Applied Radiation and Isotopes ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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Evaluation of thermal neutron irradiation field using a cyclotron-based neutron source for alpha autoradiography H. Tanaka a,n, Y. Sakurai a, M. Suzuki a, S. Masunaga a, T. Mitsumoto b, Y. Kinashi a, N. Kondo a, M. Narabayashi a, Y. Nakagawa a, T. Watanabe a, N. Fujimoto a, A. Maruhashi a, K. Ono a a b

Research Reactor Institute, Kyoto University, Osaka 590-0494, Japan Sumitomo Heavy Industries, Ltd., Tokyo 141-6025, Japan

H I G H L I G H T S

 We developed a thermal neutron irradiation field using cyclotron based epithermal neutron source combination with a water phantom for alpha autoradiography.  The uniform thermal neutron irradiation field with an intensity of 1.7  109 (cm 2 s 1) with a size of 40 mm in diameter was obtained.  Demonstration test of alpha autoradiography using a liver sample with the injection of BPA was performed.  Boron image discriminated with the background event of protons was clearly shown by means of the particle identification.

art ic l e i nf o

Keywords: Boron neutron capture therapy Cyclotron-based neutron source Alpha autoradiography

a b s t r a c t It is important to measure the microdistribution of 10B in a cell to predict the cell-killing effect of new boron compounds in the field of boron neutron capture therapy. Alpha autoradiography has generally been used to detect the microdistribution of 10B in a cell. Although it has been performed using a reactorbased neutron source, the realization of an accelerator-based thermal neutron irradiation field is anticipated because of its easy installation at any location and stable operation. Therefore, we propose a method using a cyclotron-based epithermal neutron source in combination with a water phantom to produce a thermal neutron irradiation field for alpha autoradiography. This system can supply a uniform thermal neutron field with an intensity of 1.7  109 (cm 2 s 1) and an area of 40 mm in diameter. In this paper, we give an overview of our proposed system and describe a demonstration test using a mouse liver sample injected with 500 mg/kg of boronophenyl-alanine. & 2014 Published by Elsevier Ltd.

1. Introduction At Kyoto University Research Reactor Institute (KURRI), more than 450 clinical studies of boron neutron capture therapy (BNCT) have been performed using a research reactor as of December 2013. Two boron compounds, boronophenyl-alanine (BPA) (Mishima et al., 1989) and sodium borocaptate (BSH), are used for clinical studies. Many researchers have been developing new boron compounds for application to BNCT. To confirm the effect of new boron compounds, experimental neutron irradiation of cells and mice after the injection of new boron compounds is generally performed. On the other hand, if the microdistribution of 10B in a cell can be determined, the mechanisms of cell killing in tumors or normal tissues can be identified. Alpha autoradiography has been used to

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Corresponding author. Tel.: +81 724512468. E-mail address: [email protected] (H. Tanaka).

determine the microdistribution of 10B in biological materials for BNCT. It is generally performed using a reactor-based neutron source. KURRI has two irradiation fields for alpha autoradiography, a heavy water neutron irradiation facility (HWNIF) (Sakurai and Kobayashi, 2002) and a graphite thermal column. The uniform irradiation areas of the HWNIF and graphite column are 100 mm and 20 mm in diameter, respectively. The thermal neutron intensity under 1 MW operation of the HWNIF and graphite column are 1  109 and 8  1010 (cm 2 s 1), respectively. The realization of an accelerator-based thermal neutron irradiation field is anticipated because of its easy installation at any location and stable operation. To clearly detect the microdistribution of 10B with a concentration on the order of several tens of parts per million, a thermal neutron fluence of 1012–1013 (cm 2) is necessary. Therefore, we propose a method using a cyclotron-based epithermal neutron source (C-BENS) in combination with a water phantom to produce a thermal neutron irradiation field for alpha autoradiography. The C-BENS produces epithermal neutrons

0969-8043/$ - see front matter & 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.apradiso.2014.01.011

Please cite this article as: Tanaka, H., et al., Evaluation of thermal neutron irradiation field using a cyclotron-based neutron source for alpha autoradiography. Appl. Radiat. Isotopes (2014), http://dx.doi.org/10.1016/j.apradiso.2014.01.011i

H. Tanaka et al. / Applied Radiation and Isotopes ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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contaminated with fast neutrons. In alpha autoradiography, background events such as protons emitted from reactions between fast neutrons and hydrogen nuclei or thermal neutrons and nitrogen nuclei are also detected on the track detector. The background events can be identified by the difference in the size of the etched pits. This paper presents an overview of this system and describes a performance test using a mouse liver sample injected with 500 mg/kg of BPA.

