Application of Nitroimidazole-Carbobane-Modified Phenylalanine Derivatives as Dual-Target Boron Carriers in Boron Neutron Capture Therapy.,Molecular Pharmaceutics

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Application of Nitroimidazole-Carbobane-Modified Phenylalanine Derivatives as Dual-Target Boron Carriers in Boron Neutron Capture Therapy.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2019-12-04 , DOI: 10.1021/acs.molpharmaceut.9b00898
Ruixi Li ₁ , Juanjuan Zhang ₁ , Jingxuan Guo ₁ , Yue Xu ₁ , Kunyuan Duan ₂ , Jinrong Zheng ₁ , Hao Wan ₁ , Zhenwei Yuan ₁ , Haiyan Chen ₁

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Boron neutron capture therapy (BNCT) has received extensive attention as noninvasive cell-level oncotherapy for treating solid cancer tumors. However, boron-containing drugs such as l-boronophenylalanine (BPA) and sodium borocaptate have low boron content and/or poor tumor-targeting ability, limiting their application. In this study, we designed and synthesized a series of nontoxic, dual-target boron carriers (B139, B142, and B151) with the ability to accumulate specifically in tumor cells. We found that the B139 uptake into hypoxic tumor regions was high, with a 70-fold boron content compared to BPA. In addition, in vivo observation showed that B139 can be trapped in tumor cells for a prolonged period and maintains an effective therapeutic concentration, with a peak boron concentration of 50.7 μg/g and a high tumor: blood boron ratio of >3, achieving ideal BNCT conditions. Cytotoxicity evaluation in mice further proved that B139 is safe and reliable. Therefore, B139 has great potential for BNCT application as a dual-target, safe, and efficient boron carrier.

中文翻译：

硝基咪唑碳环修饰的苯丙氨酸衍生物作为双靶硼载体在硼中子俘获治疗中的应用。

硼中子捕获疗法（BNCT）作为治疗实体癌肿瘤的无创细胞水平肿瘤疗法已受到广泛关注。但是，含硼药物，如1-硼硼苯丙氨酸（BPA）和硼酸癸酸钠具有较低的硼含量和/或较弱的肿瘤靶向能力，限制了它们的应用。在这项研究中，我们设计并合成了一系列无毒，双靶硼载体（B139，B142和B151），它们具有在肿瘤细胞中特异性蓄积的能力。我们发现缺氧肿瘤区域的B139摄取量很高，硼含量是BPA的70倍。此外，体内观察表明，B139可以长时间捕获在肿瘤细胞中，并保持有效的治疗浓度，硼的峰值浓度为50.7μg/ g，并且肿瘤与血硼的比率高，> 3，达到理想的BNCT条件。小鼠的细胞毒性评估进一步证明了B139是安全可靠的。因此，B139作为双靶，安全，高效的硼载体，在BNCT应用中具有巨大的潜力。

更新日期：2019-12-04

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