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Dendrimer Scaffold for the Amplification of In Vivo Pretargeting Ligations
Bioconjugate Chemistry ( IF 4.7 ) Pub Date : 2018-07-03 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00385
Brendon E. Cook 1, 2, 3 , Rosemery Membreno 1, 2 , Brian M. Zeglis 1, 2, 3, 4
Affiliation  

The development of immunoconjugates requires a careful balance between preserving the functionality of the antibody and modifying the immunoglobulin with the desired cargo. Herein, we describe the synthesis, development, and in vivo evaluation of a novel bifunctional dendrimeric scaffold and its application in pretargeted PET imaging. The site-specific modification of the huA33 antibody with this dendrimeric scaffold yields an immunoconjugate—sshuA33-DEN-TCO—decorated with ∼8 trans-cyclooctene (TCO) moieties, a marked increase compared to the ∼2 TCO/mAb of a nondendrimeric control immunoconjugate (sshuA33-PEG12-TCO). Pretargeted PET imaging and biodistribution experiments were used to compare the in vivo performance of these two immunoconjugates in athymic nude mice bearing subcutaneous SW1222 human colorectal cancer xenografts. To this end, the mice were administered 100 μg of each immunoconjugate followed 120 h later by the injection of a tetrazine-bearing radioligand, [64Cu]Cu-SarAr-Tz. Pretargeting with sshuA33-DEN-TCO produced excellent tumoral uptake at 24 h (8.9 ± 1.9 %ID/g), more than double that created by sshuA33-PEG12-TCO (4.1 ± 1.3 %ID/g). Critically—and somewhat surprisingly—the attachment of the G0.5 dendrimeric structures did not hamper the in vivo behavior of the immunoconjugate, suggesting that this versatile bifunctional scaffold may have applications beyond pretargeting.

中文翻译:

树枝状大分子支架用于体内预靶向结扎的扩增

免疫缀合物的开发需要在保持抗体的功能性和用所需的货物修饰免疫球蛋白之间进行仔细的平衡。在这里,我们描述了新型双功能树枝状支架的合成,开发和体内评估及其在预靶向PET成像中的应用。huA33抗体在该树枝状支架上的位点特异性修饰产生了一个免疫缀合物ss huA33-DEN-TCO,修饰了约8个反式-环辛烯(TCO)部分,与非树枝状聚合物的约2个TCO / mAb相比,显着增加对照免疫偶联物(ss huA33-PEG 12-TCO)。使用预靶向的PET成像和生物分布实验来比较这两种免疫缀合物在携带有皮下SW1222人结直肠癌异种移植物的无胸腺裸鼠中的体内表现。为此,给小鼠施用100μg的每种免疫缀合物,然后在120小时后注射带有四嗪的放射性配体[ 64 Cu] Cu-SarAr-Tz。用ss huA33-DEN-TCO进行预靶向可在24 h产生出色的肿瘤吸收(8.9±1.9%ID / g),是ss huA33-PEG 12 -TCO(4.1±1.3%ID / g)的两倍多。至关重要的(有些令人惊讶的是)G 0.5的附着 树状结构不妨碍免疫缀合物的体内行为,表明这种多功能的双功能支架可能具有超越预靶向的应用。
更新日期:2018-07-03
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