Small Molecule Cancer Drugs as Dual-Responsive, Dynamic-Covalent Cross-Linkers for PEG Hydrogels

A dual-responsive hydrogel platform in which the anticancer drug doxorubicin (DOX) functions both as a therapeutic payload and as a dynamic covalent cross-linker is presented. While hydrogels are widely explored for controlled drug delivery, decoupling network remodeling from drug release remains challenging. To address this, I engineered bifunctional DOX derivatives incorporating two orthogonal, stimulus-cleavable linkages: a pH-labile oxime bond at the DOX keto group and a reductively cleavable, self-immolative disulfide linker attached via a stable carbamate at the daunosamine amine. These DOX cross-linkers were conjugated to multiarm poly-(ethylene glycol) (PEG) and assembled into hydrogels through dynamic-covalent oxime formation. The resulting networks were stable under physiological conditions but underwent pronounced reorganization upon acidic or reductive stimulation, leading to gel dissolution without significant drug release. In contrast, sequential application of both stimuli triggered quantitative release of native DOX. This hierarchical response enables independent control over network architecture and drug activation and establishes small-molecule chemotherapeutics as functional, dual-responsive cross-linkers for programmable hydrogel drug depots.