Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, Sichuan, PR China.
Int J Pharm. 2011 Oct 31;419(1-2):85-95. doi: 10.1016/j.ijpharm.2011.07.021. Epub 2011 Jul 23.
Delivery of drugs to the brain is a major challenge due to the presence of the blood-brain barrier (BBB). The cell penetrating peptide TAT, which appears to enter cells with alacrity, can pass through the BBB efficiently. With this in mind, a novel TAT-modified liposome (TAT-LIP) was developed for overcoming the ineffective delivery of normal drug formulation to the brain. Targeting liposomal formulations are always composed of modified phospholipids as an anchor. However, cholesterol, another liposomal component, which was more stable and cheaper, has not been fully investigated as an alternative anchor. In this study, TAT was covalently conjugated with the cholesterol to prepare the liposome. The cellular uptake by brain capillary endothelial cells (BCECs) of rats and the mechanism of TAT-LIP pathway of endocytosis was explored. The blood brain barrier model in vitro was established to evaluate the transendothelial ability crossing the BBB and its transport mechanism. The biodistribution of each formulation was further identified. The results showed that the positive charge of the TAT-LIP played an important role in enhancing its brain delivery. The absorptive endocytosis might be one of the mechanisms of TAT-LIP crossing the BBB. In conclusion, the experimental data in vitro and in vivo indicated that the TAT-LIP was a promising brain drug delivery system due to its high delivery efficiency across the BBB.
向大脑输送药物是一项重大挑战，这是由于存在血脑屏障（BBB）。穿透细胞肽 TAT 似乎能够迅速进入细胞，能够有效地穿过 BBB。考虑到这一点，开发了一种新型 TAT 修饰的脂质体（TAT-LIP），以克服正常药物制剂向大脑输送的无效性。靶向脂质体制剂始终由作为锚的改性磷脂组成。然而，胆固醇是脂质体的另一个成分，它更稳定且更便宜，但尚未作为替代锚进行充分研究。在这项研究中，TAT 与胆固醇共价连接以制备脂质体。研究了 TAT-LIP 内吞作用途径的大鼠脑毛细血管内皮细胞（BCEC）摄取及其机制。建立了体外血脑屏障模型，以评估穿过 BBB 的跨内皮能力及其转运机制。进一步鉴定了每种制剂的生物分布。结果表明，TAT-LIP 的正电荷在增强其向大脑的输送中起重要作用。吸收性内吞作用可能是 TAT-LIP 穿过 BBB 的机制之一。总之，体外和体内的实验数据表明，TAT-LIP 是一种有前途的脑药物输送系统，因为它具有很高的穿过 BBB 的输送效率。
