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Theses, Ph.D


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A thesis submitted to Technological University Dublin For the Doctor of Philosophy Degree


High concentrations of silver nanoparticles (AgNP) are increasingly present as active ingredient in everyday consumable products for antibacterial purposes causing increased human exposure and high risk of adverse effect development. In this thesis, AgNP were encapsulated in dipalmitoyl phosphatidylcholine (DPPC)-based liposome (forming Lipo-AgNP), to enhance intracellular delivery and associated cytotoxicity, and suppress AgNP-induced inflammation. It was noted that as a result of the encapsulation, Lipo-AgNP induced significantly reduced cell viability of THP1 monocytes and THP1 differentiated macrophages (TDM) at a notably lower dose than that of uncoated AgNP. The induced cytotoxicity was shown to result in an increased level of DNA fragmentation causing interruption at the S-phase of the cell cycle. In addition, Lipo-AgNP induced redox imbalance through suppression of both GSH levels and ROS levels. Possibly as a consequent and in addition to increased Bax to Bcl-2 ratio, it was found that the predominate form of cell death upon exposure to Lipo-AgNP was caspase-dependent apoptosis. It was also found that the encapsulation resulted in improved intracellular uptake of the nanoparticle changing the pharmacokinetics of uncoated AgNP. It was found that AgNP induced release of IL-1β, IL-6, IL-8 and TNF-α in THP1 monocytes all of which were suppressed by Lipo-AgNP exposure. AgNP was also found to induce release of IL-6, IL-8 and TNF-α in TDMs while Lipo-AgNP suppressed these cytokine releases. However, both AgNP and Lipo-AgNP suppressed IL-1β and TNF-α release in LPS-stimulated THP1 monocytes and TDM respectively. AgNP-induce inflammation was found to be associated with induction of STAT3 protein expression in LPS-stimulated THP1 monocytes, and non-LPS- and LPS stimulated TDMs. Whereas Lipo-AgNP may have suppressed AgNP-induced iii | Page inflammation through STAT3, as its exposure was associated with STAT3 protein expression levels comparable with the control untreated cells highlighting the potential of Lipo-AgNP in treatment of bacteria induced inflammatory diseases. These findings showed that encapsulation of AgNP in DPPC liposome enhanced AgNP cytotoxicity by improving the intracellular delivery of the nanoparticle and also suppressed AgNP-induced inflammation which may be linked to the suppressed ROS generation. These processes resulted in redox imbalance within the cells causing induction of caspase dependent apoptosis.

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