α-亚麻酸-阿霉素前药的合成以及抗肿瘤活性研究  

The Synthesis of α-Linolenic Acid-Doxorubicin Conjugate and its Antitumor Activity in Vitro

作　　者：梁春辉[1] 郭焕利[1] 姚希梅[1] 庞薪莉 周四元[2] 

机构地区：[1]西安市儿童医院,陕西西安710003 [2]第四军医大学药学系药剂学教研室,陕西西安710032

出　　处：《现代生物医学进展》2014年第27期5242-5246,5252,共6页Progress in Modern Biomedicine

基　　金：陕西省自然科学基金项目(2012KTCL03-18)

摘　　要：目的:合成具有酸敏特性的α-亚麻酸-阿霉素前体药物,并观察其抗肿瘤活性以及对肿瘤细胞的靶向性。方法:以BocNHNH2、α-亚麻酸、阿霉素为主要反应原料,先后合成Boc保护的α-亚麻酰肼、α-亚麻酰肼和α-亚麻酸-阿霉素腙键连接物,采用核磁共振、质谱等方法鉴定其结构;采用LC/MS方法研究连接物在不同pH介质中的药物释放行为;采用MTT法观察连接物对人肝癌细胞HepG2、乳腺癌细胞MDA-MB-231和MCF-7细胞的毒性作用。结果:在1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC·HCl)的催化作用下,合成了α-亚麻酸-阿霉素前体药物,波谱分析提示为目标产物。通过在体外酸性条件下水解连接物,我们发现该连接物具有显著的pH值敏感性。同时在体外细胞毒性实验中,我们发现相比于游离阿霉素,该合成连接物α-亚麻酸-阿霉素对HepG2、MDA-MB-231和MCF-7三种肿瘤细胞具有更强的细胞毒性,而且细胞毒性作用可被外源性α-亚麻酸抑制。结论:α-亚麻酸-阿霉素连接物能经α-亚麻酸受体介导靶向于α-亚麻酸受体丰富的肿瘤细胞,是一种潜在的新型抗肿瘤药物。Objective： To prepare the pH-sensitive conjugate of α-linolenic acid-doxorubicin and observe its antitumor activity in vitro. Methods： Boc-LH, LH and L-DOX are synthesized with the catalyst（EDC·HCl） and the main raw materials： BocNHNH2,α-linolenic acid and doxorubicin, and characterized in terms of H1 NMR and MASS. The drugs release characteristic was performed in different pH media in vitro by the by LC/MS. The cytotoxicity effects of L-DOX on human hepatocellular carcinoma cell HepG2, human breast cancer cell line MDA-MB-231 and MCF-7 cells was measured by MTT assay. Results： With the help of EDC·HCl, the L-DOX was synthesized. The cytotoxicity of L-DOX on the three different tumor cells were stronger than doxorubicin at the same concentration,and could be inhibited by adding the freeα-linolenic acid. Conclusion： L-DOX could be targeted to tumor cells via α-linolenic acid receptor. It could be a new potential anticancer drug.

关 键 词：Α-亚麻酸 阿霉素 细胞毒性 肿瘤靶向 

分 类 号：R284[医药卫生—中药学] R730.5[医药卫生—中医学]