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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 synthesize α-linolenic acid-doxorubicin prodrug with acid sensitive properties and to observe its antitumor activity and its targeting to tumor cells. Methods: BocNHNH2, α-linolenic acid and doxorubicin were used as the main raw materials to synthesize Boc-protected α-linolenic acid hydrazide, α-linolenic acid hydrazide and α-linolenic acid-doxorubicin hydrazone bond. Resonance and mass spectrometry were used to identify the structure of the drug. The LC / MS method was used to investigate the drug release behavior of the conjugate in different pH media. The effect of the conjugate on HepG2, MDA-MB-231 and MCF- 7 cell toxicity. Results: α-Linolenic acid-doxorubicin prodrug was synthesized under the catalysis of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC · HCl) Spectral analysis suggests the target product. By hydrolyzing the linker under acidic conditions in vitro, we found that the linker has significant pH sensitivity. At the same time, in vitro cytotoxicity experiments, we found that the synthetic linker α-linolenic-doxorubicin has stronger effect on three kinds of tumor cells of HepG2, MDA-MB-231 and MCF-7 than the free doxorubicin Cytotoxicity, and cytotoxic effects can be inhibited by exogenous α-linolenic acid. CONCLUSION: α-linolenic acid-doxorubicin conjugates can be a new potential anticancer drug targeting α-linolenic acid receptor-rich tumor cells via α-linolenic acid receptor.