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In recent years, various drug delivery systems circumventing the blood–brain barrier have emerged for treating brain tumors. This study aimed to improve the efficacy of brain tumor treatment in boron neutron capture therapy (BNCT) using cerebrospinal fluid (CSF) circulation to deliver boronophenylalanine (BPA) to targeted tumors. Previous experiments have demonstrated that boron accumulation in the brain cells of normal rats remains comparable to that after intravenous (IV) administration, despite BPA being administered via CSF at significantly lower doses (approximately 1/90 of IV doses). Based on these findings, BNCT was conducted on glioma model rats at the Kyoto University Research Reactor Institute (KUR), with BPA administered via CSF. This method involved implanting C6 cells into the brains of 8-week-old Wistar rats, followed by administering BPA and neutron irradiation after a 10-day period. In this study, the rats were divided into four groups: one receiving CSF administration, another receiving IV administration, and two control groups without BPA administration, with one subjected to neutron irradiation and the other not. In the CSF administration group, BPA was infused from the cisterna magna at 8 mg/kg/h for 2 h, while in the IV administration group, BPA was intravenously administered at 350 mg/kg via the tail vein over 1.5 h. Thermal neutron irradiation (5 MW) for 20 min, with an average fluence of 3.8 × 1012/cm2, was conducted at KUR's heavy water neutron irradiation facility. Subsequently, all of the rats were monitored under identical conditions for 7 days, with pre- and post-irradiation tumor size assessed through MRI and pathological examination. The results indicate a remarkable therapeutic efficacy in both BPA-administered groups (CSF and IV). Notably, the rats treated with CSF administration exhibited diminished BPA accumulation in normal tissue compared to those treated with IV administration, alongside maintaining excellent overall health. Thus, CSF-based BPA administration holds promise as a novel drug delivery mechanism in BNCT. [ABSTRACT FROM AUTHOR]

Boron Neutron Capture Therapy (BNCT) is performed using high-intensity neutron sources; however, the energy of the primary neutrons is too high for direct patient irradiation. Thus, neutron moderation is mandatory and is performed using a device known as a Beam Shaping Assembly (BSA). Due to the differences in flux and energy spectra between neutron sources, each facility needs a dedicated BSA design, whether it is based on a nuclear reactor or, more recently, on an accelerator. Since moderation involves the loss of neutrons, typically by a factor of 1000, it is necessary to generate a very high flux before neutrons pass through the BSA. We propose a novel approach that eliminates the necessity of a BSA, BSA-free, by generating neutrons suitable in flux and energy for direct patient irradiation through the Sc(p,n) Ti reaction using near-threshold protons. Our findings demonstrate that all IAEA quality factors for BNCT can be met with existing proton accelerators. Additionally, figures of merit studied provide similar results compared to real BNCT facilities. This breakthrough opens up new avenues in BNCT, among others, the control of the neutron penetration within the human body by small changing in the proton energy. Also, it is expected simplified accelerator-based facilities in terms of manufacturing and maintenance and operation. This work is a study based on experimental data and Monte Carlo simulations. Technical challenges and safety are addressed in Discussion section. This novel proposal is under evaluation as patent. [ABSTRACT FROM AUTHOR]

In boron neutron capture therapy (BNCT), boron drugs should exhibit high intratumoral boron concentrations during neutron irradiation, while being cleared from the blood and normal organs. However, it is usually challenging to achieve such tumor accumulation and quick clearance simultaneously in a temporally controlled manner. Here, we developed a polymer-drug conjugate that can actively control the clearance of the drugs from the blood. This polymer-drug conjugate is based on a biocompatible polymer that passively accumulates in tumors. Its side chains were conjugated with the low-molecular-weight boron drugs, which are immediately excreted by the kidneys, via photolabile linkers. In a murine subcutaneous tumor model, the polymer-drug conjugate could accumulate in the tumor with the high boron concentration ratio of the tumor to the surrounding normal tissue (∼10) after intravenous injection while a considerable amount remained in the bloodstream as well. Photoirradiation to blood vessels through the skin surface cleaved the linker to release the boron drug in the blood, allowing for its rapid clearance from the bloodstream. Meanwhile, the boron concentration in the tumor which was not photoirradiated could be maintained high, permitting strong BNCT effects. In clinical BNCT, the dose of thermal neutrons to solid tumors is determined by the maximum radiation exposure to normal organs. Thus, our polymer-drug conjugate may enable us to increase the therapeutic radiation dose to tumors in such a practical situation. [Display omitted] • Pharmacokinetics was actively controlled in a light-responsive manner. • Our system could achieve the high tumor accumulation and T/B ratio simultaneously. • The active control of pharmacokinetics augmented BNCT effects. [ABSTRACT FROM AUTHOR]

L-4-[(10B)]Boronophenylalanine (BPA) is an amino acid analogue with a boron-10 moiety. It is most widely used as a boron carrier in boron neutron capture therapy. In this study, a Bayesian predictive platform of blood boron concentration based on a BPA pharmacokinetic (PK) model was developed. This platform is user-friendly and can predict the individual boron PK and optimal time window for boron neutron capture therapy in a simple way. The present study aimed to establish a PK model of L-4-boronophenylalanine and develop a Bayesian predictive platform for blood boron PKs for user-friendly estimation of boron concentration during neutron irradiation of neutron capture therapy. Whole blood boron concentrations from seven previous reports were graphically extracted and analyzed using the nonlinear mixed-effects modeling (NONMEM) approach. Model robustness was assessed using nonparametric bootstrap and visual predictive check approaches. The visual predictive check indicated that the final PK model is able to adequately predict observed concentrations. The Shiny package was used to input real-time blood boron concentration data, and during the following irradiation session blood boron was estimated with an acceptably short calculation time for the determination of irradiation time. Finally, a user-friendly Bayesian estimation platform for BPA PKs was developed to optimize individualized therapy for patients undergoing BNCT. [ABSTRACT FROM AUTHOR]

Boron Neutron Capture Therapy (BNCT) is a radiotherapy technique based on the enrichment of tumour cells with suitable 10-boron concentration and on subsequent neutron irradiation. Low-energy neutron irradiation produces a localized deposition of radiation dose caused by boron neutron capture reactions. Boron is vehiculated into tumour cells via proper borated formulations, able to accumulate in the malignancy more than in normal tissues. The neutron capture releases two high-LET charged particles (i.e., an alpha particle and a lithium ion), losing their energy in a distance comparable to the average dimension of one cell. Thus BNCT is selective at the cell level and characterized by high biological effectiveness. As the radiation field is due to the interaction of neutrons with the components of biological tissues and with boron, the dosimetry requires a formalism to express the absorbed dose into photon-equivalent units. This work analyzes a clinical case of an adenoid cystic carcinoma treated with carbon-ion radiotherapy (CIRT), located close to optic nerve and deep-seated as a practical example of how to apply the formalism of BNCT photon isoeffective dose and how to evaluate the BNCT dose distribution against CIRT. The example allows presenting different dosimetrical and radiobiological quantities and drawing conclusions on the potential of BNCT stemming on the clinical result of the CIRT. The patient received CIRT with a dose constraint on the optic nerve, affecting the peripheral part of the Planning Target Volume (PTV). After the treatment, the tumour recurred in this low-dose region. BNCT was simulated for the primary tumour, with the goal to calculate the dose distribution in isoeffective units and a Tumour Control Probability (TCP) to be compared with the one of the original treatment. BNCT was then evaluated for the recurrence in the underdosed region which was not optimally covered by charged particles due to the proximity of the optic nerve. Finally, a combined treatment consisting in BNCT and carbon ion therapy was considered to show the consistency and the potential of the model. For the primary tumour, the photon isoeffective dose distribution due to BNCT was evaluated and the resulted TCP was higher than that obtained for the CIRT. The formalism produced values that are consistent with those of carbon-ion. For the recurrence, BNCT dosimetry produces a similar TCP than that of primary tumour. A combined treatment was finally simulated, showing a TCP comparable to the BNCT-alone with overall dosimetric advantage in the most peripheral parts of the treatment volume. Isoeffective dose formalism is a robust tool to analyze BNCT dosimetry and to compare it with the photon-equivalent dose calculated for carbon-ion treatment. This study introduces for the first time the possibility to combine the dosimetry obtained by two different treatment modalities, showing the potential of exploiting the cellular targeting of BNCT combined with the precision of charged particles in delivering an homogeneous dose distribution in deep-seated tumours. [ABSTRACT FROM AUTHOR]

