Gadolinium accumulation using Gd-DTPA-incorporated
Calcium Phosphate Nanoparticles for Gd-neutron capture therapy

1Dept of Nuclear Engineering & Management, Univ ofTokyo, 2Bioengineering Dept, Univ of Tokyo, 3Polymerchemistry division, Chemical Resource Laboratory, Tokyo
Institute of Technology, 4Cooperative Unit of Medicine &Engineering, Univ of Tokyo Hospital, 5Dept of InnovativeCancer Therapeutics, Meiji Pharmaceutical University,
6Materials Engineering Dept, The University of Tokyo,
7
Research Reactor Institute, Kyoto University, 8Dept ofCardiac Surgery, The University of Tokyo Hospital, 9Deptof Thoracic Surgery, The University of Tokyo Hospital
INTRODUCTION: Gadolinium-157 has been getting
attention as an attractive agent for neutron capture therapy(NCT) because of its high thermal neutron cross section(255 000 barns), which the highest among all stableelements. However, gadolinium neutron capture reaction(Gd-NCR) results in release of gamma rays, which reduce
the localization effect of the treatment, increasing thepossible additional effect if Gd-157 is accumulated to abulk tumor cluster [1].
We synthesized Gd-DTPA-incorporated Calcium
Phosphate (Gd-DTPA/CaP) nanoparticles with two-step
preparation method by self-assembly poly(ethyleneglycol)-b-poly(aspartic acid) block copolymer, Gd-DTPA,
and CaP in aqueous solution, followed with hydrothermaltreatment. Evaluation of possible apoptosis by detecting
the DNA fragmentation following GdNCT treatment has
shown that the number of cells killed after treatment wasobserved to be similar for single and multiple injectiongroups of Gd-DTPA/CaP nanoparticles, while non-treatedgroup shows normal histology with clear cytoplasm andnucleus [3].
In this work, we evaluated the tumor accumulation ofGd atoms for single and multiple injections using GdDTPA/CaP nanoparticles.

RESULTS: Quantitative analysis from ICP-MS
measurement results of gadolinium accumulation in tumor
and several mice organs were shown in Table 1. We could
achieve the tumor-to-blood (T/B) ratio of around 2.4 at 24
hr after Gd-DTPA/CaP nanoparticles injection.
Table 1. Gd accumulation in tumor and several organsof tumor bearing mice after single injection of GdDTPA/CaP nanoparticles
Gd concentration (g/g or mL)

TumorBloodLiverSpleen
KidneyBrain

12hr24hr

5.85 ± 0.64
14.55± 0.50
10.71± 0.17
7.08 ± 0.41
2.66 ± 0.24
0.16 ± 0.01

8.03± 0.82
3.29± 0.40
16.71± 0.60
10.03± 0.30
2.13± 0.06
0.04± 0.01

Higher gadolinium accumulation in tumor site was
successfully achieved for multiple injections of GdDTPA/CaP nanoparticles as shown in Figure 1.
Gadolinium concentration reached the amount of morethan three times higher compared to those at 10 hr after the
first injection. Significant increase in gadolinium
concentration in blood plasma was also observed at 30hrafter first injection. This result indicates the prolonged
blood circulation of Gd-DTPA/CaP nanoparticles.
Plasma clearance

Tumor accumulation
A 20

B 100

Gd-DTPA/CaP
Gd-DTPA

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40200EXPERIMENTS: We carried out the biodistribution
experiments of in vivo quantitative analysis, each forsingle and multiple injections of Gd-DTPA/CaPnanoparticles. To confirm the pharmacokinetics of GdDTPA/CaP nanomicelles for 0.2 mL single injection,
tumor, blood, and other organ samples were harvested at
12 and 24 hr following nanoparticles administration. Threetimes injections of Gd-DTPA/CaP nanomicelles with 10 hr
interval were then carried out in order to achieve higher
gadolinium accumulation in tumor site. Samples from bothexperiments were analyzed using ICP-MS.

