Oxygen Consumption In Vivo by Ultra-High Dose Rate Electron Irradiation Depends Upon Baseline Tissue Oxygenation

Jacob P Sunnerberg; Armin D Tavakkoli; Arthur F Petusseau; Noah J Daniel; Austin M Sloop; Wilson A Schreiber; Jiang Gui; Rongxiao Zhang; Harold M Swartz; P Jack Hoopes; David J Gladstone; Sergei A Vinogradov; Brian W Pogue

doi:10.1016/j.ijrobp.2024.10.018

Oxygen Consumption In Vivo by Ultra-High Dose Rate Electron Irradiation Depends Upon Baseline Tissue Oxygenation

Int J Radiat Oncol Biol Phys. 2024 Oct 24:S0360-3016(24)03510-7. doi: 10.1016/j.ijrobp.2024.10.018. Online ahead of print.

Affiliations

¹ Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire.
² Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.
³ Department of Radiation Oncology, University of Missouri, Columbia, Missouri.
⁴ Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire; Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire; Dartmouth Cancer Center, Dartmouth Health, Lebanon, New Hampshire.
⁵ Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania.
⁶ Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire; Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin. Electronic address: bpogue@wisc.edu.

PMID: 39461597
DOI: 10.1016/j.ijrobp.2024.10.018

Abstract

Purpose: This study aimed to assess the impact of tissue oxygen levels on transient oxygen consumption induced by ultra-high dose rate (UHDR) electron radiation in murine flank and to examine the effect of dose rate variations on this relationship.

Methods and materials: Real-time oximetry using the phosphorescence quenching method and Oxyphor PdG4 molecular probe was employed. Continuous measurements were taken during radiation delivery on a UHDR-capable Mobetron linear accelerator. Oxyphor PdG4 was administered into the subcutaneous tissue of the flank skin 1 hour before irradiation. Skin oxygen tension (pO₂) was manipulated by adjusting oxygen content in the inhaled gas mixture and/or by vasculature compression. A skin surface radiation dose of 19.8 ± 0.3 Gy was verified using a calibrated semiconductor diode dosimeter. Dose rate was varied across the UHDR range by changing linear accelerator cone length and pulse repetition frequency.

Results: The decrease in pO₂ per unit dose during radiation delivery, termed oxygen consumption g-value (g_O2, mmHg/Gy), was significantly influenced by tissue oxygen levels in the range 0 to 65 mmHg under UHDR conditions. Within the 0 to 20 mmHg range, g_O2 exhibited a sharp increase with rising baseline pO₂, plateauing at 0.26 mmHg/Gy. Dose rate variations (mean values, 25-1170 Gy/s; per pulse doses of 2.5-9.8 Gy) were explored by varying both cone length and pulse repetition frequency (10-120 Hz) with no significant changes in g_O2. Conventional dose rate irradiation resulted in no discernible changes in pO₂.

Conclusions: The results show significant differences in the radiation-chemical effects of UHDR radiation between hypoxic and well-oxygenated tissues. Similar trends between earlier published in vitro and in vivo experiments presented herein suggest the chemical mechanisms driving the dependencies of g_O2 on pO₂ are similar, potentially underpinning the FLASH effect. Importantly, significant variations in baseline pO₂ were observed in animals kept under identical conditions, underscoring the necessity to control and monitor tissue oxygen levels for preclinical investigations and future clinical applications of FLASH radiation therapy.