Novel carbon nanodots for modulation of OxLDL mediated inflammation and inhibition of atherosclerosis

项目总结/摘要 这项研究的长期目标是开发碳纳米点作为一种新方法的基础， “纳米药理学”用于治疗心血管疾病。血管炎症及其后续 内皮功能障碍在动脉粥样硬化的发生和发展中起重要作用， 疾病氧化型低密度脂蛋白（OxLDL）是一种已知的炎症生物标志物， 基因表达和单核细胞外渗，导致动脉粥样硬化的发展。寻找新的 探讨炎症的治疗方法对动脉粥样硬化患者具有重要的临床意义。 纳米材料对纳米技术的发展很重要，碳纳米点（C点）是 在过去的十年里，尺寸低于10纳米的迷人的新来者出现在世界上， 纳米粒子由于其表面改性的可变性，绿色合成方法，独特的发光 性能和优异的生物相容性，C点引起了相当大的关注。我们细胞的结果 生存力研究表明，C-点具有低细胞毒性，这与早期的研究一致。基于我们 最近的研究，我们发现C-dots可以减少与内皮细胞中单核细胞粘附相关的Ox-LDL， 细胞，从而证明了C点的抗炎作用。另一方面， 已知活性氧（ROS）引起内皮功能障碍。利用电子顺磁 共振（EPR）光谱，最敏感和具体的技术检测活性氧，我们的研究 C-dots可直接降低超氧阴离子自由基和羟自由基的水平。这些结果 共同表明，C点具有巨大的潜力，成为一种新的“纳米药理学”， 有效治疗炎性疾病如动脉粥样硬化。广泛的研究表明， NF-κB的活化对于炎症反应的转录调节是必不可少的。因此， 假设C-dots的抗氧化特性可以抑制OxLDL诱导的单核细胞与 通过抑制NF-κB信号传导，随后调节趋化因子的表达， 粘附分子这项R15提案的具体目标是：1a）确定C-点是否抑制 OxLDL诱导的粘附分子和血管炎症标志物的表达; 1b）研究是否 内皮细胞中的NF-κB信号传导参与C-dots的抗炎机制;和2） 进行C-dots在C57 BL/6小鼠体内的生物分布和安全性研究，并观察C-dots对C57 BL/6小鼠的保护作用。 低密度脂蛋白受体（LDLr−/−）中的血管氧化应激、炎症和动脉粥样硬化 敲除小鼠建议的研究亦会为本科生提供宝贵的培训机会 对基础科学研究感兴趣。该研究项目的完成有望提供新的信息 新型碳纳米点在调节OxLDL介导的炎症中的潜在应用， 动脉粥样硬化

PROJECT SUMMARY/ABSTRACT The long-term goal of this research is to develop carbon nanodots as the foundation of a new approach to "nanopharmacology" for the treatment of cardiovascular diseases. Vascular inflammation and its subsequent endothelial dysfunction play an important role in the development and progression of atherosclerotic vascular disease. As a known biomarker of inflammation, oxidized low-density lipoprotein (OxLDL) induces inflammatory gene expression, and monocyte extravasation that leads to atherosclerotic development. A search for a new approach to the treatment of inflammation is of great clinical significance for patients with atherosclerosis. Nanomaterials are important to the development of nanotechnology and carbon nanodots (C-dots) are fascinating newcomers with sizes below 10 nm and have emerged in the past decade to the world of nanoparticles. Due to its variability on surface modifications, green synthesis methods, unique luminescence properties, and excellent biocompatibility, C-dots have drawn considerable attention. The results of our cell viability studies have shown that C-dots have low cytotoxicity, which complied with earlier studies. Based on our more recent studies, we found C-dots could reduce Ox-LDL that are related to monocyte adhesion in endothelial cells, thus demonstrating the anti-inflammatory effects of C-dots. On the other hand, the overproduction of reactive oxygen species (ROS) is known to cause endothelial dysfunction. By using electron paramagnetic resonance (EPR) spectroscopy, the most sensitive and specific technique for ROS detection, our studies have also showed that C-dots could directly lower the in vitro levels of superoxide and hydroxyl radicals. These results together suggest C-dots hold a great potential to become a new avenue of "nanopharmacology" for more effective treatment of inflammatory disorders such as atherosclerosis. Extensive studies demonstrated that the activation of NF-κB is essential for the transcriptional regulation of inflammatory response. We, therefore, hypothesize that the antioxidant properties of C-dots can suppress OxLDL-induced adhesion of monocytes to endothelial cells by inhibiting NF-κB signaling that subsequently regulates the expression of chemokine and adhesion molecules. The specific aims of this R15 proposal are: 1a) to determine whether C-dots inhibit the expression of OxLDL-induced adhesion molecule and vascular inflammatory markers; 1b) to investigate whether the NF-κB signaling in endothelial cells is involved in the anti-inflammatory mechanism(s) of C-dots; and 2) to carry out a bio-distribution and safety studies of C-dots in C57BL/6 mice, and the protective effects of C-dots on vascular oxidative stress, inflammation, and atherosclerosis in low–density lipoprotein receptor (LDLr−/−) knockout mice. The proposed studies will also provide valuable training opportunities for undergraduate students interested in basic science research. Fulfillment of this research project is expected to provide new information on the potential applications of novel carbon nanodots to modulate OxLDL mediated inflammation and atherosclerosis.