Effect Of Boron Neutron Capture Therapy Research Articles

Primary study of the relative and compound biological effectiveness model for boron neutron capture therapy based on nanodosimetry.

The current radiobiological model employed for boron neutron capture therapy (BNCT) treatment planning, which relies on microdosimetry, fails to provide an accurate representation the biological effects of BNCT. The precision in calculating the relative biological effectiveness (RBE) and compound biological effectiveness (CBE) plays a pivotal role in determining the therapeutic efficacy of BNCT. Therefore, this study focuses on how to improve the accuracy of the biological effects of BNCT. The purpose of this study is to propose new radiation biology models based on nanodosimetry to accurately assess RBE and CBE for BNCT. Nanodosimetry, rooted in ionization cluster size distributions (ICSD), introduces a novel approach to characterize radiation quality by effectively delineating RBE through the ion track structure at the nanoscale. In the context of prior research, this study presents a computational model for the nanoscale assessment of RBE and CBE. We establish a simplified model of DNA chromatin fiber using the Monte Carlo code TOPAS-nBio to evaluate the applicability of ICSD to BNCT and compute nanodosimetric parameters. Our investigation reveals that both homogeneous and heterogeneous nanodosimetric parameters, as well as the corresponding biological model coefficients α and β, along with RBE values, exhibit variations in response to varying intracellular 10B concentrations. Notably, the nanodosimetric parameter effectively captures the fluctuations in model coefficients α and RBE. Our model facilitates a nanoscale analysis of BNCT, enabling predictions of nanodosimetric quantities for secondary ions as well as RBE, CBE, and other essential biological metrics related to the distribution of boron. This contribution significantly enhances the precision of RBE calculations and holds substantial promise for future applications in treatment planning.

Boron-Containing MOF Nanoparticles with Stable Metabolism in U87-MG Cells Combining Microdosimetry To Evaluate Relative Biological Effectiveness of Boron Neutron Capture Therapy.

Accurate prediction of the relative biological effectiveness (RBE) of boron neutron capture therapy (BNCT) is challenging. The therapy is different from other radiotherapy; the dynamic distribution of boron-containing compounds in tumor cells affects the therapeutic outcome considerably and hampers accurate measurement of the neutron-absorbed dose. Herein, we used boron-containing metal-organic framework nanoparticles (BMOFs) with high boron content to target U87-MG cells and maintain the concentration of the 10B isotope in cells. The content of boron in the cells could maintain 90% (60 ppm) within 20 min compared with that at the beginning; therefore, the accurate RBE of BNCT can be acquired. The effects of BNCT upon cells after neutron irradiation were observed, and the neutron-absorbed dose was obtained by Monte Carlo simulations. The RBE of BMOFs was 6.78, which was 4.1-fold higher than that of a small-molecule boron-containing agent (boric acid). The energy spectrum of various particles was analyzed by Monte Carlo simulations, and the RBE was verified theoretically. Our results suggested that the use of nanoparticle-based boron carriers in BNCT may have many advantages and that maintaining a stable boron distribution within cells may significantly improve the efficiency of BNCT.

Development of a Gadolinium-Boron-Conjugated Albumin for MRI-Guided Neutron Capture Therapy.

