Synchrotron facilities produce ultra-high dose rate X-rays that can be used for selective cancer treatment when combined with micron-sized beams. Synchrotron microbeam radiation therapy (MRT) has been shown to inhibit cancer growth in small animals, whilst preserving healthy tissue function. However, the underlying mechanisms that produce successful MRT outcomes are not well understood, either in vitro or in vivo. this study provides new insights into the relationships between dosimetry, radiation transport simulations, in vitro cell response, and pre-clinical brain cancer survival using intracerebral gliosarcoma (9LGS) bearing rats. As part of this groundbreaking research, a new image-guided MRT technique was implemented for accurate tumor targeting combined with a pioneering assessment of tumor dose-coverage; an essential parameter for clinical radiotherapy. Based on the results of our study, we can now (for the first time) present clear and reproducible relationships between the in vitro cell response, tumor dose-volume coverage and survival post MRT irradiation of an aggressive and radioresistant brain cancer in a rodent model. our innovative and interdisciplinary approach is illustrated by the results of the first long-term MRT pre-clinical trial in Australia. Implementing personalized synchrotron MRT for brain cancer treatment will advance this international research effort towards clinical trials.

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Nanoparticles, with their distinct properties that vary from their bulk material equivalent, continue to gain popularity for studies into multi-modal applications in medicine. This research introduces the use of thulium oxide nanoparticles for biological applications and characterizes the potential of this novel nanoparticle for image-guided radiotherapy of brain cancer. In this study, we investigate the structural characteristics of this nanoparticle, and reveal a significant dose enhancement towards radioresistant brain tumour cells in vitro that also underlies an improvement in the CT image contrast of brain tumours in vivo. The thulium oxide nanoparticles utilized in the investigations described in this article were measured to be 40-45 nm from x-ray diffraction and scanning electron microscopy data. In vitro investigations assessed the cell survival and DNA damage in 9 l gliosarcoma cells following irradiation with 150 kVp orthovoltage x-rays. Immediately after the 150 kVp irradiation (15 min) an increase in the number of γ-H2AX induced foci indicates the production of more double-strand DNA breaks. Following from the short time-frame irradiation outcomes, clonogenic cell survival assays confirmed long-term radio-sensitization, with the cell sensitivity increasing by a factor of 1.32 (measured at the 10% survival fraction) for the irradiated 9 l cells exposed to thulium nanoparticles. A simple CT experiment shows that our thulium nanoparticles suspended in water at concentrations >0.5 mg ml −1 (0.05-20 mg ml −1 investigated) are clearly observable against water. Extending the CT experiment to an in vivo investigation, cellular uptake of the nanoparticles was demonstrated through CT image enhancement of the cancer site in 9-to 10-week-old Fisher rats bearing 9 l gliosarcomas, 12 days after cell implantation. The 9 l cancer is clearly visible on the CT image after injecting 40 μg of nanoparticles (2 μl at 20 mg ml −1) directly to the cancer site (5.5 mm from the dura and 3.5 mm right laterally of the bregma, 5 mm depth). To our knowledge, this work demonstrates the first application of thulium nanoparticles in biology and medicine, for radiotherapy and image guidance purposes.

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Gold nanoparticles have demonstrated significant radiosensitization of cancer treatment with x-ray radiotherapy. To understand the mechanisms at the basis of nanoparticle radiosensitization, Monte Carlo simulations are used to investigate the dose enhancement, given a certain nanoparticle concentration and distribution in the biological medium. Earlier studies have ordinarily used condensed history physics models to predict nanoscale dose enhancement with nanoparticles. This study uses Geant4-DNA complemented with novel track structure physics models to accurately describe electron interactions in gold and to calculate the dose surrounding gold nanoparticle structures at nanoscale level. The computed dose in silico due to a clinical kilovoltage beam and the presence of gold nanoparticles was related to in vitro brain cancer cell survival using the local effect model. The comparison of the simulation results with radiobiological experimental measurements shows that Geant4-DNA and local effect model can be used to predict cell survival in silico in the case of x-ray kilovoltage beams.

Microbeam Radiation Therapy (MRT) exploits tumour selectivity and normal tissue sparing with spatially fractionated kilovoltage X-ray microbeams through the dose volume effect. Experimental measurements with Ta 2 O 5 nanoparticles (NPs) in 9L gliosarcoma treated with MRT at the Australian Synchrotron, increased the treatment efficiency. Ta 2 O 5 NPs were observed to form shells around cell nuclei which may be the reason for their efficiency in MRT. In this article, our experimental observation of NP shell formation is the basis of a Geant4 radiation transport study to characterise dose enhancement by Ta 2 O 5 NPs in MRT. Our study showed that NP shells enhance the physical dose depending microbeam energy and their location relative to a single microbeam. For monochromatic microbeam energies below ∼70 keV, NP shells show highly localised dose enhancement due to the short range of associated secondary electrons. Low microbeam energies indicate better targeted treatment by allowing higher microbeam doses to be administered to tumours and better exploit the spatial fractionation related selectivity observed with MRT. For microbeam energies above ∼100 keV, NP shells extend the physical dose enhancement due to longer-range secondary electrons. Again, with NPs selectively internalised, the local effectiveness of MRT is expected to increase in the tumour. Dose enhancement produced by the shell aggregate varied more significantly in the cell population, depending on its location, when compared to a homogeneous NP distribution. These combined simulation and experimental data provide first evidence for optimising MRT through the incorporation of newly observed Ta 2 O 5 NP distributions within 9L cancer cells. Disciplines Engineering | Science and Technology Studies Publication DetailsEngels, E., Corde, S., McKinnon, S., Incerti, S., Konstantinov, K., Rozenfeld, A., Tehei, M., . Optimizing dose enhancement with Ta2O5 nanoparticles for synchrotron microbeam activated radiation therapy. Physica Medica: an international journal devoted to the applications of physics to medicine and biology, 32 (12)

Polo-like kinase 1 inhibitor BI6727 sensitizes 9L gliosarcoma cells to ionizing Polo-like kinase 1 inhibitor BI6727 sensitizes 9L gliosarcoma cells to ionizing irradiation irradiation

Recommendations for an experimental protocol for beam alignment/optimization and dosimetry relating to in vitro studies at the Imaging and Medical Beam Line of the Australian Synchrotron are presented. An evaluation of the protocol, based upon the consistency and reproducibility of in vitro experiments performed over several years at the Australian Synchrotron, is provided for the community.