Cancer cell microenvironment-responsive bio-metal-organic frameworks for anticancer drug delivery

A glutathione (GSH)-responsive metal-organic framework (MOF) was developed using biocompatible L-cystine and Zn for targeted doxorubicin (DOX) delivery. This strategy enhances drug release in the microenvironment while minimizing systemic toxicity. Disulfide-containing MOFs were synthesized using L-cystine as the ligand and Zn as the metal node. A one-pot method was developed to encapsulate DOX during synthesis. The redox-responsive behavior of the resulting DOX@MOF-Zn(cystine) was evaluated under physiological and tumor-mimicking conditions. In vitro assays revealed that the disulfide bonds in L-cystine ligand facilitate MOF degradation in the presence of GSH, triggering DOX release. DOX@MOF-Zn(cystine) exhibited significantly enhanced release under conditions mimicking the tumor microenvironment (pH 5.4, 20 mM GSH) compared to physiological conditions (pH 7.4, no GSH). Cell viability assays demonstrated minimal toxicity for blank MOFs and strong DOX-dependent anticancer effects from DOX@MOF-Zn(cystine). These findings suggest DOX@MOF-Zn(cystine) is an effective GSH-responsive drug delivery system for targeted cancer therapy. • Biocompatible MOFs synthesized using L-cystine and Zn as non-toxic materials. • One-pot method used to load doxorubicin into disulfide-linked MOFs. • GSH triggers DOX release from MOFs under tumor-like conditions. • DOX@MOF-Zn(cystine) shows high anticancer activity, pH, and GSH responsiveness. • MOF-Zn(cystine) exhibits low toxicity and effective drug delivery capability.