Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire; Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education & School of Life Science and Technology, Xidian University, Xi'an, Shaanxi, China.
Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire; Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; Department of Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.
Int J Radiat Oncol Biol Phys. 2021 Sep 1;111(1):240-248. doi: 10.1016/j.ijrobp.2021.03.056. Epub 2021 May 18.
PURPOSE: Delivery of radiation at ultrahigh dose rates (UHDRs), known as FLASH, has recently been shown to preferentially spare normal tissues from radiation damage compared with tumor tissues. However, the underlying mechanism of this phenomenon remains unknown, with one of the most widely considered hypotheses being that the effect is related to substantial oxygen depletion upon FLASH, thereby altering the radiochemical damage during irradiation, leading to different radiation responses of normal and tumor cells. Testing of this hypothesis would be advanced by direct measurement of tissue oxygen in vivo during and after FLASH irradiation. METHODS AND MATERIALS: Oxygen measurements were performed in vitro and in vivo using the phosphorescence quenching method and a water-soluble molecular probe Oxyphor 2P. The changes in oxygen per unit dose (G-values) were quantified in response to irradiation by 10 MeV electron beam at either UHDR reaching 300 Gy/s or conventional radiation therapy dose rates of 0.1 Gy/s. RESULTS: In vitro experiments with 5% bovine serum albumin solutions at 23°C resulted in G-values for oxygen consumption of 0.19 to 0.21 mm Hg/Gy (0.34-0.37 μM/Gy) for conventional irradiation and 0.16 to 0.17 mm Hg/Gy (0.28-0.30 μM/Gy) for UHDR irradiation. In vivo, the total decrease in oxygen after a single fraction of 20 Gy FLASH irradiation was 2.3 ± 0.3 mm Hg in normal tissue and 1.0 ± 0.2 mm Hg in tumor tissue (P < .00001), whereas no decrease in oxygen was observed from a single fraction of 20 Gy applied in conventional mode. CONCLUSIONS: Our observations suggest that oxygen depletion to radiologically relevant levels of hypoxia is unlikely to occur in bulk tissue under FLASH irradiation. For the same dose, FLASH irradiation induces less oxygen consumption than conventional irradiation in vitro, which may be related to the FLASH sparing effect. However, the difference in oxygen depletion between FLASH and conventional irradiation could not be quantified in vivo because measurements of oxygen depletion under conventional irradiation are hampered by resupply of oxygen from the blood.
目的：超高剂量率（UHDR）下的放射治疗，即 FLASH，最近已被证明可以优先保护正常组织免受放射损伤，而肿瘤组织则不受影响。然而，这一现象的潜在机制尚不清楚，其中最广泛考虑的假说之一是，FLASH 会导致大量氧气耗竭，从而改变照射过程中的放射化学损伤，导致正常和肿瘤细胞的辐射反应不同。通过在 FLASH 照射过程中和照射后直接测量体内组织中的氧气，可以进一步验证这一假说。
方法和材料：使用磷光猝灭法和水溶性分子探针 Oxyphor 2P 在体外用和体内在体外和体内进行氧测量。通过 10 MeV 电子束在 UHDR（达到 300 Gy/s）或常规放射治疗剂量率（0.1 Gy/s）下进行照射，定量测量单位剂量的氧变化（G 值）。
结果：在 23°C 下，5%牛血清白蛋白溶液的体外实验导致常规照射时的氧消耗 G 值为 0.19 至 0.21 毫米汞柱/ Gy（0.34 至 0.37 μM/ Gy），而 UHDR 照射时为 0.16 至 0.17 毫米汞柱/ Gy（0.28 至 0.30 μM/ Gy）。在体内，单次 20 Gy FLASH 照射后，正常组织中的总氧量下降了 2.3 ± 0.3 毫米汞柱，肿瘤组织中的总氧量下降了 1.0 ± 0.2 毫米汞柱（P <.00001），而常规模式下单次 20 Gy 照射则没有观察到氧的下降。
结论：我们的观察结果表明，在 FLASH 照射下，大块组织中不太可能出现与放射学相关的缺氧水平的氧耗竭。对于相同的剂量，FLASH 照射比体外常规照射消耗的氧气更少，这可能与 FLASH 保护效应有关。然而，由于常规照射下的氧耗竭测量受到血液中氧供应的影响，因此无法在体内定量测量 FLASH 和常规照射之间的氧耗竭差异。
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