Oxygen dynamics in FLASH radiotherapy

工程摘要 具有高精度和高空间定位的氧气传感可以为作用和效果提供新的见解 超高剂量率（UHDR）放射治疗（RT），称为FLASH-RT。 在常规剂量率（C-RT）下，FLASH-RT已被证明对正常人造成较低的放射生物学损伤。 同时仍然保持相同的肿瘤杀伤功效。这种增强的选择性被称为 “闪光”效果。氧气（O2）被认为是闪光效应的基础，有几种理论 在应用UHDR辐射时增加氧气消耗。然而，我们在体外和体内 使用磷光猝灭法的氧测量首次表明， C-RT、FLASH-RT不会导致更高，但实际上会降低每单位辐射剂量的O2消耗。此外，本发明还 我们首先确定了FLASH-RT期间的耗氧速率取决于 组织内的基线氧水平，表明氧固定效应可能是氧依赖性的。基于 根据这些结果，我们假设闪光效应不是由于氧气的快速消耗， 放射生物学缺氧，而是来自剂量率依赖性氧增强比（OER）， FLASH-RT与C-RT之间的耗氧量和损伤固定的差异。 只能通过准确测量氧分压（Δ pO 2）的急剧变化进行测试， 氧固定发生的间接生物标志物。如果这是通过过氧化氢形成的变化， SpO 2是剂量率传递参数变化引起的DNA损伤变化的理想替代物。在这 我们将开发一种独特的高分辨率O2成像方法，通过以下方式跟踪和优化FLASH的功效： 将体内磷光猝灭血氧测定法与切伦科夫激发发光成像（CELI）相结合 以动态量化组织中的氧气，空间分辨率约为1 mm。在CELI中，RT的X射线束产生 局部光场，激发组织深处的磷光， 与外部检测器，反映组织氧合。这项工作将开创一种新的氧气方法 在RT测量，并将提供机制的洞察闪光放射化学的重要潜力 为了优化FLASH-RT的放射生物学功效，威斯康星州、达特茅斯和 宾夕法尼亚大学在这个项目的实验潜力方面是无与伦比的，这项工作将从根本上提供 在关键顾问的指导下，指导RT的新能力。我们工作的组成部分是 基于具有电子和质子的原始体内数据的高影响力出版物。根本 可以在这里获得的见解是非常及时的，因为寻找FLASH效应的起源是正常的， 组织正在发生。当我们找到了解机制的方法时，这可以帮助我们优化其效果， 并测试导致其优化的组织的剂量率射束递送和氧合条件。

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 mechanisms, that can help us optimize its effect, and test the dose rate beam delivery and oxygenation conditions for tissues that lead to its optimization.