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

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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.

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Acknowledgments

We gratefully thank K. Sæterbø for implanting the dorsal window chambers in mice and culturing cells, S. Andersen, K. Pettersen and S. Moestue for providing and taking care of the mice with subcutaneous xenografts used in the in vivo MRI experiments, and B. Ytterhus and L. Dyrnes for preparation of the histological tumor sections. The work was supported by the Norwegian Cancer Society and Medical Imaging Laboratory (MI-lab, NTNU, Norway) and the National Institute of Health National Cancer Institute Grant R01 CA155432 (W.J.M.M.).

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Authors and Affiliations

  1. MI Lab, The Norwegian University of Science and Technology, Trondheim, Norway

    Sjoerd Hak, Else Marie Huuse & Olav Haraldseth

  2. Department of Circulation and Medical Imaging, The Norwegian University of Science and Technology, Trondheim, Norway

    Sjoerd Hak, Jana Cebulla, Else Marie Huuse, Henrik B. W. Larsson & Olav Haraldseth

  3. Department of Physics, The Norwegian University of Science and Technology, Trondheim, Norway

    Catharina de L. Davies

  4. Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Willem J. M. Mulder

  5. Functional Imaging Unit, Diagnostic Department, Glostrup University Hospital, Glostrup, Denmark

    Henrik B. W. Larsson

  6. Department of Medical Imaging, St. Olav’s University Hospital, Trondheim, Norway

    Olav Haraldseth

  7. MR Senteret, Institutt for sirkulasjon og bildediagnostikk, Postboks 8905, 7491, Trondheim, Norway

    Sjoerd Hak, Jana Cebulla, Else Marie Huuse & Olav Haraldseth

  8. Høgskoleringen 5, 7591, Trondheim, Norway

    Catharina de L. Davies

  9. Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1234, New York, NY, 10029, USA

    Willem J. M. Mulder

  10. Ndr. Ringvej 57, 2600, Glostrup, Denmark

    Henrik B. W. Larsson

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  1. Sjoerd Hak
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Correspondence to Sjoerd Hak.

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Hak, S., Cebulla, J., Huuse, E.M. et al. Periodicity in tumor vasculature targeting kinetics of ligand-functionalized nanoparticles studied by dynamic contrast enhanced magnetic resonance imaging and intravital microscopy. Angiogenesis 17, 93–107 (2014). https://doi.org/10.1007/s10456-013-9380-7

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  • DOI: https://doi.org/10.1007/s10456-013-9380-7

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