Of the recent biomedical studies devoted to the development of medical imaging techniques, magnetic resonance imaging (MRI) has been the subject of increased interest. MRI is a powerful diagnostic tool that offers detailed, high-resolution anatomical information by monitoring the relaxation rate of water protons in the presence of a strong magnetic field. However, two objectives that have yet to be fully achieved with MRI include generating efficient contrast and enhancing imaging sensitivity to a level that enables differentiating healthy tissue from malignant tissue. Developing an effective MRI contrast to enhance image quality has therefore become crucial to improving this promising technique.
This thesis examines the performance of surface engineered gadolinium oxide nanocrystals as T1 MRI contrast agents. Gadolinium oxide nanocrystals are formed at high temperatures in organic solvents and phase transferred into biological media using a novel sulfonic acid copolymer. The surface engineered gadolinium oxide nanocrystals were designed to exploit the plate-like geometry of nanocrystals to form surfaces that are both accessible to water and effective at preventing particle-particle aggregation. The crystals’ anisotropic shape suggests that the gadolinium surface atoms on the thin plate edges can remain uncoated and thus available to water. The relaxivities of these materials are one order of magnitude (15 times) larger than commercial T1 contrast agents and other gadolinium-containing nanoparticles. The magnetic field dependence of their relaxation rates and the relatively weak size dependence of their relaxivity suggest that inner-sphere water relaxation at the edges of the nanocrystal are responsible for the high relaxation rates. These surfaces have significant potential as T1 MRI contrast agents, offering a non-invasive imaging alternative with numerous applications, including detection and characterization of non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and tracking of stem cells in embryos.
As part of this thesis, we introduced surface functionalized gadolinium oxide nanocrystals with three different surface coatings—each with unique characteristics. These materials were chosen because they are stable in relevant biological conditions while posing distinct responses in different environments. We examined the effect of surface coating, salt, and protein on the performance of gadolinium oxide nanocrystals as MRI contrast agents. We found that their behavior was altered in plasma, implying that surface coating has an important effect on their interactions with proteins. Moreover, we showed that, unlike other studies in deionized water in which relaxivity has a linear dependency, forming strong protein binding enables relaxivity measurement to be dependent on gadolinium concentration.
Finally, we studied the possible cytotoxic effects of gadolinium oxide nanocrystals in vitro and in vivo. Since gadolinium ion is a heavy metal, it is important to ensure that it is shielded with a surface coating and is biocompatible both at the cellular level and in living animals. In vivo, the nanocrystals have a blood circulation lifetime similar to molecular gadolinium agents—sufficient for imaging process duration. Additionally, our biodistribution study showed the crystals’ rapid clearance through the liver, thus confirming its cellular uptake. Collectively, our findings reveal the crystals’ high performance as T1 MRI contrast agents.