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Targeting the tumor vasculature with engineered cystine-knot miniproteins.


ABSTRACT: 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.

SUBMITTER: Lui BG 

PROVIDER: S-EPMC6962393 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Targeting the tumor vasculature with engineered cystine-knot miniproteins.

Lui Bonny Gaby BG   Salomon Nadja N   Wüstehube-Lausch Joycelyn J   Daneschdar Matin M   Schmoldt Hans-Ulrich HU   Türeci Özlem Ö   Sahin Ugur U  

Nature communications 20200115 1


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 ch  ...[more]

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