Biocompatible Fe³⁺ and Ca²⁺ Dual Cross-Linked G‑Quadruplex Hydrogels as Effective Drug Delivery System for pH-Responsive Sustained Zero-Order Release of Doxorubicin

The ultimate aim in developing controlled drug delivery systems is to derive formulations to achieve drug release at a constant rate over a long duration. The drug release profile that follows zero-order kinetics is crucial for reduction in the drug administration frequency, reduced cytotoxicity, and improved convenience and compliance of patients. Designed drug delivery systems for achieving zero-order release are often complex, expensive, and difficult to manufacture. Herein, we demonstrate that a supramolecular hydrogel formed through the self-assembly of guanosine monophosphate (GMP) into highly ordered G-quadruplex structure and cross-linked through Fe³⁺ and Ca²⁺ ions exhibits potential for the pH-responsive controlled zero-order drug release of doxorubicin, a model chemotherapeutic drug. The fibril formation is initiated by the self-assembly of GMP into a quadruplex complex, which is cross-linked through the complexation of the phosphate groups with Fe­(III) ions, resulting in a spontaneous hydrogel formation. The Ca²⁺ ions facilitate the improvement in the mechanical integrity of the fibril network in the Fe-GMP hydrogel via cross-linking of sugar moieties. The hydrogel showed a high loading capacity for drug molecules and a pH-responsive sustained zero-order drug release over several days owing to the lowered degradability of the cross-linked hydrogel in acidic buffer stimulant. In vitro drug-release studies further established a controlled pH-triggered drug release profile. The Ca²⁺ cross-linking of the Fe-GMP hydrogel also resulted in significant enhancement in the biocompatibility of the drug delivery system. The fabrication of biocompatible, low-cost, and efficient Ca²⁺ cross-linked metal–organic hydrogels may present promising applications in biological fields.