Trans-cyclooctene-functionalized protodrugs (TCO-protodrugs)

Trans-cyclooctene (TCO)-functionalized protodrugs are a specialized class of prodrugs designed for localized activation through bioorthogonal chemistry, specifically the inverse electron-demand Diels-Alder (IEDDA) reaction (Rossin et al., 2013). In this system, a therapeutic payload is chemically caged with a TCO moiety, rendering it pharmacologically inactive. Activation occurs when the protodrug encounters a tetrazine-functionalized activator—which may be localized at a tumor site via a hydrogel or an antibody—triggering a rapid click reaction that results in the spontaneous release of the active drug (Versteegen et al., 2013). This click-to-release strategy is primarily utilized in oncology to deliver high doses of cytotoxic agents directly to the tumor microenvironment while minimizing systemic side effects. The most advanced clinical example is SQ3370, which employs a TCO-modified doxorubicin protodrug activated by a tetrazine-functionalized hydrogel (Wu et al., 2021). While highly promising for improving the therapeutic index of toxic drugs, challenges include ensuring the stability of the TCO group and the precise localization of the activator.

Other names

Click-to-release prodrugsTCO-modified drugsIEDDA-responsive prodrugsBioorthogonal protodrugs

Activation via inverse electron-demand Diels-Alder (IEDDA) reaction between a trans-cyclooctene (TCO) moiety and a tetrazine activator, followed by a spontaneous elimination reaction that releases the active drug payload.