Study on the optimal incident proton energy of ^(7)Li(p,n)^(7)Be neutron source for boron neutron capture therapy

Boron neutron capture therapy(BNCT)is recognized as a precise binary targeted radiotherapy technique that effectively eliminates tumors through the^(10)B(n,α)^(7)Li nuclear reaction.Among various neutron sources,accelerator-based sources have emerged as particularly promising for BNCT applications.The^(7)Li(p,n)^(7)Be reaction is highly regarded as a potential neutron source for BNCT,owing to its low threshold energy for the reaction,significant neutron yield,appropriate average neutron energy,and additional benefits.This study utilized Monte Carlo simulations to model the physical interactions within a lithium target subjected to proton bombardment,including neutron moderation by an MgF_(2)moderator and subsequent BNCT dose analysis using a Snyder head phantom.The study focused on calculating the yields of epithermal neutrons for various incident proton energies,finding an optimal energy at 2.7 MeV.Furthermore,the Snyder head phantom was employed in dose simulations to validate the effectiveness of this specific incident energy when utilizing a^(7)Li(p,n)^(7)Be neutron source for BNCT purposes.

Coin-structured tunable beam shaping assembly design for accelerator-based boron neutron capture therapy for tumors at different depths and sizes

In the past decade,boron neutron capture therapy utilizing an accelerator-based neutron source(ABNS)designed primarily for producing epithermal neutrons has been implemented in the treatment of brain tumors and other cancers.The specifications for designing an epithermal beam are primarily based on the IAEA-TECODC-1223 report,issued in 2001 for reactor neutron sources.Based on this report,the latest perspectives and clinical requirements,we designed an ABNS capable of adjusting the average neutron beam energy.The design was based on a 2.8 MeV,20 mA proton beam bombarding a lithium target to produce neutrons that were subsequently moderated and tuned through a tunable beam shaping assembly(BSA)which can modify the thicknesses and materials of the coin-shaped moderators,back reflectors,filters,and collimators.The simulation results demonstrated that epithermal neutron beams for deep seated tumor treatment,which were generated by utilizing magnesium fluoride with lengths ranging between 28 and 36 cm as the moderator,possessed a treatment depth of 5.6 cm although the neutron flux peak shifts from 4.5 to 1.0 keV.When utilizing a thinner moderator,a less accelerated beam power can meet the treatment requirements.However,higher powers reduced the treatment time.In contrast,employing a thick moderator can reduce the skin dose.In scenarios that required relatively low energy neutron beams,the removal of the thermal neutron filter can raise the thermal neutron flux at the beam port.And the depth of the dose rate peak could be adjusted between 0.25 and 2.20 cm by combining magnesium fluoride and polyethylene coins of different thicknesses.Hence,this device has a better adaptability for the treatment of superficial tumors.Overall,the tunable BSA provides greater flexibility for clinical treatment than common BSA designs that can only adjust the port size.

<i>In Vitro</i>Evaluation System of Pharmacokinetics and Irradiation Effect in Boron Neutron Capture Therapy (BNCT) Using Three-Dimensional Artificial Human Tumor Tissue Model

Boron neutron capture therapy (BNCT) is based on the incorporation of boron-containing drugs to cancer cells and the nuclear reaction of 10B atoms by thermal neutron irradiation results in tumor degeneration. For the development of this therapy, currently, long time and high cost consuming experiments using many animals are required. In this study, we constructed a new in vitro evaluation system for BNCT by combination of an artificial tumor tissue model, comprised of normal human dermal-derived fibroblast (NHDF) and human pancreatic cancer cell line BxPC3, and the optical plastic material CR-39 as a solid state nuclear track detector. Administration of boronophenylalanine (10BPA) as a boron-containing drug and neutron irradiation up to 2.52 × 1012 n/cm2 to the control tissue constructed by NHDF (NHDF3D) and BxPC3 cell loaded tissue (NHDF3D/BxPC3) resulted in detection of 1.6 times higher number of α-ray/recoiled Li particle tracks in NHDF3D/BxPC3 in comparison to NHDF3D, demonstrating that putative irradiation damage to cancer cells can be evaluated by this system. On a cellular level, the hit number of α-ray/recoiled Li particle tracks per single BxPC3 cells and NHDF was evaluated as 5.46 and 1.71, respectively. The tumor and normal tissue ratio (T/N ratio) was 3.19, which was corresponded with those of BPA as 2 - 4 that reported in the previous studies. This new in vitro evaluation system may provide a useful tool for a low cost, labor-saving, and non-animal method for the development of new boron-containing drugs or improvement of BNCT conditions.

