Long-range excited-state intramolecular proton transfer (ESIPT)-assisted two-photon responsive COS/H2S donor: a nanoprodrug for cancer treatment.

Recently, hydrogen sulfide (H2S) has been recognised as a promising member of the gasotransmitter family, which plays a vital role in regulating various physiological and pathological processes. Hence, the development of synthetic chemical tools capable of donating H2S in a controlled manner is an area of substantial interest. Herein, we developed a two-photon-activated photoresponsive COS/H2S donor that exploits the long-range excited-state intramolecular proton transfer (ESIPT) phenomenon in our designed system. This platform uses a photocage tethered to a thiocarbamate moiety, which, upon light irradiation, releases COS. The released COS could be rapidly hydrolysed by carbonic anhydrase and generate H2S, closely mimicking the body's well-regulated endogenous H2S production. Additionally, the incorporation of the long-range ESIPT process offers several advantages, such as (i) strong emission with a large Stokes shift and (ii) a faster photorelease rate. TD-DFT calculations carried out using the CAM-B3LYP density functional with the TZVP basis set further validated our experimental findings. Intrigued by these properties, we also developed our photoresponsive COS/H2S donor HQ-COS as a nanoprodrug (nano-HQCOS) and explored its therapeutic potential in the MDA-MB-231 triple-negative breast cancer cell line. In vitro studies demonstrated that our nano-HQCOS exhibits effective cellular internalisation and inhibits the growth of triple-negative breast cancer cells, particularly those with overexpressed carbonic anhydrase, while it is benign to the normal healthy cells.