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Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes

Nature Nanotechnology volume 12, pages 589–594 (2017)Cite this article

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Abstract

Intravenously injected nanopharmaceuticals, including PEGylated nanoparticles, induce adverse cardiopulmonary reactions in sensitive human subjects, and these reactions are highly reproducible in pigs. Although the underlying mechanisms are poorly understood, roles for both the complement system and reactive macrophages have been implicated. Here, we show the dominance and importance of robust pulmonary intravascular macrophage clearance of nanoparticles in mediating adverse cardiopulmonary distress in pigs irrespective of complement activation. Specifically, we show that delaying particle recognition by macrophages within the first few minutes of injection overcomes adverse reactions in pigs using two independent approaches. First, we changed the particle geometry from a spherical shape (which triggers cardiopulmonary distress) to either rod- or disk-shape morphology. Second, we physically adhered spheres to the surface of erythrocytes. These strategies, which are distinct from commonly leveraged stealth engineering approaches such as nanoparticle surface functionalization with poly(ethylene glycol) and/or immunological modulators, prevent robust macrophage recognition, resulting in the reduction or mitigation of adverse cardiopulmonary distress associated with nanopharmaceutical administration.

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Figure 1: Graphical and scanning electron microscopy (SEM) representation of spheres, rods and disks.
Figure 2: Changes in complement activation in pig blood, and pig haemodynamic parameters after exposure to spheres (circles), rods (triangles) and disks (squares).
Figure 3: Circulation profile of spheres, rods and disks following intravenous injection into pigs.
Figure 4: Dampening of particle-mediated haemodynamic changes in pigs following pulmonary intravascular macrophage (PIM) depletion.
Figure 5: Overcoming adverse reactions to spheres through erythrocyte ‘hitch-hiking’.

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  • 03 May 2017

    In the version of this Article originally published the first author's middle name was misspelled. His name should have read Peter Popp Wibroe. This has been corrected in all versions of the Article.

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Acknowledgements

S.M.M. acknowledges financial support by the Danish Agency for Science, Technology and Innovation (Det Strategiske Forskningsråd), reference 09-065746. T.E.M. acknowledges financial support from the European Community's Seventh Framework Programme under grant agreement no. 602699 (DIREKT). S.M. acknowledges support from the National Institutes of Health (R01HL129179). The authors thank N. Payemi (University of Copenhagen) for assisting with scanning electron microscopy studies and H. Biotech for providing the pig C5a ELISA kit.

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Authors and Affiliations

  1. Department of Pharmacy, Nanomedicine Laboratory, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen Ø, DK-2100, Denmark

    Peter Popp Wibroe & Seyed Moein Moghimi

  2. Department of Chemical Engineering and Center for Bioengineering, University of California at Santa Barbara, Santa Barbara, 93106, California, USA

    Aaron C. Anselmo, Apoorva Sarode & Samir Mitragotri

  3. Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, 0372, Norway

    Per H. Nilsson & Tom Eirik Mollnes

  4. K.G. Jebsen IRC, University of Oslo, Oslo, 0372, Norway

    Per H. Nilsson & Tom Eirik Mollnes

  5. Linnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, 391 82, Sweden

    Per H. Nilsson

  6. College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, 11439, New York, USA

    Vivek Gupta

  7. Nanomedicine Research and Education Center, Semmelweis University, Budapest & SeroScience Ltd, Budapest, Hungary

    Rudolf Urbanics & Janos Szebeni

  8. Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester, LE1 9BH, UK

    Alan Christy Hunter

  9. Reserach Laboratory, Nordland Hospital, Bodø, 8092, Norway

    Tom Eirik Mollnes

  10. K.G. Jebsen TREC, University of Tromsø, Tromsø, 9037, Norway

    Tom Eirik Mollnes

  11. Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, 7491, Norway

    Tom Eirik Mollnes

  12. Nano-Science Center, University of Copenhagen, Universitetsparken 5, Copenhagen Ø, DK-2100, Denmark

    Seyed Moein Moghimi

  13. School of Medicine, Pharmacy and Health, Durham University, Queen's Campus, Stockton-on-Tees, TS17 6BH, UK

    Seyed Moein Moghimi

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  1. Peter Popp Wibroe
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Contributions

S.M.M. and P.P.W. conceived the idea. P.P.W., A.C.A., P.H.N., A.S., V.G., R.U. and S.M.M. performed experiments. All authors designed, analysed and discussed data. P.P.W. and S.M.M. wrote the paper, with contributions from all authors. All co-authors critically revised the manuscript.

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Correspondence to Seyed Moein Moghimi.

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Wibroe, P., Anselmo, A., Nilsson, P. et al. Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes. Nature Nanotech 12, 589–594 (2017). https://doi.org/10.1038/nnano.2017.47

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