Radiation Sensitivity of <i>in Vitro</i>Evaluation System of Pharmacokinetics in Boron Neutron Capture Therapy (BNCT) Using Three-Dimensional Artificial Human Tumor Tissue Model

One of the important matters that must be determined in advance when performing BNCT treatment is the optimization of neutron irradiation time and dose. In this article, following the previous article (2.52 × 1012 n/cm2) (Case 1), double irradiation (5.04 × 1012 n/cm2) was further performed (Case 2) by verifying the radiation sensitivity performance of the artificial tumor tissue NHDF3D/BxPC3 and the possibility of evaluating the optimum neutron dose required for treatment was examined. As a result, although the radiation damage rate in the normal tissue NHDF3D and the tumor tissue BxPC3 increased in proportion to the irradiation dose due to heavy irradiation in Case 1 or more, the increase in the damage rate in the normal tissue exceeded the tumor tissue. Furthermore, the tumor/normal tissue damage ratio T/N ratio showed the maximum value in Case 1, and the dose ratio in Case 2 with a higher dose showed a tendency to decrease. From the above experimental facts, it was shown that irradiation dose optimization is possible to some extent by an evaluation method using an artificial tumor tissue.

Boron neutron capture therapy for malignant melanoma： first clinical case report in China

A phase Ⅰ/Ⅱ clinical trial for treating malignant melanoma by boron neutron capture therapy（BNCT） was designed to evaluate whether the world＇s first in-hospital neutron irradiator（IHNI） was qualified for BNCT. In this clinical trial planning to enroll 30 patients, the first case was treated on August 19, 2014. We present the protocol of this clinical trial, the treating procedure, and the clinical outcome of this first case. Only grade 2 acute radiation injury was observed during the first four weeks after BNCT and the injury healed after treatment. No late radiation injury was found during the 24-month follow-up. Based on positron emission tomography-computed tomography（PET/CT） scan, pathological analysis and gross examination, the patient showed a complete response to BNCT,indicating that BNCT is a potent therapy against malignant melanoma and IHNI has the potential to enable the delivery of BNCT in hospitals.

Boron neutron capture therapy: moving towards targeted therapy for locally recurrent head and neck squamous cell carcinoma

Locally recurrent head and neck squamous cell carcinoma(HNSCC)is often unresectable,and a repeat course of radiotherapy is associated with incremental toxicities.Boron neutron capture therapy(BNCT)is a novel targeted radiotherapy modality that can achieve a high dose gradient between cancerous and adjacent normal tissues.However,the relationships among the dose resulting from BNCT,tumor response to BNCT,and survival are not completely understood.Recently,a study published in Radiotherapy and Oncology investigated the efficacy of BNCT in the treatment of patients with locally recurrent HNSCC and the factors associated with favorable treatment response and survival.In this article,the findings,strengths and limitations of this study are discussed in depth,and the significance of the study and motivations for future research are highlighted.

Deterministic Parsing Model of the Compound Biological Effectiveness (<i>CBE</i>) Factor for Intracellular ¹⁰Boron Distribution in Boron Neutron Capture Therapy

Purpose: In defining the biological effects of the 10B(n, α)7Li neutron capture reaction, we have previously developed a deterministic parsing model to determine the Compound Biological Effectiveness (CBE) factor in Borono-Phenyl-Alanine (BPA)-mediated Boron Neutron Capture Therapy (BNCT). In present paper, we demonstrate that the CBE factor is directly and unambiguously derivable by the new formula for any case of intracellular 10Boron (10B) distribution, which is founded on this model for tissues and tumor. Method: To determine the CBE factor, we derive the following new calculation formula founded on the deterministic parsing model with three constants, CBE0, F, n and the eigen value Nth/Nmax. where, Nth and Nmax are the threshold value of boron concentration of N and saturation boron density in tissues and tumor. In order to determine these constants and the eigen values, iterative calculation technique was employed for the CEB factor and Nmax data set previously reported. Results and Conclusion: From the iterative calculation results, it is clear that the calculated CBE factor values obtained are almost identical to the original CBE factors and there is a good correlation between the original CBE factors and Nth/Nmax, when CBE0, F and n are given as 0.5, 8 and 3, respectively. These constants provide a better understanding of different types of intracellular10B distribution.

