Interaction of gold nanoparticles with lymphatic vessels

项目摘要 工程金纳米颗粒（GNP）对于许多生物医学应用是非常有吸引力的，并且提供高性能。 先进的诊断和治疗的临床潜力。然而，尽管国民生产总值的良好形象， 最近的一些报告表明了它们的不良影响。具体而言，当GNP通过 通过血管（例如，在通常使用的静脉内注射后）它们与内皮细胞相互作用 细胞内衬血管内表面，并可能导致血管功能障碍和心血管疾病 紊乱在血液播散的同时，GNP通常且容易穿透淋巴管 并直接与淋巴管内皮细胞（LECs）接触。GNP对LEC和淋巴细胞的影响 船只不详。 该提案的目标是通过监测GNP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离体淋巴管的作用及其对淋巴功能的影响 in vivo.我们的中心假设是GNPs会导致剂量和时间依赖性的淋巴功能障碍 通过与LEC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，增加一氧化氮的产生， 活性氧类，其抑制淋巴管中的收缩活性和淋巴流动。完成 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与LEC相互作用的分子机制;（2）确定GNP是否诱导LEC功能障碍。 通过与LEC的相互作用分离的LV;（3）确定GNP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之间相互作用的理解， 淋巴管因此，我们将第一次回答关键的和临床相关的问题， GNP可以诱导淋巴管功能障碍，这种功能障碍是否是相互作用的结果， GNP和淋巴管内皮之间的联系。总体而言，就其影响而言， 这项研究将有助于选择安全的GNP用于临床翻译，并满足更广泛的需求。 纳米技术社区开发一个工程的全面的生物反应概况 这是符合2014-2015年国家纳米技术倡议战略计划的纳米材料。

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.