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Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species.

ABSTRACT: Here, we highlight the potential translational benefits of delivering FLASH radiotherapy using ultra-high dose rates (>100 Gy?s-1). Compared with conventional dose-rate (CONV; 0.07-0.1 Gy?s-1) modalities, we showed that FLASH did not cause radiation-induced deficits in learning and memory in mice. Moreover, 6 months after exposure, CONV caused permanent alterations in neurocognitive end points, whereas FLASH did not induce behaviors characteristic of anxiety and depression and did not impair extinction memory. Mechanistic investigations showed that increasing the oxygen tension in the brain through carbogen breathing reversed the neuroprotective effects of FLASH, while radiochemical studies confirmed that FLASH produced lower levels of the toxic reactive oxygen species hydrogen peroxide. In addition, FLASH did not induce neuroinflammation, a process described as oxidative stress-dependent, and was also associated with a marked preservation of neuronal morphology and dendritic spine density. The remarkable normal tissue sparing afforded by FLASH may someday provide heretofore unrealized opportunities for dose escalation to the tumor bed, capabilities that promise to hasten the translation of this groundbreaking irradiation modality into clinical practice.

SUBMITTER: Montay-Gruel P

PROVIDER: S-EPMC6561167 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species.

Montay-Gruel Pierre P Acharya Munjal M MM Petersson Kristoffer K Alikhani Leila L Yakkala Chakradhar C Allen Barrett D BD Ollivier Jonathan J Petit Benoit B Jorge Patrik Gonçalves PG Syage Amber R AR Nguyen Thuan A TA Baddour Al Anoud D AAD Lu Celine C Singh Paramvir P Moeckli Raphael R Bochud François F Germond Jean-François JF Froidevaux Pascal P Bailat Claude C Bourhis Jean J Vozenin Marie-Catherine MC Limoli Charles L CL

Proceedings of the National Academy of Sciences of the United States of America 20190516 22

Here, we highlight the potential translational benefits of delivering FLASH radiotherapy using ultra-high dose rates (>100 Gy⋅s<sup>-1</sup>). Compared with conventional dose-rate (CONV; 0.07-0.1 Gy⋅s<sup>-1</sup>) modalities, we showed that FLASH did not cause radiation-induced deficits in learning and memory in mice. Moreover, 6 months after exposure, CONV caused permanent alterations in neurocognitive end points, whereas FLASH did not induce behaviors characteristic of anxiety and depression ...[more]

PMID: 31097580

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Project description:The biological application of ruthenium anticancer prodrugs for photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) is restricted by the need to use poorly penetrating high-energy photons for their activation, i.e., typically blue or green light. Upconverting nanoparticles (UCNPs), which produce high-energy light under near-infrared (NIR) excitation, may solve this issue, provided that the coupling between the UCNP surface and the Ru prodrug is optimized to produce stable nanoconjugates with efficient energy transfer from the UCNP to the ruthenium complex. Herein, we report on the synthesis and photochemistry of the two structurally related ruthenium(II) polypyridyl complexes [Ru(bpy)2(5)](PF6)2 ([1](PF6)2) and [Ru(bpy)2(6)](PF6)2 ([2](PF6)2), where bpy = 2,2-bipyridine, 5 is 5,6-bis(dodecyloxy)-2,9-dimethyl-1,10-phenanthroline, and 6 is 5,6-bis(dodecyloxy)-1,10-phenanthroline. [1](PF6)2 is photolabile as a result of the steric strain induced by ligand 5, but the irradiation of [1](PF6)2 in solution leads to the nonselective and slow photosubstitution of one of its three ligands, making it a poor PACT compound. On the other hand, [2](PF6)2 is an efficient and photostable PDT photosensitizer. The water-dispersible, negatively charged nanoconjugate UCNP@lipid/[2] was prepared by the encapsulation of 44 nm diameter NaYF4:Yb3+,Tm3+ UCNPs in a mixture of 1,2-dioleoyl-sn-glycero-3-phosphate and 1,2-dioleoyl-sn-glycero-3-phosphocholine phospholipids, cholesterol, and the amphiphilic complex [2](PF6)2. A nonradiative energy transfer efficiency of 12% between the Tm3+ ions in the UCNP and the Ru2+ acceptor [2]2+ was found using time-resolved emission spectroscopy. Under irradiation with NIR light (969 nm), UCNP@lipid/[2] was found to produce reactive oxygen species (ROS), as judged by the oxidation of the nonspecific ROS probe 2',7'-dichlorodihydrofluorescein (DCFH2-). Determination of the type of ROS produced was precluded by the negative surface charge of the nanoconjugate, which resulted in the electrostatic repulsion of the more specific but also negatively charged 1O2 probe tetrasodium 9,10-anthracenediyl-bis(methylene)dimalonate (Na4(ADMBMA)).

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Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species.

Publications

Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species.

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