Targeting the tumor vasculature with engineered cystine-knot miniproteins.,Nature Communications

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Targeting the tumor vasculature with engineered cystine-knot miniproteins.
Nature Communications ( IF 14.7 ) Pub Date : 2020-01-15 , DOI: 10.1038/s41467-019-13948-y
Bonny Gaby Lui ₁ , Nadja Salomon ₁ , Joycelyn Wüstehube-Lausch ₁ , Matin Daneschdar ₁ , Hans-Ulrich Schmoldt ₁ , Özlem Türeci ₁ , Ugur Sahin ₁

Affiliation

The extra domain B splice variant (EDB) of human fibronectin selectively expressed in the tumor vasculature is an attractive target for cancer imaging and therapy. Here, we describe the generation and characterization of EDB-specific optical imaging probes. By screening combinatorial cystine-knot miniprotein libraries with phage display technology we discover exquisitely EDB-specific ligands that share a distinctive motif. Probes with a binding constant in the picomolar range are generated by chemical oligomerization of selected ligands and fluorophore conjugation. We show by fluorescence imaging that the probes stain EDB in tissue sections derived from human U-87 MG glioblastoma xenografts in mice. Moreover, we demonstrate selective accumulation and retention of intravenously administered probes in the tumor tissue of mice with U-87 MG glioblastoma xenografts by in vivo and ex vivo fluorescence imaging. These data warrants further pursuit of the selected cystine-knot miniproteins for in vivo imaging applications.

中文翻译：

用工程化的胱氨酸结小蛋白靶向肿瘤血管。

在肿瘤脉管系统中选择性表达的人纤连蛋白的额外结构域B剪接变体（EDB）是癌症成像和治疗的有吸引力的靶标。在这里，我们描述了EDB专用光学成像探针的生成和表征。通过使用噬菌体展示技术筛选组合的胱氨酸结微蛋白文库，我们发现了具有独特基序的精美EDB特异性配体。结合常数在皮摩尔范围内的探针是通过所选配体的化学低聚和荧光团结合而产生的。我们通过荧光成像表明，探针在小鼠的人类U-87 MG胶质母细胞瘤异种移植物的组织切片中对EDB进行染色。此外，我们通过体内和离体荧光成像展示了静脉注射探针在U-87 MG胶质母细胞瘤异种移植小鼠肿瘤组织中的选择性积累和保留。这些数据保证进一步追求用于体内成像应用的所选胱氨酸结小蛋白。

更新日期：2020-01-15

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