ADMET-Guided Design and In-Silico Planning of Boron Delivery Systems for BNCT: From Transport and Biodistribution to PBPK-Informed Irradiation Windows

In this review, we examine boron-containing agents for boron neutron capture therapy (BNCT) with a focus on absorption, distribution, metabolism, excretion and toxicity (ADMET) and model-informed design. BNCT is a binary radiotherapeutic modality in which high linear energy transfer particles are generated in the vicinity of ^10B, ideally within boron-loaded tumour cells, so the therapeutic outcome depends critically on the pharmacokinetics and biodistribution of boron carriers. We survey low-molecular-weight compounds, peptide conjugates, polymeric and nanostructured platforms and cell-based vectors, and discuss how physicochemical properties, transporter engagement and nano–bio interactions govern tumour uptake, subcellular localisation and normal-tissue exposure. We also describe a shift from maximising boron content towards optimising exposure profiles using positron emission tomography (PET), physiologically based pharmacokinetic (PBPK) modelling and in silico ADMET tools to define irradiation windows. Classical agents such as boronophenylalanine (BPA) and sodium borocaptate (BSH) are contrasted with newer polymeric and metallacarborane-based carriers, with attention to brain penetration, endosomal escape, linker stability, biodegradation and elimination routes, as well as platform-specific toxicities. We argue that further progress in BNCT will depend on integrating imaging-derived kinetics with PBPK-informed dose planning and engineering subcellularly precise yet degradable carriers, and that ADMET-guided design and spatiotemporal coordination are central to achieving reproducible clinical benefit from BNCT’s spatial selectivity.