Enzyme-Triggered Chemodynamic Therapy via a Peptide-H₂ S Donor Conjugate with Complexed Fe²

Inducing high levels of reactive oxygen species (ROS) inside tumor cells is a cancer therapy method termed chemodynamic therapy (CDT). Relying on delivery of Fenton reaction promoters such as Fe²⁺ , CDT takes advantage of overproduced ROS in the tumor microenvironment. We developed a peptide-H₂ S donor conjugate, complexed with Fe²⁺ , termed AAN-PTC-Fe²⁺ . The AAN tripeptide was specifically cleaved by legumain, an enzyme overexpressed in glioma cells, to release carbonyl sulfide (COS). Hydrolysis of COS by carbonic anhydrase formed H₂ S, an inhibitor of catalase, an enzyme that detoxifies H₂ O₂ . Fe²⁺ and H₂ S together increased intracellular ROS levels and decreased viability in C6 glioma cells compared with controls lacking either Fe²⁺ , the AAN sequence, or the ability to generate H₂ S. AAN-PTC-Fe²⁺ performed better than temezolimide while exhibiting no cytotoxicity toward H9C2 cardiomyocytes. This study provides an H₂ S-amplified, enzyme-responsive platform for synergistic cancer treatment.