Abstract：
With the increased prevalence of nonalcoholic steatohepatitis (NASH) in the world, effective pharmacotherapy in clinical practice is still lacking. Previous studies have shown that dibenzazepine (DBZ), a Notch inhibitor, could alleviate NASH development in a mouse model. However, low bioavailability, poor water solubility, and extrahepatic side effects restrict its clinical application. To overcome these barriers, we developed a reactive oxygen species (ROS)-sensitive nanoparticle based on the conjugation of bilirubin to poly(ethylene glycol) (PEG) chains, taking into account the overaccumulation of hepatic ROS in the pathologic state of nonalcoholic steatohepatitis (NASH). The PEGylated bilirubin can self-assemble into nanoparticles in an aqueous solution and encapsulate insoluble DBZ into its hydrophobic cavity. DBZ nanoparticles (DBZ Nps) had good stability, rapidly released DBZ in response to H2O2, and effectively scavenged intracellular ROS of hepatocytes. After systemic administration, DBZ Nps could accumulate in the liver of the NASH mice, extend persistence in circulation, and improve the bioavailability of DBZ. Furthermore, DBZ Nps significantly improved glucose intolerance, relieved hepatic lipid accumulation and inflammation, and ameliorated NASH-induced liver fibrosis. Additionally, DBZ Nps had no significant extrahepatic side effects. Taken together, our results highlight the potential of the ROS-sensitive DBZ nanoparticle as a promising therapeutic strategy for NASH.
摘要：
随着非酒精性脂肪性肝炎（NASH）在世界范围内患病率的增加，在临床实践中仍然缺乏有效的药物治疗。以前的研究表明，二苯并氮杂卓（DBZ），缺口抑制剂，可以缓解小鼠模型中的NASH发展。然而,低生物利用度，水溶性差，肝外副作用限制了其临床应用。为了克服这些障碍，我们开发了一种基于胆红素与聚（乙二醇）（PEG）链共轭的活性氧（ROS）敏感纳米颗粒，考虑到非酒精性脂肪性肝炎（NASH）病理状态中肝脏ROS的过度积累。聚乙二醇化胆红素可以在水溶液中自组装成纳米颗粒，并将不溶性DBZ包封到其疏水腔中。DBZ纳米粒子(DBZNps)具有良好的稳定性,响应H2O2快速释放DBZ，并有效清除肝细胞的细胞内ROS。全身给药后，DBZNps可以在NASH小鼠的肝脏中积累，延长循环的持久性，提高DBZ的生物利用度。此外，DBZNps显著改善葡萄糖不耐受，减轻肝脏脂质积聚和炎症，并改善NASH诱导的肝纤维化。此外,DBZNps无明显肝外副作用。一起来看,我们的研究结果凸显了ROS敏感性DBZ纳米颗粒作为NASH治疗策略的潜力.