Gd-DTPA/CaP
Gd-DTPA% of dose/ml plasma

N. Dewi1,5, 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, Minoru
Ono4,8, Jun Nakajima4,9, and H. Takahashi1,4% of dose/g tumor tissueCO7-101020Time (h)301020Time (h)30Figure 1. Gadolinium biodistribution for multiple injections.
Higher gadolinium accumulation in tumor site was achieved
significantly after three times injection. More than 60%of injected dose of gadolinium was still observed inplasma indicating the prolonged blood circulation of GdDTPA/CaP nanoparticles.
REFERENCES:[1] Dewi N et al., Biomed & Pharmacother (2013) 67:451-7.
[2] Mi P, et al.: ACS Nano (2015) 23;9(6):5913-21.
[3] Dewi N et al., J Can.Res.Clin.Oncol. (2016) 142(4):767-75.

CO7-2

A Fundamental Experiment for the Measure Against the Activation of
the Irradiation-room Concrete at BNCT Facility (III)T. Takata, Y. Sakurai, K. Kimura1, H. Tanaka, K. Takamiya

mal neutrons was found to be slightly larger in the sample B compared to the sample A.

Research Reactor Institute, Kyoto University
1Fujita Corporation

CONCLUSION: Toward the restart of KUR operation,
the estimations for the important characteristics of theshielding materials as well as the low-activation concretematerials are planned, such as the shielding effect forneutrons and gamma rays, the generation of the secondary gamma rays, etc., using Heavy Water Neutron Irradiation Facility [3]. Also, the neutron activation analysis forthese materials and its basic ingredients using PneumaticTubes is planned to estimate the activation characteristics
from short to long time range.

INTRODUCTION: At present time, the research anddevelopment of accelerator-based neutron sources forboron neutron capture therapy (BNCT) are underway by
several research groups around the world, with Cyclotron-based BNCT Epi-thermal Neutron Source (C-BENS)
in the lead [1]. In near future, BNCT using the accelerator-based neutron sources may be carried out at several
places in the world. Compared to irradiation facilities for
X-ray and charged-particle radiation therapy, the neutron
yield is much larger at BNCT facility. Thus, the activation of concrete, which is a main structure material of theirradiation facility, becomes an issue from the viewpointsof radiation exposure of medical workers, the decommissioning of the facility, etc.. This research is intended toperform the characteristic estimation of the materials foractivation reduction and to confirm its usability at BNCTfacility. In 2016, characteristic estimation of a neutron
shielding material covering concrete wall surfaces wasperformed by using an Am-Be neutron source in the samemanner in 2014 and 2015 [2], because Kyoto University
Reactor (KUR) was not operated.
METHODS: A characteristic estimation was performed for the resin-based shielding materials containing
B4C with different particle sizes. The small-size particles
were used in the sample A, in which the B4C can be considered to be distributed homogeneously in the resin. On
the other hands, the particles with a submillimeter diameter were used in the sample B, in which the B4C waslocalized in the particles and thus considered to be distributed sparsely in the resin. These samples were prepared to have the almost same B4C concentration level asa whole volume average. Four resin sheets of 10-cm side,10-cm long and 4-mm thickness were stacked on theconcrete surface. The shielding performance against theAm-Be neutron source was estimated by activation
method of indium foils placed between the stacked resinlayers. The characteristic for fast neutron shielding wasestimated by the change in the 115In(n,n’)115mIn reaction
rate, and the characteristic for thermal neutron generation
was estimated by the change in the 115In(n,γ)116mIn reaction rate.

Fig. 1. 115In(n,n’)115mIn reaction rate as a function of
the shield thickness.

RESULTS: Figures 1 and 2 show the reaction rates forthe 115In(n,n’)115mIn and 115In(n,γ)116mIn reactions, respectively, as a function of the neutron-shield thickness of thesample A and B. From the comparison of the changes in
the 115In(n,n’)115mIn reaction rate, the shielding ability forfast neutrons was found to be almost same between thesample A and B. From the comparison of the changes in
the 115In(n,γ)116mIn reaction rate,the generation of ther-REFERENCES:[1] H. Tanaka et al., Nucl. Instr. Meth. B 267 (2009)
1970-1977.
[2] Y. Sakurai, T. Takata et al., KURRI Progress Report2015 (2016) 97.
[3] Y. Sakurai et al., Nucl. Instr. Meth. A 453 (2000)
569-596.

28056

Fig. 2. 115In(n, γ)116mIn reaction rate as a function of
the shield thickness.