Microdosimetric study of 177Lu and 225Ac combination therapy for mCRPC coupled with the mesh-type cell cluster model

Abstract

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.