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

1. Introduction

BNCT (Boron Neutron Capture Therapy) is a binary radiotherapeutic modality [ 1 , 2 , 3 ] predicated on the nuclear reaction between 10 B (boron-10) and low-energy thermal neutrons. The interaction produces high LET (Linear Energy Transfer) α-particles and lithium-7 ( 7 Li) nuclei with path lengths of approximately 5–9 μm—comparable to a single cell diameter—thus confining cytotoxicity to boron-loaded tumour cells and sparing adjacent healthy tissues. This spatial selectivity, not achievable with conventional external beam radiotherapy, offers advantages in recurrent or otherwise inoperable malignancies [ 4 , 5 ], notably glioblastoma, head-and-neck cancers, and melanoma.

Clinical success depends critically on the ADMET profile of boron-containing agents [ 6 , 7 ]. To achieve selective tumour ablation, approximately 20–35 μg of 10 B per gram of tumour tissue is required, with a T/N (tumour-to-normal tissue) ratio exceeding ~3 and a T/B (tumour-to-blood) ratio sufficiently high at the time of irradiation [ 2 , 8 , 9 ]. Accordingly, chemical design, biodistribution, metabolism, and elimination must be co-optimised within the ADMET framework.

1.1. Historical Overview and Clinical Progress

Since the early clinical explorations at Brookhaven in the 1950s, several generations of boron delivery agents have emerged. The benchmarks—BPA (Boronophenylalanine) and BSH (Sodium Borocaptate)—remain reference standards owing to known clinical pharmacokinetics and safety, albeit with limited tumour selectivity and suboptimal retention. BPA relies on LAT1 (L-Type Amino Acid Transporter 1) transport and shows heterogeneous uptake; BSH distributes largely extracellularly with minimal active transport [ 1 , 10 , 11 , 12 ]. The monograph by Sauerwein et al. (2012) integrated biokinetics with clinical translation and catalysed subsequent rational design [ 1 ]. Parallel advances in synthetic boron chemistry—particularly metallacarborane-modified nucleosides and DNA (Deoxyribonucleic Acid)-intercalating constructs—have expanded the scope of agents combining high boron payloads with favourable biophysics [ 13 , 14 , 15 ].

1.2. Emergence of ADMET-Guided Design

Historically, optimisation prioritised bulk boron concentration over PK (pharmacokinetic) metrics. Contemporary programmes integrate quantitative PK, dynamic PET/MRI (Positron Emission Tomography/Magnetic Resonance Imaging)-based imaging, and computation to predict tissue penetration and retention [ 3 , 7 , 14 ]. For example, nanocarriers—PEGylated (modified with Polyethylene Glycol) liposomes, boronated dendrimers and mesoporous silica nanoparticles—are engineered to exploit the EPR (Enhanced Permeability and Retention) effect, typically improving tumour exposure versus small molecules [ 3 , 15 , 16 ]. PEGylation prolongs systemic residence and can markedly lengthen apparent half-life relative to free BPA, improving synchronisation between peak tumour concentrations and neutron exposure [ 15 , 17 ].

1.3. Molecular Classes of Boron-Containing Agents

Boron agents for BNCT may be grouped into: (1) low-molecular-weight compounds (e.g., BPA, BSH, boronated nucleosides) [ 10 , 11 , 14 ]; (2) peptide-based conjugates, e.g., EGFR (Epidermal Growth Factor Receptor) or integrin-targeted [ 14 , 18 , 19 ]; (3) polymeric carriers, e.g., PAMAM (Epidermal Growth Factor Receptor) dendrimers, PEGylated borates [ 15 , 16 , 17 ]; (4) nanostructured materials, e.g., BN (boron nitride) nanotubes, liposomes, hybrid nanogels; and [ 20 , 21 , 22 ] (5) bio-cellular delivery systems (e.g., macrophages or stem cells) [ 18 , 21 , 23 ]. Each class exhibits distinct ADMET trade-offs: low-molecular-weight agents permeate rapidly but clear renally; polymeric/nanoparticulate systems extend circulation and improve EPR-mediated accumulation yet raise questions of biodegradation and long-term safety; cellular carriers provide pathophysiological homing, including into hypoxic regions, at the expense of higher biological variability [ 14 , 23 , 24 ].

1.4. European Contribution

European groups have played a pivotal role in metallacarborane chemistry and BNCT pharmacology. Work led by Polish institutions reported metallacarborane intercalators and boronated nucleosides with balanced lipophilicity (logP ≈ 2–3) and high chemical stability, translating into improved cellular retention in preclinical models [ 25 , 26 ]. Polish investigators have also demonstrated macrophage-mediated delivery of boron carbide nanoparticles, achieving homing into poorly perfused tumour regions and sustained intratumoural presence [ 24 ]. Across Europe, teams in Finland and Italy advanced hybrid polymer–silica carriers that enable imaging-guided delivery and controlled release. Collectively, these efforts illustrate a shift from merely maximising bulk boron to ADMET-guided optimisation of exposure, selectivity and subcellular localisation [ 13 , 14 , 15 , 21 , 23 , 24 , 27 ]. These advances in boron chemistry are paralleled by the establishment of dedicated BNCT infrastructure at the MARIA research reactor in Poland, enabling preclinical radiobiological studies [ 28 ].

1.5. Aim and Structure of the Review

This review provides an ADMET-centred analysis of boron-containing compounds and carriers relevant to BNCT, correlating chemical structure with biodistribution, metabolic fate and toxicity and PK parameters: t 1/2 (half-life), CL (clearance), V d (volume distribution). The review is organised by the five ADMET pillars, each supported by representative data, mechanistic considerations, and literature cross-references.

2. Absorption

Efficient absorption and systemic bioavailability are prerequisites for achieving therapeutic intratumoural 10 B at irradiation. Key determinants include molecular weight, lipophilicity (logP), solubility, ionisation, and membrane permeability. The principal challenge is to maximise tumour selectivity while securing sufficient exposure to deliver high T/B ratios at the time of neutron capture [ 2 , 3 , 7 , 14 , 24 ]. Table 1 , summarises key ADMET parameters discussed in this section. Foundational ADMET principles relevant to this section include classical drug-likeness and permeability heuristics, as well as the BCS (Biopharmaceutics Classification System) framework [ 29 , 30 , 31 , 32 ]. Transporter effects, which modulate apparent absorption beyond passive diffusion, are reviewed by the International Transporter Consortium and recent clinical DDI (drug–drug interaction) methodology work [ 33 ]. Complementary BNCT-focused overviews of boron-agent classes further contextualise absorption behaviour [ 34 , 35 , 36 ]. A concise platform-level overview of absorption-relevant properties across boron classes is provided in [ 23 ]. Additional class-level insights relevant to uptake and formulation are provided by reviews on CA IX (Carbonic Anhydrase IX)-targeted boron scaffolds, single-boron pharmacophores, and sugar-based/PEGylated PET-tracers [ 19 , 37 , 38 , 39 ].

2.1. Physicochemical Determinants

Key small-molecule carriers such as BPA and BSH exemplify the trade-off between permeability and selectivity. Optimising logP in the range ~2–3 while maintaining aqueous compatibility tends to favour transmembrane passage and endocytic uptake, especially when carborane motifs are balanced by polar linkers [ 13 , 14 , 15 , 59 ]. Hydrogen bond donors/acceptors, steric compactness and charge state at physiological pH collectively determine LAT1 engagement and passive diffusion [ 10 ].

BPA, an amino-acid analogue, engages LAT1, yet its low passive permeability (logP ≈ −1.2) constrains diffusion [ 14 ]. LAT1, known as SLC7A5, is the most investigated Na + - and pH-independent membrane transporter based on antiport mechanism, highly expressed in the BBB (Blood–Brain Barrier), cerebral cortex, BRB (Blood-Retina Barrier), testis, placenta, bone narrow and in various types of cancer such as malignant glioma, multiple myeloma, cholangiocarcinoma, lung, bladder, thyroid, prostate, uterine cervical and breast cancer [ 60 , 61 , 62 , 63 , 64 , 65 ]. BSH (logP ≈ −4.8) is highly hydrophilic, exhibits minimal membrane permeability and undergoes rapid renal elimination, limiting tumour accumulation [ 11 , 12 ]. Incorporation of carborane/metallacarborane motifs increases lipophilicity (often to logP 2–3) and can enhance passive and endocytic uptake without forfeiting aqueous compatibility when combined with polar linkers [ 13 , 14 , 15 , 66 ]. Reports of DNA-intercalating metallacarboranes document greater cellular uptake than BPA with sustained intracellular retention in vitro [ 13 , 14 , 67 ].

2.2. Absorptive Pathways

Absorptive pathways comprise active transport (e.g., LAT1 for BPA; nucleoside transporters for boronated nucleosides) and passive diffusion; peptide conjugates exploit receptor-mediated endocytosis (e.g., EGFR, α v β 3 –integrin, highly expressed by osteoclasts) [ 10 , 14 , 18 ]. Nanoparticles and polymers enter predominantly via clathrin/caveolin-mediated endocytosis with subsequent endosomal trafficking; design solutions include pH-labile linkers and membrane-disruptive elements to promote endosomal escape [ 15 , 21 , 22 , 62 ]. Cellular vectors such as macrophages or MSCs (mesenchymal stromal cells) function as cellular carriers, traversing barriers and releasing cargo within the tumour microenvironment [ 23 , 24 ].

2.3. Quantitative Considerations

Small-molecule BPA typically achieves rapid plasma peaks with short biological half-life, whereas PEGylated liposomes and related platforms prolong systemic exposure through reduced opsonisation and RES uptake [ 15 , 68 , 69 ]. For example, transferrin-PEG liposomes (tumour-bearing mice) achieved tumour 10 B ~35.5 µg/g and maintained tumour 10 B > 30 µg/g for ≥72 h (tumour/plasma ratio 6.0 at 72 h) [ 11 , 15 , 16 , 17 , 23 , 34 , 35 , 48 , 49 , 50 , 51 , 52 ]. PET using 18 F-BPA-fructose ( 18 F-labelled Boronophenylalanine-fructose, FBPA-Fr) supports clinically relevant tumour-to-normal brain uptake ratios in glioma patients (see Section 3.6 ), aligning PET readouts with boron analyses from surgical samples [ 8 , 9 , 70 ].

2.4. Strategies to Enhance Absorption

Approaches include: prodrugging to transiently increase lipophilicity; PEGylation to extend circulation and leverage EPR; nano-engineering particle sizes ~50–150 nm for endothelial permeability–stability balance; biological carriers for hypoxia-directed uptake; and co-administration with permeation enhancers to augment transmembrane transport [ 14 , 15 , 21 , 22 , 69 ].

2.5. Key Insights

Absorption is governed by a coupling of physicochemical design and biological transport. Optimising logP (~2–3), molecular compactness and transporter/ligand engagement yields superior cellular entry and retention for boron delivery platforms [ 14 , 15 , 24 ].

