Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-Ku, Okayama City, Okayama 700-8558, Japan.
Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Kumatori-cho, Osaka 590-0494, Japan.
Biomaterials. 2014 Mar;35(10):3396-405. doi: 10.1016/j.biomaterials.2013.12.055. Epub 2014 Jan 20.
New anti-cancer therapy with boron neutron capture therapy (BNCT) is based on the nuclear reaction of boron-10 with neutron irradiation. The median survival of BNCT patients with glioblastoma was almost twice as long as those receiving standard therapy in a Japanese BNCT clinical trial. In this clinical trial, two boron compounds, BPA (boronophenylalanine) and BSH (sodium borocaptate), were used for BNCT. BPA is taken up into cells through amino acid transporters that are expressed highly in almost all malignant cells, but BSH cannot pass through the cell membrane and remains outside the cell. We simulated the energy transfer against the nucleus at different locations of boron from outside the cell to the nuclear region with neutron irradiation and concluded that there was a marked difference between inside and outside the cell in boron localization. To overcome this disadvantage of BSH in BNCT, we used a cell-penetrating peptide system for transduction of BSH. CPP (cell-membrane penetrating peptide) is very common peptide domains that transduce many physiologically active substances into cells in vitro and in vivo. BSH-fused CPPs can penetrate the cell membrane and localize inside a cell. To increase the boron ratio in one BSH-peptide molecule, 8BSH fused to 11R with a dendritic lysine structure was synthesized and administrated to malignant glioma cells and a brain tumor mouse model. 8BSH-11R localized at the cell nucleus and showed a very high boron value in ICP results. With neutron irradiation, the 8BSH-11R administrated group showed a significant cancer killing effect compared to the 100 times higher concentration of BSH-administrated group. We concluded that BSH-fused CPPs were one of the most improved and potential boron compounds in the next-stage BNCT trial and 8BSH-11R may be applied in the clinical setting.
新型抗癌疗法硼中子俘获治疗（BNCT）基于硼-10 的核反应与中子辐照。在日本 BNCT 临床试验中，接受 BNCT 治疗的胶质母细胞瘤患者的中位生存期几乎是接受标准治疗的患者的两倍。在这项临床试验中，两种硼化合物 BPA（硼苯丙氨酸）和 BSH（硼替佐米）被用于 BNCT。BPA 通过氨基酸转运体进入细胞，这些转运体在几乎所有恶性细胞中都高度表达，但 BSH 不能穿过细胞膜，留在细胞外。我们用中子辐照模拟了从细胞外到核区不同位置硼的能量转移对核的影响，得出了硼在细胞内外定位有明显差异的结论。为了克服 BSH 在 BNCT 中的这一缺点，我们使用了细胞穿透肽系统来转导 BSH。CPP（细胞穿透肽）是一种非常常见的肽结构域，它可以将许多生理活性物质转导到体外和体内的细胞中。BSH 融合的 CPP 可以穿透细胞膜并定位于细胞内。为了增加一个 BSH-肽分子中的硼比，合成了融合了树枝状赖氨酸结构的 8BSH 和 11R，并将其施用于恶性神经胶质瘤细胞和脑肿瘤小鼠模型。8BSH-11R 定位于细胞核内，在 ICP 结果中显示出非常高的硼值。用中子辐照后，与 BSH 给药组相比，8BSH-11R 给药组表现出显著的癌症杀伤作用。我们得出结论，BSH 融合的 CPP 是下一阶段 BNCT 试验中最有改进和潜力的硼化合物之一，8BSH-11R 可能应用于临床。
