Xu Cao1, Rongxiao Zhang2, Tatiana V Esipova3, Srinivasa Rao Allu3, Ramish Ashraf4, Mahbubur Rahman4, Jason R Gunn4, Petr Bruza4, David J Gladstone2, Benjamin B Williams2, Harold M Swartz2, P Jack Hoopes5, Sergei A Vinogradov6, Brian W Pogue7. 1. Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire; Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education & School of Life Science and Technology, Xidian University, Xi'an, Shaanxi, China. 2. Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire; Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; Department of Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire. 3. Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Chemistry, School or Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania. 4. Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire. 5. Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire; Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; Department of Surgery, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire. 6. Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Chemistry, School or Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: vinograd.upenn@gmail.com. 7. Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire; Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; Department of Surgery, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire. Electronic address: brian.w.pogue@dartmouth.edu.
Abstract
PURPOSE: Delivery of radiation at ultrahigh dose rates (UHDRs), known as FLASH, has recently been shown to preferentially spare normal tissues from radiation damage compared with tumor tissues. However, the underlying mechanism of this phenomenon remains unknown, with one of the most widely considered hypotheses being that the effect is related to substantial oxygen depletion upon FLASH, thereby altering the radiochemical damage during irradiation, leading to different radiation responses of normal and tumor cells. Testing of this hypothesis would be advanced by direct measurement of tissue oxygen in vivo during and after FLASH irradiation. METHODS AND MATERIALS: Oxygen measurements were performed in vitro and in vivo using the phosphorescence quenching method and a water-soluble molecular probe Oxyphor 2P. The changes in oxygen per unit dose (G-values) were quantified in response to irradiation by 10 MeV electron beam at either UHDR reaching 300 Gy/s or conventional radiation therapy dose rates of 0.1 Gy/s. RESULTS: In vitro experiments with 5% bovine serum albumin solutions at 23°C resulted in G-values for oxygen consumption of 0.19 to 0.21 mm Hg/Gy (0.34-0.37 μM/Gy) for conventional irradiation and 0.16 to 0.17 mm Hg/Gy (0.28-0.30 μM/Gy) for UHDR irradiation. In vivo, the total decrease in oxygen after a single fraction of 20 Gy FLASH irradiation was 2.3 ± 0.3 mm Hg in normal tissue and 1.0 ± 0.2 mm Hg in tumor tissue (P < .00001), whereas no decrease in oxygen was observed from a single fraction of 20 Gy applied in conventional mode. CONCLUSIONS: Our observations suggest that oxygen depletion to radiologically relevant levels of hypoxia is unlikely to occur in bulk tissue under FLASH irradiation. For the same dose, FLASH irradiation induces less oxygen consumption than conventional irradiation in vitro, which may be related to the FLASH sparing effect. However, the difference in oxygen depletion between FLASH and conventional irradiation could not be quantified in vivo because measurements of oxygen depletion under conventional irradiation are hampered by resupply of oxygen from the blood. Published by Elsevier Inc.
PURPOSE: Delivery of radiation at ultrahigh dose rates (UHDRs), known as FLASH, has recently been shown to preferentially spare normal tissues from radiation damage compared with tumor tissues. However, the underlying mechanism of this phenomenon remains unknown, with one of the most widely considered hypotheses being that the effect is related to substantial oxygen depletion upon FLASH, thereby altering the radiochemical damage during irradiation, leading to different radiation responses of normal and tumor cells. Testing of this hypothesis would be advanced by direct measurement of tissue oxygen in vivo during and after FLASH irradiation. METHODS AND MATERIALS: Oxygen measurements were performed in vitro and in vivo using the phosphorescence quenching method and a water-soluble molecular probe Oxyphor 2P. The changes in oxygen per unit dose (G-values) were quantified in response to irradiation by 10 MeV electron beam at either UHDR reaching 300 Gy/s or conventional radiation therapy dose rates of 0.1 Gy/s. RESULTS: In vitro experiments with 5% bovine serum albumin solutions at 23°C resulted in G-values for oxygen consumption of 0.19 to 0.21 mm Hg/Gy (0.34-0.37 μM/Gy) for conventional irradiation and 0.16 to 0.17 mm Hg/Gy (0.28-0.30 μM/Gy) for UHDR irradiation. In vivo, the total decrease in oxygen after a single fraction of 20 Gy FLASH irradiation was 2.3 ± 0.3 mm Hg in normal tissue and 1.0 ± 0.2 mm Hg in tumor tissue (P < .00001), whereas no decrease in oxygen was observed from a single fraction of 20 Gy applied in conventional mode. CONCLUSIONS: Our observations suggest that oxygen depletion to radiologically relevant levels of hypoxia is unlikely to occur in bulk tissue under FLASH irradiation. For the same dose, FLASH irradiation induces less oxygen consumption than conventional irradiation in vitro, which may be related to the FLASH sparing effect. However, the difference in oxygen depletion between FLASH and conventional irradiation could not be quantified in vivo because measurements of oxygen depletion under conventional irradiation are hampered by resupply of oxygen from the blood. Published by Elsevier Inc.
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