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Title: Evaluating the suitability of nanoparticles and microspheres for diagnostics and biopharmaceutical delivery in medicine
Author: Thakur, Ajit Singh
ISNI:       0000 0004 7967 4904
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2018
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Nanoparticle and microsphere technologies have enormous diagnostic and therapeutic potential in medicine. We characterised the behaviour of Quantum Dots (QD) in live mammalian cells and discovered that QD surface coating deficiencies can lead to the formation of aggregates, which are recognised as foreign objects by the innate immune defenses of cells and actively transported along microtubules within lysosomes. Applying the principles of viral nucleotide delivery systems, we designed a nature-inspired, smart 'universal' nanoparticle for intracellular oligonucleotide delivery using a combination of natural and synthetic stimuli-responsive polymers. We then developed and tested a nature-inspired polymer alginate-poly-L-lysine-alginate (APA) microcapsule to encapsulate allogeneic cells for Factor VIII delivery in a mouse model of haemophilia A. We also developed a novel flow cytometry-based assay to evaluate the behaviour of encapsulated cells and discovered that both implanted and non-implanted APA microcapsules reduced the viability of cells, induced changes in the cytoplasmic composition and morphology of the cells, and altered the proliferation rate, suggest that the local microenvironment can significantly alter the behaviour of encapsulated cells. We then developed and tested a novel single-colour flow cytometry-based in vitro cytotoxicity assay to measure both necrotic and apoptotic cell death. We then developed and tested a novel method to potentially delay or prevent organ rejection upon transplantation using viral nanoparticles to selectively modify allogeneic donor cells ex vivo using viral mechanisms of immune evasion. To our knowledge, this was the first study to employ viral immune evasion strategies to simultaneously reduce CD8+ T cell-mediated cytotoxicity without altering Natural Killer cell-mediated cytotoxicity against allogenic human cells. Finally, we present a rare clinical case of hemicorporectomy due to chronic non-healing pressure ulcers to highlight the potential role for nanoparticles, microspheres and tissue-engineered constructs for wound healing applications via suppression of inflammation and promotion of tissue regeneration.
Supervisor: Not available Sponsor: Natural Sciences and Engineering Research Council Canada ; McMaster University ; University of Toronto
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RS Pharmacy and materia medica