Mechanism of interaction of nanoparticles with plasma proteins

Zhou Deng (2011). Mechanism of interaction of nanoparticles with plasma proteins PhD Thesis, School of Biomedical Sciences, The University of Queensland.

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Author Zhou Deng
Thesis Title Mechanism of interaction of nanoparticles with plasma proteins
School, Centre or Institute School of Biomedical Sciences
Institution The University of Queensland
Publication date 2011-07
Thesis type PhD Thesis
Supervisor Professor Rodney Minchin
Associate Professor Darren Martin
Total pages 123
Total colour pages 7
Total black and white pages 114
Language eng
Subjects 11 Medical and Health Sciences
Abstract/Summary The chemical composition, size, shape and surface characteristics of nanoparticles affect the way proteins bind to them and this, in turn, influences the way nanoparticles interact with cells and tissues. Nanoparticles bound with proteins can result in physiological and pathological changes, such as macrophage uptake, blood coagulation, protein aggregation and complement activation, but the mechanisms that lead to these changes remain poorly understood. This project first investigated the binding of human plasma proteins to commercially available TiO2, SiO2 and ZnO nanoparticles using centrifugation, followed by 2-dimensional gel electrophoresis and mass spectrometry. We found that, despite these nanoparticle having similar surface charges in buffer, they bound different plasma proteins. Agglomeration in water was observed for all of these nanoparticles and both TiO2 and ZnO further agglomerated in biological media. This led to an increase in the amount and number of different proteins bound to these nanoparticles. Using synthetic TiO2 nanorods and nanotubes, we found that the shape of the nanoparticles was also an important determinant of protein binding. Based on these results, we synthesized precisely engineered polymer-coated gold nanoparticles to study the effects of size and charge on protein binding. It was demonstrated that the polymer coat determined the surface interaction with the proteins. We found that fibrinogen was one of the commonly bound proteins to both positively and negatively charged nanoparticles. Using centrifugation techniques and enzymatic digestions, further investigation revealed differential mechanisms of fibrinogen binding by these two nanoparticles. Noticeably, the neutral hydrophilic polymers, even incorporated at a small amount, could effectively reduce the protein binding. We then showed that negatively charged poly(acrylic acid)-conjugated gold nanoparticles bind to and induce unfolding of fibrinogen. This exposed a cryptic peptide located in the C-terminus of the fibrinogen γ chain. The exposed peptide specifically interacted with Mac-1 receptors on human monocytic cells, which activated the NF-ĸB signalling pathway and led to the release of inflammatory cytokines, TNF-α and IL-8. This work identified a novel mechanism for inflammatory reactions towards nanomaterials. Interestingly, not all nanoparticles that bind to fibrinogen demonstrated this effect, as it was size-dependent as most prominent with particles of approximately 5 nm diameter. To examine the effects of size, we further investigated the interaction of fibrinogen with nanoparticles ranging from 5-22 nm in diameters. Based on the binding isotherms and kinetics of the interaction, a model for the high-affinity binding to fibrinogen was developed. The model revealed that the binding configuration of fibrinogen to the larger nanoparticles led to steric hindrance that prevented interaction with the Mac-1 receptor. Furthermore, it was demonstrated that, by fine tuning the surface characteristics and size of the particle, the potential adverse effects were avoidable. In addition, protein-induced nanoparticle aggregation was investigated.
Keyword nanoparticle
plasma protein
metal oxide
Additional Notes Printed in colour: 15, 18, 19, 75, 81, 104, 107 Landscape: 26, 27, 28

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Created: Fri, 02 Dec 2011, 12:31:52 EST by Zhou Deng on behalf of Library - Information Access Service