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Title: Synthesis and biological properties of cytotoxic lectin conjugates
Author: Ma, Long
ISNI:       0000 0001 3614 6499
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2007
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Proliferative vitreoretinopathy (PVR) is an anomalous cell proliferation condition that occurs after surgery on the retina. 5-Fluorouracil (5-FU) has been shown to be effective in reducing the incidence ofPVR in animal models and recently been used as a clinic adjunctive treatment of PVR. However, the results of such treatment have been disappointing, largely because these drugs are quickly metabolized within the eye minimizing their long-term effectiveness; high doses ofthese drugs may also be toxic to the retina. Agaricus bisporus lectin (ABL) is obtained from t~e edible common mushroom and has been shown to have reversible, dose-dependent and specific anti- proliferation activity in vitro. The aim ofthis research project is to conjugate 5-FU and ABL together by using chemical conjugation methods to give potentially potent and specific anti-proliferative activity for the treatment ofPVR. The first part of this project is to study the protein structure of the ABL, which is to find the suitable residues as conjugation targets. ABL is found as a homotetramer protein and each ofthe four subunits has a molecular mass of 16,053.8 Da. There are one cysteine and five lysines for each of the lectin subunits. The free -SH of cysteine, free -NH2 of lysine and the N-terminal amino groups are conjugation targets. The second part of the project is to modify the 5-FU with either amino or azido functional groups preparing derivatives of 5-fluorouridine which can then be conjugated to ABL. The third part of the work describes the conjugation of the modified 5-FU with ABL by using SMCC (succinirnidyI4-(N-maleimidomethyl) cyclohexane-l-carboxylate) cross linker, aconitic acid anhydrate linker, 'click' chemistry as well as the photochemistry method separately, followed by characterization by SDS-PAGE (sodium dodecyl sulphate-polyacrylamide gel electrophoresis) and the biological test. MALDI-MS (matrix-assisted laser desorption/ionization mass spectrometry) is also attempted for further characterization.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (PhD) Qualification Level: Doctoral
EThOS ID:  DOI: Not available