Molecular Imaging and Biology

, Volume 18, Issue 2, pp 191–200 | Cite as

Dynamic Measurement of Tumor Vascular Permeability and Perfusion using a Hybrid System for Simultaneous Magnetic Resonance and Fluorescence Imaging

  • Wuwei Ren
  • Andreas Elmer
  • David Buehlmann
  • Mark-Aurel Augath
  • Divya Vats
  • Jorge Ripoll
  • Markus Rudin
Research Article



Assessing tumor vascular features including permeability and perfusion is essential for diagnostic and therapeutic purposes. The aim of this study was to compare fluorescence and magnetic resonance imaging (MRI)-based vascular readouts in subcutaneously implanted tumors in mice by simultaneous dynamic measurement of tracer uptake using a hybrid fluorescence molecular tomography (FMT)/MRI system.


Vascular permeability was measured using a mixture of extravascular imaging agents, GdDOTA and the dye Cy5.5, and perfusion using a mixture of intravascular agents, Endorem and a fluorescent probe (Angiosense). Dynamic fluorescence reflectance imaging (dFRI) was integrated into the hybrid system for high temporal resolution.


Excellent correspondence between uptake curves of Cy5.5/GdDOTA and Endorem/Angiosense has been found with correlation coefficients R > 0.98. The two modalities revealed good agreement regarding permeability coefficients and centers-of-gravity of the imaging agent distribution.


The FMT/dFRI protocol presented is able to accurately map physiological processes and poses an attractive alternative to MRI for characterizing tumor neoangiogenesis.

Key words

Fluorescence molecular tomography MRI Simultaneous hybrid measurements Tumor angiogenesis Vascular permeability Perfusion 



The authors acknowledge funding by the National Competence Center for Biomedical Imaging NCCBI (AE) and the European Frame Program FP7 (FMTXCT; MR). We are also grateful to Markus Küpfer (ETHZ) for excellent technical support.

Conflict of Interest

The authors declare no conflict of interest regarding this study.

Supplementary material

11307_2015_884_MOESM1_ESM.pdf (4.2 mb)
ESM 1 (PDF 4275 kb)


