Neutron Capture Therapy Research Articles

Field tuning study and RF electromagnetic design of a continuous-wave RFQ with ramped inter-vane voltage for AB-BNCT

A compact radio frequency quadrupole (RFQ) linac for accelerator-based boron neutron capture therapy is being developed at Xi'an Jiaotong University. By adopting a ramped inter-vane voltage in the beam dynamics design, the RFQ could accelerate a continuous wave proton beam to 2.6 MeV over a length of 4 m, effectively decreasing costs and saving space. To meet the beam-dynamics requirements, both the vane width and undercut were optimized during the electromagnetic design. In addition, π-mode stabilization loops were included to increase the mode separation, and fixed tuners with varying diameters were installed to obtain close frequency-tuning sensitivity. It was established that the field unflatness can be controlled within ±1.5% when all tuners remain at their nominal insertion depth. Optimized cooling-channel design was completed, and multi-physics analysis was conducted. The water tuning coefficients of the vane and wall channels were analyzed to establish the ability to fine tune the RFQ during operation.

Influence mechanism of lithium surface oxidation on neutron yield of lithium target for accelerator-based neutron source

Lithium is generally adopted as the target to generate epithermal neutrons based on 7Li(p,n)7Be nuclear reaction for the application of accelerator-based boron neutron capture therapy (AB-BNCT). The stability of neutron yields and neutron energy spectrum are key factors for the therapeutic effects of the AB-BNCT. Owing to the active chemical properties of lithium, the surface oxidation formation of lithium may influence the soundness of the target system and the stability of neutron yields. Experimental and simulation methods were performed for a better understanding of the passivation layer formation after air exposure and the influence of the passivation layer on the neutron yield and energy spectrum. On one hand, X-ray photoelectron spectroscopy was adopted to study the chemical states of lithium after air exposure. On the other hand, particle and heavy ion transport code system (PHITS) was used to evaluate the effect of surface chemical states variation on neutron yield and energy spectrum. The simulation results indicate that the formation of Li2O with a thickness of 2 μm could mainly influence the neutron yields at the neutron emission angle of 20–90° with a maximum reduction of ∼ 10.4%.

A new proton injector based on PKU-type 2.45GHz PMECR ion source for BNCT facility

A first fully domestically Accelerator-based boron neutron capture therapy demonstration device(AB-BNCT) located in Yangtze River Delta region is being build recently. The project is held by “Xi’an Jiaotong University-Huzhou Neutron Science Laboratory” joint lab established by Xi’an Jiaotong University and Huzhou Industrial Group. The AB-BNCT facility requires a proton beam of 30 mA@40 keV at RFQ entrance, with its beam duty cycle between 0.5%-100%, and its normalized root mean square emittance less than 0.2 π.mm.mrad. Ion source group of Peking University (PKU) is in charge of the proton ion source and its low energy beam transportation section (LEBT). A PKU type compact permanent magnet 2.45 GHz ECR ion source (PKU-Type PMECR) and a two solenoid LEBT is under development for this purpose. So far, the PMECR ion source conditioning is complete and all parameters are better than required for this facility. The details will be presented in the present paper.

Boron-Containing Mesoporous Silica Nanoparticles with Effective Delivery and Targeting of Liver Cancer Cells for Boron Neutron Capture Therapy.

Nanocarriers have been researched comprehensively for the development of novel boron-containing agents in boron neutron capture therapy (BNCT). We designed and synthesized a multifunctional mesoporous silica nanoparticle (MSN)-based boron-containing agent. The latter was coated with a lipid bilayer (LB) and decorated with SP94 peptide (SFSIIHTPILPL) on the surface as SP94-LB@BA-MSN. The latter incorporated boric acid (BA) into hydrophobic mesopores, coated with an LB, and modified with SP94 peptide on the LB. SP94-LB@BA-MSN enhanced nano interface tumor-targeting ability but also prevented the premature release of drugs, which is crucial for BNCT because adequate boron content in tumor sites is required. SP94-LB@BA-MSN showed excellent efficacy in the BNCT treatment of HepG-2 cells. In animal studies with tumor-bearing mice, SP94-LB@BA-MSN exhibited a satisfactory accumulation at the tumor site. The boron content reached 40.18 ± 5.41 ppm in the tumor site 4 h after injection, which was 8.12 and 15.51 times higher than those in mice treated with boronated phenylalanine and those treated with BA. For boron, the tumor-to-normal tissue ratio was 4.41 ± 1.13 and the tumor-to-blood ratio was 5.92 ± 0.45. These results indicated that nanoparticles delivered boron to the tumor site effectively while minimizing accumulation in normal tissues. In conclusion, this composite (SP94-LB@BA-MSN) shows great promise as a boron-containing delivery agent for the treatment of hepatocellular carcinoma using BNCT. These findings highlight the potential of MSNs in the field of BNCT.

