毛菊苣总倍半萜磁性脂质体纳米粒的制备及肝靶向性研究

Cichorium glandulosum is widely distributed in xinjiang, and is used a characteristic medicinal plant for a long history. Sesquiterpene-Rich Fraction (SRF)from Cichorium glandulosum is proved to be effective for hepatoprotective. In this study, SRF was used as a model medicine to prepare the compound targeting preparation with magnetic liposome nanoparticle (MLN) as the carrier. The purpose of which is to enhance the selectivity and targeting of liver lesion sites and improve the bioavailability. The content of lactucin and lactucopicrin and pharmaceutical features as evaluation indexes are to optimize the preparation technology of SRF-MLN by using orthogonal design of L9(34). The drug loading, the entrapment efficiency, the physicochemical property of particle, and in vitro drug release characteristics, in vivo drug distribution were studied. The liver-injury model in mice was made. The content of ALT, AST, TBA, and DBIL in the serum and liver were measured. At the same time, MDA, GSH-Px, SOD activities of the different groups in liver homogenate were compared. pathological change in liver were observed and the liver-protecting mechanism of SRF-MLN was explored. This research will provide a new reference for the preparation and evaluation of liver-targeted drug delivery system of Uigur effective part.

毛菊苣总倍半萜有效部位(SRF)是从新疆特色资源毛菊苣中提取得到的一类天然倍半萜类活性成分，已证明具有确切的肝损伤保护作用。本课题以SRF为模型药物，采用磁性脂质体纳米粒(MLN)为载体制备SRF复合靶向制剂，以增强对肝病变部位的选择性和靶向性，提高生物利用度。以活性成分山莴苣素和山莴苣苦素的含量及药剂学特性为评价指标，采用正交试验设计优化毛菊苣总倍半萜有效部位磁性脂质体纳米粒(SRF-MLN)的制备工艺；通过对制剂载药量、包封率、给药载体的理化性质与体外释药行为、动物体内分布靶向性进行研究，探讨SRF-MLN作为治疗肝损伤药物靶向给药系统的可行性；建立小鼠肝损伤模型，比较各组小鼠血清ALT、AST、TBA、DBIL含量，肝组织匀浆中MDA、GSH、SOD等指标的变化，观察肝脏病理改变，探讨SRF-MLN保护肝脏机制。课题研究结果将为维药有效部位新型肝靶向给药系统的制备与评价提供参考。

本课题将具有确切肝损伤保护作用的毛菊苣总倍半萜有效部位(SRF)为模型药物，采用乙醇注入法制备毛菊苣总倍半萜脂质体(SRF-LP），再外加Fe3O4磁性纳米液制备成磁性脂质体纳米粒（SRF-MLN）。以活性成分山莴苣素的含量及药剂学特性为评价指标，采用正交试验设计优化SRF-MLN的制备工艺；以粒径、Zeta电位和包封率为考察指标，对SRF-MLN的稳定性进行了考察；分别比较了SRF、SRF-LP和SRF-MLN三种溶液在不同时间的体外释药行为及在动物体内组织分布的靶向性；采用体内药效实验，研究SRF-MLN对小鼠急性和免疫性肝损伤的保护作用。. 研究结果表明，制备的SRF-MLN平均粒径为65.35 nm， PDI为0.157，Zeta电位为-17.5mV；将SRF-MLN置于4℃冰箱中，分别于3、7、15、30 d测定其粒径、电位和包封率，结果均较稳定；体外释放研究表明，相同时间内SRF-MLN的累积释放量远低于SRF溶液，4h时仅为42.2%，12h时为93.1%；采用静脉注射SRF-MLN后，与SRF-LP相比，在肝脏中的平均滞留时间（MRT）增大了4倍，山莴苣素含量提高了大约42倍；体内药效实验结果表明，SRF-MLN能对抗急性和免疫性肝损伤引起的小鼠血清中的ALT、AST和MDA的升高，同时，提高血清中SOD的活性，减轻对肝细胞的损伤，模型组与空白组和SRF-MLN组比较，差异均有显著性意义。通过肝脏组织病理观察：SRF-MLN 三个实验组小鼠肝损伤病理改变均不同程度的好于模型组。说明SRF-MLN具有抑制肝细胞脂质过氧化、稳定肝细胞膜结构的作用，从而达到治疗肝损伤的目的。. 本课题将药物与纳米级的磁性粒子结合，通过磁性导向系统控制，将药物靶向输送到病变部位，可提高靶部位的有效血药浓度。该课题研究结果将为维药有效部位新型肝靶向给药系统的制备与评价提供参考。