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Discovery and radiopharmaceutical development of probes for prospective positron emission tomography imaging of malaria
Thesis (PhD (Biochemistry))--University of Pretoria, 2021.
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University of Pretoria
2022
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| _version_ | 1867613452252479488 |
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| access_status_str | Open Access |
| author2 | Ebenhan, Thomas |
| author_browse | Ebenhan, Thomas |
| author_facet | Ebenhan, Thomas |
| collection | Thesis |
| dc_rights_str_mv | © 2022 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. |
| description | Thesis (PhD (Biochemistry))--University of Pretoria, 2021. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/83621 |
| institution | University of Pretoria (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:36:22.373Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2022 |
| publishDateRange | 2022 |
| publishDateSort | 2022 |
| publisher | University of Pretoria |
| publisherStr | University of Pretoria |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/83621 Discovery and radiopharmaceutical development of probes for prospective positron emission tomography imaging of malaria Ebenhan, Thomas janieduvenhage777@gmail.com Zeevaart, Jan Rijn Fehrsen, Jeanni Birkholtz, Lyn-Marie Duvenhage, Janie Malaria In vivo imaging radiopharmaceuticals Plasmodium UCTD Thesis (PhD (Biochemistry))--University of Pretoria, 2021. Plasmodium falciparum is not only the most predominant human malaria parasite species in Africa but is additionally responsible for causing the most severe cases of the disease. This species’ ability to modify the host’s erythrocytes not only permits the parasite’s survival within the erythrocyte and evasion of the host’s immune system, but also results in the manifestation of devastating lethal cases of the disease known as severe malaria. There is a lack in knowledge regarding the molecular mechanisms underlying the pathogenesis of severe malaria, however, research has shown that a major role is played by the sequestration of the altered infected erythrocytes in organs and tissues of the host. Research of severe malaria has relied mostly on post-mortem studies and animal models, both of which lack translatability to the disease in humans in real time. In vivo imaging is a non-invasive technique that has been used to gain insights into numerous pathologies in real time. Nuclear imaging has been employed clinically to evaluate organ and tissue functionally and track pathophysiology and disease progression at a cellular level. Immuno-PET, in particular, combines the high sensitivity and resolution of PET imaging with the superb target specificity and affinity of monoclonal antibodies, producing functional imaging of the specific target. However, there is a lack of development of malaria-specific tracers due to the complexity of the disease. This underlines the need to develop P. falciparum-specific tracers that could be used for immuno-PET imaging and thereby achieve new perceptions into severe malaria. This doctoral study set out to develop a malaria-specific tracer that would display favourable pharmacokinetic and biodistribution properties for PET imaging. We focussed on developing radiotracer candidates that would be specific for the P. falciparum-infected erythrocyte stages that are known to sequester in tissues and cause severe malaria. Firstly, a P. falciparum-specific antibody and antibody fragment were radiolabelled with 89Zr and assessed in healthy mice for their potential for future imaging of malaria. Our efficient radiosynthesis of [89Zr]Zr-Pf-Fab and [89Zr]Zr-IIIB6 allowed further pre-clinical characterisation of the pharmacokinetics and biodistribution of these tracers with PET imaging. The favourable pharmacokinetics of [89Zr]Zr-Pf-Fab further supports PET imaging studies in malaria-infected mice, and thereby validating whether this radiotracer could be used for further clinical trial investigations. Additionally, we used phage display technology aiming to discover scFvs specific towards P. falciparum-infected erythrocytes. However, this objective was hindered by inadequate detection strategies to verify the specificity of the selected scFv clones to P. falciparum-infected erythrocytes . Furthermore, we focused on 68Ga-radiolabelling of a P. falciparum-specific peptide ([68Ga]Ga-DOTA-P1) to evaluate its potential for future in vivo imaging or antimalarial drug development. The high-quality radiosynthesis of [68Ga]Ga-DOTA-P1 granted characterisation of this radiotracer in terms of serum stability and erythrocyte binding. Both, selective binding to P. falciparum-infected erythrocytes and exquisite serum stability supports future pre-clinical characterisation by way of [68Ga]Ga-DOTA-P1-PET imaging. The overall findings in this doctoral study demonstrate innovative development of P. falciparum-specific radiotracers for prospective in vivo imaging in the clinical setting towards better understanding of severe malaria, or future research in drug development. Biochemistry PhD (Biochemistry) Unrestricted 2022-02-04T08:07:09Z 2022-02-04T08:07:09Z 2022 2021 Thesis Duvenhage, J 2021, Discovery and radiopharmaceutical development of probes for prospective positron emission tomography imaging of malaria, PhD thesis, University of Pretoria, Pretoria, viewed yymmdd http://hdl.handle.net/2263/83621 A2022 http://hdl.handle.net/2263/83621 en © 2022 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. application/pdf University of Pretoria |
| spellingShingle | Malaria In vivo imaging radiopharmaceuticals Plasmodium UCTD Discovery and radiopharmaceutical development of probes for prospective positron emission tomography imaging of malaria |
| title | Discovery and radiopharmaceutical development of probes for prospective positron emission tomography imaging of malaria |
| title_full | Discovery and radiopharmaceutical development of probes for prospective positron emission tomography imaging of malaria |
| title_fullStr | Discovery and radiopharmaceutical development of probes for prospective positron emission tomography imaging of malaria |
| title_full_unstemmed | Discovery and radiopharmaceutical development of probes for prospective positron emission tomography imaging of malaria |
| title_short | Discovery and radiopharmaceutical development of probes for prospective positron emission tomography imaging of malaria |
| title_sort | discovery and radiopharmaceutical development of probes for prospective positron emission tomography imaging of malaria |
| topic | Malaria In vivo imaging radiopharmaceuticals Plasmodium UCTD |
| url | http://hdl.handle.net/2263/83621 |