346 - Development of a Composite Microdosimetric Kinetic Model (C-MKM) Incorporating Subcellular 10 B Heterogeneity for BNCT

Purpose/Objective(s): In boron neutron capture therapy (BNCT), subcellular ¹⁰B distribution critically shapes microscale energy deposition and thus tumor cell kill. However, few biophysical models for compound biological effectiveness (CBE) explicitly account for this subcellular ¹⁰B heterogeneity. To address this gap, we introduce a subcellular ¹⁰B heterogeneity-aware, microdosimetry-driven CBE model that enables quantitative estimation of BNCT radiobiological effectiveness.

Materials/Methods: Since subcellular ¹⁰B heterogeneity modulates microdosimetric spectra and thus CBE, we built a simulation toolkit-based cellular geometry and simulation pipeline to quantify these effects. Specifically, we constructed a 3×3×3 cellular voxel matrix (cell radius 5 µm; nuclear radius 2.5 µm; membrane thickness 8 nm) and modeled intracellular ¹⁰B as concentric cytoplasmic shells spanning from the nuclear boundary to the cell membrane, with a uniform extracellular ¹⁰B background. The cytoplasm was discretized into 10 radial shells (0.25 µm each) to compute shell-specific microdosimetric spectra. We then quantified the effective fraction of a and ⁷Li tracks entering the nucleus, used it to redefine the lineal-energy spectrum f(y), and incorporated this redefined f(y) into the standard microdosimetric kinetic model (MKM) to formulate the Composite MKM (C-MKM). Finally, C-MKM was used to compute CBE for ¹⁰B distributions of common boron carriers (e.g., BPA, BSH) and validated against published experimental and previous single-scenario simulation results.

Results: We constructed a database of microdosimetric spectra and effective particle fluence coefficients across shell-specific subcellular ¹⁰B distributions. The dose-mean lineal energy y_D ranged from 21.1 to 22.6 keV/µm, while the effective particle fluence coefficients for a particles and ⁷Li ions ranged from 4.26×10^-5 to 1.76×10^-4. For HSG cells, C-MKM-calculated CBE values were 2.61 (BPA) and 1.26 (BSH) at 10% survival fraction, and 3.69 (BPA) and 1.78 (BSH) at 50% survival fraction. These estimates (Table 1) closely agree with prior simulation and experimental results, validating the proposed model.

Conclusion: The proposed C-MKM enables microscale CBE estimation by linking radial ¹⁰B distributions to microdosimetric spectra and cell-survival modeling. By integrating subcellular ¹⁰B heterogeneity, this framework improves BNCT biological dose evaluation and interpretability. It enables quantitative boron-carrier comparisons (e.g., BPA vs. BSH) and provides a mechanistic basis for BNCT treatment planning.