Mechanisms of Action in FLASH Radiotherapy: A Comprehensive Review of Physicochemical and Biological Processes on Cancerous and Normal Cells

Cells, Journal Year: 2024, Volume and Issue: 13(10), P. 835 - 835

Published: May 14, 2024

The advent of FLASH radiotherapy (FLASH-RT) has brought forth a paradigm shift in cancer treatment, showcasing remarkable normal cell sparing effects with ultra-high dose rates (>40 Gy/s). This review delves into the multifaceted mechanisms underpinning efficacy effect, examining both physicochemical and biological hypotheses biophysics. process encompasses oxygen depletion, reactive species, free radical recombination. In parallel, explores effect on immune system blood vessels treatment sites such as brain, lung, gastrointestinal tract, skin, subcutaneous tissue. investigated selective targeting cells modulation tumor microenvironment through FLASH-RT. Examining these mechanisms, we explore implications challenges integrating FLASH-RT treatment. potential to spare cells, boost response, modify vasculature offers new therapeutic strategies. Despite progress understanding FLASH-RT, this highlights knowledge gaps, emphasizing need for further research optimize its clinical applications. synthesis insights serves comprehensive resource biology, molecular biophysics researchers clinicians navigating evolution therapy.

Language: Английский

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Targeting Sub-Cellular Organelles for Boosting Precision Photodynamic Therapy

Chemical Communications, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Among various cancer treatment methods, photodynamic therapy has received significant attention due to its non-invasiveness and high efficiency in inhibiting tumour growth. Recently, specific organelle targeting photosensitizers have increasing interest their precise accumulation ability trigger organelle-mediated cell death signalling pathways, which greatly reduces the drug dosage, minimizes toxicity, avoids multidrug resistance, prevents recurrence. In this review, recent advances representative used targeted on organelles, specifically including endoplasmic reticulum, Golgi apparatus, mitochondria, nucleus, lysosomes, been comprehensively reviewed with a focus structure pathways. Furthermore, perspective future research potential challenges precision presented at end.

Language: Английский

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Stiffening cells with light

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 30, 2025

Abstract Fluorescence microscopy is widely used to observe structures and dynamic processes in living cells organisms often as if it were purely innocuous the or of interest. However, can lead phototoxicity, which affect cellular behavior erroneous interpretations observations. The major cause cell damage through phototoxicity production reactive oxygen species (ROS), form crosslinks between intracellular molecules, including proteins nucleic acids. By using profile microindentation atomic force microscopy, we demonstrate that excitation various fluorescent probes leads a large increase stiffness several types within seconds illumination. stiffening exhibits dose-dependent response, where longer exposure times exciting light are correlated with larger stiffening. This photostiffening effect explains why T loaded Fluo-4 Calcium probe stop emitting protrusion after turned on. We observed different fluorophores. showed repeated indentation alone led well blue UV absence fluoroph ore. latter case, was much smaller than when fluorophore excited. both sharp blunt indenters show occurred not only at cortex level but also deeper interior independent actin cytoskeleton organization. reproduced by incubating ROS inducer, H 2 O . photosensitizer Pheophorbide , induces specific type species, namely singlet oxygen, study reminds experimentalists crucial perform controls fluorescence. It further allows us propose exploiting new method for rapidly quantifying phototoxicity. Significance reveals direct relationship fluorescence mechanical properties. generality th phenomenon across diverse fluorophores highlights importance controlling experiments, particular complex, quantitative biology biophysical an unexpected rol e identifies proxy assessing efficacy photodynamic therapy.

Language: Английский

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Radiation therapy-induced normal tissue damage: involvement of EMT pathways and role of FLASH-RT in reducing toxicities

Radiation and Environmental Biophysics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 6, 2025

Language: Английский

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Engineered Cell Microenvironments: A Benchmark Tool for Radiobiology

ACS Applied Materials & Interfaces, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

The development of engineered cell microenvironments for fundamental mechanobiology, in vitro disease modeling, and tissue engineering applications increased exponentially during the last two decades. In such context, radiobiology is a field research aiming at understanding effects ionizing radiation (e.g., X-rays/photons, high-speed electrons, protons) on biological (cancerous) tissues cells, particular terms DNA damage leading to death. Herein, perspective provides comparative assessment overview scaffold-free, scaffold-based, organ-on-a-chip models radiobiology, highlighting opportunities, limitations, future pathways improve currently existing approaches toward personalized cancer medicine.

Language: Английский

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FLASH proton reirradiation, with or without hypofractionation, reduces chronic toxicity in the normal murine intestine, skin, and bone

Radiotherapy and Oncology, Journal Year: 2025, Volume and Issue: unknown, P. 110744 - 110744

Published: Jan. 1, 2025

Language: Английский

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Ultra-high dose rate radiotherapy overcomes radioresistance in head and neck squamous cell carcinoma