3. Distribution

PBPK (physiologically based pharmacokinetic) approaches linking time-varying boron concentrations to dose kernels are increasingly used to synchronise irradiation with peak tumour-to-blood ratios [ 70 ]. PEGylation reduces opsonisation and reticuloendothelial uptake, prolonging the terminal half-life and enabling more predictable exposure windows [ 15 , 69 ]. Key ADMET parameters discussed in this section are summarised in Table 2 . Distribution behaviour is strongly shaped by transporter expression, protein binding and tissue barriers; contemporary ITC (International Transporter Consortium) guidance and transporter-centric clinical designs provide the broader context for interpreting BNCT carriers [ 33 ]. For distribution and selectivity across contemporary agent classes, recent BNCT reviews and clinical guidance are informative [ 34 , 35 , 71 ]. Early animal studies reported in vivo organ distribution and handling of borylated ferrocenium derivatives, providing additional context for BNCT carrier interpretation [ 72 ]. Class-level distribution and selectivity considerations are summarised in [ 23 ]. Distribution and targeting considerations are further illustrated by carborane-containing polymers, BODIPY (Boron-Dipyrromethene) imaging scaffolds, and organotrifluoroborate conjugates [ 11 , 57 , 73 , 74 , 75 , 76 , 77 ].

3.1. Pharmacokinetic Determinants and Modelling

Low-molecular-weight agents such as BPA/BSH generally show limited V d (≈0.4–0.6 L/kg), consistent with extracellular confinement and rapid clearance [ 1 , 11 , 12 ]. Nanocarriers and peptide conjugates often exhibit higher V d (≈1.5–3.5 L/kg), reflecting deeper tissue penetration and longer residence, aided by PEGylation and lipid encapsulation [ 15 , 69 ]. Emerging PBPK and time-dependent boron-dose models seek to harmonise biodistribution with irradiation timing and dosimetry [ 70 ]. This concept is illustrated schematically in Figure 1 .

Strategies to enhance brain penetration include tuning particle size (50–100 nm), surface charge near neutrality, and grafting ligands for receptor-mediated transcytosis. Nevertheless, clinical translation requires balancing enhanced BBB transport with off-target uptake and potential microglial activation [ 8 , 15 , 23 ].

3.2. Tissue Distribution and Tumour Selectivity

BPA preferentially accumulates in LAT1-expressing tumours but is subject to inter and intratumoural heterogeneity [ 10 ]. BSH is comparatively non-selective with higher hepatic/renal uptake [ 11 , 12 ]. Structural targeting (e.g., nuclear-affine metallacarboranes) and ligand-directed systems (e.g., RGD, folate) can increase T/N ratios in preclinical models [ 13 , 14 , 15 , 21 ]. Cellular carriers (e.g., macrophages) have delivered more uniform intratumoural distributions, including in hypoxic/necrotic regions [ 23 , 24 ].

3.3. Blood–Brain Barrier (BBB) and Blood–Tumour Barrier (BTB)

For primary CNS tumours and metastatic brain tumours, penetration of the BBB/BTB remains a key hurdle. Importantly, primary CNS tumours exhibit different BTB anatomy and permeability compared with metastatic brain tumours arising from peripheral primary cancers such as lung and breast. According to [ 79 ] the BTB in primary CNS tumours is generally more permeable than in brain metastases. This phenomenon requires more comprehensive investigation. BBB (I) and BTB (II) anatomical structures are shown in Figure 2 .

Studies indicate that BSH does not cross the intact BBB. It is assumed that delivery of BSH to brain tumour cells relies on passive diffusion across the BTB, owing to its pathologically increased permeability compared with the normal BBB structure [ 80 , 81 , 82 ]. However, BTB permeability is often functionally insufficient for many molecules because BTB disruption is spatially heterogeneous—parts of the tumour and especially infiltrative margins retain BBB-like barrier properties, limiting passive diffusion and leading to uneven delivery [ 79 , 80 , 81 , 82 ]. In this review, we consider permeability ‘sufficient’ when it enables BNCT-relevant intratumoural 10 B levels and selectivity at the planned irradiation time (e.g., adequate tumour uptake with favourable tumour-to-blood/normal ratios) [ 82 ].

BPA/BPA-fructose partially circumvents the BBB via LAT1 transporters but shows heterogeneous uptake. PEGylated liposomes, boronated polymeric nanoparticles and boron-rich clusters can exploit receptor-mediated transcytosis or adsorptive endocytosis; functionalisation (e.g., transferrin-like ligands) and intermediate lipophilicity can improve brain exposure (predominantly in vivo, preclinical evidence for carrier platforms; clinical evidence exists for BPA/BPA-fructose), although translation into consistent clinical benefit requires further validation [ 15 , 23 , 68 , 83 ]. Mechanism of transport across BBB is shown in Figure 3 [ 84 ].

Preclinical studies on intracerebral drug delivery to brain tumours by intrathecal injection into the cerebrospinal fluid or convection-enhanced delivery directly to intracranial tumours, as potential methods of BBB/BTB bypass, show enhanced 10 B cellular uptake in lesion areas and higher T/N ratios [ 82 ]. However, these methods are highly invasive, and further work on safer BBB/BTB permeability enhancement is required. BBB/BTB permeability for therapeutic drugs can be modified by osmotic mannitol-induced opening of endothelial tight junctions. Furthermore, stimulation of endothelial cell receptors via intra-arterial administration of vasoactive compounds, ultrasound-based techniques combined with microbubble administration, and electropermeabilisation have all been reported as potential methods for clinical BNCT applications [ 9 , 79 , 82 , 85 , 86 , 87 , 88 , 89 , 90 ]. Nevertheless, despite their potential benefits, these approaches are generally considered invasive and potentially damaging. Consequently, strategies that exploit physiological BBB transport mechanisms and/or the pathophysiological properties of the BTB are being extensively developed as more advantageous and safer alternatives.

3.4. Intracellular Distribution and Organelle Targeting

Given the micrometric range of BNCT particles, subcellular localisation matters. Nuclear-accumulating metallacarborane intercalators and boronated nucleosides enhance DNA-proximate 10 B deposition, potentially increasing cytotoxic yield at equal bulk boron levels. Liposomal/polymeric carriers may localise to endo-lysosomal compartments unless engineered for triggerable release [ 13 , 14 , 15 , 25 , 26 , 67 , 91 , 92 ].

3.5. Distribution Kinetics and Clearance

Small molecules approach distribution equilibrium rapidly (≈15–30 min), whereas nano-systems often show bi-exponential kinetics with prolonged α- and β-phases owing to stealth coatings and reduced RES uptake [ 15 , 63 ]. Biodistribution patterns typically favour tumour and liver for silica/BN-based nanocarriers, with PEG minimising splenic/renal deposition relative to non-PEGylated analogues [ 15 , 21 ].

3.6. Imaging-Based Distribution Data

Clinical FBPA-PET studies in glioma demonstrate T/N ratios commonly around 2–3+ with supportive T/B values, guiding patient selection and scheduling [ 8 , 40 , 70 ]. Accelerator-based BNCT platforms and prospective trials are expanding the clinical dataset and will enable more robust ADMET-dosimetry integration [ 5 , 11 , 24 , 85 ].

4. Metabolism of Boron-Containing Agents

Successful BNCT requires that chemically stable 10 B remains associated with tumour cells long enough to match the neutron-irradiation window, while minimising residues in normal organs. Here, “metabolism” encompasses (i) enzymatic and non-enzymatic transformation of small-molecule agents and linkers, (ii) intracellular trafficking and processing that determine subcellular fate, and (iii) biodegradation of carrier matrices and ligands that release, retain, or inactivate boron payloads [ 1 , 2 , 3 , 7 , 14 , 15 , 76 , 92 , 93 ]. Table 3 provides a concise summary of the key ADMET parameters discussed in this section. In silico ADMET platforms can be used to anticipate metabolic liabilities of linkers and to triage designs prior to in vivo testing [ 34 ]. Mechanistic reviews of boron pharmacophores (including carborane-based scaffolds) summarise metabolism-relevant design trade-offs [ 34 , 35 ]. Metabolic stability of boron pharmacophores and linker design considerations are overviewed in [ 64 ]. Metabolism-relevant design trade-offs (cluster stability vs. linker liability) and polymer platforms are discussed in recent reviews and case studies [ 19 , 39 , 48 ].

4.1. Low-Molecular-Weight Agents

BPA/BPA–fructose. BPA is transported predominantly by LAT1 and, after cellular entry, does not undergo extensive biotransformation; its apparent “metabolic” behaviour is governed by reversible intracellular partitioning and relatively rapid egress from cells lacking sustained LAT1-mediated transport [ 10 ]. Clinically, the fructose complex improves aqueous handling and exposure but does not introduce a distinct metabolic pathway; PET studies with 18 F-BPA ( 18 F-labelled BPA) analogues show time-dependent tumour uptake and washout consistent with transporter-coupled distribution rather than covalent metabolism [ 8 , 40 ]. Consequently, strategies to increase functional retention rely on formulation or co-delivery that delays efflux ( Section 4.4 ) [ 3 , 15 , 17 ].

BSH. BSH is highly hydrophilic and largely extracellular; it exhibits limited membrane permeability and is cleared renally with negligible metabolic conversion, which constrains intracellular boron residence times in many tumours [ 1 , 11 , 12 ]. Attempts to alter BSH fate therefore emphasise conjugation or encapsulation rather than exploiting intrinsic biotransformation [ 3 , 7 , 27 ].

4.2. Metallacarborane and Carborane-Containing Small MOLECULES

In this review, the term “metallacarboranes” refers primarily to well-defined transition-metal bis (dicarbollide) boron clusters and their biologically functionalised derivatives, with particular emphasis on nucleoside–metallacarborane conjugates reported as chemically stable, boron-rich constructs and investigated for BNCT-relevant properties. Representative nucleoside–metallacarborane architectures and their structural characterisation are described in refs. [ 25 , 26 ], with additional structure–property discussion for nucleoside/boron-cluster conjugates in ref. [ 59 ] and broader metallacarborane medicinal-chemistry context in refs. [ 13 , 67 ]. Carborane clusters are exceptionally resistant to oxidative and hydrolytic degradation under physiological conditions, a property that underpins their use as metabolically robust boron carriers [ 7 , 13 , 14 , 15 , 25 , 26 , 41 ]. When appended to nucleosides, intercalators or other scaffolds, metabolic “soft spots” shift from the cluster to organic linkers and heteroatom-rich tethers. Reported designs mitigate premature cleavage through steric shielding, hydrolytically stable linkages, and balanced lipophilicity (logP ≈ 2–3) that reduces lysosomal sequestration without sacrificing uptake [ 7 , 13 , 14 , 15 , 25 , 26 , 41 ].

4.3. Bioconjugates: Peptides and Targeted Ligands

For peptide or small-protein conjugates, in vivo stability is dominated by proteolysis and linker chemistry. Protease-resistant backbones, cyclisation, and PEGylated spacers reduce proteolytic turnover, whereas cleavable linkers (e.g., acid-labile or enzyme-responsive) can trigger intracellular release from endosomes—minimising lysosomal degradation of the cargo [ 10 , 14 , 15 , 18 , 19 , 91 ]. Receptor cycling kinetics also shape fate: repeated endocytosis recycling can maintain intracellular exposure if the conjugate avoids rapid lysosomal destruction [ 14 , 15 ].

