Author: Claire Keun Sun Park, Atchar Sudhyadhom, Veena Venkatachalam, Noah Warner 👨🔬
Affiliation: Harvard–MIT Program in Health Sciences and Technology, Massachusetts Institute of Technology, Brigham and Women’s Hospital and Dana Farber Cancer Institute, Harvard Medical School,, Brigham and Women’s Hospital and Dana Farber Cancer Institute, Harvard Medical School 🌍
Purpose: Modern radiotherapy achieves sub-millimeter spatial accuracy but fails to account for patient- and spatially-specific variations in biological response. Free radical generation (FRG), particularly superoxide radicals, contributes to radiation-induced damage and normal tissue toxicities, but currently no real-time, non-invasive method exists to quantify FRG in vivo during irradiation. We hypothesized that paramagnetic free radical concentrations induce measurable T1 changes via paramagnetic relaxation effect. This study develops and demonstrates a novel Free radical IRradiation Emergent (FIRE) MRI framework using quantitative T1 mapping for real-time measurement of radiation-produced FRG, toward biologically-tailored dosimetry.
Methods: A high-temporal-resolution MP2RAGE-based T1 mapping protocol was developed on a clinical 0.35T ViewRay MR-Linac to measure T1 changes during simultaneous 6MV FFF irradiation and imaging. Radiation chemistry simulations identified superoxide radicals as a dominant paramagnetic species, and a superoxide relaxivity constant (10,346 M-1s-1) was experimentally derived. Validation utilized 35 biologically-relevant chemical phantoms, including water, hydroxyl free radical scavengers (FRS) (coumarin), superoxide FRS (MitoTEMPO), generalized FRS (glutathione), and radiosensitizing gold nanoparticles. Temporally-observed T1 changes and radiation-produced superoxide concentrations were assessed with area under the curve (AUC) (ms•s and μM•s) and superoxide production rate (mM/s and nM/Gy).
Results: We developed and show first-results of FIRE MRI to quantify radiation-produced FRG dynamics with sensitivity to superoxide radical generation across biologically relevant phantoms. Measured T1 dynamics yielded AUC ranging 25.08–113.62μM•s and 1264–5606ms•s with superoxide production rates, 0.273–3.45 nM/s (2.64–38.39 nM/Gy). Sensitivity and specificity to superoxide radicals was confirmed with MitoTEMPO (0.273 nM/s) showing reduced mean superoxide generation, whereas gold nanoparticles (1.32 nM/s) known to enhance hydroxyl production did not affect superoxide generation.
Conclusion: This study provides the first real-time, non-invasive method for quantifying radiation-produced superoxide FRG on a clinical MR-Linac. Our results show potential towards adapting to FRG dynamics, as a novel patient- and spatially-specific dosimetry approach to biologically-tailored radiotherapy.