  1. 1.
    Ntziachristos V, Ripoll J, Wang LV, Weissleder R (2005) Looking and listening to light: the evolution of whole-body photonic imaging. Nat Biotechnol 23:313–320CrossRefPubMedGoogle Scholar
  2. 2.
    Ntziachristos V (2010) Going deeper than microscopy: the optical imaging frontier in biology. Nat Meth 7:603–614CrossRefGoogle Scholar
  3. 3.
    Darne C, Lu Y, Sevick-Muraca EM (2013) Small animal fluorescence and bioluminescence tomography: a review of approaches, algorithms and technology update. Phys Med Biol 59:R1–R64CrossRefPubMedGoogle Scholar
  4. 4.
    Ntziachristos V, Tung C-H, Bremer C, Weissleder R (2002) Fluorescence molecular tomography resolves protease activity in vivo. Nat Med 8:757–761CrossRefPubMedGoogle Scholar
  5. 5.
    Rudin M (2005) Molecular imaging: principles and applications in biomedical research. Imperial College Press, pp 114–134Google Scholar
  6. 6.
    Ale A, Ermolayev V, Herzog E et al (2012) FMT-XCT: in vivo animal studies with hybrid fluorescence molecular tomography–X-ray computed tomography. Nat Meth 9:615–620CrossRefGoogle Scholar
  7. 7.
    Stuker F, Baltes C, Dikaiou K et al (2011) Hybrid small animal imaging system combining magnetic resonance imaging with fluorescence tomography using single photon avalanche diode detectors. IEEE Trans Med Imaging 30:1265–1273CrossRefPubMedGoogle Scholar
  8. 8.
    Judenhofer MS, Wehrl HF, Newport DF et al (2008) Simultaneous PET-MRI: a new approach for functional and morphological imaging. Nat Med 14:459–465CrossRefPubMedGoogle Scholar
  9. 9.
    Zhang K, Herzog H, Mauler J et al (2014) Comparison of cerebral blood flow acquired by simultaneous [15O] water positron emission tomography and arterial spin labeling magnetic resonance imaging. J Cereb Blood Flow Metab 34:1373–1380CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Weis SM, Cheresh DA (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17:1359–1370CrossRefPubMedGoogle Scholar
  11. 11.
    Jahng G-H, Li K-L, Ostergaard L, Calamante F (2014) Perfusion magnetic resonance imaging: a comprehensive update on principles and techniques. Korean J Radiol 15:554–577CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Ostergaard L (2005) Principles of cerebral perfusion imaging by bolus tracking. J Magn Reson Imaging 22:710–717CrossRefPubMedGoogle Scholar
  13. 13.
    Rudin M, McSheehy PMJ, Allegrini PR et al (2005) PTK787/ZK222584, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor, reduces uptake of the contrast agent GdDOTA by murine orthotopic B16/BL6 melanoma tumours and inhibits their growth in vivo. NMR Biomed 18:308–321CrossRefPubMedGoogle Scholar
  14. 14.
    Eisenblätter M, Höltke C, Persigehl T, Bremer C (2010) Optical techniques for the molecular imaging of angiogenesis. Eur J Nucl Med Mol Imaging 37:127–137CrossRefGoogle Scholar
  15. 15.
    Wall A, Persigehl T, Hauff P et al (2008) Differentiation of angiogenic burden in human cancer xenografts using a perfusion-type optical contrast agent (SIDAG). Breast Cancer Res 10:R23CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Montet X, Figueiredo J-L, Alencar H et al (2007) Tomographic fluorescence imaging of tumor vascular volume in mice. Radiology 242:751–758CrossRefPubMedGoogle Scholar
  17. 17.
    Ntziachristos V, Yodh AG, Schnall M, Chance B (2000) Concurrent MRI and diffuse optical tomography of breast after indocyanine green enhancement. Proc Natl Acad Sci U S A 97:2767–2772CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Davis SC, Samkoe KS, Tichauer KM et al (2013) Dynamic dual-tracer MRI-guided fluorescence tomography to quantify receptor density in vivo. Proc Natl Acad Sci U S A 110:9025–9030CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Choi M, Choi K, Ryu S-W et al (2011) Dynamic fluorescence imaging for multiparametric measurement of tumor vasculature. J Biomed Opt 16:046008CrossRefPubMedGoogle Scholar
  20. 20.
    Ntziachristos V, Weissleder R (2001) Experimental three-dimensional fluorescence reconstruction of diffuse media by use of a normalized Born approximation. Opt Lett 26:893–895CrossRefPubMedGoogle Scholar
  21. 21.
    Hyde D, DeKleine R, MacLaurin S et al (2008) Hybrid FMT-CT imaging of amyloid-b plaques in a murine Alzheimer’s disease model. Neuroimage. doi: 10.1016/j.neuroimage.2008.10.038 Google Scholar
  22. 22.
    Schweiger M, Arridge S (2014) The Toast++ software suite for forward and inverse modeling in optical tomography. J Biomed Opt 19:040801CrossRefPubMedGoogle Scholar

Copyright information

© World Molecular Imaging Society 2015

Authors and Affiliations

  • Wuwei Ren
    • 1
  • Andreas Elmer
    • 1
  • David Buehlmann
    • 1
  • Mark-Aurel Augath
    • 1
  • Divya Vats
    • 1
  • Jorge Ripoll
    • 2
    • 3
  • Markus Rudin
    • 1
    • 4
    • 5
  1. 1.Institute for Biomedical EngineeringUniversity and ETH ZürichZürichSwitzerland
  2. 2.Department of BioengineeringUniversidad Carlos III of MadridMadridSpain
  3. 3.Medical Imaging LaboratoryHospital General Gregorio MarañónMadridSpain
  4. 4.Institute of Pharmacology and ToxicologyUniversity of ZürichZürichSwitzerland
  5. 5.Experimental and Clinical Imaging Technologies (EXCITE)ZürichSwitzerland

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