Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier
Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier
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DOI：
10.1080/10611860290031877
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发表时间：
2002-06-01
影响因子：
4.5
通讯作者：
Alyautdin, R
中科院分区：
文献类型：
--
作者：
Kreuter, J;Shamenkov, D;Alyautdin, R
最近的研究表明，静脉注射后通常无法通过血脑屏障(BBB)的药物可以通过与聚(氰基丙烯酸丁酯)纳米颗粒结合并在聚山梨酯80上包裹来穿越这一屏障。然而，到目前为止，这种运输的机制尚不清楚。在这篇论文中，载脂蛋白可能参与了纳米颗粒结合的药物进入大脑的运输。用载脂蛋白ALL包覆六肽达拉精的聚氰基丙烯酸丁酯纳米粒子。B、CII E或J在没有或在预涂有聚山梨酯80的情况下。此外，单独用载脂蛋白E或在预包被聚山梨酯80后再用载脂蛋白E包覆洛哌丁胺纳米粒。ICR小鼠静脉注射后，采用甩尾实验测定其抗伤害阈值。在ApoEtmIUnc和C57BL/6J小鼠上测定了包被多山梨酸酯80的达拉金纳米粒的抗伤害性阈值。结果表明，只有包被聚山梨酯80和/或载脂蛋白B或E的达拉金或洛哌丁胺纳米粒才能达到抗伤害作用。在聚山梨酸酯预包被和载脂蛋白B或E包被后，这一效果显著增强。与C57BL/6J小鼠相比，载脂蛋白E基因缺陷的ApoEtmIUnc小鼠的抗伤害作用明显减弱。这些结果表明，载脂蛋白B和E参与了药物与聚氰基丙烯酸丁酯纳米颗粒之间跨血脑屏障的转运。聚山梨酯80包被纳米粒在注射后从血液中吸附这些载脂蛋白，因此似乎模仿了脂蛋白颗粒，可以通过受体介导的内吞作用被脑毛细血管内皮细胞摄取。然后，结合的药物可以通过在内皮细胞内释放后的扩散或跨细胞作用进一步输送到大脑中。
Recent studies have shown that drugs that are normally unable to cross the blood-brain barrier (BBB) following intravenous injection can be transported across this barrier by binding to poly(butyl cyanoacrylate) nanoparticles and coating with polysorbate 80. However, the mechanism of this transport so far was not known. In the present paper, the possible involvement of apolipoproteins in the transport of nanoparticle-bound drugs into the brain is investigated. Poly(butyl cyanoacrylate) nanoparticles loaded with the hexapeptide dalargin were coated with the apolipoproteins All. B, CII E, or J without or after precoating with polysorbate 80. In addition, loperamide-loaded nanoparticles were coated with apolipoprotein E alone or again after precoating with polysorbate 80. After intravenous injection to ICR mice the antinociceptive threshold was measured by the tail flick test. Furthermore, the antinociceptive threshold of polysorbate 80-coated dalargin-loaded nanoparticles was determined in ApoEtmIUnc and C57BL/6J mice. The results show that only dalargin or loperamide-loaded nanoparticles coated with polysorbate 80 and/or with apolipoprotein B or E were able to achieve an antinociceptive effect. This effect was significantly higher after polysorbate-precoating and apolipoprotein B or E-overcoating. With the apolipoprotein E-deficient ApoEtmIUnc mice the antinociceptive effect was considerably reduced in comparison to the C57BL/6J mice. These results suggest that apolipoproteins B and E are involved in the mediation of the transport of drugs bound to poly(butyl cyanoacrylate) nanoparticles across the BBB. Polysorbate 80-coated nanoparticles adsorb these apolipoproteins from the blood after injection and thus seem to mimic lipoprotein particles that could be taken up by the brain capillary endothelial cells via receptor-mediated endocytosis. Bound drugs then may be further transported into the brain by diffusion following release within the endothelial cells or, alternatively, by transcytosis.