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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 study the preparation process of folate-modified ergosta-4,6,8,22-tetraen-3-one liposomes and investigate its in vitro release behavior, toxicity and targeting to tumor cells and in vivo pharmacokinetics Study. Methods Folate-coupled ergosterol liposomes were prepared by membrane dispersion-sonication. The liposomes were characterized by transmission electron microscopy, particle size analyzer and high performance liquid chromatography (HPLC) The effect of folate-conjugated ergosterol liposomes on the in vitro cytotoxicity of cervical cancer cells (HeLa) was investigated by MTT assay, and the effect of the plasma on the release behavior was investigated. The folate receptor-mediated targeting. The blood concentration of rats after intragastric administration was measured by HPLC. The pharmacokinetic parameters were calculated by DAS2.0 software and analyzed statistically. Results The folate-coupled ergosterol liposomes showed a spherical shape with narrow particle size distribution and uniform roundness with an average particle size of 112 nm and drug entrapment efficiency of 73%. In vitro release media, the drug release curve was consistent with Higu-chi Equation, with long-term sustained release properties; in the interaction with HeLa, ergosta-4,6,8,22-tetraen-3-one, ergosterol liposomes, folate-conjugated ergosterol lipids The IC50 values were 10, 14 and 5μg.mL-1, respectively. The liposomal dosage forms significantly increased the AUC of ergosta-4,6,8,22-tetraen-3-one and prolonged its blood circulation time. Conclusion Folic acid as a guide molecule enhances the targeting of folate-conjugated ergosterol liposomes, and the folate-conjugated ergosterol liposomes are actively targeted to cervical cancer cells (HeLa), reducing the drug concentration Folic acid-linked ergosterol liposomes significantly increased the bioavailability of ergosta-4,6,8,22-tetraen-3-one and is expected to be used in the targeted therapy of tumors.