# Oxygen dynamics in FLASH radiotherapy

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $528,754

## Abstract

Project Abstract
Oxygen sensing with high precision & high spatial localization can provide new insights into the action and effects
of ultra-high dose rate (UHDR) radiation therapy (RT), known as FLASH-RT. When compared to RT delivered
at conventional dose rates (C-RT), FLASH-RT has been shown to inflict lower radiobiological damage to normal
tissues while still preserving the same tumor killing efficacy. This enhanced selectivity has become known as the
‘FLASH’ effect. Oxygen (O2) has been suggested to underpin the FLASH effect, with several theories centered
on increased consumption of oxygen upon application of UHDR radiation. However, our in vitro and in vivo
oxygen measurements using the phosphorescence quenching method were the first to show that compared to
C-RT, FLASH-RT leads not to higher, but actually lower O2 consumption per unit radiation dose. Additionally,
we have been the first to establish that the oxygen consumption rate during FLASH-RT is dependent upon the
baseline oxygen level within tissue, indicating that the oxygen fixation effect may be oxygen dependent. Based
on these results, we hypothesize that the FLASH effect originates not from fast depletion of oxygen and
radiobiological hypoxia, but rather from a dose rate dependent oxygen enhancement ratio (OER) from
differences in oxygen consumption and damage fixation between FLASH-RT vs C-RT. This original hypothesis
can be tested only with accurate measurement of the acute change in oxygen partial pressure (pO2), as an
indirect biomarker of the oxygen fixation happening. If this is via variation in peroxyl formation, measurement of
pO2 is an ideal surrogate of changes in DNA damage from variations in dose rate delivery parameters. In this
project we will develop a unique high-resolution O2 imaging method to track and optimize the FLASH efficacy by
combining phosphorescence quenching oximetry in vivo with Cherenkov Excited Luminescence Imaging (CELI)
to dynamically quantify oxygen in tissues with spatial resolution of ~1 mm. In CELI, X-ray beams of RT generate
localized optical field, which excites phosphorescence deep within tissues, and the phosphorescence, imaged
with external detectors, reflects tissue oxygenation. This work will pioneer a new approach to oxygen
measurements in RT and will provide mechanistic insight into FLASH radiochemistry with the important potential
to optimize the radiobiological efficacy of FLASH-RT. The teams and resources at Wisconsin, Dartmouth and
UPenn are unparalleled in their experimental potential for this project, and the work will provide fundamentally
new capabilities in guidance of RT, with guidance by key consultants. The components of our work have been
based upon high impact publication of original in vivo data with both electrons and protons. The fundamental
insights that can be gained here are very timely, as the search for the origins of the FLASH effect in normal
tissue is happening now. As we find ways to understand the mechan...

## Key facts

- **NIH application ID:** 10873334
- **Project number:** 5R01CA271330-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Brian William Pogue
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $528,754
- **Award type:** 5
- **Project period:** 2023-06-21 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873334

## Citation

> US National Institutes of Health, RePORTER application 10873334, Oxygen dynamics in FLASH radiotherapy (5R01CA271330-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10873334. Licensed CC0.

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