Multiscale Monte Carlo-based dosimetry of 177Lu and 211At across distinct tumor microarchitectures

Radiation emitted by therapeutic radionuclides deposit energy over micrometer-scale distances, yet practical patient dosimetry for radiopharmaceutical therapy can only currently be performed using gamma camera images whose resolution limits are much larger. Gamma camera-based dosimetry calculations may be adequate for some tissues, where the heterogeneity of the actual source microdistribution is not impactful. However, the difference in spatial scale between what can be measured and the actual radiopharmaceutical microdistribution may obscure biologically relevant dose heterogeneity, e.g., within tumors or normal organs that non-uniformly express the molecular target. This is true for widely used β-emitting radionuclides such as 177 Lu that exhibit low linear energy transfer and particle ranges of hundreds of micrometers, enabling cross-fire radiation between neighboring cells. The challenge becomes more pronounced for α-emitters such as 211 At that deposit energy over shorter distances of only tens of micrometers with LET values two to three orders of magnitude higher than β-particles. Understanding how radiation dose is impacted by the complex interactions among radionuclide emission characteristics, tumor microarchitecture, intercellular spacing, and heterogeneous targeting requires modeling frameworks capable of resolving radiation transport at cellular scales within multicellular tumor environments. At the single-cell level, the self-dose to the nucleus per decay was approximately 120-fold higher for 211 At than for 177 Lu due to the higher LET. Energy confinement analyses demonstrated that more than 90% of 211 At emission energy was absorbed within spherical micrometastases larger than ~ 300 μm, whereas 177 Lu required millimeter-scale dimensions to approach similar energy retention. In multicellular clusters, absorbed dose distributions were strongly modulated by intercellular spacing and labeling fraction. Increasing cell separation and decreasing targeting fraction produced progressively greater dose heterogeneity, particularly for 211 At, where dose delivery became dominated by self-dose with minimal cross-fire contributions. Radionuclide emission physics and tumor microarchitecture jointly determine absorbed dose distributions in RPT. α-emitters from 211 At deliver highly localized irradiation to targeted cells but are sensitive to incomplete targeting in dispersed tumor architectures, whereas β-emitters from 177 Lu provide broader cross-fire dose coverage at lower absorbed dose per decay. These findings highlight the importance of integrating radionuclide physics with tumor microenvironment characteristics when optimizing RPT strategies.