Donepezil loaded PLGA-b-PEG nanoparticles: their ability to induce destabilization of amyloid fibrils and to cross blood brain barrier in vitro
Donepezil loaded PLGA-b-PEG nanoparticles: their ability to induce destabilization of amyloid fibrils and to cross blood brain barrier in vitro
复制标题
DOI：
10.1007/s00702-016-1527-4
复制
发表时间：
2017-01-01
影响因子：
3.3
通讯作者：
Yabanoglu-Ciftci, Samiye
中科院分区：
文献类型：
--
作者：
Baysal, Ipek;Ucar, Gulberk;Yabanoglu-Ciftci, Samiye
阿尔茨海默病（AD）是一种进行性且不可逆转的神经退行性疾病。胆碱酯酶抑制剂 (ChEI) 通常用于改善 AD 神经传递的对症治疗。多奈哌齐是一种可逆、非竞争性ChEI，临床上用于AD的姑息治疗。本研究的目的是研究负载多奈哌齐的聚(乳酸-乙醇酸)-嵌段-聚(乙二醇)[PLGA-b-PEG]纳米粒子对体外原纤维形成的不稳定作用，以及使用体外BBB模型这些纳米粒子穿过血脑屏障(BBB)的能力，以及游离多奈哌齐和多奈哌齐的神经保护作用。 负载多奈哌齐的 PLGA-b-PEG 纳米颗粒。采用双乳化法制备多奈哌齐PLGA-b-PEG纳米粒。在体外测定了这些负载多奈哌齐的颗粒对淀粉样β原纤维（Aβ（1-40）和Aβ（1-42））形成的不稳定作用。研究发现纳米粒子的粒径较小，对原纤维的形成具有不稳定作用。体外BBB模型制备成功。纳米粒子显示出穿过血脑屏障的能力，并在该系统中显示出受控释放曲线。在体外 BBB 模型中，与淀粉样原纤维一起孵育的星形胶质细胞中，IL-1β、IL-6、GM-CSF、TGF-β、MCP-1 和 TNF-α 的基因和蛋白表达水平均有所增加，表明炎症增加。游离多奈哌齐和负载多奈哌齐的纳米颗粒给药引起IL-1β、IL-6、GM-CSF和TNF-α的基因和蛋白质表达水平显着的剂量依赖性下降。 TGF-β 和 MCP-1 没有观察到显着变化。
Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease. Cholinesterase inhibitors (ChEIs) are commonly used for symptomatic treatment of neural transmission improvement in AD. Donepezil is a reversible and non-competitive ChEI which is clinically used for palliative treatment of AD. The aim of the present study was to investigate the destabilizing effect of donepezil loaded poly(lactic-co-glycolic acid)-block-poly (ethylene glycol) [PLGA-b-PEG] nanoparticles on fibril formation in vitro and the ability of these nanoparticles to cross blood brain barrier (BBB) using in vitro BBB model and the neuroprotective effects of free donepezil and donepezil loaded PLGA-b-PEG nanoparticles. Donepezil loaded PLGA-b-PEG nanoparticles were prepared with double emulsion method. Destabilizing effect of these donepezil loaded particles on the amyloid-beta fibril (A beta(1-40) and A beta(1-42)) formation was determined in vitro. Nanoparticles were found to have small particle size and have destabilizing effect on fibril formation. In vitro BBB model was successfully prepared. Nanoparticles showed the ability to cross the BBB and showed a controlled release profile in this system. IL-1 beta, IL-6, GM-CSF, TGF-beta, MCP-1 and TNF-alpha levels were found to be increased in both gene and protein expression levels in astrocytes incubated with amyloid fibrils in in vitro BBB model suggesting an increased inflammation. Free donepezil and donepezil loaded nanoparticle administration caused a significant dose-dependent decrease in both gene and protein expression levels of IL-1 beta, IL-6, GM-CSF and TNF-alpha. No significant changes were observed for TGF-beta and MCP-1.