<div class="csl-bib-body">
<div class="csl-entry">Schiefer, A. (2021). <i>Towards accelerated bioorthogonal drug activation in cancer cells upon independent double-targeting</i> [Diploma Thesis, Technische Universität Wien]. reposiTUm. https://doi.org/10.34726/hss.2021.96263</div>
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dc.identifier.uri
https://doi.org/10.34726/hss.2021.96263
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dc.identifier.uri
http://hdl.handle.net/20.500.12708/18885
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dc.description
Einverständnis für die Online-Veröffentlichung nachträglich zurückgezogen
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dc.description.abstract
One of the main problems in the field of chemotherapy remains to be the off-target toxicity caused by cancer therapeutics. Many chemotherapeutics do not sufficiently differentiate between healthy cells and cancer cells and therefore damage healthy tissue too. A keyword in that context is drug targeting, which aims for the directed delivery and activation of drugs at the target zone.In general, there are two common drug targeting approaches: Strategies based on tumor-associated receptors (“active targeting”) or based on nanoparticles (“passive targeting”) for anticancer drug delivery. Both strategies have their advantages but also their limitations. Tumor-associated receptors are often also expressed on the surface of healthy cells, and due to their size and polarity, small-molecule ligands are renally excreted and thus mainly accumulate in the kidneys and bladder. Nanoparticles, on the other side, end up to a large part in the filtering organs, the liver and lungs. So, off-target toxicity remains a big challenge in both these targeting approaches.To tackle these limitations, we aim for the development of independent double-targeting as a new concept that combines established targeting strategies and takes advantage of the different pharmacokinetics of nanoparticles and small-molecule ligand conjugates. Due to the combination of bioorthogonal drug active-tion and different biodistribution profiles, we aim to substantially reduce off-target toxicity. The prodrug activation in this strategy is done via a bioorthogonal cleavage reaction between trans-cyclooctenes (TCOs) and tetrazines in a click-to-release approach.Based on preliminary work, confirming the double-targeting approach in cell experiments, the aim of this master thesis was to provide various chemical compounds for further investigation and improvement of the independent double-targeting approach.The main focus of this work was put on the eleven-step synthesis of a drug-TCO conjugate by implementing a superior TCO that shows outstanding properties regarding the efficiency of the bioorthogonal cleavage process. The synthesized TCO was successfully attached to a potent cytotoxin and modified with a C16-carbon chain as lipophilic anchor to facilitate and enhance nanoencapsu-lation. The formation of a dehydrated side-product could be prevented, and the yield was improved by examining different coupling conditions and reversing the order of synthetic steps. The synthesized compound was encapsu-lated in PLGA/PEG nanoparticles and provided for first stability experiments. In addition, three lipophilic C16-modified tetrazines were prepared and nanoencap-sulated. PLGA was conjugated to a fluorescent BODIPY-dye and used for nanoparticle synthesis to allow the monitoring of the nanoparticles in cell studies via fluorescence microscopy. In addition, a fluorescently labeled non-releasing TCO was prepared to enable the visualization of tetrazines by bioorthogonal imaging. A second TCO-drug conjugate was successfully prepared in order to compare the performances of different TCOs in this targeting strategy. The attachment of drug-TCO conjugates and tetrazines to small-molecule ligands will enable various approaches and detailed investigation of independent double-targeting and accelerated drug activation inside cells.
en
dc.language
English
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dc.language.iso
en
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dc.rights.uri
http://rightsstatements.org/vocab/InC/1.0/
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dc.subject
Click chemistry
en
dc.subject
Bioorthogonal chemistry
en
dc.subject
drug targeting
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dc.subject
tetrazines
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dc.subject
trans-cyclooctenes
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dc.title
Towards accelerated bioorthogonal drug activation in cancer cells upon independent double-targeting
en
dc.type
Thesis
en
dc.type
Hochschulschrift
de
dc.rights.license
In Copyright
en
dc.rights.license
Urheberrechtsschutz
de
dc.identifier.doi
10.34726/hss.2021.96263
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dc.contributor.affiliation
TU Wien, Österreich
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dc.rights.holder
Andrea Schiefer
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dc.publisher.place
Wien
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tuw.version
vor
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tuw.thesisinformation
Technische Universität Wien
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dc.contributor.assistant
Fröhlich, Johannes
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tuw.publication.orgunit
E163 - Institut für Angewandte Synthesechemie
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dc.type.qualificationlevel
Diploma
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dc.identifier.libraryid
AC16385756
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dc.description.numberOfPages
83
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dc.thesistype
Diplomarbeit
de
dc.thesistype
Diploma Thesis
en
dc.rights.identifier
In Copyright
en
dc.rights.identifier
Urheberrechtsschutz
de
tuw.advisor.staffStatus
staff
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tuw.assistant.staffStatus
staff
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tuw.advisor.orcid
0000-0002-9218-9722
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item.fulltext
with Fulltext
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item.grantfulltext
embargo_20990101
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item.languageiso639-1
en
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item.mimetype
application/pdf
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item.openairetype
master thesis
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item.cerifentitytype
Publications
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item.openaccessfulltext
Open Access
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item.openairecristype
http://purl.org/coar/resource_type/c_bdcc
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crisitem.author.dept
E163-03-2 - Forschungsgruppe Molekulare Chemie und Chemische Biologie
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crisitem.author.parentorg
E163-03 - Forschungsbereich Organische und Biologische Chemie