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  • 1.
    Wibroe, Peter Popp
    et al.
    Univ Copenhagen, Denmark.
    Anselmo, Aaron C
    Univ Calif Santa Barbara, USA.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. University of Oslo, Norway ;Oslo Univ Hosp, Rikshosp, NorwayRikshospitalet.
    Sarode, Apoorva
    Univ Calif Santa Barbara, USA.
    Gupta, Vivek
    St Johns Univ, USA.
    Urbanics, Rudolf
    Semmelweis Univ, Hungary.
    Szebeni, Janos
    Semmelweis Univ, Hungary.
    Hunter, Alan Christy
    Montfort Univ, UK.
    Mitragotri, Samir
    Univ Calif Santa Barbara, USA.
    Mollnes, Tom Eirik
    University of Oslo, Norway ;Oslo Univ Hosp, Rikshosp, NorwayRikshospitalet ; Nordland Hosp, Norway ; Univ Tromso, Norway ; Norwegian Univ Sci & Technol, Norway.
    Moghimi, Seyed Moein
    Univ Copenhagen, Denmark ; Univ Durham, UK.
    Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes.2017In: Nature Nanotechnology, ISSN 1748-3387, E-ISSN 1748-3395, Vol. 12, no 6, p. 589-594Article in journal (Refereed)
    Abstract [en]

    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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