| dc.description.abstract | Superparamagnetic iron oxide nanoparticles (SPIONs), primarily composed of magnetite (Fe3O4) or maghemite (γ-Fe2O3), hold great promise for biomedical applications, especially as contrast agents in magnetic resonance imaging (MRI). MRI is a non-invasive imaging technique
that generates detailed images by manipulating magnetic fields and radiofrequency pulses, but its sensitivity can be limited, particularly in detecting small lesions. To enhance MRI performance, contrast agents are employed, classified into T1 (brightening) and T2 (darkening) agents.
SPIONs, with their intrinsic magnetic properties, excellent biocompatibility, and tunable size, shape, and surface chemistry, present a versatile option to potentially replace conventional gadolinium-based agents. Despite these advantages, SPIONs currently approved or in clinical
trials face challenges, including limited sensitivity, stability issues, potential toxicity, and lack of target specificity. This underscores the need to better understand the design criteria influencing SPIONs' MRI contrast-enhancement capabilities and to develop SPIONs with improved
sensitivity, biocompatibility, stability in physiological environments, and target specificity.
This dissertation focuses on developing SPION-based MRI contrast agents to deepen our understanding of how the structural properties of SPIONs affect their contrast enhancement capabilities and biological performance. Specifically, it examines the impact of SPION size and
surface modifications on MRI contrast properties, leading to the creation of nanoparticles that outperform existing SPION-based contrast agents, and offers valuable insights for designing high-performance, next-generation MRI contrast agents.
To achieve this, the first project focused on synthesizing oleylamine-coated SPIONs with average hydrodynamic sizes ranging from 17 to 25 nm and corresponding TEM sizes of 6.8 to 14.6 nm using an optimized thermal decomposition process. The magnetite structure and
superparamagnetic properties of the nanoparticles were confirmed through X-ray diffraction and vibrating sample magnetometry analyses. The 6.8 nm and 14.6 nm SPIONs were then incorporated into synthetic high-density lipoprotein (HDL) particles, using phosphatidylcholine
(PC) lipids with varying chain lengths and saturation levels. By optimizing the lipid composition, the MRI contrast enhancement properties were fine-tuned, resulting in hybrid structures with significantly improved transverse relaxivities (r2) of up to 233 mM-1s-1 and r2/r1 ratios ranging from 84 to 450, far surpassing the performance of commercial T₂ contrast agents.
The study also investigated the role of PEGylation in stabilizing superparamagnetic HDLs and enhancing their contrast properties. Incorporating PEG-conjugated lipids at 5% of the total lipid content during synthesis achieved an optimal balance of stability, contrast
enhancement, and cell targeting, particularly in systems with SR-B1-overexpressing cells. Insufficient PEG levels compromised HDL stability under physiologically relevant conditions, while excessive PEG content diminished transverse relaxivity and targeting efficacy. These
results underscore the importance of precisely optimizing PEGylation levels to develop efficient and effective superparamagnetic HDLs.
The second part of this dissertation assessed the potential of ultrasmall manganese-doped iron oxide (MnFe2O4) nanoparticles as T1-weighted MRI contrast agents, aiming to replace conventional gadolinium-based agents. MnFe2O4 nanoparticles demonstrated superior T1
contrast properties compared to iron oxide (Fe3O4) nanoparticles synthesized under the same conditions, attributed to the high paramagnetic properties of Mn2+ and the extended lifetime of bound water molecules. Additionally, PEG coating of MnFe2O4 nanoparticles with various
molecular weights allowed for fine-tuning of MRI contrast enhancement properties while reducing macrophage uptake, potentially aiding in evading the reticuloendothelial system and subsequent clearance.
Overall, this work proposes superparamagnetic iron oxide nanoparticle-based contrast agents that have the potential to replace conventional agents. It also advances our understanding of how design parameters—such as size and surface coatings—affect MRI contrast enhancement
and biological properties of magnetic nanoparticles, laying the groundwork for the future development of safer and more efficient MRI contrast agents. | en_US |
