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Supramolecular Chemistry in Radiotracer Design


d'Orchymont, Faustine. Supramolecular Chemistry in Radiotracer Design. 2021, University of Zurich, Faculty of Science.

Abstract

Molecular imaging techniques are used in modern medicine to study biological processes from the tissue to the subcellular levels. These techniques can be incredibly sensitive, allowing the detection of small cancerous lesions, providing accurate diagnosis and monitoring of diseases. Oncological imaging relies on the use of molecular imaging agents which target and accumulate at biomarker sites.
Supramolecular chemistry offers numerous advantages as coupling strategy between molecules through intermolecular interactions. Supramolecular structures afford structural versatility and act as scaffolds, providing platforms that have the potential to be multi-functional. Taking advantage of these properties, this thesis explores the use of non-covalent, host-guest interactions in the development of new molecular imaging probes. We designed and built the first cancer-targeted, supramolecular radiotracers, using the chemistry of CB[6] and β-CD host macrocycles, for application in positron emission tomography (PET) imaging.
In Chapter 2, a small screening of phenyl and biphenyl compounds as guest molecules for β-CD was performed. The selected {β-CD:Guest} inclusion complex was involved in the synthesis of a supramolecular rotaxane-based construct using the CB[6]-β-CD-azide-alkyne cycloaddition reaction. With this rapid and efficient method for the development of interlocked systems, followed by successful radiolabelling, we developed a modular synthetic platform and synthesised our first non-covalently bound radiotracer. Kinetic studies and DFT calculations were then used to explore the properties of our new compounds and the mechanism of the CB[6]-β-CD-azide-alkyne cycloaddition reaction.
In Chapter 3, the supramolecular constructs were functionalised with ligands that bind to the established cancer biomarker prostate specific membrane antigen (PSMA) and the targeted rotaxanes were tested in vitro and in vivo by using small-animal PET imaging. We implemented the small peptide targeting vector on β-CD via a well-established monofunctionalisation method to ensure control over the stoichiometry of our supramolecular radiotracers. We also synthesise our first radiolabelled rotaxane bearing a recognised cancer targeting ligand, via the CB[6]-β-CD-azide-alkyne cycloaddition reaction. The versatility of the synthetic platform was further demonstrated with the introduction of various chelators and targeting vectors in different architectural and stoichiometric arrangements. With these modifications, we improved the affinity of the rotaxane-based constructs towards PSMA and expanded the potential applicability of our synthetic platform.
Chapter 4 explores additional characteristics of the rotaxane scaffold and the implementation of new functionalities to the constructs. First, we successfully applied the CB[6]-β-CD-azide-alkyne cycloaddition reaction in the synthesis of asymmetrical pseudorotaxanes. Second, we developed a synthetic pathway for the formation of asymmetrical rotaxanes, where one side of the axle features an optically active fluorescein moiety, and the other end is capped with a metal ion binding chelate for radiolabelling. By incorporating a fluorescent probe to the construct, we synthesised a dual modality radiolabelled and fluorescent rotaxane conjugate that targets cancer.
In Chapter 5, we developed a novel, photoactivatable rotaxane that could be radiolabelled and conjugated to various antibodies for applications in immunoPET. Photochemically-induced ligation of trastuzumab and onartuzumab with the 89Zr-radiolabelled rotaxanes led to the synthesis of two new PET radiotracers specific for the HER2/neu and c-MET cancer biomarkers, respectively. The chemical and biological properties of these radiotracers were assessed in cell binding assays and in vivo where high tumour uptake in SKOV-3 or MKN-45 xenografts was observed. These results demonstrated the viability of the rotaxane-based antibody conjugates as the first application of supramolecular chemistry to access viable, cancer-specific radiotracers for PET imaging.
Overall, this thesis explores the use of supramolecular chemistry using non-covalent host-guest interactions as a novel approach in PET radiotracer design. Cancer-specific PET radiotracers based on rotaxanes exhibit great promise for potential applications in nuclear medicine and drug design.

