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Title: Iron nanoparticles and zirconium metal-organic frameworks for therapeutic application
Author: Mehta, Joshua
ISNI:       0000 0004 9359 680X
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
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This thesis reports experiments pertaining to the synthesis of magnetic nanoparticles (NPs) and metal-organic frameworks (MOFs) targeted at biomedical applications. Chapter 1 introduces the theoretical grounding for the present work and describes the ideas which were used to inform the direction of the project. Specifically, the classes of materials researched in this work are disclosed and current literature limitations explored. Synthetic approaches are described. The ability of MOFs and NPs to fulfil the desired applications of drug delivery and magnetic heating, respectively, are discussed. Conclusions are reached as to what properties an ideal material would feature. Chapter 2 describes the experimental and analytical procedures employed in the synthesis and characterisation of the materials prepared in this work. The interdisciplinary nature of this project required a broad spectrum of instrumentation to analyse the produced materials, and these procedures are outlined. Experiments carried out in Chapter 3 sought to create and optimise a synthesis for highly magnetic Fe NPs. Various systems are presented in which modulation of reaction parameters was undertaken to achieve optimal properties in terms of magnetic behaviour and monodispersity of the afforded product. Ferrous NPs were synthesised via the thermal decomposition of iron pentacarbonyl in the presence of oleylamine, polyvinylpyrrolidone, didodecyldimethylammonium bromide, oleic acid, or mixtures thereof. Use of single surfactants led to passive oxidation of the synthesised particles. However, deployment of a dual surfactant reaction medium led to the synthesis of core@shell Fe@Fe3O4 NPs which resisted progressive oxidation of the core for > 6 months. Microscopic studies revealed a carbonaceous interface between the Fe core and oxide shell, whose presence is suggested to be critical to this sustained oxidative stability. Chapter 4 presents the synthesis of MOF NPs of differing topologies, porosities and spatial dimensions. Work undertaken sought to achieve acute control over the crystallinity, porosity and composition of zirconium based MOF, NU-901. Benzoic acid and its functionalised derivatives, p-amino-, p-dimethylamino-, p-nitro-, and p-methoxy- benzoic acids, were deployed, targeting a biologically suitable carrier. Manipulation of reaction parameters resulted in an optimised drug delivery vector containing the covalently bound therapeutic, dichloroacetic acid. Chapter 5 details the experiments undertaken looking at therapeutic loading into the biocompatible MOFs optimised in Chapter 4. Work focused on attaining a synthetic protocol which allowed impregnation of an anticancer therapeutic, Pemetrexed, into a zirconium-based MOF. Uptake of this organic drug was achieved at ~ 30 wt% relative to the MOF. Thorough analysis of the delivery construct was performed in terms of material characterisation and drug release. Release studies showed that the cargo remains internalised when the loaded MOF is submerged in water, but addition of phosphate buffered saline releases ~ 50% of the loaded drug within 4 hours, rising to complete release within 14 days. The inorganic subunits instrumental to imbuing MOFs with their underlying properties were probed in Chapter 6. Three novel zirconium clusters, Zr9O7(OH)(C7H5O2)12(C3H7O)9·(C3H7OH), Zr5O2(OH)(C9H10NO2)8(C3H7O)7·(C5H5N) and Zr5O2(C7H6NO2)8(C3H7O)8, were synthesised and analysed. This led to insights into ligand influence on cluster formation. These clusters were isolated and used in the synthesis of existing and new inorganic polymers. Whilst oxo-cluster Zr9O7(OH)(C7H5O2)12(C3H7O)9 showed in situ rearrangement to form archetypal zirconium MOF UiO-66 (Zr6O4(OH)4(1,4-benzenedicarboxylate)6), pentanuclear Zr5O2(C7H6NO2)8(C3H7O)8 was reticulated into a new breed of MOF. This was achieved by covalently appending the amino groups on the periphery of the cluster via the introduction of a dialdehyde. This allowed the interconnection of discrete clusters to form an inorganic polymer. In Chapter 7, further avenues for research are discussed. These build on the ideas developed in this thesis and highlight where immediate work efforts should be focused. Longer-term opportunities remaining from the previous chapters are elaborated on. Experimental considerations for future work are discussed and preliminary results divulged.
Supervisor: Wheatley, Andrew Sponsor: CRUK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: nanotechnology ; drug delivery ; metal-organic framework