Abstract
Since graphene nanoparticles are attracting increasing interest in relation to medical applications, it is important to understand their potential effects on humans. In the present study, we prepared graphene oxide (GO) nanoribbons by oxidative unzipping of single-wall carbon nanotubes (SWCNTs) and analyzed their toxicity in two human neuroblastoma cell lines. Neuroblastoma is the most common solid neoplasia in children. The hallmark of these tumors is the high number of different clinical variables, ranging from highly metastatic, rapid progression and resistance to therapy to spontaneous regression or change into benign ganglioneuromas. Patients with neuroblastoma are grouped into different risk groups that are characterized by different prognosis and different clinical behavior. Relapse and mortality in high risk patients is very high in spite of new advances in chemotherapy. Cell lines, obtained from neuroblastomas have different genotypic and phenotypic features. The cell lines SK-N-BE(2) and SH-SY5Y have different genetic mutations and tumorigenicity. Cells were exposed to low doses of GO for different times in order to investigate whether GO was a good vehicle for biological molecules delivering individualized therapy. Cytotoxicity in both cell lines was studied by measuring cellular oxidative stress (ROS), mitochondria membrane potential, expression of lysosomial proteins and cell growth. GO uptake and cytoplasmic distribution of particles were studied by Transmission Electron Microscopy (TEM) for up to 72 h. The results show that GO at low concentrations increased ROS production and induced autophagy in both neuroblastoma cell lines within a few hours of exposure, events that, however, are not followed by growth arrest or death. For this reason, we suggest that the GO nanoparticle can be used for therapeutic delivery to the brain tissue with minimal effects on healthy cells.
Highlights
For cancer to be treated effectively, a drug has to be delivered selectively to the site of lesion and delivery to normal cells has to be minimized
As shown in the figure a statistically significant rate of necrosis compared to controls, started with 4 μg/mL and with 20 μg/mL of graphene oxide (GO) a high percentage of cells floated in the media at 24 h and cellular debris were present at 48 and 72 h
Regarding reactive oxygen species (ROS) increased levels, our results are not consistent with those reported by other authors in other cell lines [18] because we report an increase in ROS at very low doses and after only brief exposure to GO
Summary
For cancer to be treated effectively, a drug has to be delivered selectively to the site of lesion and delivery to normal cells has to be minimized. In the case of tumors, a targeted drug delivery system is necessary in order to increase the therapeutic effect of drugs and to diminish cytotoxicity to adjacent cells. Nanotubes have been shown to be toxic for biological systems, recent studies have focused on the biosafety of GO nanoparticles in cells and live biosystems by looking at different aspects such as cell growth, viability, induction of apoptosis [4]. The highly metastatic and aggressive subtypes of neuroblastoma need new therapeutic approaches that aim to suppress malignant phenotypes and to induce differentiation of non tumorigenic elements. Rezaei et al [11] have used a graphene based gene carrier for DNA transfection into mammalian cells, with a low rate of cell death, even though the authors report a slight increase of cell death in AGS cells treated with 1 μg of GO. We show that very small doses of GO are able to induce autophagy within the first 48 h of exposure, after this time cells recover and are able to grow
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