Background: Boron‐containing compounds, such as 4‐borono‐phenylalanine (BPA) are used as drugs for cancer treatment in the framework of Boron Neutron Capture Therapy (BNCT). Neutron irradiation of boron‐rich compounds delivered to cancer cells triggers nuclear reactions that destroy cancer cells. Purpose: We provide a modeling of the thermal neutron cross section of BPA, a drug used in Boron Neutron Capture Therapy (BNCT), to quantify the competing contributions of boron absorption against hydrogen scattering, for optimizing BNCT by minimizing the latter. Methods: We perform the experimental determination of the total neutron scattering cross section of BPA at thermal and epithermal neutron energies using neutron transmission measurements. We isolate the contribution related to the incoherent scattering by hydrogen atoms as a function of the neutron energy by means of the Average Functional Group Approximation, and we calculate the probability for a neutron of being absorbed as a function of the neutron energy both for BPA and for its variants where either one or all four aromatic hydrogen atoms are substituted by 19F, and both for the samples with natural occurrence or enriched concentration of 10B. Results: While referring to the already available literature for in vivo use of fluorinated BPA, we show that fluorine‐rich variants of BPA increase the probability of neutrons being captured by the molecule. As the higher absorption efficiency of fluorinated BPA does not depend on whether the molecule is used in vivo or not, our results are promising for the higher efficiency of the boron neutron capture treatment. Conclusions: Our results suggest a new advantage using fluorinated compounds for BNCT, in their optimized interaction with neutrons, in addition to their already known capability to be used for monitoring and pharmacokinetics studies using 19F‐Nuclear Magnetic Resonance or in 18F‐Positron Emission Tomography. [ABSTRACT FROM AUTHOR]

Featured Application: Application of microdosimetric techniques to characterize the mixed radiation field in boron neutron capture therapy. This paper explores the role of microdosimetry in boron neutron capture therapy (BNCT), a cancer treatment involving the selective accumulation of boron-containing compounds in cancer cells, followed by neutron irradiation. Neutron interactions with 10B induces a nuclear reaction, releasing densely ionizing particles, specifically alpha particles and recoiling lithium-7 nuclei. These particles deposit their energy within a small tissue volume, potentially targeting cancer cells while sparing healthy tissue. The microscopic energy distribution, subject to significant fluctuations due to the short particle range, influences treatment efficacy. Microdosimetry, by studying this distribution, plays a crucial role in optimizing BNCT treatment planning. The methodology employs paired tissue equivalent proportional counters (TEPCs), one with cathode walls enriched with boron and the other without. Precise assessment of boron concentration is essential, as well as the ability to extrapolate results to the actual 10B concentration within the treatment region. The effective 10B concentrations within four boronated TEPCs, containing 10, 25, 70, and 100 ppm of 10B, have been determined. Results show variations of less than 3% from nominal values. Additionally, dose enhancement due to BNC interactions was measured and found to be proportional to the 10B concentration, with a proportionality factor of 7.7 × 10−3 per ppm of boron. Based on these findings, a robust procedure is presented for assessing the impact of BNCT in the treatment region, considering potential variations in boron content relative to the TEPC used. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is a promising modality for cancer treatment because of its minimal invasiveness. To maximize the therapeutic benefits of BNCT, the development of efficient platforms for the delivery of boron agents is indispensable. Here, carborane‐integrated immunoliposomes were prepared via an exchanging reaction to achieve HER‐2‐targeted BNCT. The conjugation of an anti‐HER‐2 antibody to carborane‐integrated liposomes successfully endowed these liposomes with targeting properties toward HER‐2‐overexpressing human ovarian cancer cells (SK‐OV3); the resulting BNCT activity toward SK‐OV3 cells obtained using the current immunoliposomal system was 14‐fold that of the l‐BPA/fructose complex, which is a clinically available boron agent. Moreover, the growth of spheroids treated with this system followed by thermal neutron irradiation was significantly suppressed compared with treatment with the l‐BPA/fructose complex. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is one of the most appealing radiotherapy modalities, whose localization can be further improved by the employment of boron-containing nanoformulations, but the fabrication of biologically friendly, water-dispersible nanoparticles (NPs) with high boron content and favorable physicochemical characteristics still presents a great challenge. Here, we explore the use of elemental boron (B) NPs (BNPs) fabricated using the methods of pulsed laser ablation in liquids as sensitizers of BNCT. Depending on the conditions of laser-ablative synthesis, the used NPs were amorphous (a-BNPs) or partially crystallized (pc-BNPs) with a mean size of 20 nm or 50 nm, respectively. Both types of BNPs were functionalized with polyethylene glycol polymer to improve colloidal stability and biocompatibility. The NPs did not initiate any toxicity effects up to concentrations of 500 µg/mL, based on the results of MTT and clonogenic assay tests. The cells with BNPs incubated at a 10B concentration of 40 µg/mL were then irradiated with a thermal neutron beam for 30 min. We found that the presence of BNPs led to a radical enhancement in cancer cell death, namely a drop in colony forming capacity of SW-620 cells down to 12.6% and 1.6% for a-BNPs and pc-BNPs, respectively, while the relevant colony-forming capacity for U87 cells dropped down to 17%. The effect of cell irradiation by neutron beam uniquely was negligible under these conditions. Finally, to estimate the dose and regimes of irradiation for future BNCT in vivo tests, we studied the biodistribution of boron under intratumoral administration of BNPs in immunodeficient SCID mice and recorded excellent retention of boron in tumors. The obtained data unambiguously evidenced the effect of a neutron therapy enhancement, which can be attributed to efficient BNP-mediated generation of α-particles. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT), advanced cancer treatment utilizing nuclear fission of 10B atom in cancer cells, is attracting increasing attention. As 10B delivery agent, sodium borocaptate (10BSH, 10B12H11SH ⋅ 2Na), has been used in clinical studies along with L‐boronophenylalanine. Recently, this boron cluster has been conjugated with lipids, polymers or nanoparticles to increase selectivity to and retentivity in tumor. In this work, anticancer nanoformulations for BNCT are designed, consisting of poly(glycerol) functionalized detonation nanodiamonds (DND−PG) as a hydrophilic nanocarrier, the boron cluster moiety (10B12H112−) as a dense boron‐10 source, and phenylboronic acid or RGD peptide as an active targeting moiety. Some hydroxy groups in PG were oxidized to carboxy groups (DND−PG−COOH) to conjugate the active targeting moiety. Some hydroxy groups in DND−PG−COOH were then transformed to azide to conjugate 10B12H112− through click chemistry. The nanodrugs were evaluated in vitro using B16 murine melanoma cells in terms of cell viability, BNCT efficacy and cellular uptake. As a result, the 10B12H112− moiety is found to facilitate cellular uptake probably due to its negative charge. Upon thermal neutron irradiation, the nanodrugs with 10B12H112− moiety exhibited good anticancer efficacies with slight differences with and without targeting moiety. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is based on the preferential uptake of 10B compounds by tumors, followed by neutron irradiation. The aim of this study was to assess, in an ectopic colon cancer model, the therapeutic efficacy, radiotoxicity, abscopal effect and systemic immune response associated with (BPA/Borophenylalanine+GB-10/Decahydrodecaborate)-BNCT (Comb-BNCT) alone or in combination with Oligo-Fucoidan (O-Fuco) or Glutamine (GLN), compared to the "standard" BPA-BNCT protocol usually employed in clinical trials. All treatments were carried out at the RA-3 nuclear reactor. Boron biodistribution studies showed therapeutic values above 20 ppm 10B in tumors. At 7 weeks post-treatment, the ratio of tumor volume post-/pre-BNCT was significantly smaller for all BNCT groups vs. SHAM (p < 0.05). The parameter "incidence of tumors that underwent a reduction to ≤50% of initial tumor volume" exhibited values of 62% for Comb-BNCT alone, 82% for Comb-BNCT+GLN, 73% for Comb-BNCT+O-Fuco and only 30% for BPA-BNCT. For BPA-BNCT, the incidence of severe dermatitis was 100%, whereas it was significantly below 70% (p ≤ 0.05) for Comb-BNCT, Comb-BNCT+O-Fuco and Comb-BNCT+GLN. Considering tumors outside the treatment area, 77% of Comb-BNCT animals had a tumor volume lower than 50 mm3 vs. 30% for SHAM (p ≤ 0.005), suggesting an abscopal effect of Comb-BNCT. Inhibition of metastatic spread to lymph nodes was observed in all Comb-BNCT groups. Considering systemic aspects, CD8+ was elevated for Comb-BNCT+GLN vs. SHAM (p ≤ 0.01), and NK was elevated for Comb-BNCT vs. SHAM (p ≤ 0.05). Comb-BNCT improved therapeutic efficacy and reduced radiotoxicity compared to BPA-BNCT and induced an immune response and an abscopal effect. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is a selective radiotherapy based on nuclear reaction that occurs when 10B atoms accumulated in cancer cells are irradiated by thermal neutrons, triggering a nuclear fission response leading to cell death. Despite its growing importance in cancer treatment, molecular characterization of its effects is still lacking. In this context, proteomics investigation can be useful to study BNCT effect and identify potential biomarkers. Hence, we performed proteomic analysis with nanoLC-MS/MS (liquid chromatography coupled to tandem mass spectrometry) on extracellular vesicles (EVs) isolated from SAS cultures treated or not with 10B-boronophenylalanine (BPA) and different doses of neutron irradiation, to study the cellular response related to both boron administration and neutrons action. Despite the interference of fetal bovine serum in the medium, we were able to stratify BPA− and BPA+ conditions and to identify EVs-derived proteins characterizing pathways potentially related to a BNCT effect such as apoptosis, DNA repair and inflammatory response. In particular, KLF11, SERPINA1 and SERPINF2 were up-regulated in BPA+, while POLE and SERPINC1 were up-regulated in BPA−. These results provide the first proteomic investigation of EVs treated with BNCT in different conditions and highlight the potentiality of proteomics for improving biomarkers identification and mechanisms understanding of BNCT. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) combines preferential tumor uptake of 10B compounds and neutron irradiation. Electroporation induces an increase in the permeability of the cell membrane. We previously demonstrated the optimization of boron biodistribution and microdistribution employing electroporation (EP) and decahydrodecaborate (GB-10) as the boron carrier in a hamster cheek pouch oral cancer model. The aim of the present study was to evaluate if EP could improve tumor control without enhancing the radiotoxicity of BNCT in vivo mediated by GB-10 with EP 10 min after GB-10 administration. Following cancerization, tumor-bearing hamster cheek pouches were treated with GB-10/BNCT or GB-10/BNCT + EP. Irradiations were carried out at the RA-3 Reactor. The tumor response and degree of mucositis in precancerous tissue surrounding tumors were evaluated for one month post-BNCT. The overall tumor response (partial remission (PR) + complete remission (CR)) increased significantly for protocol GB-10/BNCT + EP (92%) vs. GB-10/BNCT (48%). A statistically significant increase in the CR was observed for protocol GB-10/BNCT + EP (46%) vs. GB-10/BNCT (6%). For both protocols, the radiotoxicity (mucositis) was reversible and slight/moderate. Based on these results, we concluded that electroporation improved the therapeutic efficacy of GB-10/BNCT in vivo in the hamster cheek pouch oral cancer model without increasing the radiotoxicity. [ABSTRACT FROM AUTHOR]