Noninvasive monitoring of boron agent biodistribution is required in advance of neutron capture therapy. In this study, we developed a gadolinium-boron-conjugated albumin (Gd-MID-BSA) for MRI-guided neutron capture therapy. Gd-MID-BSA was prepared by labeling bovine serum albumin with a maleimide-functionalized gadolinium complex and a maleimide-functionalized closo-dodecaborate orthogonally. The accumulation of Gd-MID-BSA in tumors in CT26 tumor-bearing mice reached a maximum at 24 h after the injection, as confirmed by T1-based MRI and biodistribution analysis using inductively coupled plasma optical emission spectrometry. The concentrations of boron and gadolinium in the tumors exceeded the thresholds required for boron neutron capture therapy (BNCT) and gadolinium neutron capture therapy (GdNCT), respectively. The boron concentration ratios of tumor to blood and tumor to normal tissues satisfied the clinical criteria, indicating the reduction of undesired nuclear reactions of endogenous nuclei. The molar ratio of boron to gadolinium in the tumor was close to that of Gd-MID-BSA, demonstrating that the accumulation of Gd-MID-BSA in the tumor can be evaluated by MRI. Thermal neutron irradiation with Gd-MID-BSA resulted in significant suppression of tumor growth compared to the group injected with a boron-conjugated albumin without gadolinium (MID-BSA). The neutron irradiation with Gd-MID-BSA did not cause apparent side effects. These results demonstrate that the conjugation of gadolinium and boron within the albumin molecule offers a novel strategy for enhancing the therapeutic effect of BNCT and the potential of MRI-guided neutron capture therapy as a promising treatment for malignant tumors.

Targeting M-MDSCs enhances the therapeutic effect of BNCT in the 4-NQO-induced murine head and neck squamous cell carcinoma model.

Malignant head and neck squamous cell carcinoma (HNSCC) is characterized by a poor prognosis and resistance to conventional radiotherapy. Infiltrating myeloid-derived suppressive cells (MDSCs) is prominent in HNSCC and is linked to immune suppression and tumor aggressiveness. This study aimed to investigate the impact of boron neutron capture therapy (BNCT) on the MDSCs in the tumor microenvironment and peripheral blood and to explore the potential for MDSCs depletion combined with BNCT to reactivate antitumor immunity. Carcinogen, 4-NQO, -induced oral tumors were irradiated with a total physical dose of 2 Gy BNCT in Tsing Hua Open Reactor (THOR). Flow cytometry and immunohistochemistry accessed the dynamics of peripheral MDSCs and infiltrated MDSCs within the tumor microenvironment. Mice were injected with an inhibitor of CSF-1 receptor (CSF-1R), PLX3397, to determine whether modulating M-MDSCs could affect mice survival after BNCT. Peripheral CD11b+Ly6ChighLy6G- monocytic-MDSCs (M-MDSCs), but not CD11b+Ly6CloLy6Ghigh polymorphonuclear-MDSCs (PMN-MDSCs), increased as tumor progression. After BNCT treatment, there were temporarily decreased and persistent increases of M-MDSCs thereafter, either in peripheral blood or in tumors. The administration of PLX-3397 hindered BNCT-caused M-MDSCs infiltration, prolonged mice survival, and activated tumor immunity by decreasing tumor-associated macrophages (TAMs) and increasing CD8+ T cells. M-MDSCs were recruited into 4-NQO-induced tumors after BNCT, and their number was also increased in peripheral blood. Assessment of M-MDSCs levels in peripheral blood could be an index to determine the optimal intervention window. Their temporal alteration suggests an association with tumor recurrence after BNCT, making M-MDSCs a potential intervention target. Our preliminary results showed that PLX-3397 had strong M-MDSCs, TAMs, and TIL (tumor-infiltrating lymphocyte) modulating effects that could synergize tumor control when combined with BNCT.

Dendritic Structures Functionalized with Boron Clusters, in Particular Carboranes, and Their Biological Properties.

The presence of a large number of boron atoms in boron clusters make them attractive tools for the treatment of cancer using boron neutron capture therapy (BNCT). Since the quantity of boron atoms present in the target cell directly affects the effectiveness of BNCT, the idea of gathering a high number of boron atoms in a single entity has emerged many years ago. In this perspective, using hyper-branched macromolecules such as dendrimers appears as an interesting solution. In this review, we will first present the synthesis of diverse dendritic entities (dendrimers, dendrons, and Janus dendrimers) that incorporate boron clusters, in particular carboranes, anywhere in their structure. Four parts of this review present the synthesis of dendrimers having boron clusters on the surface, or inside their structure, of dendrons and of Janus dendrimers, bearing boron clusters. Practically all these boronated dendritic structures were synthesized with the objective to study their biological properties, but in fact only a few of them have been tested against cancerous cells, and even a smaller number was tested in BNCT experiments. The biological experiments are discussed in the fifth part of this review. A good efficiency is generally observed with the boronated dendrimers, even in animal models, with an increase in their mean survival time (MST).

