叶酸修饰麦角甾酮脂质体的制备及体外评价和药动学研究  

Preparation of Folate-targeted Ergosta-4,6,8(14),22-tetraen-3-one Liposomes and Its Evaluation in Vitro and Pharmacokinetic Studies

作　　者：梁旭华[1] 樊君[1] 孙洋[1] 魏嵩[1] 谭春雷[1] 姚飞[1] 刘璐莎[1] 

机构地区：[1]西北大学化工学院,西安710069

出　　处：《中国药学杂志》2012年第12期979-983,共5页Chinese Pharmaceutical Journal

摘　　要：目的研究叶酸修饰的麦角甾-4,6,8,22-四烯-3-酮脂质体的制备工艺,考察其体外释放行为、对肿瘤细胞的毒性和靶向性,并进行体内药动学研究。方法采用薄膜分散-超声法制备了叶酸偶联麦角甾酮脂质体;用透射电镜、粒径分析仪和高效液相色谱法(HPLC)对其进行表征;以动态透析法测定其体外释药特性及血浆对释放行为的影响;四甲基偶氮唑盐(MTT)法考察叶酸偶联麦角甾酮脂质体对宫颈癌细胞(HeLa)的体外毒性作用,并结合肿瘤细胞摄取实验考察其经叶酸受体介导的靶向性;HPLC测定灌胃后大鼠血药浓度,采用DAS2.0软件计算药动学参数,并进行统计分析。结果叶酸偶联麦角甾酮脂质体形态呈球形,粒径分布窄,均匀圆整,平均粒径为112 nm,药物包封率达73%;体外释放介质中,药物释放曲线符合Higu-chi方程,具有长效缓释性能;在与HeLa的相互作用中,麦角甾-4,6,8,22-四烯-3-酮、麦角甾酮脂质体、叶酸偶联麦角甾酮脂质体的IC50值分别为10,14,5μg.mL-1;脂质体剂型显著增加了麦角甾-4,6,8,22-四烯-3-酮的AUC,延长了其在血液循环中的时间。结论叶酸作为导向分子提高了叶酸偶联麦角甾酮脂质体的靶向性,使叶酸偶联麦角甾酮脂质体主动靶向作用于宫颈癌细胞(HeLa),降低了给药浓度,制成叶酸偶联麦角甾酮脂质体显著提高了麦角甾-4,6,8,22-四烯-3-酮的生物利用度,可望用于肿瘤的靶向治疗。OBJECTIVE To prepare folate-conjugated ergosta-4,6,8,22-tetraen-3-one liposomes （FLE）. Then to study the re- lease feature of FLE in vitro and the cytotoxicity and targeting ability of it via folate receptor-mediated endocytosis on tumor cells in vitro. Pharmacokinetic characterization was also studied in rats. METHODS The characteristics were measured by transmission elec- tron microscope （TEM） , laser light scattering granularity equipment and HPLC. Dialytic method was used to determine ergone release rate of FLE in vitro. The eytotoxicity and targeting ability of FLE on HeLa in vitro was measured by MTT assay. The concentrations of ergone in plasma of rats and their pharmaeokinetic behaviors after oral administration were studied by HPLC. The pharmacokinetie pa- rameters were computed by software DAS2. 0. RESULTS The prepared FLE was round and uniform, and the mean particle size was 112 nm. The encapsulating efficiency of it reached 73%. The experiment of drug release in vitro follows Higuchi releasing process and showed significant sustained-release feature. The IC50 of ergone, LE and FLE was 10, 14, 5 μg· mL^-1, respectively. Compared with ergone solution, AUC in FLE had increased significantly. And the residence time of ergone was prolonged. CONCLUSION The FLE were characterized by sustained-release performance, target recognition, and low toxic and side effect and did improve the bioavailabili- ty of ergone significantly. It can also be expected to be used for tumor by targeting therapy.

关 键 词：叶酸 麦角甾-4 6 8 22-四烯-3-酮 缓释性能 细胞毒性 靶向性 体内药动学 

分 类 号：R944[医药卫生—药剂学] R969.1[医药卫生—药学]