2. Materials and methods 2.1. Thermal neutron field using C-BENS

CR-39

The information of C-BENS such as a moderator, fast neutron and gamma contamination is briefly described in Tanaka et al. (2009, 2011). It consists of a cyclotron accelerator, beam transport tube, neutron production target, moderator, and collimator. The cyclotron accelerator produces protons with an energy and beam current of 30 MeV and 1 mA, respectively. The protons are injected to a neutron production target made up of beryllium via a beam transport tube with a scanning magnet that can control the proton beam size. The energy of high-energy neutrons emitted from the reaction between beryllium and protons is reduced from 30 MeV to the epithermal region of around 20 keV by the moderator, which consists of lead, iron, aluminum, and calcium fluoride. To supply the thermal neutrons for alpha autoradiography, a water phantom in the shape of a cube 20 cm on a side was used. In order to estimate the thermal neutron flux at the sample setting position, the thermal neutron distribution was measured using gold activation methods. A gold wire was set at the center of a water phantom at a depth of 20 mm in the lateral direction. After irradiation of the water phantom, the activation of the gold wire was measured by a germanium semiconductor detector. The thermal neutron distribution was estimated from the activation ratio of a gold wire covered by a cadmium tube. To estimate the neutron spectrum at the sample position and compare it with the measured results, the Monte Carlo simulation code MCNPX (Gregg et al., 2005) was used.

CR-39

CR-39

2.2. Alpha autoradiography Fig. 1 shows a schematic of the layout used for alpha autoradiography. First, BPA (500 mg/kg) was injected into the tail vein of a mouse [Fig. 1(a)]. 1 h after BPA injection, the liver was isolated and rapidly frozen using liquid nitrogen [Fig. 1(b)]. A frozen section with a thickness of 5 μm was placed on a CR-39 track detector. A liver section sample covered with an airtight plastic bag was placed in a water phantom at a depth of 20 mm and irradiated with thermal neutrons for 1 h [Fig. 1(c)]. After irradiation, the CR-39 detector was etched by a 6 N NaOH solution for 1 h at 60 1C [Fig. 1(d)]. The etched pits were observed by a microscope.

3. Results and discussion 3.1. Thermal neutron distribution in water phantom Fig. 2 shows the distribution of reaction rate of gold wire in the beam direction in the center of the water phantom obtained using a collimator 150 mm in diameter. The closed and opened circles show the measured results for gold wire and gold wire covered with the cadmium tube, respectively. The solid and broken lines show the simulated results using MCNPX for gold wire and gold wire covered with the cadmium tube, respectively. The simulation

Fig. 1. Schematic of layout for the alpha autoradiography method.

results agreed well with the measured results. The intensity of the thermal neutron flux at a depth of 20 mm was estimated to be 1.7  109 (n cm 2 s 1). Fig. 3 shows the thermal neutron distribution for the upper, lower, left, and right quadrants in the lateral direction. A uniform distribution within 20 mm from the center was confirmed. Samples with an area of 40 mm in diameter can be uniformly irradiated using our thermal neutron field with an intensity of 1.7  109 (cm 2 s 1). Fig. 4 shows the neutron spectra at a depth of 20 mm in a water phantom derived from a simulation using MCNPX. Fast neutrons with energies greater than 1 MeV remained. The dose rate of fast neutron was estimated to be 0.037 Gy/min. To apply the source in alpha autoradiography, the etched pits created by recoil protons should be identified. 3.2. Alpha autoradiography Fig. 5 shows a microscopy image of a liver section after BPA injection with a magnification of 40 times. Etched pits clearly appear under these conditions (e.g., irradiation time and etching

Please cite this article as: Tanaka, H., et al., Evaluation of thermal neutron irradiation field using a cyclotron-based neutron source for alpha autoradiography. Appl. Radiat. Isotopes (2014), http://dx.doi.org/10.1016/j.apradiso.2014.01.011i

H. Tanaka et al. / Applied Radiation and Isotopes ∎ (∎∎∎∎) ∎∎∎–∎∎∎

Au reaction ratio(atm-1 C-1)

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Au Exp. Au Cal. Cd-covered-Au Exp. Cd-covered-Au Cal.

