CO7-1

Evaluation of Boron-containig Rare Earth Oxides Nanoparticles as an Agentfor Boron Neutron Capture Therapy	 T. Nagasaki, R. Kawasaki, S, Iizuka, H. Yukawa, Y. Tsujimoto, M. Kirihata1, K. Tomita2, K. Katagiri3, K. Ono4, S.
Masunaga4, and Y. Sakurai4
Graduate School of Engineering, Osaka City University,
1
BNCT Research Center, Osaka Prefecture University,
2
School of Science, Tokai University
3
Institute of Engineering, Hiroshima University
4
Research Reactor Institute, Kyoto University

Fig. 1 TEM images of boron-containing rare earth oxide
nanoparticles; (A) SmBO3; (B) GdBO3; (C) YBO3.

INTRODUCTION: Boron Neutron Capture Therapy(BNCT) is a highly selective cancer therapy that can target single tumor cell without causing excessive radiation
damage around normal cells. The success of BNCT depends on the delivery that 10B compounds accumulate
effectively inside the tumor cells. Clinically, boronophenylalanine (BPA) and borocaptate sodium (BSH) arecurrently used for BNCT as boron delivery agents but
these agents have some disadvantages on accumulation or
selectivity toward tumor tissue. In addition, the efficacy
of boron neutron capture reaction is suppressed due tolow neutron fluence. In this study, in order to improve theefficiency of neutron capture reaction, we used boron
containing rare earth oxides nanoparticle (SmBO3,
GdBO3, YBO3). When their diameter is suitable sizes,
these nanoparticles could be significantly accumulated intumor tissue with EPR effect. Moreover, the particle
doped with europium can possess the fluorescence. This
fluorescent nanoparticles are expected as novel borondelivery drugs that can diagnose and treat cancer simultaneously and efficiently.

Fig. 2 Comparison of the antitumor efficacy withrare earth oxides/chondroitin sulfate complex.

cokinetics by using BALB/c mice bearing colon26 murine carcinoma. The highest boron concentration of
YBO3 nanoparticle in tumor tissue was observed at 6hours after administration by i.p. Then, BNCT was performed on tumor-bearing mice. Two hundred µl of
nanoparticle solution (concentration of 10B: 132 ppm
with SmBO3 and GdBO3, 88 ppm with YBO3) were injected by i.p. before 6 hr of neutron irradiation at Kyoto
University Research Reactor (1 MW, 90 min, 4.1×1012
neutron/cm2). By irradiation, YBO3 nanoparticle showedstrongest antitumor effect among used rare earth oxides
nanoparticles (Fig 2).
As the nanoparticle of the rare earth oxide could contain huge boron atoms per particle, it can deliver efficiently a lot of boron toward tumor tissue with EPR effect. Especially, As yttrium had no shield effect toward
neutron, YBO3 showed highest BNCT effect. Therefore,
this YBO3 nanoparticle is promising toward next generation BNCT.

EXPERIMENTS: The cell colorectal cancer line colon26 were used in this study. Boron containing rareearth oxides nanoparticles were synthesized by homogeneous precipitation method. Cationic nanoparticle arecoated with anionic chondroitin sulfate (XBO3/ch, X: Sm,
Gd, Y). Boron concentration was estimated by ICP-AES.
Cytotoxicity of nanoparticle was estimated by WST assay.
RESULTS AND DISCUSSION: The TEM images
showed that the particle haves spherical shape with relatively homogenous distribution and its diameter is about
100 nm (Fig. 1). The result indicates that its size is suita	 blefor EPR effect. Moreover, we evaluated its pharma-

REFERENCE:[1] K. Fujita et al., J. Ceram. Soc. Jpn., 98, 991(1990).

