Michaelis K, Hoffmann M M, Dreis S, Herbert E, Alyautdin R N, Michaelis M, Kreuter J, Langer K
Institute for Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Marie-Curie-Strasse 9, D-60439 Frankfurt, Germany.
J Pharmacol Exp Ther. 2006 Jun;317(3):1246-53. doi: 10.1124/jpet.105.097139. Epub 2006 Mar 22.
Drug delivery to the brain is becoming more and more important but is severely restricted by the blood-brain barrier. Nanoparticles coated with polysorbates have previously been shown to enable the transport of several drugs across the blood-brain barrier, which under normal circumstances is impermeable to these compounds. Apolipoprotein E was suggested to mediate this drug transport across the blood-brain barrier. In the present study, apolipoprotein E was coupled by chemical methods to nanoparticles made of human serum albumin (HSA-NP). Loperamide, which does not cross the blood-brain barrier but exerts antinociceptive effects after direct injection into the brain, was used as model drug. Apolipoprotein E was chemically bound via linkers to loperamide-loaded HSA-NP. This preparation induced antinociceptive effects in the tail-flick test in ICR mice after i.v. injection. In contrast, nanoparticles linked to apolipoprotein E variants that do not recognize lipoprotein receptors failed to induce these effects. These results indicate that apolipoprotein E attached to the surface of nanoparticles facilitates transport of drugs across the blood-brain barrier, probably after interaction with lipoprotein receptors on the brain capillary endothelial cell membranes.
药物向脑内的递送正变得越来越重要，但受到血脑屏障的严重限制。先前已表明，包覆聚山梨酯的纳米颗粒能够使几种药物穿过血脑屏障，而在正常情况下，这些化合物无法透过血脑屏障。有人提出载脂蛋白E介导这种药物穿过血脑屏障的转运。在本研究中，通过化学方法将载脂蛋白E偶联到人血清白蛋白制成的纳米颗粒（HSA-NP）上。洛哌丁胺不能穿过血脑屏障，但直接注射到脑内后会发挥镇痛作用，将其用作模型药物。载脂蛋白E通过连接子化学结合到负载洛哌丁胺的HSA-NP上。静脉注射后，这种制剂在ICR小鼠的甩尾试验中诱导出镇痛作用。相比之下，与不识别脂蛋白受体的载脂蛋白E变体相连的纳米颗粒未能诱导出这些作用。这些结果表明，附着在纳米颗粒表面的载脂蛋白E可能在与脑毛细血管内皮细胞膜上的脂蛋白受体相互作用后，促进药物穿过血脑屏障的转运。
