211At-labeled immunoconjugate via a one-pot three-component double click strategy: practical access to α-emission cancer radiotherapeutics
211At-labeled immunoconjugate via a one-pot three-component double click strategy: practical access to α-emission cancer radiotherapeutics
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DOI：
10.1039/c8sc04747b
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发表时间：
2019-02-21
期刊：
影响因子：
8.4
通讯作者：
Tanaka, Katsunori
中科院分区：
文献类型：
--
作者：
Fujiki, Katsumasa;Kanayama, Yousuke;Tanaka, Katsunori
阿尔法放射治疗有可能成为最有效的癌症治疗方法之一。在这里，我们报告了一种简便的合成AT-211标记的免疫结合物，用于阿尔法发射分子靶向治疗。我们合成了一种用闭合十硼酸(2-)修饰的四嗪探针，该修饰基团与At-211形成生物可利用的稳定络合物。在不降低抗体结合亲和力的情况下，我们采用一锅三组分双点标记法，用十硼四氮和TCO-醛探针将十硼酸结合到曲妥珠单抗(抗HER2抗体)上。用RIKEN Nishina中心回旋加速器产生的AT-211标记十硼酸结合的曲妥珠单抗，可以产生高放射性At-211，很容易提供AT-211标记的曲妥珠单抗，最大比活性为15MBq mg(-1)，并保留了天然结合亲和力。瘤内注射At-211标记的曲妥珠单抗，BALB/c裸鼠体内接种有HER2表达的表皮样癌细胞，可在靶肿瘤部位有效积聚，并有效抑制肿瘤生长。
alpha-Emission radiotherapeutics has potential to be one of most effective cancer therapeutics. Herein, we report a facile synthesis of an At-211-labeled immunoconjugate for use as an alpha-emission molecular targeting therapy. We synthesized a tetrazine probe modified with closo-decaborate(2-), a prosthetic group that forms a bioavailable stable complex with At-211. Our one-pot three-component double-click labeling method was used to attach decaborate to trastuzumab (anti-HER2 antibody) using decaboratetetrazine and TCO-aldehyde probes without reducing the antibody binding affinity. Labeling the decaborate-attached trastuzumab with At-211 produced in the cyclotron at the RIKEN Nishina Center, at which highly radioactive At-211 can be produced, readily furnished the At-211-labeled trastuzumab with a maximum specific activity of 15 MBq mg(-1) and retention of the native binding affinity. Intratumor injection of the At-211-labeled trastuzumab in BALB/c nude mice implanted with HER2-expressing epidermoid cancer cells yielded efficient accumulation at the targeted tumor site as well as effective suppression of tumor growth.