Development of Nanosensors to Image Macrophage Polarization

项目摘要 外周动脉疾病(PAD)是一种动脉粥样硬化的心血管疾病 斑块在体内的动脉内堆积。PAD减少了流向四肢的血液流量，并可以 进展为严重的肢体缺血(CLI)，最终导致肢体丧失。血运重建的程序是 通常用于挽救缺血组织，在恢复血流的同时，再灌流 组织导致额外的损伤，导致严重的炎症和氧化损伤，这可能 助长了进一步的损害和疾病的循环。因此，最近的临床前研究评估了 药物治疗与血管重建相结合，以控制炎性级联反应。在……里面 为了了解疾病的进展和随后的康复，能够 在原位可视化炎症过程。特别是，巨噬细胞等炎性细胞表现出 多个相互竞争的表型状态取决于其局部的、瞬时的微环境。它会 因此，理想的非侵入性成像巨噬细胞表型随时间的变化作为结果 疾病或愈合的进展。目前的成像方法要么灵敏度低，要么空间分辨率低。 决议，或两者兼而有之。因此，需要对体内巨噬细胞进行非侵入性实时成像。 具有很高的敏感性、特异性、深度渗透性和分辨率。 我们的团队已经开发出纳米增强的超声波和光声相结合的技术 (US/PA)成像，与当前的成像方法相比具有优势。特别是，US/PA成像 可以帮助可视化和监控一组高度协调的炎症事件，范围包括 毫秒到天数。组织的高分辨率成像是可能的，信号可以通过 相当大的感兴趣体积区域，允许组织结构的3D可视化。最后， 使用无毒、生物兼容的纳米结构，包括光学染料、金纳米颗粒和其他 生物相容材料、细胞和分子超声引导的PA成像是可能的。因此，美国/PA 利用合适的纳米传感器进行成像有可能成为一种重要的 对一般炎症，特别是巨噬细胞极化的研究具有敏感性和特异性。 这项提议的总体目标是开发和测试一套独特的基于纳米颗粒的探测器， 对巨噬细胞的极化状态很敏感，并可以使用高分辨率在体内可视化， 多路US/PA成像。

Project Summary Peripheral artery disease (PAD) is a form of cardiovascular disease in which atherosclerotic plaque builds up within the arteries of the body. PAD reduces blood flow to the extremities and can progress to critical limb ischemia (CLI) and, ultimately, loss of limb. Revascularization procedures are commonly used to salvage the ischemic tissue, and while they restore blood flow, the reperfusion of tissues induces additional injury, resulting in severe inflammation and oxidative damage that can contribute to a cycle of further damage and disease. Recent preclinical studies have therefore evaluated drug therapies in combination with revascularization in order to control the inflammatory cascade. In order to understand disease progression and subsequent healing, it is critically important to be able to visualize inflammatory processes in situ. In particular, inflammatory cells such as macrophages exhibit multiple, competing phenotypic states depending on their local, transient microenvironment. It would therefore be ideal to non-invasively image macrophage phenotypic changes over time as a result of disease or healing progression. Current imaging approaches have either low sensitivity or spatial resolution, or both. Therefore, there is a need for non-invasive real-time imaging of macrophages in vivo with high sensitivity, specificity, depth penetration and resolution. Our group has developed nanoparticle-augmented combined ultrasound and photoacoustic (US/PA) imaging which has advantages over current imaging approaches. In particular, US/PA imaging can help to visualize and monitor a highly orchestrated set of events in inflammation ranging from milliseconds to days. High-resolution imaging of tissue is possible, and signals can be acquired over a reasonably large volumetric region of interest, permitting 3D visualization of tissue structures. Finally, using non-toxic, biocompatible nanoconstructs consisting of optical dyes, gold nanoparticles, and other biocompatible materials, cellular and molecular US-guided PA imaging is possible. Therefore, US/PA imaging with the appropriate nanosensors has the potential to become an important tool of sufficient sensitivity and specificity for studying inflammation in general and macrophage polarization in particular. The overall goal of this proposal is to develop and test a unique suite of nanoparticle-based probes that are sensitive to macrophage polarization state and can be visualized in vivo using high-resolution, multiplex US/PA imaging.