Image-Guided Neutron Capture Therapy Using the Gd-DO3A-BTA Complex as a New Combinatorial Treatment Approach.

Ki-Hye Jung,Kyeong Min Kim,Jung Young Kim,Han-Jun Kim,Seyoung Oh,Ji-Ae Park,Kyo Chul Lee,Yongmin Chang,Yong Jin Lee,Hee-Kyung Kim,Mi Hyun Kim,Eun-Ji Choi,Sun Hee Do

doi:10.1155/2018/3727109

Abstract

Gadolinium-neutron capture therapy (Gd-NCT) is based on the nuclear capture reaction that occurs when 157Gd is irradiated with low energy thermal neutrons to primarily produce gamma photons. Herein, we investigated the effect of neutron capture therapy (NCT) using a small molecular gadolinium complex, Gd-DO3A-benzothiazole (Gd-DO3A-BTA), which could be a good candidate for use as an NCT drug due to its ability to enter the intracellular nuclei of tumor cells. Furthermore, MRI images of Gd-DO3A-BTA showed a clear signal enhancement in the tumor, and the images also played a key role in planning NCT by providing accurate information on the in vivo uptake time and duration of Gd-DO3A-BTA. We injected Gd-DO3A-BTA into MDA-MB-231 breast tumor-bearing mice and irradiated the tumors with cyclotron neutrons at the maximum accumulation time (postinjection 6 h); then, we observed the size of the growing tumor for 60 days. Gd-DO3A-BTA showed good therapeutic effects of chemo-Gd-NCT for the in vivo tumor models. Simultaneously, the Gd-DO3A-BTA groups ([Gd-DO3A-BTA(+), NCT(+)]) showed a significant reduction in tumor size (p < 0.05), and the inhibitory effect on tumor growth was exhibited in the following order: [Gd-DO3A-BTA(+), NCT(+)] > [Gd-DO3A-BTA(+), NCT(−)] > [Gd-DO3A-BTA(−), NCT(+)] > [Gd-DO3A-BTA(−), NCT(−)]. On day 60, the [Gd-DO3A-BTA(+), NCT(+)] and [Gd-DO3A-BTA(−), NCT(−)] groups exhibited an approximately 4.5-fold difference in tumor size. Immunohistochemistry studies demonstrated that new combinational therapy with chemo-Gd-NCT could treat breast cancer by both the inhibition of tumor cell proliferation and induction of apoptosis-related proteins, with in vivo tumor monitoring by MRI.

Highlights

Neutron capture therapy (NCT) is a well-known approach to cancer treatment based on the accumulation of neutron capture agents at the tumor site [1], followed by irradiation with thermal neutrons
(∼0.1 mmol Gd/kg). e MR image reveals clear tumor enhancement, which increased for 6 h before gradually decreasing (Figure 1(b)). is result is consistent with the biodistribution data reported in our previous study [9], demonstrating that we can effectively define the starting point of NCT with in vivo MR imaging
A small animal study was performed in which mice were irradiated with a neutron beam at 6 h p.i. to determine the optimal time at which the highest uptake of Gd-DO3A-BTA into the tumor tissue occurred

Summary

Introduction

Neutron capture therapy (NCT) is a well-known approach to cancer treatment based on the accumulation of neutron capture agents at the tumor site [1], followed by irradiation with thermal neutrons. NCT is a very e ective technique for cancer treatment because the thermal neutrons with low energy do not cause damage to normal cells that lack the neutron capture compounds. Erefore, the strategy for the accumulation of NCT compounds speci cally within the tumor is critical to avoid damage to normal tissues [2,3,4,5]. E data show high uptake of the contrast agents into tumor cells at 5 mins, but they exhibit very low uptake at 2 hrs. A 50–200 μg 157Gd/g tumor was reported as an effective cancer treatment

Methods

Results

Conclusion