Quantitative Autoradiography-Based Stochastic Microscale Dosimetry for α-Emitter Radiopharmaceutical Therapy
Abstract
Purpose
Mean absorbed dose is commonly used to interpret radiopharmaceutical therapy outcomes. For α-emitter radiopharmaceutical therapy (αRPT), however, energy deposition is stochastic at the cellular scale, while tissue-level Monte Carlo-based microdosimetry is computationally infeasible. We therefore present a computationally tractable stochastic microscale dosimetry framework using autoradiography of tumors treated in vivo with αRPT.
Methods
Tumor sections from mice treated with 255Ac-αRPT were imaged using quantitative autoradiography at near-cellular resolution. Microscale energy deposition was modeled using Geant4 simulations of primary decays in cell-sized voxels, recording absorbed dose in the source and neighboring voxels as reusable single-event dose realizations. Stochastic microscale dosimetry was performed by combining autoradiography-derived activity maps with these realizations using Poisson-based convolution or direct bootstrap resampling, yielding voxel-wise dose and hit probability estimates without repeated Monte Carlo transport.
Results
Autoradiography-derived stochastic dosimetry revealed pronounced microscale heterogeneity in tumor irradiation not captured by mean absorbed dose. Across tumors (n=14), most cell-sized voxels exhibited a substantial probability of receiving no α-particle traversals, with P(D=0) frequently exceeding 25% even in the highest activity regions. This arises from low α-particle fluence at the cellular scale, such that elevated uptake still yields large variability in cellular irradiation, forming a patchwork of neighboring irradiated and non-irradiated cells. The bootstrap-based implementation completed whole-tumor microscale dosimetry within ~15 minutes on a desktop PC. Probability-based dose metrics showed improved correspondence with DNA damage markers compared to mean absorbed dose.
Conclusion
Stochastic microscale dosimetry derived directly from quantitative autoradiography demonstrates that α-emitter therapy produces spatially heterogeneous irradiation patterns not captured by mean absorbed dose metrics. The resulting patchwork of irradiated and non-irradiated neighboring cells provides a plausible physical basis for large tissue-level responses to αRPT despite low average cellular hit probabilities. This experimentally grounded and computationally practical framework establishes a new foundation for interpreting heterogeneous biological response in αRPT.