羟基喜树碱转铁蛋白隐形纳米泡囊的制备和体内外评价.docVIP

羟基喜树碱转铁蛋白隐形纳米泡囊的制备和体内、外评价 洪鸣凰，裴元英 （复旦大学 药学院，上海 200032） 摘要：目的 以羟基喜树碱（hydroxycamptothecin, HCPT）为模型药物，制备转铁蛋白（Transferrin, Tf）修饰隐形纳米泡囊，探索聚乙二醇（polyethylene glycol，PEG）修饰的隐形化效果与Tf修饰的主动靶向相结合，有效递送药物到达肿瘤部位的可行性。 方法 以人工合成的聚乙二醇化聚十六烷基氰基丙烯酸酯（PEG-PHDCA）为表面修饰材料，共价连接氧化的Tf，采用薄膜水化-超声分散法制备载HCPT隐形纳米泡囊（Tf-PEG-NS），考察粒径、包封率、体外释放、细胞毒性、细胞摄取和细胞内分布，大鼠药动学和S180荷瘤小鼠体内组织分布，抗肿瘤疗效。 结果 Tf-PEG-NS粒径为116nm，包封率为(93.00±0.38)%，体外释放48h达90%。体外KB细胞对Tf-PEG-NS的摄取呈现浓度与时间依赖性，且在低温条件或者过量Tf的存在下，摄取受到抑制。与市售注射剂、普通泡囊和PEG修饰泡囊（PEG-NS）相比，Tf-PEG-NS对KB、K562、S180三种肿瘤细胞毒性最强；胞内药物摄取量，尤其是细胞核最多；肿瘤部位药时曲线下面积最大；抗肿瘤活性最强，对S180荷瘤小鼠的肿瘤抑制率达71%。结论 所制备的转铁蛋白修饰隐形纳米泡囊可作为有效的载体递送HCPT至肿瘤细胞发挥疗效。 关键词：转铁蛋白；羟基喜树碱；非离子表面活性剂泡囊；聚乙二醇；肿瘤靶向 Preperation of Transferrin Modified Hydroxycamptothecin Loaded PEGylated Niosomes and Its Evaluation in Vitro and in Vivo HONG Ming-huang, PEI Yuan-ying﹡ ( School of Pharmacy, Fudan University, Shanghai 200032,China) ABSTRACT：OBJECTIVE To exploit the possibility of combination of the stealth action by polyethylene glycol cyanoacrylate-co-hexadecyl cyanoacrylate (PEG-PHDCA) modified niosomes and active targeting function of transferrin (Tf) by transferrin receptor-mediated endocytosis to promote drug delivery to solid tumor following intravenous administration with hydroxycamptothecin (HCPT) as model drug. METHODS HCPT-loaded PEG-niosomes (PEG-NS) were prepared by thin-film hydration and ultrasound method; Tf was coupled to terminal amino group of PEG to produce the active targeting vesicles (Tf-PEG-NS). The particle sizedistribution, entrapment rate, in vitro release, cytotoxicity, cell uptake, intracellular drug distribution, in vivo pharmacokinetics in rats, tissue distribution and antitumor effect in S180 tumor mice model were determined. RESULTS The prepared Tf-PEG-NS with average diameters of 116nm showed sustained release profile in vitro. The uptake of Tf-PEG-NS into KB cells was concentration and time dependent, which could be inhibited by low temperature and free Tf. Compared with HCPT injection, nonstea