# Nucleophile-triggered prodrug release from polymer hydrogels

## TL;DR

A new method creates prodrugs that can be activated by specific signals and incorporated into materials, enabling controlled drug release for cancer treatment.

## Contribution

A versatile method for creating tertiary amine-based prodrugs with dual functionality for signal-triggered activation and polymer conjugation.

## Key findings

- Prodrugs were activated using biomarker nucleophiles like amino acids and glutathione.
- Hydrogels with anti-cancer prodrugs inhibited A549 lung cancer cell migration by ∼100% in vitro.
- The method allows covalent incorporation of prodrugs into polymer materials via clickable azido-group units.

## Abstract

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 upon signal activation for in vitro cancer models with ∼100% wound closure inhibition of A549 small lung cancer cells. We anticipate that this new strategy for the development of responsive prodrug-conjugate incorporated materials will lead to further advancements in drug delivery and specialized therapeutics.

A versatile method for tertiary amine-based prodrugs enables signal-triggered activation and polymer conjugation, allowing controlled, biomarker-responsive release from prodrug-labelled hydrogels with inhibited lung cancer cell migration in vitro.