On-Demand Cascade Release of Hydrophobic Chemotherapeutics from a Multicomponent Hydrogel System

A multicomponent hydrogel drug-delivery platform with covalent incorporation of core-cross-linked star (CCS) polymers has been fabricated through dual cross-linking reactions. The presence of amphiphilic CCS polymers enhances the mechanical stability of the network and allows for immobilization of hydrophobic chemotherapeutics (e.g., doxorubicin: DOX) within a hydrophilic matrix. Thanks to thiol-responsive disulfide segments, the hybrid network is selectively degradable upon exposure to the glutathione-rich tumor environment, leading to an on-demand cascade release of payloads in a prolonged manner. After network degradation, the integrity of the therapeutic cargos is still well-protected by the CCS polymeric carriers. A cellular study demonstrated efficient internalization of released drug-containing CCS polymers by HeLa cells, intracellular delivery of encapsulated drugs following pH-mediated erosion of the CCS containers, and excellent cytocompatibility of this hydrogel system.