Reduction-Responsive Chitosan-Based Injectable Hydrogels for Enhanced Anticancer Therapy.

Selective delivery of anticancer drug molecules to the tumor site enhances local drug dosages, which leads to the death of cancer cells while simultaneously minimizing the negative effects of chemotherapy on other tissues, thereby improving the patient's quality of life. To address this need, we developed reduction-responsive chitosan-based injectable hydrogels via the inverse electron demand Diels-Alder reaction between tetrazine groups of disulfide-based cross-linkers and norbornene groups of chitosan derivatives, which were applied to the controlled delivery of doxorubicin (DOX). The swelling ratio, gelation time (90-500 s), mechanical strength (G'~350-850 Pa), network morphology, and drug-loading efficiency (≥92%) of developed hydrogels were investigated. The in vitro release studies of the DOX-loaded hydrogels were performed at pH 7.4 and 5.0 with and without DTT (10 mM). The biocompatibility of pure hydrogel and the in vitro anticancer activity of DOX-loaded hydrogels were demonstrated via MTT assay on HEK-293 and HT-29 cancer cell lines, respectively.

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.