药物分子偶联用功能性聚酯-聚氨基酸共聚物的合成与表征

Synthesis and Characterization of Functional Polyester-co-poly (amino acid) Copolymers for Drug Molecules Conjugation

目的:合成系列具有功能侧基,用于偶联抗癌药或避孕疫苗等生物活性物质的生物医用聚酯-聚氨基酸共聚物,用做靶向肿瘤治疗或免疫避孕的药物控制释放载体。方法:合成功能性单体3-苄氧羰基乙基吗啉-2,5-二酮(BEMD),在辛酸亚锡的作用下通过开环聚合与ε-己内酯共聚,经催化氢化反应脱除苄氧保护基团,获得功能侧基为羧丙基的聚(ε-己内酯)-co-(乙醇酸-alt-L-谷氨酸)(PCGG)共聚物。核磁共振氢谱、凝胶渗透色谱、差示扫描量热仪、水接触角测定等手段表征共聚物;3T3成纤维细胞初步考察共聚物的细胞毒性。结果:所得单体的纯度在99.7%以上;共聚物的共聚组成与单体投料比基本一致,随着BEMD投料比的增加,共聚物的分子量减小;随着BEMD在共聚物中共聚组成的增加,聚合物熔点降低,亲水性增强;短期的体外细胞毒性考察表明所得聚合物均无细胞毒性。结论:通过调控不同聚合条件可合成具有不同物理性能的PCGG共聚物,有望在共聚物的羧基侧基上偶联抗癌药或避孕疫苗等生物活性分子,用做靶向肿瘤治疗或免疫避孕的药物载体。

Objective： To synthesize a series of biomedical polyester- co- poly （amino acid） copolymers with functional side groups for conjugation of anti - cancer drugs or bioactive agents such as contraceptive polypeptides, which would be used as controlled release drug carriers for targeted oneotherapy or immunoeon-traception. Methods ： Functional cyclic monomer of 3-[（benzyloxyearbonyl）ethyl]morpholine - 2,5 - di- one （BEMD） was synthesized and then eopolymerized with ε-eaprolactone through ring -opening polymerization catalyzed by stannous oetoate. After removing the protective benzyloxy groups via catalytic hydrogenation, poly（ε- caprolactone）-co-[（glycolic acid ）-alt-（L - glutamic acid）]s （PCGG） with functional side carboxylic groups were obtained and characterized by means of ^1H - NMR, GPC, DSC and water contact angle measurement. The cytotoxicity of the eopolymers was evaluated by culturing the 3T3 cells on their films in vitro within short period. Results： The purity of BEMD was beyond 99.7%. The mole fraction of the BMED units in the copolymers was nearly equal to the monomer feed molar ratio and the molecular weight of the eopolymers was decreased with the increasing of the amount of BMED in the copolymerization. The crystal melting temperature of the copolymers was decreased with the increasing of the content of L - glutamic acid and inversely the hydrophilicity was increased. No cytotoxicity of the copolymers was found in the in vitro evaluated period. Conclusion： PCGG copolymers with different physical properties could be synthesized by varying different polymerization parameters. The side carboxylic groups of the copolymers could be used to conjugate anti - cancer drugs for targeted oncotherapy or contraceptive polypeptides for immunocontraeeption.