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Title: Developing superparamagnetic iron oxide nanoparticles as targeted cancer nanomedicine
Author: Abdollah, M. R. A.
ISNI:       0000 0004 7229 6541
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Superparamagnetic Iron Oxide Nanoparticles (SPIONs) have unique properties with potential application in targeted cancer treatment; including the ability to generate heat when placed in an external alternating magnetic field. However, challenges such as rapid circulatory clearance by the reticuloendothelial system (RES), the need for effective functionalisation with cancer-targeting agents and heterogeneity of SPIONs, remain to be overcome. The work in this thesis aims to develop SPIONs by addressing these challenges. Ferucarbotran (Resovist®), a clinically approved MRI contrast SPION with excellent heating potential was investigated. Three main hypotheses were tested; that RES uptake of SPIONs could be blocked in vitro and in vivo, that specific targeting could be achieved by functionalising SPIONs with non-immunoglobulin cancer-targeting proteins and that product heterogeneity could be addressed by physical separation. Studies included: (i) Interactions of SPIONs with different cell types (ii) Blocking cell uptake using polysaccharide derivatives (iii) Conjugation strategies to link SPIONs to near-infrared dyes to trace their blood levels (iv) Enhancing the circulatory retention of SPIONs via RES blocking (v) Site-specific conjugation methods to functionalise SPIONs with cancer targeting protein (vi) Cellular- and immuno-assays to test the binding of functionalised SPIONs to target antigen (vii) Size exclusion chromatography (SEC) to fractionate SPIONs. Results showed that Ferucarbotran was unspecifically internalised by all tested cell lines. A range of sulfated polysaccharides were shown to block this uptake in vitro and in vivo leading to prolonged circulatory times. Ferucarbotran was successfully functionalised with cancer-targeting protein and bound specifically to target antigen in ELISA. Cellular assays with a range of cell lines revealed the generalised altered behaviour of SPIONs upon surface modification with proteins. SEC successfully fractionated Ferucarbotran into more homogeneous products with improved heating properties. In conclusion, these results are consistent with the proposed hypotheses and form a platform for addressing the challenges of SPIONs-based cancer nanomedicine.
Supervisor: Chester, K. A. ; Pankhurst, Q. ; Minogue, S. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available