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

Hydrogen sulfide (H₂S) 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 H₂S to cancer cells for extended periods of time suppresses cancer progression. However, one major challenge in therapeutic applications of H₂S is its controlled delivery. To solve this problem, polymeric micelles are developed containing H₂S donating-anethole dithiolethione (ADT) groups, with H₂S release profiles optimal for suppressing cancer cell proliferation. The micelles release H₂S upon oxidation by reactive oxygens species (ROS) that are present inside the cells. The H₂S release profiles can be controlled by changing the polymer design. Furthermore, the micelles that show a moderate H₂S 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 H₂S release profiles using a micelle approach for realizing the full therapeutic potential of H₂S in cancer treatment.