背景:超高剂量率辐射(UHDR)在纯水中产生的过氧化氢(H2O2)较少,正如一些实验研究表明的那样,并被用作理论有效性的论据,该理论认为FLASH由于活性氧(ROS)产生较少而节省了正常组织。相比之下,大多数蒙特卡洛模拟研究都得出了相反的结论。
目的:我们旨在揭示UHDR对纯水中H2O2产生的影响及其潜在机制,作为蒙特卡罗模拟的基准。我们假设溶剂化电子(eaq-${\\mathrm{e}}_{\\mathrm{aq}}^-$)去除羟基自由基(•OH)的反应,H2O2的前体,是UHDR导致H2O2(G[H2O2])的较低G值(分子/100eV)的原因,因为:1,eaq-${\\mathrm{e}}_{{\\mathrm{aq}}^-$和•OH之间的三阶反应对UHDR增加的瞬时ROS浓度比•OH自反应产生H2O2的两阶反应更敏感;2,eaq-${\\mathrm{e}_{^$$$$$$$$$$$这意味着eaq-${\\mathrm{e}}_{{\\mathrm{aq}}^-$将主导•OH的竞争,并从UHDR的赛道间效应中受益更多。同时,我们还通过实验验证了在常规辐照中导致较低G(H2O2)的长寿命自由基的理论,这是在一些模拟研究中提到的。
方法:通过AmplexUltraRed测定法测定H2O2。430.1MeV/u碳离子(50和0.1Gy/s),9MeV电子(600和0.62Gy/s),使用和200kVX射线管(10和0.1Gy/s)。对于三种水(实际低氧:1%O2;低氧:1%O2和5%CO2;常氧:21%O2),未起泡和用N2O起泡的样品,eaq的清除剂-${\\mathrm{e}}_{\\mathrm{aq}}}^-$,在不同的绝对剂量水平下用常规和UHDR辐照碳离子和电子。用硝酸钠(NaNO3)溶解的常氧水,eaq的另一个清道夫-${\\mathrm{e}}_{\\mathrm{aq}}}^-$,用X射线辐照N2O,以验证低LET电子束的结果。
结果:UHDR导致比常规辐照更低的G(H2O2)。O2和CO2都可以增进G(H2O2)。N2O增加UHDR和常规辐照的G(H2O2),并消除了碳离子之间的差异。然而,N2O在电子常规辐照中降低G(H2O2),但在UHDR的情况下增加G(H2O2),最终没有G(H2O2)的剂量率依赖性。三次泄漏的碳UHDR的G(H2O2)不低于一次泄漏的UHDR。然而,电子束对于三次溢出的UHDR比一次溢出的UHDR显示更低的G(H2O2)。具有N2O或NaNO3的常氧水都可以消除X射线的H2O2产生的剂量率依赖性。
结论:对于高LET碳和低LET电子和X射线束,UHDR具有比常规辐照更低的G(H2O2)。这两个拾荒者为eaq-${\\mathrm{e}}_{{\\mathrm{aq}}}^-$,N2O和NaNO3,消除了G(H2O2)的剂量率依赖性,这表明eaq-${\\mathrm{e}}_{{\\mathrm{aq}}^-$是UHDR降低G(H2O2)的原因。三次溢出的UHDR与一次溢出的UHDR表明,减少常规辐照的G(H2O2)的残余自由基的假设可能仅对低LET电子束有效。
BACKGROUND: Ultrahigh dose-rate radiation (UHDR) produces less hydrogen peroxide (H2O2) in pure water, as suggested by some experimental studies, and is used as an argument for the validity of the theory that FLASH spares the normal tissue due to less reactive oxygen species (ROS) production. In contrast, most Monte Carlo simulation studies suggest the opposite.
OBJECTIVE: We aim to unveil the effect of UHDR on H2O2 production in pure water and its underlying mechanism, to serve as a benchmark for Monte Carlo simulation. We hypothesized that the reaction of solvated electrons ( e aq - ${\\mathrm{e}}_{{\\mathrm{aq}}}^ - $ ) removing hydroxyl radicals (•OH), the precursor of H2O2, is the reason why UHDR leads to a lower G-value (molecules/100 eV) for H2O2 (G[H2O2]), because: 1, the third-order reaction between e aq - ${\\mathrm{e}}_{{\\mathrm{aq}}}^ - $ and •OH is more sensitive to increased instantaneous ROS concentration by UHDR than a two-order reaction of •OH self-reaction producing H2O2; 2, e aq - ${\\mathrm{e}}_{{\\mathrm{aq}}}^ - $ has two times higher diffusion coefficient and higher reaction rate constant than that of •OH, which means e aq - ${\\mathrm{e}}_{{\\mathrm{aq}}}^ - $ would dominate the competition for •OH and benefit more from the inter-track effect of UHDR. Meanwhile, we also experimentally verify the theory of long-lived radicals causing lower G(H2O2) in conventional irradiation, which is mentioned in some simulation studies.
METHODS: H2O2 was measured by Amplex UltraRed assay. 430.1 MeV/u carbon ions (50 and 0.1 Gy/s), 9 MeV electrons (600 and 0.62 Gy/s), and 200 kV x-ray tube (10 and 0.1 Gy/s) were employed. For three kinds of water (real hypoxic: 1% O2; hypoxic: 1% O2 and 5% CO2; and normoxic: 21% O2), unbubbled and bubbled samples with N2O, the scavenger of e aq - ${\\mathrm{e}}_{{\\mathrm{aq}}}^ - $ , were irradiated by carbon ions and electrons with conventional and UHDR at different absolute dose levels. Normoxic water dissolved with sodium nitrate (NaNO3), another scavenger of e aq - ${\\mathrm{e}}_{{\\mathrm{aq}}}^ - $ , and bubbled with N2O was irradiated by x-ray to verify the results of low-LET electron beam.
RESULTS: UHDR leads to a lower G(H2O2) than conventional irradiation. O2 and CO2 can both increase G(H2O2). N2O increases G(H2O2) of both UHDR and conventional irradiation and eliminates the difference between them for carbon ions. However, N2O decreases G(H2O2) in electron conventional irradiation but increases G(H2O2) in the case of UHDR, ending up with no dose-rate dependency of G(H2O2). Three-spilled carbon UHDR does not have a lower G(H2O2) than one-spilled UHDR. However, the electron beam shows a lower G(H2O2) for three-spilled UHDR than for one-spilled UHDR. Normoxic water with N2O or NaNO3 can both eliminate the dose rate dependency of H2O2 production for x-ray.
CONCLUSIONS: UHDR has a lower G(H2O2) than the conventional irradiation for both high LET carbon and low LET electron and x-ray beams. Both scavengers for e aq - ${\\mathrm{e}}_{{\\mathrm{aq}}}^ - $ , N2O and NaNO3, eliminate the dose-rate dependency of G(H2O2), which suggests e aq - ${\\mathrm{e}}_{{\\mathrm{aq}}}^ - $ is the reason for decreased G(H2O2) for UHDR. Three-spilled UHDR versus one-spilled UHDR indicates that the assumption of residual radicals reducing G(H2O2) of conventional irradiation may only be valid for low LET electron beam.