4.4. Polymeric and Lipid Carriers

Polymeric dendrimers and PEGylated liposomes protect boron payloads from premature efflux and metabolism by slowing opsonisation and reticuloendothelial uptake; their effective half-lifes are therefore controlled by colloidal stability, stealth coatings and gradual matrix erosion rather than classical xenobiotic metabolism [ 15 , 52 , 68 , 69 ]. PEG corona density, particle size and surface charge govern protein corona formation and downstream clearance; insufficient stealth accelerates hepatic and splenic processing, curtailing the therapeutic window [ 16 , 17 , 56 ]. Within cells, endosomal–lysosomal trafficking can entrap carriers; endosomolytic components or pH-responsive gates are used to achieve cytosolic release before degradative processing reduces functional boron content [ 15 , 16 , 17 ].

4.5. Inorganic Nanoplatforms

Functionalised mesoporous silica nanoparticles (MSNs) do not undergo enzymatic metabolism; their fate reflects surface chemistry and biodegradation into silicic acid over extended timescales. Gatekeepers and ligand shells dictate when and where boron is released; careful control of linker stability is required to prevent premature shedding in blood or rapid endo-lysosomal degradation after uptake [ 20 , 21 , 53 , 54 , 55 ]. As with polymeric systems, protein corona evolution influences cellular routing and organ-level processing [ 21 , 56 ].

4.6. Cell-Based Delivery Systems

Macrophages and related cellular carriers internalise boron payloads and traffic them into hypoxic and poorly perfused tumour regions. In this context, “metabolism” comprises intracellular processing of the payload (e.g., nanoparticle dissolution or linker cleavage) and carrier cell viability and activation state, which together govern release kinetics at the disease site. Available data indicate that macrophage-borne boron carbide nanoparticles can maintain payload integrity during homing and enable sustained intratumoural release (in vitro macrophage loading; in vivo tumour homing/retention), thereby prolonging intratumoural residence without chemical modification of the boron core [ 23 , 24 ].

4.7. Analytical Read-Outs and Modelling of Metabolic Fate

Dynamic PET with 18 F-BPA analogues offers a non-invasive surrogate for time-dependent boron handling in LAT1-positive tissues, informing whether apparent loss reflects distributional washout rather than chemical turnover [ 8 , 40 , 87 ]. Integrating such data into physiologically based pharmacokinetic and dose-planning frameworks allows explicit scheduling of irradiation to coincide with peak tumour-to-blood ratios and to account for carrier-specific retention versus clearance processes. Contemporary reviews emphasise aligning subcellular localisation with BNCT radiobiology to maximise high-LET yield per retained 10 B atom [ 3 , 14 , 83 ].

4.8. Design Principles from a Metabolism Perspective

Favour chemically inert boron cores and shift control to linkers and trafficking; tune linkers for on-target release while resisting plasma degradation [ 7 , 13 , 14 , 15 , 25 , 26 , 41 ].

Reduce endo-lysosomal loss by incorporating pH-labile or membrane-active features to promote endosomal escape [ 14 , 15 , 16 , 17 ].

Exploit transporter biology without creating new liabilities; for LAT1-mediated entry, adjust polarity and sterics to curb rapid efflux while retaining engagement [ 3 , 10 , 14 , 15 , 61 ].

Engineer carrier shells for controlled processing; PEG density, size and surface chemistry govern protein corona formation, RES uptake and intracellular routing [ 15 , 16 , 52 , 56 ].

Leverage biological carriers when microenvironmental access is limiting; release kinetics then arise from cellular turnover rather than chemical degradation [ 23 , 24 ].

Couple measurement to planning; use PET-derived kinetics and PBPK-informed scheduling to match irradiation to periods of maximal on-target retention [ 8 , 40 , 70 , 83 , 92 ].

5. Excretion of Boron-Containing Agents

The elimination of boron carriers determines the width of the therapeutic window, the off-target dose to radiosensitive organs, and the long-term safety profile. For BNCT agents, “excretion” encompasses glomerular filtration and tubular handling for low-molecular-weight compounds, hepatobiliary elimination following uptake by hepatic sinusoidal endothelium and Kupffer cells, and MPS (mononuclear phagocyte system)/RES processing of nano and biocarriers, often preceded by protein corona formation. Excretion-relevant ADMET parameters across representative agents are summarised in Table 4 . Elimination considerations for BPA/BSH and newer classes are discussed in current BNCT guidance and reviews [ 34 , 78 ]. Early animal work on borylated ferrocenium derivatives provides additional context on organ distribution and handling [ 72 ]. Elimination routes and practical safety context for boron classes are discussed in [ 23 ]. Elimination and material handling can be informed by reports on 2D boron nitride nanosheets and tracer pharmacokinetics [ 58 , 95 , 96 ].

5.1. General Principles and Elimination Pathways

Small, hydrophilic molecules are typically cleared rapidly by the kidneys; increased lipophilicity and plasma protein binding reduce filtration and may favour hepatobiliary routes. For nanoparticles and supramolecular carriers, hydrodynamic size, surface chemistry (including PEG density and charge), and the acquired biomolecular corona govern MPS recognition and organ retention, thereby shaping biliary versus renal elimination and any lymphatic drainage component [ 49 , 50 , 51 , 96 ]. In practice, systems that avoid opsonisation and remain below renal filtration size cut-offs are more likely to undergo efficient urinary clearance; larger or poorly “stealthed” constructs preferentially accumulate in liver and spleen before slowing hepatobiliary excretion [ 49 , 50 , 51 ].

5.2. Low-Molecular-Weight Agents

BPA/BPA–fructose. After LAT1-mediated uptake and redistribution, BPA is eliminated predominantly via the kidneys; clinical PET kinetics consistently show relatively rapid blood clearance with time-dependent tumour washout, reflecting transporter biology more than metabolic turnover [ 3 , 40 , 68 ]. Adjusting infusion schedules and irradiation timing aims to exploit transiently favourable tumour-to-blood ratios while limiting renal exposure [ 3 , 14 ].

BSH. Sodium borocaptate, being highly hydrophilic and largely extracellular, exhibits rapid renal elimination with modest cellular retention; hepatobiliary clearance is limited relative to urinary excretion [ 1 , 11 , 12 ].

5.3. Bioconjugates (Peptides, Targeted Ligands)

Peptide conjugates below the renal filtration size tend to be cleared renally unless protected by plasma binding or sustained receptor engagement; proteolysis generates smaller fragments that further favour urinary elimination. Where conjugates engage high-turnover endocytic pathways, intracellular routing to lysosomes can precede efflux of catabolites and subsequent renal clearance. Linker design (e.g., acid-labile, enzyme-responsive) modulates when intracellular release occurs and may indirectly alter the balance between renal and biliary routes [ 14 , 15 , 18 , 19 , 91 ].

5.4. Polymeric and Lipid Carriers

PEGylated liposomes and dendrimers generally exhibit prolonged circulation with progressive uptake by the MPS in liver and spleen; elimination typically proceeds via hepatobiliary excretion of lipidic or polymeric catabolites and, to a lesser extent, renal clearance of low-molecular fragments. Higher PEG density and near-neutral surface charge reduce opsonisation and slow RES capture, whereas insufficient stealth accelerates hepatic processing and shortens systemic exposure [ 15 , 16 , 17 , 52 ]. Re-engineering endosomal escape may paradoxically increase apparent elimination if it accelerates cytosolic release and subsequent renal clearance of small payloads [ 16 , 17 , 52 ].

5.5. Inorganic Nanoplatforms

Functionalised mesoporous silica nanoparticles (MSNs) do not undergo enzymatic metabolism; instead, they experience gradual biodegradation to silicic acid, with rates governed by particle size, porosity and surface functionalisation. Depending on corona composition and organ uptake, elimination can involve slow hepatobiliary routes, with urinary excretion of soluble degradation products. Gatekeepers and ligand shells, while enabling on-target release, also influence organ retention and therefore the timescale of excretion [ 20 , 21 , 52 , 54 ].

5.6. Cell-Based Delivery Systems

For macrophage-mediated delivery, the primary determinant of excretion is the fate of the carrier cell and the persistence of the internalised payload. After tumour homing and release, residual payload may be sequestered by local phagocytes or cleared via lymphatics and hepatic pathways; when cargo consists of inert boron carbide nanoparticles, systemic redistribution is limited and elimination depends on slow biological turnover rather than classical renal or biliary routes.

5.7. Transporters and Clinical Pharmacology

Although most BNCT carriers are not classic substrates for drug-metabolising enzymes, renal and hepatic transporters modulate apparent clearance of small molecules and catabolites. Contemporary guidance highlights clinically relevant transporters, e.g., OATs (Organic Anion Transporters)/OCTs (Organic Cation Transporters), OATP (Organic Anion Transporting Polypeptides/BCRP (Breast Cancer Resistance Protein)/P-gp (P-Glycoprotein) and study designs for evaluating transporter-mediated interactions; such principles are valuable when BNCT agents are co-administered with supportive medications that may affect renal secretion or biliary efflux [ 33 , 46 ].

5.8. Design Principles for Favourable Elimination

Match elimination route to clinical scheduling: for BPA and similar small molecules, fast renal clearance demands irradiation windows aligned to peak tumour exposure; for nanocarriers, anticipate slower hepatobiliary excretion and plan accordingly. Exploit size and stealth judiciously: maintain hydrodynamic sizes and surface chemistries that avoid excessive RES uptake while not preventing eventual elimination; higher PEG density and neutrality generally prolong circulation but may also delay clearance [ 16 , 17 , 49 , 50 , 51 ].

Design degradability without premature loss: for polymeric and silica systems, incorporate controlled-degradation features that permit eventual elimination (renal or biliary) after the therapeutic window, avoiding long-term organ retention [ 20 , 21 , 52 , 53 , 54 , 55 ].

Consider transporter context: when feasible, avoid strong interactions with renal/hepatic transporters liable to drug–drug interactions in multi-agent regimens; consult transporter frameworks when planning clinical protocols [ 33 ].

6. Toxicity and Safety of Boron-Containing Agents

Clinical translation of BNCT depends on delivering a cytocidal high-LET dose selectively to tumour while maintaining acceptable systemic and organ-specific safety. Toxicity arises from (i) the carrier itself (chemical/biological effects), (ii) off-target boron deposition in normal tissues exposed during irradiation, and (iii) platform-specific liabilities (e.g., nanocarrier MPS uptake, peptide immunogenicity) [ 1 , 2 , 3 , 4 , 5 , 7 , 14 , 83 , 93 , 97 ]. A compact cross-platform comparison of safety endpoints and mitigations is provided in Table 5 . A recent review on boron nanodrugs for BNCT provides an integrated overview of efficacy, biodistribution and safety issues for nano-scale delivery systems [ 98 ].

