Molecular Tracers and Contrast Agents
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Improving Contrast Agents to Obtain Clearer Magnetic Resonance Images

Imaging techniques, including PET, SPECT, MRI, and microCT, are valuable tools in preclinical research just as their counterparts are in clinical diagnostics.

A range of imaging techniques can be employed to obtain structural and functional information about cells and organs, and to acquire insights into molecular activity, such as tissue metabolism. In preclinical research, this can facilitate the determination of biological responses to environmental changes or pharmaceutical compounds under development. In medicine, imaging can identify the presence of cancerous tissue, evaluate healthy tissue, assess bodily functions, diagnose disease, and monitor the effects of a treatment.

The information that can be obtained using such modalities can be increased by using contrast agents, since they can make images easier to interpret.

Research to support the development of new, more effective contrast agents is thus an important enabler of numerous scientific advances.

Contrast agents for magnetic resonance imaging

MRI has become a particularly valuable radiological tool since it provides anatomical information across almost all organs and soft tissues within the body without the need for harmful ionising radiation. It allows distinction between normal and diseased tissue and can be used to perform functional evaluation, such as tissue perfusion.

Contrast-enhanced MRI is commonly used to increase the difference in relaxation characteristics of normal and pathologic tissues. A variety of different categories of contrast agents are currently available for preclinical use. These include paramagnetic agents, such as gadolinium and manganese, superparamagnetic agents, such as iron oxide and iron platinum, and protein-based agents, such as β-galactosidase-activated contrast agents.

The use of contrast agents facilitates the detection of malignant lesions and can enable more accurate characterization of different types of lesions1. The small difference in relaxation properties between a tumour and healthy tissue may be insufficient to produce obvious differences in signal intensity and this can be increased by intravenous administration of a contrast agent. Elusive pathologies thus become more obvious in the presence of a contrast agent, thereby aiding diagnosis.

It is also possible to improve the contrast of different tissues, for example to highlight blood vessels. This can be increased further by using two contrast agents with complementary mechanisms. This is particularly useful when imaging the liver. A superparamagnetic iron oxide is used to darken the background liver and gadolinium serves to brighten the vessels2.

The drive for contrast agents to maximise the information that can be acquired through MRI has resulted in extensive research to develop new, more effective and convenient agents.

Magnetic nanoparticle (MNP) tracers for MRI

Magnetic nanoparticles (MNPs) represent a potential new generation of diagnostic agents for MRI that have improved specificity and safety3. Magnetic nanoparticles accelerate the longitudinal relaxation rate of neighbouring water molecules, which can be translated into increased  signal.

MNPs are usually enclosed in a coating to prevent an immune response being raised against them. The coating may be a sugar, other polymer, such as polyethylene glycol (PEG) and polyvinyl alcohol (PVA), or proteins with high specificity. The type of coating used can affect the properties, such as hydrophilicity and half-life, and distribution, for example by facilitating or inhibiting phagocytosis, of an MNP4. Careful choice of coating can thus be used for targeted accumulation of contrast agent in the area of interest. For example, MNPs coated with amino groups selectively target carcinomatous brain cells without invading the whole brain.

Several studies have examined the toxicity potential of different types of MNPs with a range of surface coatings and have generally found low or no toxicity associated with these nanoparticles until high exposure levels (>100 mg/ml)5.

There has been increasing interest in MNPs with a manganese core since these have enhanced magnetic properties compared with the usual iron (Fe) oxide MNPs. However, despite very promising results in in vitro assessments of MNPs as imaging agents for MRI, the translation to clinical use has been limited6.

Superparamagnetic iron oxide nanoparticles are the only clinically approved metal oxide nanoparticles. This is largely the result of MNPs being more widely tested in invertebrate models than in mammalian models. This limits the progression of potentially effective agents to become available for clinical use. To overcome this obstacle in advancing MNPs as potential agents for clinical MRI, researchers have identified the zebrafish as an excellent model for intermediate evaluations of toxicity.

Evaluating MNPs as MRI contrast agents

MNPs of 3–20 nm diameter with ferrite and manganese ferrite oxide cores were recently evaluated in zebrafish6. The MNPs produced were characterised by 1H nuclear magnetic resonance (NMR) spectroscopy using a Bruker Ascend 400 NMR spectrometer and their relaxivities determined using Bruker Minispec and BioSpec spectrometers.

Exposure of mouse microglial cells to the engineered MNPs in vitro resulted in minimal toxicity, with cell viability remaining above 90 %. The Fe1 and Fe2 MNPs showed the lowest toxicity, and since the Fe2 MNP presented the best characteristics for a potential MRI contrast agent, this MNP was selected for further testing in mice. In vivo MRI testing was conducted using a 9.4 T Bruker BioSpec instrument equipped with a 400mT/m gradient coil and a transmit-receive volume resonator with 40 mm inner diameter.

The Fe2 MNP showed very good MRI contrast and caused no toxicity in mice6. Relaxivities were measured at both low (1.44 T) and high (9.4 T) magnetic fields, and similar trends were observed in both cases. At low magnetic field, the small MNPs behaved as dual T1/T2 contrast agents and the large MNPs behaved exclusively as T2 contrast agents. At high magnetic field, all MNPs were suitable for use as T2 contrast agents.

This latest research confirms the suitability of MNPs as contrast agents for high field MRI, which is gaining more relevance clinically. In addition, it highlights the importance of evaluating MNP toxicity in animal models rather than in vitro and demonstrates that the zebrafish provides a suitable indication of in vivo toxicity in mammals.

References

1.       Clough TJ, et al. Ligand design strategies to increase stability of gadolinium-based magnetic resonance imaging contrast agents. Nat Commun. 2019;10(1):1420. www.ncbi.nlm.nih.gov/pmc/articles/PMC6441101

2.       Yokoo T, et al. Biomed Res Int. 2015; 2015: 387653. www.ncbi.nlm.nih.gov/pmc/articles/PMC4569760/

3.       González‐Mancebo D, et al. HoF3 and DyF3 Nanoparticles as Contrast Agents for High‐Field Magnetic Resonance Imaging. Part Part Syst Charact. 2017;34(10):1700116. https://doi.org/10.1002/ppsc.

4.       Dulińska-Litewka J, et al. Superparamagnetic Iron Oxide Nanoparticles—Current and Prospective Medical Applications. Materials (Basel). 2019 Feb; 12(4): 617. www.ncbi.nlm.nih.gov/pmc/articles/PMC6416629/

5.       Jun Sung K, et al. Toxicity and Tissue Distribution of Magnetic Nanoparticles in Mice. Toxicological Sciences 89(1), 2006, 338–347
doi.org/10.1093/toxsci/kfj027

6.       Becerro AI, et al. HoF3 and DyF3 Nanoparticles as Contrast Agents for High-Field Magnetic Resonance Imaging. Particle & Particle Systems Characterization 2017;34(10). https://doi.org/10.1002/ppsc.201700116

7.       Caroa C, et al. Comprehensive Toxicity Assessment of PEGylated Magnetic Nanoparticles for in vivo applications. Colloids and Surfaces B: Biointerfaces 2019;177:253–259. doi.org/10.1016/j.colsurfb.2019.01.051.