title: Interactions between silica nanoparticles and phospholipid membranes.
abstract: Silica nanoparticles (SNPs) are widely used for biomedical applications. However, their parenteral administration may induce hemolysis. Molecular mechanisms leading to this effect are still controversially discussed. We therefore used a combination of biophysical techniques to investigate the interaction of hemolytic and non-hemolytic SNPs with model phospholipid membranes.
  
  
  
  Interaction of SNPs with membranes was studied using a dye-leakage assay, dynamic light scattering (DLS), isothermal titration calorimetry, and solid state nuclear magnetic resonance.
  
  
  
  The dye leakage assay revealed that only hemolytic, negatively charged SNPs, but not non-hemolytic positively charged SNPs, destabilized POPC based phospholipid bilayers. Interaction of SNPs with lipid vesicles leading to particle agglomeration was demonstrated by DLS. Isothermal titration calorimetry confirmed the interaction between negatively charged SNPs and phospholipids, which is characterized by an exothermic reaction enthalpy ΔH(0)SNP of -0.04cal/g at 25°C. Calorimetric titrations at different temperatures revealed a molar heat capacity change of zero. This finding excluded a contribution of electrostatic interactions. Mechanistic insight was provided by solid state phosphorus-31 NMR and deuterium NMR measurements.
  
  
  
  Our results demonstrate that electrostatic interaction between hemolytic SNPs and model phospholipid membranes is negligible. SNPs induce membrane destabilization and adsorptive processes induced by agglomeration of phospholipid vesicles. The interaction is driven by van der Waals forces at the level of the hydration layer on the vesicles surface.
authors.affiliation: Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Basel, Switzerland.
authors.forename: Helene
authors.initials: H
authors.lastname: Kettiger
authors.affiliation: Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Basel, Switzerland.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Québatte
authors.affiliation: Bruker BioSpin AG, Industriestrasse 26, 8117 Fällanden, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Perrone
authors.affiliation: Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Basel, Switzerland. Electronic address: joerg.huwyler@unibas.ch.
authors.forename: Jörg
authors.initials: J
authors.lastname: Huwyler
mesh_terms: D041961:Deuterium Exchange Measurement; D009682:Magnetic Resonance Spectroscopy; D008567:Membranes, Artificial; D053758:Nanoparticles / Q000737:chemistry*; D010713:Phosphatidylcholines / Q000737:chemistry*; D012822:Silicon Dioxide / Q000737:chemistry*
chemical_list: D008567:Membranes, Artificial; D010713:Phosphatidylcholines; D012822:Silicon Dioxide; C017251:1,2-oleoylphosphatidylcholine
keywords: Hemolysis; Isothermal titration calorimetry; Silica nanoparticles; Solid state nuclear magnetic resonance