Mechanism of liver injury and design of drug delivery system for the liver.

肝损伤机制及肝脏给药系统设计。

• 批准号: 11480255
• 负责人: WATANABE Yoshifumi
• 金额: $ 3.71万
• 依托单位: Tokyo Institute of Technology
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11480255/
• 关键词: Hepatitis; Drug Delivery; Hepatic lectin; apoptosis; caspase; PVLA; アシアロ糖タンパク質レセプター; Caspase

Any clinically effective therapy does not exist for fulminant hepatitis. The main mechanism of hepatitis is due to the cell death of hepatocytes in the liver. In fact, various hepatitis can be suppressed by the administration of apoptosis inhibitors. However, these inhibitors do not have the specificity for hepatocytes, thus, showed various side effects in vivo. Therefore, we developed hepatocyte-specific nanoparticles composed of poly-lactic acid bearing galactose polymer (PVLA) on the surface. The nanoparticles encapsulated caspase (excutioner of apoptosis) inhibitor specifically interacted with hepatocytes and release the contents in the cytosol for longer period, i.e., more than 24 h compared to the control (1 h). As a result, this type of nanoparticles efficiently suppressed the Fas-mediated and IFN-gamma-mediated hepatocyte cell death in vitro. In addition, these nanoparticles also inhibited the T-cell mediated mouse hepatitis, which is thought to be a typical model of human virus hepatitis, in vivo. In vivo, the nanoparticles specifically accumulated in the hepatocytes of the liver. These particles did not accumulate in other organs. These particles showed the organ specificity and elongated effective period.

对于暴发性肝炎，尚无任何临床有效的治疗方法。肝炎的主要机制是由于肝脏中肝细胞的细胞死亡。事实上，多种肝炎可以通过施用细胞凋亡抑制剂来抑制。然而，这些抑制剂对肝细胞不具有特异性，因此在体内表现出多种副作用。因此，我们开发了由表面带有聚乳酸的半乳糖聚合物（PVLA）组成的肝细胞特异性纳米颗粒。纳米颗粒封装的 caspase（凋亡执行者）抑制剂与肝细胞特异性相互作用，并在胞质溶胶中释放内容物的时间更长，即与对照（1 小时）相比，超过 24 小时。结果，这种类型的纳米颗粒在体外有效抑制了 Fas 介导和 IFN-γ 介导的肝细胞死亡。此外，这些纳米粒子还抑制了 T 细胞介导的小鼠肝炎，这被认为是体内人类病毒肝炎的典型模型。在体内，纳米颗粒特异性地积聚在肝脏的肝细胞中。这些颗粒没有积聚在其他器官中。这些颗粒表现出器官特异性并延长了有效期。

项目成果

I.Shibuya,T.Akaike,Y.Watanabe: "Design of temporally and spatially controlled drug delivery system for the treatment of liver diseasres in mice."Hepatology. 32. 1299-1307 (2000)

I.Shibuya，T.Akaike，Y.Watanabe：“用于治疗小鼠肝病的时空控制药物输送系统的设计。”肝病学。

J.Shibuya,T.Akaike,Y.Watanabe: "Suppression of Fas-mediated hepatic apoptosis by caspase inhibitor encapsulated nanoparticles bearing PVLA."Biotech.lett.. 22. 1855-1859 (2000)

J.Shibuya，T.Akaike，Y.Watanabe：“通过半胱天冬酶抑制剂封装的带有 PVLA 的纳米颗粒抑制 Fas 介导的肝细胞凋亡。”Biotech.lett.. 22. 1855-1859 (2000)

I. Shibuya: "Design of temporally and spatially controlled drug delivery system for the treatment of liver diseases in mice"Hepatology. 32. 1299-1307 (2000)

I.涉谷：“用于治疗小鼠肝脏疾病的时空控制药物输送系统的设计”肝病学。

渡辺恵史, 渋谷功, 赤池敏宏: "DDSによる肝疾患治療"Drug Delivery System. 16. 39-49 (2001)

Keiji Watanabe、Isao Shibuya、Toshihiro Akaike：“使用 DDS 治疗肝脏疾病”药物输送系统。16. 39-49 (2001)。

I.Ajioka, T.Akaike, Y.Watanabe: "Ethanolamine is a co-mitogenic factor for proliferation of primary hepatocytes"J.Cell.Biochem.. 84. 249-263 (2002)

I.Ajioka、T.Akaike、Y.Watanabe：“乙醇胺是原代肝细胞增殖的共同有丝分裂因子”J.Cell.Biochem.. 84. 249-263 (2002)