An in situ slow-releasing H₂S donor depot with long-term therapeutic effects for treating ischemic diseases

Therapeutic angiogenesis is essential for rescuing necrotic tissues in cases of ischemic disease. The exogenous hydrogen sulfide (H₂S) donor, diallyl trisulfide (DATS), has been investigated as a therapeutic agent that promotes angiogenesis. However, the short half-life of generated H₂S limits its therapeutic efficacy. In an attempt to overcome this difficulty, a poly(D,L-lactic-co-glycolic acid) microparticle system that contains DATS (DATS@MPs) is prepared as an in situ depot for the controlled release of H₂S, providing slow release and long-term effectiveness. The results of in vitro investigations indicate that the slow-released DATS from the DATS@MPs depot yields a longer intracellular production of H₂S than that from a free DATS depot. The intracellular generation of H₂S favors the translocation of the transcription factor, Nrf2, from the cytosol to nuclei, potentially upregulating the gene expressions of antioxidant enzymes, ultimately increasing cellular resistance to oxidative stress. Intramuscular injection of the slow-releasing H₂S donor depot DATS@MPs in an ischemic limb that is experimentally generated in a mouse model promotes therapeutic angiogenesis and protects cells from apoptosis and tissues from necrosis, ultimately salvaging the limb. These analytical results reveal that DATS@MPs is potentially useful in H₂S-based therapy for treating ischemic diseases.