ESTRO 2021 Abstract Book


ESTRO 2021

was observed which is indicative of the presence of senescence. Furthermore, as expected, irradiated glands exhibited a lower number of CD24 hi /CD29 hi stem cell enrichment marker expressing cells. Moreover, the ability to form organoids from cells isolated from irradiated salivary glands was reduced. However, after passaging of dispersed organoid cells from glands obtained at 14 days after irradiation, and to a lesser extent at 30 days post-irradiation, organoid forming efficiency (OFE) recovered. Cells obtained from glands at 90, 180 and 360 days post-irradiation, however, had irreversibly lost their ability to form organoids, which is indicative of a time-dependent loss of regenerative potential. Next, the conditioned medium produced by irradiated or unirradiated organoids was used to supplement medium for fresh unirradiated organoid cultures. After incubation with the conditioned medium, OFE was significantly reduced compared to when exposing these cells to the medium produced by unirradiated organoids. This observation indicated that the irradiated microenvironment compromised the self-renewal potential of mSGSCs. Conclusion Thus, early after irradiation, the regenerative potential of surviving mSGSCs seems to be comparable to that of unirradiated stem cells when taken out of a deleterious environment. At later time points, stem cells lose their regenerative potential suggesting permanent environmental-related changes in stemness. RNA sequencing and ATAC sequencing analyses are ongoing to characterize factors and mechanisms that negatively influence stemness after irradiation. Modulation of these factors might improve the stem cell regenerative potential and enhance the efficiency of stem cell therapy to restore the functionality of irradiated salivary glands. Purpose or Objective Microbeam radiosurgery, commonly referred to as microbeam radiotherapy, is a radiation modality that targets tumors with radiosurgical doses spatially fractionated into microbeams of exceptionally high doses (hecto-Gy). We explored using relatively lower doses of the spatially fractionated microbeams to transiently increase the transport of drugs across the blood vessel walls. We employed i) the Chick Chorioallantoic Membrane (CAM) to study the duration of the increased vascular transport across the vessel walls, and ii) the murine melanoma model to explore how this high vascular transportation affects the delivery of gold nanoparticles and consequently tumor control. Materials and Methods I rradiations took place at the European Synchrotron. The CAM received a square radiation field (1 x 1 cm) of microbeams 50 µm wide, spaced by 200 µm from their centers, delivering a dose of 1 Gy to 75% of the tissue and 100 Gy to 25% (as microbeams). We recorded live videos of the CAM under the microscope to observe the vascular flow of FITC-Dextran injected after irradiation. The melanoma model consists of B16-F10 cells implanted in the ears of the mice. The melanomas received a square radiation field (8 x 8 mm) delivering 2.8 Gy to most of the tissue and 150 Gy in the microbeams, which served as a priming vascular dose. This priming dose aimed to increase the transport of gold nanoparticles through the vascular wall, similar to FITC-dextran in the CAM model. Forty-five minutes after exposure to the priming dose, the mice received a tail-vein injection of a solution containing 1 mg/ml per bodyweight of gold nanoparticles (15 nm diameter). Forty-eight hours later, the melanomas were exposed to ablative doses of 7.4 Gy with 400 Gy in the microbeam with the same geometry as above. Results The irradiation of the CAM resulted in a transient increase in vascular permeability to FITC-dextran outside the vessel walls, which started 15 minutes post-irradiation and reached its peak between 45-120 min. The vascular permeability window closed 4 hours after irradiation. Our data suggest that the priming dose (2.8 Gy, 150 Gy microbeams) increased the transportation of gold nanoparticles to the tumor in the melanoma model, which allowed for better efficacy of the ablative dose (7.4 Gy, 400 Gy microbeams). We observed that the priming vascular dose increased significantly the median survival time of mice that received gold nanoparticles and microbeam irradiation. In contrast, without priming dose, there were no differences in survival between mice receiving the radiation dose alone or in combination with gold nanoparticles. Conclusion In conclusion, the CAM model study demonstrated that microbeam radiosurgery can prime the blood vessels for increased drug transportation of varying molecular weights. The melanoma study showed that the priming vascular dose could effectively increase the accumulation of gold nanoparticles in the tumor, and the gold nanoparticles could boost the ablative dose and increase tumor survival. OC-0065 Overcoming radioresistance with the hypoxia-activated prodrug CP-506: a pre-clinical in vivo study A. Yaromina 1 , L. Koi 2 , A. van der Wiel 1 , N.G. Lieuwes 1 , J. Theys 1 , L. Dubois 1 , M. Krause 3 , P. Lambin 1 1 Maastricht University, Department of Precision Medicine, The D-Lab and The M-Lab, GROW – School for Oncology and Developmental Biology, Maastricht, The Netherlands; 2 OncoRay – National Center for Radiation Research in Oncology and Helmholtz-Zentrum Dresden - Rossendorf, Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiooncology–OncoRay, Dresden, Germany; 3 OncoRay – National Center for Radiation Research in Oncology; and Helmholtz-Zentrum Dresden - Rossendorf, Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiooncology–OncoRay; German Cancer Consortium (DKTK), partner site Dresden; German Cancer OC-0064 Microbeam radiosurgery enhances drug delivery across the vascular wall: results from 2 animal models C. Fernandez 1 , V. Trappetti 1 , J. Fazzari 1 , O. Martin 1 , V. Djonov 1 1 University of Bern, Institute of Anatomy, Bern, Switzerland

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