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.

任何临床上有效的治疗方法都不存在于重型肝炎。肝炎的主要发病机制是肝细胞死亡。事实上，各种肝炎都可以通过给予细胞凋亡抑制剂来抑制。然而，这些抑制剂不具有肝细胞的特异性，因此在体内表现出各种副作用。因此，我们研制了表面含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。纳米粒包裹的半胱氨酸天冬氨酸氨基转移酶(Caspase)抑制物与肝细胞特异性地相互作用，并在胞浆中释放更长的时间，即比对照(1h)释放更多的内容物。结果表明，该纳米粒在体外能有效抑制Fas和干扰素-γ介导的肝细胞死亡。此外，这些纳米颗粒还在体内抑制T细胞介导的小鼠肝炎，这被认为是典型的人类病毒性肝炎模型。在体内，纳米颗粒特异性地积累在肝脏的肝细胞中。这些颗粒没有在其他器官中积聚。这些颗粒表现出器官特异性，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。

T. Haruyama: "Regulation and significance of hepatocyte-derived matrix metalloproteinases ( MMP) in liver remodeling"Biochem. Biophys. Res. Commun.. 273. 681-686 (2000)

T. Haruyama：“肝细胞源性基质金属蛋白酶（MMP）在肝脏重塑中的调节和意义”Biochem。

T.Haruyama,I.Ajioka,T.Akaike,Y.Watanabe: "Regulation and significance of hepatocyte-derived matrix metalloproteinases (MMPs) in liver remodeling."Biochem.Biophys.Res.Commun.. 273. 681-686 (2000)

T.Haruyama、I.Ajioka、T.Akaike、Y.Watanabe：“肝细胞源性基质金属蛋白酶 (MMP) 在肝脏重塑中的调节和意义。”Biochem.Biophys.Res.Commun.. 273. 681-686 (2000)