Design and Validation of Liposomal ApoE2 Gene Delivery System to Evade Blood-Brain Barrier for Effective Treatment of Alzheimer's Disease.
Design and Validation of Liposomal ApoE2 Gene Delivery System to Evade Blood-Brain Barrier for Effective Treatment of Alzheimer's Disease.
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DOI：
10.1021/acs.molpharmaceut.0c00461
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发表时间：
2021-02-01
影响因子：
4.9
通讯作者：
Singh, Jagdish
中科院分区：
文献类型：
--
作者：
Arora, Sanjay;Layek, Buddhadev;Singh, Jagdish
将基于基因的治疗剂靶向大脑是积极寻求治疗阿尔茨海默病（AD）的策略。最近的研究发现载脂蛋白E（ApoE）亚型在清除大脑中的毒性淀粉样β蛋白中的作用。ApoE 2同工型有益于预防AD发展，而ApoE 4是该疾病的主要促成因素。在本文中，我们证明了有效的脑靶向传递的ApoE 2编码质粒DNA（pApoE 2）使用葡萄糖转运蛋白-1（glut-1）靶向脂质体。脂质体表面功能化的glut-1靶向配体甘露糖（MAN）和细胞穿透肽（CPP），以提高脑靶向和细胞内化，分别。在各种CPP中，狂犬病病毒糖蛋白肽（RVG）或穿透素（Pen）被选为细胞穿透增强剂。双重（RVGMAN和PenMAN）功能化脂质体在100 nM磷脂浓度下具有细胞相容性，并且与单功能化和未修饰（普通）脂质体相比，在bEnd.3细胞、原代神经元和星形胶质细胞中表现出显著更高的ApoE 2表达。在体外BBB模型下培养的神经元中，双重修饰的脂质体也显示出比其他制剂对照高约2倍的蛋白质表达。这些结果很好地转化为体内功效研究，在单次尾静脉施用RVGMAN和PenMAN官能化脂质体后，C57 BL/6小鼠脑中pApoE 2的转染显著更高，而没有任何明显的毒性迹象。这些结果说明了表面修饰的脂质体用于安全和脑靶向递送pApoE 2基因以有效治疗AD的潜力。
Targeting gene-based therapeutics to the brain is a strategy actively sought to treat Alzheimer’s disease (AD). Recent findings discovered the role of apolipoprotein E (ApoE) isoforms in the clearance of toxic amyloid beta proteins from the brain. ApoE2 isoform is beneficial for preventing AD development, whereas ApoE4 is a major contributing factor to the disease. In this paper, we demonstrated efficient brain-targeted delivery of ApoE2 encoding plasmid DNA (pApoE2) using glucose transporter-1 (glut-1) targeted liposomes. Liposomes were surface-functionalized with a glut-1 targeting ligand mannose (MAN) and a cell-penetrating peptide (CPP) to enhance brain-targeting and cellular internalization, respectively. Among various CPPs, rabies virus glycoprotein peptide (RVG) or penetratin (Pen) was selected as a cell-penetration enhancer. Dual (RVGMAN and PenMAN)-functionalized liposomes were cytocompatible at 100 nM phospholipid concentration and demonstrated significantly higher expression of ApoE2 in bEnd.3 cells, primary neurons, and astrocytes compared to monofunctionalized and unmodified (plain) liposomes. Dual-modified liposomes also showed ~2 times higher protein expression than other formulation controls in neurons cultured below the in vitro BBB model. These results translated well to in vivo efficacy study with significantly higher transfection of pApoE2 in the C57BL/6 mice brain following single tail vein administration of RVGMAN and PenMAN functionalized liposomes without any noticeable signs of toxicity. These results illustrate the potential of surface-modified liposomes for safe and brain-targeted delivery of the pApoE2 gene for effective AD therapy.
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