Study of neutron production and moderation for sulfur neutron capture therapy

Neutron capture therapy with Sulfur-33, similar to boron neutron capture therapy with Boron-10, is effective in treating some types of tumors including ocular melanoma. The key point in sulfur neutron capture therapy is whether the neutron beam flux and the resonance capture cross section of ^(33)S(n;α)^(30) Si reaction at 13.5 keV can achieve the requirements of radiotherapy. In this research,the authors investigated the production of 13.5 keV neutron production and moderation based on an accelerator neutron source. A lithium glass detector was used to measure the neutron flux produced via near threshold^7 Li(p,n)~7 Be reaction using the time-of-flight method. Furthermore, the moderation effects of different kinds of materials were investigated using Monte Carlo simulation.

Neutron Capture Therapy (NCT) & In-Hospital Neutron Irradiator (IHNI)——a new technology on binary targeting radiation therapy of cancer

BNCT is finally becoming "a new option against cancer".The difficulties for its development progress of that firstly is to improve the performance of boron compounds,secondly,it is the requirements of quantification and accuracy upon radiation dosimetry evaluation in clinical trials.Furthermore,that is long anticipation on hospital base neutron sources.It includes dedicated new NCT reactor,accelerator based neutron sources,and isotope source facilities.In addition to reactors,so far,the technology of other types of sources for clinical trials is not yet completely proven.The In-Hospital Neutron Irradiator specially designed for NCT,based on the MNSR successfully developed by China,can be installed inside or near the hospital and operated directly by doctors.The Irradiator has two neutron beams for respective treatment of the shallow and deep tumors.It is expected to initiate operation in the end of this year.It would provide a safe,low cost,and effective treatment tool for the NCT routine application in near future.

Targeting the organelle for radiosensitization in cancer radiotherapy

Radiotherapy is a well-established cytotoxic therapy for local solid cancers, utilizing high-energy ionizing radiation to destroy cancer cells. However, this method has several limitations, including low radiation energy deposition, severe damage to surrounding normal cells, and high tumor resistance to radiation. Among various radiotherapy methods, boron neutron capture therapy (BNCT) has emerged as a principal approach to improve the therapeutic ratio of malignancies and reduce lethality to surrounding normal tissue, but it remains deficient in terms of insufficient boron accumulation as well as short retention time, which limits the curative effect. Recently, a series of radiosensitizers that can selectively accumulate in specific organelles of cancer cells have been developed to precisely target radiotherapy, thereby reducing side effects of normal tissue damage, overcoming radioresistance, and improving radiosensitivity. In this review, we mainly focus on the field of nanomedicine-based cancer radiotherapy and discuss the organelle-targeted radiosensitizers, specifically including nucleus, mitochondria, endoplasmic reticulum and lysosomes. Furthermore, the organelle-targeted boron carriers used in BNCT are particularly presented. Through demonstrating recent developments in organelle-targeted radiosensitization, we hope to provide insight into the design of organelle-targeted radiosensitizers for clinical cancer treatment.

Nanostructured boron agents for boron neutron capture therapy:a review of recent patents

Boron neutron capture therapy(BNCT)is a potential radiation therapy modality for cancer,and tumortargeted stable boron-10(10B)delivery agents are an important component of BNCT.Currently,two low-molecular-weight boron-containing compounds,sodium mercaptoundecahydrocloso-dodecaborate(BSH)and boronophenylalanine(BPA),are mainly used in BNCT.Although both have suboptimal tumor selectivity,they have shown some therapeutic benefit in patients with high-grade glioma and several other tumors.To improve the efficacy of BNCT,great efforts have been devoted for the development of new boron delivery agents with better uptake and favorable pharmacokinetic profiles.This article reviews the application and research progress of boron nanomaterials as boron carriers in boron neutron capture therapy and hopes to stimulate people’s interest in nanomaterial-based delivery agents by summarizing various kinds of boron nanomaterial patents disclosed in the past decade.

Evaluation of neutron beam characteristics for D-BNCT01 facility

An accelerator-based Boron Neutron Capture Therapy(AB-BNCT)experimental facility called D-BNCT01 has been recently completed and is currently able to generate a high-intensity neutron beam for BNCTrelated research.In this study,we perform several experiments involving water phantoms to validate the Monte Carlo simulation results and analyze the neutron beam characteristics.According to our measurements,D-BNCT01 can generate a neutron flux about 1.2×10^(8)n/cm^(2)/s at the beam port using a 5 kW proton beam.Our results also show that the thermal neutron flux depth distribution inside the water phantom is in good agreement with simulations.We conclude that D-BNCT01 may be effectively employed for BNCT research.

