Investigation the potential of Boron neutron capture therapy (BNCT) to treat the lung cancer

Introduction: Boron neutron capture therapy (BNCT) is recommended to treat glioblastoma. It is well known that neutrons are more effective treatment than photons to treat hypoxic tumors due to interaction with the nucleus and production of heavy particles. Objective: To evaluate the suitability of BNCT for treating lung cancer, neutron dose distributions was calculated in lung tumor volume and in peripheral organs at risk (OARs).Materials and Methods: Dose distribution to treat lung cancer was calculated by MCNPX code. An elliptical tumor with volume of 27cm3 was centered in the left lung of ORNL phantom and was irradiated with a rectangular field of neutron. Recommended neutron spectrums of MIT and CNEA-MEC were used as a neutron source. The tumor was loaded with different concentrations of Boron 0, 10, 30 and 60 ppm to evaluate the delivered dose to OARs. Results: neutron absorbed dose rate in the tumor was 2.2×10-3, 2.6×10-3, 3.4×10-3 and 4.7×10-3 Gy/s for boron concentrations of 0, 10, 30 and 60 ppm, respectively in MIT. Moreover, the similar results in CNEA-MEC was 1.2×10-3, 1.6×10-3, 2.5×10-3 and 3.7×10-3 Gy/s. Among all, heart absorbed the maximum neutron dose rate of 1.7×10-4 and 1.6×10-4 Gy/s in MIT and CNEA, respectively. For all energy’s bins of spectrums, the neutrons flux is decreased as it penetrates the lung. Conclusion: The implemented model was successful in calculating the dose to organs using BNCT. An Increase in boron concentrations in tumor results in an increase in the absorbed doses while dose uniformity deteriorates. Results showed that the MIT source is well suited to treat deep lung tumors while maintaining the OARs’ dose within the threshold dose.

The element boron is not renowned among biologists, short of a few specialists who know that it is an essential nutrient for plants and an element in boromycin—an antibiotic compound produced by Streptomyces . Yet, on the whole, molecular biologists and, in particular, those in drug development seem to have little use for carbon's left‐hand neighbour in the periodic table. This is about to change. Currently, boron is largely produced in Turkey and the USA, and is used in a wide range of products, including glass, detergents, fire retardants, fibres to reinforce plane fuselages and body armour, and in superhard materials. Now, both researchers and the pharmaceutical industry are showing an increasing interest in boron as an alternative to carbon in drug design. > …both researchers and the pharmaceutical industry are showing an increasing interest in boron as an alternative to carbon in drug design A series of recent scientific and commercial developments indicate that boron‐based compounds are interesting drug candidates against all disease categories and might even speed up drug development. Pharmaceutical companies have already increased their boron research, particularly GlaxoSmithKline (GSK; Brentford, UK), which announced a US$2.5 billion investment in the US company Anacor (Palo Alto, CA, USA) in November 2008. Anacor was founded in 2002 to develop boron‐based antibacterial drugs, but has since expanded into antivirals and other targets with its boron‐based platform. Co‐founders Lucy Shapiro and Stephen Benkovic began collaborating in 2001 to look for novel inhibitors of several newly identified bacterial target sites that, they thought, could lead to more effective antibiotics. “They randomly inserted boron and got good activity,” said David Perry, CEO of Anacor. This serendipitous discovery led to the formation of Anacor a year later. “We were lucky,” Perry conceded. “At that stage we had no idea what the broader potential of boron …

Introduction: The Monte Carlo simulation is used to enhance reliability in the experiments related to nuclear instruments. in addition, that is used to calculate the different components of the neutron and gamma ray fluxes in boron neutron capture therapy(BNCT) and neutron capture (NCT)applications. BNCT is one of the methods in radiotherapy, that is used the neutron beam for kill the cancer cells. The neutron activation analysis(NAA) is the method for identify light elements that the neutron is captured with light elements nucleus and emits characteristic gamma rays. Materials and Methods: the MCNPX code was used for calculation. Boron and other light elements exist in the liver tissue. The BNCT special set geometry was designed. In this designed, light elements analysis is performed simultaneously with the neutron therapy. The effective parameters such as source location, source type, detector location, detector material, patient couch, energy of source, moderator, collimator type, length and thickness of collimator, distance between sample and source, opening of collimator, geometry and location of detector was designed. Results: the best neutron source for BNCT and light element analysis is expanded neutron spectrum produced by the reactor with Paraffin moderator. Neutron Source Generator with every moderator had low efficiency. Collimator made of graphite, graphene and carbon compounds had better neutron output spectrum. Sodium iodide detector is suitable for the detection of light elements gamma rays. The collimator length 20 cm and thickness 6cm. The detectors are placed in a cylindrical arrangement and They should not be exposed to direct neutron radiation. Conclusion: the MCNP study is one of the best methods for BNCT and NCT. the NAA and BNCT is possible Performing Simultaneously. The expanded neutron spectrum from reactors is suitable for NAA and BNCT.

Objective To provide the scientific basis for investigating and developing neutron source of boron neutron capture therapy(BNCT) by means of studying the characterization of~7Li(P,n)~7Be neutron yields iuduced by an accelerator. Methods When acceleration voltage were 3.0, 2.8 and 2.6 MeV.proton fluxes were accelerated to strike Li target to produce~7Li(P,n)~7Be reaction,and the produced neutron fluxes activated~(115)In metal foils at different directions. γ-rays emitted from~(115)In foil neutron threshold reaction were measured. Radioactivity of~(115)In foil were calculated and differential cross sections of~7Li(P,n)~7Be were analyzed.Results Neutron fluxes with numerous energy sources were produced at different directions after the nuclear reaction~7Li(P,n)~7Be.When the neutron fluxes had the same directions with the proton beam, the differential cross sections of ~7Li(P,n)~7Be were about 50 mb/mr,but the differential cross sections declined to 30 mb/mr when the angles between the neutron fluxes and the proton beams were 60 degree.Some neutrons with higher energy reached the behind area because of the elastic scattering of neutrons and affected the differential cross sections of the field.Conclusions The neutron distributions can be easily determined simultaneously at several directions via foil activation method.The influence of elastic scattering of neutrons and other metals should be taken into account. After the production of~7Li(P,n)~7Be was slowed down,thermal neutron and epithermal neutrons which were suitable for BNCT should be acquired.As BNCT neutron source,the flux of proton beam should be over 10 mA. Key words: Neutron; Differential cross section; Boron neutron capture therapy; Foil activation; Accelerator

Objective To design a scheme of epithermal neutron beam used for boron neutron capture therapy (BNCT).Methods Based on Tsinghua University experimental reactor and its No.1 passage,five schemes comprised of moderate materials,absorbing materials of thermal neutron and γ shielding materials were designed according to different locations of materials placed in No.1 passage.To select a proper scheme from five schemes,the neutron fluence rate,the neutron dose rate and γ dose rate at exit of beam in each scheme were calculated with Monte Carlo simulating methods and then contrasted with BNCT technique criterion.Results The scheme of epithermal neutron beam meeting technical requirements of BNCT was obtained,in which the thickness of moderate material,absorbing materials of thermal neutron and γ shielding materials are 53.5 cm,2 mm and 9 cm,respectively.Conclusions The theoretical scheme could provide some reference to realize BNCT on reactor. Key words: BNCT; Monte Carlo method; simulation and calculation; Epithermal neutron radiation field

Boron Neutron Capture Therapy (BNCT) is a radiotherapy technique based on the enrichment of tumour cells with suitable 10-boron concentration and on subsequent neutron irradiation. Low-energy neutron irradiation produces a localized deposition of radiation dose caused by boron neutron capture reactions. Boron is vehiculated into tumour cells via proper borated formulations, able to accumulate in the malignancy more than in normal tissues. The neutron capture releases two high-LET charged particles (i.e., an alpha particle and a lithium ion), losing their energy in a distance comparable to the average dimension of one cell. Thus BNCT is selective at the cell level and characterized by high biological effectiveness. As the radiation field is due to the interaction of neutrons with the components of biological tissues and with boron, the dosimetry requires a formalism to express the absorbed dose into photon-equivalent units. This work analyzes a clinical case of an adenoid cystic carcinoma treated with carbon-ion radiotherapy (CIRT), located close to optic nerve and deep-seated as a practical example of how to apply the formalism of BNCT photon isoeffective dose and how to evaluate the BNCT dose distribution against CIRT. The example allows presenting different dosimetrical and radiobiological quantities and drawing conclusions on the potential of BNCT stemming on the clinical result of the CIRT. The patient received CIRT with a dose constraint on the optic nerve, affecting the peripheral part of the Planning Target Volume (PTV). After the treatment, the tumour recurred in this low-dose region. BNCT was simulated for the primary tumour, with the goal to calculate the dose distribution in isoeffective units and a Tumour Control Probability (TCP) to be compared with the one of the original treatment. BNCT was then evaluated for the recurrence in the underdosed region which was not optimally covered by charged particles due to the proximity of the optic nerve. Finally, a combined treatment consisting in BNCT and carbon ion therapy was considered to show the consistency and the potential of the model. For the primary tumour, the photon isoeffective dose distribution due to BNCT was evaluated and the resulted TCP was higher than that obtained for the CIRT. The formalism produced values that are consistent with those of carbon-ion. For the recurrence, BNCT dosimetry produces a similar TCP than that of primary tumour. A combined treatment was finally simulated, showing a TCP comparable to the BNCT-alone with overall dosimetric advantage in the most peripheral parts of the treatment volume. Isoeffective dose formalism is a robust tool to analyze BNCT dosimetry and to compare it with the photon-equivalent dose calculated for carbon-ion treatment. This study introduces for the first time the possibility to combine the dosimetry obtained by two different treatment modalities, showing the potential of exploiting the cellular targeting of BNCT combined with the precision of charged particles in delivering an homogeneous dose distribution in deep-seated tumours.