Therapeutic Efficacy, Radiotoxicity and Abscopal Effect of BNCT at the RA-3 Nuclear Reactor Employing Oligo-Fucoidan and Glutamine as Adjuvants in an Ectopic Colon Cancer Model in Rats.

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.

5-Aminolevulinic acid increases boronophenylalanine uptake into glioma stem cells and may sensitize malignant glioma to boron neutron capture therapy

Boron neutron capture therapy (BNCT) is a high-LET particle radiotherapy clinically tested for treating malignant gliomas. Boronophenylalanine (BPA), a boron-containing phenylalanine derivative, is selectively transported into tumor cells by amino acid transporters, making it an ideal agent for BNCT. In this study, we investigated whether the amino acid 5-aminolevulinic acid (ALA) could sensitize glioma stem cells (GSCs) to BNCT by enhancing the uptake of BPA. Using human and mouse GSC lines, pre-incubation with ALA increased the intracellular accumulation of BPA dose-dependent. We also conducted in vivo experiments by intracerebrally implanting HGG13 cells in mice and administering ALA orally 24 h before BPA administration (ALA + BPA-BNCT). The ALA preloading group increased the tumor boron concentration and improved the tumor/blood boron concentration ratio, resulting in improved survival compared to the BPA-BNCT group. Furthermore, we found that the expression of amino acid transporters was upregulated following ALA treatment both in vitro and in vivo, particularly for ATB0,+. This suggests that ALA may sensitize GSCs to BNCT by upregulating the expression of amino acid transporters, thereby enhancing the uptake of BPA and improving the effectiveness of BNCT. These findings have important implications for strategies to improve the sensitivity of malignant gliomas to BPA-BNCT.

Pharmacokinetic Study of 14C-Radiolabeled p-Boronophenylalanine (BPA) in Sorbitol Solution and the Treatment Outcome of BPA-Based Boron Neutron Capture Therapy on a Tumor-Bearing Mouse Model.

Boron neutron capture therapy (BNCT) is a binary cancer treatment that combines boron administration and neutron irradiation. The tumor cells take up the boron compound and the subsequent neutron irradiation results in a nuclear fission reaction caused by the neutron capture reaction of the boron nuclei. This produces highly cytocidal heavy particles, leading to the destruction of tumor cells. p-boronophenylalanine (BPA) is widely used in BNCT but is insoluble in water and requires reducing sugar or sugar alcohol as a dissolvent to create an aqueous solution for administration. The purpose of this study was to investigate the pharmacokinetics of 14C-radiolabeled BPA using sorbitol as a dissolvent, which has not been reported before, and confirm whether neutron irradiation with a sorbitol solution of BPA can produce an antitumor effect of BNCT. In this study, we evaluated the sugar alcohol, sorbitol, as a novel dissolution aid and examined the consequent stability of the BPA for long-term storage. U-87 MG and SAS tumor cell lines were used for invitro and invivo experiments. We examined the pharmacokinetics of 14C-radiolabeled BPA in sorbitol solution, administered either intravenously or subcutaneously to a mouse tumor model. Neutron irradiation was performed in conjunction with the administration of BPA in sorbitol solution using the same tumor cell lines both invitro and invivo. We found that BPA in sorbitol solution maintains stability for longer than in fructose solution, and can therefore be stored for a longer period. Pharmacokinetic studies with 14C-radiolabeled BPA confirmed that the sorbitol solution of BPA distributed through tumors in much the same way as BPA in fructose. Neutron irradiation was found to produce dose-dependent antitumor effects, both invitro and invivo, after the administration of BPA in sorbitol solution. In this report, we demonstrate the efficacy of BPA in sorbitol solution as the boron source in BNCT.

