Lanthanide Nanoparticles as Contrast Agents for In Vivo Dual Energy Microcomputed Tomography of the Mouse Vasculature

Dual energy (DE) computed tomography (CT) has the capability to influence medicine and pre-clinical research by providing quantitative information that can detect nascent lesions, identify perfusion restoration or inhomogeneities within tissues, and recognize the presence of calcium deposits. A wide variety of instrumentation techniques and scan protocols have been developed for DE CT, with a common goal of acquiring a pair of images that reports the attenuation of a given volume to two different x-ray distributions. While DE image acquisition has benefitted from technical advancements in CT, the contrast agents that are used are still predominantly composed of iodinated small molecules, which first appeared in the 1970s. Recent work has demonstrated that lanthanide-based contrast agents have optimized properties for DE decomposition, specifically when using in vivo micro-CT scanners. By adopting nanoparticle design strategies that were developed for disease therapeutics and diagnosis, this thesis takes advantage of existing technical advancements in nanotechnology and polymer science to develop a long-circulating contrast agent that can be used for in vivo micro‑CT and DE micro‑CT imaging of the mouse vasculature. The contrast agents that were developed provided a high loading of 100 mg/mL of lanthanide for intravenous injections of mice, and introduced CT contrast enhancements of at least 245 HU. The contrast was maintained for at least 30 minutes, and for as long as one hour, which exceeds the in vivo micro-CT scan time requirements. Furthermore, although the synthesis techniques and in vivo scans were demonstrated using model lanthanides such as gadolinium and erbium, they can easily be substituted by any other lanthanide. By using a fast-filter switcher to obtain interleaved scans, the feasibility of an in vivo DE CT technique that produces decomposed quantitative images of soft tissue, bone and gadolinium-enhanced vessels was demonstrated, which can be used with any pre-clinical, gantry-based micro-CT scanner. When used in combination with the DE CT technique presented, the long-circulating lanthanide contrast agents that were developed in this thesis have the potential to become powerful tools for pre-clinical research on the microvasculature.