Nanoassemblies of Disulfide-Bridged Bile Acid Dimers as Therapeutics Agents for Hepatic Ischemia/Reperfusion Injury
Nanoassemblies of Disulfide-Bridged Bile Acid Dimers as Therapeutics Agents for Hepatic Ischemia/Reperfusion Injury
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DOI：
10.1021/acsabm.0c01554
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发表时间：
2021-04-07
影响因子：
4.7
通讯作者：
Lee, Dongwon
中科院分区：
文献类型：
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作者：
Hong, Seri;Lee, Yeongjong;Lee, Dongwon
缺血/再灌注损伤（ischemia/reperfusion injury，IR）是由缺血组织的血流恢复引起的，被认为是缺血性损伤的矛盾加重。再灌注后即刻产生大量活性氧（reactive oxygen species，ROS）如过氧化氢（hydrogen peroxide，H2O2），引起氧化应激，在IR损伤的发病机制中起重要作用。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）是三级胆汁酸之一，可促进抗氧化剂谷胱甘肽（GSH）的生成，并发挥保肝、细胞保护和抗凋亡作用。然而，熊去氧胆酸的临床应用主要受到其水溶性差和生物利用度低的限制。在这项研究中，通过利用自组装二硫键桥接的二聚体前药的概念，我们开发了一种二硫键桥接的UDCA二聚体（ssUDCA）作为肝IR损伤的治疗剂。ssUDCA在水溶液、过氧化氢条件下可自组装成稳定的纳米球，并发挥抗炎和抗凋亡活性。在肝脏IR损伤的小鼠模型中，ssUDCA（5 mg/kg）通过抑制ROS产生和抑制促炎细胞因子显著减轻IR损伤。因此，我们的研究结果为有效治疗肝脏IR损伤提供了一种有希望的策略，并对二硫键桥接UDCA纳米组装体在制药应用中的影响提供了深入的见解。
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 (H2O2) 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 H2O2, 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.