Kazan Federal University

Kazan University chemists offer new type of contrast agent for magnetic resonance imaging

Scientists at the Institute of Chemistry have developed a new type of contrast agent for magnetic resonance imaging (MRI) – bovine serum albumin nanoparticles doped with manganese (II) ions. The results of the study are published in International Journal of Biological Macromolecules.

The extensive research, supported by a grant from the Russian Science Foundation, was carried out by researchers: Associate Professors Rustem Zairov and Timur Mukhametzyanov of the Department of Physical Chemistry, Senior Researcher Bulat Akhmadeev of the Laboratory of Materials for Hydrogen Energy and Conventional Energy with Low Carbon Footprint, Lab Researcher Alexey Dovzhenko, and junior researchers Timur Kornev, a second-year PhD student, and Vadim Vasilyev, a fourth-year student. The research group also included scientists from Kazan National Research Technological University, Kazan National Research Technical University, and the Institute of Organic and Physical Chemistry of the Kazan Scientific Center of the Russian Academy of Sciences.

The use of biomolecules in the development of nanomaterials is a well-known way to increase its biocompatibility. Blood proteins are the most common biological objects of study, as they have a unique ability to bind and transfer various substrates, including metal ions. Due to controlled soft denaturation, the properties of native, i.e. original proteins can be dramatically changed. In the case of this development, the protein in question is bovine serum albumin (BSA), which is a more accessible model of human serum albumin (HSA). Modification of the properties of protein molecules and further cross-linking with certain cross-linking agents allows to fix the obtained functional characteristics and synthesize nanoparticles.

“Bovine serum albumin is a classical protein that is the closest and most actively investigated model of human serum albumin. The primary function of this protein in the human body is transport – it reversibly binds various biomolecules and transports them. BSA is the most commercially available protein, its cost relative to other proteins is low, so many biological studies that claim for further application in biomedical purposes are conducted on bovine serum albumin. We found that bovine serum albumin in its native (initial) state is able to bind manganese ions in a ratio of 1:1. In this case, the formed complex, in which the manganese ion (Mn2+) is bound, say, with a high molecular weight ligand, is able to increase the relaxation of water protons by several orders of magnitude. By selecting experimental conditions by desolvation with an organic solvent, we achieved a mild non-thermal denaturation of the protein,” comments Rustem Zairov.

In the denatured state the protein is able to bind 4 manganese ions, Zairov notes. Thus, it becomes possible to increase manganese loading by 4 times. Further, by adding glutaric aldehyde, the scientists cross-linked denatured protein molecules to form nanoparticles. Such particles, says the Associate Professor, have a size of about 100 nanometers, which is very suitable for biomedical applications – they are able to cross various barriers in the body.

The participants of the study achieved a ratio of Mn2+ ions to protein – 4:1, studied the magnetic relaxation characteristics and showed that the particles are very biocompatible, by the type of Fenton reaction they have a very weak catalytic activity. They are characterized by low hemolytic activity and hemagglutination (at concentrations less than 110 micromol/L). Scientists are confident such nanoparticles are promising candidates for use as contrast agents in MRI scans; they exhibit unusually high relaxivity values compared to other manganese particles at the 100-unit level (longitudinal relaxivity, 98.9 mM-1s-1; transverse relaxivity, 133.6 mM-1s-1).

“As you know, more than 30 percent of modern MRI procedures are performed with the administration of contrast agents. It is clear that MRI is by far the most widely used method for non-invasive diagnosis of tumor diseases. In some cases, contrast injection is required to locate the tumor site, including cancerous tumors, for highly accurate diagnosis. For this purpose, contrast agents are injected, all of which are complex compounds of gadolinium (Gd). Gd3+ is such an ion, which has seven unpaired electrons, and due to its unique magnetic properties, it effectively accelerates the relaxation of water protons,” says Zairov.

The scientist adds that unlike manganese, which is found in the human body, gadolinium can cause nephrotoxicity – toxicity towards the kidneys leading to nephrogenic systemic fibrosis as well as some neurodegenerative diseases.

“The question is now increasingly being raised that gadolinium needs to be replaced with something more ‘bio-friendly’, and this is where Mn2+ comes in. This ion has an electronic configuration d5, the number of unpaired electrons, it is inferior to gadolinium: the relaxivity of the manganese(II) aqua ion is slightly lower than the relaxivity of the gadolinium(III) aqua ion (9 and 16, respectively). Despite this, in a certain ligand environment or in the composition of nanoparticles, the use of manganese may give a better result,” explains the scientist. “Existing MRI contrast agents are not so effective, at least their relaxivity values lie in the range of 3.5 – 9.9. The relaxivity of nanoparticles obtained by our group reaches about 100 units. This is a significant breakthrough in the field of contrast agent development, as it exceeds the corresponding relaxivity values of current, commercially available MRI contrast agents based on gadolinium by more than an order of magnitude. That is, with manganese, which initially loses to gadolinium but is more biocompatible, we were able to achieve higher relaxivity. At the same time, together with biologists, it was shown that the resulting nanoparticles do not cause toxic effects, hemagglutination and do not generate reactive oxygen species.”

The research was conducted under the supervision of Marat Ziganshin, Director of the Institute of Chemistry, and Asiya Mustafina, Head of the Laboratory of Physical Chemistry of Supramolecular Systems at the Institute of Organic and Physical Chemistry.

In the near future, the technology may be used in biomedicine to establish contrast between healthy and diseased tissues during diagnostics using magnetic resonance imaging.

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