Interaction of gold nanoparticles with lymphatic vessels

项目总结 工程金纳米颗粒(GNPs)在许多生物医学领域的应用非常吸引人，并且具有很高的 先进诊断和治疗的临床潜力。然而，尽管GNPs的形象良好，但日益增长的 最近的一些报告指出了它们的不良影响。具体地说，当GNPs通过 生物体通过血管(例如，在常用的静脉注射后)与内皮细胞相互作用 细胞排列在血管内表面，可能导致血管功能障碍和心血管疾病 精神错乱。在血液扩散的同时，GNPs通常很容易穿透淋巴管 与淋巴管内皮细胞(LECs)直接接触。GNPs对晶状体上皮细胞和淋巴管的影响 船只不明。 这项建议的目标是通过监测GNPs和淋巴管之间的相互作用 GNP对单个淋巴管内皮细胞和单个分离淋巴管的作用，进而影响淋巴功能 在活体内。我们的中心假设是，GNPs导致剂量和时间依赖性的淋巴功能障碍 血管通过与LECs的直接相互作用。我们认为GNP诱导LEC的分子机制 功能障碍涉及内皮型一氧化氮合酶的激活，一氧化氮的产生增加，以及 抑制淋巴管中的收缩活动和淋巴流动的活性氧物种。要完成 这个项目我们计划将我们在淋巴研究、单细胞分析和纳米医学方面的专业知识与 我们团队开发的技术平台的力量，包括光声流式细胞术 和高分辨率光热显微镜。我们将通过以下具体目标来实现我们的目标：(1) 探讨GNP-LEC相互作用的分子机制；(2)确定GNP是否导致细胞功能障碍 通过与LECs的相互作用分离LV；(3)明确GNPs对体内LV功能的影响。 这些目标的成功实现将促进我们对GNPs和GNPs之间相互作用的理解 淋巴管。因此，我们将第一次回答这个关键的和临床相关的问题： GNP可导致淋巴管功能障碍，以及这种功能障碍是否是相互作用的结果 在GNPs和淋巴管内皮细胞之间。总体而言，在其影响的背景下，从 这项研究将有助于选择安全的GNPs用于临床翻译，并满足更广泛的需求 纳米技术社区为工程开发全面的生物响应简档 符合2014-2015年国家纳米技术倡议战略规划的纳米材料。

PROJECT SUMMARY Engineering gold nanoparticles (GNPs) are very attractive for many biomedical applications and offer high clinical potential for advanced diagnosis and therapy. However, despite favorable profile of GNPs, the growing number of recent reports have indicated their undesired effects. Specifically, when GNPs disseminate through the organism by blood vessels (e.g., after commonly used intravenous injection) they interact with endothelial cells lining the inner surface of blood vessels and may cause vascular dysfunctions and cardiovascular disorders. Simultaneously with blood dissemination, GNPs commonly and easily penetrate lymphatic vessels and directly contact with lymphatic endothelial cells (LECs). The impact of GNPs on LECs and lymphatic vessels is unknown. The goal of this proposal is to study the interaction between GNPs and lymphatic vessels by monitoring of GNP effects on single LECs and individual isolated lymphatic vessels in vitro, and, then, on lymphatic function in vivo. Our central hypothesis is that GNPs cause dose- and time-dependent dysfunction of lymphatic vessels through direct interaction with LECs. We suggest that molecular mechanisms of GNP-induced LEC dysfunction involve activation of endothelial nitric oxide synthases, increasing production of nitric oxide and reactive oxygen species which inhibit contractile activity and lymph flow in lymphatic vessels. To accomplish this project we plan to integrate our expertise in lymphatic research, single-cell analysis and nanomedicine with the power of technological platforms that were developed by our team, including photoacoustic flow cytometry and high-resolution photothermal microscopy. We will pursue our goal through the following specific aims: (1) Explore molecular mechanisms of GNP-LEC interaction; (2) Determine whether GNPs induce dysfunction of isolated LV through interaction with LECs; (3) Define the impact of GNPs on LV function in vivo. Successful completion of these aims will advance our understanding of the interaction between GNPs and lymphatic vessels. Thus, for the first time, we will answer the critical and clinically relevant question of whether GNPs can induce dysfunction of lymphatic vessels, and whether this dysfunction is a result of interaction between GNPs and lymphatic endothelium. Overall, in the context of its impact, the knowledge gained from this research will help to select safe GNPs for clinical translation and addresses the needs of the broader nanotechnology community to develop comprehensive biological response profiles for an engineering nanomaterials that is in line with the Strategic Plan of National Nanotechnology Initiative for 2014-2015.