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Direct Real‐Time Monitoring of Prodrug Activation by Chemiluminescence
Angewandte Chemie International Edition ( IF 16.6 ) Pub Date : 2018-06-19 , DOI: 10.1002/anie.201804816
Samer Gnaim 1 , Anna Scomparin 2 , Sayantan Das 1 , Rachel Blau 2 , Ronit Satchi-Fainaro 2 , Doron Shabat 1
Affiliation  

The majority of theranostic prodrugs reported so far relay information through a fluorogenic response generated upon release of the active chemotherapeutic agent. A chemiluminescence detection mode offers significant advantages over fluorescence, mainly due to the superior signal‐to‐noise ratio of chemiluminescence. Here we report the design and synthesis of the first theranostic prodrug monitored by a chemiluminescence diagnostic mode. As a representative model, we prepared a prodrug from the chemotherapeutic monomethyl auristatin E, which was modified for activation by β‐galactosidase. The activation of the prodrug in the presence of β‐galactosidase is accompanied by emission of a green photon. Light emission intensities, which increase with increasing concentration of the prodrug, were linearly correlated with a decrease in the viability of a human cell line that stably expresses β‐galactosidase. We obtained sharp intravital chemiluminescent images of endogenous enzymatic activity in β‐galactosidase‐overexpressing tumor‐bearing mice. The exceptional sensitivity achieved with the chemiluminescence diagnostic mode should allow the exploitation of theranostic prodrugs for personalized cancer treatment.

中文翻译:

通过化学发光直接实时监测前药活化

迄今为止,大多数治疗疗法前药都通过释放活性化学治疗剂时产生的荧光反应来传递信息。化学发光检测模式具有比荧光显着的优势,这主要是由于化学发光的信噪比更高。在这里,我们报告通过化学发光诊断模式监测的第一个治疗药物前药的​​设计和合成。作为代表模型,我们从化学治疗性的单甲基澳瑞他汀E制备了前药,该药经β-半乳糖苷酶活化后可被修饰。在存在β-半乳糖苷酶的情况下,前药的活化伴随着绿色光子的发射。发光强度随着前药浓度的增加而增加,与稳定表达β-半乳糖苷酶的人类细胞株活力降低呈线性相关。我们在过表达β-半乳糖苷酶的荷瘤小鼠中获得了内源性酶活性的清晰的体内化学发光图像。化学发光诊断模式具有出色的敏感性,应允许开发治疗性前药用于个性化的癌症治疗。
更新日期:2018-06-19
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