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

Hydrogen sulfide (H₂ 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 H₂ S to cancer cells for extended periods of time suppresses cancer progression. However, one major challenge in therapeutic applications of H₂ S is its controlled delivery. To solve this problem, polymeric micelles are developed containing H₂ S donating-anethole dithiolethione (ADT) groups, with H₂ S release profiles optimal for suppressing cancer cell proliferation. The micelles release H₂ S upon oxidation by reactive oxygens species (ROS) that are present inside the cells. The H₂ S release profiles can be controlled by changing the polymer design. Furthermore, the micelles that show a moderate H₂ 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 H₂ S release profiles using a micelle approach for realizing the full therapeutic potential of H₂ S in cancer treatment.