PLGA nanoparticles modified with a BBB-penetrating peptide co-delivering Aβ generation inhibitor and curcumin attenuate memory deficits and neuropathology in Alzheimer's disease mice.
PLGA nanoparticles modified with a BBB-penetrating peptide co-delivering Aβ generation inhibitor and curcumin attenuate memory deficits and neuropathology in Alzheimer's disease mice.
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用 BBB 穿透肽共同递送 Aβ 生成抑制剂和姜黄素修饰的 PLGA 纳米粒子可减轻阿尔茨海默病小鼠的记忆缺陷和神经病理学
DOI：
10.18632/oncotarget.20944
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发表时间：
2017-10-06
期刊：
影响因子：
--
通讯作者：
Liu RT
中科院分区：
文献类型：
--
作者：
Huang N;Lu S;Liu XG;Zhu J;Wang YJ;Liu RT
阿尔茨海默病(AD)是最常见的痴呆类型，其特征是AD患者脑内淀粉样蛋白(Aβ，Aβ)聚集体导致细胞外老年斑的形成和神经元的丢失。在临床试验中，常规策略未能治疗AD，部分原因是受试药物的溶解性差、生物利用度低，以及无法通过血脑屏障(BBB)。此外，AD是一种复杂的、多因素的神经退行性疾病；单靶点策略可能不足以预防AD的过程。在这里，我们设计了一种新型的聚丙交酯-乙醇酸共聚纳米粒，通过负载Aβ生成抑制剂S1(PQVGHL肽)和姜黄素来靶向AD发生发展中的有害因素，并通过与针对转铁蛋白受体的铁模拟肽CRT(环状CRTIGPSVC肽)结合来提高血脑屏障的通透性。载药PLGA纳米粒和CRT偶联PLGA纳米粒的平均粒径分别为128.6 nm和139.8 nm。Y迷宫和新物体识别测试结果表明，我们的PLGA纳米颗粒显著改善了转基因AD小鼠的空间记忆和识别能力。此外，PLGA纳米粒还能显著降低AD小鼠脑内Aβ、ROS、肿瘤坏死因子-α和IL-6水平，提高超氧化物歧化酶活性和突触数目。与其他PLGA纳米粒相比，共载S1和姜黄素的CRT多肽修饰的PLGA纳米粒对AD小鼠的治疗效果最好，提示偶联CRT多肽、包裹S1和姜黄素的PLGA纳米粒在治疗AD方面发挥了相应的作用。
Alzheimer's disease (AD) is the most common form of dementia, characterized by the formation of extracellular senile plaques and neuronal loss caused by amyloid β (Aβ) aggregates in the brains of AD patients. Conventional strategies failed to treat AD in clinical trials, partly due to the poor solubility, low bioavailability and ineffectiveness of the tested drugs to cross the blood-brain barrier (BBB). Moreover, AD is a complex, multifactorial neurodegenerative disease; one-target strategies may be insufficient to prevent the processes of AD. Here, we designed novel kind of poly(lactide-co-glycolic acid) (PLGA) nanoparticles by loading with Aβ generation inhibitor S1 (PQVGHL peptide) and curcumin to target the detrimental factors in AD development and by conjugating with brain targeting peptide CRT (cyclic CRTIGPSVC peptide), an iron-mimic peptide that targets transferrin receptor (TfR), to improve BBB penetration. The average particle size of drug-loaded PLGA nanoparticles and CRT-conjugated PLGA nanoparticles were 128.6 nm and 139.8 nm, respectively. The results of Y-maze and new object recognition test demonstrated that our PLGA nanoparticles significantly improved the spatial memory and recognition in transgenic AD mice. Moreover, PLGA nanoparticles remarkably decreased the level of Aβ, reactive oxygen species (ROS), TNF-α and IL-6, and enhanced the activities of super oxide dismutase (SOD) and synapse numbers in the AD mouse brains. Compared with other PLGA nanoparticles, CRT peptide modified-PLGA nanoparticles co-delivering S1 and curcumin exhibited most beneficial effect on the treatment of AD mice, suggesting that conjugated CRT peptide, and encapsulated S1 and curcumin exerted their corresponding functions for the treatment.
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