AGuIX are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been observed with different types of irradiations in vitro and in vivo on a large number of cancer types (brain, lung, melanoma, head and neck…). The review concludes with the second generation of AGuIX nanoparticles and the first preliminary results on human.

BackgroundRecent demonstrations of normal tissue sparing by high dose, high dose rate FLASH radiotherapy have driven considerable interest in its application to improve clinical outcomes. However, there remains significant uncertainty about the underlying mechanisms of FLASH sparing, and how deliveries can be optimised to maximize benefit from this effect. Rapid oxygen depletion has been suggested as a potential mechanism by which these effects occur, but has yet to be quantitatively tested against experimental data. MethodsModels of oxygen kinetics during irradiation were used to develop a time-dependent model of the Oxygen Enhancement Ratio (OER) in mammalian cells that incorporates oxygen depletion. The characteristics of this model were then explored in terms of the dose-and dose rate dependence of the OER. This model was also fit to experimental data from both in vitro and in vivo datasets. ResultsIn cases of FLASH radiotherapy, this model suggests that oxygen levels can be depleted by amounts which are sufficient to impact on radiosensitivity only in conditions of intermediate oxygen tension, with no effect seen at high or very low oxygen levels. The model also effectively reproduced the dose, dose rate and oxygen tension dependence of responses to FLASH radiotherapy in a range of systems, with model parameters compatible with published data. ConclusionsOxygen depletion provides a credible quantitative model to understand the biological effects of FLASH radiotherapy and is compatible with a range of experimental observations of FLASH sparing. These results highlight the need for more detailed quantification of oxygen depletion under high dose rate radiation exposures in relevant systems, and the importance of oxygen tension in target tissues for FLASH sparing to be observed.

This roadmap outlines the potential roles of metallic nanoparticles (MNPs) in the field of radiation therapy. MNPs made up of a wide range of materials (from Titanium, Z=22, to Bismuth, Z=83) and a similarly wide spectrum of potential clinical applications, including diagnostic, therapeutic (radiation

Radiation exposures at ultra-high dose rates (UHDR) at several orders of magnitude greater than in current clinical radiotherapy have been shown to manifest differential radiobiological responses compared to conventional dose rates (CONV). This has led to studies investigating the application of UHDR for therapeutic advantage (FLASH-RT) which have gained significant interest since the initial discovery in 2014 that demonstrated reduced lung toxicity with equivalent levels of tumour control compared with conventional dose-rate radiotherapy. Many subsequent studies have demonstrated the potential protective role of FLASH-RT in normal tissues, yet the underlying molecular and cellular mechanisms of the FLASH effect remain to be fully elucidated. Here, we summarise the current evidence of the FLASH effect and review FLASH-RT studies performed in preclinical models of normal tissue response. To critically examine the underlying biological mechanisms of responses to UHDR radiation exposures, we evaluate in vitro studies performed with normal and tumour cells. Differential responses to UHDR vs CONV irradiation recurrently involve reduced inflammatory processes and differential expression of pro-and anti-inflammatory genes. In addition, frequently reduced levels of DNA damage or misrepair products are seen after UHDR irradiation. So far, it is not clear what signal elicits these differential responses, but there are indications for involvement of reactive species. Different susceptibility to FLASH effects observed between normal and tumour cells may result from altered metabolic and detoxification pathways and/or repair pathways used by tumour cells. We summarize the current theories that may explain the FLASH effect and highlight This article is protected by copyright. All rights reserved.3 important research questions which are key to a better mechanistic understanding and, thus, the future implementation of FLASH-RT in the clinic. -INTRODUCTIONRadiation therapy (RT) remains a critical part of clinical cancer care prescribed to > 50% of patients in high-income countries and contributes to more than 30% of all long-term cancer survivors 1,2 . Technological advances in imaging and RT delivery techniques have resulted in major improvements in patient survival through improved precision and ability to conform dose to the tumour targets whilst minimising dose to surrounding organs at risk (OARs). In addition to improvements in technical radiotherapy, major research efforts have been made to exploit the unique radiobiological responses that occur at ultra-high dose rates (UHDR). In comparison to conventional clinical dose rates (CONV) in the region of 0.01-0.40 Gy/s, UHDR radiotherapy was originally established using microsecond pulses of 5 MeV electrons with intra-pulse dose rate in the range 10 6 -10 7 Gy/s, time-averaged dose rate > 40 Gy/s and

While the workshop was co-sponsored by the NCI and RSS, the comments in this report are strictly the opinions of the co-authors and does not constitute endorsement of these results and/or treatments by the NCI and RSS or consensus of all the co-authors on each of the points. This report is designed to stimulate further formal research and development to explore the future clinical application of these novel therapies and not for implementation into routine clinical practice.