硼中子俘获治疗(BNCT)中心建筑设计思考与实践--以东莞市人民医院硼中子俘获治疗中心为例

硼中子俘获治疗(Boron Neutron Capture Therapy,简称BNCT)技术为我国肿瘤治疗带来技术性革新。由于BNCT治疗装置及其工艺的特殊性,其所需建筑的设计相对于普通医疗建筑有不少的特点和难点。该文概述了BNCT技术及治疗中心的发展,总结了该类建筑在设计上的重点难点,并以东莞市人民医院硼中子俘获治疗中心为实例,分析了该项目的设计特点,总结了相关实践经验。

Boron neutron capture therapy: Current status and future perspectives

The development of new accelerators has given a new impetus to the development of new drugs and treatment technologies using boron neutron capture therapy(BNCT).We analyzed the current status and future directions of BNCT for cancer treatment,as well as the main issues related to its introduction.This review highlights the principles of BNCT and the key milestones in its development:new boron delivery drugs and different types of charged particle accelerators are described;several important aspects of BNCT implementation are discussed.BCNT could be used alone or in combination with chemotherapy and radiotherapy,and it is evaluated in light of the outlined issues.For the speedy implementation of BCNT in medical practice,it is necessary to develop more selective boron delivery agents and to generate an epithermal neutron beamwith definite characteristics.Pharmacological companies and research laboratories should have access to accelerators for large-scale screening of new,more specific boron delivery agents.

Boron delivery agents for neutron capture therapy of cancer

Boron neutron capture therapy(BNCT)is a binary radiotherapeutic modality based on the nuclear capture and fission reactions that occur when the stable isotope,boron-10,is irradiated with neutrons to produce high energy alpha particles.This review will focus on tumor-targeting boron delivery agents that are an essential component of this binary system.Two low molecular weight boron-containing drugs currently are being used clinically,boronopheny-lalanine(BPA)and sodium borocaptate(BSH).Although they are far from being ideal,their therapeutic efficacy has been demonstrated in patients with high grade gliomas,recurrent tumors of the head and neck region,and a much smaller number with cutaneous and extra-cutaneous melanomas.Because of their limitations,great effort has been expended over the past 40 years to develop new boron delivery agents that have more favorable biodistribution and uptake for clinical use.These include boron-containing porphyrins,amino acids,polyamines,nucleosides,peptides,monoclonal antibodies,liposomes,nanoparticles of various types,boron cluster compounds and co-polymers.Cur-rently,however,none of these have reached the stage where there is enough convincing data to warrant clinical biodistribution studies.Therefore,at present the best way to further improve the clinical efficacy of BNCT would be to optimize the dosing paradigms and delivery of BPA and BSH,either alone or in combination,with the hope that future research will identify new and better boron delivery agents for clinical use.

Boron neutron capture therapy for vulvar melanoma and genital extramammary Paget’s disease with curative responses

Background:Although the most commonly recommended treatment for melanoma and extramammary Paget’s disease(EMPD)of the genital region is wide surgical excision of the lesion,the procedure is highly invasive and can lead to functional and sexual problems.Alternative treatments have been used for local control when wide local exci-sion was not feasible.Here,we describe four patients with genital malignancies who were treated with boron neutron capture therapy(BNCT).Methods:The four patients included one patient with vulvar melanoma(VM)and three with genital EMPD.They underwent BNCT at the Kyoto University Research Reactor between 2005 and 2014 using para-boronophenylalanine as the boron delivery agent.They were irradiated with an epithermal neutron beam between the curative tumor dose and the tolerable skin/mucosal doses.Results:All patients showed similar tumor and normal tissue responses following BNCT and achieved complete responses within 6 months.The most severe normal tissue response was moderate skin erosion during the first 2 months,which diminished gradually thereafter.Dysuria or contact pain persisted for 2 months and resolved com-pletely by 4 months.Conclusions:Treating VM and EMPD with BNCT resulted in complete local tumor control.Based on our clinical expe-rience,we conclude that BNCT is a promising treatment for primary VM and EMPD of the genital region.

