Abstract
Boron neutron capture therapy (BNCT) is a unique anticancer technology that has demonstrated its efficacy in numerous phase I/II clinical trials with boronophenylalanine (BPA) and sodium borocaptate (BSH) used as 10B delivery agents. However, continuous drug administration at high concentrations is needed to maintain sufficient 10B concentration within tumors. To address the issue of 10B accumulation and retention in tumor tissue, we developed MMT1242, a novel boron-containing α-d-mannopyranoside. We evaluated the uptake, intracellular distribution, and retention of MMT1242 in cultured cells and analyzed biodistribution, tumor-to-normal tissue ratio and toxicity in vivo. Fluorescence imaging using nitrobenzoxadiazole (NBD)-labeled MMT1242 and inductively coupled mass spectrometry (ICP-MS) were performed. The effectiveness of BNCT using MMT1242 was assessed in animal irradiation studies at the Kyoto University Research Reactor. MMT1242 showed a high uptake and broad intracellular distribution in vitro, longer tumor retention compared to BSH and BPA, and adequate tumor-to-normal tissue accumulation ratio and low toxicity in vivo. A neutron irradiation study with MMT1242 in a subcutaneous murine tumor model revealed a significant tumor inhibiting effect if injected 24 h before irradiation. We therefore report that 10B-MMT1242 is a candidate for further clinical BNCT studies.
Highlights
Boron neutron capture therapy (BNCT) is a binary anticancer technology that was first proposed by Locher in 1936 and has since been further developed and improved by a number of research groups all over the world
Our murine subcutaneous tumor model irradiation study showed that MMT1242 had a significant tumor-inhibiting effect with the injection 24 h prior to neutron irradiation
Fluorescence microscopy revealed the intracellular distribution of NBD-labeled MMT1242 (NBD1242) in CT26 tumor cells as diffuse and broad (Figure 4)
Summary
Boron neutron capture therapy (BNCT) is a binary anticancer technology that was first proposed by Locher in 1936 and has since been further developed and improved by a number of research groups all over the world. It commands attention as a state-of-the-art, minimally invasive cancer treatment that functions as a single cell level-selective tumoricidal therapy [1,2,3,4,5,6,7] It employs a stable boron-10 (10 B) isotope-containing compound injected into the patient and neutron irradiation produced at a nuclear reactor (or accelerator) and once the appropriate form of 10 B-boron-containing compound has selectively accumulated in malignant tumor cells by a drug delivery system (DDS), the subsequent neutron irradiation of the tumor area induces alpha particles and Li nuclei emission within a 10 micrometer span, limiting the BNCT effect to tumor cells with accumulated boron and sparing the surrounding normal cells without boron accumulation [2,3,4,8,9]. Phase I/II clinical trials of BNCT were conducted for patients with glioblastoma and the early results suggest that BNCT is effective in selected cases [10,11,12].
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