To treat superficial tumors using accelerator-based boron neutron capture therapy (ABBNCT), a technique was investigated, based on which, a single-neutron modulator was placed inside a collimator and was irradiated with thermal neutrons. In large tumors, the dose was reduced at their edges. The objective was to generate a uniform and therapeutic intensity dose distribution. In this study, we developed a method for optimizing the shape of the intensity modulator and irradiation time ratio to generate a uniform dose distribution to treat superficial tumors of various shapes. A computational tool was developed, which performed Monte Carlo simulations using 424 different source combinations. We determined the shape of the intensity modulator with the highest minimum tumor dose. The homogeneity index (HI), which evaluates uniformity, was also derived. To evaluate the efficacy of this method, the dose distribution of a tumor with a diameter of 100 mm and thickness of 10 mm was evaluated. Furthermore, irradiation experiments were conducted using an ABBNCT system. The thermal neutron flux distribution outcomes that have considerable impacts on the tumor's dose confirmed a good agreement between experiments and calculations. Moreover, the minimum tumor dose and HI improved by 20 and 36%, respectively, compared with the irradiation case wherein a single-neutron modulator was used. The proposed method improves the minimum tumor volume and uniformity. The results demonstrate the method's efficacy in ABBNCT for the treatment of superficial tumors. [ABSTRACT FROM AUTHOR]

Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/ mp53) or neo vector (SAS/ neo) were inoculated subcutaneously into left hind legs of nude mice. After the subcutaneous administration of a 10B-carrier, boronophenylalanine-10B (BPA) or sodium mercaptododecaborate-10B (BSH), at two separate concentrations, the 10B concentrations in tumors were measured using γ-ray spectrometry. The tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) tumor cells, then were administered with BPA or BSH. Subsequently, the tumors were irradiated with reactor neutron beams during the time of which 10B concentrations were kept at levels similar to each other. Following irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of BrdU-unlabeled quiescent (Q) and total (= P  + Q) tumor cells were assessed based on the frequencies of micronucleation using immunofluorescence staining for BrdU. In both SAS/ neo and SAS/ mp53 tumors, the compound biological effectiveness (CBE) values were higher in Q cells and in the use of BPA than total cells and BSH, respectively. The higher the administered concentrations were, the smaller the CBE values became, with a clearer tendency in SAS/ neo tumors and the use of BPA than in SAS/ mp53 tumors and BSH, respectively. The values for BPA that delivers into solid tumors more dependently on uptake capacity of tumor cells than BSH became more alterable. Tumor micro-environmental heterogeneity might partially influence on the CBE value. The CBE value can be regarded as one of the indices showing the level of intratumor heterogeneity. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is a binary therapeutic technique employing a boron agent to be delivered to the tumor site followed by the irradiation of neutrons. Biofunctional molecules/nanoparticles labeled with F-18 can provide an initial pharmacokinetic profile of patients to guide the subsequent treatment planning procedure of BNCT. Borono phenylalanine (BPA), recognized by the l-type amino acid transporter, can cross the blood-brain barrier and be accumulated in gliomas. The radiofluoro BNCT agents are reviewed by considering (1) less cytotoxicity, (2) diagnosing and therapeutic purposes, (3) aqueous solubility and extraction route, as well as (4), the trifluoroborate effect. A trifluoroborate-containing amino acid such as fluoroboronotyrosine (FBY) represents an example with both functionalities of imaging and therapeutics. Comparing with the insignificant cytotoxicity of clinical BPA with IC50 > 500 μM, FBY also shows minute toxicity with IC50 > 500 μM. [18F]FBY is a potential diagnostic agent for its tumor to normal accumulation (T/N) ratio, which ranges from 2.3 to 24.5 from positron emission tomography, whereas the T/N ratio of FBPA is greater than 2.5. Additionally, in serving as a BNCT therapeutic agent, the boron concentration of FBY accumulated in gliomas remains uncertain. The solubility of 3-BPA is better than that of BPA, as evidenced by the cerebral dose of 3.4%ID/g vs. 2.2%ID/g, respectively. While the extraction route of d-BPA differs from that of BPA, an impressive T/N ratio of 6.9 vs. 1.5 is noted. [18F]FBPA, the most common clinical boron agent, facilitates the application of BPA in clinical BNCT. In addition to [18F]FBY, [18F] trifluoroborated nucleoside analog obtained through 1,3-dipolar cycloaddition shows marked tumoral uptake of 1.5%ID/g. Other examples using electrophilic and nucleophilic fluorination on the boron compounds are also reviewed, including diboronopinacolone phenylalanine and nonsteroidal anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is a binary cancer therapy that involves boron administration and neutron irradiation. The nuclear reaction caused by the interaction of boron atom and neutron produces heavy particles with highly cytocidal effects and destruct tumor cells, which uptake the boron drug. p-Boronophenylalanine (BPA), an amino acid derivative, is used in BNCT. Tumor cells with increased nutrient requirements take up more BPA than normal tissues via the enhanced expression of LAT1, an amino acid transporter. The current study aimed to assess the correlation between the expression of LAT1 and the uptake capacity of BPA using genetically modified LAT1-deficient/enhanced cell lines. We conducted an in vitro study, SCC7 tumor cells wherein LAT1 expression was altered using CRISPR/Cas9 were used to assess BPA uptake capacity. Data from The Cancer Genome Atlas (TCGA) were used to examine the expression status of LAT1 in human tumor tissues, the potential impact of LAT1 expression on cancer prognosis and the potential cancer indications for BPA-based BNCT. We discovered that the strength of LAT1 expression strongly affected the BPA uptake ability of tumor cells. Among the histologic types, squamous cell carcinomas express high levels of LAT1 regardless of the primary tumor site. The higher LAT1 expression in tumors was associated with a higher expression of cell proliferation markers and poorer patient prognosis. Considering that BPA concentrate more in tumors with high LAT1 expression, the results suggest that BNCT is effective for cancers having poor prognosis with higher proliferative potential and nutritional requirements. [ABSTRACT FROM AUTHOR]