Boronophenylalanine‐Containing Polydopamine Nanoparticles for Enhanced Combined Boron Neutron Capture Therapy and Photothermal Therapy for Melanoma Treatment

AbstractMelanoma, the most aggressive skin cancer type, is challenging to treat due to its high metastatic potential and low response to conventional therapies. Innovative approaches, including combination therapies, are crucial for enhancing treatment efficacy while minimizing side effects. It is developed boronophenylalanine‐containing polydopaine (B‐PDA) nanoparticles by encapsulating boronophenylalanine in polydopamine through nitrogen‐boronate coordination, targeting both boron neutron capture therapy (BNCT) and photothermal therapy (PTT). With stability and biocompatibility under physiological conditions, these nanoparticles utilize the phenylalanine residues in BPA to target the overexpressed neutral amino acid transporter 1 (LAT1) in melanoma cells, resulting in enhanced cell‐specific targeting. B‐PDA nanoparticles demonstrated significant photothermal effects under external stimulation, inducing localized heating and triggering heterogeneous tumor cell death, thereby enhancing sensitivity to BNCT. Combining BNCT and PTT, the B‐PDA nanoparticles offer a promising strategy for melanoma treatment.

Application of stoichiometric CT number calibration method for dose calculation of tissue heterogeneous volumes in boron neutron capture therapy.

Monte Carlo simulation code is commonly used for the dose calculation of boron neutron capture therapy. In the past, dose calculation was performed assuming a homogeneous mass density and elemental composition inside the tissue, regardless of the patient's age or sex. Studies have shown that the mass density varies with patient to patient, particularly for those that have undergone surgery or radiotherapy. A method to convert computed tomography numbers into mass density and elemental weights of tissues has been developed and applied in the dose calculation process using Monte Carlo codes. A recent study has shown the variation in the computed tomography number between different scanners for low- and high-density materials. The aim of this study is to investigate the effect of the elemental composition inside each calculation voxel on the dose calculation and the application of the stoichiometric CT number calibration method for boron neutron capture therapy planning. Monte Carlo simulation package Particle and Heavy Ion Transport code System was used for the dose calculation. Firstly, a homogeneous cubic phantom with the material set to ICRU soft tissue (four component), muscle, fat, and brain was modelled and the NeuCure BNCT system accelerator-based neutron source was used. The central axis depth dose distribution was simulated and compared between the four materials. Secondly, a treatment plan of the brain and the head and neck region was simulated using a dummy patient dataset. Three models were generated; (1) a model where only the fundamental materials were considered (simple model), a model where each voxel was assigned a mass density and elemental weight using (2) the Nakao20 model, and (3) the Schneider00 model. The irradiation conditions were kept the same between the different models (irradiation time and irradiation field size) and the near maximum (D1%) and mean dose to the organs at risk were calculated and compared. A maximum percentage difference of approximately 5% was observed between the different materials for the homogeneous phantom. With the dummy patient plan, a large dose difference in the bone (greater than 12%) and region near the low-density material (mucosal membrane, 7%-11%) was found between the different models. A stoichiometric CT number calibration method using the newly developed Nakao20 model was applied to BNCT dose calculation. The results indicate the importance of calibrating the CT number to elemental composition for each individual CT scanner for the purpose of BNCT dose calculation along with the consideration of heterogeneity of the material composition inside the defined region of interest.

Neutron Activation Analysis Based on AB-BNCT Treatment Room.

