Nitric oxide facilitates the targeting Kupffer cells of a nano-antioxidant for the treatment of NASH.
Nitric oxide facilitates the targeting Kupffer cells of a nano-antioxidant for the treatment of NASH.
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DOI：
10.1016/j.jconrel.2021.11.039
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发表时间：
2021-11
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通讯作者：
Hitoshi Maeda;Yu Ishima;J. Saruwatari;Yuki Mizuta;Yuki Minayoshi;Shota Ichimizu;Hiroki Yanagisawa;Taisei Nagasaki;Kengo Yasuda;S. Oshiro;M. Taura;M. McConnell;K. Oniki;Kayoko Sonoda;T. Wakayama;M. Kinoshita;T. Shuto;H. Kai;Motohiko Tanaka;Yutaka Sasaki;Y. Iwakiri;M. Otagiri;Hiroshi Watanabe;Panayiotis D. Megaloikonomos
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作者：
Hitoshi Maeda;Yu Ishima;J. Saruwatari;Yuki Mizuta;Yuki Minayoshi;Shota Ichimizu;Hiroki Yanagisawa;Taisei Nagasaki;Kengo Yasuda;S. Oshiro;M. Taura;M. McConnell;K. Oniki;Kayoko Sonoda;T. Wakayama;M. Kinoshita;T. Shuto;H. Kai;Motohiko Tanaka;Yutaka Sasaki;Y. Iwakiri;M. Otagiri;Hiroshi Watanabe;Panayiotis D. Megaloikonomos
库普弗细胞是活性氧（ROS）的关键来源，参与非酒精性脂肪性肝炎（NASH）的脂肪性肝炎和纤维化的发展。我们最近开发了一种多硫化和甘露糖基化的人血清白蛋白（SH-Man-HSA），这是一种靶向库普弗细胞的纳米抗氧化剂，其中白蛋白上的甘露糖基单位允许它们通过甘露糖受体C型1 （MRC1）被库普弗细胞特异性摄取，并且其中的多硫化赋予抗氧化活性。本研究的目的是探讨SH-Man-HSA对NASH模型小鼠的治疗潜力。在小鼠和/或NASH患者的肝脏中，我们观察到肝叶血流量减少，Kupffer细胞MRC1表达下调，单独使用SH-Man-HSA未能改善NASH的病理表型。然而，一氧化氮（NO）供体恢复肝脏血流，增加甘露糖受体C型2 （MRC2）的表达，而不是MRC1。因此，SH-Man-HSA和NO供体联合治疗可改善氧化应激相关病理。最后，我们开发了一种混合型纳米抗氧化剂（SNO-Man-HSA），通过SH-Man-HSA的亚硝化。这种纳米药物有效地将NO和硫醇基团传递到肝脏，具有与SH-Man-HSA和NO供体联合治疗相当的肝脏保护作用。这些发现表明，SNO-Man-HSA具有作为治疗NASH的新型纳米疗法的潜力。
Kupffer cells are a key source of reactive oxygen species (ROS) and are implicated in the development of steatohepatitis and fibrosis in nonalcoholic steatohepatitis (NASH). We recently developed a polythiolated and mannosylated human serum albumin (SH-Man-HSA), a nano-antioxidant that targets Kupffer cells, in which the mannosyl units on albumin allows their specific uptake by Kupffer cellsviathe mannose receptor C type 1 (MRC1), and in which the polythiolation confers antioxidant activity. The aim of this study was to investigate the therapeutic potential of SH-Man-HSA in NASH model mice. In livers from mice and/or patients with NASH, we observed a reduced blood flow in the liver lobes and the down-regulation in MRC1 expression in Kupffer cells, and SH-Man-HSA alone failed to improve the pathological phenotype in NASH. However, the administration of a nitric oxide (NO) donor restored hepatic blood flow and increased the expression of the mannose receptor C type 2 (MRC2) instead of MRC1. Consequently, treatment with a combination of SH-Man-HSA and an NO donor improved oxidative stress-associated pathology. Finally, we developed a hybrid type of nano-antioxidant (SNO-Man-HSA)viatheS-nitrosation of SH-Man-HSA. This nanomedicine efficiently delivered both NO and thiol groups to the liver, with a hepatoprotective effect that was comparable to the combination therapy of SH-Man-HSA and an NO donor. These findings suggest that SNO-Man-HSA has the potential for functioning as a novel nano-therapy for the treatment of NASH.