Synthesis of functionalized chitosan hydrogels for pH-responsive drug delivery

Hydrogels based on chitosan (CS) are promising platforms for drug delivery due to their biocompatibility and versatility. However, their inherent hydrophilicity limits the encapsulation and sustained release of poorly water-soluble drugs. Chemical modification strategies, such as N-alkylation and cyclodextrin (CD) conjugation, have been independently explored to overcome these limitations. However, no prior study has investigated the simultaneous incorporation of alkyl chains and β-cyclodextrin into CS via a one-step reductive amination process. In this work, a series of ketone-functionalized chitosan (k-f-CS) and β-cyclodextrin/ketone-functionalized chitosan (βCDk-f-CS) hydrogels was synthesized using acetone, butanone, pentanone, hexanone, and β-cyclodextrin monoaldehyde. The resulting hydrogels were first characterized by spectroscopic techniques and rheological studies. Subsequently, they were processed into porous sponges, which were evaluated for swelling and rifampicin (RIF) loading and release. RIF was selected as a model Class II drug due to its low solubility and pH-dependent instability. The sponges exhibited high drug loading capacity and pH-sensitive behavior with reduced RIF release under acidic conditions and prolonged release profiles under physiological conditions. Additionally, the hydrogels demonstrated hemocompatibility and antibacterial activity. This study presents a novel one-step approach to simultaneously modify CS with alkyl chains and βCD, yielding hydrogels with synergistic properties for the encapsulation and controlled release of RIF. Moreover, the materials can be processed into sponges, facilitating handling and further enhancing their suitability for advanced drug delivery applications.