採択課題番号 26005	
 含ホウ素希土類酸化物のＢＮＣＴ薬剤としての評価	 （阪市大院・工）長﨑	
 
	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  健、河崎	  陸、飯塚俊輔、湯川寛子、辻本裕貴、櫻本昌士

	
 

通常採択	
 

（阪府大・21研究機構）切畑光統（東海大・理）冨田恒之（広大・工）片桐清文（大阪府大BNCTｾﾝﾀｰ）服部能英（京大・原子炉）小野公二、増永慎一郎、櫻井良憲、田中浩基
	
 

132

CO7-2

In vivo Evaluation of Gd-DTPA-incorporated Calcium Phosphate Nanoparticles
as Neutron Capture Therapy Agent

N. Dewi1, P. Mi2,3, H. Yanagie1,4,5, Y. Sakurai4, H.
Cabral2 , N. Nishiyama3, K. Kataoka2,6, Y. Sakurai7, H.
Tanaka7, M. Suzuki7, S. Masunaga7, K. Ono7, H.
Takahashi1,4

mice group with higher concentration of gadolinium.
Nevertheless, further investigation is necessary toconfirm the reason of moderate tumor growth
suppression in multiple-injected mice group.

1

Dept of Nuclear Engineering & Management, Univ ofTokyo, 2Bioengineering Dept, Univ of Tokyo, 3Polymer
chemistry division, Chemical Resource Laboratory,
Tokyo Institute of Technology, 4Cooperative Unit ofMedicine & Engineering, Univ of Tokyo Hospital, 5DeptofInnovative
Cancer
Therapeutics,
Meiji
Pharmaceutical University, 6Materials Engineering
Dept, The University of Tokyo, 7Research Reactor
Institute, Kyoto University
INTRODUCTION: Gadolinium-157 has been getting
attention as alternative for neutron capture therapy(NCT) agent because of its high thermal neutron crosssection (255 000 barns), which the highest among all
stable elements. However, compared to short range
secondary particles produced after neutron captureby 10B isotope currently used for clinical trial of NCT,
gadolinium neutron capture reaction (Gd-NCR) results
in release of gamma rays, which reduce the localization
effect of the treatment, which on the other side isincreasing the possible additional effect if Gd-157 isaccumulated to a bulk tumor cluster.
In this work, we performed in vivo evaluation oftumor growth suppression on multiple-injections GdDTPA/CaP nanoparticles mice as continued work fromprevious evaluation on single-injected group [1].

Figure 1. Experimental procedure for multipleinjected tumor-bearing mice.

EXPERIMENTS: In vivo evaluation was performedon colon-26 tumor-bearing mice irradiated for 60
minutes at nuclear reactor facility of Kyoto University
Research Reactor Institute with average neutron fluenceof 1.8 × 1012 n/cm2. Experimental procedure formultiple-injected groups is illustrated in Fig. 1.
Antitumor effect was evaluated on the basis of thechange in tumor growth and survival rate of the mice.
RESULTS: Higher gadolinium accumulation in tumor
site was successfully achieved for multiple injections of
Gd-DTPA/CaP nanoparticles, up to more than threetimes compared to single injection (data not shown).
There was no acute toxicity in the treated mice,indicating the promising possibility of Gd-DTPA/CaP as
Gd-NCT agent. However, we could not observe better
tumor growth suppression after GdNCT treatment,
which indicates the possibility of neutron depression on

Figure 2. Tumor growth suppression comparison
between single-injected and multiple-injected GdDTPA/CaP.
REFERENCES:[1] Dewi N et al., KURRI Progress Report (2013) CO7-21.
[2] Dewi N et al., Biomed & Pharmacother (2013) 67:451-7.
[3] Mi P, et al.: J Cont. Release (2014) 174:63-7.

採択課題番号 26014 中性子捕捉療法法の一般外科領域癌への展開に向けた基礎的研究

通常採択（東大・原子力国際専攻）高橋浩之、柳衛宏宣、Novriana Dewi（東大・獣医）柳川将志、飯塚智也（東大・心臓外科）櫻井由里子、毛利きくえ （京大・原子炉）小野公二、増永慎一郎、鈴木 実、櫻井良憲

133CO7-3Development of a Phantom for Estimation of Beam Quality in BNCT
tron dose is increased to almost 50% greater than a purewater phantom for which the fast neutron dose contribution is at most 10%.

