NIR-degradable and biocompatible hydrogels derived from hyaluronic acid and coumarin for drug delivery and bio-imaging

In this work, bioorthogonal and photodegradable hydrogels derived from norbornene (Nb) functionalized hyaluronic acid and a water soluble coumarin-based cross-linker possessing terminal tetrazine (Tz) groups, were developed for NIR-responsive release of doxorubicin (DOX). The inverse electron demand Diels-Alder cross-linking reaction between Nb and Tz functionalities formed the hydrogels at physiological conditions, whereas N2 gas liberated during the reaction created pores in the hydrogels. The gelation time ranges (about 5-20 min) and the viscoelastic behavior (G' ~ 346-1380 Pa) demonstrated that the resulting hydrogels were injectable and possessed tunable mechanical properties. Moreover, hydrogels released the encapsulated DOX upon NIR irradiation, owing to the NIR-responsive cleavage of coumarin-ester, and consequently, induced anti-tumor activity in BT-20 cancer cells. Additionally, the hydrogels could be excited at various wavelengths of the visible spectrum and can emit green to red fluorescence, demonstrating their simultaneous photo-responsive drug release and bio-imaging applications.