• From 2010, KUR transitioned its operations from high-enrichment fuel to low-enrichment fuel. • The neutron energy spectrum of KUR-HWNIF has not been reevaluated with high accuracy since then. • The neutron energy spectrum of KUR-HWNIF was reevaluated using the multifoil activation method. • The reevaluated neutron absorption dose rate remained acceptable for BNCT biological viewpoint. The Heavy-Water Thermal Neutron Facility at Kyoto University Research Reactor (KUR) has been operational for boron neutron capture therapy (BNCT) since May 1974. Following a facility construction update in 1996, the facility name was changed to the Heavy-Water Neutron Irradiation Facility (HWNIF), and the neutron energy spectra were evaluated using the multifoil activation method. In May 2010, the KUR transitioned its operations from high-enrichment fuel to low-enrichment fuel. However, the neutron energy spectrum in the KUR-HWNIF has not been reevaluated with high accuracy since then. This paper reports the reevaluation of the neutron energy spectrum for the standard epithermal-neutron irradiation mode using the multifoil activation method. Based on the reevaluated results, the epithermal- and fast-neutron fluxes increased by approximately 34 % and 19 %, respectively. The neutron absorption dose rate at evaluation point was approximately 17 % lower than the previous one; however, it remained acceptable from the perspective of BNCT biological irradiation. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is a radiotherapy technology that selectively kills tumor cells via the 10B(n, α)7Li reactions. Epithermal neutrons (0.5 eV–10 keV) are emitted and converted into thermal neutrons, which have a larger neutron capture reaction cross-section, by slowing down in the human body before reaching the tumor. Recently, the development of an epithermal neutron absolute flux intensity measurement technique has become crucial for real-time in-vivo dose monitoring in BNCT. In this study, a concept for a measurement system consisting of multiple compact scintillator with optical fibers detectors covered with neutron absorbers of various thicknesses is proposed. The designed system achieves a consistent response to epithermal neutrons with a theoretical coefficient of variation not higher than 5% for both LiCAF and EJ-254 scintillators. The theoretical feasibility of the proposed measurement system was investigated by an irradiation experiment carried out at the heavy water neutron irradiation facility at the Kyoto University Reactor. The experimental results indicated that further improvement and refinement are necessary to meet the high accuracy and precision required for real-time dose monitoring in clinical applications. • A scintillator-based compact system used for real-time neutron flux measurement. • Using multiple detectors covered by absorbers to modify the detector response. • Consistent response to epi-thermal neutrons from 0.5 eV to 10 keV. • Irradiation experiments using a therapeutic neutron beam. • Applications in real-time in-vivo dose monitoring for BNCT. [ABSTRACT FROM AUTHOR]

SAS cells were subcutaneously grafted in nude mice and 30 min after administration of BPA-fructose at 500 mg/kg bodyweight, tumors were mock-irradiated (E) or locally irradiated for 60 min with neutron beam, ((F), BNCT). (C) Mouse plasma HMGB1 levels of C57BL/6 mice without tumor xenograft 3 days after mock irradiation or BNCT measured using ELISA kit (Novus Biologicals). Figure Graph: Figure 4 Changes in HMGB1 levels and localization in response to neutron irradiation with BPA in SAS cell-derived tumors. [Extracted from the article]

Boron neutron capture therapy is a low-invasive cancer therapy based on the neutron fission process that occurs upon thermal neutron irradiation of 10B-containing compounds; this process causes the release of alpha particles that selectively damage cancer cells. Although several clinical studies involving mercaptoundecahydro-closo-dodecaborate and the boronophenylalanine–fructose complex are currently ongoing, the success of this promising anticancer therapy is hampered by the lack of appropriate drug delivery systems to selectively carry therapeutic concentrations of boron atoms to cancer tissues, allowing prolonged boron retention therein and avoiding the damage of healthy tissues. To achieve these goals, numerous research groups have explored the possibility to formulate nanoparticulate systems for boron delivery. In this review. we report the newest developments on boron vehiculating drug delivery systems based on nanoparticles, distinguished on the basis of the type of carrier used, with a specific focus on the formulation aspects. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy is a unique treatment method that aims to kill the tumor cells with the help of heavy particles. Particles resulting from the interaction of the tumor region containing 10B atoms with thermal or epithermal neutrons have the most important role in this treatment method. In this study, gamma radiation reaching healthy tissues, which is the result of 10B (n,α )7Li reaction, was investigated. A simulation suitable for boron neutron capture therapy treatment, including the human head model, was created by the Monte Carlo N-Particle (MCNP) program. By using five different neutron energies, the gamma radiations resulting from the 10B(n,α )7 Li reaction in the determined regions, close to the tumor tissue, were investigated. It was observed that the healthy tissue between the tumor area and the surface is exposed to the highest gamma flux and the highest gamma radiation absorption. It was also observed that these values increase as neutron energy decreases. It was found that the gamma doses received by some regions outside the neutron irradiation area could be significant. It has been understood that the change in neutron energy may cause significant changes in gamma radiation values reaching healthy tissues, especially in regions close to the surface. In boron neutron capture therapy treatments, the neutrons sent to the tumor should be selected depending on the location of the tumor and the size of the tumor area. This study contains significant data about photon doses in healthy tissues around the brain region treated using different neutron energies with the boron neutron capture therapy technique. [ABSTRACT FROM AUTHOR]