Boron neutron capture therapy (BNCT) is an ideal binary targeted radiotherapy for treating refractory tumors. An accelerator-based BNCT (AB-BNCT) neutron source has attracted more and more attention due to its advantages such as higher neutron yield in the keV energy region, less gamma radiation, and higher safety. In addition to 10 B, neutrons also react with other elements in the treatment room during BNCT to produce many activation products. Due to the long half-life of some activation products, there will be residual radiation after the end of treatment and the shutdown of the accelerator, which has adverse effects on radiation workers. Therefore, the ambient dose equivalent rate in the treatment room needs to be evaluated. The AB-BNCT neutron source model proposed by Li is studied in this paper. Based on the Monte Carlo method, the Geant4 platform was used to simulate the dose induced by radionuclides near the Beam Shaping Assembly (BSA) of the source. It is concluded that the concrete wall contributed the most to the radiation dose. The dose rate of 2.45 μSv h -1 after 13 min of shutdown meets the dose rate limit of 2.5 μSv h -1 , at which point it is safe for workers to enter the treatment room area.

Carborane-FAPI conjugate: A potential FAP-targeted boron agent with improved boron content

Boron neutron capture therapy (BNCT) has received extensive attention as an advanced binary radiotherapy method. However, BNCT still faces poor selectivity of boron agent and is insufficient boron content in tumor tissues. To improve the tumor-targeted ability and boron content, this research aims to design, synthesize and preliminary evaluate a new borane agent Carborane-FAPI, which coupling the o-carborane to the compound skeleton of a mature fibroblast activating protein (FAP) inhibitor (FAPI). FAP is a tumor-associated antigen. FAP expressed lowly in normal organs and highly expressed in tumors, so it is a potential target for diagnosis and treatment. Boronophenylalanine (BPA) is the most widely investigated BNCT drug in present. Compared with BPA, the boron content of a single molecule is increased and drug targeting is enhanced. The results show that Carboaren-FAPI has low toxicity to normal cells, and selective enrichment in tumor tissues. It is a promising boron drug that has the potential to be used in BNCT.

Thickness-dependent neutron detection efficiency of LiF-Si-based active neutron detector for boron neutron capture therapy

A LiF-Si-based active neutron detector was developed for the measurement of real-time BNCT neutron beam. Thermal-neutron detection efficiencies were adjustable to the neutron beam intensities at various measurement locations by simply exchanging the LiF neutron converter, while minimizing sensitivity to photons. The neutron detection efficiency ranges from 8 × 10−7 to 8 × 10−4 cm2. The thermal-neutron detection efficiencies were experimentally obtained by placing the neutron detectors inside an education reactor. Experimental results were verified using a Monte Carlo simulation technique. The simulated thermal-neutron detection efficiencies were in good agreement with the experimental results within the range of experimental uncertainties. Discrepancies in both sets of results were due to an insufficient assessment of LiF density and flatness. Surface-density neutron detection efficiencies were proposed to more accurately measure neutron fluence rates.

The current status and future perspectives of clinical boron neutron capture therapy trials

PurposeSeveral hundreds of patients have been so far treated in clinical trials with boron neutron capture therapy (BNCT).MethodsThis is a non-systematic review of clinical trials with BNCT, with special emphasis on the more recent trials.ResultsThe conducted trials have been relatively small single-arm studies and included mostly the patients with head and neck carcinomas resistant to traditional treatment modalities and glioblastomas. In general, the efficacy results have been promising and BNCT has been relatively well tolerated, even in the patients who have already been treated with conventional radiotherapy or chemoradiation. The most frequent adverse events have been similar to those associated with the conventional radiotherapy. At present, there is no evidence how the efficacy of BNCT would compare to the standard treatment modalities in earlier treatment lines.ConclusionsMost of the existing studies have been performed with reactor-based facilities, but there is now a rapidly increasing number of linear accelerator-based BNCT sites, and the clinical research is apparently activating again. This, combined with the increased knowledge on cancer biology and novel types of oncological therapies, opens possibilities to study innovative boron carriers and to combine BNCT with modern oncological therapies in the future clinical trials. To conduct larger phase III trials, multicenter approaches are encouraged to be applied, keeping in mind the importance of joint instructions and quality control measurements.

