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Title: The safety and immunostimulatory properties of amorphous silica nanoparticles < 10 nm in diameter
Author: Vis, Bradley
ISNI:       0000 0004 7227 2195
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2018
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Humans are exposed to high levels of amorphous silica on a daily basis, via the diet and the use of cosmetic and pharmaceutical products. Amorphous silica particles (10-200 nm) have also been developed for use in biomedical applications, including as binding agents in tissue repair, drug and gene therapy delivery agents, coatings for medical contrast agents and as vaccine adjuvants. Numerous studies have already been conducted to evaluate the cellular toxicity of these silica particles but still little is known about their effects both in vitro and in vivo, especially of nanosilica particles under 10 nm in diameter. The aim of this thesis was to investigate the cellular and in vivo activity of < 10 nm diameter nanosilica particles with different properties (e.g., size and dissolution rate in dilute conditions) as it may infer upon safety after exposure via the diet and intravenous administration (biomedical applications). First, the cytotoxicity of sub-10 nm nanosilica particles, fully characterized by size, dissolution rate, zeta-potential and by NMR spectroscopy, on immune cell function was assessed using transformed and cancerous cell lines and primary cells. The particles were toxic to the immune cells in a dose dependent manner and impaired certain cellular functions. Primary cells were most susceptible to nanosilica induced death and, of the primary cells, phagocytes were most susceptible to its cytotoxicity. Further investigations were conducted to assess the effect of nanosilica on T cells, as there was evidence suggesting that nanosilica particles were directly interacting with these cells. Nanosilica particles 3.6 nm in diameter were found to have a significant effect on T cell function. The particles induced numerous markers of T cell activation, including CD25 and CD69 on CD4 T cells, CD8 T cells, gamma-delta T cells and NK/NKT cells, CD95 on CD4 and CD8 T cells, CD40L, FoxP3, LAP, GARP on CD4 T cells, and IFN-gamma production, but it did not induce T cell proliferation. The particles were found to activate T cells regardless of their antigenic specificity. Further investigations showed that nanosilica interacts with the T cell receptor complex, the first documented case of a non MHC-coated nanoparticle directly interacting with this receptor complex. The nanoparticulate induced signalling through Zap70, LAT, and, eventually, through NFAT but not through MAPK. Similar signalling in the literature has been shown to induce a hyporesponsive T cell state (anergy) or activation induced cell death. The induction of the CD25 and CD69 T cell activation markers was limited to nanosilica particles below 10 nm in size, while similarly sized iron hydroxide nanoparticles (3-5 nm) only induced low levels of CD69 expression on T helper cells. Finally, it was shown that nanosilica is capable of inducing T cell activation in whole blood, though the T cell responses were greatly attenuated. Although identification of activation pathway in vivo remains elusive, the nanosilica particles were shown to have therapeutic value, decreasing murine subcutaneous tumour growth rate and significantly reducing the formation of lung metastases. Whether these in vivo responses are related to T cell activation identified in vitro remains unclear.
Supervisor: Jugdaohsingh, Ravin Sponsor: HS Pharma
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: T cell activation ; toxicity ; amorphous silica nanoparticles ; synthesis ; primary peripheral cells ; safety