Radiation-induced liver diseases, including liver fibrosis, occurs when radiation damages the liver. Basic research on hepatic fibrosis, which is a late radiation injury, is necessary for evaluating adverse liver events occurring after boron neutron capture therapy. This study was conducted to establish a method for analyzing the negative effect such as fibrosis in the liver tissue after boron neutron capture therapy. Female C57BL6 mice were injected with p-boronophenylalanine solution subcutaneously at 2 h before neutron irradiation. Masson trichrome staining was performed to determine the degree of liver fibrosis. The degree of fat accumulation in mouse normal liver tissue after boron neutron capture therapy was evaluated using hematoxylin and eosin staining and triglyceride quantification. Western blotting was performed to determine the expression level of Sonic Hedgehog. Liver fat accumulation and fibrosis were significantly increased in the neutron irradiation group injected with p-boronophenylalanine compared with control group. In addition, Sonic Hedgehog expression was increased in response to boron neutron capture therapy-induced liver injury and was involved in liver fibrosis. Hepatocellular fat accumulation and Hedgehog signaling activation may be indicators of adverse events related to boron neutron capture therapy associated with liver fibrosis. [ABSTRACT FROM AUTHOR]

In June 2020, the Japanese government approved boron neutron capture therapy for the treatment of head and neck cancer. The treatment is usually performed in a single fraction, with the neutron irradiation time being approximately 30–60 min. As neutrons scatter in air and loses its intensity, it is preferable to bring the patient as close to the beam port as possible to shorten the irradiation time. However, this can be a challenge, especially for patients with head and neck cancer, as the shoulders are an obstacle to a clean positioning. In this study, a novel neutron collimation system for an accelerator based neutron source was designed to allow for a more comfortable treatment, without compromising the irradiation time. Experimental measurements confirmed the simulation results and showed the new collimator can reduce the irradiation time by approximately 60% (under the same condition where the distance between the source and the patient surface was kept the same). The dose delivered to the surrounding healthy tissue was reduced with the new collimator, showing a 25% decrease in the D50 of the mucosal membrane. Overall, the use of the newly designed collimator will allow for a more comfortable treatment of the head and neck region, reduce the treatment time, and reduce the dose delivered to the surrounding healthy tissue. [ABSTRACT FROM AUTHOR]

While boron neutron capture therapy (BNCT) depends primarily on the short flight range of the alpha particles emitted by the boron neutron capture reaction, gadolinium neutron capture therapy (GdNCT) mainly relies on gamma rays and Auger electrons released by the gadolinium neutron capture reaction. BNCT and GdNCT can be complementary in tumor therapy. Here, we studied the combined effects of BNCT and GdNCT when boron and gadolinium compounds were co-injected, followed by thermal neutron irradiation, and compared these effects with those of the single therapies. In cytotoxicity studies, some additive effects (32‒43%) were observed when CT26 cells were treated with both boron- and gadolinium-encapsulated PEGylated liposomes (B- and Gd-liposomes) compared to the single treatments. The tumor-suppressive effect was greater when BNCT was followed by GdNCT at an interval of 10 days rather than vice versa. However, tumor suppression with co-injection of B- and Gd-liposomes into tumor-bearing mice followed by neutron beam irradiation was comparable to that observed with Gd-liposome-only treatment but lower than B-liposome-only injection. No additive effect was observed with the combination of BNCT and GdNCT, which could be due to the shielding effect of gadolinium against thermal neutrons because of its overwhelmingly large thermal neutron cross section. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is a radiation therapy that selectively kills cancer cells and is being actively researched and developed around the world. In Korea, development of the proton linear accelerator-based BNCT system has completed development, and its anti-cancer effect in the U-87 MG subcutaneous xenograft model has been evaluated. To evaluate the efficacy of BNCT, we measured 10B-enriched boronophenylalanine (BPA) uptake in U-87 MG, FaDu, and SAS cells and evaluated cell viability by clonogenic assays. In addition, the boron concentration in the tumor, blood, and skin on the U-87 MG xenograft model was measured, and the tumor volume was measured for 4 weeks after BNCT. In vitro, the intracellular boron concentration was highest in the order of SAS, FaDu, and U-87 MG, and cell survival fractions decreased depending on the BPA treatment concentration and neutron irradiation dose. In vivo, the tumor volume was significantly decreased in the BNCT group compared to the control group. This study confirmed the anti-cancer effect of BNCT in the U-87 MG subcutaneous xenograft model. It is expected that the proton linear accelerator-based BNCT system developed in Korea will be a new option for radiation therapy for cancer treatment. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT), a cellular-level particle radiation therapy, combines boron compounds selectively delivered to tumor tissue with neutron irradiation. Boronophenylalanine (BPA) is a boron compound widely used in malignant melanoma, malignant brain tumors, and recurrent head and neck cancer. However, neither basic nor clinical research was reported for the treatment of gastric cancer using BPA. Selective distribution of boron in tumors rather than that in blood or normal tissue prior to neutron irradiation is required for the successful treatment of BNCT. This study evaluated the pharmacokinetics and safety of 10B-labeled BPA (10B-BPA, abbreviated as BPA) and its uptakes in gastric cancer. Pharmacokinetics and safety were evaluated in Sprague-Dawley (SD) rats intravenously injected with BPA. The uptakes of boron in gastric cancer cell line MKN45 and in cell-derived xenografts (CDX) and patient-derived xenografts (PDX) animal models were measured. The results showed that the boron concentration in the blood of rats decreased fast in the first 30 min followed by a steady decrease following the observation time, having a half-life of 44.11 ± 8.90 min and an AUC-last of 815.05 ± 62.09 min×mg/ml. The distribution of boron in different tissues (heart, liver, lung, stomach, and small intestine) of rats revealed a similar pattern in blood except for that in the brain, kidney, and bladder. In MKN45 cells, boron concentration increased in a time- and concentration-dependent manner. In both CDX and PDX animal models, the boron is preferentially distributed in tumor tissue rather than in blood or normal tissues. In addition, BPA had no significant adverse effects in rats. Taken together, the results suggested that BPA revealed a fast decrease in boron concentration in rats and is more likely to distribute in tumor cells and tissue. [ABSTRACT FROM AUTHOR]

The iBNCT project aims to develop "iBNCT001," a demonstration device of the linac-based neutron irradiation facility for boron neutron capture therapy (BNCT) application. iBNCT001 generates an epithermal neutron beam by irradiating 8 MeV protons accelerated by a linac onto a beryllium target. Currently, the linac can drive an average proton current of 2.1 mA. Several experiments were performed using a water phantom to confirm the main physical characteristics of the neutron beam produced at the irradiation position. The measurement results demonstrated that the maximum thermal neutron flux achievable in the phantom volume was approximately 1.36 × 10 9 cm − 2 s − 1 when a normal beam collimator with a 120 mm diameter was used. This neutron beam intensity was sufficient to complete the irradiation within 30 min using the BNCT approach. In addition to normal beam collimators, extended collimators that protrude 100 mm from the wall were developed. By using an extended collimator, it is possible to prevent interference of the patient's body with the wall when irradiating head and neck cancers. The measurement results for the extended collimator demonstrated that irradiation with the collimator could be completed within 1 h when the neutron beam is generated with an average proton current of 2.1 mA. [ABSTRACT FROM AUTHOR]