6.1. Clinical Safety Experience and Normal Tissue Effects

Modern trials and clinical series, particularly with accelerator-based BNCT for recurrent head-and-neck cancer and other indications, report toxicity profiles dominated by expected radiotherapy-like adverse events in the irradiated field (mucositis, dermatitis, xerostomia), with systemic events generally mild to moderate when BPA or BSH are employed according to contemporary protocols [ 4 , 39 , 83 , 92 , 93 , 97 , 99 ]. Dose planning that integrates time-dependent tumour-to-blood ratios reduces normal tissue dose and correlates with acceptable acute and subacute toxicity in prospective cohorts [ 5 , 70 , 83 , 92 , 93 , 99 ].

6.2. Small-Molecule Agents

BPA/BPA–fructose. Clinical use is associated most commonly with transient nausea, flushing and infusion-related symptoms; significant organ toxicity is uncommon at recommended exposures when irradiation is scheduled to favourable T/B windows. Because BPA relies on LAT1-mediated transport, heterogeneity in transporter expression can lead to variable normal tissue uptake, which is mitigated by PET-based selection and scheduling [ 3 , 8 , 10 , 14 , 40 ].

BSH. With its largely extracellular distribution and rapid renal elimination, BSH shows modest tumour selectivity and correspondingly conservative safety margins; organ toxicities are primarily constrained by irradiation geometry and blood concentration at the time of neutron exposure [ 1 , 11 , 40 , 92 ].

6.3. Bioconjugates and Targeted Ligands

Peptide and ligand-bearing constructs introduce platform risks: proteolysis (yielding reactive fragments), potential immunogenicity, and off-target binding where receptors are expressed on normal tissues. Rational design (protease-resistant backbones, constrained/cyclised scaffolds, stable yet triggerable linkers) reduces these liabilities; nonetheless, receptor density heterogeneity implies that patient selection and imaging confirmation remain crucial to limit unintended normal tissue dose during irradiation [ 14 , 15 , 18 , 19 , 91 ].

6.4. Plymeric and Lipid Carriers

PEGylated liposomes and dendrimers prolong circulation and can enhance tumour exposure, but they interact with the MPS, driving hepatic/splenic deposition. Safety considerations therefore include hepatosplenic enlargement, alteration of liver enzymes, complement activation, and—less commonly—infusion reactions; these are mitigated by optimising PEG density, surface charge and size, as well as by step-wise dosing where appropriate [ 15 , 16 , 17 , 52 ]. Endosomal escape motifs that improve intracellular delivery must be balanced against membrane-active toxicity at high concentrations.

6.5. Inorganic Nanoplatforms

Functionalised mesoporous silica nanoparticles (MSNs) are not metabolised enzymatically but undergo gradual biodegradation to silicic acid, the rate of which depends on particle size, porosity and surface chemistry. Reported safety concerns reflect long-term organ retention if degradation is slow and inflammatory responses modulated by protein corona composition; design strategies that favour biodegradation after the therapeutic window and neutral corona profiles generally improve tolerability [ 20 , 21 , 54 , 55 , 56 , 98 ].

6.6. Cell-Based Delivery Systems

Macrophage-mediated delivery offers deep penetration into hypoxic tumour territories but raises distinct safety questions: persistence of carrier cells, ectopic accumulation, and immune activation. Preclinical work shows tumour homing with sustained intratumoural presence and limited systemic redistribution of inert boron carbide payloads; translation requires GMP (Good Manufacturing Practice)-compliant manufacturing, release criteria, and monitoring for cytokine-related events [ 23 , 24 ].

6.7. Radiobiology-Informed Risk Management

Because the path length of α/ 7 Li particles is micrometric, toxicity from BNCT is tightly coupled to where boron resides at irradiation. Contemporary radiobiology overviews emphasise aligning subcellular localisation—with a preference for DNA-proximal boron for efficacy—with sparing of normal tissues, especially in organs at risk adjacent to the target volume. PET read-outs (e.g., with 18 F-BPA analogues) combined with PBPK-aware dose planning reduce normal tissue exposure by matching neutron fields to windows of maximal tumour selectivity [ 8 , 40 , 70 , 83 , 92 ].

6.8. Drug–Drug Interactions and Supportive Care

While BNCT agents are not classical substrates for drug-metabolising enzymes, small boronated molecules and catabolites can be substrates of renal or hepatic transporters. Guidance from the International Transporter Consortium and recent clinical methodology highlights the need to consider transporter-mediated interactions when planning antiemetics, analgesics or other supportive medications that might alter renal secretion or biliary efflux [ 33 ]. For nanoplatforms and bioconjugates, interactions are more likely to be physicochemical/biological (e.g., complement activation, opsonisation) than enzymatic, and should be addressed through premedication policies and infusion-rate control where indicated.

6.9. Practical Design Principles (Safety)

Engineer selectivity first: subcellular localisation and tumour selectivity (T/N, T/B at irradiation) are dominant determinants of toxicity in BNCT; imaging-guided scheduling is central to risk reduction [ 3 , 4 , 5 , 8 , 22 , 40 , 70 , 83 , 93 , 99 ].

Minimise pro-inflammatory cues: favour PEGylation and near-neutral surfaces to reduce opsonisation/complement activation for nanoplatforms; avoid highly cationic designs associated with haemolysis or membrane damage [ 15 , 16 , 17 ].

Implement time-controlled degradability: for inorganic/polymeric carriers, design controlled post-treatment biodegradation, to prevent long-term organ retention while preserving intratumoural residence during therapy [ 20 , 21 , 53 , 54 ].

Constrain peptide/ligand risk: use protease-resistant motifs and validate receptor expression in normal tissues to limit off-target uptake; consider immunogenicity screening for repeated dosing [ 14 , 15 , 18 , 19 , 91 ].

Account for transporters and co-medications: map plausible transporter liabilities for small molecules and plan supportive therapy to avoid increasing systemic exposure or altering renal clearance [ 33 ].

6.10. Genetic and Oxidative Safety

Genetic and oxidative risks associated with boron-containing agents arise from two separable sources: (i) material intrinsic effects (e.g., surface reactivity of inorganic frameworks, redox or photoactive motifs, linker-driven off-target chemistry) and (ii) BNCT irradiation when boron is mislocalised to normal tissues. Contemporary radiobiology underscores that the micrometric range of the α/ 7 Li particles confines DNA injury to boron-loaded cells; hence, genotoxicity in healthy tissues is primarily a function of biodistribution at the instant of irradiation, rather than of intrinsic mutagenicity of the carrier [ 83 , 92 ]. For small molecules (BPA/BPA-fructose, BSH), clinical and translational reports have not identified consistent genotoxic signals at therapeutic exposures when irradiation is scheduled to favourable tumour-to-blood ratios and patient selection uses PET read-outs [ 3 , 4 , 5 , 8 , 40 , 92 , 93 ]. For supramolecular and inorganic platforms (PEGylated liposomes/dendrimers; mesoporous silica), oxidative read-outs largely reflect protein corona composition, endo-lysosomal residence and long-term organ retention; neutral coronas, controlled post-treatment biodegradation (for silica), and calibrated endosomal-escape features mitigate these risks. Boron nitride nanosheets prepared under sustainable, biocompatible protocols likewise exhibit favourable oxidative profiles contingent on surface passivation and synthesis route [ 89 ]. Overall, genetic safety is dictated by selective localisation at the time of neutron exposure and by surface/linker engineering that minimises ROS (Reactive Oxygen Species)-linked stress during residence within the reticuloendothelial system [ 15 , 16 , 17 , 54 , 55 , 56 , 83 , 95 ].

6.11. In Vivo Toxicological Profiles and NOAEL (No-Observed-Adverse-Effect Level) Values

For inorganic borates/boric acid outside the BNCT context, classical toxicology synthesises organ-level hazards and NOAEL benchmarks in animals; these reviews provide a conservative backdrop for interpreting systemic exposure (notably renal) and for framing dose-setting in boron-containing platforms [ 100 ]. In nanomedicine, clearance-centred analyses relate hydrodynamic size, PEG density, surface charge and corona formation to organ sequestration and elimination, offering practical levers to reduce long-term tissue burden and to interpret hepatic or splenic findings under repeat dosing [ 49 , 50 , 51 ]. Translational BNCT series indicate that with contemporary BPA/BSH protocols, imaging-guided scheduling and PBPK-aware planning, systemic toxicity is usually limited and dominated by field-restricted radiotherapy reactions rather than multi-organ failure, aligning with clinically acceptable safety margins [ 4 , 101 ]. For mesoporous silica and polymeric carriers, in vivo profiles improve when matrices are degradable on clinically relevant timescales and when surfaces limit opsonisation, thereby facilitating eventual elimination and tempering chronic organ retention [ 20 , 21 , 52 , 54 ]. Precise NOAELs are compound-, species- and regimen-dependent; where they exist, they should be invoked in context and not extrapolated across platforms without adjustment for formulation and exposure kinetics [ 101 ].

6.12. Immunotoxicity and Inflammatory Responses [ 14 , 15 , 16 , 17 , 18 , 20 , 54 , 56 , 91 ]

Immunotoxicity with BNCT delivery systems is generally platform-determined. For liposomes and dendrimers, principal concerns include complement activation and mononuclear phagocyte system (MPS/RES) uptake, exacerbated by low PEG density, cationic surfaces or “sticky” coronas; mitigation relies on increasing PEG coverage, maintaining near-neutral charge, moderating infusion rates, and using premedication where indicated. For mesoporous silica and related inorganics, inflammatory signatures track with biodegradation kinetics and surface chemistry; designs that promote neutral coronas and triggerable (pH/enzyme-labile) gates tend to suppress innate activation and favour “silent” clearance. Peptide/ligand conjugates carry risks of immunogenicity and off-target binding where receptors are expressed in normal tissues; protease-resistant scaffolds, validated receptor maps and monitoring for infusion reactions are prudent safeguards. Cell-based carriers may elicit cytokine responses contingent on cell activation state and persistence; GMP-compliant manufacture, explicit release criteria, and protocolised clinical monitoring are required. In practice, surface neutrality, controlled degradability and calibrated intracellular escape reduce inflammatory risk, while precise irradiation timing minimises radiogenic inflammation in normal tissues adjacent to the target volume. For a compact cross-platform comparison of safety endpoints and mitigations, see Table 5 .

7. Key Insights

7.1. Absorption

Transporter biology dominates small-molecule entry: LAT1 for BPA and nucleoside transporters for selected boronated bases, while formulations such as BPA–fructose primarily modulate exposure without creating new biotransformation pathways [ 8 , 10 , 14 , 23 , 29 , 30 , 32 , 40 ]. For nano and polymeric systems, hydrodynamic size (≈50–150 nm), near-neutral surface charge and PEGylation govern epithelial/endothelial passage and endocytic uptake; optimising these variables improves synchrony between tumour exposure and irradiation [ 11 , 15 , 16 , 17 , 23 , 48 , 49 , 50 , 51 ]. Carborane motifs increase lipophilicity and membrane interaction; balancing logP (~2–3) with polar linkers enhances uptake while mitigating lysosomal sequestration [ 7 , 13 , 14 , 15 , 41 , 42 , 43 , 44 ]. In practice, transporter-aware design combined with pro-retention features (e.g., endosomal escape, linker selection) and PET tracers, where available, allows absorption trajectories to be quantified and scheduled [ 8 , 38 , 39 , 40 , 57 , 58 ].

