Systematic development of targeting systams for prevention of tissue damages in organ transplantation

器官移植中预防组织损伤的靶向系统的系统开发

• 批准号: 08557145
• 负责人: HASHIDA Mitsuru
• 金额: $ 4.16万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08557145/
• 关键词: organ transplantation; immunosuppressant; chemical modification; tissue damage; reactive oxygen species; superoxide disumutase; macromolecular prodrug; tacrolimus; 細胞傷害; 活性酵素; マクロファージ

The purpose of the present study was to develop novel drug delivery systems for prevention of the tissue damages in organ transplantation. A macromolecuar prodrug of tacrolimus (FK506), a powerful immunosuppressant agent, and several derivatives of superoxide dismutase (SOD), an antioxidant enzyme, were developed. Macromolecular prodrug of FK506, FK506-dextran conjugate.was synthesized and the coupling molar ratio was approximately 1 : 1(dextram : FK506). FK506 was released from the conjugate by a chemical hydrolysis with a half-life of 150hr in phosphate buffer. In vitro immunosuppressive activity of the conjugate assessed by rat lymphocyte stimulation test was almost comparable to that of free FK506, suggesting biologically active FK506 could be liberated from the conjugate. In vivo biodistribution studies demonstrated that conjugation with the dextran derivative dramatically changed the pharmacokinetic properties of FK506 after intravenous injection in rats. AUC of the FK506-dextran … More conjugate was almost 2000 times higher than that of free FK506 and organ uptake clearances of the conjugate were significantly smaller than those of free drug. These results suggest that the FK506-dextran conjugate behaves as a prodrug of FK506 with an extended blood circulating time and can be expected to have an improved therapeutic potency. On the other hand, chemical modification was carried out on SOD without significant loss of its enzymatic activity. Among them, glycosylated SOD derivatives, galactosylated and mannosylated SOD,were successfully delivered to the liver parenchmal and non-parenchymal cells, respectively, via receptor-mediated endocytosis. The therapeutic effects of the SOD derivatives wereevaluated in rat models. The SOD derivatives showed superior preventive effects in hepatic ischemia/reperfusion injury compared with unmodified SOD.Thus, the present study has demonstrated that the FK506-dextran conjugate and SOD derivatives would be useful delivery systems for the prevention of organ damages in organ transplantation. Less

本研究的目的是开发新的药物传递系统，以预防器官移植中组织损伤。研究了免疫抑制剂他克莫司（FK506）的大分子前药及其抗氧化酶超氧化物歧化酶（SOD）衍生物。FK506的大分子前药，FK506-葡聚糖缀合物。结果表明，偶联摩尔比约为1:1 （dextram: FK506）。FK506在磷酸盐缓冲液中通过化学水解从共轭物中释放出来，半衰期为150hr。大鼠淋巴细胞刺激试验表明，该偶联物的体外免疫抑制活性与游离FK506几乎相当，表明该偶联物可以释放出具有生物活性的FK506。体内生物分布研究表明，与葡聚糖衍生物结合可显著改变FK506在大鼠体内静脉注射后的药代动力学特性。FK506-葡聚糖的AUC是游离FK506的近2000倍，其器官摄取清除率明显小于游离FK506。这些结果表明，FK506-葡聚糖缀合物作为FK506的前药，具有延长血液循环时间的作用，有望提高治疗效果。另一方面，对SOD进行化学修饰后，其酶活性没有明显下降。其中，糖基化SOD衍生物，半乳糖化和甘露糖基化SOD分别通过受体介导的内吞作用被成功地递送到肝实质细胞和非实质细胞。在大鼠模型上评价SOD衍生物的治疗效果。SOD衍生物对肝脏缺血再灌注损伤的预防作用优于未修饰的SOD。因此，本研究表明fk506 -葡聚糖缀合物和SOD衍生物将成为器官移植中预防器官损伤的有效递送系统。少

项目成果

Hideki Hirabayashi: "Development and pharmacokinetics of galactosylated poly-L-glutamic acid as a biodegradable carrier for liver-specific drug delivery." Pharmaceutical Research. 13(6). 880-884 (1996)

Hideki Hirabayashi：“半乳糖基化聚-L-谷氨酸作为肝脏特异性药物输送的可生物降解载体的开发和药代动力学。”

Toshihide Takagi: "Augmented inhibitory effect of superoxide dismutase on siperoxide anion release from macrophages by direct cationization." Biochimica et Biophysica Acta. 1335(1,2). 91-98 (1997)

Toshihide Takagi：“通过直接阳离子化增强超氧化物歧化酶对巨噬细胞释放双氧阴离子的抑制作用。”

Satoshi Kondo: "Mannosylated superoxide dismutase inhibits hepatic reperfusion injury in rats." Journal of Surgical Research. 60. 36-40 (1996)

Satoshi Kondo：“甘露糖化超氧化物歧化酶可抑制大鼠肝再灌注损伤。”

Ken Akamatsu: "Synthesis and biodistribution study of liver-specific prostaglandin E_1 polymeric conjugate." International Journal of Pharmaceutics. 155(1). 65-74 (1997)

Ken Akamatsu：“肝脏特异性前列腺素 E_1 聚合缀合物的合成和生物分布研究。”

S.Kondo: "Mannosylated superoxide dismutase inhibits hepatic reperfusion injury in rats." J.Surg.Res.60. 36-40 (1996)

S.Kondo：“甘露糖化超氧化物歧化酶可抑制大鼠肝再灌注损伤。”