Hyaluronic acid and K-carrageenan metal ionic cross-linked polymers: a promising injectable hydrogels for prolonged chemotherapeutic drug delivery

Hydrogel-based drug delivery technologies have garnered considerable interest in the biomedical field, aiming to overcome the challenges associated with conventional treatments. This investigation reports a novel injectable hydrogel composed of non-chemically modified hyaluronic acid and κ-carrageenan, crosslinked using a Fe(III)-ethylenediaminetetraacetic acid (EDTA) complex for the delivery of a chemotherapeutic agent. The system exhibits shear-thinning behavior, possessing both appropriate rheological and drug-release properties, thereby eliminating the need for chemical or thermoresponsive additives. This study examines this system in the context of chemotherapeutic delivery, providing a novel approach to achieving biocompatibility, structural flexibility, injectability, and prolonged release properties. The developed hydrogels were evaluated <i>in vitro</i> for their ability to deliver the model drug daunorubicin (DNR). Physicochemical characterizations of hydrogels, including FTIR, DSC, and SEM analysis, were carried out. Furthermore, the rheological properties, <i>in vitro</i> release, swelling, degradation, and cytotoxicity of the developed hydrogels were evaluated. Homopolymer hydrogels of metal ion crosslinked HA, KCG, and hybrid hydrogels of HA-KCG were developed and evaluated. All studied hydrogels can control DNR release; compared to homopolymer hydrogels, the HA-KCG hybrid hydrogels showed a better swelling ratio, a slower degradation rate, and a higher capability to prolong DNR release over 16 days. In addition, the evaluated hydrogels exhibit shear-thinning properties and diverse viscoelastic properties, as well as enhanced DNR cytotoxic activities. Overall, Injectable self-healing hydrogels of HA and KCG interpenetrating polymer networks (IPNs) produced by metal ionic crosslinking were successfully created, exhibiting shear-thinning ability and thixotropic properties, making them a potential candidate for localized chemotherapeutic drug delivery.