Speaker
Description
Objective: Heightened interest in alpha-emitting radiopharmaceutical therapies has created a need for methods capable of resolving their highly heterogeneous activity and dose distributions at microscopic scales. Because alpha particles travel less than approximately 100 μm in tissue, macroscopic activity and mean-dose estimates may not represent local cellular exposure. We aim to develop a quantitative Timepix4-based framework for reconstructing energy-resolved alpha-particle fluence from thin biological tissue sections and relating these measurements to spatial dose and biological response.
Methods: Timepix4 will be characterised using monoenergetic and plurienergetic alpha sources. Particle energy will be reconstructed from calibrated time-over-threshold measurements and multi-pixel cluster properties. Thin water-equivalent absorber layers will be used to determine energy-loss and detection-efficiency functions as a function of source depth, supported by Geant4 simulations of particle transport, emission angle, and detector geometry.
The framework will then be applied to thin serial liver and lung sections containing alpha-emitting radiopharmaceuticals. Timepix4 measurements will quantify alpha-event density, energy distributions, spatial heterogeneity, and fluence over time. Adjacent sections will undergo histological and, where collection conditions permit, DNA-damage or cell-death analysis. Detector maps will be compared with gamma counting or conventional autoradiography where available. As a focused extension, free and hydroxyapatite-associated Radium-223 may be compared to investigate mineral retention, daughter ingrowth, and time-dependent changes in the measured alpha spectrum.
Results: Calibration and reconstruction are ongoing. Feasibility assessment demonstrates that intact millimetre-scale samples cannot be characterised directly because only alpha particles originating within approximately tens of micrometres of the detector-facing surface can escape. Thin tissue sections and water-equivalent absorbers have therefore been selected to permit quantitative evaluation of energy loss, detection efficiency, and spatial fluence.
Outlook & Discussion: The resulting dataset will provide paired detector measurements, tissue geometries, radionuclide distributions, and Geant4-derived dose estimates for machine-learning development. Models could classify particle events, reconstruct incident alpha energy and probable emission depth from cluster properties, and learn surrogate relationships between measured fluence and spatial dose. Ultimately, an uncertainty-aware surrogate model could provide rapid, tissue-specific dose predictions while identifying regions requiring full Monte Carlo simulation, supporting more practical personalised dosimetry in alpha-emitting radiopharmaceutical therapy.