Evaluation of a Novel Boron-Containing α-d-Mannopyranoside for BNCT
Evaluation of a Novel Boron-Containing α-d-Mannopyranoside for BNCT
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DOI：
10.3390/cells9051277
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发表时间：
2020-05-01
期刊：
影响因子：
6
通讯作者：
Matsumura, Akira
中科院分区：
文献类型：
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作者：
Tsurubuchi, Takao;Shirakawa, Makoto;Matsumura, Akira
硼中子俘获疗法 (BNCT) 是一种独特的抗癌技术，已在使用硼苯丙氨酸 (BPA) 和硼醇钠 (BSH) 作为 B-10 递送剂的众多 I/II 期临床试验中证明了其功效。然而，需要持续高浓度给药以维持肿瘤内足够的 B-10 浓度。为了解决 B-10 在肿瘤组织中积累和滞留的问题，我们开发了 MMT1242，一种新型含硼 α-d-吡喃甘露糖苷。我们评估了培养细胞中 MMT1242 的摄取、细胞内分布和保留，并分析了体内生物分布、肿瘤与正常组织的比率和毒性。使用硝基苯并恶二唑 (NBD) 标记的 MMT1242 和电感耦合质谱 (ICP-MS) 进行荧光成像。在京都大学研究堆的动物辐射研究中评估了使用 MMT1242 的 BNCT 的有效性。 MMT1242 在体外表现出高摄取和广泛的细胞内分布，与 BSH 和 BPA 相比具有更长的肿瘤保留时间，在体内具有足够的肿瘤与正常组织积累比和低毒性。在皮下小鼠肿瘤模型中使用 MMT1242 进行的中子辐照研究表明，如果在辐照前 24 小时注射，可产生显着的肿瘤抑制效果。因此，我们报告 B-10-MMT1242 是进一步临床 BNCT 研究的候选者。
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 B-10 delivery agents. However, continuous drug administration at high concentrations is needed to maintain sufficient B-10 concentration within tumors. To address the issue of B-10 accumulation and retention in tumor tissue, we developed MMT1242, a novel boron-containing alpha -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 B-10-MMT1242 is a candidate for further clinical BNCT studies.