γ-聚谷氨酸-D-半乳糖酯化衍生物-顺铂复合物的制备及其肝靶向性分析

Preparation and Liver-Targeted Activity of Poly (γ-glutamic acid)-D-Galactose-Esterifiable Derivative Cisplatin Complex Compound

制备一种γ-聚谷氨酸-D-半乳糖酯化衍生物-顺铂复合物[Poly(γ-glutamic acid)-D-galactose esterifiable derivative-Cisplatin Complex Compound,γ-D+-DDP],并考察其体内靶向性。通过生物发酵获得大分子γ-聚谷氨酸[Poly(γ-glutamic acid),γ-PGA],利用酸降解得到可以作为药物载体的小分子γ-聚谷氨酸;利用凝胶色谱柱检验小分子γ-聚谷氨酸的分子量;利用HPLC检测释放的游离顺铂含量,得到复合物在小鼠体内靶向性分布情况;利用HE组织切片染色,观察脏器受损伤情况及靶向分布。实验结果表明:成功获得γ-聚谷氨酸-D-半乳糖酯化衍生物-顺铂复合物,该复合物载药率达9.4%～10.2%;HPLC结果表明注射复合物后,肝脏中药物显著增加而肾脏中药物分布明显减少,大大减少了肾毒性,肝靶向作用明显。因此,γ-聚谷氨酸-D-半乳糖酯化衍生物-顺铂复合物是一种有效的具有肝靶向性的抗肿瘤药物,具有潜在的临床应用价值;通过生物发酵获得的γ-聚谷氨酸可用于药物载体,赋予药物新的特点。

DDP could be easily incorporated into poly （γ-glutamic acid） -D-galactose esterifiable derivative through a covalent bond. The yield of DDP incorporation into the γ-PGA was 9.4% - 10.2%. The DDP was released in tile initial 8h in a burst manner, and thereafter in a sustained manner. The results that the conjugation of DDP to poly （γ-glutamie acid） -D-galaetose esterifiable derivative not only reduced the toxicity of the DDP but also enhanced antitumor activity and the targeting ability. The vivo experiments conclusively established that the γ-D ＋ -DDP compound was much less toxic to animals than DDP alone. A direct evaluation showed that mice treated with γ-D ＋ -DDP compound at a dose of 7.5 mg/kg displayed significant tumor regression. Furthermore, the implanted solid tumors disappeared completely from 35% of the H22 tumor-bearing mice after γ-D^＋ -DDP compound administration. The aforementioned results of biodistributions of the prepared γ-D^ ＋ -DDP compound in various organs in normal mice demonstrated that the γ-D^＋ -DDP compound had a specific interaction with liverg parenchymal cells and H22 hepatocellular carcinoma tumor cells via ligand receptor recognition. In conclusion, the results indicated that the γ-D^＋ -DDP compound prepared can effectively target the site of hepatoma tumor via the recognition and significantly reduce its size. The γ-D^ ＋ -DDP compound was less toxic than the free DDP, and could effectively reduce xenografted H22 hepatocellular carcinoma ceils in KM mice and prolong the survival of KM mice grafted with H22 hepatocellular carcinoma tumor cells. Therefore, the prepared γ -D ^＋ -DDP compound may be used as a potential drug delivery system for the targeted delivery to liver cancers or other liver diseases.