The accelerator based epithermal neutron source for Boron Neutron Capture Therapy (BNCT) is proposed, created and used in the Budker Institute of Nuclear Physics. In 2014, with the support of the Russian Science Foundation created the BNCT laboratory for the purpose to the end of 2016 get the neutron flux, suitable for BNCT. For getting 3 mA 2.3 MeV proton beam, was created a new type accelerator - tandem accelerator with vacuum isolation. On this moment, we have a stationary proton beam with 2.3 MeV and current 1.75 mA. Generation of neutrons is carried out by dropping proton beam on to lithium target as a result of threshold reaction 7Li(p,n)7Be. Established facility is a unique scientific installation. It provides a generating of neutron flux, including a monochromatic energy neutrons, gamma radiation, alpha-particles and positrons, and may be used by other research groups for carrying out scientific researches. The article describes an accelerator neutron source, presents and discusses the result of experiments and declares future plans.

Objective To explore the effect of boron neutron capture therapy(BNCT)on human brain glioma U87 cell line and its mechanisms.Method U87 cells in exponential phase were divided into 6 groups:untreated control,60Co γ 4 Gy,60Co γ 8 Gy,nuclear reactor exposure without boronophenylalanine (BPA)3.5 Gy,BNCT 4 Gy and BNCT 8 Gy.The anti-tumor effects were analyzed through cell morphology,the Annexin V/PI assay by flow cytometer(FCM),and methyl thiazolyl tetrazolium(MTT)assay.The expression of P53 protein was studied by immunocytochemistry and the expression of BCL-2 protein and BAX protein were measured by western blot.Results Typical morphological changes were observed after BNCT irradiation.The apoptotic rates were observed 48 h after irradiation with 65.1%and 85.9%for BNCT 4 Gy and 8 Gy.BNCT showed higher apoptotic rates than those of γ-ray control irradiation (P＜0.01).The expression level of P53 protein was negative in U87,while positive expression of P53 protein was observed in BNCT 4 Gy and 8 Gy groups.BNCT promoted BAX protein expression,at the same time it also inhibited BCL-2 expression.Conclusions BNCT can inhibit the growth of U87 significantly in a dose-dependent and time-dependent patterns. Key words: Boron neutron capture therapy; Glioma; Apoptosis

Purpose: The feasibility of FWT-70-40(M) dosimeter was studied for gamma dose measurement in a neutron and gamma mixed field. Furthermore, it was adopted as another dosimeter to determine the gamma dose in an epithermal neutron beam for Boron Neutron Capture Therapy (BNCT). Material and Methods: The dosimeter used in this article was FWT-70 series of type FWT-70-40 (M). Using the Co-60 source of 29190 curies, which located in the Nuclear Science and Technology Development Center of National Tsing Hua University, performed calibration of the gamma dose sensitivity. The radiation sensitivity and the range of the linear response were obtained by irradiating the dosimeter with various dose rates and different total dose. Besides, this dosimeter was also irradiated with high neutron flux in the reactor core of the Tsing Hua Open pool Reactor (THOR) to investigate the neutron influence and activation. And then it was adopted as another dosimeter to measure the gamma dose in the BNCT facility at THOR. Results: Experimental data show that: (1) the threshold of linear response is 2 Gy, while the up limitation is 7 kGy for average gamma energy of 1.25 MeV; (2) the major product of the neutron activation is Na-24. The accumulated self-exciting dose for Na-24 is only 1.12 mGy during its average life-time for irradiation of total thermal neutron fluence of 3.6E12 nth/cm^2. Conclusions: Because of the self-exciting dose reduced from neutron activation can be neglected for gamma dose measurement in neutron and gamma mixed field, and the threshold of linear response is 2 Gy, the FWT-70-40 (M) dosimeter not only can be used for high dose rate Co-60 irradiation field and the high energy electron beam for medical purpose, but also can be used for gamma dose measurement in an epithermal neutron beam for boron neutron capture therapy.