7.2. Distribution

Clinical distribution is heterogeneous and indication-dependent: BPA shows LAT1-linked tumour uptake with moderate T/N ratios on PET (see Section 3.6 ), whereas BSH remains largely extracellular with lower selectivity [ 1 , 3 , 8 , 10 , 11 , 12 , 14 , 23 , 34 , 78 ]. PEGylated carriers extend circulation but are progressively taken up by MPS organs (liver, spleen); ligand grafting can redirect a fraction towards tumours, whereas BBB entry generally requires specific targeting mechanisms [ 11 , 15 , 16 , 23 , 34 , 35 , 49 , 50 , 51 , 52 , 68 ]. Subcellular localisation is critical given the micrometric range of BNCT particles: DNA-proximal constructs, such as metallacarborane intercalators, can increase radiobiological yield at similar bulk boron levels [ 13 , 14 , 15 , 41 , 43 , 44 ]. Integration of PBPK-based planning with imaging read-outs allows irradiation to be scheduled at maximal T/B ratios and within platform-specific biodistribution windows [ 8 , 40 , 70 , 92 ].

7.3. Metabolism

Carborane clusters are metabolically robust; liabilities are shifted to linkers and attached scaffolds, where hydrolysis can be controlled via amide/urea linkages, steric shielding and appropriate lipophilicity [ 7 , 13 , 14 , 15 , 41 , 42 , 43 , 44 , 45 ]. Polymeric and lipid carriers undergo colloidal processing rather than classical enzymatic metabolism; their fate is dictated by protein corona formation, stealth properties and intracellular routing [ 11 , 15 , 16 , 17 , 23 , 48 , 49 , 50 , 51 , 56 ].

MSNs degrade slowly to silicic acid, with surface chemistry and gate design controlling the timing of payload release and material clearance [ 20 , 21 , 54 , 55 ]. For BPA/BSH, most apparent “metabolic” behaviour reflects distributional washout, so linker and gate design should align intracellular release with the planned irradiation window [ 3 , 8 , 14 , 22 , 37 , 40 , 70 ].

7.4. Excretion

Small hydrophilic agents are predominantly cleared renally, whereas nano and polymeric systems tend to follow hepatobiliary routes after MPS uptake, with clearance rates governed by degradability and corona evolution [ 1 , 3 , 11 , 12 , 15 , 23 , 49 , 50 , 51 , 56 ]. Controlled degradability of matrices enables eventual elimination while preserving sufficient exposure during therapy [ 20 , 21 , 52 , 54 , 55 ]. Consequently, particle size and stealth should be tuned for predictable clearance, and irradiation should be planned near the pharmacokinetic peak for small molecules or within the exposure plateau for long-circulating carriers [ 8 , 40 , 49 , 50 , 51 , 69 ].

7.5. Toxicity

Most observed clinical toxicities resemble conventional radiotherapy-related effects within the irradiated field; systemic events are generally mild when scheduling aligns with favourable T/B ratios [ 4 , 5 , 83 , 92 , 93 , 97 , 99 ]. Platform-specific risks include complement activation (liposomes, dendrimers), inflammatory responses with slowly degradable inorganics, and immunogenicity or off-target binding for peptide/ligand conjugates [ 14 , 15 , 18 , 20 , 21 , 52 , 53 , 54 , 55 , 91 ]. These risks can be mitigated by surface neutrality and adequate PEG coverage, controlled biodegradation, validated receptor expression maps and appropriate supportive care protocols, while PET/PBPK-based planning helps minimise normal tissue dose [ 8 , 14 , 15 , 40 , 52 , 54 , 55 , 56 , 69 , 83 , 92 ].

These key insights can be mapped back onto the design control framework outlined in Figure 4 , emphasising how quantitative ADMET goals translate into concrete choices of BNCT carrier platforms.

8. Conclusions and Outlook

Structure–performance relationship and practical implications. For BNCT, the most useful structure–performance relationship is the link between molecular structure (or carrier architecture) and PK/BD, because efficacy depends on delivering sufficient 10 B to tumour tissue within the irradiation window while limiting normal tissue exposure [ 1 , 7 , 14 , 15 ].

BPA (commonly formulated as BPA–fructose) remains the principal clinical benchmark due to transporter-associated tumour uptake and the availability of human PK models used to support scheduling [ 8 , 40 , 62 , 63 , 95 ]. BSH is a complementary reference compound: it is chemically robust and strongly hydrophilic, which favours rapid clearance and largely extracellular distribution, but typically provides limited tumour selectivity unless delivery conditions are optimised [ 1 , 9 , 78 , 81 ].

Boron clusters (carboranes and metallacarboranes) offer high boron content and metabolic stability; therefore, performance is often determined by substituents and linkers that control charge, lipophilicity and intracellular retention [ 13 , 41 , 59 ]. Nucleoside–metallacarborane conjugates provide well-defined examples of this design space and have been structurally characterised in the cited primary literature [ 25 , 26 ], with broader context discussed in recent reviews [ 13 , 61 ]. DNA-associated boron constructs have also been explored as a strategy to influence microdistribution at the cellular level, but their development ultimately hinges on in vivo PK/BD and clearance [ 14 , 66 ].

For liposomes, micelles, dendrimers and inorganic carriers, “structure” is best captured by architectural descriptors (size, surface chemistry/PEGylation/ligands, stability and payload form), which govern circulation time, RES uptake, tumour penetration and clearance [ 15 , 16 , 56 ]. Representative examples discussed here include transferrin-modified PEG liposomes for boron payload delivery [ 17 ], core-polymerised boron-conjugated micelles with engineered pharmacokinetics [ 83 ], and macrophage-mediated transport of boron carbide nanoparticles to poorly perfused tumour regions [ 24 ].

Taken together, the most consistent interpretation is obtained when delivery concepts are supported by in vivo PK/BD (and, where relevant, imaging) and when clearance is characterised on clinically compatible timescales [ 15 , 16 , 39 , 58 , 70 ]. Approaches supported mainly by in vitro uptake or associated with persistent organ retention should be treated as preliminary until in vivo biodistribution, clearance and reproducibility are established [ 15 , 16 , 56 ].

Dimodality of BNCT and interdisciplinary collaborative research imply that the development in the multidisciplinary scientific areas and evaluation of new technologies is in demand. To achieve high effectiveness of BNCT, an adequate therapeutic dose delivery is desired. The ADMET framework allows defining input parameters for treatment plan establishment and BNCT implementation. Quantitative theranostics approach, subcellular precision of targeting molecules providing long-circulating yet degradable platforms design, biological vectors evaluation, and transporter-aware pharmacology are the main pillars indicating future directions of BNCT development.

8.1. Future Directions

Quantitative theranostics. Systematically combined PET-derived kinetics (e.g., 18 F-labelled amino acids and sugars) with PBPK models and time-resolved dosimetry to personalise neutron field timing and reduce the risk of normal tissue exposure [ 8 , 38 , 39 , 40 , 57 , 58 , 70 , 92 ]. Table 6 summarises the in silico toolbox that underpins ADMET-guided optimisation of BNCT agents and treatment schedules.

Subcellular precision. Further develop nuclear-affine boron pharmacophores and triggerable gates to maximise DNA-proximate 10 B at a given total boron load, with an emphasis on linker chemistries that couple endosomal escape to controlled intracellular release [ 13 , 14 , 15 , 41 , 43 , 44 ].

Long-circulating yet degradable platforms. Design long-circulating carriers with well-characterised biodegradation profiles to balance exposure and clearance, and to define post-treatment degradation timeframes that avoid chronic organ retention [ 11 , 15 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 68 , 69 ].

Biological vectors. Cell-based delivery under GMP conditions with robust release criteria and clinical monitoring frameworks to exploit homing into hypoxic tumour regions while maintaining safety [ 23 , 24 ].

Transporter-aware pharmacology. Map LAT1 and other clinically relevant transporters across indications to stratify patients and to anticipate drug–drug interactions affecting renal and hepatic transport [ 10 , 14 , 33 , 61 ].

8.2. Perspective

Research on BNCT is conducted at the intersection of radiobiology, medical chemistry, medical physics, medicine, dosimetry and nuclear engineering. The main challenge is spatiotemporal correlation of boron dose deposition, namely high-LET dose delivery within the therapeutic window in which boron is concentrated at the specified subcellular location within the tumour but it hardly ever accumulates in normal tissues. The ADMET framework clarifies chemical and biophysical therapy pillars providing a basis for treatment plan establishment and adequate physical dose deposition in target volume to achieve an expected therapeutic effect and minimise side effects: transporter engagement and formulation (absorption), PBPK-synchronised tissue exposure (distribution), linker- and route-of-entry control (metabolism), degradability-tuned clearance (excretion), and platform-aware risk management (toxicity). Progress over the next few years is likely to be driven by imaging-guided treatment planning evaluation, specific subcellularly targeting carriers and materials that combine prolonged circulation with predictable degradation, enabling BNCT to deliver its spatial therapeutic selectivity with reproducible clinical benefit.

Acknowledgments

The authors express gratitude to all collaborating research teams contributing to the development of boron pharmacology and BNCT translational studies.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Author Contributions

Conceptualisation, K.E.W.; software, K.E.W. and Z.M.; formal analysis, K.E.W.; resources, K.E.W., E.B., Ł.B., M.D., N.K., Z.M., E.W. and M.Z.; data curation, K.E.W., E.B., Ł.B., M.D., N.K., Z.M., E.W. and M.Z.; writing—original draft preparation, K.E.W.; writing—review and editing, K.E.W., E.B., Ł.B., M.D., N.K., Z.M., E.W. and M.Z.; visualisation, K.E.W., M.D. and N.K.; super-vision, K.E.W.; project administration, K.E.W.; funding acquisition, K.E.W. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript: ADMET Absorption, Distribution, Metabolism, Excretion and Toxicity AEs Adverse Effects BBB Blood–Brain Barrier BCRP Breast Cancer Resistance Protein BN Boron Nitride BNCT Boron Neutron Capture Therapy BODIPY Boron-Dipyrromethene BPA p-Boronophenylalanine BPA-fructose Boronophenylalanine-fructose, BPA-Fr 18 F-BPA 18 F-labelled Boronophenylalanine, FBPA 18 F-BPA-fructose 18 F-labelled Boronophenylalanine-fructose, FBPA-Fr BCS Biopharmaceutics Classification System BRB Blood–Retina Barrier BSH Sodium Mercaptoundecahydro-closo-Dodecaborate (Sodium Borocaptate) BTB Blood–Tumour Barrier CA IX Carbonic Anhydrase IX CARPA Complement Activation-Related PseudoAllergy CL Clearance CNS Central Nervous System DDI Drug–Drug Interaction DNA Deoxyribonucleic Acid EPR Enhanced Permeability and Retention (effect) EGFR Epidermal Growth Factor Receptor GMP Good Manufacturing Practice ITC International Transporter Consortium LAT1 L-Type Amino Acid Transporter 1, SLC7A5 LET Linear Energy Transfer LB models Ligand Binding models logP Logarithm of the Partition Coefficient (octanol/water) Low-MW Low-Molecular-Weight MPS Mononuclear Phagocyte System MRI Magnetic Resonance Imaging MSCs Mesenchymal Stromal Cells MSNs Mesoporous Silica Nanoparticles NOAEL No-Observed-Adverse-Effect Level NR Not reported in this review OATs Organic Anion Transporters OATPs Organic Anion Transporting Polypeptides OCTs Organic Cation Transporters PAMAM Polyamidoamine PBPK Physiologically Based Pharmacokinetic PK Pharmacokinetic PK/BD Pharmacokinetic and biodistribution PEG Polyethylene Glycol PEGylated Modified with Polyethylene Glycol PET Positron Emission Tomography PET/MRI Positron Emission Tomography/Magnetic Resonance Imaging P-gp P-Glycoprotein QC Quality Control RES Reticuloendothelial System RGD Arginine–Glycine–Aspartate (integrin-binding motif) RO5 Lipinski’s Rule of five ROS Reactive Oxygen Species RT-like Radiation Therapy-like t 1/2 half-life T/B Tumour-to-Blood Ratio T/N Tumour-to-Normal Tissue Ratio V d Volume of Distribution

