Evaluation of the Dual-Modal usage of contrast agents by means of Synchrotron X-ray Computed Microtomography and Magnetic Resonance Imaging using Macrophages loaded with Barium Sulfate and Gadolinium Nanoparticles for Detection and Monitoring in Animal Disease Models

Abstract

To My Family. A B S T R A C TTechnical improvements of imaging devices during the last two decades have led to the development of so called hybrid imaging modalities, containing at least two different imaging modalities in the same machine. Hybrid imaging allows the combination of multi-modal images and the extraction of both complementary and synergistic information, which is useful for more accurate and reliable diagnosis. Within this framework there was an increased need for multi-modal contrast agents. During the last decade development of multi-modal contrast agents have hence received further attention.Recent developments of X-ray based imaging techniques now also offers imaging in other regimes, than standard absorption based imaging, e.g. phase contrast imaging, which exploits the refraction and phase-shift of the incident X-ray beam at tissue-interfaces. It has been shown that phase contrast imaging is more sensitive than classical clinical radiography, especially in soft-tissue applications, such as mammography.This thesis focuses on evaluating the dual-modal Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) capabilities of contrast agents. For such purposes a gadolinium based contrast agent is of high interest, due to its paramagnetic properties, which while present inside a magnetic field will hence interact with the protons spins of water (in tissue and fat) and shorten their the T1 relaxation time, thereby creating a positive image contrast in MRI. Furthermore, the X-ray Mass Attenuation Coefficient (MAC) of gadolinium is relatively high, thus suggesting its potential use, also as a CT contrast agent.Gadolinium nanoparticles can be loaded into cells, such as macrophages, which offers the possibility to track cells inside entire organisms. In the first step the uptake of gadolinium nanoparticles inside cells was investigated, together with a test for toxicity. To show the potential of using gadolinium nanoparticle loaded macrophages for functional imaging of inflammation, an acute allergic airway inflammation mouse model (mimicking asthma in humans) was used and analyzed by in-situ synchrotron phase contrast CT. This animal model was chosen, since macrophages are one of the main effector cells in asthma, where especially their ability to migrate is of crucial interest, which up until now was not possible to study in-situ. v In the first step this approach was evaluated using macrophages loaded with a clinical contrast agent containing barium sulphate, since this agent is known to provide high contrast in CT. In the ultimate step a combination of both barium sulphate and gadolinium nanoparticle loaded macrophages was used in the same mouse model (mimicking human asthma) and analyzed by dual modal Synchrotron phase contrast CT and Micro Magnetic Resonance Imaging (µ-MRI).Complementary results in terms of the biodistribution of injected macrophages could only be obtained by the combination of both synchrotron phase contrast CT and µ-MRI, where the first modality allows a detailed local...

Investigation of nanoparticle-cell interactions for development of next generation of biocompatible MRI contrast agents

“…On the other hand, significantly different relaxation times for samples of macrophages incubated with different nanoparticles synthesized in this work were measured, indicating the increased uptake of GdNP capped to Sorbitol by the cells, and that the Sorbitol is indeed captured by the nanoparticles rather than released into solution during the synthesis. This can explain contrast enhancement of 228% was observed for the cells incubated with Sorbitol caped GdNP, reported in 91 .…”

“…Taking together the remarkable contrast enhancement observed for the cells incubated with Sorbitol caped GdNP 91 and their improved biocompatibility, we conclude that Sorbitol capping of gadolinium oxide nanoparticles is promising for the design of next generation of MRI contrast agents.…”