Hashida M, Akamatsu K, Nishikawa M, Yamashita F, Yoshikawa H, Takakura Y
Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
Pharmazie. 2000 Mar;55(3):202-5.
Based on the relationship between in vivo disposition of macromolecules and their physicochemical and biological characteristics obtained through clearance concept-based pharmacokinetic analysis, polymeric prodrugs of prostaglandin E1 (PGE1) were designed stepwise and evaluated on their targeting and therapeutic efficiencies. Although galactosylated poly-L-glutamic acid with a ethylene diamine (ED) spacer (Gal-ED-PLGA) showed good targeting efficacy in mice, its PGE1 conjugate synthesized by the carbonyldiimidazole method failed to show therapeutic effects probably due to inactivation of PGE1 during conjugation and lack of release in the tissue. In order to overcome these problems, PGE1 was conjugated to galactosylated poly-(L-glutamic acid) hydrazide (Gal-HZ-PLGA) via hydrazone bond. The PGE1-Gal-HZ-PLGA conjugate labeled with [111In] or [3H]PGE1 rapidly accumulated in the liver parenchymal cells after intravenous injection. In addition, PGE1 conjugate effectively inhibited the increase of GPT level in plasma, while free PGE1 indicated no therapeutic efficacy even at more than ten times higher doses, in carbon tetrachloride-induced hepatitis mice. These findings suggest potentials of polymeric targeting systems of PGE1 to hepatocyte utilizing galactose recognition.
基于通过基于清除概念的药代动力学分析获得的大分子体内处置与其物理化学和生物学特性之间的关系，逐步设计了前列腺素E1（PGE1）的聚合物前药，并对其靶向和治疗效率进行了评估。尽管带有乙二胺（ED）间隔基的半乳糖基化聚-L-谷氨酸（Gal-ED-PLGA）在小鼠中显示出良好的靶向效果，但其通过羰基二咪唑法合成的PGE1缀合物未能显示出治疗效果，这可能是由于缀合过程中PGE1失活以及在组织中缺乏释放。为了克服这些问题，通过腙键将PGE1与半乳糖基化聚（L-谷氨酸）酰肼（Gal-HZ-PLGA）缀合。用[111In]或[3H]PGE1标记的PGE1-Gal-HZ-PLGA缀合物静脉注射后迅速在肝实质细胞中积累。此外，在四氯化碳诱导的肝炎小鼠中，PGE1缀合物有效抑制了血浆中GPT水平的升高，而游离PGE1即使在剂量高出十倍以上时也没有治疗效果。这些发现表明利用半乳糖识别的PGE1聚合物靶向系统对肝细胞具有潜在应用价值。