Boron uptake of boronophenylalanine and the effect of boron neutron capture therapy in cervical cancer cells

There are few studies about boron neutron capture therapy (BNCT) for cervical cancer. The present study evaluated the biodistribution of boronophenylalanine (BPA) and the effect of BNCT on cervical cancer cell lines. BPA exposure and neutron irradiation of cervical cancer cell lines resulted in decreased survival fraction compared to irradiation only. In vivo cervical cancer tumor boron concentration was highest at 2.5 h after BPA intraperitoneal administration, and higher than in the other organs. BNCT may be effective against cervical carcinoma.

HER-2-targeted boron neutron capture therapy using an antibody-conjugated boron nitride nanotube/β-1,3-glucan complex.

The development of boron agents with integrated functionality, including biocompatibility, high boron content, and cancer cell targeting, is desired to exploit the therapeutic efficacy of boron neutron capture therapy (BNCT). Here, we report the therapeutic efficacy of BNCT using a HER-2-targeted antibody-conjugated boron nitride nanotube/β-1,3-glucan complex. The anticancer effect of BNCT using our system was 30-fold that of the clinically available boron agent l-BPA/fructose complex.

Development of Brain-Tumor-Targeted Benzothiazole-Based Boron Complex for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) is a precision treatment technology that ideally damages only boron-accumulating cells. The effectiveness of BNCT depends on the amount of boron in the tumor cells and the concentration ratio between normal and tumor tissues. Therefore, for successful brain-tumor treatment using BNCT, it is essential to develop a drug with high blood-brain barrier (BBB) permeability and high tumor accumulation. The benzothiazole-based boron complex 4-(benzo[d]thiazol-2-yl)phenylboronic acid (BTPB) is a hydrophobic, low-molecular-weight compound that has shown high BBB permeability and brain accumulation. The highest boron concentration of BTPB is 36.11 ± 2.73 μg/g (at 1 h post-injection) in the brain, and the highest brain/blood ratio is 3.94 ± 0.46 (at 2 h post-injection), which is sufficient for the BNCT drug condition. In addition, BTPB showed good tumor-targeting ability in vivo in a U87MG glioma tumor model. In this study, we conducted a biological evaluation of BTPB compared to boronophenylalanine as a novel drug for BNCT.

The Anti-Tumor Effect of Boron Neutron Capture Therapy in Glioblastoma Subcutaneous Xenograft Model Using the Proton Linear Accelerator-Based BNCT System in Korea.

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.

In vivo evaluation of the effects of combined boron and gadolinium neutron capture therapy in mouse models

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.

Effects of Boron Neutron Capture Therapy on the Growth of Subcutaneous Xenografts of Human Colorectal Adenocarcinoma SW-620 in Immunodeficient Mice.

Boron neutron capture therapy (BNCT) can become an instrument for patients with malignant neoplasms of the rectum and colon. Here we evaluate the effectiveness of BNCT performed at the accelerator based epithermal neutron source at G. I. Budker Institute of Nuclear Physics, Siberian Division of Russian Academy of Sciences, in relation to subcutaneous xenografts of human colon adenocarcinoma SW-620 in SCID mice. Utilization of BNCT with boronоphenylalanine (BPA) and sodium borocaptate (BSH), which were injected intravenously into the retroorbital sinus, resulted in a significant decrease in tumor volumes compared to the control group (no radiation).

