Paper Title
Exogenous Delivery Of Hydrogen Sulfide By Dats-Loaded Plga Microparticles For The Treatment Of Ischemic Disease

Abstract
In critical limb ischemia, the occlusion of blood vessels results in tissue hypoxia, followed by intense inflammatory responses and increased oxidative stresses, which ultimately limits the survival of the suffered cells. Hydrogen sulfide (H2S) has become recognized as an important signaling molecule, contributing to many physiological and pathological processes. The protective role in combating cellular apoptosis, oxidative stress, as well as promoting angiogenesis prompted vast interest in the possibility of developing new therapies by delivery exogenous H2S for the treatment of ischemic diseases. In this study, a drug delivery system of poly(lactic-co-glycolic acid) (PLGA) was employed to load diallyl trisulfide (DATS), an organosulfide that can generate H2S upon reacting with glutathione, to administer exogenous H2S for treating ischemic diseases. By providing exogenous H2S, a receptive cell environment in the target tissue can be realized, and thus the survival rate of the suffered cells as well as the therapeutic effects can be improved considerably. The DATS-loaded PLGA microparticles (MPs) was fabricated by single emulsion. Our in vitro results demonstrate that the DATS-loaded PLGA MPs can enhance cell viability of C2C12 mouse myoblasts under hypoxia/oxidative stresses. In the in vivo experiments, intramuscular administration of the DATS-loaded MPs was performed for the treatment of ischemic mouse hindlimb. The animals that received saline, free DATS or empty MPs serve as controls. We found that therapeutic angiogenesis was enhanced and blood flow recovery and limb salvage were ultimately achieved. The strategy that uses DATS-loaded PLGA MPs may provide a new means of delivering the exogenous H2S for the treatment of ischemic diseases. Index Terms - Therapeutic angiogenesis; H2S donor; critical limb ischemia; oxidative stress; controlled release