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 in vitro 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, in vitro 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.