RGD环肽修饰纳米脂质体显著降低氧化苦参碱抗大鼠四氯化碳肝纤维化有效剂量与用药频次  

Cyclic RGD-peptide-modified nanoliposome significantly reduced the effective dosage and administration frequency of oxymatrine on CCl_4-induced hepatic fibrosis in rats

作　　者：唐东[1] 吴建新[1] 陆伟跃[2] 陈源文[1] 葛文松[1] 朱长红[1] 周韵斓[1] 熊敏莉[1] 范建高[1] 

机构地区：[1]上海交通大学医学院附属新华医院消化内科,上海200092 [2]复旦大学上海康复靶向药物研究中心

出　　处：《胃肠病学和肝病学杂志》2011年第8期696-702,共7页Chinese Journal of Gastroenterology and Hepatology

基　　金：国家自然科学基金资助项目(30672675)

摘　　要：目的构建RGD环肽修饰纳米脂质体(cRGD-NL),利用其包封氧化苦参碱(OM),比较单纯低浓度OM(2 mg/kg体质量,2次/周)和含相应量OM的携OM纳米脂质体(NL-OM)或携OM环肽修饰纳米脂质体(cRGD-NL-OM)对大鼠四氯化碳(CCl4)肝纤维化影响,明确cRGD-NL-OM能否有效降低OM抗肝纤维化有效剂量和用药频次。方法 SD大鼠分6组(每组8只):正常对照组、模型(CCl4)组、单纯NL干预(CCl4+NL)组、单纯OM干预(CCl4+OM)组、NL-OM干预(CCl4+NL-OM)组和cRGD-NL-OM干预(CCl4+cRGD-NL-OM)组。各组按OM 2 mg/kg体质量、每周2次药量于造模4周后给予相应药物或容媒,给药4周后处死动物,采集血清和肝组织标本。HE和Masson染色观察病理学组织变化,生化分析或ELISA检测血清肝功能胶原代谢变化;荧光定量PCR检测Ⅰ型胶原α2链(COL1A2)mRNA水平;免疫印记法检测α-平滑肌肌动蛋白(α-SMA)表达。结果 与模型组相比,cRGD-NL-OM组和NL-OM组大鼠血清学指标及肝组织病理学改善显著,同时COL1A2 mRNA水平及α-SMA表达显著下降,且cRGD-NL-OM较NL-OM组改善更为明显。相反,单纯NL组及单纯OM组各项指标与模型组相比无显著差异。结论 cRGD-NL-OM显著降低OM抗大鼠肝纤维化有效剂量与用药频次,该新剂型有重要的临床应用前景。Objective To investigate whether cRGD-NL-OM could reduce the effective dosage and administration frequency of oxymatrine on carbon tetrachloride（CCl_4）-induced hepatic fibrosis in rats by structuring cyclic RGD-peptide modified nanoliposome（cRGD-NL） to encapsulate oxymatrine and comparing the antifibrotic effect between low dosage OM（2 mg/kg,q2w） alone and oxymatrine nanoliposome（with or without cRGD modification） delivering similiar amount of oxymatrine.Methods Sprague-Dawely rats were divided into 6 groups（n=8 per group）： normal group,model（CCl_4） group,NL-treated（CCl_4＋NL） group,OM-treated（CCl_4＋OM） group,NL-OM-treated（CCl_4＋NL-OM） group and cRGD-NL-OM-treated（CCl_4＋cRGD-NL-OM） group.After modeling for 4 weeks,corresponding drugs or vehicles were given twice a week for another 4 weeks in each group（OM 2 mg/kg body mass）.At the end of 8th week,all animals were sacrificed to sample serum and livers.HE and Masson staining were performed for evaluation of liver histopathological changes;liver function and collagen metabolism status were determined by biochemical analysis and ELISA respectively;collagen type 1 alpha 2（COL1A2） mRNA was measured by quantitative real-time PCR;the expression of α-smooth muscle actin（α-SMA） was detected by Western blot.Results Compared with model group,cRGD-NL-OM group and NL-OM treatment group significantly improved the serum indexes and liver histopathology,COL1A2 mRNA expression and α-SMA protein level also significantly decreased in the two groups.Moreover,cRGD-NL-OM treatment group showed further improvement than NL-OM-treated group.In contrast,NL-treated group and OM-treated group showed no significant improvement compared with model group.Conclusion cRGD-NL-OM could significantly reduce the effective antifibrotic dosage and administration frequency of oxymatrine.This new compound may be promising for clinical ap plication.

关 键 词：氧化苦参碱 肝纤维化 RGD环肽 纳米脂质体 

分 类 号：R575[医药卫生—消化系统]