Y. Sakurai, T. Takata, N. Fujimoto, H. Tanaka, N. Kondo,
Y. Nakagawa, M. Suzuki
Research Reactor Institute, Kyoto University
INTRODUCTION: After the restart of the operation of
Kyoto University Reactor (KUR) in May 2010, 235 clinical studies of boron neutron capture therapy (BNCT)
have already been carried out as of May 2015 [1]. Also,
the BNCT clinical trial using Cyclotron-based BNCT
Epi-thermal Neutron Source (C-BENS) started in November 2012 [2]. In the while, the research and development into several types of accelerator-based irradiation
systems are underway by several research groups in theworld at present time. With this situation in mind, it isimportant that the physical and biological estimations fordose quantity and quality are performed consistently
among several irradiation fields, and that the equivalencyof BNCT is guaranteed, even across BNCT systems. The
individuality of irradiation fields can stand out for the
beam-quality characteristic of the incident fast neutrons,
such as the mixing ratio and neutron energy spectrum.
The aim of this research is the development of the phantom made of specialized materials for the estimation of
the beam quality. In 2014, a feasibility study on the estimation of relative biological effectiveness (RBE) for fastneutrons, based on the simulation and experimental dataobtained for the proto-type “beam-quality estimation
phantom”.

Fig. 1. Depth distributions of total dose rate and its
breakdown in the pure water phantom.

METHODS: As a beam-quality estimation phantom, aphantom of 10% LiOH solution with 95%-enriched Li-6
was prepared [3]. The simulated thermal and fast neutron
fluxes were converted into absorbed dose rates in normal
tissue [4]. The composition for normal tissue was assumed to be H:11.1, C:12.7, N:2.0, O:74.2 in weight percent [5], and the density was assumed to be 1.0 g/cm3.
The operation power of KUR was 1 MW.

Fig. 2. Depth distributions of total dose rate and its
breakdown in the 10%-6LiOH phantom.

RESULTS: Figures 1 and 2 show the depth distributionsof the total dose rate and its breakdown in the pure water
phantom and the 10%-6LiOH phantom, respectively. In
the pure water phantom as shown in Fig. 1, the contribution of gamma rays is dominant and it becomes larger at
depth, over the interior of the phantom. In the
10%-6LiOH phantom as shown in Fig. 2, the thermal
neutron dose rate decreases to below almost one-thirtiethof the fast neutron dose rate. In addition, the gamma-ray
dose rate decreases to the same order as the fast neutron
dose rate.

REFERENCES:[1] Y. Sakurai et al., Nucl. Instr. Meth. A 453 (2000)
569-596.
[2] H. Tanaka et al., Nucl. Instr. Meth. B 267 (2009)
1970-1977.
[3] Y. Sakurai et al., Proc. 14th Int. Congr. Neutron Capture Therapy (Comision Nacional de Energia Atomica) (2010) 254-256.
[4] R.S. Caswell et al., Radiat. Res. 83 (1980) 217-254.
[5] W.S. Synder et al., Report of the Task Group on Reference Man (Pergamon Press, Oxford, 1975).

CONCLUSION: The condition for a larger contributionof fast neutron dose is realized in the 10%-6LiOH phantom. It can be expected that the accuracy for RBE estimations in biological experiments would improve using
the 10%-6LiOH phantom as the contribution of fast neu-

採択課題番号 26034
ＢＮＣＴのための線質評価ファントムの開発（京大・原子炉）櫻井良憲、田中浩基、藤本 望、近藤夏子、仲川洋介、鈴木
134

通常採択
実

CO7-4

A Fundamental Experiment for the Measure Against the Activation of the
Irradiation-room Concrete at BNCT Facility

Y. Sakurai, T. Takata, K. Kimura1, H. Tanaka, K. Takamiyahydrogen density was smaller. From the comparison forthe latter activity, it was found that the generation of thesecondary thermal neutrons was decreased to almost one
fifth for the resin with B4C. In the while, the activity,
namely the thermal neutron intensity, was increased according to the thickness. This is due to the influence forthe secondary thermal neutrons generated in the concrete.

