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目的:化学全合成聚苹果酸(poly(β-malic acid),PMLA),将其作为高分子药物载体,制备聚苹果酸-羟喜树碱前药(PMLA-HCPT)。研究其体外释药特点和体外细胞毒性。方法:以L-天冬氨酸为原料,通过化学方法全合成PMLA,通过酰胺键键合羟基喜树碱(HCPT)。通过红外光谱、核磁共振光谱表征该前药的结构,利用体外动态透析的方法模拟体外释药特点,用高效液相色谱法测定不同pH值聚合物药物中前喜树碱的释药特性。采用人卵巢癌HO-8910细胞系研究该前药的体外毒性。结果:①经核磁共振表征PMLA-HCPT前药合成完成。②在pH 5.6、pH 6.8及pH 7.4的PBS缓冲体系16 h中,羟喜树碱药物累积释放率分别为76.8%,47.2%和18.1%,证实PMLA-HCPT中羟喜树碱的释放具有pH依赖性。③细胞实验证实PMLA-HCPT的细胞毒性和游离的HCPT相比没有降低。结论:PMLA是一种良好的药物载体材料,PMLA-HCPT有望成为具有pH敏感性的聚合物前药。
OBJECTIVE: To synthesize PMLA-HCPT completely by chemical synthesis of poly (β-malic acid) (PMLA) as polymer carrier. To study its in vitro release characteristics and in vitro cytotoxicity. Methods: L-aspartic acid was used as the starting material to synthesize PMLA chemically and to bind hydroxy camptothecin (HCPT) via amide bond. The structures of the prodrugs were characterized by FTIR and NMR. The in vitro release characteristics of the prodrugs were simulated by dynamic dialysis in vitro, and the release characteristics of CPT in different pH value polymers were determined by high performance liquid chromatography. In vitro toxicity of this prodrug was investigated using human ovarian cancer HO-8910 cell line. Results: (1) The synthesis of PMLA-HCPT prodrugs was confirmed by 1H NMR. ② The cumulative release rates of hydroxycamptothecin were 76.8%, 47.2% and 18.1% in PBS buffer system of pH 5.6, pH 6.8 and pH 7.4, respectively. The release of hydroxycamptothecin in PMLA-HCPT was confirmed to have pH Dependency. ③ cell experiments confirmed that the cytotoxicity of PMLA-HCPT compared with the free HCPT did not reduce. Conclusion: PMLA is a good drug carrier material, PMLA-HCPT is expected to become a pH-sensitive polymer prodrug.