References

1. Sauerwein W.A. Wittig A. Moss R. Nakagawa Y. Neutron Capture Therapy: Principles and Applications Springer Berlin/Heidelberg, Germany 2012

2. Dymova M.A. Taskaev S.Y. Richter V.A. Kuligina E.V. Boron Neutron Capture Therapy: Current Status and Future Perspectives Cancer Commun. 2020 40 406 421 10.1002/cac2.12089 PMC7494062 32805063

3. Monti Hughes A. Hu N. Optimizing Boron Neutron Capture Therapy (BNCT) to Treat Cancer: An Updated Review on the Latest Developments on Boron Compounds and Strategies Cancers 2023 15 4091 10.3390/cancers15164091 37627119 PMC10452654

4. Cheng X. Li F. Liang L. Boron Neutron Capture Therapy: Clinical Application and Challenges Curr. Oncol. 2022 29 622 10.3390/curroncol29100622 PMC9601095 36290899

5. Kawabata S. Suzuki M. Hirose K. Tanaka H. Kato T. Goto H. Narita Y. Miyatake S.-I. Accelerator-Based BNCT for Patients with Recurrent Glioblastoma: A Multicenter Phase II Study Neurooncol Adv. 2021 3 vdab067 10.1093/noajnl/vdab067 34151269 PMC8209606

6. Zhou Y.-T. Cheng K. Liu B. Cao Y.-C. Fan J.-X. Liu Z.-G. Zhao Y.-D. Recent Progress of Nano-Drugs in Neutron Capture Therapy Theranostics 2024 14 3193 3212 10.7150/thno.95034 38855185 PMC11155403

7. Coghi P. Li J. Hosmane N.S. Zhu Y. Next Generation of Boron Neutron Capture Therapy (BNCT) Agents for Cancer Treatment Med. Res. Rev. 2023 43 1809 1830 10.1002/med.21964 37102375

8. Watanabe T. Yoshikawa T. Tanaka H. Kinashi Y. Kashino G. Masunaga S. Hayashi T. Uehara K. Ono K. Suzuki M. Pharmacokinetic Study of 14C-Radiolabeled p-Boronophenylalanine (BPA) in Sorbitol Solution and the Treatment Outcome of BPA-Based Boron Neutron Capture Therapy on a Tumor-Bearing Mouse Model Eur. J. Drug Metab. Pharmacokinet. 2023 48 443 453 10.1007/s13318-023-00830-y 37198368

9. Fukuda H. Response of Normal Tissues to Boron Neutron Capture Therapy (BNCT) with 10B-Borocaptate Sodium (BSH) and 10B-Paraboronophenylalanine (BPA) Cells 2021 10 2883 10.3390/cells10112883 34831105 PMC8616460

10. Hu K. Yang Z. Zhang L. Xie L. Wang L. Xu H. Josephson L. Liang S.H. Zhang M.-R. Boron Agents for Neutron Capture Therapy Coord. Chem. Rev. 2020 405 213139 10.1016/j.ccr.2019.213139

11. Zhang X. Rendina L.M. Müllner M. Carborane-Containing Polymers: Synthesis, Properties, and Applications ACS Polym. Au 2024 4 7 33 10.1021/acspolymersau.3c00030 38371730 PMC10870755

12. Tang F. Wei Y. Zhang S. Wang J. Gu W. Tang F. Peng X. Wei Y. Liu J. Chen W. Evaluation of Pharmacokinetics of Boronophenylalanine and Its Uptakes in Gastric Cancer Front. Oncol. 2022 12 925671 10.3389/fonc.2022.925671 35903711 PMC9314552

13. Gos M. Cebula J. Goszczyński T.M. Metallacarboranes in Medicinal Chemistry: Current Advances and Future Perspectives J. Med. Chem. 2024 67 8481 8501 10.1021/acs.jmedchem.4c00157 38769934

14. Seneviratne D.S. Saifi O. Mackeyev Y. Malouff T. Krishnan S. Next-Generation Boron Drugs and Rational Translational Studies Driving the Revival of BNCT Cells 2023 12 1398 10.3390/cells12101398 37408232 PMC10216459

15. Oloo S.O. Smith K.M. Vincente M.d.G.H. Multi-Functional Boron-Delivery Agents for Boron Neutron Capture Therapy of Canceres Cancers 2023 15 3277 10.3390/cancers15133277 37444386 PMC10340061

16. Pitto-Barry A. Polymers and Boron Neutron Capture Therapy (BNCT): A Potent Combination Polym. Chem. 2021 12 2035 2044 10.1039/D0PY01392G

17. Maruyama K. Ishida O. Kasaoka S. Takizawa T. Utoguchi N. Shinohara A. Chiba M. Kobayashi H. Eriguchi M. Yanagie H. Intracellular Targeting of Sodium Mercaptoundecahydrododecaborate (BSH) to Solid Tumors by Transferrin-PEG Liposomes, for Boron Neutron-Capture Therapy (BNCT) J. Control. Release 2004 98 195 207 10.1016/j.jconrel.2004.04.018 15262412

18. Seneviratne D. Advani P. Trifiletti D.M. Chumsri S. Beltran C.J. Bush A.F. Vallow L.A. Exploring the Biological and Physical Basis of Boron Neutron Capture Therapy (BNCT) as a Promising Treatment Frontier in Breast Cancer Cancers 2022 14 3009 10.3390/cancers14123009 35740674 PMC9221373

19. Song S. Gao P. Sun L. Kang D. Kongsted J. Poongavanam V. Zhan P. Liu X. Recent Developments in the Medicinal Chemistry of Single Boron Atom-Containing Compounds Acta Pharm. Sin. B 2021 11 3035 3059 10.1016/j.apsb.2021.01.010 34729302 PMC8546671

20. Zhang X. Li Y. Hosmane N.S. Zhou Y. Nanostructured Boron Agents for Boron Neutron Capture Therapy: A Review of Recent Patents Med. Rev. 2023 3 425 443 10.1515/mr-2023-0013 PMC10811353 38283251

21. Monti Hughes A. Importance of Radiobiological Studies for the Advancement of Boron Neutron Capture Therapy (BNCT) Expert. Rev. Mol. Med. 2022 24 e14 10.1017/erm.2022.7 35357286

22. Li X. He P. Wei Y. Qu C. Tang F. Li Y. Application and Perspectives of Nanomaterials in Boron Neutron Capture Therapy of Tumors Cancer Nano 2025 16 25 10.1186/s12645-025-00324-3

23. Ali F. S Hosmane N. Zhu Y. Boron Chemistry for Medical Applications Molecules 2020 25 828 10.3390/molecules25040828 32070043 PMC7071021

24. Wróblewska A. Kruszakin R. Migdał P. Pędzich Z. Pajtasz-Piasecka E. Macrophages as Carriers of Boron Carbide Nanoparticles Dedicated to BNCT J. Nanobiotechnology 2024 22 183 10.1186/s12951-024-02397-5 38622691 PMC11017526

25. Olejniczak A.B. Plešek J. Leśnikowski Z.J. Nucleoside–Metallacarborane Conjugates for Base-Specific Metal Labeling of DNA Chem. A Eur. J. 2007 13 311 318 10.1002/chem.200600740 17103465

26. Leśnikowski Z.J. Paradowska E. Olejniczak A.B. Studzińska M. Seekamp P. Schüßler U. Gabel D. Schinazi R.F. Plešek J. Towards New Boron Carriers for Boron Neutron Capture Therapy: Metallacarboranes and Their Nucleoside Conjugates Bioorganic Med. Chem. 2005 13 4168 4175 10.1016/j.bmc.2005.04.042 15878666

27. Wójciuk K. Dorosz M. Prokopowicz R. AB028. Selected 10-Atom Derivatives of Mercaptoborate as Substrates for the Coupling Reaction with the Neurotransmitter Protein Ther. Radiol. Oncol. 2025 9 AB028 10.21037/tro-25-ab028

28. Michaś E. Dorosz M. Wójciuk K. Tymińska K. Wiliński M. Maciak M. Domański S. Wojtania G. Bartosik Ł. Małkiewicz A. Reactor Laboratory for Biomedical Research in National Centre for Nuclear Research in Poland Pol. J. Med. Phys. Eng. 2021 27 119 122 10.2478/pjmpe-2021-0014

29. Lipinski C.A. Lombardo F. Dominy B.W. Feeney P.J. Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings Adv. Drug Deliv. Rev. Erratum in Adv. Drug Deliv. Rev. 2001 , 46 , 3–26. https://doi.org/10.1016/S0169-409X(00)00129-0. 1997 23 3 25 10.1016/S0169-409X(96)00423-1 11259830

30. Veber D.F. Johnson S.R. Cheng H.-Y. Smith B.R. Ward K.W. Kopple K.D. Molecular Properties That Influence the Oral Bioavailability of Drug Candidates J. Med. Chem. 2002 45 2615 2623 10.1021/jm020017n 12036371

31. Amidon G.L. Lennernäs H. Shah V.P. Crison J.R. A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability Pharm. Res. 1995 12 413 420 10.1023/A:1016212804288 7617530

32. Lipinski C.A. Lead- and Drug-like Compounds: The Rule-of-Five Revolution Drug Discov. Today: Technol. 2004 1 337 341 10.1016/j.ddtec.2004.11.007 24981612

33. Paglialunga S. Benrimoh N. Van Haarst A. Innovative Approaches to Optimize Clinical Transporter Drug–Drug Interaction Studies Pharmaceutics 2024 16 992 10.3390/pharmaceutics16080992 39204337 PMC11359485

34. Xu H. Liu J. Li R. Lin J. Gui L. Wang Y. Jin Z. Xia W. Liu Y. Cheng S. Novel Promising Boron Agents for Boron Neutron Capture Therapy: Current Status and Outlook on the Future Coord. Chem. Rev. 2024 511 215795 10.1016/j.ccr.2024.215795

35. Murilla R.M. Edilo G.G. Budlayan M.L.M. Auxtero E.S. Boron Delivery Agents in BNCT: A Mini Review of Current Developments and Emerging Trends Nano TransMed 2025 4 100081 10.1016/j.ntm.2025.100081

