双重介导脂质体脑靶向给药系统的研究

项目名称： 双重介导脂质体脑靶向给药系统的研究

项目编号： No.81202469

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 谢英

作者单位： 北京大学

项目金额： 23万元

中文摘要： 血脑屏障（BBB）的存在限制了药物在中枢神经系统（CNS）的应用，脑部给药系统的研究有望为目前已有的CNS药物提供广阔的应用前景。本课题基于BBB的结构特点，设计了受体介导和吸附介导双重修饰的脂质体作为脑靶向新型药物传递系统。以噬菌体展示技术高通量筛选得到的TAT-PTD肽段序列为基础，应用多肽合成技术和BBB体外模型，设计合成筛选得到高BBB穿透性细胞穿透肽PTB；应用流式细胞技术研究双重介导脂质体PTB/OX-26-PEG-L中两种导向分子的密度，确定处方和制备方法，进行质量评价；应用BBB模型通过干预实验探讨其转运能力和转运机制；体内研究99mTc标记脂质体药动学、组织分布以及ABC现象；应用大鼠C6脑胶质瘤模型，评价包载阿霉素脂质体的药效学。本项目力求通过细胞水平和在体水平的系统研究，得到高稳定性、高转运效率、高选择性的脑靶向给药系统，为CNS疾病的治疗提供理论依据和研究基础。

中文关键词： 血脑屏障；脂质体；受体介导；吸附介导；

英文摘要： The exist of blood-brain barrier(BBB) restrained lots of drugs to be applied in the treatment of central nervous system(CNS) diseases. A drug delivery system targeting to the brain would provide a promising prospect to the drugs which have been used in clinic. On account of the construction features of BBB, we designed a novel dual-mediated liposomal delivery system targeting to the brain, involving in absorptive-mediated and receptor-mediated. In the project, we would design and synthesis a series of cell penetrating peptids(CPP) according to a Phage Display-Based High-Throughput Screening System and screen them on the model of BBB in vitro to obtain a high-penetrating CPP which was called PTB(peptide targeting to brain).OX-26, a monoclonal antibody to transferrin receptor on BBB, acted as receptor-mediated ligand here. Furthermore，we would investigate the density of each peptide used in PTB/OX26-PEGylated liposomes by using Flow cytometry(FCM), and then make sure of the formulation of the dual-mediated liposomes. The qualities of PTB/OX-26-PEGylated liposmes would be estimated before its transport mechanism was studied on the BBB model. In vivo studies, pharmacokinetics as well as bio-distribution and accelerated blood clearance(ABC) phenomenon were observed by using 99mTc labelled lipsosomes. Pharmacodyn

英文关键词： blood-brain barrier；liposomes；receptor mediated；absorptive mediated；