Browsing by Author "Zeevaart, Jan Rijn"

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    Complexation of trivalent lanthanides by three diphosphonate ligands in the blood plasma
    (1997) Zeevaart, Jan Rijn; Jackson, Graham Ellis; Jarvis, N V
    It has been shown that ¹⁵³Sm complexed with the bone seeking ligand ethylene-diaminetetramethylene phosphonate (EDTMP) is effective in pain palliation therapy of bone cancer. Blood plasma models for this ligand with Sm(III) and Ho(III) have been successfully constructed explaining the differences between ¹⁵³SmEDTMP and ¹⁶⁶HoEDTMP. The latter isotope is preferred because of its more energetic β particle, thought to improve the therapeutic effect of the radiopharmaceutical. However, ¹⁶⁶HoEDTMP is not an effective pain palliation agent and consequently the search for a more effective bone cancer therapeutic radiopharmaceutical involving ¹⁶⁶Ho continues. A ligand is being sought which complexes Ho(III) with a formation constant high enough to survive competition from blood plasma ligands but not so high to prevent ¹⁶⁶Ho from being accessible to metastases. EDTMP is unsuitable as such a ligand because of its inability to compete with citrate for complexation of Ho(III). For this study three diphosphonate ligands applied in radiation imaging of bone or nonradiative treatment of osteoporosis were chosen. They are APD (1-hydroxy-3-aminopropylidene- diphosphonic acid), MDP (methylenediphosphonic acid) and HEDP (1- hydroxy-ethylene-diphosphonic acid). Formation constants for the complexation of Ca(II), Mg(II), Zn(II), Sm(III) and Ho(III) with all of these ligands were measured using potentiometry and polarography. The latter was used to complement potentiometry in systems where precipitates formed. The complexation of Cd(II) by HEDP was used to compare the two techniques and to show that the values found by either technique are comparable. NMR studies were attempted on some complexes in solution to investigate the role the of the hydroxy-group (APD and HEDP) in complexation. The program ECCLES was used together with the formation constants measured in this study to predict the speciation of Ho(III) and Sm(III) with these three ligands in blood plasma. The results gathered for Ho(III) and APD were used as an indication and in an application to an ethical committee before animal testing. A baboon test was carried out using ¹⁶⁶HoAPD, the most promising system. The resulting bone-uptake and side-effects found in the animal study confirmed the predictions made by ECCLES. It proved that ¹⁶⁶HoAPD would be ineffective as a therapeutic agent due to high liver uptake. Valuable information on how a future radiopharmaceutical should be designed was obtained in this study.
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    The development of a radiolabelled macromolecule as a therapeutic agent for the treatment of cancer
    (2015) Driver, Cathryn Helena Stanford; Parker, Iqbal; Hunter, Roger; Zeevaart, Jan Rijn
    One of the major focus areas of anticancer therapy is the design of new radiotherapeutic agents that are able to specifically target and destroy cancer cells with minimal side effects and damage to healthy, normal cells. This thesis describes studies towards the synthesis of a macromolecular bioconjugate that was designed to: i) co-ordinate a radioisotope through a tetra-amine macrocycle (cyclam), ii) lead to passive tumour targeting via the EPR effect and a suitably large carrier such as human serum albumin and iii) induce active targeting through a glucose moiety recognised by the over-expressed glucose transporters on the surface of highly metabolically active cancer cells. The various cyclam functionalisation strategies explored were relatively unsuccessful, but eventually a bis-aminal cyclam was successfully converted, through nucleophilic substitution, into a precursor pro-conjugate: a di-functionalised cyclam containing a β-glycoside tether and a long chain primary alkylamine. The glycoside tether was synthesised via glycosylation of a glycosyl iodide with decandiol followed by oxidation of the terminal hydroxyl group to an acid chloride for cyclam acylation. The second linker attached to cyclam was synthesised by conversion of decanediol to a brominated alkyl amine. This amine would then be converted into a maleimide functionality suitable for Michael addition with a free thiol group contained within the proposed bio-carrier to form the desired bioconjugate. Further studies described towards the synthetic construction of the bioconjugate include: 1) The construction of a maleimide group 2) The attachment of an imaging radioisotope, ⠹⠹m Tc, or therapeutic isotope, ¹⠰³ Pd, to the pro- conjugate and other glucose-cyclam precursors 3) The determination of the potential uptake of the bioconjugate through glucose transporters by using a fluorescent dansyl-glucose compound as a model and monitoring its uptake into WHCO1 oesophageal cancer cells. 4) The HPLC analysis of the coupling of a glucose-maleimide model compound to bovine serum albumin to investigate the Michael addition of the free thiol in HSA to a maleimide 5) The development of a potentially alternative nanoparticle carrier by synthesis of palladium and magnetic nanoparticles with commercially available thioglucose or glucuronic acid moieties as the surface targeting and stabilising agent. In summary, this thesis outlines a number of synthetic, radiological and biological aspects towards the development of a fully functioning radiolabelled macromolecular bioconjugate that could be tested for improved targeted cancer radiotherapy.
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