溶酶体可降解的铂药偶联物的设计与制备研究

发布时间：2018-06-17 17:01

本文选题：铂类前体药物 + 缬氨酸-瓜氨酸二肽连接体　；参考：《东南大学》2015年硕士论文

【摘要】：恶性肿瘤是人类生命安全的重要威胁之一,其发病率及致死率一直居高不下。在众多治疗恶性肿瘤的方法中,化疗药物应用范围广、治疗效果佳。其中,铂类抗肿瘤药物因其细胞毒性大、治疗效果好而被广泛应用。但因其毒副作用大、水溶性差、易产生耐药性而受到限制。为克服这些缺陷,可对铂类抗肿瘤药物结构进行改进,增强其水溶性。设计新型的载药分子,将其与铂类抗肿瘤药物结合制备前体药物,增强其在血液循环中的稳定性。将铂类抗肿瘤前体药物与一些靶向分子结合,增强其特异性。本论文以顺铂、顺式-二氯(1,2-环己二胺)铂、谷氨酸为原料,制备新型的二价铂类抗肿瘤药物,采用红外光谱、核磁氢谱、质谱方法对其进行结构表征,确定得到目标产物。设计并合成一种可被溶酶体降解的以缬氨酸-瓜氨酸二肽为基础的连接体,将其与新型二价铂类抗肿瘤药物偶联制备前体药物。采用红外光谱、核磁氢谱、核磁碳谱、质谱的方法对每步产物进行结构表征,可确定目标产物已得到。以牛血清蛋白(BSA)为模型,将其与上述铂类前药偶联并进行活性研究。偶联物中铂类前药与BSA分子比分别为5.42、5.23；BSA-铂类前药偶联物累积释药率在细胞破碎液环境中45h可以分别达到68.23%、67.94%,而在pH 7.2磷酸缓冲液所模拟的人体正常pH环境下60h最大可达到27.43%、27.21%；给药浓度相同情况下,偶联物的细胞存活率比顺铂要高；偶联物给药浓度达到铂浓度为50μM时,细胞存活率均大于50%。
[Abstract]:Malignant tumor is one of the most important threats to human life. In many methods of treating malignant tumor, chemotherapeutic drugs are widely used and have good therapeutic effect. Among them, platinum antitumor drugs are widely used because of their high cytotoxicity and good therapeutic effect. However, its toxicity and side effects are large, water solubility is poor, and it is easy to produce drug resistance. In order to overcome these defects, the structure of platinum antitumor drugs can be improved to enhance their water solubility. A novel drug carrier was designed and combined with platinum antitumor drugs to prepare precursor drugs to enhance their stability in blood circulation. Platinum antitumor precursor drugs were combined with some target molecules to enhance their specificity. In this paper, a new type of divalent platinum anticancer drugs were prepared from cisplatin, cis-dichloro-1-chloride-2-cyclohexanediamine) platinum and glutamic acid. Their structures were characterized by IR, NMR and MS, and the target products were determined. A ligand based on valine-citrullinate dipeptide was designed and synthesized, which could be degraded by lysosome and coupled with a new type of divalent platinum antitumor drug to prepare precursor drugs. The structure of each product was characterized by infrared spectrum, nuclear magnetic hydrogen spectrum, nuclear magnetic carbon spectrum and mass spectrometry, and the target product was confirmed to have been obtained. Bovine serum protein (BSA) was used as a model to study its activity by coupling with the above platinum prodrugs. The ratio of platinum prodrug to BSA molecule was 5.42 ~ 5.23% and the cumulative release rate of BSA-platinum prodrug conjugate was 68.23 ~ 67.94 and 27.43 ~ 27.21 respectively in the cell crushing solution for 45 h, and the maximum value was 27.43 ~ 27.21 in the normal pH environment of pH 7.2 phosphoric acid buffer. The cell survival rate of the conjugate was higher than that of cisplatin under the same administration concentration, and the cell survival rate was higher than that of cisplatin when the concentration of platinum was 50 渭 M.
【学位授予单位】：东南大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：TQ460.1

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