title: Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes.
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.
authors.affiliation: Nanomedicine Laboratory, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Peter Popp
authors.initials: PP
authors.lastname: Wibroe
authors.affiliation: Department of Chemical Engineering and Center for Bioengineering, University of California at Santa Barbara, Santa Barbara, California 93106, USA.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Anselmo
authors.affiliation: Department of Immunology, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway.|K.G. Jebsen IRC, University of Oslo, 0372 Oslo, Norway.|Linnaeus Centre for Biomaterials Chemistry, Linnaeus University, 391 82 Kalmar, Sweden.
authors.forename: Per H
authors.identifier: 0000-0002-7192-5794
authors.initials: PH
authors.lastname: Nilsson
authors.affiliation: Department of Chemical Engineering and Center for Bioengineering, University of California at Santa Barbara, Santa Barbara, California 93106, USA.
authors.forename: Apoorva
authors.initials: A
authors.lastname: Sarode
authors.affiliation: College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York 11439, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Gupta
authors.affiliation: Nanomedicine Research and Education Center, Semmelweis University, Budapest &SeroScience Ltd, Budapest, Hungary.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Urbanics
authors.affiliation: Nanomedicine Research and Education Center, Semmelweis University, Budapest &SeroScience Ltd, Budapest, Hungary.
authors.forename: Janos
authors.initials: J
authors.lastname: Szebeni
authors.affiliation: Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK.
authors.forename: Alan Christy
authors.initials: AC
authors.lastname: Hunter
authors.affiliation: Department of Chemical Engineering and Center for Bioengineering, University of California at Santa Barbara, Santa Barbara, California 93106, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Mitragotri
authors.affiliation: Department of Immunology, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway.|K.G. Jebsen IRC, University of Oslo, 0372 Oslo, Norway.|Reserach Laboratory, Nordland Hospital, 8092 Bodø, Norway.|K.G. Jebsen TREC, University of Tromsø, 9037 Tromsø, Norway.|Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
authors.forename: Tom Eirik
authors.initials: TE
authors.lastname: Mollnes
authors.affiliation: Nanomedicine Laboratory, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.|Nano-Science Center, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen Ø, Denmark.|School of Medicine, Pharmacy and Health, Durham University, Queen's Campus, Stockton-on-Tees TS17 6BH, UK.
authors.forename: Seyed Moein
authors.initials: SM
authors.lastname: Moghimi
mesh_terms: D000818:Animals; D003167:Complement Activation / Q000187:drug effects; D004912:Erythrocytes / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D053758:Nanoparticles / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D013552:Swine
chemical_list: D011092:Polyethylene Glycols