Functionalized nanocarrier combined seizure-specific vector with P-glycoprotein modulation property for antiepileptic drug delivery
Functionalized nanocarrier combined seizure-specific vector with P-glycoprotein modulation property for antiepileptic drug delivery
复制标题
功能化纳米载体结合癫痫特异性载体与 P-糖蛋白调节特性，用于抗癫痫药物输送
DOI：
10.1016/j.biomaterials.2015.09.041
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发表时间：
2016-01-01
期刊：
影响因子：
14
通讯作者：
Hong, Zhen
中科院分区：
文献类型：
--
作者：
Liu, Jiansheng;He, Yajing;Hong, Zhen
尽管目前可用的抗癫痫药物（AED）的最佳治疗方案，约三分之一的癫痫患者仍然是药物难治性的。血脑屏障上多药外排转运蛋白（如P-糖蛋白（P-gp））的区域特异性过表达可能通过降低AED的靶浓度而导致多药耐药（MDR）。因此，开发可以调节P-gp功能以及促进靶向AED递送的纳米药物是癫痫干预的一种有前途的策略。为了实现这一点，我们试图利用色氨酸的主动靶向功能的组合的可能性，通过转运蛋白介导的内吞作用和克服MDR的普朗尼克嵌段共聚物。本文以色氨酸衍生物（TD）为功能化载体，制备了一种包封LTG的PluronicP 123/F127混合胶束（TD-PF/LTG），用于促进AEDs向致痫灶的释放。TD-PF/LTG粒径约20 nm，呈球形，包封率高。用毛果芸香碱建立大鼠癫痫模型，以评价掺入LTG的聚合物胶束制剂与游离LTG制剂相比的脑渗透效率。研究表明，TD-PF/LTG比PF/LTG以及游离LTG更有效地将药物递送到脑，尤其是海马。增强的靶向递送可归因于致痫灶处色氨酸摄取增加以及纳米材料的P-gp调节特性。两者合计，TD-共轭普朗尼克胶束显示出有前途的潜力，作为一个纳米平台，用于交付抗癫痫药物在难治性癫痫。(C)2015爱思唯尔有限公司版权所有。
Despite optimal therapeutic regimen with currently available antiepileptic drugs (AEDs), approximately a third of epilepsy patients remain drug refractory. Region-specific overexpression of multidrug efflux transporters at the blood brain barrier, such as P-glycoprotein (P-gp), might contribute to multidrug resistance (MDR) by reducing target concentrations of AEDs. Therefore, development of nanomedicine that can modulate P-gp function as well as facilitate targeted AEDs delivery represents a promising strategy for epilepsy intervention. To achieve this, we sought to exploit the possibility of combination of active targeting function of tryptophan by transporter-mediated endocytosis and overcoming MDR by Pluronic block copolymers. Herein, a tryptophan derivate (TD) functionalized Pluronic P123/F127 mixed micelles encapsulating LTG (TD-PF/LTG) was developed to promote AEDs delivery to epileptogenic focus. TD-PF/LTG was about 20 nm in diameter with a spherical shape and high encapsulation efficiency. A rat epilepsy model with pilocarpine was established to evaluate the brain penetration efficiency of the LTG-incorporated polymeric micellar formulation, compared with free LTG formulations. Studies showed that TD-PF/LTG was more efficient than PF/LTG as well as free LTG in delivering the drug to the brain, especially the hippocampus. The enhanced targeted delivery could be ascribed to the increased tryptophan uptake at epileptogenic focus as well as P-gp modulation property of the nanomaterial. Taken together, TD-conjugated Pluronic micelles showed promising potential as a nanoplatform for the delivery of AEDs in refractory epilepsy. (C) 2015 Elsevier Ltd. All rights reserved.