Unraveling the role of boron microdistribution in BNCT dosimetry of glioblastoma multiforme: combined theoretical and experimental insights

Objective. Boron neutron capture therapy is a cancer radiotherapy that uses the selective uptake of boron compounds by tumor cells, followed by neutron irradiation. Conventional dosimetry generally assumes a homogeneous boron distribution within tissues, yet evidence indicates intracellular heterogeneity. This work aims to improve the photon isoeffective dose model (PID) for glioblastoma multiforme (GBM) by incorporating subcellular-scale effects: (i) a correction factor for the stochastic nature of energy deposition due to intracellular boron localization, and (ii) the treatment of the nucleus-to-cytoplasm boron concentration ratio as a stochastic variable. Approach. The boron-10 microdistribution in U-87 glioblastoma cells was quantified for the first time through neutron autoradiography, revealing preferential accumulation in the nucleus. Following these experimental data, the nucleus-to-cytoplasm boron concentration ratio was described by a lognormal random variable, consistent with biological uptake processes. The correction factor was applied to the dosimetry of U-87 radiobiological data. Then, updated radiobiological parameters and subcellular-scale effects were integrated into the PID formalism and applied to a clinical case of GBM. Main results. The outcome was a Microdosimetric PID, which extends conventional PID by explicitly including intracellular boron heterogeneity. Applied to U-87 data, proposed corrections revealed a 47% reduction in the compound biological effectiveness factor compared to conventional calculations, showing that neglecting subcellular distribution substantially overestimates the boron dose. For the clinical case, the total dose and 1 year progression-free survival (PFS) differed only by 4% and 3%, respectively, compared to conventional dosimetry. However, perturbation analyses indicated that under higher intracellular heterogeneity, plausible in vivo, the deviations could become substantial (up to 22% in dose and 68% in PFS). Significance. These findings highlight the relevance of subcellular-scale modeling. The proposed microdosimetric model, grounded on experimentally derived microdosimetric corrections, provides a robust framework to improve both the accuracy and the personalization of BNCT treatment planning.