Reactive Oxygen Species‐Triggered Hydrogen Sulfide Release and Cancer‐Selective Antiproliferative Effect of Anethole Dithiolethione‐Containing Polymeric Micelles

Abstract Hydrogen sulfide (H 2 S) is a gaseous signaling molecule in the human body and has attracted attention in cancer therapy due to its regulatory roles in cancer cell proliferation and migration. Accumulating evidence suggests that continuous delivery of H 2 S to cancer cells for extended periods of time suppresses cancer progression. However, one major challenge in therapeutic applications of H 2 S is its controlled delivery. To solve this problem, polymeric micelles are developed containing H 2 S donating‐anethole dithiolethione (ADT) groups, with H 2 S release profiles optimal for suppressing cancer cell proliferation. The micelles release H 2 S upon oxidation by reactive oxygens species (ROS) that are present inside the cells. The H 2 S release profiles can be controlled by changing the polymer design. Furthermore, the micelles that show a moderate H 2 S release rate exert the strongest anti‐proliferative effect in human colon cancer cells in in vitro assays as well as the chick chorioallantoic membrane cancer model, while the micelles do not affect proliferation of human umbilical vein endothelial cells. This study shows the importance of fine‐tuning H 2 S release profiles using a micelle approach for realizing the full therapeutic potential of H 2 S in cancer treatment.