Polyvinylpyrrolidone-coated gold nanoparticles inhibit endothelial cell viability, proliferation, and ERK1/2 phosphorylation and reduce the magnitude of endothelial-independent dilator responses in isolated aortic vessels.
Polyvinylpyrrolidone-coated gold nanoparticles inhibit endothelial cell viability, proliferation, and ERK1/2 phosphorylation and reduce the magnitude of endothelial-independent dilator responses in isolated aortic vessels.
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DOI：
10.2147/ijn.s133093
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发表时间：
2017
影响因子：
8
通讯作者：
Azzawi M
中科院分区：
文献类型：
--
作者：
Mohamed T;Matou-Nasri S;Farooq A;Whitehead D;Azzawi M
金纳米颗粒（AuNPs）展示了药物递送和成像诊断的临床潜力。由于AuNP在生理流体中聚集，聚合物表面改性被用于使其稳定并提高其在血液中的保留时间。然而，金纳米颗粒对血管功能的影响仍然知之甚少。在本研究中，我们研究了金纳米颗粒及其稳定剂对内皮细胞（EC）和血管舒张功能的影响。柠檬酸盐稳定的金纳米粒子（12±3 nm）的合成和表面修饰使用巯基聚乙二醇（mPEG）和聚乙烯吡咯烷酮（PVP）聚合物。它们被分离的EC和整个血管的摄取使用透射电子显微镜可视化，并使用电感耦合等离子体质谱定量。分别使用自动细胞计数、流式细胞术和蛋白质印迹法测定它们对EC增殖、活力、细胞凋亡和ERK 1/2信号通路的生物学效应。使用离体小鼠主动脉血管环评估内皮依赖性和非依赖性血管舒张功能。金纳米颗粒在30分钟的暴露内位于内皮内体中，而它们的表面修饰随着时间的推移延迟了这种细胞摄取。暴露24小时后，所有金纳米粒子（包括聚合物修饰的金纳米粒子）均诱导细胞凋亡并降低细胞活力/增殖。这些抑制作用在暴露48小时后丧失（除了PVP修饰的AuNP）。此外，所有AuNPs降低乙酰胆碱（ACh）诱导的ERK 1/2磷酸化，ERK 1/2是细胞功能的关键信号蛋白。mPEG修饰的AuNPs具有比PVP修饰的AuNPs更低的细胞抑制作用。柠檬酸盐稳定的金纳米粒子没有改变ACh诱导的内皮依赖性血管舒张，但衰减硝普钠诱导的内皮非依赖性反应。PVP修饰的金纳米粒子减弱乙酰胆碱诱导的扩张，而mPEG修饰的金纳米粒子没有，虽然这是剂量相关的。我们证明，mPEG修饰的金纳米粒子在治疗剂量下显示出较低的细胞生长抑制作用，并且比PVP修饰的金纳米粒子对血管扩张功能的损害更小，这表明作为诊断成像和治疗剂的潜力更大。
Gold nanoparticles (AuNPs) demonstrate clinical potential for drug delivery and imaging diagnostics. As AuNPs aggregate in physiological fluids, polymer-surface modifications are utilized to allow their stabilization and enhance their retention time in blood. However, the impact of AuNPs on blood vessel function remains poorly understood. In the present study, we investigated the effects of AuNPs and their stabilizers on endothelial cell (EC) and vasodilator function. Citrate-stabilized AuNPs (12±3 nm) were synthesized and surface-modified using mercapto polyethylene glycol (mPEG) and polyvinylpyrrolidone (PVP) polymers. Their uptake by isolated ECs and whole vessels was visualized using transmission electron microscopy and quantified using inductively coupled plasma mass spectrometry. Their biological effects on EC proliferation, viability, apoptosis, and the ERK1/2-signaling pathway were determined using automated cell counting, flow cytometry, and Western blotting, respectively. Endothelial-dependent and independent vasodilator functions were assessed using isolated murine aortic vessel rings ex vivo. AuNPs were located in endothelial endosomes within 30 minutes’ exposure, while their surface modification delayed this cellular uptake over time. After 24 hours’ exposure, all AuNPs (including polymer-modified AuNPs) induced apoptosis and decreased cell viability/proliferation. These inhibitory effects were lost after 48 hours’ exposure (except for the PVP-modified AuNPs). Furthermore, all AuNPs decreased acetylcholine (ACh)-induced phosphorylation of ERK1/2, a key signaling protein of cell function. mPEG-modified AuNPs had lower cytostatic effects than PVP-modified AuNPs. Citrate-stabilized AuNPs did not alter endothelial-dependent vasodilation induced by ACh, but attenuated endothelial-independent responses induced by sodium nitroprusside. PVP-modified AuNPs attenuated ACh-induced dilation, whereas mPEG-modified AuNPs did not, though this was dose-related. We demonstrated that mPEG-modified AuNPs at a therapeutic dosage showed lower cytostatic effects and were less detrimental to vasodilator function than PVP-modified AuNPs, indicating greater potential as agents for diagnostic imaging and therapy.