Oxygen depletion in FLASH ultra-high-dose-rate radiotherapy: A molecular dynamics simulation
Oxygen depletion in FLASH ultra-high-dose-rate radiotherapy: A molecular dynamics simulation
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DOI：
10.1002/mp.14548
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发表时间：
2020-11-08
期刊：
影响因子：
3.8
通讯作者：
Mohan, Radhe
中科院分区：
文献类型：
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作者：
Abolfath, Ramin;Grosshans, David;Mohan, Radhe
目的 我们提出第一性原理分子动力学 (MD) 模拟，并阐述氧消耗假说机制，以解释超高剂量率 (UHDR) FLASH 放射治疗中观察到的正常组织损伤的减轻。方法我们在充满 H2O 和 O2 分子的模拟盒中模拟 DNA 片段（也代表 RNA 和蛋白质等其他生物分子）的损伤。使用蒙特卡罗轨道结构代码 Geant4-DNA 模拟阿秒物理相互作用（电离、电子和振动激发）。电离后，立即使用从头开始的 Car-Parrinello 分子动力学 (CPMD) 模拟来识别 DNA 分子周围的哪些 H2O 和 O2 分子转化为活性氧 (ROS)。随后，利用具有反作用力场（ReaxFF）的MD模拟了ROS的飞秒至纳秒反应，以说明由于ROS之间的强耦合，ROS合并成新型非活性氧（NROS）。构建了一个粗粒度模型来描述宏观层面上ROS聚集和NROS团聚物形成的相关集体现象，这与MD模拟获得的底层微观路径一致。结果时间依赖性分子模拟揭示了UHDR产生的ROS之间亚稳态和瞬态意大利面条状复合物的形成。在 UHDR 下产生的较高 ROS 密度下，通过羟基 (.OH) 自由基之间的吸引电极性力、氢键和磁偶极-偶极相互作用介导，产生绞链（即 NROS）。与传统剂量率 (CDR) 产生的孤立且稀疏的 ROS 相比，NROS 的移动性往往不如细胞生物分子。我们将这种效应归因于抑制每个粒子轨迹引起的生物分子损伤。在给定的氧气水平下，随着剂量率的增加，NROS链的大小和数量增加，相应地有毒ROS成分的数量减少。类似地，在给定的高剂量率下，随着氧含量的增加，NROS 链的大小和数量也会增加，直到达到最佳氧含量。超过该水平，存在的氧气量可能足以使 NROS 链的产生饱和，从而逆转 UHDR 的节约效应。 结论 我们表明，假设在 FLASH 剂量率下，氧气耗尽会在飞秒至纳秒内发生，该氧气耗尽会在照射后的飞秒至纳秒内发生。该机制由 ROS 复合物 (NROS) 链的缓慢动态控制。在生理含氧（约 4-5% 氧气）条件下（即在正常组织中），NROS 比缺氧条件下（例如 10-15%）更丰富，UHDR 造成的氧气消耗可能不足以保护组织。
Purpose We present a first-principles molecular dynamics (MD) simulation and expound upon a mechanism of oxygen depletion hypothesis to explain the mitigation of normal tissue injury observed in ultra-high-dose-rate (UHDR) FLASH radiotherapy.Methods We simulated damage to a segment of DNA (also representing other biomolecules such as RNA and proteins) in a simulation box filled with H2O and O2 molecules. Attoseconds physical interactions (ionizations, electronic, and vibrational excitations) were simulated by using the Monte Carlo track structure code Geant4-DNA. Immediately after ionization, ab initio Car-Parrinello molecular dynamics (CPMD) simulation was used to identify which H2O and O2 molecules surrounding the DNA molecule were converted into reactive oxygen species (ROS). Subsequently, the femto- to nanosecond reactions of ROS were simulated by using MD with reactive force field (ReaxFF), to illustrate ROS merging into new types of non-reactive oxygen species (NROS) due to strong coupling among ROS. A coarse-grained model was constructed to describe the relevant collective phenomenon at the macroscopic level on ROS aggregation and formation of NROS agglomerates consistent with the underlying microscopic pathways obtained from MD simulations.Results Time-dependent molecular simulations revealed the formation of metastable and transient spaghetti-like complexes among ROS generated at UHDR. At the higher ROS densities produced under UHDR, stranded chains (i.e., NROS) are produced, mediated through attractive electric polarity forces, hydrogen bonds, and magnetic dipole-dipole interactions among hydroxyl (.OH) radicals. NROS tend to be less mobile than cellular biomolecules as opposed to the isolated and sparsely dense ROS generated at conventional dose rates (CDR). We attribute this effect to the suppression of biomolecular damage induced per particle track. At a given oxygen level, as the dose rate increases, the size and number of NROS chains increase, and correspondingly the population of toxic ROS components decreases. Similarly, at a given high dose rate, as the oxygen level increases, so do the size and number of NROS chains until an optimum level of oxygen is reached. Beyond that level, the amount of oxygen present may be sufficient to saturate the production of NROS chains, thereby reversing the sparing effects of UHDRs.Conclusions We showed that oxygen depletion, hypothesized to lead to lower normal-tissue toxicity at FLASH dose rates, takes place within femto- to nanoseconds after irradiation. The mechanism is governed by the slow dynamics of chains of ROS complexes (NROS). Under physoxic (approximate to 4-5% oxygen) conditions (i.e., in normal tissues), NROS are more abundant than in hypoxic conditions (e.g., 10-15%), oxygen depletion by UHDRs may not be sufficient for tissue sparing.