted therapy, and immunotherapy [2]. Chemotherapy has remained as one of the most common therapy methods for the treatment of different kinds of cancers. To be successful, chemotherapy may be dependent on several factors, including optimization of drug delivery to a specific targeting site, minimizing undesirable side effects to normal cells [3]. The application of nanotechnology in chemotherapeutics has huge potential to overcome the problems faced in drug delivery, and provides a platform for the development of a multi-functional drug delivery nano-system for theranostic nanomedicine [5]. Several nanomaterial-based chemotherapeutics have been successfully translated to clinical applications, the successful clinical translation of promising nanotherapy from benchside to bedside still faces plenty of hurdles. The inconsistency between the pre-clinical and clinical studies and the heterogeneity found in tumors may be suggested as two of the major challenges that nanomaterial-based anti-tumor therapies are facing for translational medicine [6]
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