Signal-triggered release of allyl-caged tertiary amine drugs from polymer hydrogels

We present a new method to obtain tertiary amine-based prodrugs with dual functionality, enabling (i) signal-triggered drug activation and (ii) covalent incorporation in polymer materials through a clickable azido-group unit on the molecular prodrug scaffold. Using nucleophilic substitution on an electron deficient azido-phenyl allyl bromide scaffold, we were able to obtain prodrugs from a variety of amine drug candidates. Subsequent drug activation was initiated by using S or N-terminal biomarker nucleophiles including amino acids, a neurotransmitter, and glutathione as chemical signals. Hydrogel scaffolds labelled with anti-cancer or antibiotic prodrugs were tested in aqueous and cellular media. Through this strategy, we achieved controlled drug release for in vitro cancer models (2D monolayer), which showed complete wound closure inhibition of A549 small lung cancer cells upon signal activation. We anticipate that this strategy for the development of responsive prodrug-conjugate incorporated materials will lead to further advancements in drug delivery and specialized therapeutics.