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Gd complex of DO3A-benzothiazole conjugate for neutron capture therapy
Ki-Hye Jung1, Ji-Ae Park1, Jung Young Kim1, Yongmin Chang2,3, Tae-Jeong Kim4, Hee-Kyung Kim4, Kyo Chul Lee1, Joo Hyun Kang1, and Yong Jin Lee1

1Division of RI-Convergence Research, Korea Institute of Radiological & Medical Sciences, Seoul, Korea, Republic of, 2Department of Medical & Biological Engineering, Kyungpook National University, Daegu, Korea, Republic of, 3Department of Radiology and Molecular Medicine, Kyungpook National University, Daegu, Korea, Republic of, 4Institute of Biomedical Engineering Research, Kyungpook National University, Daegu, Korea, Republic of

Synopsis

We have presented a strategy for incorporating low-molecular-weight Gd(III) chelate for dual non-invasive MR contrast agent and NCT, without the necessity of loading individual contrast therapeutic drugs, which is usually required in theranostics. The Gd-DO3A-BTA injected and neutron irradiated group, the tumor growth was significantly suppressed. This information could provide a basis for the prospect of obtaining a synergistic or cumulative action of chemotherapy (ChT) and Gd-NCT. We examined the neutron capture irradiation of MDA-MB-231 mice in the presence of Gd-DO3A-BTA. The results indicate that Gd-DO3A-BTA is suitable neutron capture agent for Gd-NCT.

Introduction

Gadolinium neutron capture therapy (Gd-NCT) is a cancer therapy which utilized γ-rays and electron emitted by 157Gd (n, γ) 158Gd reaction to kill tumor cells. A general requirement of a suitable NCT agent after accumulation in the target tumor is that upon exposure to thermal neutrons, it should emit radiation of sufficient energy a tissue penetration depth, so that the majority of cancer cells are killed with limited exposure of healthy tissues to γ-rays or ionizing irradiation. Moreover, paramagnetic Gd(III) chelates can enhance the T1-weighted contrast for MRI, which could be exploited to delineate the outline and location of tumors for MR imaging guided Gd-NCT. Therefore, an effective Gd-NCT drug would ideally combine diagnostic and therapeutic properties. We have recently developed Gd(III) complex for targeting in tumor, which dual MR cancer imaging and therapy by Gd-NCT.1

Material and Methods

The Gd-DO3A-BTA was prepared according to literature method.1 The neutron irradiations were performed with an MC-50 cyclotron (Scanditronix, Sweden). Neutrons were generated by 35 MeV protons irradiating on the beryllium target. MDA-MB-231 tumor cells (5 ｘ 106 cells mL-1) suspended in RPMI-1640 medium without fetal bovin serum and penicillin-streptomycin were incubated into subcutaneous tissue (sc) of female BALB/c nude mice (6 weeks, 18-25 g of body weight) in both legs, irradiating only one. Gd-DO3A-BTA was administered intravenously as a bolus (0.2 mmol/kg) in a tail vein ten female mice bearing MDA-MB-231 tumor. After 6 h, the mice were locally irradiated with thermal neutron beam for 4 min of 0.3 Gy. One side was irradiated with thermal neutron beam. The other side was shielded from thermal neutron using Teflon. The tumor size was measured before and after irradiation, and the volume (V) was calculated using the follow equation:

V = (a ｘ b2)/2

Where (a) and (b) are the major and minor axes of the tumor measured by caliper.

Results and Discussion

The change in the tumor volume in the mice after the neutron irradiation is shown in Fig. 1. Without thermal neutron irradiation, Gd-DO3A-BTA affect tumor growth rates by antitumor activity of BTA, and tumor volumes increased by over 15-fold at day 60. The Gd-DO3A-BTA injected and neutron irradiated group, the tumor growth was significantly suppressed. It means tumor volume was less than 50%, compared with than in the none gadolinium administered and neutron irradiation group, 60 days after the neutron irradiation. This information could provide a basis for the prospect of obtaining a synergistic or cumulative action of chemotherapy (ChT) and Gd-NCT.

Conclusions

We have presented a strategy for incorporating low-molecular-weight Gd(III) chelate for dual non-invasive MR contrast agent and NCT, without the necessity of loading individual contrast therapeutic drugs, which is usually required in theranostics. The Gd-DO3A-BTA had high therapeutic efficiency for Gd-NCT against solid tumors, as the high accumulation of the Gd-DO3A-BTA in tumor tissues could effectively damage cancer cells by γ-rays or electron emission from the Gd nuclides. We examined the neutron capture irradiation of MDA-MB-231 mice in the presence of Gd-DO3A-BTA. The results indicate that Gd-DO3A-BTA is suitable neutron capture agent for Gd-NCT.

Acknowledgements

This work was supported by Nuclear R&D Program of the National Research Foundation of Korea government (MEST) (2012M2A2A7013480).

References

1. H. K. Kim, M. K. Kang, K. H. Jung, S. H. Kang, Y. H. Kim, J. C. Jung, G. H. Lee, Y. Chang, T. J. Kim, J. Med. Chem. 2013, 56, 8104-8111.

Figures

Figure 1. (a) MR images of MDA-MB-231 tumors derived from balb/c nude mice treated with Gd-DO3A-BTA and control after the end of treatment. (b) Images of mice bearing subcutaneous MDA-MB-231 tumors 60 days after Gd-NCT. (c) Changes in tumor volume as measured by a caliper.

Proc. Intl. Soc. Mag. Reson. Med. 25 (2017)
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