Applications of tetrazines in chemical biology

The need for chemoselective bond formation within complex biological systems has \ndriven much research in chemical biology and chemical medicine and has allowed \ncontrol over the structure and biological properties of a range of chemical entities. \nReactions that are highly biocompatible, selective and occur at low concentration are \nclassified as being bioorthogonal. \n \nAlthough bioorthogonal reactions have been successfully applied to bioconjugation \nand imaging in living systems, only a few examples exist of bioorthogonal reactions \nbeing utilised for the activation of prodrugs. The tetrazine mediated inverse electron \ndemand Diels-Alder reaction is characterized by excellent reaction rates and high \nbiocompatibility in both in vitro and in vivo applications. To date, this chemistry has \nfound only limited application in prodrug activation or drug release strategies. \n \nHerein, a series of tetrazine-trigger systems are reported in which an active drug is \nliberated from its inactive form upon triggering with tetrazine. It is shown that the \nrelease of encapsulated and conjugated drugs from polymeric nanoparticles can be \ntriggered by tetrazines providing an on-demand release within biological systems. In \na totally new approach that fully complies with the principle of bioorthogonality by \navoiding the generation of any by-products, tetrazine was utilised as a prodrug \nscaffold leading to symbiotic and traceless dyadic prodrug activation. The \nsimultaneous formation of two active drugs (here the anticancer drug camptothecin \nand a known micro RNA inhibitor) was confirmed and validated within a biological \nenvironment. \n \nThe use of tetrazines as a trigger to activate or release an active drug will open new \ndirections in the field of chemical biology/medicine.