Research Reactor Institute, Kyoto University
Fujita Corporation

1

INTRODUCTION: At present time, the research anddevelopment into several types of accelerator-based neutron sources for boron neutron capture therapy (BNCT)
are underway by several research groups in the world,with Cyclotron-based BNCT Epi-thermal Neutron Source(C-BENS) at the head of the list [1]. In near future,
BNCT using the accelerator-based neutron sources may
be carried out at several places in the world. Unlike thefacilities for radiation therapy and charged-particle therapy, the neutron yield is larger at BNCT facility. Then,the activation of concrete, which is a main structure of
the irradiation room, is larger. The use of low-activation
concrete is prefer in the viewpoints of the decrease of
exposure under the work in the irradiation room, the decommissioning of the irradiation room, etc.. This research is intended to perform the characteristic estimation
for low-activation concrete and confirm its usability at
BNCT facility. In 2014, a fundamental experiment for themeasure against the activation of concrete using an
Am-Be neutron source was performed, because the operation of Kyoto University Reactor (KUR) was limited.

CONCLUSION: From this experiment, it was realizedagain that the measure for the low activation of concreteitself, namely the development of low-activation concrete
was important, even if the measure against the activation
was performed using the neutron shield. The estimations
for the important characteristics of low-activation concrete are planned, such as short-life activation, long-life
activation, the shielding effect for neutrons and gamma
rays, the generation of the secondary gamma rays, etc.,
when the KUR operation is restarted.

METHODS: A characteristic estimation was performed
for the measure against the activation using a neutron
shield for a commercially available normal concrete. A
resin containing B4C, which is under development, wasused as a neutron shield. This shield weakens neutron
intensity to reach the concrete, by that high-energy neutrons are moderated by hydrogen in the resin and thermal
neutrons are absorbed by boron in B4C. As nine resin
sheets of 10-cm side, 10-cm long and 2-mm thickness
were stacked on the concrete surface, the shielding performance against the Am-Be neutron source was estimated by foil activation method. Indium foil was used as
an activation foil. The shielding characteristic for fastneutrons was estimated by the activity change forIn-113(n,n’)In-113m reaction, and the generating characteristic for the secondary thermal neutrons was estimatedby the activity change for In-115(n,γ)In-116m reaction.

Fig. 1. Activity changes dependent on the thickness
for the resin without B4C.

RESULTS: Figure 1 shows the activity changes dependent on the thickness for the resin without B4C. Figure 2 shows the activity changes dependent on the thickness for the resin with B4C. In these figures, the activity
changes for In-113(n,n’)In-113m and In-115(n,γ)In-116m are drawn. From the comparison for the former activity, it was found that the shielding effect for fastneutrons was a little smaller for the resin with B4C, as its

Fig. 2. Activity changes dependent on the thickness
for the resin with B4C.
REFERENCES:[1] H. Tanaka et al., Nucl. Instr. Meth. B 267 (2009)
1970-1977.

採択課題番号 26035
ＢＮＣＴ施設用低放射化コンクリートの特性評価（京大・原子炉）櫻井良憲、田中浩基、高宮幸一
135

通常採択

CO7-5

Radiosensitizing effect of purinergic antagonists on thedamage of melanoma by BNCT

M. Tsukimoto1, N. Mori1, K. Nishino1, T. Suzuki1, K.
Horie1, K. Tanamachi1, D. Kitahara1, N. Kondo2, S. Masunaga2, Y. Sakurai2, R. Abe1
12

Tokyo University of Sciences
Research Reactor Institute, Kyoto University

INTRODUCTION: Radiation exposure causes DNA
damage, and DNA repair systems are essential to rescue
damaged cells. Release of extracellular nucleotides, suchas ATP, from cells plays a role in signaling via P2 receptors. We have reported that autocrine/paracrine signaling
through P2X7-dependent ATP release and activation of
P2Y6 and P2Y12 receptors serves to amplify the cellularresponse to DNA damage caused by γ-irradiation [1-3].
BNCT is one of the new radiation therapy that mainlyuse α-ray derive from 10B(n,α)7Li reaction. 10B is delivered to the cell as 10B-bromophenylalanine (BPA). Since
it is known that melanoma tend to incorporate phenylalanine, 10B-BPA is well incorporated into melanoma.
γ-ray is low-LET radiation, and BNCT is high-LET radiation. γ-Irradiation causes DNA damage by indirect
action effect, which is mediated by reactive oxygen species. However, BNCT causes DNA damage by direct
action. It is known that direct action effect is stronger
than indirect action effect. Further, BNCT can irradiate
cells from inside of the cell.
Recently, we have showed involvement of P2
receptors in DNA damage repair after γ-ray irradiation in
A549 cells [2]. However, it has not yet been clear the
involvement of P2 receptors in BNCT-induced DNA
damage response. If the activation of P2X7, P2Y6, orP2Y12 receptor are involved in BNCT-induced DNA
damage response, the antagonists of these P2 receptors
enhance cytotoxicity of cancer cells by BNCT. Here, weinvestigated the radiosensitizing effect of P2 receptor
antagonist on BNCT-induced DNA damage response andcytotoxicity.

