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目的:合成具有酸敏特性的叶酸-氨基己酸-阿霉素连接物,并观察其抗肿瘤活性以及对肿瘤细胞的靶向性。方法:首先将叶酸与氨基己酸连接,然后利用腙键与阿霉素连接,采用核磁共振、质谱等方法鉴定其结构;采用MTT法观察连接物对叶酸受体表达阳性的口腔表皮样癌细胞KB细胞及叶酸受体表达阴性肺癌A549细胞的毒性作用。结果:在氮羟基琥珀酰亚胺和二环己基碳二亚胺的催化作用下,合成了叶酸-氨基己酸-阿霉素连接物,波谱分析提示为目标产物。与游离阿霉素相比,连接物对KB细胞具有更强的细胞毒性,而且细胞毒性作用可被外源性叶酸抑制;而连接物对A549细胞的毒性弱于游离阿霉素,而且外源性游离叶酸对其细胞毒性没有显著影响。结论:叶酸-氨基己酸-阿霉素连接物能经叶酸受体介导靶向于叶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 the folate-aminocaproic acid-doxorubicin conjugate with acid-sensitive properties and to observe its antitumor activity and its targeting to tumor cells. Methods: Folic acid was first linked to aminocaproic acid and then linked to doxorubicin using hydrazone bond. The structure was identified by nuclear magnetic resonance spectroscopy and mass spectrometry. MTT was used to detect the expression of folate receptor on oral epidermoid carcinoma cells Toxicity of KB Cells and Folate Receptor Expression Negative Lung Cancer A549 Cells. Results: Folic acid-aminocaproic acid-doxorubicin conjugates were synthesized under the catalysis of N-hydroxysuccinimide and dicyclohexylcarbodiimide. The spectral analysis suggested the target product. Compared with the free doxorubicin, the connector is more cytotoxic to KB cells, and the cytotoxic effect can be inhibited by exogenous folic acid; while the linker is less toxic to A549 cells than the free doxorubicin, and exogenous Sexual folic acid has no significant effect on its cytotoxicity. CONCLUSION: Folic acid-aminocaproic acid-doxorubicin conjugates can be a novel potential anti-tumor drug targeting folate receptor-rich tumor cells via folate receptors.