Background: BNCT (Boron Neutron Capture Therapy) is a tumor-selective particle radiotherapy that combines preferential boron accumulation in tumors and neutron irradiation. Although p-boronophenylalanine (BPA) has been clinically used, new boron compounds are needed for the advancement of BNCT. Based on previous studies in colon tumor-bearing mice, in this study, we evaluated MID:BSA (maleimide-functionalized closo-dodecaborate conjugated to bovine serum albumin) biodistribution and MID:BSA/BNCT therapeutic effect on tumors and associated radiotoxicity in the hamster cheek pouch oral cancer model. Methods: Biodistribution studies were performed at 30 mg B/kg and 15 mg B/kg (12 h and 19 h post-administration). MID:BSA/BNCT (15 mg B/kg, 19 h) was performed at three different absorbed doses to precancerous tissue. Results: MID:BSA 30 mg B/kg protocol induced high BSA toxicity. MID:BSA 15 mg B/kg injected at a slow rate was well-tolerated and reached therapeutically useful boron concentration values in the tumor and tumor/normal tissue ratios. The 19 h protocol exhibited significantly lower boron concentration values in blood. MID:BSA/BNCT exhibited a significant tumor response vs. the control group with no significant radiotoxicity. Conclusions: MID:BSA/BNCT would be therapeutically useful to treat oral cancer. BSA toxicity is a consideration when injecting a compound conjugated to BSA and depends on the animal model studied. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is a next-generation radiotherapy that combines neutron beams with boron compounds that selectively accumulate in cancer cells. Because this therapy requires neutrons for irradiation, compact accelerator-based neutron source devices that can be installed in hospitals are being developed around the world. Clinical trials of several devices have been conducted in Japan, China, and South Korea. The most advanced device was approved by the Japanese regulatory authorities in 2020. As a result, BNCT with the device is being implemented as an insured therapy for recurrent head and neck cancer at two hospitals in Japan. Thus, the development of accelerator-based neutron generators is proceeding in the field of BNCT. However, much remains to be done to establish this therapy as a common cancer treatment and to make it available worldwide. Dosimetry methods in BNCT are one of the issues. In the treatment, the dose given to a patient by neutron irradiation has to be estimated accurately. However, it is difficult to measure neutrons accurately and in real time. Currently, the neutron dose delivered to patients during treatment is not measured. Instead, the current of the charged particles that irradiate the neutron target material is measured to indirectly evaluate the neutron fluence and dose. In addition, accurate dose estimation based on reactions with neutrons and various elements in a human body uses the Monte Carlo method, which is computationally time-consuming. To address these dosimetry issues, several neutron fluence and dose measurement methods are being developed. This review briefly describes the current dosimetry methods and then presents several methods under development that allow real-time neutron measurements applicable to BNCT. • BNCT. • Dosimetry. • Neutron measurement. • Real-time measurement. • Microdosimetry. [ABSTRACT FROM AUTHOR]

Multidisciplinary therapy centered on radical surgery for resectable pancreatic cancer is expected to prolong prognosis, but relies on CA19-9 biomarker levels to determine treatment strategy. Boron neutron capture therapy (BNCT) is a chemoradiotherapy using tumor hyperaccumulator boron drugs and neutron irradiation. The purpose of this study is to investigate novel boron drug agents for BNCT for pancreatic cancer. Bioinformatics was used to evaluate the uptake of current boron amino acid (BPA) drugs for BNCT into pancreatic cancer. The expression of the amino acid transporter LAT1, a BPA uptake transporter, was low in pancreatic cancer and even lower in high CA19-9 pancreatic cancer. In contrast, the glucose transporter was high in high CA19-9 pancreatic cancers and inversely correlated with LAT1 expression. Considering the low EPR effect in pancreatic cancer, we synthesized a small molecule Glucose-BSH, which is boron BSH bound to glucose, and confirmed its specific uptake in pancreatic cancer. uptake of Glucose-BSH was confirmed in an environment compatible with the tumor microenvironment. The therapeutic efficacy and safety of Glucose-BSH by therapeutic neutron irradiation were confirmed with BNCT. We report Glucose-BSH boron drug discovery study of a Precision Medicine BNCT with application to high CA19-9 pancreatic cancer. • Boron neutron capture therapy (BNCT) is a chemoradiotherapy using boron agents and neutron irradiation; the cancer accumulation capacity of boron agents is the key to its application in pancreatic cancer. • We successfully developed a boron-based drug targeting a glucose transporter that is highly expressed in pancreatic cancer. • BNCT using the sugar-binding boron drug developed in this study is a novel therapy as BNCT targeting pancreatic cancer with high CA19-9 levels. [ABSTRACT FROM AUTHOR]

This study aimed to identify the optimal conditions for delivering sufficient doses to deep-seated lesions within short irradiation times for two boron carriers of different T / N ratios. The therapeutic depth and irradiation time of a neutron beam for beam shaping assemblies (BSAs) with a Li or Be target and a MgF 2 or CaF 2 moderator were examined with the fast-neutron dose per epithermal neutron (FNR) as a parameter. When T / N = 3.61, the therapeutic depth was almost saturated at an FNR of about 10 × 10−13 Gy cm2; when the FNR value was about 10 × 10−13 Gy cm2, the therapeutic depth of the neutron beam for the BSA with a Be target and a MgF 2 moderator was almost identical to that for the neutron beam for the BSA with a Be target and a CaF 2 moderator, and slightly greater than those for the neutron beams for the BSAs with a Li target and a MgF 2 or CaF 2 moderator; moreover, the irradiation time of the neutron beam for the BSA with a Be target and a MgF 2 moderator was shorter than that for the neutron beam for the BSA with a Be target and a CaF 2 moderator. When T / N = 100, the therapeutic depths of the neutron beams for the BSAs varied greatly depending on the FNR, and were greater than the corresponding values for T / N = 3.61. We therefore concluded that the BSA with a Be target and a MgF 2 moderator that produced a neutron beam with an FNR of about 10 × 10−13 Gy cm2 is optimal for delivering sufficient doses to deep-seated lesions in short irradiation times when T / N = 3.61, and stricter control over FNR is required when T / N = 100. • Beam shaping assemblies (BSAs) for AB-BNCT were designed when T / N = 3.61. • The BSA models included a Li or Be target and a MgF 2 or CaF 2 moderator. • The beam had a fast-neutron dose per epithermal neutron (FNR) as a parameter. • The BSA with a Be target and a MgF 2 moderator maximized the therapeutic depth. • The BSA with a Be target and a MgF 2 moderator minimized the irradiation time. [ABSTRACT FROM AUTHOR]

Our group is currently developing a multilayer neutron spectrometer based on moderator combination selection to evaluate neutron energy spectra in irradiation fields for boron neutron capture therapy (BNCT). In a previous study, we optimally selected (based on simulations) liquid moderator combinations of the spectrometer to achieve high accuracy in the evaluated neutron energy spectra. According to the optimization result, we conducted a spectrometer verification test in the BNCT irradiation field at the Heavy Water Neutron Irradiation Facility of Kyoto University Reactor (KUR-HWNIF). The neutron energy spectrum result was evaluated, and the uncertainty was found to be less than 15%. The experimental results prove that the multilayer neutron spectrometer based on moderator combination selection effectively evaluates the neutron energy spectrum in a BNCT irradiation field. [ABSTRACT FROM AUTHOR]

Experimentally ensuring the quality of neutron beam before patient treatment is a topic of central importance for a boron neutron capture therapy (BNCT) facility. The procedure of beam quality assurance currently adopted at THOR-BNCT lacks a direct indication related to the energy distribution of neutrons. A new device based on multiple activation foils was therefore proposed to provide a quick confirmation of the unchanged neutron spectrum before patient irradiation. The device’s responses to the THOR-BNCT neutron beam are presented. A series of experimental tests were repeated to establish the baseline performance of the device, and further numerical simulations were conducted to determine its sensitivities to various perturbations in the reference spectrum. To increase the rigorousness of beam quality assurance by supplementing additional information about neutron spectrum, the device has been suggested to assist the role of Au/Cu activation foils in the current procedure as and when required. [ABSTRACT FROM AUTHOR]

