Akamatsu K, Yamasaki Y, Nishikawa M, Takakura Y, Hashida M
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
J Pharmacol Exp Ther. 1999 Sep;290(3):1242-9.
A polymeric prodrug of prostaglandin E(1) (PGE(1)) was synthesized using galactosylated poly(L-glutamic acid hydrazide) (Gal-HZ-PLGA) as a biodegradable and targetable carrier to hepatocytes. Poly(L-glutamic acid hydrazide) was prepared by reacting poly(gamma-benzyl-L-glutamate) with hydrazine monohydrate, followed by reaction with 2-imino-2-methoxyethyl-1-thiogalactosides to obtain Gal-HZ-PLGA after i.v. injection. (111)In-labeled galactosylated poly(L-glutamic acid hydrazide) ((111)In-Gal-HZ-PLGA) rapidly accumulated in the liver in a dose-dependent manner, whereas (111)In-poly(L-glutamic acid hydrazide) did not, indicating the involvement of a galactose-specific mechanism in the uptake of (111)In-Gal-HZ-PLGA. Fractionation of liver cells revealed that (111)In-Gal-HZ-PLGA was preferentially taken up by liver parenchymal cells. After being taken up by the liver, (111)In-Gal-HZ-PLGA was gradually degraded, and radioactive metabolites with low molecular weight were detected within 10 min after injection. Then, PGE(1) or [(3)H]PGE(1) was coupled to Gal-HZ-PLGA via a hydrazone bond under mild conditions to obtain PGE(1) conjugate. After i.v. injection, [(3)H]PGE(1) conjugate was rapidly taken up by the liver (more than 80% of the dose). After injection of the conjugate, (3)H radioactivity remained in the liver, representing about 70% of the dose, even at 24 h, whereas little radioactivity remained in the organ at 1 h after the injection of free [(3)H]PGE(1). Finally, its pharmacological activity was examined in mice with fulminant hepatitis induced by peritoneal injection of carbon tetrachloride. The i.v. injection of PGE(1) conjugate at a dose of 1 mg (0.074 mg PGE(1))/kg effectively inhibited the increase of plasma glutamic pyruvic transaminase activity, whereas twice this dose (0.15 mg/kg) of free PGE(1) had little effect. These results suggest that the PGE(1) conjugate is an excellent polymeric prodrug of PGE(1) for hepatitis therapy.
以半乳糖基化聚（L - 谷氨酸酰肼）（Gal - HZ - PLGA）作为可生物降解且可靶向肝细胞的载体，合成了前列腺素E(1)（PGE(1)）的聚合物前药。聚（L - 谷氨酸酰肼）通过使聚（γ - 苄基 - L - 谷氨酸）与水合肼反应制备，随后与2 - 亚氨基 - 2 - 甲氧基乙基 - 1 - 硫代半乳糖苷反应，经静脉注射后得到Gal - HZ - PLGA。（111）铟标记的半乳糖基化聚（L - 谷氨酸酰肼）（（111）In - Gal - HZ - PLGA）以剂量依赖性方式迅速在肝脏中蓄积，而（111）In - 聚（L - 谷氨酸酰肼）则不然，这表明半乳糖特异性机制参与了（111）In - Gal - HZ - PLGA的摄取。肝细胞分级分离显示（111）In - Gal - HZ - PLGA优先被肝实质细胞摄取。被肝脏摄取后，（111）In - Gal - HZ - PLGA逐渐降解，注射后10分钟内检测到低分子量的放射性代谢产物。然后，在温和条件下通过腙键将PGE(1)或[（3）H]PGE(1)与Gal - HZ - PLGA偶联，得到PGE(1)缀合物。经静脉注射后，[（3）H]PGE(1)缀合物迅速被肝脏摄取（超过剂量的80%）。注射缀合物后，即使在24小时时，（3）H放射性仍保留在肝脏中，占剂量的约70%，而注射游离[（3）H]PGE(1)后1小时该器官中几乎没有放射性残留。最后，在通过腹腔注射四氯化碳诱导爆发性肝炎的小鼠中检测其药理活性。以1毫克（0.074毫克PGE(1)）/千克的剂量静脉注射PGE(1)缀合物可有效抑制血浆谷丙转氨酶活性的升高，而两倍此剂量（0.15毫克/千克）的游离PGE(1)几乎没有效果。这些结果表明，PGE(1)缀合物是用于肝炎治疗的优异的PGE(1)聚合物前药。