Problems and prospects of clinical trials of boron neutron capture therapy

<p indent="0mm">Boron neutron capture therapy (BNCT) is an intracellular radiotherapy that exploits the neutron capture and fission reaction of the boron isotope, ¹⁰B. As a binary targeted tumor therapy based on intracellular radiotherapy, BNCT brings new hope to cancer patients. In 2012, the team from the Third Xiangya Hospital of Central South University, together with Prof. Yongmao Zhou’s team, started the clinical trial of BNCT in China based on the in-hospital neutron irradiator-1 (IHNI-1), and completed the first trial of BNCT in September 2014. The following is the summarization of the clinical trial: The first patient, a <sc>53 years</sc> old man with black plaque found on the left anterior palmar <sc>7 years</sc> ago, was diagnosed as malignant melanoma after pathological examination. The patient completed boron phenylalanine (BPA) drug uptake test and neutron irradiation in September 2014. After irradiation, no tumor tissue was indicated by PET-CT and pathological examination. The team continued to complete drug uptake tests and/or neutron irradiation for a total of 20 cases, including 2 cases of early malignant melanoma, who survived in the <sc>5 years</sc> of follow-up. The rest 17 patients were in advanced cancer stage, among which 8 patients had local tumor shrinkage and 9 patients were not suitable for irradiation because ¹⁰B in tumor tissue did not reach the required concentration for treatment. The trial validated the safety of IHNI-1 and boron-containing agent, and the anti-tumor effects of BNCT. However, the board application of BNCT is limited by the lack of targeted boron delivery agent. Currently available boron-containing agents cannot concentrate in tumor lesions of some patients at an early stage, resulting in the impracticable status of BNCT for these patients. Even though some difference was observed in the concentration of ¹⁰B between tumor and normal tissues in some cancer patients at an advanced stage, the difference is not large enough for in the safe application of total body irradiation by IHNI-1. On the other hand, patients at advanced stage can only enjoy little survival benefits when local radiotherapy was accomplished. We highly recommend metastatic and recurrent tumors, and advanced tumors insensitive to current chemotherapy and radiotherapy as the major indications of BNCT. The pivotal task of BNCT research is to develop targeted boron delivery agent which can achieve sufficiently high boron concentration in tumor tissue against normal tissue (<italic>T</italic>/<italic>N</italic>). Based on the clinical trial and clinical experience mentioned above, we propose that a boron drug achieving a <italic>T</italic>/<italic>N</italic> ratio higher than 10, combined with large area or whole-body neutron irradiation, might be a sign of the maturity of BNCT technology. The current available boron drugs are mainly composed of small molecules of amino acid derivatives such as BPA, which are concentrated in tumor tissues through the high metabolic mechanism of tumor tissues. The shortcomings of these drugs include off-target effects and low concentration in the tumor tissue. Deoxy glucose isotope is a tracer widely used in tumor screening; nanotechnologies such as nanosphere technology also shows good application in tumor drug concentration, and drugs assembled by antibodies and small molecule targeting ligands are becoming increasingly mature. These might be the potential directions for future boron drug development. In addition, the study and parameter design of neutron irradiation can be adjusted according to the development of boron drugs. However, neutron sources should consider irradiation area and depth to meet the requirements of large area or whole-body neutron irradiation, as the major application scenario of BNCT is to treat metastatic and recurrent tumors, and advanced tumors. Ultimately, well-designed clinical studies can be used to validate the efficiency of the newly developed boron drugs and neutron irradiation related techniques, and to give feedback for the improvement of these drugs and techniques.

TB-6 Experimental evaluation of the therapeutic potential of boron neutron capture therapy in primary central nervous system lymphoma

Background: High-dose methotrexate and whole brain radiation therapy (WBRT) is the recommended treatment for primary central nervous system lymphoma (PCNSL). Although the initial treatment is successful, the recurrence rate is high and the prognosis is poor. Boron neutron capture therapy (BNCT) is a nuclear reaction-based tumor cell-selective particle irradiation that occurs when non-radioactive boron-10 is irradiated with neutrons to produce α particles (10B [n, α] 7Li). In this study, we conducted a basic research to explore the possibility of BNCT as a treatment option for PCNSL. Methods: Cellular uptake of boron using human lymphoma cell-lines after exposure to boronophenylalanine (BPA) were evaluated. The cytotoxicity of lymphoma cells by photon irradiation or neutron irradiation with BPA were also evaluated. The lymphoma cells were implanted into the mouse brain and the bio-distribution of boron after administration of BPA were measured. In neutron irradiation studies, the therapeutic effect of BNCT on mouse CNSL models were evaluated in terms of survival time. Results: The boron concentration in lymphoma cells after BPA exposure was sufficiently high, and lymphoma cells showed cytotoxicity by photon irradiation, and also by BNCT. In in vivo bio-distribution study, lymphoma cells showed enough uptake of BPA with well contrasted to the brain. In the neutron irradiation experiment, the BNCT group showed a significant prolongation in their survival time compared to the control group. Conclusions: In our study, BNCT showed its effectiveness for PCNSL in a mouse brain tumor model. PCNSL is a radio-sensitive tumor with a extremely good response rate, but it also has a high recurrence rate / a high rate of adverse events, so there is no effective treatment for recurrence after treatment. Our translational study showed that BNCT is possibly have an important role against PCNSL during the therapy lines as a new treatment option for PCNSL patients.

