H₂S-releasing polymer micelles for studying selective cell toxicity

We report the preparation of S-aroylthiooxime (SATO) functionalized amphiphilic block copolymer micelles that release hydrogen sulfide (H₂S), a gaseous signaling molecule of relevance to various physiological and pathological conditions. The micelles release H₂S in response to cysteine with a half-life of 3.3 h, which is substantially slower than a related small molecule SATO. Exogenous administration of H₂S impacts growth and proliferation of cancer cells; however, the limited control over H₂S generation from inorganic sulfide sources results in conflicting reports. Therefore, we compare the cellular cytotoxicity of SATO-functionalized micelles, which release H₂S in a sustained manner, to Na₂S, which releases H₂S in a single dose. Our results show that H₂S-releasing micelles significantly reduce the survival of HCT₁₁₆ colon cancer cells relative to Na₂S, GYY₄₁₃₇, and a small molecule SATO, indicating that release kinetics may play an important role in determining toxicity of H₂S toward cancer cells. Furthermore, H₂S-releasing micelles are well tolerated by immortalized fibroblasts (NIH/₃T₃ cells), suggesting a selective toxicity of H₂S toward cancer cells.