Metal Mediated Mechanisms of Drug Release

Authors
Stenton, Benjamin James  ORCID logo  https://orcid.org/0000-0001-5852-2803

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Type
Thesis
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Abstract

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.

Date
2018-04-27
Advisors
Bernardes, Goncalo
Keywords
Bioorthogonal, decaging, linker, ADC, antibody-drug conjugate, targeted drug delivery, drug delivery, bifunctional linker, protein modification, organometallic, catalysis, chemotherapy, cancer, bioconjugation, conjugation
Qualification
Doctor of Philosophy (PhD)
Awarding Institution
University of Cambridge
Sponsorship
EPSRC