Folate receptor-mediated boron-10 containing carbon nanoparticles as potential delivery vehicles for boron neutron capture therapy of nonfunctional pituitary adenomas

Invasive nonfunctional pituitary adenomas(NFPAs) are difficult to completely resect and often develop tumor recurrence after initial surgery.Currently,no medications are clinically effective in the control of NFPA.Although radiation therapy and radiosurgery are useful to prevent tumor regrowth,they are frequently withheld because of severe complications.Boron neutron capture therapy(BNCT) is a binary radiotherapy that selectively and maximally damages tumor cells without harming the surrounding normal tissue.Folate receptor(FR)-targeted boron-10 containing carbon nanoparticles is a novel boron delivery agent that can be selectively taken up by FR-expressing cells via FR-mediated endocytosis.In this study,FR-targeted boron-10 containing carbon nanoparticles were selectively taken up by NFPAs cells expressing FR but not other types of non-FR expressing pituitary adenomas.After incubation with boron-10 containing carbon nanoparticles and following irradiation with thermal neutrons,the cell viability of NFPAs was significantly decreased,while apoptotic cells were simultaneously increased.However,cells administered the same dose of FR-targeted boron-10 containing carbon nanoparticles without neutron irradiation or received the same neutron irradiation alone did not show significant decrease in cell viability or increase in apoptotic cells.The expression of Bcl-2 was down-regulated and the expression of Bax was up-regulated in NFPAs after treatment with FR-mediated BNCT.In conclusion,FR-targeted boron-10 containing carbon nanoparticles may be an ideal delivery system of boron to NFPAs cells for BNCT.Furthermore,our study also provides a novel insight into therapeutic strategies for invasive NFPA refractory to conventional therapy,while exploring these new applications of BNCT for tumors,especially benign tumors.

Clinical trials for treating recurrent head and neck cancer with boron neutron capture therapy using the Tsing-Hua Open Pool Reactor

Head and neck(HN)cancer is an endemic disease in Taiwan,China.Locally recurrent HN cancer after full-dose irradia-tion poses a therapeutic challenge,and boron neutron capture therapy(BNCT)may be a solution that could provide durable local control with tolerable toxicity.The Tsing-Hua Open Pool Reactor(THOR)at National Tsing-Hua University in Hsin-Chu,provides a high-quality epithermal neutron source for basic and clinical BNCT research.Our first clinical trial,entitled“A phase I/II trial of boron neutron capture therapy for recurrent head and neck cancer at THOR”,was carried out between 2010 and 2013.A total of 17 patients with 23 recurrent HN tumors who had received high-dose photon irradiation were enrolled in the study.The fructose complex of l-boronophenylalanine was used as a boron carrier,and a two-fraction BNCT treatment regimen at 28-day intervals was used for each patient.Toxicity was acceptable,and although the response rate was high(12/17),re-recurrence within or near the radiation site was common.To obtain better local control,another clinical trial entitled“A phase I/II trial of boron neutron capture therapy combined with image-guided intensity-modulated radiotherapy(IG-IMRT)for locally recurrent HN cancer”was initiated in 2014.The first administration of BNCT was performed according to our previous protocol,and IG-IMRT was initiated 28 days after BNCT.As of May 2017,seven patients have been treated with this combination.The treatment-related toxicity was similar to that previously observed with two BNCT applications.Three patients had a complete response,but locoregional recurrence was the major cause of failure despite initially good responses.Future clinical trials combining BNCT with other local or systemic treatments will be carried out for recurrent HN cancer patients at THOR.

医院中子照射器治疗束中子参数测量

为了对医院中子照射器的设计指标进行验证,利用金箔活化法测量了其治疗束出口处中子注量率,并采用金刚石探测单元的扫描装置测量治疗束出口处热中子、超热中子、快中子和γ射线注量率的径向分布。结果显示,在30 kW满功率运行时,热中子束及超热中子束出口中心处,热中子注量率分别为1.75×10^(9)cm^(-2)·s^(-1)和6.57×10^(7)cm^(-2)·s^(-1),超热中子注量率分别为1.41×10^(7)cm^(-2)·s^(-1)和3.14×10^(8)cm^(-2)·s^(-1);治疗束主要分布在束流孔径内,靠近束流边缘会出现指数级下降现象。该测量结果为医院中子照射器开展后续相关测试及实验提供了参数支持。

BNCT人头体模内剂量分布计算

用修正的Synder人头体模几何模型和ICRU—46中的材料数据,用MCNP-4B程序对0.0253eV、1keV、2keV、10keV、100keV、1MeV单能中子束,0.2、0.5、1、2、5、10MeV单能光子束,以及与当前硼中子俘获治疗(BNCT)临床中使用的超热中子相似的超热中子束,计算了在人头体模中的剂量分布,计算结果与有关文献报道的结果一致,初步校验了我们正在编制的BNCT治疗计划软件。