Current status and future trends in particle therapy – lessons from an interdisciplinary workshop

PurposeTo provide an introduction to the special issue containing the proceedings of the workshop on cancer therapy using hadrons (proton, carbon ions or boron neutron capture therapy) that was held in Pavia in October 2023 and organized by CNAO and IAEA.MethodsPapers contained in the issue are briefly summarized.ResultsThis issue contains a collection of papers from the workshop that provide a great opportunity to learn about the status and progress of this technology.ConclusionsParticle therapy is exponentially growing worldwide. While several clinical trials are now providing convincing evidence of the effectiveness of the treatment in tumor control and reduced toxicity, the technology remains expensive and the cost effectiveness is still under debate. The IAEA-CNAO workshop provided a clear picture of the state of the art and future prospective of this technology.

Advancing 2D reaction rate measurements in BNCT: Validation of the indirect neutron radiography method

The precise characterization of neutron beams is a cornerstone of Boron Neutron Capture Therapy (BNCT). While Instrumental Neutron Activation Analysis (INAA) is the standard technique for neutron flux measurement, it is limited in its ability to capture two-dimensional (2D) reaction rate distributions. This study aims to validate the Indirect Neutron Radiography (INR) method for 2D reaction rate quantification, addressing critical variables such as temperature sensitivity and signal fading. We designed and constructed an optimized INR platform comprising an Imaging Plate (IP), readout device, activation detectors (copper foils), and real-time temperature monitoring. Comprehensive experiments were conducted to investigate the impact of ambient temperature and fading time on IP signal reliability. A robust calibration curve was formulated, linking IP signals to dose deposition metrics, thereby enabling precise reaction rate assessments. The study found that IP signals are minimally sensitive to temperature variations (less than 0.1% change per 1 °C), but are subjected to linear fading over time, necessitating stringent temperature control and time-dependent signal corrections. A mathematical relationship between IP signals and dose deposition was established, represented by Y = 20,500 × x0.01803-21103. Application of the INR method revealed that the depth-dependent reaction rates in copper strips closely aligned with those acquired through INAA, exhibiting a relative deviation of less than 5% within a 4cm depth range inside the phantom. Our findings demonstrate that the INR method offers a robust alternative to traditional INAA for capturing 2D reaction rates, effectively addressing complexities like temperature sensitivity and signal fading. While challenges persist, particularly in the realm of measurement errors, this study lays the groundwork for further methodological refinements and broadens the scope for future research in BNCT neutron beam characterization.

Macrophages as carriers of boron carbide nanoparticles dedicated to boron neutron capture therapy

BackgroundThe use of cells as carriers for the delivery of nanoparticles is a promising approach in anticancer therapy, mainly due to their natural properties, such as biocompatibility and non-immunogenicity. Cellular carriers prevent the rapid degradation of nanoparticles, improve their distribution, reduce cytotoxicity and ensure selective delivery to the tumor microenvironment. Therefore, we propose the use of phagocytic cells as boron carbide nanoparticle carriers for boron delivery to the tumor microenvironment in boron neutron capture therapy.ResultsMacrophages originating from cell lines and bone marrow showed a greater ability to interact with boron carbide (B4C) than dendritic cells, especially the preparation containing larger nanoparticles (B4C 2). Consequently, B4C 2 caused greater toxicity and induced the secretion of pro-inflammatory cytokines by these cells. However, migration assays demonstrated that macrophages loaded with B4C 1 migrated more efficiently than with B4C 2. Therefore, smaller nanoparticles (B4C 1) with lower toxicity but similar ability to activate macrophages proved to be more attractive.ConclusionsMacrophages could be promising cellular carriers for boron carbide nanoparticle delivery, especially B4C 1 to the tumor microenvironment and thus prospective use in boron neutron capture therapy.Graphical

Boron nanoparticles (BNPs) produced by ns-laser ablation in water: synthesis and characterization

