DOTA-tetrazine probes with modified linkers for tumor pretargeting
DOTA-tetrazine probes with modified linkers for tumor pretargeting
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DOI：
10.1016/j.nucmedbio.2017.09.001
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发表时间：
2017-12-01
影响因子：
3.1
通讯作者：
Robillard, Marc S.
中科院分区：
文献类型：
--
作者：
Laeppchen, Tilman;Rossin, Raffaella;Robillard, Marc S.
简介：基于应变反式环辛烯（TCO）和缺电子四嗪（Tz）之间的生物正交逆电子需求狄尔斯-阿尔德（IEDDA）反应的预靶向放射免疫成像和治疗方法近年来取得了令人印象深刻的结果，并已被证明是生物预靶向系统的重要替代方案。改进后的TCO-抗体缀合物，我们在这里报告我们的评价一系列新的放射性标记的Tz-probes.Methods：四个新的Tz-探针合成，放射性标记的镥-177，其特征在于在体外的亲脂性，反应性和稳定性在PBS和小鼠血清。在体内的生物分布概况和肿瘤靶向潜力的探针进行了评估，在LS 174 T荷瘤小鼠pretargeted与TCO-抗体缀合物使用non-pretargeted小鼠作为control.Results：放射性标记的所有探针进行高产率提供Lu-177标记的四嗪在>95%的放射化学纯度，无需任何进一步的纯化。在小鼠血清中，探针的半衰期在8至13小时之间变化，但最亲脂的探针[Lu-177]1b除外，其血清半衰期小于1小时。该探针还显示出最快的血液清除（t（1/2）= 5.4 min），比PEG连接的探针[Lu-177]3和[Lu-177]4快2倍以上，甚至比没有PEG连接体的其他小探针[Lu-177]la和[Lu-177]2快3倍。在预靶向实验中，铅探针[Lu-177]4（类似于6%ID/g）的肿瘤摄取最接近[Lu-177]2，其次是[Lu-177]3和[Lu-177]la。虽然所有更小和更亲脂性的探针都遭受增加的肝脏摄取，但具有额外负电荷的PEG连接的探针[1711]3令人惊讶地显示出所有探针中最高的肾脏摄取。结论：一些新的四嗪探针的体外性能证明与已建立的铅探针[Lu-177]Lu-DOTA-PEG（11）-Tz（[Lu-177]4）相当。然而，体内肿瘤预靶向研究显示肿瘤摄取较低，非靶器官摄取增加。(C)2017爱思唯尔公司All rights reserved.
Introduction: Pretargeted radioimmunoimaging and -therapy approaches building on the bioorthogonal inverse electron-demand Diels-Alder (IEDDA) reaction between strained trans-cyclooctenes (TCO) and electron deficient tetrazines (Tz) have yielded impressive results in recent years and have proven a vital alternative to biological pretargeting systems. After improvement of the TCO-antibody conjugates, we here report on our evaluation of a new series of radiolabeled Tz-probes.Methods: Four new Tz-probes were synthesized, radiolabeled with lutetium-177, and characterized in vitro in terms of lipophilicity, reactivity, and stability in PBS and mouse serum. The in vivo biodistribution profile and tumor-targeting potential of the probes were evaluated in LS174T tumor-bearing mice pretargeted with TCO-antibody conjugates using non-pretargeted mice as control.Results: Radiolabeling of all probes proceeded in high yields providing the Lu-177-labeled tetrazines in >95% radiochemical purity without any further purification. In mouse serum, half-lives of the probes varied between 8 and 13 h, with the exception of the most lipophilic probe, [Lu-177]1b, with a serum half-life of less than 1 h. This probe also showed the fastest blood clearance (t(1/2) = 5.4 min), more than 2-fold faster than PEG-linked probes [Lu-177]3 and [Lu-177]4, and even 3 -fold faster than the other small probes without the PEG-linker, [Lu-177]la and [Lu-177]2. In the pretargeting experiments, tumor uptake of the lead probe [Lu-177]4 (similar to 6 %ID/g) was most closely approached by [Lu-177]2, followed by [Lu-177]3 and [Lu-177]la. While all the smaller and more lipophilic probes suffered from increased liver uptake, the PEG-linked probe [1711]3 with its additional negative charge surprisingly showed the highest kidney uptake among all of the probes.Conclusion: The in vitro performance of some of the new tetrazine probes turned out to be comparable to the established lead probe [Lu-177]Lu-DOTA-PEG(11)-Tz ([Lu-177]4). However, tumor pretargeting studies in vivo showed lower tumor uptake and increased uptake in non-target organs. (C) 2017 Elsevier Inc. All rights reserved.