Enzyme-Triggered Chemodynamic Therapy via a Peptide-H 2 S Donor Conjugate with Complexed Fe 2 .

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 Fe 2+ , CDT takes advantage of overproduced ROS in the tumor microenvironment. We developed a peptide-H 2 S donor conjugate, complexed with Fe 2+ , termed AAN-PTC-Fe 2+ . 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 H 2 S, an inhibitor of catalase, an enzyme that detoxifies H 2 O 2 . Fe 2+ and H 2 S together increased intracellular ROS levels and decreased viability in C6 glioma cells compared with controls lacking either Fe 2+ , the AAN sequence, or the ability to generate H 2 S. AAN-PTC-Fe 2+ performed better than temezolimide while exhibiting no cytotoxicity toward H9C2 cardiomyocytes. This study provides an H 2 S-amplified, enzyme-responsive platform for synergistic cancer treatment.