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

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.