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Title: Functionalised gold nanoparticles for theranostics
Author: Chabloz, Nicolas Gregory
ISNI:       0000 0004 7657 8976
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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New contrast agents based on the DO3A and DOTAGA moieties can be synthesised and attached to the surface of small spherical gold nanoparticles, with a core diameter of around 2-4 nm. This is achieved through the use of a dithiocarbamate tether to robustly anchor these complexes to the surface. In addition to the stronger attachment to the nanoparticles, the dithiocarbamate severely reduces the rotation of the paramagnetic species. This restriction of rotation is further optimised through the use of a piperazine linker that enforces a 'double locking' mechanism, through the amide and the dithiocarbamate. The DO3A derivative is first described in Chapter 2, in which its synthesis, stability towards transmetallation and relaxivity are investigated. It is revealed that the compound can be synthesised in a relatively large scale (>1g) and has an extremely good stability, as almost no transmetallation occurs after 45h even in the presence of 10 equivalents of zinc. The compound forms complexes with three separate metals to generate mono-, bi- and tri-gadolinium species which produce up to a 6.5-fold increase in the overall relaxivity for the tri-gadolinium complex. Both new contrast agents are anchored to the surface of gold nanoparticles through a straightforward 'one-pot' synthetic route, generating stable and monodisperse particles. A dramatic boost in relaxivity is achieved through this attachment, from 4.5 mM-1 s-1 to 34.3 mM-1 s-1 for the first generation surface units and 5.0 mM-1 s-1 to 31.7 mM-1 s-1, at 10 MHz and 37 ºC. The incorporation of additional surface units, to achieve a stealth character (PEG), higher cellular uptake (thioglucose) and targeting (folic acid), is achieved in a straightforward and flexible way utilising the same 'one-pot' synthetic route. These additional surface units display little negative impact on the relaxivity or stability of these non-cytotoxic particles. Increased cellular uptake occurs when these surface units are combined and the cellular internalisation behaviour is confirmed through the use of a BODIPY derivative. The use of a lipoic acid derivative of a zinc porphyrin allows the addition of photodynamic therapy (PDT) to the assembly. In the absence of light, no cytotoxicity is noted with these nanoparticles but close to 80% cell death is achieved after only 30 min irradiation with a laser. The relaxivity of these particles at high magnetic field (127.8 MHz) is 1.5-fold higher than that of commercially utilised Dotarem®, making these non-cytotoxic, theranostic agents suitable for in vivo investigations.
Supervisor: Wilton-Ely, James Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral