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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: In this study, a K5 polysaccharide-doxorubicin prodrug (K5-DOX) with p H-sensitive properties was prepared using the heparin precursor K5 polysaccharide linked to the antitumor drug doxorubicin (DOX) Nature and activity were evaluated. Methods: K5-DOX was prepared by Schiff base reaction. The effects of DOX loading, morphology of K5-DOX in solution and drug release in vitro were investigated. Its in vitro cellular uptake and cytotoxicity were evaluated by human cervical cancer He La cells. Results: The successful preparation of K5-DOX, DOX content of 17.4%. Drug release studies showed that DOX release rate of K5-DOX under p H 5.0 acidic conditions was much higher than that of DOX release at physiological p H 7.4, with p H-responsiveness. The surface of the nanoparticles is negatively charged and shows excellent properties against sera in 10% fetal bovine serum (FBS) solution. The results of cellular uptake showed that K5-DOX can be quickly taken up by the cells and its cellular uptake rate is much higher than that of the free doxorubicin. In vitro cytotoxicity results show that, K5-DOX has good antitumor activity. Conclusion: The results show that K5-DOX is a potentially valuable anti-tumor pro-drug, K5 polysaccharide is expected to become a new generation of drug carriers.