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Indirect Radiohalogenation of Targeting Proteins: Labelling Chemistry and Biological Characterisation
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In about half of all newly diagnosed cancer cases, conventional treatment is not adequately curative, mainly due to the failure of conventional techniques to find and kill residual cells and metastases, which might consist of only a few malignant cells, without causing unacceptable complications to healthy tissue. To solve the problem a more selective delivery of cytotoxic substances to tumour cells is needed. The approach applied here is called ‘tumour targeting’ and implies the use of biomolecules that recognise specific molecular structures on the malignant cell surface. Such molecules are then used for a selective transport of toxic agents to the cancer cells.

The use of radionuclides as cytotoxic substances has a number of advantages: 1) radiation does not cause severe resistance; 2) there is a cross-fire effect and 3) smaller amounts of nuclides are required than other cytotoxic substances to cause the same damage. Such an approach is called radionuclide tumour therapy. Several factors are important for the success of radionuclide therapy, such as the pharmacokinetics of the radiolabelled substance and its radiocatabolites, as well as the physical and chemical properties of the radiolabel used.

Nuclear properties of the label should be consistent with the problem to be solved: primary diagnostics; quantification of pharmacokinetics and dose planning; or therapy. From this point of view, radiohalogens are an attractive group of radiolabels. Halogens have nuclides with a variety of physical properties while the chemical and biological properties of halogens are very similar. The same labelling procedures can be used for all heavy halogens, i.e. bromine, iodine and astatine. It has been demonstrated that the biodistribution of proteins labelled with different heavy halogens is quite similar.

The main goal of the study was to develop protein radiohalogenation methods that provide a stable halogen-protein bond, convenient labelling chemistry that preserves the binding properties of proteins, long intracellular retention of radioactivity in targeted cells and quick release of radiohalogenated catabolites from the blood circulation. Radiohalogenation of proteins using indirect methods was studied, including optimisation of labelling chemistry and biological characterisation of some labelled conjugates. Two groups for indirect radiohalogenation were used, representing two different labelling principles: activated ester of benzoic acid (1) and the derivative of closo-dodecaborate anion (2). The non-phenolic linker (1) as well as the borate-halogen moiety (2) probably prevent dehalogenation. The negative charge of the potential catabolic products of (2) might trap radiohalogens intracellularly.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 47
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1238
Keywords [en]
Cell and molecular biology, radiohalogenation
Keywords [sv]
Cell- och molekylärbiologi
National Category
Biochemistry and Molecular Biology
Research subject
Biomedical Radiation Science
Identifiers
URN: urn:nbn:se:uu:diva-3349ISBN: 91-554-5576-X (print)OAI: oai:DiVA.org:uu-3349DiVA, id: diva2:162467
Public defence
2003-04-26, Rudbeck Sal, Rudbeck Laboratoriet, Uppsala, 13:15
Opponent
Supervisors
Available from: 2003-04-03 Created: 2003-04-03Bibliographically approved
List of papers
1. Optimization of iodination of [125I]-N-succinimidyl-para-iodobenzoate using Chloromine-T for labeling of proteins
Open this publication in new window or tab >>Optimization of iodination of [125I]-N-succinimidyl-para-iodobenzoate using Chloromine-T for labeling of proteins
2000 (English)In: Journal of Radioanalytical and Nuclear Chemistry, ISSN 0236-5731, E-ISSN 1588-2780, Vol. 246, no 1, p. 207-213Article in journal (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90194 (URN)
Available from: 2003-04-03 Created: 2003-04-03 Last updated: 2017-12-14Bibliographically approved
2.
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4. Polyhedral boron clasters as linkers for attachment of radiohalogens to tumor targeting proteins. II. Radioiodination of monoclonal antibody using potassium [125I]-4-(isothiocyanatobenzylammonio)-iodo-decahydro-closo-dodecaborate (Iodo-DABI)
Open this publication in new window or tab >>Polyhedral boron clasters as linkers for attachment of radiohalogens to tumor targeting proteins. II. Radioiodination of monoclonal antibody using potassium [125I]-4-(isothiocyanatobenzylammonio)-iodo-decahydro-closo-dodecaborate (Iodo-DABI)
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-90197 (URN)
Available from: 2003-04-03 Created: 2003-04-03 Last updated: 2015-03-24Bibliographically approved
5.
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