Pluronic P85-coated poly(butylcyanoacrylate) nanoparticles overcome phenytoin resistance in P-glycoprotein overexpressing rats with lithium-pilocarpine-induced chronic temporal lobe epilepsy
Pluronic P85-coated poly(butylcyanoacrylate) nanoparticles overcome phenytoin resistance in P-glycoprotein overexpressing rats with lithium-pilocarpine-induced chronic temporal lobe epilepsy
复制标题
Pluronic P85 包被的聚（氰基丙烯酸丁酯）纳米颗粒克服了 P-糖蛋白过度表达的锂-毛果芸香碱诱导的慢性颞叶癫痫大鼠的苯妥英耐药性。
DOI：
10.1016/j.biomaterials.2016.04.021
复制
发表时间：
2016-08-01
期刊：
影响因子：
14
通讯作者：
Zhou, Liemin
中科院分区：
文献类型：
--
作者：
Fang, Ziyan;Chen, Shuda;Zhou, Liemin
血脑屏障（BBB）中P-糖蛋白（Pgp）的过度表达被认为可以降低脑内药物浓度，从而抑制耐药性癫痫的抗惊厥作用。最近，聚（氰基丙烯酸正丁酯）（PBCA）纳米颗粒系统被证明可以克服BBB的障碍，将药物输送到大脑中。为了确定普朗尼克P85-包被的苯妥英聚（氰基丙烯酸丁酯）纳米颗粒（P85-PHT-PBCA-NPs）是否将PHT靶向脑，通过对锂-匹罗卡品诱导的慢性颞叶癫痫后PHT治疗的反应筛选BBB中过表达Pgp的PHT抗性大鼠，然后通过使用微透析测量脑PHT浓度直接验证PHT转运。然后，将PHT抗性大鼠分为三组，分别用PHT、PHT + tariquidar（TQD）或P85-PHT-PBCA-NPs治疗。PHT + TQD和P85-PHT-PBCA-NPs在PHT抗性大鼠中显示出抗惊厥活性，并且与在经受PHT处理的动物中观察到的相比，增加了脑/血浆中PHT浓度的曲线下面积的比率。然而，在P85-PHT-PBCA-NP处理后肝脏/血浆和肾脏/血浆中的PHT浓度的比率远低于在PHT + TQD处理后测量的那些。因此，Pgp过表达降低了患有耐药性癫痫的受试者的脑中的治疗药物浓度，并且P85-PHT-PBCA-NP可以增加这些药物浓度。(C)2016爱思唯尔有限公司版权所有。
P-glycoprotein (Pgp) overexpression in the blood brain barrier (BBB) is hypothesized to lower brain drug concentrations and thus inhibit anticonvulsant effects in drug-resistant epilepsy. Recently, the poly(butylcyanoacrylate) (PBCA) nanoparticle system was shown to overcome the obstacle of the BBB to deliver drugs into the brain. To determine whether pluronic P85-coated phenytoin poly(butylcyanoacrylate) nanoparticles (P85-PHT-PBCA-NPs) target PHT to the brain, PHT-resistant rats overexpressing Pgp in the BBB were screened by response to PHT treatment after chronic temporal lobe epilepsy induced by lithium-pilocarpine, followed by direct verification of PHT transport via measurement of brain PHT concentrations using microdialysis. Thereafter, the PHT-resistant rats were divided into three groups, which were treated with PHT, PHT + tariquidar (TQD), or P85-PHT-PBCA-NPs. PHT + TQD and P85-PHT-PBCA-NPs showed anticonvulsant activity in the PHT-resistant rats and increased the ratio of the area under the curve of the PHT concentrations in the brain/plasma in comparison with that observed in animals subjected to PHT treatment. However, the ratios of the PHT concentrations in the liver/plasma and kidney/plasma following P85-PHT-PBCA-NPs treatment were much lower than those measured following PHT + TQD treatment. Thus, Pgp overexpression decreases therapeutic drug concentrations in the brains of subjects with drug-resistant epilepsy and P85-PHT-PBCA-NPs could increase these drug concentrations. (C) 2016 Elsevier Ltd. All rights reserved.