Enzyme‐Triggered Chemodynamic Therapy via a Peptide‐H <sub>2</sub> S Donor Conjugate with Complexed Fe <sup>2+</sup>
Yumeng Zhu, William R. Archer, Katlyn F. Morales, Michael D. Schulz, Yin Wang, John B. Matson
Abstract
Abstract 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.