Efficacy of Boron Neutron Capture Therapy in Primary Central Nervous System Lymphoma: In Vitro and In Vivo Evaluation.

Background: Boron neutron capture therapy (BNCT) is a nuclear reaction-based tumor cell-selective particle irradiation method. High-dose methotrexate and whole-brain radiation therapy (WBRT) are the recommended treatments for primary central nervous system lymphoma (PCNSL). This tumor responds well to initial treatment but relapses even after successful treatment, and the prognosis is poor as there is no safe and effective treatment for relapse. In this study, we aimed to conduct basic research to explore the possibility of using BNCT as a treatment for PCNSL. Methods: The boron concentration in human lymphoma cells was measured. Subsequently, neutron irradiation experiments on lymphoma cells were conducted. A mouse central nervous system (CNS) lymphoma model was created to evaluate the biodistribution of boron after the administration of borono-phenylalanine as a capture agent. In the neutron irradiation study of a mouse PCNSL model, the therapeutic effect of BNCT on PCNSL was evaluated in terms of survival. Results: The boron uptake capability of human lymphoma cells was sufficiently high both in vitro and in vivo. In the neutron irradiation study, the BNCT group showed a higher cell killing effect and prolonged survival compared with the control group. Conclusions: A new therapeutic approach for PCNSL is urgently required, and BNCT may be a promising treatment for PCNSL. The results of this study, including those of neutron irradiation, suggest success in the conduct of future clinical trials to explore the possibility of BNCT as a new treatment option for PCNSL.

Enhancing the effectiveness of boron neutron capture therapy (BNCT) for cancer treatment

Boron neutron capture therapy (BNCT) has the potential to kill tumours without harming normal cells and could therefore prove revolutionary in cancer treatment. BNCT is a treatment that focuses on how the chemical element boron has a high likelihood of causing nuclear reactions with neutrons. A key focus for some researchers is the idea that the nuclear reaction of boron occurs in proportion to the number of optimal energy neutrons and the concentration of boron at the tumour location and they believe that if this could be properly harnessed, the treatment would be dramatically improved. Dr Sachie Kusaka, Graduate School of Engineering, Osaka University, Japan, is part of a team of researchers working to improve the effectiveness of BNCT for brain tumour. Kusaka has identified an alternative route to deliver the boron drug BPA efficiently to the brain by avoiding the blood-brain barrier, and named the route "boron cerebrospinal fluid administration method". "Administering the drug into the cerebrospinal fluid could enable more boron to be efficiently delivered to the brain tumour,' says Kusaka.

Evaluation of local, regional and abscopal effects of Boron Neutron Capture Therapy (BNCT) combined with immunotherapy in an ectopic colon cancer model.

