Non-invasive monitoring of tumor-vessel infarction by retargeted truncated tissue factor tTF–NGR using multi-modal imaging
- 583 Downloads
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.
KeywordsMolecular imaging Magnetic resonance imaging Ultrasound imaging Truncated tissue factor Tumor targeting Vascular targeting Tumor vessel infarction Tumor-homing peptides
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.
- 12.Kessler TA, Pfeifer A, Silletti S, Mesters RM, Berdel WE, Verma I, Cheresh D (2002) Matrix metalloproteinase/integrin interactions as target for anti-angiogenic treatment strategies. Ann Hematol 8(Suppl. 2):S69–S70Google Scholar
- 31.Bieker R, Kessler T, Schwöppe C, Padró T, Persigehl T, Bremer C, Dreischalück J, Kolkmeyer A, Heindel W, Mesters RM, Berdel WE (2009) Infarction of tumor vessels by NGR-peptide directed targeting of tissue factor. Experimental results and first-in-man experience. Blood 113:5019–5027PubMedCrossRefGoogle Scholar
- 38.Dreischalück J, Schwöppe C, Spieker T, Kessler T, Tiemann K, Liersch R, Schliemann C, Kreuter M, Kolkmeyer A, Hintelmann H, Mesters RM, Berdel WE (2010) Vascular infarction by subcutaneous application of tissue factor targeted to tumor vessels with NGR-peptides: activity and toxicity profile. Int J Oncol 37:1389–1397PubMedGoogle Scholar
- 40.Schwöppe C, Zerbst C, Fröhlich M, Schliemann C, Kessler T, Liersch R, Overkamp L, Holtmeier R, Stypmann J, Dreiling A, König S, Höltke C, Lücke M, Müller-Tidow C, Mesters RM, Berdel WE (2013) Anticancer therapy by tumor vessel infarction with polyethylene glycol conjugated retargeted tissue factor. J Med Chem 56(6):2337–2347PubMedCrossRefGoogle Scholar
- 50.Kim KW, Lee JM, Jeon YS, et al. (2013) Vascular disrupting effect of CKD-516: preclinical study using DCE-MRI. Invest New Drugs. doi: 10.1007/s10637-012-9915-6
- 51.Shenoi MM, Iltis I, Choi J, et al. (2013) Nanoparticle Delivered Vascular Disrupting Agents (VDAs): Use of TNF-alpha conjugated Gold Nanoparticles for Multimodal Cancer Therapy. Mol Pharm. doi: 10.1021/mp300505w