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Title: Metal mediated mechanisms of drug release
Author: Stenton, Benjamin James
ISNI:       0000 0004 7652 4097
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2018
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In this thesis will be described research towards the development of bioorthogonal bond-cleavage reactions, and their applications in targeted drug delivery (Figure 1). The first project relates to the development of a palladium mediated bond-cleavage or "decaging" reaction which can cause a propargyl carbamate to decompose and release an amine. This was further developed by the incorporation of a protein modification handle which allowed an amine-bearing drug to be covalently ligated to a protein by a palladium-cleavable linker. This chemistry was demonstrated by the conjugation of the anticancer drug doxorubicin to a tumour targeted anti-HER2 nanobody. The drug could then be delivered to cancer cells upon addition of a palladium complex. The second project relates to the development of a platinum mediated bond-cleavage reaction. This was developed with the aim of using platinum-containing anticancer drugs - such as cisplatin - as a catalyst to cause drug release reactions in tumours. In this reaction an alkyne-containing amide can decompose to release an amine upon addition of platinum complexes, and was applied to the release of prodrugs of the cytotoxins monomethylauristatin E and 5-fluorouracil in cancer cells. A cisplatin-cleavable antibody-drug conjugate was designed and synthesised, and progress towards its biological evaluation will be discussed.
Supervisor: Bernardes, Goncalo Sponsor: EPSRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Bioorthogonal ; decaging ; linker ; ADC ; antibody-drug conjugate ; targeted drug delivery ; drug delivery ; bifunctional linker ; protein modification ; organometallic ; catalysis ; chemotherapy ; cancer ; bioconjugation ; conjugation