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One step prodrug trigger for targeted release of drugs

A tetrazine small-molecule trigger for activating prodrugs has been developed. Active molecules, such as a therapeutic drug or imaging fluorophore, can be caged within a polymer nanoparticle for controlled release at a targeted site.

Cancer cell


Delivery of therapeutic agents as prodrugs (e.g. Doxorubicin)

Medical imaging


Comprehensive in vitro analysis.


A Patent Cooperation Treaty application has been file.


Licensing and/or collaborative research.


Many drugs cannot be taken directly as they are unstable under physiological conditions and/or toxic. Using a ‘prodrug’ is the common solution, where the drug is masked, and activated by de-masking at the target site. There is a general need for controlled-release drugs that offer a more effective dose and minimise side effects, particularly for cancer treatment. A promising recent approach has sought to exploit a bio-orthogonal reaction using tetrazine as the trigger to unmask the prodrug.


The vinyl group is small and chemically stable; active molecules with a vinyl ether mask are easier to prepare and less disruptive than current masking groups used with a tetrazine trigger. Custom designed tetrazines are stable under physiological conditions, and allow a controlled rate of reaction. Unmasking by tetrazine is also a one-step reaction, with no catalyst or biological species required, and the by-products are safe. Furthermore, masked molecules can be conjugated within a polymer nanoparticle with linkers that self-immolate upon reaction with tetrazine. This allows targeted and effective release of the active cargo at a specific site, such as a tumour.

Extensive in vitro data; for example, tetrazine-controlled release of Doxorubicin from a Polyethylene Glycol (PEG) nanoparticle to trigger cell death in an environment of prostate cancer cells.


  • Controlled reactivity, and stable under physiological conditions
  • Exploits a simple bio-orthogonal release reaction with tetrazine
  • Selective release for controlled dose and enhanced cellular uptake
  • Medication is more effective and side-effects are reduced


Neumann et al.: Chem. Commun. 2016, 52, 11223 ChemBioChem 2017, 18, 91

Please note, the featured image is purely illustrative.

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