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Title: Applications of tetrazines in chemical biology
Author: Neumann, Kevin
ISNI:       0000 0004 7229 4183
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2018
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The need for chemoselective bond formation within complex biological systems has driven much research in chemical biology and chemical medicine and has allowed control over the structure and biological properties of a range of chemical entities. Reactions that are highly biocompatible, selective and occur at low concentration are classified as being bioorthogonal. Although bioorthogonal reactions have been successfully applied to bioconjugation and imaging in living systems, only a few examples exist of bioorthogonal reactions being utilised for the activation of prodrugs. The tetrazine mediated inverse electron demand Diels-Alder reaction is characterized by excellent reaction rates and high biocompatibility in both in vitro and in vivo applications. To date, this chemistry has found only limited application in prodrug activation or drug release strategies. Herein, a series of tetrazine-trigger systems are reported in which an active drug is liberated from its inactive form upon triggering with tetrazine. It is shown that the release of encapsulated and conjugated drugs from polymeric nanoparticles can be triggered by tetrazines providing an on-demand release within biological systems. In a totally new approach that fully complies with the principle of bioorthogonality by avoiding the generation of any by-products, tetrazine was utilised as a prodrug scaffold leading to symbiotic and traceless dyadic prodrug activation. The simultaneous formation of two active drugs (here the anticancer drug camptothecin and a known micro RNA inhibitor) was confirmed and validated within a biological environment. The use of tetrazines as a trigger to activate or release an active drug will open new directions in the field of chemical biology/medicine.
Supervisor: Bradley, Mark ; Lusby, Paul Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: bioorthogonal reactions ; tetrazines ; prodrug scaffolding ; tetrazine-trigger systems ; polymeric nanoparticles