Targeting calcium-crosslinked alginate hydrogel in a living subject using a synthetic anion receptor

Alginate hydrogels are widely utilized in different medical applications as drug excipients, wound dressings, and tissue engineering scaffolds. However, selective delivery of molecular payload to unmodified alginate hydrogels in complex biological media remains a significant challenge. This study presents a novel supramolecular approach for targeting unmodified alginate hydrogels using synthetic zinc(ii) bis(2,2'-dipicolylamine) (ZnBDPA) coordination complexes. Recognizing the polyanionic nature of alginate, we demonstrate that ZnBDPA receptors exhibit high binding affinity for the carboxylate groups on an alginate polymer backbone. Solution-state titration and dye displacement assays confirmed strong binding of a ZnBDPA receptor to different polycarboxylates including alginate. Subsequent hydrogel loading and leakage experiments found that a fluorescent ZnBDPA receptor molecule readily transferred into calcium-crosslinked alginate microspheres and remained trapped, unlike an untargeted control dye. Moreover, release of the trapped ZnBDPA receptor could be triggered by adding pyrophosphate as a receptor binding and displacement agent. Finally, in vivo fluorescence imaging of a living mouse revealed that intravenously administered ZnBDPA receptor selectively targeted a subcutaneously implanted alginate microsphere. These findings establish ZnBDPA as an effective delivery vehicle for alginate hydrogel implants within a living subject, offering a versatile platform for loading and controlled release of molecular payload.