An extended local effect model for Auger-emitting radionuclide therapy

Objective. Auger-emitting radionuclide therapy is strongly influenced by spatial and temporal dose distributions of radionuclides within a cell. The local effect model (LEM) was extended to predict the radiobiological effects resulting from both spatial and temporal subcellular dose distributions of Auger-emitting radionuclides.Approach. Radionuclides of¹⁰³Pd,¹¹¹In, and¹²⁵I were prominent candidates for Auger-therapy. Their dose point kernels, calculated using the Geant4-DNA toolkit, were used to determine the nanometer-scale dose distribution characteristics of the radionuclides. These kernels were integrated into the LEM to investigate the treatment scenarios for three cell lines of MDA-MB-468, SQ20B, and 231-H2N. Then, the extended LEM was completed by implementing a full Monte Carlo simulation for a kinetic extension of the giant loop binary lesion model. The simulation took into account not only heterogeneities of source locations but also varying dose and DNA repair rates for specific radionuclides and cell lines. It was validated against publishedin vitroexperimental results available for¹¹¹In. We then used the model to quantify the impact of subcellular localization and cellular activity of radionuclides on biological effectiveness. In addition, it was applied to compute tumor control probability (TCP) for micrometastases.Main results. This model provides a mechanistic basis for evaluating biological effectiveness across various radionuclide species and cell lines by accounting for their intrinsic radiosensitivity. Validation against experimental data for¹¹¹In showed close agreement in survival fractions. Furthermore, the model quantified a RBE dependence on subcellular localization, reaching up to an RBE₁₀of 4.19 in the case of intranuclear¹²⁵I in 231-H2N. It could also capture dose-rate effects at high uptake activities. Correspondingly, the derived TCP curves revealed significant variations depending on the radionuclide species and the intranuclear uptake fraction.Significance. The extended LEM was established as a mechanistic platform that integrated nanometer-scale dose distributions with cell-specific DNA damage kinetics.