Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease that mainly erodes joints and surrounding tissues [1,2,3,4] and if it is not treated in time, it can cause joint deformities and loss of function. It is often accompanied by tissue and organ injury, including cardiovascular and lung [5,6,7]. The pathogenesis of RA is still not clear, therefore, an ideal drug has not been found to completely cure this type of disease [8,9]. At present, the treatment of RA is mainly based on non-steroidal anti-inflammatory drugs, glucocorticoids, traditional anti-rheumatic drugs, and biological agents for improving the condition of the disease [10,11,12]. However, the specific treatment of RA is still a dilemma in modern medicine.
Poly(lactic acid) (PLA) is produced by the polymerization of lactic acid. Because of its excellent properties such as good biocompatibility and degradability, it has been widely studied since it was discovered [13,14,15,16]. The initial raw material of PLA is plant starch, which produces extremely low pollution during the production process, and can also be completely decomposed into CO2 and H2O after use and utilized by nature [17,18]. Due to its excellent performance, PLA has been recognized to be a new type of green and environmentally friendly polymer material. Because of its biodegradability, PLA can be mixed with specific drugs to produce microparticles . When these microparticles reach the action site, they slowly decompose into CO2 and H2O, and the drug is gradually released at the corresponding action site, therefore, improving the therapeutic index [13,14,20,21].
Hydrogen sulfide (H2S) has always been considered to be a poisonous gas with a smell similar to rotten eggs, and it is produced in large quantities in some polluted environments . With the deepening of research, recent studies have found that H2S is also an important physiological gas molecule and is considered to be the third gasotransmitter after nitric oxide (NO) and carbon monoxide (CO) [23,24]. Endogenous H2S is produced via the catalyzation of cystathionine pyridoxal-5-phosphate dependent enzymes, including cystathionine-β-synthase (CBS), cystathionine-y-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST). In human blood, the concentration of H2S at normal physiological levels is about 40 µM, and the local concentration in the brain can reach more than 100 µM. As a gas signal molecule, H2S could reduce high glucose-induced myocardial injury  or kidney injury , however, the half-life of direct administration of H2S is too short, and it is also difficult to precisely control the dosage. Therefore, it is of great significance to study a series of H2S donor which could be used as a CSE substrate to further release H2S in a relatively slow manner [27,28]. S-allyl-cysteine (SAC) is an extract in garlic, which could reduce the area of myocardial infarction by regulating the level of H2S in ischemic myocardial tissue [29,30]. According to the structure of SAC, our group synthesized a compound called S-propargyl-cysteine (SPRC, also known as ZYZ-802) [31,32,33], which is a compound with a similar structure to SAC (Figure 1). Our previous study found that SPRC could be used as a new type of H2S donor for ischemia-hypoxic cell models and the treatment of coronary artery ligation rat myocardial infarction models [32,34]. In addition, SPRC could also exert its neuroprotective effect through its anti-inflammatory effect [35,36]. Recent studies have also shown that SPRC could treat rheumatoid arthritis in rats by regulating endogenous H2S [31,37,38]. However, the instant release of H2S by SPRC might prevent its clinical use, hence, how to achieve a sustained release of H2S in vivo through SPRC remains to be a challenging problem.
In this study, we aim to solve the problem that SPRC might prompt the H2S in an instant manner, a SPRC-loaded PLA-based microsphere was successfully prepared (SPRC@PLA), which showed sustained release of SPRC in vitro, therefore, elevating the plasma H2S concentration for almost 3 days. Through this long elevation period, the administration interval for treating RA has also been increased as compared with that determined in a previous study .