Li Yuancheng, Lim Esther, Fields Travis, Wu Hui, Xu Yaolin, Wang Y Andrew, Mao Hui
Department of Radiology and Imaging Sciences, Emory University, 1841 Clifton Road NE, Atlanta, Georgia 30329, United States.
Division of Research, Philadelphia College of Osteopathic Medicine-Georgia Campus, 625 Old Peachtree Road NW, Suwanee, Georgia 30039, United States.
ACS Biomater Sci Eng. 2019 Jul 8;5(7):3595-3605. doi: 10.1021/acsbiomaterials.9b00086. Epub 2019 Jun 10.
Alzheimer's disease (AD) is a growing global healthcare burden affecting the aging population and society. Given the lack of effective treatment to AD, early detection at the prodromal stage and timely monitoring of changes during progression are considered the best approach to control and intervene in disease progression. "Liquid biopsy" of AD biomarkers amyloid-β peptides (Aβs) and tau proteins in the cerebrospinal fluid (CSF) or blood samples holds great promises for cost-effective, widely accessible, and easy-administrated noninvasive detection and follow-up of AD. However, current detection methods have not yet demonstrated sufficient sensitivity and specificity using neither Aβs nor tau proteins biomarkers. One major challenge of accurate detection and measurement of biomarker levels in biofluidic samples is the biofouling effect with nonspecific adsorption of unwanted biomolecules, such as various serum proteins, on the surface of targeted detecting agents or devices, causing false-positive and false-negative findings. In this study, antibiofouling polymer polyethylene glycol--allyl glycidyl ether (PEG--AGE) coated magnetic iron oxide nanoparticles (IONPs) capable of suppressing the nonspecific interactions with biomolecules, especially proteins, were investigated for the immunomagnetic capturing of Aβ40 and Aβ42 peptides and tau protein spiked in CSF- and serum-mimicking samples using corresponding antibodies conjugated as targeting ligands. Antibody-conjugated antibiofouling IONPs demonstrated improved specificity (>90%) and sensitivity (>95%) over those of antibody-conjugated magnetic micron beads (Dynabeads, ∼50% specificity and 30-40% sensitivity) widely used as magnetic separating agents under the same experimental conditions with the presence of nontargeted interfering proteins. The antibody-conjugated IONPs also exhibited significantly higher sensitivities (80-90%) and better performance of capturing Aβs and tau protein from the human whole blood samples than antibody-conjugated Dynabeads (∼20%).
阿尔茨海默病（AD）是一个日益严重的全球医疗保健负担，影响着老年人口和社会。鉴于缺乏针对AD的有效治疗方法，前驱期的早期检测以及疾病进展过程中的变化及时监测被认为是控制和干预疾病进展的最佳方法。脑脊液（CSF）或血液样本中AD生物标志物淀粉样β肽（Aβs）和tau蛋白的“液体活检”对于AD的经济高效、广泛可及且易于管理的无创检测和随访具有巨大潜力。然而，目前使用Aβs和tau蛋白生物标志物的检测方法尚未显示出足够的灵敏度和特异性。在生物流体样本中准确检测和测量生物标志物水平的一个主要挑战是生物污染效应，即不需要的生物分子（如各种血清蛋白）在靶向检测剂或设备表面的非特异性吸附，导致假阳性和假阴性结果。在本研究中，研究了能够抑制与生物分子（尤其是蛋白质）非特异性相互作用的抗生物污染聚合物聚乙二醇 - 烯丙基缩水甘油醚（PEG - AGE）包覆的磁性氧化铁纳米颗粒（IONPs），用于使用作为靶向配体偶联的相应抗体免疫磁捕获添加到模拟CSF和血清样本中的Aβ40和Aβ42肽以及tau蛋白。在存在非靶向干扰蛋白的相同实验条件下，与广泛用作磁分离剂的抗体偶联磁性微米珠（Dynabeads，特异性约为50%，灵敏度为30 - 40%）相比，抗体偶联的抗生物污染IONPs表现出更高的特异性（>90%）和灵敏度（>95%）。抗体偶联的IONPs从人全血样本中捕获Aβs和tau蛋白的灵敏度（80 - 90%）也显著高于抗体偶联的Dynabeads（约20%），并且具有更好的性能。