EXPERIMENTS:
Mouse melanoma B16 cells wereincubated with 1 mM 10B-BPA and P2Y12 receptor
antagonist clopidogrel. B16 cells were irradiated with
γ-rays and thermal neutron beams from a nuclear reactor(Kyoto University Research Reactor Institute;1 MW) atroom temperature for a suitable time. After irradiation,
the cells were incubated in humidified atmosphere of 5%
CO2 in air at 37 oC.
The irradiated cells were fixed in 4% paraformaldehyde
in PBS for 10 min at room temperature and permeabilized in 0.1% Triton X-100 for 5 min on ice. After incu-

bation in blocking buffer (10% FBS in PBS) for 1 h, thefixed cells were incubated with primary antibody against
γH2AX for 24 h at 4 oC and with 2nd antibody conjugatedwith FITC for 1 h. Counterstaining with Hoechst 33258
was used to verify the location and integrity of nuclei.
Fluorescence images were obtained with a laser scanningconfocal microscopy.
On the other hand, cell viability of irradiated cells
were measured by colony formation assay. 1.0 x 103
cells were seeded in a 100 mm dish. After incubation for
1 week, the cells were stained with 0.5% crystal violet.
Colonies containing more than 50 cells were counted.
RESULTS: First, we tested the effect of BNCT on cell
survival rate by the colony formation assay. Survival
fraction of BNCT group decreased compared with groupof γ-irradiated cells. In addition, the cytotoxic effect of
BNCT was enhanced by pre-treatment with clopidogrel(Fig.1A). Next, we tested DNA damage response after
BNCT by analyzing γH2AX focus formation. Formationof γH2AX foci that remain for 48hr was increased by
BNCT. The BNCT-induced increase of γH2AX foci was
suppressed by pretreatment with clopidogrel (Fig. 1B).
From these results, it was suggested that P2Y12 receptor participated in DNA damage repair caused by BNCT.
(A)

(B)

Fig.1 The effect of clopidogrel on BNCT-induced
DNAdamage responce
REFERENCES:[1] Tsukimoto M. et al., Radiat. Res. (2010) 173(3):298-309.
[2] Nishimaki N et al., DNA Repair (Amst). (2012) 11(8): 657-65.
[3] Ide S. et al., J Toxicol Sci. (2014) 39(1):15-23.

採択課題番号 26061	
 	
 	
 DNA 鎖損傷修復抑制効果をもつプリン受容体阻害薬を用いた
通常採択
BNCTによる抗癌増強効果	
 	 	
 （東京理科大・薬）月本光俊、森夏樹、西野圭祐、棚町圭祐、北原大輔、（東京理科大・生命研）
鈴木利宙、堀江	  和峰（京大・原子炉）櫻井良憲、増永慎一郎、近藤夏子	
 136

CO7-6 Feasibility Study for Establishing QA Method for Hospital- and Reactor-based BNCTTPR20,10 of a medical linac and the energy dependence ofthe film to gamma-rays, Monte Carlo simulation(BEAMnrc ver. 4.2.4. [6]) was used, and comparison of
PDDs between measurement and simulation with the
BEAMnrc were performed. Therefore, contribution of the
gamma-rays was subtracted from the output of the film.

