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Title: Radioimmunotherapy with yttrium macrocycles
Author: Norman, Timothy John
ISNI:       0000 0001 3449 2005
Awarding Body: Durham University
Current Institution: Durham University
Date of Award: 1994
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Monoclonal antibody fragments (Fab') which recognise tumour-associated antigens provide an ingenious means of selectively targeting a therapeutic radionuclide to a tumour for radioimmunotherapy. The radionuclide yttrium-90, a long range β(^-) emitter, was chosen to deliver a sterilising dose of radiation to the tumour. A selection of novel functionalised macrocyclic ligands based on a 1,4,7,10-tetraazacyclododecane skeleton have been synthesised, and the stabilities of their yttrium (III) and gadolinium (III) complexes studied in vitro through association and dissociation measurements, and in vivo through animal biodistribution studies. The radiolabelled complexes do not dissociate in vivo. Maleimides are compounds which are capable of selectively reacting with a thiol of an antibody fragment. Selective functionalisation of one of the yttrium binding macrocyclic ligands with either one or three maleimides has been carried out, and the resulting compounds conjugated to tumour seeking humanised antibody fragments. Subsequent radiolabelling with (^90)Y, gave the desired tumour targeting drug for use in radioimmunotherapy. Acridines are a class of intercalating agents which are capable of reversibly binding to DNA. A maleimide functionalised ligand derivatised with acridine was formed. Conjugation of this compound to antibody fragments capable of entering a tumour cell, may permit drug binding to tumour cell DNA, and thus enhance the targeting efficacy of the radiolabelled conjugate.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Cancer; Radiotherapy