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Targeting the tumor vasculature with engineered cystine-knot miniproteins.
- Source :
-
Nature communications [Nat Commun] 2020 Jan 15; Vol. 11 (1), pp. 295. Date of Electronic Publication: 2020 Jan 15. - Publication Year :
- 2020
-
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.
- Subjects :
- Amino Acid Motifs
Animals
Binding Sites
Cell Line, Tumor
Cystine-Knot Miniproteins chemistry
Cystine-Knot Miniproteins genetics
Cystine-Knot Miniproteins therapeutic use
Fibronectins genetics
Fluorescent Dyes chemistry
Fluorescent Dyes therapeutic use
Glioblastoma diagnostic imaging
Glioblastoma metabolism
Humans
Mice
Mice, Nude
Optical Imaging
Peptide Library
Protein Engineering
Recombinant Proteins chemistry
Recombinant Proteins genetics
Surface Plasmon Resonance
Xenograft Model Antitumor Assays
Cystine-Knot Miniproteins metabolism
Fibronectins metabolism
Glioblastoma blood supply
Recombinant Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 31941901
- Full Text :
- https://doi.org/10.1038/s41467-019-13948-y