published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

In this work, novel Gd(III) complexes endowed with non-steroidal anti-inflammatory drugs (NSAIDs) were synthesised and their targeting properties towards sites of inflammation were studied in U87 xenograft and rheumatoid arthritis animal models. The Tb(III) analogues were also synthesised and their photophysical properties were studied. Six new Gd(III) DO3A-amide complexes bearing different linkers, ethylenediamine (GdL1), hexamethylenediamine (GdL2), 2,2’-oxydiethylamine (GdL3), 4,7,10-trioxa-1,13-tridecanediamine (GdL4), trans-1,4-cyclohexanediamine (GdL5), and 1,4-phenylenediamine (GdL6) were incorporated to mefenamic acid (MA) moiety, a common NSAID. The syntheses, relaxometric properties by NMR techniques, hydration number determinations by luminescence lifetime measurements, lipophilicities by UV-Vis spectrometry, serum albumin binding properties by tryptophan emission-quenching experiments, cytotoxicities by MTT assay, cellular uptake properties; MRI scans on U87 sxenograft and rheumatoid arthritis animal models, and biodistributions of these new complexes were discussed. GdL1-L6 possess one bound water molecule and GdL2-L5 show higher relaxivities than Gd-DOTA (4.21 mM?1s?1, 300 MHz, 25oC), a clinically used MRI contrast agent (CA). The relaxivities at 300 and 400 MHz respectively at 25oC are in the descending order of GdL4 (5.70 and 4.87 mM?1?1) > GdL3 (4.94 and 4.07 mM?1s?1) > GdL2 (4.60 and 4.07 mM?1s?1) > GdL5 (4.41 and 4.12 mM?1s?1) > GdL6 (3.98 and 3.31 mM?1s?1) > GdL1 (3.96 and 3.56 mM?1s?1). GdL1-L5 show low cytotoxicities towards HeLa cells at 1000 μM. The MRI scans of GdL1-L6 on U87 xenograft show strong intensity boost immediately after administration. The intensity enhancements persist for more than 90 mins and complete clearances are found after 24 h post-administration. Their MRI scans on arthritis model also show prolonged retention. It is concluded that the retention is related to the targeting on inflammatory mediators of the complexes. All complexes show superior retention and intensity enhancements in kidney, liver, tumour and arthritis joint than Gd-DOTA. GdL1-L6 are therefore potential candidates as universal MRI CAs. Three new Gd(III) DO3A-amide complexes bearing respectively benzoic acid (GdL7), salicylic acid (GdL8), and methylated salicylic acid (GdL9), one known Gd(III) DTPA-bissalicylic acid (GdL10) complex and one new Gd(III) DTPA-bismethylated salicylic acid (GdL11) were synthesised and investigated. Their syntheses, relaxivities, hydration numbers, pH dependent photophysical properties, cytotoxicities, cellular uptake properties and MRI scans on arthritis rat model were discussed. All GaL7-L11 possess one bound water molecule and show lower relaxivities than Gd-DOTA. The relaxivities at 300 MHz at 25oC are in the descending order of GdL10 (3.64 mM?1s?1) > GdL9 (3.53 mM?1s?1) > GdL11 (2.69 mM?1s?1) > GdL8 (2.10 mM?1s?1) > GdL7 (1.99 mM?1s?1). Their Tb(III) analogue (TbL7-L11) show pH dependent UV-Vis and photoluminescence spectra which are consequences of protonation or deprotonation of the carboxylic acid, hydroxyl and amide groups. It is concluded that the pH change alters energy transfer efficiency and the ligand triplet energy level. GdL7-L11 show low cytotoxicities in MTT assay. Specifically, GdL8 is examined on arthritis rat model to give a comparable intensity at the arthritis joint to Gd-DOTA but having a longer retention time. LnL8 has therefore demonstrated its potential as both a MRI CA to target inflammation sites and a pH dependent luminescence probe. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Errata pasted onto front end-paper. / Bibliography: leaves 173-188. / xii, 188 leaves : ill. (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Describes a comprehensive study of a select but informative set of crown ether ligands that may potentially be used in the development of a fluorescent lead (II) specific probe. / Thesis (Ph.D.)--University of Adelaide, Dept. of Chemistry, 1999

Thesis (Ph.D.). / Written for the Dept. of Chemistry. Title from title page of PDF (viewed 2008/07/23). Includes bibliographical references.

