Iron Oxide Core - Titanium Oxide Shell Nanocomposite and Nanoconjugate Effects on Neuroblastoma.

摘要

Fe3O4 core - TiO2 shell nanocomposites and nanoconjugates have a variety of properties that confer a multi-modal functionality ideal for the treatment of neuroblastoma. This study examines these functionalities separately and in combination, in the treatment of neuroblastoma.;Bare Fe3O4 core - TiO2 shell nanocomposites were evaluated for their potential as a radiosensitizer of neuroblastoma. Modest radiosensitization was initially observed, while after coating with DOPAC, a metabolite of dopamine, radiosensitization was significantly enhanced. This sensitization was associated with increased DNA double strand breaks, and may be due to a modulation in the size, aggregation, subcellular localization, and protein interactions of these DOPAC coated nanocomposites compared to uncoated nanocomposites.;This study next determined if MIBG, a neuroblastoma radiotherapeutic, could be conjugated to and targeted through these nanocomposites. We found that unconjugated MIBG, when added to cells in culture, is distributed throughout the cell, but not within the nucleus. If radioactive MIBG could be localized to the nucleus, its therapeutic effectiveness could be increased. MIBG was conjugated to an Fe3O4 core - TiO2 shell nanocomposite and its effect on uptake, localization, and cell viability determined. Next, a nuclear targeting peptide was conjugated to these MIBG-nanoconjugates and, through cryo-XFM tomography, we demonstrated nuclear localization of MIBG loaded nanoconjugates.;Another goal of this study was to examine the effects of radiation on tumor and non-tumor disease in two animal species (Peromyscus leucopus and Mus musculus). While the primary objective was to how disease expression varied between two morphologically similar species after irradiation, another objective was to determine if there were radiation associated pathologies which might interfere with the evaluation of the effectiveness of combination radiation and nanocomposite treatment in a particular animal model. We found that the response of these animals to radiation was diverse, making between-species predictions of specific tumors and diseases difficult even between these morphologically similar species. These results imply that future animal studies combining radiation with nanocomposites should be carefully evaluated, as confounding tumors (particularly adrenal tumors) may affect treatment effectiveness, in addition to a concern about the general validity of approaches that use animal data to infer human effects of particular treatments.