Boron nanoparticles (BNPs) are attractive nanomaterials for their employment in many applications, such as neutron detection, boron neutron capture therapy, proton boron capture therapy and nuclear fusion. Depending on the specific application, 10B or 11B isotopes can be used.Nevertheless, there are significant challenges in developing suitable BNPs using both conventional chemical synthesis routes and dry fabrication techniques. In this study we report BNPs directly synthetised in water by pulsed Laser Ablation in Liquid (PLAL). Nanoparticles of elemental boron have been generated by laser ablation of a sintered 10B target in MilliQ water by employing ns laser pulse. The ablation resulted in BNPs and boron target micro-fragments with hydrogen gas and boric acid as by-products. Simple washing steps were used to obtain clean BNPs in water. The BNPs showed a narrow size distribution between 3 and 4 nm and their stability in water was induced by a thin layer of boron oxide surrounds BNPs. The BNPs were fully characterized by the chemical and structural point of view employing several techniques. A discussion on boron chemical reactions during laser ablation in water and after the NPs were released in solution was done.

Fluorine-18 labeling PEGylated 6-boronotryptophan for PET scanning of mice for assessing the pharmacokinetics for boron neutron capture therapy of brain tumors

Two tryptophan compound classes 5- and 6-borono PEGylated boronotryptophan derivatives have been prepared for assessing their aqueous solubility as formulation of injections for boron neutron capture therapy (BNCT). The PEGylation has improved their aqueous solubility thereby increasing their test concentration in 1 mM without suffering from toxicity. In-vitro uptake assay of PEGylated 5- and 6-boronotryptophan showed that the B-10 concentration can reach 15–50 ppm in U87 cell whereas the uptake in LN229 cell varies. Shorter PEG compound 6-boronotryptophanPEG200[18F] was obtained in 1.7 % radiochemical yield and the PET-derived radioradioactivity percentage in 18 % was taken up by U87 tumor at the limb of xenograft mouse. As high as tumor to normal uptake ratio in 170 (T/N) was obtained while an inferior radioactivity uptake of 3 % and T/N of 8 was observed in LN229 xenografted mouse.

Profile of miRNAs in small extracellular vesicles released from glioblastoma cells treated by boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a tumor cell-selective particle-radiation therapy. In BNCT, administered p-boronophenylalanine (BPA) is selectively taken up by tumor cells, and the tumor is irradiated with thermal neutrons. High-LET α-particles and recoil 7Li, which have a path length of 5-9μm, are generated by the capture reaction between 10B and thermal neutrons and selectively kill tumor cells that have uptaken 10B. Although BNCT has prolonged the survival time of malignant glioma patients, recurrences are still to be resolved. miRNAs, that are encapsulated in small extracellular vesicles (sEVs) in body fluids and exist stably may serve critical role in recurrence. In this study, we comprehensively investigated microRNAs (miRNAs) in sEVs released from post-BNCT glioblastoma cells. Glioblastoma U87 MG cells were treated with 25 ppm of BPA in the culture media and irradiated with thermal neutrons. After irradiation, they were plated into dishes and cultured for 3 days in the 5% CO2 incubator. Then, sEVs released into the medium were collected by column chromatography, and miRNAs in sEVs were comprehensively investigated using microarrays. An increase in 20 individual miRNAs (ratio > 2) and a decrease in 2 individual miRNAs (ratio < 0.5) were detected in BNCT cells compared with non-irradiated cells. Among detected miRNAs, 20 miRNAs were associated with worse prognosis of glioma in Kaplan Meier Survival Analysis of overall survival in TCGA. These miRNA after BNCT may proceed tumors, modulate radiation resistance, or inhibit invasion and affect the prognosis of glioma.

Translational research of boron neutron capture therapy for spinal cord gliomas using rat model

Boron neutron capture therapy (BNCT) is a type of targeted particle radiation therapy with potential applications at the cellular level. Spinal cord gliomas (SCGs) present a substantial challenge owing to their poor prognosis and the lack of effective postoperative treatments. This study evaluated the efficacy of BNCT in a rat SCGs model employing the Basso, Beattie, and Bresnahan (BBB) scale to assess postoperative locomotor activity. We confirmed the presence of adequate in vitro boron concentrations in F98 rat glioma and 9L rat gliosarcoma cells exposed to boronophenylalanine (BPA) and in vivo tumor boron concentration 2.5 h after intravenous BPA administration. In vivo neutron irradiation significantly enhanced survival in the BNCT group when compared with that in the untreated group, with a minimal BBB scale reduction in all sham-operated groups. These findings highlight the potential of BNCT as a promising treatment option for SCGs.