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Fig. 2. Distribution of reaction rate of gold wire in the beam direction in water phantom obtained using a collimator 150 mm in diameter. Fig. 5. Pit distribution on liver sample after injection of 500 mg/kg BPA. 9

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Fig. 3. Thermal neutron distribution in the lateral direction at a depth of 20 mm in water phantom obtained using a collimator 150 mm in diameter.

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Fig. 6. Particle identification using difference in sizes of pits.

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Fig. 4. Simulated neutron spectrum at a depth of 20 mm in water phantom.

time). However, this image includes not only alpha particles or lithium nuclei, which are generated by the reaction 10B(n,α)7Li, but also protons generated by the 14N(n,p)14C reaction or elastic scattering of fast neutrons. The range of 14C nucleus with the energy of 42 keV in CR-39 is only 182 nm. Furthermore, most of

the 14C nuclei are stopped in the tissue sample. Thus, pits created by 14C nuclei are not able to detect. To obtain images containing only boron, the etched pits caused by protons should be removed. We demonstrate particle identification using the size of the etched pits. The etched pits caused by the injection of charged particles with a low linear energy transfer (LET) are smaller than those caused by heavy charged particles with a high LET. Fig. 6 shows the frequency distribution of the area of etched pits on the CR-39 detector. The software of image processing developed by the Nippon Steel & Sumikin Technology Co., Ltd. in Japan was applied to our study. The area of etched pits on CR-39 is dependent on the LET. In Fig. 6, the valley between events of protons and heavy charged particles was shown at the area of 30 (arbitrary unit). A few events of proton are remained over the area of 30. However, the number of proton events was negligible compared with heavy charged particle events. The proton events were distinguished by choosing pits with areas smaller than 30. Fig. 7 shows an expanded image of the area enclosed by a rectangle in Fig. 5. The upper panel shows the etched pits before particle identification. The lower panel shows an image containing only boron after particle identification. It was found that all the particles were identified. This result shows that a boron image can be obtained using a thermal neutron field contaminated with

Please cite this article as: Tanaka, H., et al., Evaluation of thermal neutron irradiation field using a cyclotron-based neutron source for alpha autoradiography. Appl. Radiat. Isotopes (2014), http://dx.doi.org/10.1016/j.apradiso.2014.01.011i

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4. Conclusions A thermal neutron irradiation field using a cyclotron-based epithermal neutron source in combination with a water phantom was applied to alpha autoradiography. The thermal neutron distribution was evaluated by the gold activation method. A uniform thermal neutron irradiation field with an intensity of 1.7  109 (n cm 2 s 1) and a size of 40 mm in diameter was obtained. Alpha autoradiography using a mouse liver sample after BPA injection was demonstrated. A boron image free of background proton events was clearly obtained by means of particle identification. The results show that the thermal neutron irradiation field obtained using a C-BENS and water phantom can be applied to alpha autoradiography.

References

Fig. 7. Particle discrimination using difference in size of pits (a) before identification and (b) after identification.

Mishima, Y., et al., 1989. Treatment of malignant-melanoma by single thermalneutron capture therapy with melanoma-seeking B-10-compound. Lancet 12, 388–389. Sakurai, Y., Kobayashi, T., 2002. The medical-irradiation characteristics for neutron capture therapy at the Heavy Water Neutron Irradiation Facility of Kyoto University Research Reactor. Med. Phys. 29 (10), 2328–2337. Tanaka, H., et al., 2009. Characteristics comparison between a cyclotron-based neutron source and KUR-HWNIF for boron neutron capture therapy. Nucl. Instrum. Methods Phys. Res., Sect. B 267, 1970–1977. Tanaka, H., et al., 2011. Experimental verification of beam characteristics for cyclotron-based epithermal neutron source (C-BENS). Appl. Radiat. Isot. 69 (12), 1642–1645. Gregg, et al., 2005. MCNPX 2.5.0—new features demonstrated. In: Proceedings of the MC2005 Conference, Chattanooga, TN, April 17–21, 2005.

high-energy neutrons by means of particle identification using the size of the etched pits.

Please cite this article as: Tanaka, H., et al., Evaluation of thermal neutron irradiation field using a cyclotron-based neutron source for alpha autoradiography. Appl. Radiat. Isotopes (2014), http://dx.doi.org/10.1016/j.apradiso.2014.01.011i

Evaluation of thermal neutron irradiation field using a cyclotron-based neutron source for alpha autoradiography.

It is important to measure the microdistribution of (10)B in a cell to predict the cell-killing effect of new boron compounds in the field of boron ne...
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