36. Kawasaki R. Miura Y. Kono N. Fujita S. Yamana K. Ikeda A. Boron Agent Delivery Platforms Based on Natural Products for Boron Neutron Capture Therapy ChemMedChem 2024 19 e202400323 10.1002/cmdc.202400323 38830821

37. Kugler M. Nekvinda J. Holub J. El Anwar S. Das V. Šícha V. Pospíšilová K. Fábry M. Král V. Brynda J. Inhibitors of CA IX Enzyme Based on Polyhedral Boron Compounds ChemBioChem 2021 22 2741 2761 10.1002/cbic.202100121 33939874

38. Simone M.I. Diastereoselective Synthesis of the Borylated D-Galactose Monosaccharide 3-Boronic-3-Deoxy-d-Galactose and Biological Evaluation in Glycosidase Inhibition and in Cancer for Boron Neutron Capture Therapy (BNCT) Molecules 2023 28 4321 10.3390/molecules28114321 37298796 PMC10254170

39. Li Z. Chen J. Kong Z. Shi Y. Xu M. Mu B.-S. Li N. Ma W. Yang Z. Wang Y. A Bis-Boron Boramino Acid PET Tracer for Brain Tumor Diagnosis Eur. J. Nucl. Med. Mol. Imaging 2024 51 1703 1712 10.1007/s00259-024-06600-5 38191817

40. Fukuda H. Honda C. Wadabayashi N. Kobayashi T. Yoshino K. Hiratsuka J. Takahashi J. Akaizawa T. Abe Y. Ichihashi M. Pharmacokinetics of 10B-p-Boronophenylalanine in Tumours, Skin and Blood of Melanoma Patients: A Study of Boron Neutron Capture Therapy for Malignant Melanoma Melanoma Res. 1999 9 75 84 10.1097/00008390-199902000-00010 10338337

41. Marfavi A. Kavianpour P. Rendina L.M. Carboranes in Drug Discovery, Chemical Biology and Molecular Imaging Nat. Rev. Chem. 2022 6 486 504 10.1038/s41570-022-00400-x 37117309

42. Das B.C. Nandwana N.K. Das S. Nandwana V. Shareef M.A. Das Y. Saito M. Weiss L.M. Almaguel F. Hosmane N.S. Boron Chemicals in Drug Discovery and Development: Synthesis and Medicinal Perspective Molecules 2022 27 2615 10.3390/molecules27092615 35565972 PMC9104566

43. Issa F. Kassiou M. Rendina L.M. Boron in Drug Discovery: Carboranes as Unique Pharmacophores in Biologically Active Compounds Chem. Rev. 2011 111 5701 5722 10.1021/cr2000866 21718011

44. Scholz M. Hey-Hawkins E. Carbaboranes as Pharmacophores: Properties, Synthesis, and Application Strategies Chem. Rev. 2011 111 7035 7062 10.1021/cr200038x 21780840

45. Zhang J. Zhang Z. Huang Z. Li M. Yang F. Wu Z. Guo Q. Mei X. Lu B. Wang C. Isotoosendanin Exerts Inhibition on Triple-Negative Breast Cancer through Abrogating TGF-β-Induced Epithelial–Mesenchymal Transition via Directly Targeting TGFβR1 Acta Pharm. Sin. B 2023 13 2990 3007 10.1016/j.apsb.2023.05.006 37521871 PMC10372922

46. Zamek-Gliszczynski M.J. Taub M.E. Chothe P.P. Chu X. Giacomini K.M. Kim R.B. Ray A.S. Stocker S.L. Unadkat J.D. Wittwer M.B. Transporters in Drug Development: 2018 ITC Recommendations for Transporters of Emerging Clinical Importance Clin. Pharma Ther. 2018 104 890 899 10.1002/cpt.1112 PMC8211378 30091177

47. Chu X. Liao M. Shen H. Yoshida K. Zur A.A. Arya V. Galetin A. Giacomini K.M. Hanna I. Kusuhara H. Clinical Probes and Endogenous Biomarkers as Substrates for Transporter Drug-Drug Interaction Evaluation: Perspectives From the International Transporter Consortium Clin. Pharma Ther. 2018 104 836 864 10.1002/cpt.1216 30347454

48. Shi Y. Fu Q. Li J. Liu H. Zhang Z. Liu T. Liu Z. Covalent Organic Polymer as a Carborane Carrier for Imaging-Facilitated Boron Neutron Capture Therapy ACS Appl. Mater. Interfaces 2020 12 55564 55573 10.1021/acsami.0c15251 33327054

49. Longmire M. Choyke P.L. Kobayashi H. Clearance Properties of Nano-Sized Particles and Molecules as Imaging Agents: Considerations and Caveats Nanomedicine 2008 3 703 717 10.2217/17435889.3.5.703 18817471 PMC3407669

50. Alexis F. Pridgen E. Molnar L.K. Farokhzad O.C. Factors Affecting the Clearance and Biodistribution of Polymeric Nanoparticles Mol. Pharm. 2008 5 505 515 10.1021/mp800051m 18672949 PMC2663893

51. Yu M. Zheng J. Clearance Pathways and Tumor Targeting of Imaging Nanoparticles ACS Nano 2015 9 6655 6674 10.1021/acsnano.5b01320 26149184 PMC4955575

52. Chis A.A. Dobrea C. Morgovan C. Arseniu A.M. Rus L.L. Butuca A. Juncan A.M. Totan M. Vonica-Tincu A.L. Cormos G. Applications and Limitations of Dendrimers in Biomedicine Molecules 2020 25 3982 10.3390/molecules25173982 32882920 PMC7504821

53. Li L. Liu T. Fu C. Tan L. Meng X. Liu H. Biodistribution, Excretion, and Toxicity of Mesoporous Silica Nanoparticles after Oral Administration Depend on Their Shape Nanomed.: Nanotechnol. Biol. Med. 2015 11 1915 1924 10.1016/j.nano.2015.07.004 26238077

54. Narayan R. Nayak U.Y. Raichur A.M. Garg S. Mesoporous Silica Nanoparticles: A Comprehensive Review on Synthesis and Recent Advances Pharmaceutics 2018 10 118 10.3390/pharmaceutics10030118 30082647 PMC6160987

55. Zhang Y. Lin X. Chen X. Fang W. Yu K. Gu W. Wei Y. Zheng H. Piao J. Li F. Strategies to Regulate the Degradation and Clearance of Mesoporous Silica Nanoparticles: A Review IJN 2024 19 5859 5878 10.2147/IJN.S451919 38887691 PMC11182361

56. Monopoli M.P. Åberg C. Salvati A. Dawson K.A. Biomolecular Coronas Provide the Biological Identity of Nanosized Materials Nat. Nanotech 2012 7 779 786 10.1038/nnano.2012.207 23212421

57. Confalonieri L. Imperio D. Erhard A. Fallarini S. Compostella F. Del Grosso E. Balcerzyk M. Panza L. Organotrifluoroborate Sugar Conjugates for a Guided Boron Neutron Capture Therapy: From Synthesis to Positron Emission Tomography ACS Omega 2022 7 48340 48348 10.1021/acsomega.2c06551 36591151 PMC9798496

58. Chen X.-P. Hsu F.-C. Huang K.-Y. Hsieh T.-S. Farn S.-S. Sheu R.-J. Yu C.-S. Fluorine-18 Labeling PEGylated 6-Boronotryptophan for PET Scanning of Mice for Assessing the Pharmacokinetics for Boron Neutron Capture Therapy of Brain Tumors Bioorganic Med. Chem. Lett. 2024 105 129744 10.1016/j.bmcl.2024.129744 38614152

59. Dąbrowska A. Matuszewski M. Zwoliński K. Ignaczak A. Olejniczak A.B. Insight into Lipophilicity of Deoxyribonucleoside-boron Cluster Conjugates Eur. J. Pharm. Sci. 2018 111 226 237 10.1016/j.ejps.2017.09.036 28986193

60. Zhang Y. Cheng Q. Xu Y. Yao K. Syeda M.Z. Xu J. Wu J. Wang Z. Tang L. Mu Q. LAT1 Targeted Brain Delivery of Temozolomide and Sorafenib for Effective Glioma Therapy Nano Res. 2023 16 9743 9751 10.1007/s12274-023-5568-3

61. Puris E. Gynther M. Auriola S. Huttunen K.M. L-Type Amino Acid Transporter 1 as a Target for Drug Delivery Pharm. Res. 2020 37 88 10.1007/s11095-020-02826-8 32377929 PMC7203094

62. Yan R. Müller J. Zhang Y. Singer S. Xia L. Zhong X. Gertsch J. Altmann K.M. Zhou Q. Mechanism of Substrate Transport and Inhibition of the Human LAT1-4F2hc Amino Acid Transporter Cell Discov. 2021 7 16 10.1038/s41421-021-00247-4 33758168 PMC7988154

63. Scalise M. Scanga R. Console L. Galluccio M. Indiveri C. The Antiport Mechanism of the Human LAT1 Transporter: Defining the Molecular Determinants by Means of Wet and Dry Approaches Biochem. Biophys. Res. Commun. 2025 777 152277 10.1016/j.bbrc.2025.152277 40616981

64. Häfliger P. Charles R.-P. The L-Type Amino Acid Transporter LAT1—An Emerging Target in Cancer Int. J. Mol. Sci. 2019 20 2428 10.3390/ijms20102428 31100853 PMC6566973

65. Scalise M. Scanga R. Console L. Galluccio M. Marzano F. Magrì A. Pochini L. Indiveri C. Crossing the Borders: The Amino Acid Transporter LAT1 (SLC7A5) in the Blood-Brain Barrier Neurochem. Int. 2025 191 106070 10.1016/j.neuint.2025.106070 41067390

66. Kaniowski D. Ebenryter-Olbińska K. Sobczak M. Wojtczak B. Janczak S. Leśnikowski Z. Nawrot B. High Boron-Loaded DNA-Oligomers as Potential Boron Neutron Capture Therapy and Antisense Oligonucleotide Dual-Action Anticancer Agents Molecules 2017 22 1393 10.3390/molecules22091393 28832537 PMC6151803

67. Goszczyński T.M. Fink K. Metallacarboranes: Abiotic Scaffolds for Advanced Drug Discovery Future Med. Chem. 2025 17 2193 2196 10.1080/17568919.2025.2557181 40926699 PMC12452483

68. Mallesch J.L. Moore D.E. Allen B.J. McCarthy W.H. Jones R. Stening W.A. The Pharmacokinetics of P-Boronophenylalanine.Fructose in Human Patients with Glioma and Metastatic Melanoma Int. J. Radiat. Oncol. *Biol. *Phys. 1994 28 1183 1188 10.1016/0360-3016(94)90493-6 8175404

69. Kiger W.S. III Palmer M.R. Riley K.J. Zamenhof R.G. Busse P.M. A Pharmacokinetic Model for the Concentration of 10 B in Blood after Boronophenylalanine-Fructose Administration in Humans Radiat. Res. 2001 155 611 618 10.1667/0033-7587(2001)155[0611:APMFTC]2.0.CO;2 11260663

