Kommersant: They are harmless and give light. How lanthanides help the young science of theranostics
St Petersburg University scientists have established patterns related for changing the shape and size of nanoparticles used in theranostics, an innovative field of medicine, by adding various lanthanides to the structure.
The use of particles of a certain shape and size is important in anti-cancer therapy and MRI diagnostics. In these fields, it is required to use the smallest particles, since they penetrate cells more easily and are able to move freely through vessels and veins without clogging small capillaries.
Theranostics is a young and actively developing field of medicine that explores the opportunities of creating and using medications that allow for a simultaneous diagnosis of diseases and their therapy, with the help of special combination materials-drugs. The creation of such materials has become possible only in recent years, largely as a result of nanotechnology development.
These drugs make it possible to: find in the patient’s body an affected area that requires treatment; deliver the necessary medicine there; and immediately visualise the affected area for the doctor in real-time mode, either by optical spectroscopy or using the widely used MRI method. Scientists note that combination drugs do not have a negative effect on the patient’s body and cause less discomfort during treatment.
The practical component is crucial for the development of such drugs, but there are also important fundamental issues. One of such issues is the one related to the relationship between the useful properties of drugs and the sizes of micro- and nanoparticles in the form of which drugs are produced.
St Petersburg University scientists have studied nanoparticles based on sodium and yttrium fluorides and rare earth elements, chemically inert and insoluble substances that do not harm the body. In addition, these elements, as a rule, have a brighter luminescence (glow). In future, they can be used as stains for luminescent microscopy, as well as for medical purposes, for example, when conducting non-invasive tumour diagnostics.
During their work, the team of researchers led by Andrey Mereshchenko, Doctor of Chemistry, Associate Professor in the Department of Laser Chemistry and Laser Material Science of St Petersburg University, synthesised several dozen compounds. In each case, they varied the composition of the resulting material by adding various salts of rare earth elements. This was necessary for the accumulation of experimental material for further analysis. The scientists applied the classical approach of the St Petersburg University’s school of thought in chemistry. That made it possible to find and explain fundamental patterns in the properties of substances using the Periodic Law discovered in 1869 by the famous University scientist Dmitri Mendeleev.
Previously, St Petersburg University chemists synthesised new luminescent nanoparticles to be used in laser microscopy and in diagnostics of various diseases with the use of contrast. These nanoparticles were also created on the basis of rare earth metals, yttrium and europium, with the addition of gadolinium ions.
As a result, the scientists managed to obtain particles ranging in size from 80 to 1,100 nanometres. One nanometre is one billionth of a metre. It should be noted that the size and shape of the particles directly depend on the nature of the rare earth ion. This dependence is nonmonotonic. Particles decrease from left to right in the series of lanthanides in the periodic table, from lanthanum to gadolinium (the 57th to the 64th elements of the periodic table) and increase in the second part of this series, from gadolinium to lutetium (the 64th to the 71st elements of the periodic table). All particles are shaped as hexagonal prisms. Their diameter—height ratio also depends on the nature of the rare earth ion, which ensures a change in the geometric parameters of the particles when using various components of the drug.
Currently, the team continues their work. It is now aimed at optimising the directed synthesis of particles with multifunctional properties. They need to be capable of emitting light after being subjected to UV rays, electromagnetic field and other disturbances (luminescence), and at the same time be applicable as a composition of MRI contrasts.
Andrey Mereshchenko, Doctor of Chemistry, Associate Professor in the Department of Laser Chemistry and Laser Material Science at St Petersburg University, answered the questions asked by Kommersant Nauka.
What is theranostics?
Theranostics is a young field of medicine. Its name is made up of two words, ’therapy’ and ’diagnostics’, reflecting the objects that researchers are working on in this direction. That is creation and study of materials making it possible to conduct both the diagnosis of a disease and its treatment.
How do the combination drugs used in this treatment—and-study work?
