Department of Bionanotechnology and Bioconvergence Engineering, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea.
Department of Polymer Nano Science and Technology, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea.
ACS Appl Bio Mater. 2021 Apr 19;4(4):3145-3154. doi: 10.1021/acsabm.0c01554. Epub 2021 Apr 7.
Ischemia/reperfusion (IR) injury is induced by the restoration of blood flow to the prolonged ischemic tissues and is considered as the paradoxical exacerbation of ischemic damages. A large amount of reactive oxygen species (ROS) such as hydrogen peroxide (HO) produced immediately after reperfusion induces oxidative stress, which plays an essential role in the pathogenesis of IR injury. It is therefore critical to suppress oxidative stress for the prevention and treatment of IR injury. Ursodeoxycholic acid (UDCA), one of the tertiary bile acids, promotes the generation of antioxidant glutathione (GSH) and also exerts hepatoprotective, cytoprotective, and antiapoptotic effects. However, the clinical uses of UDCA are limited mainly by its poor water solubility and low bioavailability. In this study, by exploiting the concept of self-assembling disulfide-bridged dimeric prodrugs, we developed a disulfide-bridged UDCA dimer (ssUDCA) as a therapeutic agent of hepatic IR injury. ssUDCA could self-assemble into stable nanospheres under aqueous conditions, scavenge HO, and exert anti-inflammatory and antiapoptotic activities. In a mouse model of hepatic IR injury, ssUDCA (5 mg/kg) significantly alleviated the IR injury by suppressing ROS production and inhibiting proinflammatory cytokines. Therefore, our findings offer a promising strategy for the effective treatment of hepatic IR injury and also provide deep insights into the impact of disulfide-bridged UDCA nanoassemblies in pharmaceutical applications.
缺血/再灌注（IR）损伤是由延长的缺血组织血流恢复引起的，被认为是缺血损伤的矛盾加剧。大量的活性氧（ROS），如再灌注后立即产生的过氧化氢（HO），会引起氧化应激，这在 IR 损伤的发病机制中起着至关重要的作用。因此，抑制氧化应激对于预防和治疗 IR 损伤至关重要。熊去氧胆酸（UDCA）是一种次级胆汁酸，可促进抗氧化谷胱甘肽（GSH）的生成，还具有肝保护、细胞保护和抗凋亡作用。然而，UDCA 的临床应用主要受到其较差的水溶性和低生物利用度的限制。在这项研究中，我们利用自组装二硫键桥联二聚体前药的概念，开发了一种二硫键桥联的 UDCA 二聚体（ssUDCA）作为治疗肝 IR 损伤的药物。ssUDCA 可以在水相条件下自组装成稳定的纳米球，清除 HO，并发挥抗炎和抗凋亡作用。在肝 IR 损伤的小鼠模型中，ssUDCA（5mg/kg）通过抑制 ROS 生成和抑制促炎细胞因子显著减轻了 IR 损伤。因此，我们的发现为有效治疗肝 IR 损伤提供了一种有前途的策略，并为二硫键桥联 UDCA 纳米组装体在药物应用中的影响提供了深入的见解。
