Development of Nanosensors to Image Macrophage Polarization

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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.