A fast convolution-based method for microdosimetric comparison of²⁵⁵Ac,²¹¹At,¹⁷⁷Lu and¹⁶¹Tb at the cell cluster scale

Area of Science:

• Nuclear medicine and radiation oncology.
• Biophysics and radiobiology.
• Computational modeling and simulation.

Background:

• Targeted radionuclide therapy (TRT) efficacy depends on energy deposition patterns, influenced by radionuclide properties and cellular environment.
• Distinct spatial energy deposition from different radionuclides impacts cell cluster response in TRT.
• Understanding these differences is crucial for optimizing TRT strategies.

Purpose of the Study:

• To compare dose deposition, microdosimetric characteristics, and population responses of Actinium-225 (²²⁵Ac), Astatine-211 (²¹¹At), Lutetium-177 (¹⁷⁷Lu), and Terbium-161 (¹⁶¹Tb) at the cell-cluster scale.
• To evaluate the influence of subcellular source localization, labeling fraction, cluster size, and activity heterogeneity on TRT outcomes.

Main Methods:

• A cubic lattice cell cluster model based on PC-3 cells was constructed.
• Particle-tracking simulations using PHITS calculated nuclear S values and microdosimetric quantities.
• Fast Fourier Transform (FFT)-based convolution and a microdosimetric kinetic (MK) model assessed dose distribution and tumor control probability (TCP).

Main Results:

• Convolution methods showed good agreement ( < 5% deviation) with direct PHITS simulations for cluster-averaged S values.
• Alpha emitters (²²⁵Ac, ²¹¹At) exhibited steeper dose-mean lineal energy (y*) gradients compared to beta emitters (¹⁷⁷Lu, ¹⁶¹Tb).
• ²²⁵Ac required ~3 orders of magnitude less activity per cell for a 0.9 TCP compared to ¹⁷⁷Lu and ¹⁶¹Tb, with heterogeneity amplifying dose requirements.

Conclusions:

• A rapid, convolution-based framework enables systematic cell-cluster-scale comparisons of TRT radionuclides.
• Alpha-emitting radionuclides demonstrate superior efficacy at the cellular level due to their unique energy deposition characteristics.
• Findings provide a basis for optimizing radionuclide selection and treatment planning in targeted radionuclide therapy.