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 3, 2025

Abstract Radiotherapy (RT) resistance in head and neck squamous cell carcinoma (HNSCC) significantly hampers local control patient prognosis. This study investigated the efficacy molecular mechanisms of high-energy X-ray-based ultra-high dose rate radiotherapy (UHDR-RT) overcoming RT resistance. The established RT-resistant HNSCC lines animal models were subjected to UHDR-RT or conventional (Conv-RT) via a high-power rhodotron accelerator. Cellular assays assessed malignant phenotype, viability, degree DNA damage, whereas vivo evaluations focused on tumor proliferation immune microenvironment (TiME). Transcriptome sequencing Olink proteomics employed explore underlying involved. In vitro experiments indicated that suppressed radioresistant invasion, while promoting apoptosis exacerbating damage. contrast, its radiosensitive cells was comparable Conv-RT. studies using patient-derived xenograft nude mice demonstrated only partially reversed Transcriptomic proteomic analyses C57BL/6J revealed predominant role TiME modulating reversing radioresistance. Immunofluorescence flow cytometry confirmed increased CD8 + T an M1/M2 macrophage ratio post-UHDR-RT. Mechanistically, activated cells, which stimulated M1 macrophages through paracrine IFN-γ signaling, thereby enhancing activation. Furthermore, secreted CXCL9, turn reactivated forming feedforward loop amplified elucidates dual directly inducing damage TiME, highlighting potential treating HNSCC.

Language: Английский

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Radiotherapy and skin cancers – An essential collaboration for onco-dermatology

Annales de Dermatologie et de Vénéréologie, Journal Year: 2025, Volume and Issue: 152(1), P. 103359 - 103359

Published: March 1, 2025

Language: Английский

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Oxygen Depletion and the Role of Cellular Antioxidants in FLASH Radiotherapy: Mechanistic Insights from Monte Carlo Radiation-Chemical Modeling

Antioxidants, Journal Year: 2025, Volume and Issue: 14(4), P. 406 - 406

Published: March 28, 2025

FLASH radiotherapy is a novel irradiation modality that employs ultra-high mean dose rates exceeding 40–150 Gy/s, far surpassing the typical ~0.03 Gy/s used in conventional radiotherapy. This advanced technology delivers high doses of radiation within milliseconds, effectively targeting tumors while minimizing damage to surrounding healthy tissues. However, precise mechanism differentiates responses between tumor and normal tissues not yet understood. study primarily examines ROD hypothesis, which posits oxygen undergoes transient radiolytic depletion following pulse. We developed computational model investigate effects rate on radiolysis an aqueous environment mimics confined cellular space subjected instantaneous pulses energetic protons. employed multi-track chemistry Monte Carlo simulation code, IONLYS-IRT, has been optimized this homogeneous aerated medium. medium composed water, alongside carbon-based biological molecules (RH), radiation-induced bio-radicals (R●), glutathione (GSH), ascorbate (AH−), nitric oxide (●NO), α-tocopherol (TOH). Our closely monitors temporal variations these components, specifically focusing consumption, from initial picoseconds one second after exposure. Simulations reveal transiently depleted through its reaction with R● radicals, consistent prior research, but also disulfide radical anions (GSSG●−) roughly equal proportions. Notably, we show that, contrary some reports, peroxyl radicals (ROO●) formed are neutralized by recombination reactions. Instead, rapidly antioxidants present irradiated cells, AH− ●NO proving be most effective preventing propagation harmful peroxidation chain Moreover, our identifies critical threshold below effect, as predicted cannot fully manifest. By comparing findings existing experimental data, determine hypothesis alone entirely explain observed effect. indicate might significantly contribute effect mitigating and, turn, enhancing radioprotection. Additionally, lends support may partially insufficient phenomenon, suggesting involvement additional mechanisms or factors warranting further investigation.

Language: Английский

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Characterization of commercial detectors for absolute proton UHDR dosimetry on a compact clinical proton synchrocyclotron

Medical Physics, Journal Year: 2025, Volume and Issue: unknown

Published: April 23, 2025

Abstract Background Modern compact proton synchrocyclotrons can achieve ultra‐high dose rates (40 Gy/s) to support ultra‐high‐dose‐rate (UHDR) preclinical experiments utilizing pencil beam scanning (PBS) protons. Unique is a pulsed time structure as compared the quasi‐continuous nature of other accelerators like isochronous cyclotrons. Thus, high instantaneous currents in order several µA must be generated UHDRs. This will lead doses‐per‐pulse (DPP), which may cause significant charge recombination for ionization chambers, characterized accurate UHDR dosimetry programs. Purpose In this work, we investigate suitability various commercial radiation detectors using PBS beams from synchrocyclotron (IBA ProteusONE). achieved by cross‐calibrating them with conventional rates, measuring (P ion ) and polarity correction factors pol determining absorbed delivered all detectors. Methods An IBA ProteusONE was initially tuned UHDRs 228 MeV protons at 0° gantry angle. Various detectors, including Razor Chamber, Nano Diode, microDiamond, were cross‐calibrated against PPC05 plane‐parallel chamber (PPIC) that had an ADCL calibration coefficient 59.23 cGy/nC. Then, chambers exposed P subsequently calculated. calculated two methods: TRS‐398 methods Niatel's model. Finally, absolute doses determined cross‐compared. Results Faraday cup measurements performed single spot beam, nozzle current isocenter 129.5 nA during irradiations 98.61% maximum theoretical rate. Repeated yielded percentage standard deviation 0.8%, higher than 0.120% when similar repeated beams. found relatively dose‐rate independent investigated. lowest (1.0097) corresponding values 1.0214 1.0294 respectively, model closely matched if V H /V L ratio kept 2.5 2.0 detector. Absolute cross‐calibration generally within ± 1% measurements. However, Diode over‐respond up 3.79% beams, rendering unsuitable dosimetry. Conclusion comprehensively evaluated synchrocyclotron. ionic chambers. Other diode detector, investigated (PPC05, Razor, Nano, microDiamond) one another used

Language: Английский

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