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Background Both 177Lu and 225Ac are suitable for radio-ligand therapy (RLT) in metastatic castration-resistant prostate cancer (mCRPC) as tumor-targeted radio-ligands when labeled with prostate-specific membrane antigen (PSMA). However, their microdosimetric distribution in prostate cancer tissue can differ, leading to varying therapeutic outcomes. Methods In this study, a three-dimensional mesh-type cell cluster model was constructed using realistic tomography images of a prostate cancer cell line to investigate the combination ratio of two nuclides for combination therapy of mCRPC, and the specific energy distributions of cell nucleus and the macroscopic dose levels resulting from varying activities of 177Lu and 225Ac were compared using Geant4 simulations. Various factors were taken into account such as the source region (cell surface, cytoplasm, and nucleus), the activity range (104-1.2×105 Bq for 225Ac and 6×106-1.2×108 Bq for 177Lu), and the cellular model type (concentric sphere simple geometry-type model and mesh-type model). A link was established between tumor control probability (TCP) and several parameters, like radionuclide activities, cell nucleus specific energy distributions, and average doses of the cell cluster. Results Despite having a similar average nucleus absorbed dose within the cluster, 225Ac exhibited a more dispersed nucleus-specific energy distribution, indicating a higher degree of dispersion than 177Lu. In order to achieve a therapeutic effect of 90% TCP, it is crucial that the cell nucleus absorbs an adequate dose of radiation, while considering the proportion of PSMA internalization in each compartment of the cell. The required activity of 177Lu was approximately 417 times that of 225Ac to reach the same effect. A certain amount of 225Ac can be mixed into 177Lu for combination therapy to increase TCP and minimize the dose inhomogeneity. For example, 4.6×104 Bq and 5.8×104 Bq of 225Ac can be mixed into 5×106 Bq of 177Lu to achieve TCPs of 90% and 98%, respectively. Conclusion A microdosimetric simulation was performed coupled with the realistic mesh-type cell cluster model, and the microdosimetric distribution characteristics of 177Lu and 225Ac in the prostate cancer cell clusters were evaluated in this work. The outcome of combination therapy for 177Lu and 225Ac was predicted, which can serve a dose reference for clinical therapy of mCRPC.

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The mesh-type models are superior to voxel models in cellular dose assessment coupled with Monte Carlo codes. The aim of this study was to expand the micron-scale mesh-type models based on the fluorescence tomography of real human cells, and to investigate the feasibility of these models in the application of various irradiation scenarios and Monte Carlo codes. Six different human cell lines, including pulmonary epithelial BEAS-2B, embryonic kidney 293T, hepatocyte L-02, B-lymphoblastoid HMy2.CIR, Gastric mucosal GES-1, and intestine epithelial FHs74Int, were adopted for single mesh-type models reconstruction and optimization based on laser confocal tomography images. Mesh-type models were transformed into the format of polygon mesh and tetrahedral mesh for the GATE and PHITS Monte Carlo codes, respectively. The effect of model reduction was analyzed by dose assessment and geometry consideration. The cytoplasm and nucleus doses were obtained by designating monoenergetic electrons and protons as external irradiation, and S values with different “target-source” combinations were calculated by assigning radioisotopes as internal exposure. Four kinds of Monte Carlo codes were employed, i.e., GATE with “Livermore,” “Standard” and “Standard and Geant4-DNA mixed” models for electrons and protons, as well as PHITS with “EGS” mode for electrons and radioisotopes. Multiple mesh-type real human cellular models can be applied to Monte Carlo codes directly without voxelization when combined with certain necessary surface reduction. Relative deviations between different cell types were observed among various irradiation scenarios. The relative deviation of nucleus S value reaches up to 85.65% between L-02 and GES-1 cells by 3H for the “nucleus-nucleus” combination, while that of 293T and FHs74Int nucleus dose for external beams at a 5.12 cm depth of water is 106.99%. Nucleus with smaller volume is far more affected by physical codes. There is a considerable deviation for dose within BEAS-2B at the nanoscale. The multiple mesh-type real cell models were more versatile than voxel models and mathematical models. The present study provided several models which can easily be extended to other cell types and irradiation scenarios for RBE estimations and biological effect predictions, including radiation biological experiments, radiotherapy and radiation protection.