Peptide-Based Optical uPAR Imaging for Surgery: In Vivo Testing of ICG-Glu-Glu-AE105

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Abstract

Near infrared intra-operative optical imaging is an emerging technique with clear implications for improved cancer surgery by enabling a more distinct delineation of the tumor margins during resection. This modality has the potential to increase the number of patients having a curative radical tumor resection. In the present study, a new uPAR-targeted fluorescent probe was developed and the in vivo applicability was evaluated in a human xenograft mouse model. Most human carcinomas express high level of uPAR in the tumor-stromal interface of invasive lesions and uPAR is therefore considered an ideal target for intra-operative imaging. Conjugation of the flourophor indocyanine green (ICG) to the uPAR agonist (AE105) provides an optical imaging ligand with sufficiently high receptor affinity to allow for a specific receptor targeting in vivo. For in vivo testing, human glioblastoma xenograft mice were subjected to optical imaging after i.v. injection of ICG-AE105, which provided an optimal contrast in the time window 6-24 h post injection. Specificity of the uPAR-targeting probe ICG-AE105 was demonstrated in vivo by 1) no uptake of unconjugated ICG after 15 hours, 2) inhibition of ICG-AE105 tumor uptake by a bolus injection of the natural uPAR ligand pro-uPA, and finally 3) the histological colocalization of ICG-AE105 fluorescence and immunohistochemical detected human uPAR on resected tumor slides. Taken together, our data supports the potential use of this probe for intra-operative optical guidance in cancer surgery to ensure complete removal of tumors while preserving adjacent, healthy tissue.

Original languageEnglish
Article numbere0147428
JournalPloS one
Volume11
Issue number2
Number of pages15
ISSN1932-6203
DOIs
Publication statusPublished - 2016

Keywords

  • Animals
  • Cell Line, Tumor
  • Diagnostic Imaging
  • Dipeptides
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Fluorescent Dyes
  • Humans
  • Indocyanine Green
  • Ligands
  • Mice
  • Mice, Nude
  • Neoplasms
  • Oligopeptides
  • Optical Imaging
  • Peptides
  • Protein Stability
  • Receptors, Urokinase Plasminogen Activator
  • Journal Article

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