The use of intravascular contrast in magnetic resonance imaging (MRI) presents some unique challenges but researchers are finding new ways to tackle them using familiar contrast agents in unfamiliar ways.
The challenges of intravascular imaging
MRI is an extremely powerful tool for non-invasive imaging in both a preclinical setting and the clinic. It works by harnessing differences in the longitudinal and transverse relaxation time of water protons between different tissues. Contrast agents, such as those based on gadolinium (III), can increase relaxation times and consequently improve contrast enhancement.
Most MR contrast agents in use are of a low-molecular weight. This means they can be rapidly eliminated from the body – an important factor in limiting toxicity. However, it also results in a reduced window for high-resolution imaging, due to their short blood half-life, and they easily leak from the blood into the extracellular space in a non-specific manner. Both factors impede imaging accuracy.
In fields such as magnetic resonance angiography (MRA) and tumour imaging, there is therefore a need for contrast agents that can remain in the blood, organs or tumour tissue for extended periods of time.
Developments in macromolecular imaging agents
Researchers have made several attempts to overcome the drawbacks associated with low-molecular weight gadolinium-based agents. Strategies have included the use of gadolinium nanoparticles, developing agents that will couple to albumin in the blood serum and generating biodegradable high-molecular weight polymers.
Macromolecular gadolinium-based complexes have been shown to take much longer to clear from the body, which is highly advantageous for imaging but a major impediment to utility because of toxicity. This is because the longer the Gadolinium-based complex is in the body, the more likely it will be metabolised and release highly toxic gadolinium (III) ions.
The challenge is to find an ideal imaging macromolecule – one which will accumulate in the tissue of interest long enough to permit accurate high-resolution imaging before rapidly clearing from the body.
A novel gadolinium-based polymer
In a 2012 study, presented at the International Society for Magnetic Resonance in Medicine conference, Kirchherr et al. created a gadolinium-based macromolecule by conjugating the low-molecular weight Gd-DTPA to GadoSpin. GadoSpin is a gadolinium-based high molecular weight biodegradable polymer that is specifically intended for pre-clinical use.
The team found that the longitudinal and transverse relaxivities of the polymer were more than three times higher compared with Gd-DTPA alone, indicating a high level of contrast enhancement.
Following intravenous injection in mice, the researchers found that the Gd-DTPA polymer remained in the vascular system for a prolonged period of time. They estimated the half-life at around 2 hours in comparison to 6 minutes with Gd-DTPA alone. However, at 24 hours the polymer had still been completely eliminated, primarily through glomerular filtration.
By contrast, the signal intensity with Gd-DPTA alone rapidly decreased shortly after administration due to strong extravasation and fast renal elimination. Therefore, 35 minutes after administration, the polymer was still able to provide good enhancement of the blood vessels in the kidney, while in animals administered with Gd-DTPA, enhancement had returned to baseline levels.
The researchers say that their findings suggest that the polymer has optimal biocompatibility and clearance properties and the wide acquisition timeframe it provides could be ideal for use in MRA, as well as studies of renal structure and function.
Imaging systems in preclinical research
Kirchherr et al. used two Bruker instruments to conduct their research. The first - the minispec – was used to calculate the T1- and T2- relaxation times of water containing increasing concentrations of Gd-DTPA or polymeric Gd-DPTA.
In their in vivo experiments, the researchers used a small animal imaging MRI Bruker BioSpec scanner. The Bruker BioSpec range is available with field strengths from 4.7 to 21 Tesla. All BioSpec machines use Ultra Shield Refrigerated Magnet Technology which is designed to drastically reduce the magnetic field to which the operator is exposed. And, by harnessing the latest pulse tube cryo-cooler technology, BioSpec scanners deliver optimal artefact-free performance with no unwanted vibration. With bore widths from 11 to 40 cm, the BioSpec range can provide this level of imaging in all animals in the preclinical setting.
- Fink C, et al. Magnetic resonance angiography with blood-pool contrast agents: future applications. Eur Radiol 2007; 17 Suppl 2: B38-44.
- Kirchherr A, et al. (2012) Characterization of a novel gadolinium-based high molecular weight polymer as an intravascular MR contrast agent. Poster presented at ISMRM Annual Meeting, Melbourne, Australia.
- Lee GH, et al. Blood-pool and targeting MRI contrast agents: From Gd-chelates to Gd-nanoparticles. Eur J Inorg Chem 2012; 12: 1924-1933.
- Lu Z-R, et al. Polydisulfide Gd(III) chelates as biodegradable macromolecular magnetic resonance imaging contrast agents. Int J Nanomedicine 2006; 1: 31-40.
- Mohs AM & Lu Z-R. Gadolinium(III)-based blood-pool contrast agents for magnetic resonance imaging: status and clinical potential. Expert Opin Drug Deliv 2007; 4: 149-164.
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