可拮抗血清快速胞吞的K5多糖-阿霉素前体药物及其体外评价

In vitro evaluation of K5-DOX prodrug with a serum resistant and rapid endocytosis activity

目的:本研究利用肝素前体K5多糖连接抗肿瘤药物阿霉素(doxorubicin,DOX)制备具有p H敏感特性的K5多糖-阿霉素前体药物(K5-DOX),并在体外对其理化性质和活性进行评价。方法:通过希夫碱反应制备K5-DOX,对DOX负载量、K5-DOX在溶液中的形貌和体外药物释放等性质进行了考察。通过人宫颈癌He La细胞对其体外细胞摄取和细胞毒性进行评价。结果:成功制备K5-DOX,DOX含量为17.4%。药物释放研究发现,K5-DOX在p H 5.0酸性条件下DOX的释放速率远高于生理p H 7.4时DOX的释放速率,具有p H响应性。纳米粒子表面带负电荷,在含10%胎牛血清(FBS)溶液中表现出可拮抗血清的优良特性。细胞摄取结果表明,K5-DOX可迅速被细胞摄取,且其细胞摄取率远高于游离阿霉素。体外细胞毒性结果表明,K5-DOX具有良好的抗肿瘤活性。结论:结果表明,K5-DOX是一种具有潜在应用价值的抗肿瘤前体药物,K5多糖有望成为新一代药物载体。

Objective： To construct K5-DOX prodrug by conjugating K5 polysaccharide with the anticancer drug doxorubicin （DOX） , and evaluate the characteristics and activities of KS-DOX prodrug in vitro. Methods： KS-DOX prodrug was prepared via Schiff＇s base. The DOX loading amount, morphology, in vitro release behavior and cytotoxicity of KS-DOX were determined, respectively. Results： The DOX loading amount of KS-DOX was 17.4%. The release of DOX from the KS-DOX prodrug was faster in acidic solution of pH 5.0 than in physiological solution of pH 7.4, showing a pH-triggered manner. The surface charge of KS-DOX in water was negative, and showed a favorable serum resistant feature in the medium containing 10% FBS. Moreover, KS-DOX prodrug showed efficient anticancer activity in vitro, and also had rapid cellular internalization as compared with free DOX. Conclusion： The KS-DOX prodrug may be a potential candidate for cancer therapy.