Acid and Glutathione Dual-Responsive, Injectable and Self-Healing Hydrogels for Controlled Drug Delivery

Considering the complexity of physiological microenvironments and the risks of surgical infection, there still remains critical demand to develop a hydrogel as a drug release platform with multifunctional properties, including good neutral stability and sensitive multiple stimuli-responsive behaviors, as well as injectable and self-healing properties. Herein, we present a facile preparation of injectable, self-healing hydrogels with acid and glutathione (GSH) dual-responsiveness for controlled drug delivery. Initially, the anticancer drug camptothecin (CPT) was premodified with disulfide bonds and attached to poly(ethylenimine) (PEI) via the Schiff base reaction, resulting in PEI-CPT. Subsequently, OSA-IR780 was synthesized through the Schiff base reaction involving IR780 with amine groups (IR780-NH₂) and oxidized sodium alginate with aldehyde groups (OSA). The formation of PEI-CPT/OSA-IR780 hydrogels with various solid contents occurred rapidly within 40 s through a simple mixing process of the aqueous solution of PEI-CPT and OSA-IR780. These hydrogels exhibited remarkable stability under neutral conditions and controlled release of CPT upon exposure to simulated tumor environments characterized by acidic conditions and elevated GSH concentrations. Furthermore, they had significant injectable and self-healing properties due to the dynamically imine-cross-linked networks. In addition, the prepared hydrogels exhibited long-term biodegradability and biocompatibility. Collectively, these features indicate the great potential of PEI-CPT/OSA-IR780 hydrogels as therapeutic delivery vehicles.