The workshop 'Research Needs for Neutron Capture Therapy', held in Williamsburg, VA, May 9-12. 1995 addressed key issues and questions related to optimization of boron neutron capture therapy (BNCT), in general, and to the possibility of success of the present BNCT trials at the Brookhaven National Laboratory (BNL) and Massachusetts Institute of Technology (MIT), in particular. Both trials use nuclear fission reactors as neutron sources for BNCT of glioblastoma multiforme (BNL) and of deep seated melanoma (MIT). Presentations and discussions focussed on optimal boron-labeled compounds, mainly for brain tumors such as glioblastoma multiforme, and the best mode of compound delivery to the tumor. Also, optimizing neutron irradiation with dose delivery to the tumor cells and the issues of dosimetry of BNCT especially in the brain were discussed. Planning of treatment and of follow-up of patients, coordination of BNCT at various treatment sites, and the potential of delivery BNCT to various types of cancer with an appropriately tailored protocol were additional issues. The need for multicentric interdisciplinary cooperation among the different medical specialties was highlighted.

Objective To investigate the inhibition of boron neutron capture therapy(BNCT) on SHG44 glioma cell line and its mechanism. Methods Methyl thiazolyl tetrazolium(MTY) assay was used to measure the level of the proliferation of SHG44. GE staining, Hoechst33342 fluorescence staining, transmission electron microscope(TEM) were applied to observe the changes in cell morphology. The effects of BNCT on cell apoptotic rate was observed by flow cytometer (FCM). The expression of Bcl-2 and Bax protein was measured by Western blot. Results The proliferation of SHG44 was obviously inhibited by BNCT in a dose-dependent manner. The results of FCM showed that the apoptotic cell rate 48 h after irradiation with 4 and 8 Gy 63.2% and 88.3%, respectively. Western blot analysis showed BNCT promoted Bax protein expression, but inhibited Bcl-2 expression. Conclusions BNCT inhibits the proliferation of SHG44 cell, induces apeptesis and promote the expression of Bax but inhibits the expression of Bcl-2. Key words: Boron neutron capture therapy(BNCT); SHG44; Apoptosis

Introduction: Recently head and neck cancer has pay attention to many researchers. Its therapeutic methods include surgery, chemotherapy, radiotherapy and Boron neutron capture therapy (BNCT). BNCT is better than conventional radiotherapy because it targets the tumor cell. This method involves two steps of infusion of stable 10B and then neutron radiation with a suitable intensity and energy. The BNCT in combination with boronphenylalanine (BPA) and borocaptate sodium (BSH) that was make using the epithermal neutron. BSH and PBA are used as 10B carriers. Epithermal neutrons reach to thermal transiting through tissues of the body. When 10B absorbed thermal neutrons, the α and 7Li particles produced in the 10B (n, α) 7Li reaction are of high linear energy. Transfer radiation have a short range of one cell diameter. Materials and Methods: Monte Carlo simulations were performed with MCNPX2.6 and RO31 MIRD phantom. The neutron source was employed the surface disk with 10 diameters and the range of energy was considered from 1ev-10Kev. The results of neutron and gamma dose at various depths was calculated using tally F4 and F6 in MCNPX2.6 code. Results: Relative Dose was obtained at various depths based on energy changes for gamma, fast and thermal neutron. The results of this study have shown increases of optimum energy as the tumor get deeper respect to the skin. In addition, an analytical relation was proposed for energy optimization with the position of the tumor. Conclusion: The optimum neutron energy dependence was investigated for neck tumor in different depths. These results provide useful information to the physicians to choice best optimum energy neutron beam in BNCT method.

