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.

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.

<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.

Enhanced boron neutron capture therapy(BNCT)through controlled drug release via boron-loaded nanofiber mats

Boron neutron capture therapy(BNCT)is a novel binary therapy combining boron targeted drugs and neutron irradiation,which can selectively and effectively kill cancer cells at the cellular scale.Controlled release of boron drug and its accumulation in tumor sites are the crux of BNCT.Here,we developed a^(10)B-boric acid(^(10)BA)-loaded nanofiber applying for BNCT by in situ administration.The nanofibers were obtained by electrospinning technique using polyethylene glycol/polylactide(PEO/PLA)block copolymers.By changing the ratio of hydrophilicity to hydrophobicity of the nanofibers,the controlled release and the effective accumulation of boron 10 isotope(^(10)B)were achieved in situ.The^(10)B content in tumor could reach to 2540μg/g,significantly exceeding the required level of 20–50μg/g for BNCT operation.Utilizing pertinent DNA damage experiments,direct evidence and quantified data of BNCT-induced DNA damage in tumor cells were obtained for the first time.Transcriptome sequencing was employed to predict the molecular mechanisms and potential signaling pathways of BNCT,providing theoretical basis for future combined therapies.The antitumor efficiency of BNCT was demonstrated by establishing mice model of subcutaneous tumor and tumor recurrence.The research presents a novel boron-loaded nanofiber mats for BNCT,which enables controlled drug release and holds significant potential in the treatment of unresectable or postoperative residual tumors.

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.

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 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 ceils 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.

Shielding effectiveness of boron-containing ores in Liaoning province of China against gamma rays and thermal neutrons

In this study, the mass attenuation coefficient of boron-containing ores in the Liaoning province of China was calculated using Win XCOM software to investigate the shielding effectiveness of these ores against gamma rays. The mass attenuation coefficients were also calculated using MCNP-4 B code and compared with Win XCOM results; consequently, a good consistency between the results of Win XCOM and MCNP-4 B was observed. Furthermore, the G-P fitting method was used to evaluate the values of exposure buildup factor(EBF) in the energy range of 0.015–15 Me V up to 40 mean free paths. Among the selected ores, boron-bearing iron concentrate ore(M3)was determined to be the best gamma ray shielding ore owing to its higher values of mass attenuation coefficient and equivalent atomic number and lower value of EBF.Moreover, American Evaluated Nuclear Data File(ENDF/B-VII) was used to analyze the shielding effectivenessagainst thermal neutrons. It was determined that Szaibelyite(M2) is the best thermal neutron shielding material.This study would be useful for demonstrating the potential of boron-containing ores for applications in the field of nuclear engineering and technology.

Evaluation of sodium borocaptate(BSH)and boronophenylalanine(BPA)as boron delivery agents for neutron capture therapy(NCT)of cancer:an update and a guide for the future clinical evaluation of new boron delivery agents for NCT

Boron neutron capture therapy(BNCT)is a cancer treatment modality based on the nuclear capture and fission reactions that occur when boron-10,a stable isotope,is irradiated with neutrons of the appropriate energy to produce boron-11 in an unstable form,which undergoes instantaneous nuclear fission to produce high-energy,tumoricidal alpha particles.The primary purpose of this review is to provide an update on the first drug used clinically,sodium borocaptate(BSH),by the Japanese neurosurgeon Hiroshi Hatanaka to treat patients with brain tumors and the second drug,boronophenylalanine(BPA),which first was used clinically by the Japanese dermatologist Yutaka Mishima to treat patients with cutaneous melanomas.Subsequently,BPA has become the primary drug used as a boron delivery agent to treat patients with several types of cancers,specifically brain tumors and recurrent tumors of the head and neck region.The focus of this review will be on the initial studies that were carried out to define the pharmacokinetics and pharmacodynamics of BSH and BPA and their biodistribution in tumor and normal tissues following administration to patients with high-grade gliomas and their subsequent clinical use to treat patients with highgrade gliomas.First,wewill summarize the studies thatwere carried out in Japan with BSH and subsequently at our own institution,The Ohio State University,and those of several other groups.Second,we will describe studies carried out in Japan with BPA and then in the United States that have led to its use as the primary drug that is being used clinically for BNCT.Third,although there have been intense efforts to develop new and better boron delivery agents for BNCT,none of these have yet been evaluated clinically.The present reportwill provide a guide to the future clinical evaluation of new boron delivery agents prior to their clinical use for BNCT.

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。

环保型钆硼柔性热中子吸收材料特性研究

本文以聚苯乙烯-乙烯-丁二烯-苯乙烯(SEBS)为基体、以Gd_(2)O_(3)、B_(4)C为功能填料,研制了一种柔性热中子吸收材料。SEM测试结果表明,不同含量的材料中Gd_(2)O_(3)和B_(4)C微米颗粒分布相对均匀;XRD和FT-IR测试结果表明,Gd_(2)O_(3)、B_(4)C与基体SEBS未发生化学反应,属于物理性混合。通过实验和蒙特卡罗模拟进行热中子屏蔽性能验证,对照组材料的实验透射率为31.97%~35.35%,实验组材料的实验和模拟透射率分别为32.11%~36.54%和26.26%~31.31%。对实验组进行了热中子面透射率均匀性测试,结果表明,(10%Gd_(2)O_(3)+40%B_(4)C)/SEBS和(30%Gd_(2)O_(3)+40%B_(4)C)/SEBS材料的平均透射率分别为34.34%和31.60%,所有采样点的绝对偏差在±0.5%以内,标准差为0.33%和0.26%,离散系数为0.0096和0.0082。该柔性材料有效弥补了传统刚性射线屏蔽材料的不足,在核设施异形复杂结构表面包覆防护和可穿戴辐射防护服领域具有潜在应用价值。

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.

基于钚铍中子源的硼表辐射屏蔽分析

压水堆核电站一回路水中硼浓度的连续监测装置称为硼表,在硼表正常工作过程中,需要使用活度满足硼浓度在线监测要求的中子源。为了确保操作人员在调试、使用硼表过程中,人员受照剂量不超限值,并掌握硼表周围的中子、伽马剂量分布情况,使用MCNP软件对基于钚铍中子源的硼表进行了辐射屏蔽计算,测量了硼表探测装置外部六个方位的辐射剂量分布,并将计算结果与测量结果进行了对比。研究结果表明,探测装置外部的中子、伽马剂量率计算值与测量值符合较好,硼表探测装置周围剂量率分布测量结果表明剂量率随距离下降趋势明显,只要控制操作时间及操作距离,可确保人员辐射安全。

磁控溅射制备碳化硼薄膜的结构与成分分析

近年来国际上^(3)He资源的短缺造成了基于^(3)He的中子探测器高昂的成本,而以碳化硼薄膜作为中子转换层的硼基中子探测器逐渐成为了最有前景的替代方案。通过直流磁控溅射制备了Ti/B_(4)C多层膜,并使用透射电子显微镜(TEM)、飞行时间二次离子质谱(ToF-SIMS)、X射线光电子能谱(XPS)等手段对薄膜的结构与成分进行表征。结果表明:Ti层存在结晶情况;H、O、N元素为薄膜内部的主要杂质,且多分布于Ti层与B_(4)C-on-Ti过渡层中;更高的本底真空度能够降低碳化硼薄膜内的杂质含量,提高B含量占比;中子探测效率测试结果证明本底真空度的提高能够有效提高碳化硼中子转换层的效率。