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

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 ²²⁵Ac, ¹⁷⁷Lu, and ²¹²Pb, 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 ²²⁵Ac (alpha emitter), ¹⁷⁷Lu (beta emitter), and ²¹²Pb (mixed alpha/beta emitter). Simulations accounted for physical, physicochemical, and chemical stages, with validation against published data for ¹⁷⁷Lu and ²²⁵Ac. Results: Alpha emitter ²²⁵Ac exhibited the highest DSB/Gbp/decay (1.646 in nucleus geometry) and absorbed dose (0.256 Gy/decay), followed by ²¹²Pb (0.455 DSB/Gbp/decay, 0.0684 Gy/decay), and ¹⁷⁷Lu (0.0058 DSB/Gbp/decay, 0.0007 Gy/decay). DSB yields increased with proximity to the nucleus, with ²²⁵Ac showing up to 284 times greater DSB/Gbp/decay than ¹⁷⁷Lu. Validation showed < 10% divergence from reference studies. Conclusions: Geant4-DNA simulations highlight the superior radiobiological effectiveness of alpha emitters, particularly ²²⁵Ac, 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.