Thesis (Ph. D.)--University of Hong Kong, 2001. / Includes bibliographical references.

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

In this work, a series of DTPA based Ln complexes containing one or two chromophores with different degrees of conjugation were synthesized. The proton relaxivities of Gd(III) analogues were investigated as potential MRI contrast agents while the photoluminescence of Eu(III) and Tb(III) analogues were studied for their applications in optical probes for cellular imaging. Later investigation indicates that only emissions from the chromophores could be measured upon long wavelength photon excitations in the microscope. With suitable ligand design, novel dual functional imaging probes were finally synthesized and these showed good luminescence intensity and image contrast in both in-vivo and in-vitro studies. Eight DTPA based Ln (III) complexes LnL1-L8 containing one or two chromophores which include benzene, 2-aminopyridine, 3-amino-pyridine and 4-aminopyridinewere synthesized. The syntheses, relaxometric properties, hydration numbers, quantum yields, sensitization efficiencies, brightnesses, cytotoxicities and cellular uptake properties were discussed. Those mono-substituted complexes show higher relaxivity, while the di-substituted complexes show lower relaxivity than Gd-DTPA (4.17 mM-1 s-1),a clinically used MRI contrast agent(CA).The di-substituted Tb(III)/Eu(III) analogues show lower sensitization efficiency than the mono-substituted ones in the energy transfer process. Therefore, the experimental results clearly illustrate that the complex with one chromophorein the DTPA system is a better option for being used as a MRI contrast agent and an optical probe. Another eight new mono-substituted DTPA based Ln(III) complexes LnL9-L16 containing extended conjugated chromophores were synthesized and investigated. The phenyl derivatives and naphthyl derivatives were added onto the para-position of 2-aminopyridine that was employed as the chromophore. All GdL9-L16possess one bound water molecule and show higher relaxivity than Gd-DTPA. The relaxivities at 300 MHz at 25oC are in the descending order of GdL15(5.37 mM-1s-1) > GdL16(5.23 mM-1s-1) > GdL13(5.12 mM-1s-1) > GdL14(5.06 mM-1s-1) > GdL11(4.96 mM-1s-1) > GdL12(4.83 mM-1s-1) > GdL10(4.80 mM-1s-1) > GdL9(4.50 mM-1s-1). Their quantum yields, sensitization efficiencies and brightnesses are greatly improved because of the highly conjugated chromophores. Moreover, they all showed low cytotoxicity to cells in a MTT assay and a high accumulation in cells in cellular uptake studies. However, no emission from the Eu(III) ion was detected from the Eu(III) analogues upon long wavelength photon excitation in the cell imaging studies, only the emissions from the chromophores were observed. Two mono-substituted DTPA based Ln(III) complexes containing anthracenyl derivatives as the chromophore LnL17-L18 and two DTPA-based binuclear Ln(III) complexes LnL19-L20were synthesized and investigated. Among the four complexes, GdL18 shows the highest relaxivity (4.65 mM-1s-1) and the highest fluorescent quantum yield (2.45%).It also has low cytotoxicity to cells in MTT assay and high accumulation in cells in cellular uptake study. In addition, GdL18shows very strong binding interaction towards serum albumin, i.e. 318,400mol-1dm3for HSA and 90,200 mol-1dm3for BSA. In preliminary studies, GdL18can both give good luminescence intensity and image contrast in both in vitro cell imaging and in vivo MRI studies. Therefore, GdL18 is considered as a potential candidate for use as a dual functional MRI/optical imaging probe. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / toc / Chemistry / Doctoral / Doctor of Philosophy

No description available.

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 158-167).

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 171-179).

Thesis (Ph.D.)--University of Hong Kong, 2001. / Includes bibliographical references. Also available in print.

Thesis--Catholic University of America. / Biography. Includes bibliographical references.