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Ferri-liposomes as an MRI-visible drug-delivery system for targeting tumours and their microenvironment

Nature Nanotechnology volume 6, pages 594–602 (2011)Cite this article

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Abstract

The tumour microenvironment regulates tumour progression and the spread of cancer in the body. Targeting the stromal cells that surround cancer cells could, therefore, improve the effectiveness of existing cancer treatments. Here, we show that magnetic nanoparticle clusters encapsulated inside a liposome can, under the influence of an external magnet, target both the tumour and its microenvironment. We use the outstanding T2 contrast properties (r2 = 573–1,286 s−1 mM−1) of these ferri-liposomes, which are ∼95 nm in diameter, to non-invasively monitor drug delivery in vivo. We also visualize the targeting of the tumour microenvironment by the drug-loaded ferri-liposomes and the uptake of a model probe by cells. Furthermore, we used the ferri-liposomes to deliver a cathepsin protease inhibitor to a mammary tumour and its microenvironment in a mouse, which substantially reduced the size of the tumour compared with systemic delivery of the same drug.

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Figure 1: Characterization of the magnetic nanocarrier system.
Figure 2: MR contrast properties of electrostatically stabilized FMIO nanoparticles.
Figure 3: Monitoring the targeting and release of ferri-liposomes in vivo.
Figure 4: Anti-tumour effect of magnetically targeted ferri-liposomes containing cysteine protease inhibitor JPM-565.
Figure 5: In vivo detection of fluorescent ferri-liposomes in tumours.

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Acknowledgements

The authors thank Yu.F. Ivanov (Tomsk Scientific Center) for transmission electron microscopy, G. Kapun (National Institute of Chemistry) for scanning electron microscopy, M. Škarabot (Jozef Stefan Institute) for atomic force microscopy, J. Ščančar and M. Vahčič (Jozef Stefan Institute) for flame atomic absorption spectrometry, I.V. Sukhodolo, R.I. Pleshko, A.N. Dzuman, I.V. Milto and L.M. Ogorodova (Siberian State Medical University) for help in the acute toxicity study, and A. Sepe, M. Butinar, M. Trstenjak-Prebanda and A. Petelin (Jozef Stefan Institute), O.G. Terekhova (Tomsk Scientific Center), M. Tacke and N. Klemm (Institut für Molekulare Medizin und Zellforschung) for technical and methodological assistance, G. Salvesen (Sanford-Burnham Medical Research Institute) for valuable discussions, and R.H. Pain (Jozef Stefan Institute) for critical reading of the manuscript. JPM-565 was kindly provided by the Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute. The research leading to these results was supported in part by the European Community's Seventh Framework Programme FP7/2007-2011 (grant agreement no. 201279, Microenvimet, O.V., T.R., C.P. and B.T.), the Slovenian Research Agency (research grant no. P1-0140, B.T.), the Russian Foundation for Basic Research (project no. 07-04-12170, E.P.N.), the United States Civilian Research and Development Foundation (project no. Y4-C16-05, A.A.M and V.I.I.) and the DFG SFB 850 (to T.R., C.P. and R.Z.).

Author information

Author notes

  1. Ivan Psakhye

    Present address: Present address: Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Martinsried 82152, Germany,

Authors and Affiliations

  1. Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute, Ljubljana, SI-1000, Slovenia

    Georgy Mikhaylov, Ivan Psakhye, Vito Turk, Boris Turk & Olga Vasiljeva

  2. Department of Condensed Matter Physics, Jozef Stefan Institute, Ljubljana, SI-1000, Slovenia

    Ursa Mikac

  3. Centre of Excellence EN-FIST, Ljubljana, SI-1000, Slovenia

    Ursa Mikac

  4. Tomsk Scientific Center, Siberian Branch of Russian Academy of Sciences, Tomsk, 634055, Russia

    Anna A. Magaeva, Volya I. Itin, Evgeniy P. Naiden & Sergey G. Psakhye

  5. Institut für Molekulare Medizin und Zellforschung, Albert-Ludwigs-Universität Freiburg, Freiburg, 79104, Germany

    Liane Babes, Thomas Reinheckel & Christoph Peters

  6. BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-Universität Freiburg, Freiburg, 79104, Germany

    Thomas Reinheckel & Christoph Peters

  7. Department of Hematology and Oncology, University Medical Center Freiburg, Freiburg, 79106, Germany

    Robert Zeiser

  8. Department of Pathology, Microbiology and Immunology, Stanford University School of Medicine, California, 94305, USA

    Matthew Bogyo

  9. Center of Excellence CIPKEBIP, Ljubljana, SI-1000, Slovenia

    Vito Turk & Boris Turk

  10. Institute of Strength Physics and Materials Science, Tomsk, 634021, Russia

    Sergey G. Psakhye

  11. Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, SI-1000, Slovenia

    Boris Turk

  12. Center of Excellence Nanosciences and Nanotechnology, Ljubljana, SI-1000, Slovenia

    Boris Turk

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  1. Georgy Mikhaylov
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Contributions

G.M., U.M., I.P., S.G.P., B.T. and O.V. conceived and designed the experiments. G.M., U.M., L.B. and O.V. performed the experiments. G.M., U.M., S.G.P., B.T. and O.V. analysed the data. T.R., C.P. and R.Z. contributed transgenic mouse models and animal imaging. M.B. contributed JPM-565 inhibitor. A.A.M., V.I.I., E.P.N. and S.G.P. supplied the magnetic nanoparticles. S.G.P., V.T., B.T. and O.V. supervised the project. G.M., S.G.P., B.T. and O.V. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Boris Turk or Olga Vasiljeva.

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The authors declare no competing financial interests.

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Mikhaylov, G., Mikac, U., Magaeva, A. et al. Ferri-liposomes as an MRI-visible drug-delivery system for targeting tumours and their microenvironment. Nature Nanotech 6, 594–602 (2011). https://doi.org/10.1038/nnano.2011.112

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