Thesis (Ph.D.) - University of Glasgow, 1996. / Ph.D. thesis submitted to the Faculty of Medicine, Department of Division of Developmental Medicine, University of Glasgow, 1996. Includes bibliographical references: p. 118-132. Print version also available.

Thesis (M.S.)--University of Missouri-Columbia, 2007. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on September 30, 2008) Includes bibliographical references.

Thesis (Ph. D.)--University of Texas at Austin, 1999. / Vita. Includes bibliographical references (leaves 226-240). Available also in a digital version from Dissertation Abstracts.

Thesis (Ph. D.)--University of Hong Kong, 2005.

A series of fluorescent probes based on different signal transduction mechanisms for the detection of Fe3+, Zn2+, histidine and pH was designed and synthesized. Their photophysical properties, binding abilities and the further application in cell imaging were fully evaluated. Building on the groundwork of our previous study, molecular scaffold 19 has been appended to spirobenzopyran fluorophore to furnish a highly selective and sensitive Zn2+ sensor. To broaden the application scope of this trifunctional receptive molecule, 19 was incorporated onto rhodamine, antipyrine and coumarin moieties to give 20, 21 and 23, respectively. Probe 20 operative on a chelation-enhanced fluorescence mechanism exhibited highly selective response to Fe3+ with 2:1 stoichiometry of 20-Fe3+ complex. However, a possible tendency of probe 20 to hydrolyze induced by Fe3+ and the unsuccessful attempt of cell imaging would limit its application scope. Probe 21 with O-N-N-N-N-ligand showed a highly selective and sensitive detection of Zn2+. The probe displayed suppressed response to Cd2+ which is the most common interference ion in zinc metal detection. The binding of Zn2+ to probe 21 inhibited the photoinduced electron transfer process originating from the lone pair of the nitrogen atom in the antipyrine moiety to quinoline fluorophore. Therefore, a turn-on fluorescent probe was developed. A moderate binding constant with 1:1 stoichiometry of 21-Zn2+ complex was established by fluorescence titration. The binding mechanism was fully explained by 1H NMR titration. To our delight, probe 21 was successfully applied for recognizing Zn2+ in living cells. The preparation of probe 23 was achieved by appendage of 19 to coumarin derived fluorophore and the probe exhibited a good selectivity and fluorescent turn-off property to Cu2+. The 1:1 stoichiometry of 23-Cu2+ ensemble can serve as an efficient probe for the detection of histidine and biothiols. In the presence of NEM, the influence of biothiols could be eliminated. Furthermore, this sensing ensemble was also used in the detection of histidine in hard-to-transfect U87MG cells with very low cytotoxicity. Based on our group’s previous work on the spiropyran platform, a novel ratiometric near-infrared pH probe 27 operating on an excited-state intramolecular electron transfer mechanism was developed. The pKa was calculated to be 5.9 and the ring-opening/ring-closing mechanism triggered by protons was reasonably explained by 1H NMR titration. However, this spiropyran-based probe was found to be unsuitable for cell imaging. To continue the innovation of pH sensing and extend its application in bioimaging, a series of ratiometric pH probes 32 and 38 characterized by their high quantum yield working in the NIR range was developed. The appendage of N,O-disubstituted hemiaminal ether moiety onto coumarin fluorophore with C=C double bond conferred the sensory material with the ability to display a pH-dependent ratiometric output operating on the ring-opening/ring-closing mechanism. The pKa of 32 and 38 were 6.9 and 5.8 – 6.0, respectively, which rendered them suitable for pH measurement in near-neutral and acidic media. A preliminary work of intracellular pH measurement was also conducted and promising results were obtained

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