Researchers at the University of Basel have developed a new type of nanoparticle, which improves the contrast tenfold compared to usual contrast agents. And this is only one of the advantages of the new nanoparticles. COMPAMED-tradefair.com talked to Prof. Cornelia Palivan, who is one of the research group’s leader, about the new contrast agent.
Prof. Palivan, how do contrast agents work in an MRI?
Prof. Cornelia G. Palivan: Magnetic resonance imaging is a non-invasive technique that is widely used in cardiovascular, neurological, and oncological diagnostics. Imaging is based on contrast generated by tissue-dependent variations in relaxation times of protons (from water and fat molecules), which is improved by the presence of contrast agents.
We use contrast agents to see changes of the tissue in more detail, for example the presence of a tumor. The proton’s relaxation time in normal tissue is a little bit different compared to those in a tumor tissue. When you introduce contrast agents based, for example, on gadolinium complexes, this relaxation time will change significantly. Therefore, in the region of the tumor you will see a higher contrast compared to normal tissue.
What is the problem with commonly used contrast agents?
Palivan: Normal, free gadolinium ions are extremely toxic. Therefore, the aim of chemists is to complex gadolinium with different ligands resulting in non-toxic stable complexes. There is for example the contrast agent Dotarem, where a small ligand is attached to gadolinium. The quality as a contrast agent is also related to the movement of these complexes. If they move slower, the contrast will be higher. Therefore, there are research groups complexing gadolinium with polymers, for example. These complexes will move slower, inducing a higher MRI contrast.
With our research we went one step further and complexed gadolinium ions to nanoparticles resulting in an increase of the contrast by ten times compared to Dotarem.
What kind of nanoparticles are these, that you have designed in your research project as a new contrast agent? What are they made of?
Palivan: These contrast agents are nanoparticles obtained by co-assembly of heparin-polymers with trapped gadolinium ions, and stimuli-responsive peptides. These nanoparticles were designed to combine multiple properties: (i) a long blood circulation of nanoparticles due to the selection of the heparin–polymer system, (ii) an increased MRI contrast due to the presence of Gd3+ in a coordinated form to avoid toxicity, and (iii) a responsiveness to environmental changes due to the reduction-sensitive peptide. In a reductive environment, the peptides are released from the nanoparticles, increasing the accessibility of Gd3+ for water molecules, and therefore increasing MRI contrast.
A second advantage is the fact, that we can localize high concentration of gadolinium on each nanoparticle. That means, we can localize this contrast agent in the region where it is necessary. Another advantage is the non-toxicity. When people hear anything about nanoparticles, they immediately think that they are dangerous. But this is only the case for inorganic nanoparticles. But the nanoparticles that we use are organic, based on polymers, heparin and peptides. We did toxicity tests, which proved that the nanoparticles are not toxic, without and with gadolinium ions attached to them. In addition, the presence of peptides induces a stimuli-responsive behavior of this contrast agent: it shows a higher MRI contrast in reductive conditions, which are specific for regions with increased reduction potential, such as cancerous tissues.
Palivan: No, these nanoparticles as contrast agents are only in the very early stage of research, where we prove the concept. You have to keep in mind, for every drug-related application the admission procedure is very long. Now, we are at the very beginning. We have the idea, the system. We know that it is active and we know that it is not toxic, but we have to optimize all the conditions. After that, we have to go to tests on animals. Only then, if everything is okay, we can go further. In the pharmaceutical domain, each of these steps is a long story, because there are a lot of very strict limitations and regulations. If all the tests will be successful, we can go to clinical trial. But it is a long way to go.
With the newfound insights, are there other possible uses, except for the MRI?
Palivan: The nanoparticles with gadolinium are specific for MRI. But the big advantage of these nanoparticles is, that we can attach different molecules based on electrostatic interaction with heparin, as for example, different drugs. And in this case we can obtain a drug delivery system with stimuli-responsive behavior. That means the nanoparticles can be used not only for MRI, but depending on what kind of molecule we attach, we have a very large field, where they can be used.