Trans-cyclooctene–tetrazine linker system (TCO–tetrazine)

The trans-cyclooctene (TCO)–tetrazine linker system is a premier bioorthogonal chemistry platform based on the inverse electron-demand Diels-Alder (IEDDA) reaction. This system is characterized by its exceptional reaction kinetics, which are several orders of magnitude faster than other click chemistry reactions like the azide-alkyne cycloaddition (Blackman et al., 2008). In therapeutic applications, it is primarily used for pre-targeting strategies and click-to-release mechanisms. For instance, a TCO-modified antibody or biopolymer is first administered to localize at a disease site, followed by the administration of a tetrazine-linked prodrug or imaging agent that reacts specifically with the TCO at the site (Rossin et al., 2010). This approach minimizes systemic toxicity by ensuring that the active drug is only released or concentrated where the primary targeting agent is bound. The system is currently being evaluated in clinical trials, such as with the SQ3370 platform, demonstrating its potential to transform drug delivery and diagnostic imaging (Wu et al., 2021).

Other names

Inverse electron-demand Diels-Alder (IEDDA) pairBioorthogonal click chemistry pairTCO-Tz ligation systemTrans-cyclooctene-tetrazine click chemistryClick-to-release system

The system functions through a [4+2] cycloaddition between a strained alkene (trans-cyclooctene) and an electron-deficient 1,2,4,5-tetrazine, followed by a spontaneous retro-Diels-Alder reaction that eliminates nitrogen gas to form a stable dihydropyridazine linkage.