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Squalenoyl adenosine nanoparticles provide neuroprotection after stroke and spinal cord injury

Nature Nanotechnology volume 9, pages 1054–1062 (2014)Cite this article

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Abstract

There is an urgent need to develop new therapeutic approaches for the treatment of severe neurological trauma, such as stroke and spinal cord injuries. However, many drugs with potential neuropharmacological activity, such as adenosine, are inefficient upon systemic administration because of their fast metabolization and rapid clearance from the bloodstream. Here, we show that conjugation of adenosine to the lipid squalene and the subsequent formation of nanoassemblies allows prolonged circulation of this nucleoside, providing neuroprotection in mouse stroke and rat spinal cord injury models. The animals receiving systemic administration of squalenoyl adenosine nanoassemblies showed a significant improvement of their neurologic deficit score in the case of cerebral ischaemia, and an early motor recovery of the hindlimbs in the case of spinal cord injury. Moreover, in vitro and in vivo studies demonstrated that the nanoassemblies were able to extend adenosine circulation and its interaction with the neurovascular unit. This Article shows, for the first time, that a hydrophilic and rapidly metabolized molecule such as adenosine may become pharmacologically efficient owing to a single conjugation with the lipid squalene.

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Figure 1: Preparation and characterization of SQAd nanoassemblies (NAs).
Figure 2: Systemic administration of SQAd nanoassemblies (NAs) provides significant neuroprotection in a mouse model of cerebral ischaemia.
Figure 3: Pharmacological efficiency of the SQAd nanoassemblies (NAs) in a model of spinal cord injury in rats.
Figure 4: Absence of side effects and systemic toxicity following intravenous injection of SQAd nanoassemblies (NAs).
Figure 5: SQAd nanoassemblies (NAs) are a reservoir of adenosine in the systemic circulation.
Figure 6: Internalization of the SQAd nanoassemblies (NAs) by human cerebral endothelial cells (hCMEC/D3).

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  • 03 December 2014

    In the version of this Article originally published, the affiliations of Hakan Eroglu, Omer Faruk Turkoglu, Seçil Caban, Oya Tagit, Niko Hildebrandt and Yilmaz Capan were incorrect. This error has now been corrected in the online versions of the Article.

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Acknowledgements

The research leading to these results received funding from the European Research Council (allocated to P.C.), under the European Community's Seventh Framework Programme FP7/2007-2013 (grant agreement no. 249835). A.G. is supported by a NerF-ENP fellowship provided by the Région Ile-de-France. T.D.'s work is supported by the Turkish Academy of Sciences. M.Y. is supported by a limited grant by L'Oréal, Turkey. H.E. has been supported by the Hacettepe University Scientific Research Project (project no. 013D04301002). O.T. is supported by the European Union Seventh Framework Programme FP7/2007-2013 (grant agreement no. 246556). The authors thank D. Sobot (Institut Galien Paris-Sud XI) for help with flow cytometry experiments, O. Bawa and P. Opolon (Institut Gustave Roussy) for analysis of the morphology on stained slides, M. Wittner (Institut Gustave Roussy) for the haematology study, S. Beurlet (VEBIO Lab) for biochemical dosages and M. Parrod (Bertin PHARMA) for the radio-HPLC analysis.

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Authors and Affiliations

  1. Institut Galien Paris-Sud UMR CNRS 8612, Faculty of Pharmacy, University of Paris-Sud XI, Châtenay-Malabry, 92296, France

    Alice Gaudin, Sinda Lepetre-Mouelhi, Julie Mougin, Sabrina Valetti, Hélène Chacun, Didier Desmaële, Karine Andrieux & Patrick Couvreur

  2. Labex d'Excellence NanoSaclay,

    Alice Gaudin, Sinda Lepetre-Mouelhi, Julie Mougin, Sabrina Valetti, Hélène Chacun, Didier Desmaële, Karine Andrieux & Patrick Couvreur

  3. Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, 06100, Turkey

    Müge Yemisci, Buket Dönmez-Demir & Turgay Dalkara

  4. Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara, 06100, Turkey

    Hakan Eroglu, Seçil Caban & Yilmaz Capan

  5. Department of Neurosurgery, Ankara Ataturk Research & Education Hospital, Bilkent Ankara, 06800, Turkey

    Omer Faruk Turkoglu

  6. Department of Anatomy, Faculty of Medicine, Hacettepe University, Ankara, 06100, Turkey

    Mustafa Fevzi Sargon

  7. CEA Saclay, iBiTecS-S/SCBM, Labex LERMIT, Gif-sur-Yvette, 91191, France

    Sébastien Garcia-Argote, Grégory Pieters, Olivier Loreau & Bernard Rousseau

  8. NanoBioPhotonics, Institut d'Electronique Fondamentale, University of Paris-Sud XI, Orsay Cedex, 91405, France

    Oya Tagit & Niko Hildebrandt

  9. EA3544, Faculty of Pharmacy, University of Paris-Sud XI, Châtenay-Malabry, 92296, France

    Yannick Le Dantec

  10. Institut d'Innovation Thérapeutique, IFR141 ITFM, Faculty of Pharmacy, University of Paris-Sud XI, Châtenay-Malabry, 92296, France

    Valérie Nicolas

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  1. Alice Gaudin
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Contributions

P.C. and T.D. conceived and designed the research. A.G. designed and performed the nanoparticle preparation, the side effects and toxicity experiments, the stability and in vivo pharmacokinetic/biodistribution studies and the in vitro experiments. S.L. developed and performed the SQAd synthesis, D.D. helped with analysing the chemical results. B.R., S.G.A., G.P. and O.L. developed and performed the radiolabelled compound synthesis. T.D. and M.Y. designed and performed the cerebral ischaemia experiments. B.D-D. performed the histological stainings and countings for cerebral ischaemia experiments. S.C. and Y.C. were in charge of nanoparticle preparation for the cerebral ischaemia experiments. H.E., O.F.T. and A.G. designed and performed the spinal cord injury experiments. M.F.Z. performed the ultrastructural evaluation of the spinal cord injury experiments. A.G., O.T. and N.H designed and performed the FRET nanoassemblies experiments. Y.L.D and A.G. performed the sleep cycle experiments. J.M. performed the HPLC analysis. S.V. performed the complement activation experiments. H.C. helped to analyse the radioactivity data and V.N. helped to analyse the confocal data. P.C., T.D., K.A., A.G. and M.Y. co-wrote the paper. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Karine Andrieux or Patrick Couvreur.

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The authors declare no competing financial interests.

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Gaudin, A., Yemisci, M., Eroglu, H. et al. Squalenoyl adenosine nanoparticles provide neuroprotection after stroke and spinal cord injury. Nature Nanotech 9, 1054–1062 (2014). https://doi.org/10.1038/nnano.2014.274

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