Theranostic drugs can be varied in their chemical nature. The all have one thing in common, i.e. the opportunity to combine the drug-induced effect and the sensory one. From the perspective of therapeutic properties, such compounds or any drugs based on them should be able to treat the affected areas of the human body at the cellular level. Like killing cancer cells. Therefore, they must either contain active chemical forms that have a direct effect on the biochemistry of processes in the affected area, or be a source of such effect. In the first case, these can be compounds of platinum, for example. They do have a toxic effect on cancer cells. In the second case, these can be compounds that are able to create a physical effect that helps destroy harmful cells. Radioactivity caused by using radioisotopes may be such an effect. Or heat that appears in some compounds when they are irradiated with light of a certain wavelength. As for the sensory properties that allow diagnostics, here we can mention the possibility of creating luminescent labels or MRI contrast agents. Luminescent labels enable you to literally ’highlight’ the affected area of living tissue by irradiating it with light. MRI contrasts make it possible to perform magnetic resonance imaging and visualise a 3D picture of the location of tissues in the human body. And all this is performed without painful intervention in the body by surgical methods.
How are they developed?
The development of such compounds is a complex physical and chemical process. If the required effect is needed at the cellular level, such drugs must have certain sizes, so we have to work in the nano- and micro-range. Nanoparticle synthesis takes several stages. It is extremely demanding on the purity of the reagents and control over the conditions for the synthesis, because it is at this stage that the particles are given functional properties. Functionalisation is provided by the introduction of certain chemical components into the particles. For example, to create particles used in a MRI contrast, gadolinium ions can be added to the compound, while europium or terbium ions can be added to impart luminescent properties. And these are not the only examples. Effective additives and the selection of their optimal amount is an area for research work, which is partly applied and partly fundamental.
Why did scientists at St Petersburg University study nanoparticles based on sodium and yttrium fluorides and rare earth elements?
Yttrium-sodium fluoride is often used as a solid matrix to create theranostic drugs. This compound plays the same role as magnesium stearate in glycine tablets. The active ingredient there is the amino acid glycine in a small amount. For ease of use, it is placed in a tablet with an inactive component that forms the body of the tablet. This substance itself has no therapeutic purpose and does not affect the body. In our case, sodium-yttrium fluoride is used as a basis for introducing key chemical components into a substance. These components are rare earth ions. And the goal of the study was to solve a fundamental problem regarding any theranostic drugs based on such a matrix. The problem is as follows: how the nature and amount of added ions affect the size and morphology of the resulting nanoparticles. The solution of this problem is fundamentally important for the creation of drugs, since it becomes possible to predict the particle size and shape before the synthesis stage.
How was the research implemented?
Two series of particles were studied. All of them consisted of an yttrium-sodium fluoride matrix, and various ions of rare earth elements were added to all of them. The difference between the series was in the number of added ions. The particles were obtained by the autoclave method. Aqueous solutions of the initial components for synthesis were stirred at room temperature, and then placed in autoclaves and kept at elevated pressure and temperature for about a day. After that, colourless powders were obtained, which were investigated by instrumental methods. Since the purpose of the work was to obtain data on the relationship between the composition and size-morphology of particles, the key part of the work was X-ray diffraction analysis and scanning electron microscopy. These methods of analysis make it possible to find the size of particles and their shape, as well as the structural features of the crystal lattice.
What did it show?
An analysis of the particles obtained during the research showed that they all had a size in the range from 80 to 1,100 nanometres, while the size and shape of the particles were directly dependent on the nature of the rare earth ion. It was also found that that dependence was nonmonotonic. Particles decrease from left to right in the series of lanthanides in the periodic table, from lanthanum to gadolinium, and increase in the second part of this series, from gadolinium to lutetium. All particles are shaped as hexagonal prisms. Their diameter—height ratio also depends on the nature of the rare earth ion, which ensures a change in the geometric parameters of the particles when using various components of the drug.
How can this data be used in medicine?
The results obtained are important, first of all, for the development of theranostic drugs based on rare earth ions and sodium-yttrium fluoride and the selection of their optimal composition. That is, the obtained data is primarily of interest to researchers in the fields of materials science and medicine. They create drugs in laboratories and conduct the first tests with them, optimising the formula.