Alanine and glutathione targeting of dopamine- or ibuprofen-coupled polypeptide nanocarriers increases both crossing and protective effects on a blood-brain barrier model.

IF 6.2 1区 医学 Q1 NEUROSCIENCES
Mária Mészáros, Thi Ha My Phan, Judit P Vigh, Gergő Porkoláb, Anna Kocsis, Anikó Szecskó, Emese K Páli, Nárcisz M Cser, Tamás F Polgár, Gábor Kecskeméti, Fruzsina R Walter, Jens C Schwamborn, Tamás Janáky, Jeng-Shiung Jan, Szilvia Veszelka, Mária A Deli
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引用次数: 0

Abstract

Background: Targeting the blood-brain barrier (BBB) is a key step for effective brain delivery of nanocarriers. We have previously discovered that combinations of BBB nutrient transporter ligands alanine and glutathione (A-GSH), increase the permeability of vesicular and polypeptide nanocarriers containing model cargo across the BBB. Our aim was to investigate dopamine- and ibuprofen-coupled 3-armed poly(L-glutamic acid) nanocarriers targeted by A-GSH for transfer across a novel human co-culture model with induced BBB properties. In addition, the protective effect of ibuprofen containing nanoparticles on cytokine-induced barrier damage was also measured.

Method: Drug-coupled nanocarriers were synthetized and characterized by dynamic light scattering and transmission electron microscopy. Cellular effects, uptake, and permeability of the nanoparticles were investigated on a human stem cell-based co-culture BBB model with improved barrier properties induced by a small molecular cocktail. The model was characterized by immunocytochemistry and permeability for marker molecules. Nanocarrier uptake in human brain endothelial cells and midbrain organoids was quantified by spectrofluorometry and visualized by confocal microscopy. The mechanisms of cellular uptake were explored by addition of free targeting ligands, endocytic and metabolic inhibitors, co-localization of nanocarriers with intracellular organs, and surface charge modification of cells. The protective effect of ibuprofen-coupled nanocarriers was investigated against cytokine-induced barrier damage by impedance and permeability measurements.

Results: Targeted nanoformulations of both drugs showed elevated cellular uptake in a time-dependent, active manner via endocytic mechanisms. Addition of free ligands inhibited the cellular internalization of targeted nanocarriers suggesting the crucial role of ligands in the uptake process. A higher permeability across the BBB model was measured for targeted nanocarriers. After crossing the BBB, targeted dopamine nanocarriers subsequently entered midbrain-like organoids derived from healthy and Parkinson's disease patient-specific stem cells. The ibuprofen-coupled targeted nanocarriers showed protective effects against cytokine-induced barrier damage.

Conclusion: BBB-targeted polypeptide nanoparticles coupled to therapeutic molecules were effectively taken up by brain organoids or showing a BBB protective effect indicating potential applications in nervous system pathologies.

丙氨酸和谷胱甘肽靶向多巴胺或布洛芬偶联多肽纳米载体增加血脑屏障模型的交叉和保护作用。
背景:靶向血脑屏障(BBB)是纳米载体有效脑递送的关键步骤。我们之前已经发现血脑屏障营养转运配体丙氨酸和谷胱甘肽(A-GSH)的组合,增加了含有模型货物的囊泡和多肽纳米载体穿过血脑屏障的通透性。我们的目的是研究多巴胺和布洛芬偶联的3臂聚l -谷氨酸纳米载体通过a - gsh靶向转移到具有诱导血脑屏障特性的新型人类共培养模型中。此外,还测定了纳米布洛芬对细胞因子诱导的屏障损伤的保护作用。方法:合成药物偶联纳米载体,采用动态光散射和透射电镜对其进行表征。细胞效应、纳米颗粒的摄取和通透性在人类干细胞共培养血脑屏障模型上进行了研究,该模型由小分子鸡尾酒诱导,屏障性能得到改善。通过免疫细胞化学和标记分子的通透性对模型进行表征。用荧光光谱法定量测定了纳米载体在人脑内皮细胞和中脑类器官中的摄取情况,并用共聚焦显微镜观察了纳米载体在人脑内皮细胞和中脑类器官中的摄取情况。通过添加自由靶向配体、内吞和代谢抑制剂、纳米载体与细胞内器官的共定位以及细胞表面电荷修饰来探索细胞摄取的机制。通过阻抗和通透性测量,研究了布洛芬偶联纳米载体对细胞因子诱导的屏障损伤的保护作用。结果:两种药物的靶向纳米制剂通过内吞机制以时间依赖性、活性方式显示细胞摄取升高。游离配体的加入抑制了靶向纳米载体的细胞内化,这表明配体在摄取过程中起着至关重要的作用。靶纳米载体在血脑屏障模型中具有更高的渗透率。在穿过血脑屏障后,靶向多巴胺纳米载体随后进入来自健康和帕金森病患者特异性干细胞的中脑样器官。布洛芬偶联的靶向纳米载体对细胞因子诱导的屏障损伤具有保护作用。结论:靶向血脑屏障的多肽纳米颗粒与治疗分子偶联可被脑类器官有效吸收或显示出血脑屏障保护作用,这表明其在神经系统疾病中的潜在应用前景。
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来源期刊
Fluids and Barriers of the CNS
Fluids and Barriers of the CNS Neuroscience-Developmental Neuroscience
CiteScore
10.70
自引率
8.20%
发文量
94
审稿时长
14 weeks
期刊介绍: "Fluids and Barriers of the CNS" is a scholarly open access journal that specializes in the intricate world of the central nervous system's fluids and barriers, which are pivotal for the health and well-being of the human body. This journal is a peer-reviewed platform that welcomes research manuscripts exploring the full spectrum of CNS fluids and barriers, with a particular focus on their roles in both health and disease. At the heart of this journal's interest is the cerebrospinal fluid (CSF), a vital fluid that circulates within the brain and spinal cord, playing a multifaceted role in the normal functioning of the brain and in various neurological conditions. The journal delves into the composition, circulation, and absorption of CSF, as well as its relationship with the parenchymal interstitial fluid and the neurovascular unit at the blood-brain barrier (BBB).
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