The aim of the present study was to evaluate the local and regional therapeutic efficacy and abscopal effect of BNCT mediated by boronophenyl-alanine, combined with Bacillus Calmette-Guerin (BCG) as an immunotherapy agent in this model. The local effect of treatment was evaluated in terms of tumor response in the irradiated tumor-bearing right hind flank. Metastatic spread to tumor-draining lymph nodes was analyzed as an indicator of regional effect. The abscopal effect of treatment was assessed as tumor growth inhibition in the contralateral (non-irradiated) left hind flank inoculated with tumor cells 2 weeks post-irradiation. The experimental groups BNCT, BNCT + BCG, BCG, Beam only (BO), BO +BCG, SHAM (tumor-bearing, no treatment, same manipulation) were studied. BNCT and BNCT + BCG induced a highly significant local anti-tumor response, whereas BCG alone induced a weak local effect. BCG and BNCT + BCG induced a significant abscopal effect in the contralateral non-irradiated leg. The BNCT + BCG group showed significantly less metastatic spread to tumor-draining lymph nodes vs SHAM and vs BO. This study suggests that BNCT + BCG-immunotherapy would induce local, regional and abscopal effects in tumor-bearing animals. BNCT would be the main effector of the local anti-tumor effect whereas BCG would be the main effector of the abscopal effect. Although the local effect of BNCT has been widely evidenced, this is the first study to show the local, regional and abscopal effects of BNCT combined with immunotherapy, contributing to comprehensive cancer treatment with combined therapies.

Tissue Architecture Influences the Biological Effectiveness of Boron Neutron Capture Therapy in In Vitro/In Silico Three-Dimensional Self-Assembly Cell Models of Pancreatic Cancers

Simple SummaryBoron neutron capture therapy (BNCT) is becoming one of the most promising radiotherapies for aggressive cancers, but the detailed cellular mechanisms of BNCT remain largely underexplored. Solid tumors are composed of heterogeneous cell populations, which create a 3-dimensional complicated microenvironment for tumor progression. To recapture the influences of the microenvironment on BNCT efficacy, we applied a self-assembly 3D cell culture system with two different types of pancreatic cancer cells. In contrast to previous findings with γ-ray exposure, we found that the 3D architecture of pancreatic tumor can facilitate the susceptibility of cancer cells to BNCT, as compared to 2D tissue structure; a computer simulation model was established to further confirm this unexpected finding. These outcomes can contribute to better understanding of the radiobiology of BNCT, and the developed models may facilitate the recent development in personalized radiotherapy.Pancreatic cancer is a leading cause of cancer death, and boron neutron capture therapy (BNCT) is one of the promising radiotherapy techniques for patients with pancreatic cancer. In this study, we evaluated the biological effectiveness of BNCT at multicellular levels using in vitro and in silico models. To recapture the phenotypic characteristic of pancreatic tumors, we developed a cell self-assembly approach with human pancreatic cancer cells Panc-1 and BxPC-3 cocultured with MRC-5 fibroblasts. On substrate with physiological stiffness, tumor cells self-assembled into 3D spheroids, and the cocultured fibroblasts further facilitated the assembly process, which recapture the influence of tumor stroma. Interestingly, after 1.2 MW neutron irradiation, lower survival rates and higher apoptosis (increasing by 4-fold for Panc-1 and 1.5-fold for BxPC-3) were observed in 3D spheroids, instead of in 2D monolayers. The unexpected low tolerance of 3D spheroids to BNCT highlights the unique characteristics of BNCT over conventional radiotherapy. The uptake of boron-containing compound boronophenylalanine (BPA) and the alteration of E-cadherin can partially contribute to the observed susceptibility. In addition to biological effects, the probability of induced α-particle exposure correlated to the multicellular organization was speculated to affect the cellular responses to BNCT. A Monte Carlo (MC) simulation was also established to further interpret the observed survival. Intracellular boron distribution in the multicellular structure and related treatment resistance were reconstructed in silico. Simulation results demonstrated that the physical architecture is one of the essential factors for biological effectiveness in BNCT, which supports our in vitro findings. In summary, we developed in vitro and in silico self-assembly 3D models to evaluate the effectiveness of BNCT on pancreatic tumors. Considering the easy-access of this 3D cell-assembly platform, this study may not only contribute to the current understanding of BNCT but is also expected to be applied to evaluate the BNCT efficacy for individualized treatment plans in the future.