Objective To study the effect and mechanism of boron neutron capture therapy (BNCT) on cell cycle procession in human glioma stem cells (GSCs) in vitro,and to analyze the difference of sensitivity for BNCT on GSCs and glioma cells.Methods Firstly,uptake of boronophenylalarine (BPA) on human GSCs SU2 and glioma cells SHG-44 was detected.Then the cells enriched boron-10 (10B) were irradiated by In-Hospital Neutron Irradiator (IHNI-1).The radiation sensitivity was measured using clonogenic survival assay.The proliferation was examined by MTT assay.The cell cycle procession was determined using flow cytometry.The protein expression of cyclin B1,CDK1 and P21[WAF1] were detected by Western blot.Results 10B concentration of SU2 and SHG-44 cells arrived at (1.76 ±0.28) and (2.50 ±0.12) μg/107cells at 24 h in 5 mMBPA.After radiation by IHNI-1,the survival fraction and viability of cells enriched 10B were decreased significantly (P ＜ 0.05 orP ＜ 0.01),compared with those of 10B-free.The BNCT sensitivity of SU2 cells was lower than that of SHG-44 cells (P ＜ 0.05).The proportion of G2/M phase of SU2 and SHG-44 cells was increased after BNCT compared with that of 10B-free(P ＜ 0.05).The protein levels of cyclin B1 and CDK1 were decreased(P ＜ 0.01),and that of P21[WAF1] was increased(P ＜ 0.01).Conclusions The BNCT sensitivity of GSCs was lower than that of glioma cells.BNCT could inhibite cell regeneration and proliferation and make G2/M to be blocked by inhibition of cell cycle protein formation. Key words: Boron neutron capture therapy; Glioma stem cells ; Cell cycle

Objective To study the effect and underlying mechanism of boron neutron capture therapy (BNCT) on human melanoma cells.Methods The situation of boronophenylalanine (BPA) uptake of human melanoma cells A375 was detected and then the boron-10 (10B) enriched cells were irradiated by an in-hospital neutron irradiator (IHNI-1).The radiation sensitivity was measured using clonogenic survival assay,the proliferation was examined by MTT assay,apoptosis was determined using flow cytometry,and the protein expression of cytochrome C in cytosol and activation of caspase-9 was detected by Western blot.Results 10B concentration in A375 cells approached to (2.884 ± 0.148)μg/107 cells after 24 h culture with BPA,which met the requirement of BNCT.At 2.1 min after neutron radiation,the survival fraction of BNCT group was decreased to 58％ of control (t =2.964,P ＜ 0.05).At 24 h after BNCT,the cell viability was decreased to 83％ of control (t =3.286,P ＜ 0.05),the apoptosis ratio was (55.2 ± 7.9) ％ (t =9.754,P ＜ 0.05),and the protein level of cytochrome C in cytosol and the activativity of caspase-9 were also enhanced (t =7.625,8.307,P ＜ 0.05).Conclusions Human melanoma cells can be killed by BNCT due to apoptosis through a mitochondrial pathway. Key words: Boron neutron capture therapy; Boronophenylalanine; In-hospital neutron irradiator; Apoptosis

Boron neutron capture therapy (BNCT) is a targeted radiation therapy that significantly increases the therapeutic ratio relative to conventional radiotherapeutic modalities. BNCT is a binary approach: A boron-10 (10B)-labeled compound is administered that delivers high concentrations of 10B to the target tumor relative to surrounding normal tissues. This is followed by irradiation with thermal neutrons or epithermal neutrons which become thermalized at depth in tissues. The short range (5-9 microm) of the alpha and 7Li particles released from the 10B(n,alpha)7Li neutron capture reaction make the microdistribution of 10B of critical importance in therapy. The radiation field in tissues during BNCT consists of a mixture of components with differing LET characteristics. Studies have been carried out in both normal and neoplastic tissues to characterize the relative biological effectiveness of each radiation component. The distribution patterns and radiobiological characteristics of the two 10B delivery agents in current clinical use, the amino acid p-boronophenylalanine (BPA) and the sulfhydryl borane (BSH), have been evaluated in a range of normal tissues and tumor types. Considered overall, BSH-mediated BNCT elicits proportionately less damage to normal tissue than does BNCT mediated with BPA. However, BPA exhibits superior in vivo tumor targeting and has proven much more effective in the treatment of brain tumors in rats. In terms of fractionation effects, boron neutron capture irradiation modalities are comparable with other high-LET radiation modalities such as fast-neutron therapy. There was no appreciable advantage in increasing the number of daily fractions of thermal neutrons beyond two with regard to sparing of normal tissue in the rat spinal cord model. The experimental studies described in this review constitute the radiobiological basis for the new BNCT clinical trials for glioblastoma at Brookhaven National Laboratory, at the Massachusetts Institute of Technology, and at the High Flux Reactor, Petten, The Netherlands. The radiobiology of experimental and clinical BNCT is discussed in detail.