Controlling Drug Release From Supramolecular Polymer Surfaces by a Click‐To‐Release Reaction

ABSTRACT Here, we introduce the combination of reactive supramolecular additives with a covalent click‐to‐release reaction. Hereto, a reactive supramolecular trans‐cyclooctene (TCO) additive is synthesized to trigger the release of a cytotoxic drug from a ureido‐pyrimidinone (UPy) based supramolecular material by soluble tetrazine (Tz) administration. Therefore, two reactive additives are designed. First, to monitor the reaction, a fluorescent UPy‐TCO‐Cy5 additive is synthesized and incorporated in a supramolecular polymer material. Reaction with Tz shows an increase in fluorescent signal in the supernatant, indicating successful release. Next, a cytotoxic UPy‐TCO‐MMC additive is synthesized and incorporated in a supramolecular polymer material where reaction with Tz results in the cell death of breast cancer cells. This study presents a new strategy for on‐demand localized drug delivery to cells from a supramolecular surface.