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Angiogenesis

, Volume 17, Issue 1, pp 235–246 | Cite as

Non-invasive monitoring of tumor-vessel infarction by retargeted truncated tissue factor tTF–NGR using multi-modal imaging

  • Thorsten Persigehl
  • Janine Ring
  • Christoph Bremer
  • Walter Heindel
  • Richard Holtmeier
  • Jörg Stypmann
  • Michael Claesener
  • Sven Hermann
  • Michael Schäfers
  • Caroline Zerbst
  • Christoph Schliemann
  • Rolf M. Mesters
  • Wolfgang E. Berdel
  • Christian SchwöppeEmail author
Original Paper

Abstract

The fusion protein tTF–NGR consists of the extracellular domain of the thrombogenic human tissue factor (truncated tissue factor, tTF) and the peptide GNGRAHA (NGR), a ligand of the surface protein CD13 (aminopeptidase N), upregulated on endothelial cells of tumor vessels. tTF–NGR preferentially activates blood coagulation within tumor vasculature, resulting in tumor vessel infarction and subsequent tumor growth retardation/regression. The anti-vascular mechanism of the tTF–NGR therapy approach was verified by quantifying the reduced tumor blood-perfusion with contrast-enhanced ultrasound, the reduced relative tumor blood volume by ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging, and by in vivo-evaluation of hemorrhagic bleeding with fluorescent biomarkers (AngioSense680) in fluorescence reflectance imaging. The accumulation of tTF–NGR within the tumor was proven by visualizing the distribution of the iodine-123-labelled protein by single-photon emission computed tomography. Use of these multi-modal vascular and molecular imaging tools helped to assess the therapeutic effect even at real time and to detect non-responding tumors directly after the first tTF–NGR treatment. This emphasizes the importance of imaging within clinical studies with tTF–NGR. The imaging techniques as used here have applicability within a wider scope of therapeutic regimes interfering with tumor vasculature. Some even are useful to obtain predictive biosignals in personalized cancer treatment.

Keywords

Molecular imaging Magnetic resonance imaging Ultrasound imaging Truncated tissue factor Tumor targeting Vascular targeting Tumor vessel infarction Tumor-homing peptides 

Notes

Acknowledgments

We would like to thank Ina Winkler, Kathrin Höke, Klaudia Niepagenkemper, Justina Mbah, Rebecca Roß, Heike Hintelmann and Dirk Reinhardt for technical assistance. J.R. and C.Z. contributed experiments in partial fulfillment of the requirements to obtain a PhD title. This work was supported by grants of the Deutsche Krebshilfe e.V. (109245 to W.E. Berdel), the Deutsche Forschungsgemeinschaft [SFB656, projects C08, C03, C06, and Z05, EXC 1,003 Cells in Motion-Cluster of Excellence), the Sybille-Hahne-Stiftung, and the Interdisziplinäres Zentrum für Klinische Forschung (IZKF, Core Unit PIX (SmAP, SAMRI, ECHO, OPTI)].

Conflict of interest

R.M.M. and W.E.B. share a patent on vascular targeting with TF constructs. The other authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Thorsten Persigehl
    • 1
    • 8
  • Janine Ring
    • 1
  • Christoph Bremer
    • 1
  • Walter Heindel
    • 1
  • Richard Holtmeier
    • 2
  • Jörg Stypmann
    • 2
    • 3
  • Michael Claesener
    • 4
  • Sven Hermann
    • 5
  • Michael Schäfers
    • 4
    • 5
  • Caroline Zerbst
    • 6
  • Christoph Schliemann
    • 6
  • Rolf M. Mesters
    • 6
  • Wolfgang E. Berdel
    • 6
    • 7
  • Christian Schwöppe
    • 6
    Email author
  1. 1.Department of Clinical RadiologyUniversity of MuensterMünsterGermany
  2. 2.Interdisciplinary Center of Clinical Research (IZKF Muenster)University of MuensterMünsterGermany
  3. 3.Division of Cardiology, Department of Cardiovascular MedicineUniversity of MuensterMünsterGermany
  4. 4.Department of Nuclear MedicineUniversity of MuensterMünsterGermany
  5. 5.European Institute for Molecular Imaging (EIMI), Mendelstr. 11University of MuensterMünsterGermany
  6. 6.Department of Medicine A (Hematology, Hemostaseology, Oncology and Pneumology)University of MuensterMünsterGermany
  7. 7.Cluster of Excellence EXC 1003-Cells in MotionUniversity of MuensterMünsterGermany
  8. 8.Department of Clinical RadiologyUniversity Hospital CologneCologneGermany

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