Large-Scale Synthesis of Uniform and Extremely Small-Sized Iron Oxide Nanoparticles for High-Resolution T₁ Magnetic Resonance Imaging Contrast Agents

Abstract

Uniform and extremely small-sized iron oxide nanoparticles (ESIONs) of < 4 nm were synthesized via the thermal decomposition of iron-oleate complex in the presence of oleyl alcohol. Oleyl alcohol lowered the reaction temperature by reducing iron-oleate complex, resulting in the production of small-sized nanoparticles. XRD pattern of 3 nm-sized nanoparticles revealed maghemite crystal structure. These nanoparticles exhibited very low magnetization derived from the spin-canting effect. The hydrophobic nanoparticles can be easily transformed to water-dispersible and biocompatible nanoparticles by capping with the poly(ethylene glycol)-derivatized phosphine oxide (PO-PEG) ligands. Toxic response was not observed with Fe concentration up to 100 μg/mL in MTT cell proliferation assay of POPEG-capped 3 nm-sized iron oxide nanoparticles. The 3 nm-sized nanoparticles exhibited a high r(1) relaxivity of 4.78 mM(-1) s(-1) and low r(2)/r(1) ratio of 6.12, demonstrating that ESIONs can be efficient T(1) contrast agents. The high r(1) relaxivities of ESIONs can be attributed to the large number of surface Fe(3+) ions with 5 unpaired valence electrons. In the in vivo T(1)-weighted magnetic resonance imaging (MRI), ESIONs showed longer circulation time than the clinically used gadolinium complex-based contrast agent, enabling high-resolution imaging. High-resolution blood pool MR imaging using ESIONs enabled clear observation of various blood vessels with sizes down to 0.2 mm. These results demonstrate the potential of ESIONs as T(1) MRI contrast agents in clinical settings.

Octapod iron oxide nanoparticles as high-performance T2 contrast agents for magnetic resonance imaging

“…However, there are several challenges for using T 2 contrast agents (for example, Feridex and Resovist) in the clinic. As they are intrinsically negative contrast agents, falsepositive diagnosis may be found in the hypointense areas, such as blood pooling, calcification and metal deposition [9][10][11] . In particular, these commercially available T 2 contrast agents were synthesized in aqueous media and, consequently, exhibit poor crystallinity and relatively low relaxivity 12 .…”

Molecular Imaging with 68Ga Radio-Nanomaterials: Shedding Light on Nanoparticles

“…This drawback has focused research on finding methods for developing IONPs that serve as positive contrast agents for T1-weighted MRI. Studies have demonstrated that the downsizing of IONP core or coating thickness causes a shift on the NP magnetic behavior from superparamagnetic towards paramagnetic, thus creating T1-weighted MRI contrast agents [72,[87][88][89].…”

Functionalized nanomaterials: their use as contrast agents in bioimaging: mono- and multimodal approaches

“…This class of probe primarily consists of Gd(III)-based complexes; incorporation of these smart probes into the NPs will further enhance their efficiency in molecular imaging applications. Very recently, the use of an improved hydrolysis method of inorganic salts assisted by incubation in a water bath led to water-soluble extremely small-sized metal-iron oxide NPs (IONPs), iron-oxide based NPs: MFe 2 O 4 (ESIONs) (M = Fe, Zn, Ni) NPs with average sizes of 4-5 nm [76,77] . The r 1 relaxivities and the r 2 /r 1 ratios of these NPs were more than 5 and < 3, respectively, which indicated that they were good candidates as T 1 -weighted MRI CAs.…”

“…To solve this problem, specific methods based on either pulse sequences [101,102] , design [103] , or size control [76] of NPs have been developed by researchers to generate a bright contrast from the IONPs.…”