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Title: Nanostar based platforms for enhanced blood brain barrier crossing
Author: Lopes Rodrigues, Rosalia Cristina
ISNI:       0000 0004 9350 6333
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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The availability of drugs to treat diseases of the central nervous systems is severely restricted by the presence of the blood brain barrier (BBB). The blood-brain barrier prevents the passage of more than 98% of small molecules and 100% of large molecule pharmaceutics. With the rapid progression of neurodegenerative conditions arising with the increase in life expectancy, central nervous system disorders are now the leading cause of death in the United Kingdom, highlighting the urgent need to develop new strategies to effectively cross the blood brain barrier. Nanoscale particles have shown great potential for specifically identifying and binding to the BBB and are currently being investigated for enhanced brain penetration. In this work, the effect of a complex multispiked nanoparticle morphology on BBB penetration is investigated as an alternative to the conventionally used spherical nano-vehicles. Specifically, a platform matrix of plasmonic gold nanoparticles in the shape of gold stars were designed for specific brain targeting and effective transcytosis. The nanostars were synthesised with a highly controllable spectrum of properties including size, surface spikiness and morphology. Successful conformal surface biofunctionalisation with the BBB targeting protein transferrin was achieved for the complex stars and conformational changes due to packing was observed at high concentration of protein. The shape and functional properties of the nanostars was thus preserved after coating. The high surface area of the nanostars enabled superior loading capacity with the transferrin targeting moieties. In transwell transport studies the human brain endothelial cell line hCMEC/D3 showed preferential uptake of AuStrs over spherical nanoparticles. It was found that AuStrs with high aspect ratio, and spiky surface topology constituted the best transcytotic agents. TEM analysis demonstrated that AuStrs penetrate through the cells, not through the tight junctions, thus validating a transcellular transport mechanism. It is demonstrated that the extent of transcytosis and cell uptake can be tuned based on nanostructure geometry and surface biofunctionalization. This thesis provides important insights of the nano-bio interface for the future design of BBB penetrating agents.
Supervisor: Ryan, Mary P. ; Porter, Alexandra E. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral