Work

In silico assessment of cellular damage from Lu‐177, Ac‐225, and Pb‐212 therapeutic radionuclides

Year: 2025

Type: article

Abstract: Background Targeted radionuclide therapy (TRT) has emerged as a unique and effective treatment modality for cancer. Monte Carlo simulations have greatly advanced investigations into radiation‐caused DNA damage, including the complexity of this damage. Purpose This study aimed to evaluate DNA damage induced by high‐linear energy transfer therapeutic radionuclides used in TRT, specifically 225 Ac, 177 Lu, and 212 Pb, using Geant4‐DNA Monte Carlo simulations. Methods The Geant4‐DNA toolkit, incorporating the “molecularDNA” example, was employed to simulate radiation interactions within a human fibroblast cell model featuring a fractal chromatin fiber geometry within an ellipsoidal nucleus. Three source geometries (membrane, cytoplasm, nucleus) were modeled to assess the impact of radionuclide localization. Key metrics, including absorbed dose, double‐strand break (DSB) yield, single‐strand break/DSB ratio, and DSB/Gbp/decay, were calculated for 225 Ac (alpha emitter), 177 Lu (beta emitter), and 212 Pb (mixed alpha/beta emitter). Simulations accounted for physical, physicochemical, and chemical stages, with validation against published data for 177 Lu and 225 Ac. Results Alpha emitter 225 Ac exhibited the highest DSB/Gbp/decay (1.646 in nucleus geometry) and absorbed dose (0.256 Gy/decay), followed by 212 Pb (0.455 DSB/Gbp/decay, 0.0684 Gy/decay), and 177 Lu (0.0058 DSB/Gbp/decay, 0.0007 Gy/decay). DSB yields increased with proximity to the nucleus, with 225 Ac showing up to 284 times greater DSB/Gbp/decay than 177 Lu. Validation showed < 10% divergence from reference studies. Conclusions Geant4‐DNA simulations highlight the superior radiobiological effectiveness of alpha emitters, particularly 225 Ac, for inducing DNA damage and emphasize the importance of source localization. These findings enhance our understanding of TRT's radiobiological effects and can be used to support development of refined therapeutic strategies.

Source: Medical Physics

DOI: 10.1002/mp.70089

Authors: Konstantinos P. Chatzipapas, Konstantinos Papachristou, Dimitris Visvikis, Sebastien Incerti, John D. Hazle, George C. Kagadis