This thesis examines the toxicity of metallic and organometallic nanoparticles which have applications in the medical field. Commercially available Silver particles} used to create bactericidal surfaces} are tested against two human in vitro cell models to investigate the sensitivity of the models and the toxicity of the particles. No toxicity to a human blood brain barrier in vitro cell model arises from concentrations of particles likely to be encountered. Significant toxicity however is demonstrated in a human placental in vitro cell model} raising concerns for maternal exposure to Silver particles and selecting the placental cell model for further study. A novel polymer nanoparticle drug delivery system capable of encapsulating a wide variety of lipophilic drugs is described. Extensive characterisation demonstrates successful encapsulation of fluorescent} water insoluble} Tris-(8-hydroxyquinolinato) Aluminium (III) (AlQ3) a molecule with antibiotic potential. The AlQ3 nanoparticles are tested against a human placental in vitro cell model} at physiologically relevant doses} finding no significant toxicity to the cell membrane} metabolism} nucleus or viability. Confocal experiments with concomitant organelle staining confirm cellular internalisation and examine the AlQ3 intracellular localisation. The antibacterial properties of AlQ3 nanoparticles are then demonstrated by the treatment of human keratinocytes infected with Methicillin Resistant Staphylococcus Aureus (MRSA). The polymer nanoparticle delivery system is then further examined by synthesising nanoparticles of the chemotherapeutic analogue} Tris-(8-hydroxyquinolinato) Gallium (lit) (Ga~). Ga~ having undergone phase I human clinical trials} provides an ideal example of an insoluble drug molecule whilst allowing for direct comparison to the AlQ3 nanoparticles. Characterisation confirms the formation of nanoparticles suitable for passive disease targeting with the potential for extended blood circulation. Toxicity testing against a human placental in vitro cell model shows significant toxicity to the cell membrane} metabolism} nucleus and viability. Confocal experiments confirm the GaQ3 nanoparticles follow the same intracellular pathway as the AlQ3 nanoparticles elucidating further the mechanism of toxicity.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:665462 |
| Date | January 2013 |
| Creators | Hauser, Jonathon Charles |
| Publisher | University of Bristol |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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