Abstract
BackgroundNeuroblastoma is the most common extracranial solid malignancy in childhood which, despite the current progress in radiotherapy and chemotherapy protocols, still has a high mortality rate in high risk tumors. Nanomedicine offers exciting and unexploited opportunities to overcome the shortcomings of conventional medicine. The photocatalytic properties of Fe3O4 core-TiO2 shell nanocomposites and their potential for cell specific targeting suggest that nanoconstructs produced using Fe3O4 core-TiO2 shell nanocomposites could be used to enhance radiation effects in neuroblastoma. In this study, we evaluated bare, metaiodobenzylguanidine (MIBG) and 3,4-Dihydroxyphenylacetic acid (DOPAC) coated Fe3O4@TiO2 as potential radiosensitizers for neuroblastoma in vitro.ResultsThe uptake of bare and MIBG coated nanocomposites modestly sensitized neuroblastoma cells to ionizing radiation. Conversely, cells exposed to DOPAC coated nanocomposites exhibited a five-fold enhanced sensitivity to radiation, increased numbers of radiation induced DNA double-strand breaks, and apoptotic cell death. The addition of a peptide mimic of the epidermal growth factor (EGF) to nanoconjugates coated with MIBG altered their intracellular distribution. Cryo X-ray fluorescence microscopy tomography of frozen hydrated cells treated with these nanoconjugates revealed cytoplasmic as well as nuclear distribution of the nanoconstructs.ConclusionsThe intracellular distribution pattern of different nanoconjugates used in this study was different for different nanoconjugate surface molecules. Cells exposed to DOPAC covered nanoconjugates showed the smallest nanoconjugate uptake, with the most prominent pattern of large intracellular aggregates. Interestingly, cells treated with this nanoconjugate also showed the most pronounced radiosensitization effect in combination with the external beam x-ray irradiation. Further studies are necessary to evaluate mechanistic basis for this increased radiosensitization effect. Preliminary studies with the nanoparticles carrying an EGF mimicking peptide showed that this approach to targeting could perhaps be combined with a different approach to radiosensitization – use of nanoconjugates in combination with the radioactive iodine. Much additional work will be necessary in order to evaluate possible benefits of targeted nanoconjugates carrying radionuclides.Graphic abstract
Highlights
Neuroblastoma is the most common extracranial solid malignancy in childhood which, despite the current progress in radiotherapy and chemotherapy protocols, still has a high mortality rate in high risk tumors
Modification of nanocomposite surface coating affects size, aggregation, and cellular uptake We examined how the coating of nanocomposites with Dihydroxyphenylacetic acid (DOPAC) or DOPAC conjugated to MIBG might affect nanoconjugate physical characteristics considering that the same nanocomposite colloid was used for preparation of the three final nanoconstructs
It should be noted that MIBG was conjugated to Iron oxide (Fe3O4)@Titanium dioxide (TiO2) nanocomposites via a DOPAC linker through a reaction using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and with MIBG as the molecule in higher excess
Summary
Neuroblastoma is the most common extracranial solid malignancy in childhood which, despite the current progress in radiotherapy and chemotherapy protocols, still has a high mortality rate in high risk tumors. The current standard of care for neuroblastoma entails multiple treatment modalities, all of which have a deleterious effect on health (Maris 2010). Even targeted therapies such as radioactive metaiodobenzylguanidine (MIBG) carry with it numerous treatment-related hurdles ranging from myelosuppression as the dose-limiting toxicity, to difficulties in isolating young radio-iodine treated children which is essential for protection of caregivers (DuBois and Matthay 2008; Matthay et al 2012,2007). New approaches with targeted therapies are under investigation; few are as efficient for relapsed neuroblastoma as treatment with radioactive MIBG. We wished to explore whether the nanoparticles themselves had the capacity to increase sensitivity to radiation
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