title: Influence of agglomeration and specific lung lining lipid/protein interaction on short-term inhalation toxicity.
abstract: Lung lining fluid is the first biological barrier nanoparticles (NPs) encounter during inhalation. As previous inhalation studies revealed considerable differences between surface functionalized NPs with respect to deposition and toxicity, our aim was to investigate the influence of lipid and/or protein binding on these processes. Thus, we analyzed a set of surface functionalized NPs including different SiO2 and ZrO2 in pure phospholipids, CuroSurf(TM) and purified native porcine pulmonary surfactant (nS). Lipid binding was surprisingly low for pure phospholipids and only few NPs attracted a minimal lipid corona. Additional presence of hydrophobic surfactant protein (SP) B in CuroSurf(TM) promoted lipid binding to NPs functionalized with Amino or PEG residues. The presence of the hydrophilic SP A in nS facilitated lipid binding to all NPs. In line with this the degree of lipid and protein affinities for different surface functionalized SiO2 NPs in nS followed the same order (SiO2 Phosphate ∼ unmodified SiO2 < SiO2 PEG < SiO2 Amino NPs). Agglomeration and biomolecule interaction of NPs in nS was mainly influenced by surface charge and hydrophobicity. Toxicological differences as observed in short-term inhalation studies (STIS) were mainly influenced by the core composition and/or surface reactivity of NPs. However, agglomeration in lipid media and lipid/protein affinity appeared to play a modulatory role on short-term inhalation toxicity. For instance, lipophilic NPs like ZrO2, which are interacting with nS to a higher extent, exhibited a far higher lung burden than their hydrophilic counterparts, which deserves further attention to predict or model effects of respirable NPs.
authors.affiliation: a BASF SE Material Physics , Ludwigshafen , Germany .
authors.forename: Wendel
authors.initials: W
authors.lastname: Wohlleben
authors.affiliation: b Department of Chemicals and Product Safety , German Federal Institute for Risk Assessment (BfR) , Berlin , Germany .
authors.forename: Marc D
authors.initials: MD
authors.lastname: Driessen
authors.affiliation: c Department of Pharmacy, Biopharmaceutics and Pharmaceutical Technology , Saarland University , Saarbrücken , Germany .
authors.forename: Simon
authors.initials: S
authors.lastname: Raesch
authors.affiliation: c Department of Pharmacy, Biopharmaceutics and Pharmaceutical Technology , Saarland University , Saarbrücken , Germany .
authors.forename: Ulrich F
authors.initials: UF
authors.lastname: Schaefer
authors.affiliation: c Department of Pharmacy, Biopharmaceutics and Pharmaceutical Technology , Saarland University , Saarbrücken , Germany .
authors.forename: Christine
authors.initials: C
authors.lastname: Schulze
authors.affiliation: a BASF SE Material Physics , Ludwigshafen , Germany .
authors.forename: Bernhard von
authors.initials: Bv
authors.lastname: Vacano
authors.affiliation: d IBE R& D gGmbH, Institute for Lung Health , Münster , Germany .
authors.forename: Antje
authors.initials: A
authors.lastname: Vennemann
authors.affiliation: d IBE R& D gGmbH, Institute for Lung Health , Münster , Germany .
authors.forename: Martin
authors.initials: M
authors.lastname: Wiemann
authors.affiliation: c Department of Pharmacy, Biopharmaceutics and Pharmaceutical Technology , Saarland University , Saarbrücken , Germany .
authors.forename: Christian A
authors.initials: CA
authors.lastname: Ruge
authors.affiliation: e BASF SE Biophysics & Proteomics , Ludwigshafen , Germany .
authors.forename: Herbert
authors.initials: H
authors.lastname: Platsch
authors.affiliation: f Biomedical Technology Center , Westfälische Wilhelms-University , Münster , Germany .
authors.forename: Sarah
authors.initials: S
authors.lastname: Mues
authors.affiliation: f Biomedical Technology Center , Westfälische Wilhelms-University , Münster , Germany .
authors.forename: Rainer
authors.initials: R
authors.lastname: Ossig
authors.affiliation: g Department of Proteomics , Helmholtz Centre for Environmental Research (UFZ) , Leipzig , Germany .
authors.forename: Janina M
authors.initials: JM
authors.lastname: Tomm
authors.affiliation: f Biomedical Technology Center , Westfälische Wilhelms-University , Münster , Germany .
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schnekenburger
authors.affiliation: h Institute of Energy and Environmental Technology (IUTA) E.V , Air Quality & Sustainable Nanotechnology , Duisburg , Germany .|i Center for Nanointegration CENIDE , University of Duisburg-Essen , Duisburg , Germany , and.
authors.forename: Thomas A J
authors.initials: TA
authors.lastname: Kuhlbusch
authors.affiliation: b Department of Chemicals and Product Safety , German Federal Institute for Risk Assessment (BfR) , Berlin , Germany .
authors.forename: Andreas
authors.initials: A
authors.lastname: Luch
authors.affiliation: c Department of Pharmacy, Biopharmaceutics and Pharmaceutical Technology , Saarland University , Saarbrücken , Germany .|j Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS) , Helmholtz Centre for Infection Research (HZI) , Saarbrücken , Germany.
authors.forename: Claus-Michael
authors.initials: CM
authors.lastname: Lehr
authors.affiliation: b Department of Chemicals and Product Safety , German Federal Institute for Risk Assessment (BfR) , Berlin , Germany .
authors.forename: Andrea
authors.initials: A
authors.lastname: Haase
mesh_terms: D000818:Animals; D001688:Biological Products / Q000737:chemistry; D001798:Blood Proteins / Q000737:chemistry; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D019570:Inhalation Exposure / Q000009:adverse effects*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D010316:Particle Size; D010743:Phospholipids / Q000737:chemistry*; D011485:Protein Binding; D000066970:Protein Corona / Q000737:chemistry; D011506:Proteins / Q000737:chemistry*; D011663:Pulmonary Surfactants / Q000737:chemistry* / Q000302:isolation & purification; D012822:Silicon Dioxide / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D013499:Surface Properties; D013552:Swine; D015040:Zirconium / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity
chemical_list: D001688:Biological Products; D001798:Blood Proteins; D010743:Phospholipids; D000066970:Protein Corona; D011506:Proteins; D011663:Pulmonary Surfactants; D012822:Silicon Dioxide; D015040:Zirconium; C068291:poractant alfa; C028541:zirconium oxide
keywords: Lipid corona; lung surfactant; protein corona; silica nanoparticles; surface functionalization