Abstract

Molecular imaging techniques are used in modern medicine to study biological processes from the tissue to the subcellular levels. These techniques can be incredibly sensitive, allowing the detection of small cancerous lesions, providing accurate diagnosis and monitoring of diseases. Oncological imaging relies on the use of molecular imaging agents which target and accumulate at biomarker sites.
Supramolecular chemistry offers numerous advantages as coupling strategy between molecules through intermolecular interactions. Supramolecular structures afford structural versatility and act as scaffolds, providing platforms that have the potential to be multi-functional. Taking advantage of these properties, this thesis explores the use of non-covalent, host-guest interactions in the development of new molecular imaging probes. We designed and built the first cancer-targeted, supramolecular radiotracers, using the chemistry of CB[6] and β-CD host macrocycles, for application in positron emission tomography (PET) imaging.
In Chapter 2, a small screening of phenyl and biphenyl compounds as guest molecules for β-CD was performed. The selected {β-CD:Guest} inclusion complex was involved in the synthesis of a supramolecular rotaxane-based construct using the CB[6]-β-CD-azide-alkyne cycloaddition reaction. With this rapid and efficient method for the development of interlocked systems, followed by successful radiolabelling, we developed a modular synthetic platform and synthesised our first non-covalently bound radiotracer. Kinetic studies and DFT calculations were then used to explore the properties of our new compounds and the mechanism of the CB[6]-β-CD-azide-alkyne cycloaddition reaction.
In Chapter 3, the supramolecular constructs were functionalised with ligands that bind to the established cancer biomarker prostate specific membrane antigen (PSMA) and the targeted rotaxanes were tested in vitro and in vivo by using small-animal PET imaging. We implemented the small peptide targeting vector on β-CD via a well-established monofunctionalisation method to ensure control over the stoichiometry of our supramolecular radiotracers. We also synthesise our first radiolabelled rotaxane bearing a recognised cancer targeting ligand, via the CB[6]-β-CD-azide-alkyne cycloaddition reaction. The versatility of the synthetic platform was further demonstrated with the introduction of various chelators and targeting vectors in different architectural and stoichiometric arrangements. With these modifications, we improved the affinity of the rotaxane-based constructs towards PSMA and expanded the potential applicability of our synthetic platform.
Chapter 4 explores additional characteristics of the rotaxane scaffold and the implementation of new functionalities to the constructs. First, we successfully applied the CB[6]-β-CD-azide-alkyne cycloaddition reaction in the synthesis of asymmetrical pseudorotaxanes. Second, we developed a synthetic pathway for the formation of asymmetrical rotaxanes, where one side of the axle features an optically active fluorescein moiety, and the other end is capped with a metal ion binding chelate for radiolabelling. By incorporating a fluorescent probe to the construct, we synthesised a dual modality radiolabelled and fluorescent rotaxane conjugate that targets cancer.
In Chapter 5, we developed a novel, photoactivatable rotaxane that could be radiolabelled and conjugated to various antibodies for applications in immunoPET. Photochemically-induced ligation of trastuzumab and onartuzumab with the 89Zr-radiolabelled rotaxanes led to the synthesis of two new PET radiotracers specific for the HER2/neu and c-MET cancer biomarkers, respectively. The chemical and biological properties of these radiotracers were assessed in cell binding assays and in vivo where high tumour uptake in SKOV-3 or MKN-45 xenografts was observed. These results demonstrated the viability of the rotaxane-based antibody conjugates as the first application of supramolecular chemistry to access viable, cancer-specific radiotracers for PET imaging.
Overall, this thesis explores the use of supramolecular chemistry using non-covalent host-guest interactions as a novel approach in PET radiotracer design. Cancer-specific PET radiotracers based on rotaxanes exhibit great promise for potential applications in nuclear medicine and drug design.

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Additional indexing

Item Type:Dissertation (monographical)
Referees:Holland Jason Philip, Juricek Michal, Zerbe Oliver
Communities & Collections:07 Faculty of Science > Department of Chemistry
UZH Dissertations
Dewey Decimal Classification:540 Chemistry
Language:English
Place of Publication:Zurich
Date:2021
Deposited On:09 Feb 2022 07:13
Last Modified:19 Dec 2023 16:18
OA Status:Closed