Design of Polymeric Supramolecular-assembly for Targeted Therapy of Liver

用于肝脏靶向治疗的聚合物超分子组装体的设计

• 批准号: 09308035
• 负责人: AKAIKE Toshihiro
• 金额: $ 17.09万
• 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 (A)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09308035/
• 关键词: Liver specific Therapy; Hepatocyte; Asialoglycoprotein-receptor; Biomimetics; Gene-transfection of hepatic lectin; Hyaluronic acid receptor; nanoparticle; polymeric supra-molecular assembly; 肝臓; バイオミメティック; 肝レクチン; グルコーストランスポーター; バイオミメティック糖質高分子

In order to design amphiphilic glycopolymers for targeted therapy of liver, oligosaccharide-carrying polymers which can recognize various kinds of liver cells were synthesized. Polymeric micel of lactose-carrying polystyrene (PVLA) and its coated nanoparticle were found out to be efficiently incorporated into hepatocyte mediated by asialogly coprotein receptor (ASGP-R). Poly (lactic acid) nanopaticles coated with PVLA involving caspase inhibitor (Z-Asp) were successfully targeted to hepatocytes in liver and effectively released to rescue hepatitis related cell apoptosis.The transfections of ASGP-R consisting of hepatic lectin 1 and 2 (HL-1,2) into CHO-Kl cells indicated that oligomeric association of HL-1 and 2 are responsible to higher cell-recognition of PVLA-coated nanoparticle.Based on the finding, dendritic graft copolymers of poly (L-lysine) main chain and arabiogalactan (β-galactos rich multi-anntenary polysaccharide) as DNA carrier were synthesized and evaluated for the recognition by ASGP-R of hepatocytes and hepatoma cells.Hyaluronic acid carrying poly (L-lysine) were also synthesized to be applied for specific DNA-targeting to liver sinusoidal endothelial cells.The concept of supramolecular-assembly systems such as polymeric micels, nanoparticles and polymer complex are successfully proposed.

为了设计用于肝脏靶向治疗的两亲性糖基共聚物，合成了能够识别多种肝细胞的寡糖载体聚合物。载乳糖聚苯乙烯(PVLA)聚合物胶束及其包被纳米粒可通过去唾液酸辅蛋白受体(ASGP-R)有效地掺入肝细胞。含有半胱氨酸酶抑制剂(Z-Asp)的PVLA包被的聚乳酸纳米粒成功地靶向于肝脏中的肝细胞，并有效地被释放以挽救肝炎相关细胞的凋亡。由肝脏凝集素1和2(HL-1，2)组成的ASGP-R被转染CHO-K1细胞表明，HL-1和2的寡聚结合导致了PVLA包被的纳米粒具有更高的细胞识别能力。基于这一发现，合成了聚(L-赖氨酸)主链与阿拉伯半乳糖(β-Galactos富含多年生多烯类多糖)为载体的树枝状接枝共聚物，并研究了其对肝细胞和肝癌细胞的识别作用；合成了载玻尿酸的聚(L-赖氨酸)用于肝窦内皮细胞的特异性基因靶向。

项目成果

Itsuki Ajioka, Toshihiro Akaike, and Yoshifumi Watanabe: "Expression of Vascular Endothelial Growth Factor Promotes Colonization, Vascularization, and Growth of Transplanted Hepatic Tissues in the Mouse"Hepatology. 29(2). 396-4021 (1999)

Ituki Ajioka、Toshihiro Akaike 和 Yoshifumi Watanabe：“血管内皮生长因子的表达促进小鼠移植肝组织的定植、血管化和生长”肝病学。

Jeong-Ung PARK, Tsutomu ISHIHARA, Arihiro KANO, Toshihiro AKAIKE, Atsushi MARUYAMA: "Preparation of Dendritic Graft Copolymer Cosisiting of Poly-(L-Lysine) and Arabinogalactan as a Hepatocyte Specific DNA Carrier"Biochem. & Biotechnol.. 29(4). 353-3701 (1

Jeong-Ung PARK、Tsutomu ISHIHARA、Arihiro KANO、Toshihiro AKAIKE、Atsushi MARUYAMA：“作为肝细胞特异性 DNA 载体的聚（L-赖氨酸）和阿拉伯半乳聚糖共聚的树突状接枝共聚物的制备”Biochem。

Ryotaro Takei, Keun-Hong Park, Hirohiko Ise, Atsushi Maruyama,Ph.D., Yasuhito Ebara,Ph.D., Yoshio Okahata,Ph.D., and Toshihiro Akaike,Ph.D.: "Coated Antireceptor Antibody as an Extracellular Matrix for Liver Tissue Engineering." Tissue Engineering. 3(3).

Ryotaro Takei、Keun-Hong Park、Hirohiko Ise、Atsushi Maruyama 博士、Yasuhito Ebara 博士、Yoshio Okahata 博士和 Toshihiro Akaike 博士：“包被抗受体抗体作为

H.Ise: "Analysis of Cell Viability and Differential Activity of Mouse Hepatocytes under 3D and 2D Culture in Agarose Gel"Biotechnology Letters. 21. 209-213 (1999)

H.Ise：“琼脂糖凝胶中 3D 和 2D 培养下小鼠肝细胞的细胞活力和差异活性分析”生物技术快报。

A.Maruyama, T.Ishihara, T.Akaike, J.S.Kim, S.W.Kim.: "A nanoparticle DNA carrier with poly (L-lysine) grafted polysaccharidecopolymer and poly (D, L-lactic acid)" Bioconjugate Chem. 8. 735-742 (1997)

A.Maruyama、T.Ishihara、T.Akaike、J.S.Kim、S.W.Kim.：“一种具有聚（L-赖氨酸）接枝多糖共聚物和聚（D，L-乳酸）的纳米颗粒 DNA 载体”Bioconjugate Chem。