Angiogenesis

, Volume 17, Issue 1, pp 93–107 | Cite as

Periodicity in tumor vasculature targeting kinetics of ligand-functionalized nanoparticles studied by dynamic contrast enhanced magnetic resonance imaging and intravital microscopy

  • Sjoerd Hak
  • Jana Cebulla
  • Else Marie Huuse
  • Catharina de L. Davies
  • Willem J. M. Mulder
  • Henrik B. W. Larsson
  • Olav Haraldseth
Original Paper

Abstract

In the past two decades advances in the development of targeted nanoparticles have facilitated their application as molecular imaging agents and targeted drug delivery vehicles. Nanoparticle-enhanced molecular imaging of the angiogenic tumor vasculature has been of particular interest. Not only because angiogenesis plays an important role in various pathologies, but also since endothelial cell surface receptors are directly accessible for relatively large circulating nanoparticles. Typically, nanoparticle targeting towards these receptors is studied by analyzing the contrast distribution on tumor images acquired before and at set time points after administration. Although several exciting proof-of-concept studies demonstrated qualitative assessment of relative target concentration and distribution, these studies did not provide quantitative information on the nanoparticle targeting kinetics. These kinetics will not only depend on nanoparticle characteristics, but also on receptor binding and recycling. In this study, we monitored the in vivo targeting kinetics of αvβ3-integrin specific nanoparticles with intravital microscopy and dynamic contrast enhanced magnetic resonance imaging, and using compartment modeling we were able to quantify nanoparticle targeting rates. As such, this approach can facilitate optimization of targeted nanoparticle design and it holds promise for providing more quantitative information on in vivo receptor levels. Interestingly, we also observed a periodicity in the accumulation kinetics of αvβ3-integrin targeted nanoparticles and hypothesize that this periodicity is caused by receptor binding, internalization and recycling dynamics. Taken together, this demonstrates that our experimental approach provides new insights in in vivo nanoparticle targeting, which may proof useful for vascular targeting in general.

Keywords

DCE-MRI Intravital microscopy Targeted nanoparticles Targeting kinetics Vascular targeting 

Supplementary material

10456_2013_9380_MOESM1_ESM.mpg (3.8 mb)
Supplementary material 1 (MPG 3914 kb)
10456_2013_9380_MOESM2_ESM.docx (19 kb)
Supplementary material 2 (DOCX 18 kb)

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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Sjoerd Hak
    • 1
    • 2
    • 7
  • Jana Cebulla
    • 2
    • 7
  • Else Marie Huuse
    • 1
    • 2
    • 7
  • Catharina de L. Davies
    • 3
    • 8
  • Willem J. M. Mulder
    • 4
    • 9
  • Henrik B. W. Larsson
    • 2
    • 5
    • 10
  • Olav Haraldseth
    • 1
    • 2
    • 6
    • 7
  1. 1.MI LabThe Norwegian University of Science and TechnologyTrondheimNorway
  2. 2.Department of Circulation and Medical ImagingThe Norwegian University of Science and TechnologyTrondheimNorway
  3. 3.Department of PhysicsThe Norwegian University of Science and TechnologyTrondheimNorway
  4. 4.Translational and Molecular Imaging InstituteIcahn School of Medicine at Mount SinaiNew YorkUSA
  5. 5.Functional Imaging Unit, Diagnostic DepartmentGlostrup University HospitalGlostrupDenmark
  6. 6.Department of Medical ImagingSt. Olav’s University HospitalTrondheimNorway
  7. 7.MR Senteret, Institutt for sirkulasjon og bildediagnostikkTrondheimNorway
  8. 8.TrondheimNorway
  9. 9.Mount Sinai School of MedicineNew YorkUSA
  10. 10.GlostrupDenmark

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