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.

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 ad- dition to reactors, so far, the technology of other types of sources for clinical trials is not yet completely proven. The In- Hospital Neutron lrradiator 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.

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.

About Radiation in ^natGd for Neutron Capture Therapy

In the present work, based on publications dedicated to ^natGd natural gadolinium isotopes, characteristics of secondary particles are analysed in details for various neutron-induced reactions. Characteristics of the secondary particles produced in these reactions that make significant contribution to absorbed dose are estimated. It is also established that the main contribution to the absorbed dose is made by secondary particles produced in interactions of neutrons and ^155Gd and ^157Gd isotopes. From comparison of gamma-radiation spectra it is defined that the amount of γ-quanta with energies 0-400 keV （i.e. effective γ-quanta） produced in the （n,γ）-reaction by ^155Gd is higher than that by ^157Gd. Compared spectra of other particles （internal conversion electrons, Auger electrons, x-ray radiation） have shown that earlier used average values of their energy must be defined more precisely. When biological objects are irradiated for approximately 30 minutes by epithermal neutrons in the ^natGd NCT （Gadolinium-based neutron-capture therapy）, one should take into account energies of secondary particles produced by ^152Gd, ^154Gd, ^156Gd, ^158Gd and ^160Gd isotopes as they have high linear energy transfer （LET）. It is demonstrated that when combined, all these secondary particles can make significant contribution to the absorbed dose at neutron-irradiation of biological objects by the ^natGd NCT technique.

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.

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 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 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.

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.

Gadolinium Neutron Capture Reaction-Induced Nucleodynamic Therapy Potentiates Antitumor Immunity

A nuclear reaction-induced dynamic therapy,denoted as nucleodynamic therapy(NDT),has been invented that triggers immunogenic cell death and successfully treats metastatic tumors due to its unexpected abscopal effect.Gadolinium neutron capture therapy(GdNCT)is binary radiotherapy based on a localized nuclear reaction that produces high-energy radiations(e.g.,Auger electrons,γ-rays,etc.)in cancer cells when^(157Gd)is irradiated with thermal neutrons.Yet,its clinical application has been postponed due to the poor ability of Auger electrons andγ-rays to kill cells.Here,we engineered a^(157Gd)-porphyrin framework that synergizes GdNCT and dynamic therapy to efficiently produce both•OH and immunogenic 1O2 in cancer cells,thereby provoking a strong antitumor immune response.This study unveils the fact and mechanism that NDT heats tumor immunity.Another unexpected finding is that the Auger electron can be the most effective energy-transfer medium for radiation-induced activation of nanomedicines because its nanoscale trajectory perfectlymatches the size of nanomaterials.Inmouse tumormodels,NDT causes nearly complete regression of both primary and distant tumor grafts.Thus,this^(157Gd)-porphyrin framework radioenhancer endows GdNCT with the exotic function of triggering dynamic therapy;its applicationmay expand in clinics as a new radiotherapy modality that utilizes GdNCT to provoke whole-body antitumor immune response for treating metastases,which are responsible for 90%of all cancer deaths.

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.

L3-Edge Jump and Shift on White-Line of Pd Interlayer for Trilaminar Neutron Production Target under H2^＋ Irradiation

Interlayer Pd for the Li/Pd/Cu neutron target for BNCT （boron neutron capture therapy） was characterized after 0.1-5 keV H2^＋ irradiation by XAFS （X-ray absorption fine structure） technique, and following conclusions were derived： （1） from the XAFS observation of white line of Pd, remarkable Pd L3 edge jump was found in 1.1-3 times higher than before irradiation in low irradiation fluence; （2） this fact indicates increase of hole density in Pd 4d-band, whereas, no change was observed for XASF spectra of Ag sample under the same irradiation conditions; （3） remarkable Pd L3 edge shift of 0.12-0.66 eV was also found with increase of H2＋ irradiation energy in low fluence, and drastically decreased after peak in high irradiation energy and fluence; （4） implanted protons deposited in Pd as negative under the balance of electron population enhanced by proton irradiation and charge transfer.

Hexagonal boron nitride nanomaterials for biomedical applications

Hexagonal boron nitride(h-BN)nanomaterials are a rising star in the field of biomedicine.This review presents an overview of the progress in h-BN nanomaterials for biological applications.It begins with a general introduction of the structural characteristics of h-BN,followed by the brief introduction of its physical and chemical properties,including thermal,band and mechanical properties,chemical reactivity,biodegradability and biocompatibility,then emphasizes on the recent progress in the biomedical applications including drug delivery,boron neutron capture therapy(BNCT),bioimaging and nanozyme,and ends with the challenges and perspectives related to the biomedical applications.The advantages of BN nanomaterials used for biomedical applications were analyzed,and their problems were also discussed,inspiring the future rational designs of the BN nanomedicines.