Between 1952 and 1992 more than 200 large radiobiology studies were conducted in research institutes throughout Europe, North America and Japan to determine the effects of external irradiation and internal emitters on the life span and tissue toxicity development in animals. At Argonne National Laboratory, 22 external beam studies were conducted on nearly 700 beagle dogs and 50,000 mice between 1969 and 1992. These studies helped to characterize the effects of neutron and gamma irradiation on lifespan, tumorigenesis, and mutagenesis across a range of doses and dosing patterns. The records and tissues collected at Argonne during that time period have been carefully preserved and redisseminated. Using these archived data ongoing statistical work has been done and continues to characterize quality of radiation, dose, dose rate, tissue, and gender specific differences in the radiation responses of exposed animals. The ongoing application of newly developed molecular biology techniques to the archived tissues has revealed gene specific mutation rates following exposure to ionizing irradiation. The original and ongoing work with this tissue archive is presented here as a case study of a more general trend in the radiobiology mega studies. These experiments helped form the modern understanding of radiation responses in animals, and continue to inform development of new radiation models. Recent archival efforts have facilitated open access to the data and materials produced by these studies and so a unique opportunity exists to expand this continued research.
A nanoconjugate was composed of metal oxide nanoparticles decorated with peptides and fluorescent dye and tested for DNA cleavage following UV light activation. The peptide design was based on a DNA binding domain, the so called KH domain of the hnRNPK protein. This “KH peptide” enabled cellular uptake of nanoconjugates and their entry into cell nuclei. The control nanoconjugate carried no peptide; it consisted only of the metal oxide nanoparticle prepared an Fe3O4@TiO2 nanocomposite and the fluorescent dye alizarin red S. These components of either construct are responsible for nanoconjugate activation by UV light and the resultant production of reactive oxygen species (ROS). Production of ROS at different subcellular locations causes damage to different components of cells: only nanoconjugates inside cell nuclei can be expected to cause DNA cleavage. Degradation of cellular DNA with KH peptide decorated nanoconjugates exceeded the DNA damage obtained from control, no-peptide nanoconjugate counterparts. Moreover, caspase activation and cell death were more extensive in the same cells.
The targeted delivery of Fe3O4@TiO2 nanoparticles to cancer cells is an important step in their development as nanomedicines. We have synthesized nanoparticles that can bind the Epidermal Growth Factor Receptor, a cell surface protein that is overexpressed in many epithelial type cancers. In order to study the subcellular distribution of these nanoparticles, we have utilized the sub-micron resolution of X-ray Fluorescence Microscopy to map the locationof Fe3O4@TiO2 NPs and other trace metal elements within HeLa cervical cancer cells. Here we demonstrate how the higher resolution of the newly installed Bionanoprobe at the Advanced Photon Source at Argonne National Laboratory can greatly improve our ability to distinguish intracellular nanoparticles and their spatial relationship with subcellular compartments.
Purpose: To test in vivo, in a rabbit VX2 liver cancer model, a nanocomposite made with Fe3O4 core and TiO2 shell as a possible radiosensitization agent. Methods: This study was approved by the institutional ACUC. Rabbits were implanted in liver with pairs of VX2 tumors distantly enough to allow irradiation of only one of the two tumors. The tumors were allowed to grow until clearly detectable by magnetic resonance imaging, followed by Computed Tomography (CT) simulation to identify and contour the tumors. Each rabbit was anesthetized, and immobilized in supine position. Isocenter was placed during the CT simulation and the rabbit was tattooed. After the CT, each rabbit was injected with nanoparticles and put under observation until recovery. The core-shell nanoparticles were surface covered with glucose (glut-NPs) and delivered intravenously to 6 rabbits. A radiation oncologist contoured the target volumes. The gross target volume included a hepatic tumor in one lobe; 1 - 3 mm expansion was done to create the clinical target volume and another 1-2 mm expansion to create the planning target volume (PTV). The control hepatic tumor was contoured and the treatment plan objective was to deliver more than 95% of the prescribed dose to the PTV while sparing the control tumor. A certified radiation physicist created the treatment plan. Dose Volume Histograms were created and the radiation oncologist approved the plan. Irradiation usually utilized 2 - 3 beams, delivering 2 Gy as a single fraction using Linear Accelerator. All 6 rabbits treated with nanoparticles the day before (14-18h previously) and 3 radiation-only (not glut-NPs treated) animals were irradiated so that only one of the tumors received radiation. The animals were terminated 3 days after irradiation and the tumors were harvested. Several view-fields with at 3-10 x 103 cells were automatically scored using the NanoZoomer and percentage of Ki67 positive cells, as a marker of proliferation was determined in each tumor. TUNEL assay was done as well. Results: In each rabbit the larger tumor of the pair was irradiated. In no-NP treated animals that led to the fact that irradiated tumors at 3 days after irradiation generally still had greater number of proliferating cells than the non-irradiated tumor sections. Conversely, in glut-NPs treated rabbits, irradiation led to a decrease of Ki-67 positive cells compared to the paired non-irradiated glut-NPs treated tumors. Three-day time-point was better suited for evaluation of tumor proliferation changes. TUNEL analysis showed higher apoptotic cell numbers in glut-NPs treated tumors (p=0.049). Combination of radiation with glut-NP treatment showed only a mild trend for increased apoptosis compared to non-irradiated glut-NPs treated tumors, this trend was not statistically significant (p=0.53). Conclusion: These data suggest that the glut-NPs show a considerable promise for radiosensitization. Note: This abstract was not presented at the meeting. Citation Format: Tamer Refaat, Derek West, kathleen R. Harris, Vamsi Parini, William Liu, Beau Wanzer, Lydia Finney, Andrew C. Larson, Jonathan Bautista, Vythialinga Sathiaseelan, Bharat Mittal, Tatjana Paunesku, Gayle Woloschak. Development of Fe3O4@TiO2 core-shell nanocomposites as radiosensitizers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4913. doi:10.1158/1538-7445.AM2014-4913
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