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
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/174457 |
| Date | January 2011 |
| Creators | Leung, Ho-hon, Arthur., 梁浩瀚. |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Source | http://hub.hku.hk/bib/B47752774 |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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