Magnetic resonance imaging (MRI) contrast agents have had a significant impact on the value of MRI by enhancing the visibility of internal bodily structures such as organs and vasculature.
MRI contrast agents contain paramagnetic or superparamagnetic metal ions that enhance the MRI signal properties of tissue and increase the sensitivity of the technique in detecting and characterizing various pathologies and pathological processes.
Gadolinium-Based Contrast Agents
Contrast agents are used for about one-third of the 60 million MRI procedures performed worldwide every year, most of which employ the element gadolinium. These gadolinium-based contrast agents (GBCAs) have generally been proven safe to use over the years, but evidence has now emerged showing that gadolinium can accumulate and deposit in brain tissue.
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The Pharmacovigilance and Risk Assessment Committee of the European Medicines Agency has now recommended that, aside from the use of GBCAs for scans that meet an important diagnostic need or joint scans where only a low concentration is required, all other linear intravenous GBCAs be suspended. This has led researchers to look for new MRI contrast agents with a superior safety profile.
Superparamagnetic Iron Oxide Nanoparticles
Alternative contrast agents that have been in clinical use for the MRI-based clinical imaging of various conditions are superparamagnetic iron oxide nanoparticles (SPIONs). These have been used to image the liver, lymph nodes, cardiovascular system and intestines.
SPIONs are composed of a nano-sized iron oxide crystal core coated with an organic dextran or carboxydextran shell.
These particles, which are usually around 100 nm in size, are retained by the reticuloendothelial system (RES) − the network of cells and tissues involved in phagocytosis that are found throughout the body, particularly in the blood, liver, lungs, spleen, lymph nodes, bone marrow and general connective tissue.
In MRI, these particles have a strong T2 effect (magnetic susceptibility) and produce a drop in T2* weighting that means they can be detected at very low concentrations and that the sensitivity of MRI can be increased to almost the cellular level. One feature of SPIONs is their enhanced accumulation in the liver, which has made them a highly valued contrast agent in hepatic MRI.
Low concentrations of two SPIONs, namely ferumoxides and ferucarbotran have been used to non-invasively distinguish between simple steatosis (benign liver condition) and non-alcoholic steatohepatitis (NASH), which is strongly associated with cardiovascular and renal comorbidities.
Safety Concerns Over SPIONs
Despite the promise these agents have shown, as well as their having been approved for MRI in the past, several concerns surround the use of clinically-approved SPIONs and ferucarbotran and ferumoxides have now been withdrawn from the market.
Amongst the risks that have been described for the intravenous administration of iron oxide-based nanosystems, the most concerning one is the risk of hypersensitivity reactions. The administration of the SPION ferumoxytol, for example, has been associated with multiple cases of anaphylaxis. In 2015, the FDA issued the strongest type of warning about the risks of ferumoxytol administration, after a search of the FDA’s pharmacovigilance database identified 79 cases of hypersensitivity reactions. Today, no intravenous iron oxide-containing agents are approved for clinical imaging, highlighting the need for a safe iron oxide-based contrast agent.
Desirable Features of SPIONs
Studies have shown that depending on their size and coating, SPION-based contrast agents may circulate for extended periods and induce undesired effects once administered intravenously.
Desirable SPION features therefore include the ability to control their composition, size, shape, and surface chemistry and extensive research has been carried out into their synthesis and surface modification in efforts to yield desirable properties.
Testing SPIONdex
In a recent study by Harald Unterweger (University Hospital Erlangen, in Germany) and colleagues, the researchers analysed a newly developed dextran-coated SPION called SPIONdex. Using Bruker’s D8 Advance X-ray diffraction system, the team determined the crystalline phases in SPIONdex and using Bruker’s 7T ClinScan and 7T Pharmascan systems, they performed ultra-high-field MRI for full characterization of the nanoparticles.
In vitro experiments showed that SPIONdex demonstrated excellent hemocompatibility and did not induce hemolysis, complement or platelet activation, plasma coagulation, or leukocyte procoagulant activity.
It has previously been shown that pigs are extremely sensitive to infused nano-formulations, so to test whether SPIONdex could trigger hypersensitivity, Unterweger and team intravenously administered SPIONdex in a pig model and performed the complement activation-related pseudoallergy (CARPA) test.
The intravenous bolus administration of undiluted SPIONdex did not trigger CARPA in pigs, not even upon administration of 5mg/kg.
Furthermore, size-tunability studies showed that a radical reduction in particle size to less than 30nm (ultra-small superparamagnetic iron oxide nanoparticle [USPION]) was achievable, without any deleterious effect on hemo- and biocompatibility, thereby underscoring the potential of the nanoparticles for organ/application-dependent adaptation.
Unterweger and team say the excellent biocompatibility, superb safety profile and size-tunability of SPIONdex demonstrated in this study suggest that these particles represent a suitable candidate for a new-generation MRI contrast agent.
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