The radiation emitted from the beam aperture of the boron neutron capture therapy (BNCT) system includes not only neutrons with a wide energy range but also γ -ray, which is an undesirable dose for patients. Therefore, it is necessary to evaluate the γ -ray dose appropriately. Several methods have been proposed to evaluate the γ -ray dose in a neutron field. However, eliminating the influence of neutrons is challenging, and developing a more versatile and highly accurate measurement method is desired. We aimed to validate the γ -ray dose measurement method in a neutron field combining a commercial thermoluminescence dosimeter (TLD) named Mg 2 SiO 4 : Tb (TLD-MSO-S) and 6LiF sintered capsule for quality assurance. As a characteristic evaluation, the variation in sensitivity between TLD rods and dose linearity was determined using a medical linear accelerator. Furthermore, the perturbation and contribution of neutron dose were determined by Monte Carlo simulation, and measurements were performed at the accelerator-based BNCT system. We have found that γ -ray dose can be evaluated with an accuracy of and within ±7% between calculated and measured values and ±7% of reproducibility. • The method of γ -ray dose evaluation combining Mg 2 SiO 4 : Tb (TLD-MSO-S) and 6LiF sintered capsule in the neutron field was presented. • The factors used for γ -ray dose evaluation were determined by calibration using linear accelerator and MCNP calculations, and then verified in the neutron irradiation field. • The measured γ -ray dose can be evaluated with an accuracy of and within ±7% between calculation results and ±7% of reproducibility. [ABSTRACT FROM AUTHOR]

The purpose of this study was to outline the course and profile of adverse events specific to boron neutron capture therapy (BNCT) for head and neck cancer. This was a sub-analysis of the phase II JHN002 trial. Patients received 400 mg/kg borofalan(10B), followed by neutron irradiation. The course of adverse events after BNCT was documented in the JHN002 Look Up study. Patients were grouped into face/front (FF), face/lateral (FL) and neck (N) beam groups according to the point of skin incidence of the epithermal neutron beam axis, and the profile of adverse events dependent on beam incidence position was examined. The courses of adverse events in eight recurrent squamous cell carcinoma (R-SCC) and 13 recurrent or locally advanced non-SCC cases were analyzed. Median interval to complete recovery was 23 days (interquartile range (IQR), 14–48 days) for oral mucositis, 40 days (IQR, 24–56 days) for dermatitis, 58 days (IQR, 53–80 days) for dysgeusia and 156 days (IQR, 82–163 days) for alopecia. In the FF beam group, parotitis (P  = 0.007) was less frequent, while oral mucositis (P  = 0.032), fatigue (P  = 0.002), conjunctivitis (P  = 0.001), epistaxis (P  = 0.001) and abdominal discomfort (P  = 0.029) tended to be more frequent than in the FL and N beam groups. Courses and irradiation site-specific profiles of adverse events in BNCT for head and neck cancer were identified. This profile may be useful for considering interventions to prevent exacerbation of treatment-related adverse events on BNCT. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is an attractive approach to treat invasive malignant tumours due to binary heavy-particle irradiation, but its clinical applications have been hindered by boron delivery agents with low in vivo stability, poor biocompatibility, and limited application of combinational modalities. Here, we report boronsome, a carboranyl-phosphatidylcholine based liposome for combinational BNCT and chemotherapy. Theoretical simulations and experimental approaches illustrate high stability of boronsome. Then positron emission tomography (PET) imaging with Cu-64 labelled boronsome reveals high-specific tumour accumulation and long retention with a clear irradiation background. In particular, we show the suppression of tumour growth treated with boronsome with neutron irradiation and therapeutic outcomes are further improved by encapsulation of chemotherapy drugs, especially with PARP1 inhibitors. In sum, boronsome may be an efficient agent for concurrent chemoradiotherapy with theranostic properties against malignancies. Boron neutron capture therapy is a type of cancer therapy but is associated with insufficient boron delivery and with poor biocompatibility. Here, the authors constructed boronated lipids to generate - boronsome - and show the system can reduce tumour growth. [ABSTRACT FROM AUTHOR]

Sufficient boron-10 isotope (10B) accumulation by tumor cells is one of the main requirements for successful boron neutron capture therapy (BNCT). The inability of the clinically registered 10B-containing borophenylalanine (BPA) to maintain a high boron tumor concentration during neutron irradiation after a single injection has been partially solved by its continuous infusion; however, its lack of persistence has driven the development of new compounds that overcome the imperfections of BPA. We propose using elemental boron nanoparticles (eBNPs) synthesized by cascade ultrasonic dispersion and destruction of elemental boron microparticles and stabilized with hydroxyethylcellulose (HEC) as a core component of a novel boron drug for BNCT. These HEC particles are stable in aqueous media and show no apparent influence on U251, U87, and T98G human glioma cell proliferation without neutron beam irradiation. In BNCT experiments, cells incubated with eBNPs or BPA at an equivalent concentration of 40 µg 10B/mL for 24 h or control cells without boron were irradiated at an accelerator-based neutron source with a total fluence of thermal and epithermal neutrons of 2.685, 5.370, or 8.055 × 1012/cm2. The eBNPs significantly reduced colony-forming capacity in all studied cells during BNCT compared to BPA, verified by cell-survival curves fit to the linear-quadratic model and calculated radiobiological parameters, though the effect of both compounds differed depending on the cell line. The results of our study warrant further tumor targeting-oriented modifications of synthesized nanoparticles and subsequent in vivo BNCT experiments. [ABSTRACT FROM AUTHOR]

Simple Summary: Boron neutron capture therapy (BNCT) is a non-invasive therapeutic technique for treating malignant tumors, however, there is a lack of methods to evaluate its therapeutic efficacy. Herein, we investigated whether high mobility group box 1 (HMGB1) is a potential biomarker of BNCT response in tumor cells and mice in combination with 10B-p-boronophenylalanine in the Kyoto University Nuclear Reactor. We observed an increased extracellular HMGB1 release in cancer cells 24 h post-BNCT irradiation, compared to that observed with an equivalent dose of gamma-ray irradiation. High levels of plasma HMGB1 were observed on day 3 post-BNCT irradiation in a xenograft mouse model. These levels were stably detected even when the size of the tumor decreased, suggesting that HMGB1 is a potential biomarker for the therapeutic efficacy of BNCT. Boron neutron capture therapy (BNCT) is a non-invasive therapeutic technique for treating malignant tumors, however, methods to evaluate its therapeutic efficacy and adverse reactions are lacking. High mobility group box 1 (HMGB1) is an inflammatory molecule released during cell death. Therefore, we aimed to investigate HMGB1 as a biomarker for BNCT response, by examining the early responses of tumor cells to 10B-boronophenylalanine (BPA)-based BNCT in the Kyoto University Nuclear Reactor. Extracellular HMGB1 release was significantly increased in human squamous carcinoma SAS and melanoma A375 cells 24 h after neutron irradiation but not after γ-irradiation. At 3 days post-BPA-based BNCT irradiation in a SAS xenograft mouse model, plasma HMGB1 levels were higher than those in the non-irradiation control, and HMGB1 was detected in both nuclei and cytoplasm in tumor cells. Additionally, increased plasma HMGB1 levels post-BNCT irradiation were detected even when tumors decreased in size. Collectively, these results indicate that the extracellular HMGB1 release occurs at an early stage and is persistent when tumors are reduced in size; therefore, it is a potential biomarker for evaluating the therapeutic response during BNCT. [ABSTRACT FROM AUTHOR]