S. Nakamura1, 2, A. Urushiyama2, T. Nishio3, C. Kurokawa4, A. Wakita1, M. Ito1, M. Munechika5, H. Okamoto1, Y.
Sakurai6, H. Tanaka6, N. Fujimoto6 and J. Itami1
1

Department of Radiation Oncology, National Cancer
Center2
Rikkyo University
3
Graduate School of Biomedical & Health Sciences, Hiroshima University
4
Department of Radiology, Juntendo University
5
Department of Human Sciences, Tokyo Metropolitan
University
6
Research Reactor Institute, Kyoto University

RESULTS: The comparison of PDDs between measurement and simulation was performed with a medical
linac of 4, 6, 10, and 15 MV photon beam in National
Cancer Center (NCC), Tokyo, Japan. The difference of
those beams between the measurement and the simulation
was within 0.59%. The relationship between TPR20,10 andthe calculated energy dependence which was normalized
in the value of 6MV photon beam in NCC. With using
those relationship and BEAMnrc, energy dependence ofthe film in the medical linac in Juntendo University andthat in KURR was 1.002±0.003, and 0.986±0.002, respectively. Outputs of the TLD after irradiation in KURR
were multiplied by a value of the ratio of energy dependence in KURR to that in Juntendo University, and themultiplied values were subtracted from the dose with thefilm. The relationship between the thermal neutron fluence and the dose with the film was shown in Fig. 1. The
thermal neutron fluence was proportional to the dose withthe film.

INTRODUCTION: In general, boron neutron capture
therapy (BNCT) is currently performed using a nuclear
reactor [1], [2]. Recent researches [3], [4], [5] have madepossible to acquire an adequate amount of neutrons byaccelerator and hospital-based accelerator-BNCT hascome into reality. Therefore, National Cancer Center,
Tokyo, Japan, is planning to install an accelerator-based
BNCT system. Hospital-based accelerator-BNCT system
has a lot of advantages. For example, there is no need tomove a patient to the reactor. However, the hospital-based system also has disadvantages. In the hospital-based BNCT system, with compared with the reactor-based BNCT system, the measurement for a beam of
BNCT is asked for the simplified method because thehospital-based system is restricted by an area of the institute. The purpose of this study is to establish the QA
method for hospital-based BNCT.
EXPERIMENTS: In order to measure easily the neutron
beam, new film was developed. The new film consistedof thermos luminescence phosphor. After exposure of theradiation, the output of the film with heated was red by
CCD. Signal intensity was measured as the amount oflilght. The relationship of the film between the signal anddoses were acquired with 6 MV photon beam of a medical linac in Juntendo University, Tokyo, Japan. The relationship between the signal and neutron fluence was analyzed in this study because the signal was evaluated as
the dose. The experiment of neutron irradiation was performed in Kyoto University Research Reactor (KURR).
In order to evaluate the film, the thermal neutron fluence
was measured with the film and a gold foil, and theseresults were compared. However, the beam of the KURR
contained both neutrons and gamma-rays. Therefore, thedose from gamma-rays was measured with the thermoluminescence dosimter (TLD) since the film also had
sensitivity to photons. The contribution from the gamma-rays to the film was considered by the result of the
TLD. In order to evaluate a relationship between theFig. 1. The relationship between the dose with thefilm and thermal neutron fluence.
REFERENCES:[1] K. Nakai et al., Appl. Radiat. Isotopes., 69(12):1790-1792; (2011)[2] S. Masunaga et al., Br. J. Radiol., 85(1011): 249-258;(2012)[3] S. Kamada et al., Appl. Radiat. Isotopes., 88:
195-197; (2014)[4] H. Kumada et al., Appl. Radiat. Isotopes., 88:
211-215; (2014)[5] H. Tanaka et al., Appl. Radiat. Isotopes., 69:
1642-1645; (2014)[6] DWO Rogers et al., Med. Phys., 22: 503-524; (1995)

共同通常
通常採択
採択課題番号 26068
BNCT 照射場の QA/QC に関する基礎研究（国立がんセ・放治）中村 哲志、岡本 裕之、脇田 明尚、伊藤 昌司、伊丹 純、（広島大院・
医歯薬）西尾 禎治、（首都大・人間）宗近 正義、（京大・原子炉）櫻井 良憲、田中 浩基、藤本 望

137