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Title: Modelling the transport of nanoparticles across the blood-brain barrier using an agent-based approach
Author: Fullstone, G. J. M.
ISNI:       0000 0004 8503 3935
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Diseases affecting the Central Nervous System (CNS), consisting of the brain and spinal cord, will account for an estimated 11.84% of all deaths by 2015, with few effective treatment options. This is partly a consequence of poor penetrance of blood-borne molecules, including almost all therapeutics, into the CNS. This is due to the existence of a blood-brain barrier, severely limiting potential therapeutic intervention. Nanoparticles are diverse nanoscale particles that have recently been demonstrated to be able to improve drug penetrance across the blood-brain barrier, by targeting endogenous transport systems. However, further methods to improve their general delivery to the CNS and specific delivery to different regions of the CNS are required. Here, agent-based modelling has been utilised to simulate blood flow in a capillary at the blood-brain barrier. This modelling approach has demonstrated the importance of a number of biological, physiological and physical factors that affect nanoparticle uptake to the CNS. This model was used to demonstrate how the fluid dynamics in capillaries enhances nanoparticle distribution to the vessel wall interface. These simulations have demonstrated that by tuning nanoparticle properties, including ligand density, receptor-ligand affinity and size, general delivery by transcytosis can be improved. Moreover, particular nanoparticle formulations can target high levels, but not low levels, of receptor expression at the blood-brain barrier thus providing a method to improve specific delivery into particularly CNS regions. Furthermore, nanoparticles can be formulated to stabilise nanoparticle binding under different flow conditions. In particular during regional blood flow increases, called functional hyperaemia, which aid access of nutrients to that region of the CNS. It is predicted from these simulations that this could be harnessed to further improve specificity of delivery. Finally, chemotactic nanoparticles are shown to have an improved distribution to the vessel wall interface and penetration through the CNS tissue.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available