70. Ailuno G. Balboni A. Caviglioli G. Lai F. Barbieri F. Dellacasagrande I. Florio T. Baldassari S. Boron Vehiculating Nanosystems for Neutron Capture Therapy in Cancer Treatment Cells 2022 11 4029 10.3390/cells11244029 36552793 PMC9776957

71. Barth R.F. Kabalka G.W. Yang W. Huo T. Nakkula R.J. Shaikh A.L. Haider S.A. Chandra S. Evaluation of Unnatural Cyclic Amino Acids as Boron Delivery Agents for Treatment of Melanomas and Gliomas Appl. Radiat. Isot. 2014 88 38 42 10.1016/j.apradiso.2013.11.133 24393770 PMC4049841

72. Weissfloch L. Wagner M. Probst T. Senekowitsch-Schmidtke R. Tempel K. Molls M. A New Class of Drugs for BNCT? Borylated Derivatives of Ferrocenium Compounds in Animal Experiments Biometals 2001 14 43 49 10.1023/A:1016686321179 11368274

73. Kalot G. Godard A. Busser B. Pliquett J. Broekgaarden M. Motto-Ros V. Wegner K.D. Resch-Genger U. Köster U. Denat F. Aza-BODIPY: A New Vector for Enhanced Theranostic Boron Neutron Capture Therapy Applications Cells 2020 9 1953 10.3390/cells9091953 32854219 PMC7565158

74. Huang W. Pan Y. Zhong T. He S. Qi Y. Huang Y. Near-Infrared 10 B-BODIPY for Precise Guidance of Tracer Imaging and Treatment in Boron Neutron Capture Therapy Chem. Commun. 2025 61 9079 9082 10.1039/D5CC01671A 40401390

75. Shao C. Lian G. Jin G. Nido-Carborane Encapsulated by BODIPY Zwitterionic Polymers: Synthesis, Photophysical Properties and Cell Imaging J. Saudi Chem. Soc. 2021 25 101345 10.1016/j.jscs.2021.101345

76. Ordóñez-Hernández J. Planas J.G. Núñez R. Carborane-Based BODIPY Dyes: Synthesis, Structural Analysis, Photophysics and Applications Front. Chem. 2024 12 1485301 10.3389/fchem.2024.1485301 39564434 PMC11574714

77. Kumar P.P.P. Saxena S. Joshi R. BODIPY Dyes: A New Frontier in Cellular Imaging and Theragnostic Applications Colorants 2025 4 13 10.3390/colorants4020013

78. Barth R.F. Gupta N. Kawabata S. Evaluation of Sodium Borocaptate (BSH) and Boronophenylalanine (BPA) as Boron Delivery Agents for Neutron Capture Therapy (NCT) of Cancer: An Update and a Guide for the Future Clinical Evaluation of New Boron Delivery Agents for NCT Cancer Commun. 2024 44 893 909 10.1002/cac2.12582 PMC11337926 38973634

79. Blethen K.E. Arsiwala T.A. Fladeland R.A. Sprowls S.A. Panchal D.M. Adkins C.E. Kielkowski B.N. Earp L.E. Glass M.J. Pritt T.A. Modulation of the Blood-Tumor Barrier to Enhance Drug Delivery and Efficacy for Brain Metastases Neuro-Oncol. Adv. 2021 3 v133 v143 10.1093/noajnl/vdab123 PMC8633736 34859240

80. Yoshida F. Matsumura A. Yamamoto T. Kumada H. Nakai K. Enhancement of Sodium Borocaptate (BSH) Uptake by Tumor Cells Induced by Glutathione Depletion and Its Radiobiological Effect Cancer Lett. 2004 215 61 67 10.1016/j.canlet.2004.06.023 15374633

81. Wittig A. Stecher-Rasmussen F. Hilger R.A. Rassow J. Mauri P. Sauerwein W. Sodium Mercaptoundecahydro-Closo-Dodecaborate (BSH), a Boron Carrier That Merits More Attention Appl. Radiat. Isot. 2011 69 1760 1764 10.1016/j.apradiso.2011.02.046 21420870

82. Lan G. Song Q. Luan Y. Cheng Y. Targeted Strategies to Deliver Boron Agents across the Blood–Brain Barrier for Neutron Capture Therapy of Brain Tumors Int. J. Pharm. 2024 650 123747 10.1016/j.ijpharm.2023.123747 38151104

83. Sumitani S. Oishi M. Yaguchi T. Murotani H. Horiguchi Y. Suzuki M. Ono K. Yanagie H. Nagasaki Y. Pharmacokinetics of Core-Polymerized, Boron-Conjugated Micelles Designed for Boron Neutron Capture Therapy for Cancer Biomaterials 2012 33 3568 3577 10.1016/j.biomaterials.2012.01.039 22326646

84. Targeted Drug Delivery: Concepts and Design Advances in Delivery Science and Technology Devarajan P.V. Jain S. Springer International Publishing Berlin/Heidelberg, Germany 2015 10.1007/978-3-319-11355-5

85. Chen W. Mehta S.C. Lu D.R. Selective Boron Drug Delivery to Brain Tumors for Boron Neutron Capture Therapy Adv. Drug Deliv. Rev. 1997 26 231 247 10.1016/S0169-409X(97)00037-9 10837545

86. Sprowls S.A. Arsiwala T.A. Bumgarner J.R. Shah N. Lateef S.S. Kielkowski B.N. Lockman P.R. Improving CNS Delivery to Brain Metastases by Blood–Tumor Barrier Disruption Trends Cancer 2019 5 495 505 10.1016/j.trecan.2019.06.003 31421906 PMC6703178

87. Barth R.F. Yang W. Rotaru J.H. Moeschberger M.L. Boesel C.P. Soloway A.H. Joel D.D. Nawrocky M.M. Ono K. Goodman J.H. Boron Neutron Capture Therapy of Brain Tumors: Enhanced Survival and Cure Following Blood–Brain Barrier Disruption and Intracarotid Injection of Sodium Borocaptate and Boronophenylalanine Int. J. Radiat. Oncol. *Biol. *Phys. 2000 47 209 218 10.1016/S0360-3016(00)00421-1 10758326

88. Barth R.F. Yang W. Bartus R.T. Moeschberger M.L. Goodman J.H. Enhanced Delivery of Boronophenylalanine for Neutron Capture Therapy of Brain Tumors Using the Bradykinin Analog Cereport (Receptor-Mediated Permeabilizer-7) Neurosurgery 1999 44 351 359 10.1097/00006123-199902000-00062 9932889

89. Yang W. Barth R.F. Rotaru J.H. Moeschberger M.L. Joel D.D. Nawrocky M.M. Goodman J.H. Soloway A.H. Boron Neutron Capture Therapy of Brain Tumors: Enhanced Survival Following Intracarotid Injection of Sodium Borocaptate with or without Blood-Brain Barrier Disruption Int. J. Radiat. Oncol. *Biol. *Phys. 1997 37 663 672 10.1016/S0360-3016(96)00082-X 9112465

90. Garg T. Bhandari S. Rath G. Goyal A.K. Current Strategies for Targeted Delivery of Bio-Active Drug Molecules in the Treatment of Brain Tumor J. Drug Target. 2015 23 865 887 10.3109/1061186X.2015.1029930 25835469

91. Marforio T.D. Carboni A. Calvaresi M. In Vivo Application of Carboranes for Boron Neutron Capture Therapy (BNCT): Structure, Formulation and Analytical Methods for Detection Cancers 2023 15 4944 10.3390/cancers15204944 37894311 PMC10605826

92. Kulvik M.E. Vähätalo J.K. Benczik J. Snellman M. Laakso J. Hermans R. Järviluoma E. Rasilainen M. Färkkilä M. Kallio M.E. Boron Biodistribution in Beagles after Intravenous Infusion of 4-Dihydroxyborylphenylalanine–Fructose Complex Appl. Radiat. Isot. 2004 61 975 979 10.1016/j.apradiso.2004.05.022 15308178

93. Zhou T. The Current Status and Novel Advances of Boron Neutron Capture Therapy Clinical Trials Am. J. Cancer Res. 2024 14 429 447 10.62347/HBBE6868 38455422 PMC10915318

94. Silva M.P. Saraiva L. Pinto M. Sousa M.E. Boronic Acids and Their Derivatives in Medicinal Chemistry: Synthesis and Biological Applications Molecules 2020 25 4323 10.3390/molecules25184323 32967170 PMC7571202

95. Llenas M. Cuenca L. Santos C. Bdikin I. Gonçalves G. Tobías-Rossell G. Sustainable Synthesis of Highly Biocompatible 2D Boron Nitride Nanosheets Biomedicines 2022 10 3238 10.3390/biomedicines10123238 36551994 PMC9775030

96. Ahmad F. Boron Nanocomposites for Boron Neutron Capture Therapy and in Biomedicine: Evolvement and Challenges Biomater. Res. 2025 29 0145 10.34133/bmr.0145 40008112 PMC11850861

97. Rudawska A. Szermer-Olearnik B. Szczygieł A. Mierzejewska J. Węgierek-Ciura K. Żeliszewska P. Kozień D. Chaszczewska-Markowska M. Adamczyk Z. Rusiniak P. Functionalized Boron Carbide Nanoparticles as Active Boron Delivery Agents Dedicated to Boron Neutron Capture Therapy IJN 2025 20 6637 6657 10.2147/IJN.S516534 40438187 PMC12118811

98. Wan J. Lv L. Chang Y. Li J. Xing G. Chen K. Boron Nanodrugs for Boron Neutron Capture Therapy Appl. Radiat. Isot. 2025 225 112044 10.1016/j.apradiso.2025.112044 40695157

99. Wang L.-W. Liu Y.-W.H. Chu P.-Y. Liu H.-M. Peir J.-J. Lin K.-H. Huang W.-S. Lo W.-L. Lee J.-C. Lin T.-Y. Boron Neutron Capture Therapy Followed by Image-Guided Intensity-Modulated Radiotherapy for Locally Recurrent Head and Neck Cancer: A Prospective Phase I/II Trial Cancers 2023 15 2762 10.3390/cancers15102762 37345099 PMC10216174

100. Li L. Liu L. Hu Z. Lu Y. Liu Q. Jin S. Zhang Q. Zhao S. Chou S. Understanding High-Rate K + -Solvent Co-Intercalation in Natural Graphite for Potassium-Ion Batteries Angew. Chem. Int. Ed. 2020 59 12917 12924 10.1002/anie.202001966 32298024

101. Baker S.J. Ding C.Z. Akama T. Zhang Y.-K. Hernandez V. Xia Y. Therapeutic Potential of Boron-Containing Compounds Future Med. Chem. 2009 1 1275 1288 10.4155/fmc.09.71 21426103

102. Fu L. Shi S. Yi J. Wang N. He Y. Wu Z. Peng J. Deng Y. Wang W. Wu C. ADMETlab 3.0: An Updated Comprehensive Online ADMET Prediction Platform Enhanced with Broader Coverage, Improved Performance, API Functionality and Decision Support Nucleic Acids Res. 2024 52 W422 W431 10.1093/nar/gkae236 38572755 PMC11223840