Iron Oxide Nanoparticles as T₁ Contrast Agents for Magnetic Resonance Imaging: Fundamentals, Challenges, Applications, and Prospectives

Abstract

Gadolinium‐based chelates are a mainstay of contrast agents for magnetic resonance imaging (MRI) in the clinic. However, their toxicity elicits severe side effects and the Food and Drug Administration has issued many warnings about their potential retention in patients’ bodies, which causes safety concerns. Iron oxide nanoparticles (IONPs) are a potentially attractive alternative, because of their nontoxic and biodegradable nature. Studies in developing IONPs as T1 contrast agents have generated promising results, but the complex, interrelated parameters influencing contrast enhancement make the development difficult, and IONPs suitable for T1 contrast enhancement have yet to make their way to clinical use. Here, the fundamental principles of MRI contrast agents are discussed, and the current status of MRI contrast agents is reviewed with a focus on the advantages and limitations of current T1 contrast agents and the potential of IONPs to serve as safe and improved alternative to gadolinium‐based chelates. The past advances and current challenges in developing IONPs as a T1 contrast agent from a materials science perspective are presented, and how each of the key material properties and environment variables affects the performance of IONPs is assessed. Finally, some potential approaches to develop high‐performance and clinically relevant T1 contrast agents are discussed.

Magnetic Nanoparticles in Biology and Medicine: Past, Present, and Future Trends

“…This is due, in part, to toxicity concerns that are amplified by black box warnings issued by the US Food and Drug Administration (FDA) after studies showed small, but measurable, risks of serious adverse events (0–1%) and anaphylaxis (0.02–0.2%) after ferumoxytol administration [ 66 , 85 ]. Additionally, radiologists are not as experienced in interpreting the dark contrast provided by IOP in transverse water relaxation time (T 2 )-enhanced MR images [ 85 , 86 ]. Dark contrast enhancement and susceptibility artifacts from IOP can result in misdiagnosis and an overestimation of lesion margins [ 70 , 85 , 86 , 87 ].…”

“…Additionally, radiologists are not as experienced in interpreting the dark contrast provided by IOP in transverse water relaxation time (T 2 )-enhanced MR images [ 85 , 86 ]. Dark contrast enhancement and susceptibility artifacts from IOP can result in misdiagnosis and an overestimation of lesion margins [ 70 , 85 , 86 , 87 ]. A second issue has been the reluctance of pharmaceutical companies to produce IOP contrast agents.…”

Gold Nanoparticles in Cancer Theranostics

“…Under an external magnetic field, magnetic nuclei align to allow resonance through a radiofrequency pulse (Zhou et al, 2019). The resolution of MRI for disease diagnosis can be affected by using MRI contrast agents that improve the contrast by shortening the longitudinal (T 1 ) or transverse (T 2 ) relaxation times of protons (Jeon et al, 2020). Although superparamagnetic iron oxide nanoparticles (SPION) were used to be applied as contrast agents of T 2 -weighted MRI, clinics no longer allow SPIONs in vivo because of their ROS toxicity causing severe cellular damage and inflammatory responses (Kwon et al, 2017).…”

A Perspective on Modelling Metallic Magnetic Nanoparticles in Biomedicine: From Monometals to Nanoalloys and Ligand-Protected Particles

“…Currently, the majority of T2 contrast agents are iron oxide based superparamagnetic NPs (SPIONs) coated with dextran, silicates, or other polymers with variable T2 relaxivities [100][101][102]. Recent studies investigating the transformation of SPIONs into T1 contrast agents have generated some promising results, but effective contrast enhancement is still lacking, due to the unknown relaxation mechanisms, and nanoparticulate T1 contrast agents have yet to be approved for clinical use [103][104][105][106]. This flexibility makes iron oxide NPs attractive for detecting specific biological tissues, but their relatively large sizes still impede cell penetration and delivery, while lower values of their magnetic moments require increased clinical uptake to compensate for the poor contrast obtained when compared to gadolinium-based agents.…”