Smart Temperature‐Sensitive Injectable Methylcellulose‐Based Hydrogels: Design and Optimization for Sustained Drug Release

Abstract Methylcellulose (MC)‐based thermoresponsive hydrogels have recently emerged as effective materials for the controlled and sustained release of pharmaceutical agents. This is mainly due to the thermoresponsive properties of MC, which exhibits a unique sol state at room temperature that facilitates its injection and subsequent transition into a gel under physiological conditions, thus ensuring controlled drug release in response to body temperature. Notably, the sol‐gel transition temperature of MC‐based hydrogels is reversible and can be modulated by the addition of salts and polymers acting as cross‐linking agents, which confers considerable versatility to the material for various clinical applications. In this work, a series of MC‐based hydrogels were synthesized, including MC homopolymer hydrogel and composite hydrogels with chitosan (CH), pectin (Pec), and polyethylene glycol (PEG). The developed hydrogels were compared in terms of injectability, thermoreversibility, mechanical properties, degradation and swelling behavior. The thermoreversible MC/PEG hydrogel was selected exhibiting the highest stability, the highest ability of controlled release of rhodamine B, used as a test molecule, and the most rapid gelation at 37°C (~70 s). MC/PEG was thus used for the encapsulation of the anticancer drug doxorubicin (Dox), proving to be an effective carrier for its controlled release. Interestingly, the influence of MC/PEG thermoreversibility on the drug release was verified, demonstrating the feasibility of controlling the drug release rate with temperature changes. The cytocompatibility of the MC/PEG hydrogel was proven by in vitro viability tests, which demonstrated also that the Dox‐loaded hydrogel was able to significantly reduce the viability and proliferation of human tumor‐derived cells with results comparable to the free drug. Additional metabolic activity assays (MTT) conducted on human and rat cell lines further reinforced the broad biocompatibility of the MC/PEG hydrogel.