Purpose: Optical imaging of ionizing radiation is a possible method for dose distribution measurements. However, it is not clear whether the imaging method is also applicable to neutrons. To clarify this, we performed the imaging of neutrons in water from boron neutron capture therapy (BNCT) systems. Such systems require efficient distribution measurements of neutrons for quality assessment (QA) of the beams. Method: A water‐filled phantom was irradiated from the side with an epithermal neutron beam, in which a lithium‐containing zinc sulfate (Li‐ZnS(Ag)) plate was set in the beam direction, and during this irradiation the scintillation of the plate was imaged using a cooled charge‐coupled device (CCD) camera. In the imaging, Li‐6 in the Li‐ZnS(Ag) plate captures neutrons and converts them to alpha particles (He‐4) and tritium (H‐3), while ZnS(Ag) in the Li‐ZnS(Ag) plate produces scintillation light in the plate. We also conducted Monte Carlo simulation and compared its results with the experimental results. Results: The image of the emitted light from the Li‐ZnS(Ag) plate was clearly obtained with an imaging time of 0.5 s. The depth and lateral profiles of the measured image using the Li‐ZnS(Ag) plate showed the same shapes as the neutron distributions measured with gold foil, within a difference of 8%. The destructive effect of neutrons on the CCD camera increased approximately three times, but the unit was still working after the measurement. Conclusion: The optical imaging of neutrons in water is possible, and it has the potential to be a new method for efficient QA as well as for research on neutrons. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is considered to have potential for cancer therapy based on the nuclear reaction between boron (10B) atoms and thermal neutrons, yielding 4He2+ (α) and 7Li3+ ions. These heavy particles induce the destruction of biomolecules within short path length of 5–9 μm, resulting in a limited cytotoxic effect to 10B‐containing cells. Herein, we report on the design and synthesis of DNA‐targeting BNCT agents equipped with homo‐ and hetero‐dimeric macrocyclic polyamine units and their Zn2+ complexes. It was hypothesized that the dizinc(II) complexes of these ligands would recognize two adjacent thymidines (thymidyl(3'–5')thymidine), resulting in an efficient contact with DNA and an efficient breakdown of DNA upon thermal neutron irradiation. To test this hypothesis, we performed a DNA interaction study and a biological evaluation such as cytotoxicity and intracellular uptake activity using cancer and normal cells. BNCT experiments utilizing the corresponding 10B‐enriched compounds were also conducted. [ABSTRACT FROM AUTHOR]

Purpose To examine whether hypoxia and Hif-1α affect sensitivity of murine squamous cell carcinoma cells to boron neutron capture therapy (BNCT). Materials and methods SCC VII and SCC VII Hif-1α-deficient mouse tumor cells were incubated under normoxic or hypoxic conditions, and cell survival after BNCT was assessed. The intracellular concentration of the 10B-carrier, boronophenylalanine-10B (BPA), was estimated using an autoradiography technique. The expression profile of SLC7A5, which is involved in the uptake of BPA, and the amount of DNA damage caused by BNCT with BPA were examined. A cell survival assay was performed on cell suspensions prepared from tumor-bearing mice. Results Hypoxia ameliorated SCC VII cell survival after neutron irradiation with BPA, but not BSH. Hypoxia-treated SCC VII cells showed decreased intracellular concentrations of BPA and the down-regulated expression of the SLC7A5 protein. BPA uptake and the SLC7A5 protein were not decreased in hypoxia-treated Hif-1α-deficient cells, the survival of which was lower than that of SCC VII cells. More DNA damage was induced in SCC VII Hif-1α-deficient cells than in SCC VII cells. In experiments using tumor-bearing mice, the survival of SCC VII Hif-1α-deficient cells was lower than that of SCC VII cells. Conclusion. Hypoxia may decrease the effects of BNCT with BPA, whereas the disruption of Hif-1α enhanced sensitivity to BNCT with BPA. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is an effective binary radiation therapy that depends on nuclear capture reactions. In recent years, BNCT can be performed without a reactor owing to the development of accelerator-based neutron sources. A new BNCT irradiation facility is proposed, which is based on a 15 mA 2.5 MeV proton accelerator with a 100 μm thickness natural lithium target as a neutron converter. A great quantity of studies has shown that neutron beams with different spectra have unique therapeutic effects on tumors. An appropriate neutron beam for BNCT is obtained by Beam Shaping Assembly (BSA) and the moderator plays a main role in determining the BSA outlet beam spectrum. To figure out the dose distribution in phantom with various kinds of neutron spectrum modes during BNCT, a series of cases are calculated by MCNPX code. The results give a database for treatment of brain tumors with BNCT by using different moderators. • A new accelerator-based neutron source for BNCT is proposed. • The quality of therapeutic neutron beam is evaluated by using Snyder phantom. • The optimal moderator configuration for treating brain tumors in various degree of depth is presented. [ABSTRACT FROM AUTHOR]

Boron Neutron Capture Therapy (BNCT) is a radiotherapy whose effect is due to the combination of low-energy neutron irradiation prior chemical targeting of tumour tissues with boron-10. The context of this work is the design of a clinical BNCT facility based on a Radio-Frequency Quadrupole proton accelerator, manufactured by the Italian National Institute of Nuclear Physics (INFN). Such a machine can provide a neutron beam suitable for the treatment of deep-seated tumours when coupled to a beryllium target and a Beam Shaping Assembly whose main constituent is densified lithiated aluminium fluoride. This paper refines the design of the facility, already addressed in preliminary studies, from the point of view of dosimetric quantities in the room and in the patient. The presented calculations have been performed with different Monte Carlo codes, and assess the time evolution of the dose due to the neutron activation of the irradiated materials. A comprehensive evaluation of the dose absorbed in the healthy organs of the patient is provided, with focus on the residual radioactivity of the patient urine, for three different treatment positions. Borated concrete is confirmed to be the best material for constructing the walls of the treatment room. A lead shielding at the beam-port is proposed to reduce the gamma dose at the irradiation position due to the activation of the Beam Shaping Assembly. • Calculations of activation and dosimetry help in designing the treatment room. • Radiation protection is pivotal for the design of a BNCT facility. • Borated concrete walls reduce the activation of tissues and urine. • Borated concrete walls reduce the ambient dose due the neutron activation. • A beamport shield decreases ambient dose due to materials activation. [ABSTRACT FROM AUTHOR]

In cancer therapeutics, boron neutron capture therapy (BNCT) requires a platform for selective and efficient 10B delivery into tumor tissues for a successful treatment. However, the use of carborane, a promising candidate with high boron content and biostability, has significant limitations in the biomedical field due to its poor water-solubility and tumor-selectivity. To overcome these hurdles, we present in this study a fluorescent nano complex, combining fluorescent carborane and sodium hyaluronate for high boron concentration and tumor-selectivity. Tumor cells actively internalized the complex through binding hyaluronan to CD44, overexpressed on the tumor cell surface. Furthermore, the subcellular distribution of this complex could also be detected due to its fluorescent properties. Moreover, after thermal neutron irradiations, the complex produced excellent cytotoxicity, equal to or greater than that of the clinically-used BPA-fructose. Therefore, this novel complex could be potentially more suitable for BNCT than the boron agent. [Display omitted] • Hydrophobic pyrene-substituted o- carborane (CBP-H) was dissolved in water via the complexation with sodium hyaluronate (HA). • The strong fluorescence properties from CBP-H enabled to visualize subcellular distribution of boron agents. • The complex shows excellent BNCT efficacy affecting viability in tumor cells. [ABSTRACT FROM AUTHOR]

In boron neutron capture therapy (BNCT), boron drugs should accumulate selectively within a tumor and be quickly cleared from blood and normal organs. However, it is usually challenging to achieve the efficient tumor accumulation and the quick clearance simultaneously. Here we report the complex composed of a fructose-modified poly(ethylene glycol)-poly(l -lysine) block copolymer and p -boronophenylalanine, termed PEG-P[Lys/Lys(fructose)]-BPA, as a boron delivery system permitting selective accumulation within the target tumor with quick clearance from normal organs as well as blood. Our PEG-P[Lys/Lys(fructose)]-BPA could be internalized into tumor cells through LAT1 amino acid transporter-mediated endocytosis and retain in the targeted cells, thereby accomplishing more efficient accumulation and retention in a subcutaneous tumor than clinically used fructose-BPA complexes. Importantly, the moderately cationic property of the polymer facilitated renal clearance and PEG-P[Lys/Lys(fructose)]-BPA exhibited high accumulation contrast between the target tumor and the blood/normal organ. Finally, upon thermal neutron irradiation, PEG-P[Lys/Lys(fructose)]-BPA significantly inhibited the tumor growth in mice. PEG-P[Lys/Lys(fructose)]-BPA may be a promising boron delivery system for BNCT. [Display omitted] [ABSTRACT FROM AUTHOR]