Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17 Block 3 Southern Renmin Road, Chengdu, People's Republic of China.
Int J Nanomedicine. 2012;7:163-75. doi: 10.2147/IJN.S23771. Epub 2012 Jan 6.
An intimidating challenge to transporting drugs into the brain parenchyma is the presence of the blood-brain barrier (BBB). Glucose is an essential nutritional substance for brain function sustenance, which cannot be synthesized by the brain. Its transport primarily depends on the glucose transporters on the brain capillary endothelial cells. In this paper, the brain-targeted properties of glucose-modified liposomes using polyethylene glycols with different chain lengths as the linkers were compared and evaluated to establish an optimized drug-delivery system.
Coumarin 6-loaded liposomes (GLU200-LIP, GLU400-LIP, GLU1000-LIP, and GLU2000-LIP) composed of phospholipids and glucose-derived cholesterols were prepared by thin-film dispersion-ultrasound method. The BBB model in vitro was developed to evaluate the transendothelial ability of the different liposomes crossing the BBB. The biodistribution of liposomes in the mice brains was identified by in vivo and ex vivo nearinfrared fluorescence imaging and confocal laser scanning microscopy and further analyzed quantitatively by high-performance liquid chromatography.
Glucose-derived cholesterols were synthesized and identified, and coumarin 6-loaded liposomes were prepared successfully. The particle sizes of the four types of glucose-modified liposomes were around or smaller than 100 nm with a polydispersity index less than 0.300. GLU400-LIP, GLU1000-LIP, and GLU2000-LIP achieved higher cumulative cleared volumes on BBB model in vitro after 6 hours compared with GLU200-LIP (P < 0.05) and were significantly higher than that of the conventional liposome (P < 0.001). The qualitative and quantitative biodistribution results in the mice showed that the accumulation of GLU1000-LIP in the brain was the highest among all the groups (P < 0.01 versus LIP).
The data indicated that GLU400-LIP, GLU1000-LIP, and GLU2000-LIP all possess the potential of brain targeting, among which GLU1000-LIP, as a promising drug-delivery system, exhibited the strongest brain delivery capacity.
将药物输送到脑实质是一个具有挑战性的难题，这是因为存在血脑屏障（BBB）。葡萄糖是维持大脑功能所必需的营养物质，大脑本身不能合成葡萄糖。其运输主要依赖于脑毛细血管内皮细胞上的葡萄糖转运体。在本文中，我们比较和评估了不同链长的聚乙二醇作为连接物的葡萄糖修饰脂质体的脑靶向特性，以建立优化的药物传递系统。
采用薄膜分散-超声法制备由磷脂和葡萄糖衍生胆固醇组成的香豆素 6 载脂质体（GLU200-LIP、GLU400-LIP、GLU1000-LIP 和 GLU2000-LIP）。体外建立 BBB 模型，评估不同脂质体穿过 BBB 的跨内皮能力。通过体内和离体近红外荧光成像和共聚焦激光扫描显微镜鉴定脂质体在小鼠大脑中的分布，并通过高效液相色谱进一步进行定量分析。
成功合成和鉴定了葡萄糖衍生胆固醇，并制备了香豆素 6 载脂质体。四种葡萄糖修饰脂质体的粒径均在 100nm 左右或以下，多分散指数小于 0.300。与 GLU200-LIP 相比，GLU400-LIP、GLU1000-LIP 和 GLU2000-LIP 在体外 BBB 模型 6 小时后达到更高的累积清除体积（P<0.05），且明显高于普通脂质体（P<0.001）。小鼠体内定性和定量分布结果表明，GLU1000-LIP 在脑内的积累量在所有组中最高（P<0.01 与 LIP 相比）。
数据表明，GLU400-LIP、GLU1000-LIP 和 GLU2000-LIP 均具有脑靶向的潜力，其中 GLU1000-LIP 作为一种有前途的药物传递系统，表现出最强的脑递送能力。