Unlocking the potential: phenylboronic acid as a nuclear-targeting boron agent for neutron capture therapy.

It has been proposed that boron neutron capture therapy (BNCT) holds promise as a treatment modality for melanoma. However, the effectiveness of boron agents in delivery remains a critical issue to be addressed for BNCT. To this end, phenylboronic acid, which exhibits good water solubility and low cytotoxicity similar to BPA, has been investigated as a potential nuclear-targeting boron agent. The boron concentration of phenylboronic acid was found to be 74.47 ± 12.17ng/106 B16F10 cells and 45.77 ± 5.64ng/106 cells in the nuclei. Molecular docking experiments were conducted to investigate the binding of phenylboronic acid to importin proteins involved in nuclear transport. The potential of phenylboronic acid to serve as a desirable nucleus-delivery boron agent for neutron capture therapy in melanoma warrants further exploration.

Synthesis of 2D-Material(G,GO,rGO,h-BN)-Magnetic(Fe,Fe3O4)Nanocomposites

For the purpose of synthesizing 2D-Material–Magnetic nanocomposites, several new modifications of existing 2D-materials synthesis methods by exfoliation and chemical synthesis from liquid charge are developed. Using them, graphene (G), graphene oxide (GO), reduced graphene oxide (rGO) and hexagonal boron nitride (h-BN) matrix magnetic nanocomposites for the first time are obtained by coating or intercalation their nanoparticles with ferromagnetic iron (Fe) or ferrimagnetic iron oxide – magnetite (Fe3O4). These materials are prospective for variety of high tech applications. In particular, h-BN–Fe3O4 composite nanoparticles can serve for neutron-capturing boron isotope 10B effective delivery agents in BNCT (Boron Neutron Capture Therapy) of cancer as they allow the controlling by an external magnetic field targeting to tumor tissue.

Clinical Results and Prognostic Factors in Boron Neutron Capture Therapy for Recurrent Squamous Cell Carcinoma of the Head and Neck Under the Japan National Health Insurance System: A Retrospective Study of the Initial 47 Patients

PurposeRecurrent head and neck cancer presents a therapeutic challenge due to cumulative toxicity from initial radiation therapy, limiting re-irradiation options. Boron neutron capture therapy (BNCT) offers a promising alternative, selectively delivering a radical dose to tumors while sparing adjacent normal tissue. This study investigates the initial clinical outcomes and prognostic factors associated with BNCT for recurrent squamous cell carcinoma of the head and neck. Materials and MethodsThis retrospective analysis investigated the initial 47 patients treated with BNCT between May 2020 and February 2021 in Japan. All patients had received radiotherapy with a median dose of 70 Gy (range, 44–176) prior to BNCT. Median tumor size was 11 cm3 (range, 1–117 cm3), with 23% of tumors larger than 30 cm3, and 87% of patients had prior systemic therapy. The most common prescribed dose to the pharyngeal mucosa was 15 Gy-Eq (36%), followed by 18 Gy-Eq (34%). The minimum dose given to tumor was 27.4 Gy-Eq (range, 13.3–45.2). In 23 patients, 18F-FBPA-PET was performed within 1 week before BNCT, tumor to blood 10B ratio was 3.5 (range, 2.0–8.7). ResultsEfficacy analysis revealed a 51% complete response rate and a 74% overall response rate. Disease-free survival rates at 1 and 2 years were 34.6% and 26.6%, respectively. Overall survival rates at 1 and 2 years were 86.1% and 66.5%, respectively. Multivariate analysis revealed that, among the patient characteristics, whether the lesion was mucosal had a significant impact on achieving complete response. ConclusionsThis study provided valuable insights into the early integration of BNCT into routine clinical practice, highlighting its efficacy and safety. Technical improvements are needed to ensure precise dose administration. Ongoing prospective studies, such as the phase II REBIVAL study, will further elucidate the role of BNCT in recurrent head and neck cancer.