Nanodisks for MRI
Magnetic microdisks will help to improve the informativeness of existing methods of examination of internal organs
Phys Tech blog on Naked Science website
Researchers in Russia and the USA have developed magnetic nanostructures recorded by induction methods with record sensitivity, including in the body of laboratory animals in vivo. The resulting magnetic microdisks will increase the sensitivity and informativeness of various imaging methods of organs and tissues, such as magnetic resonance imaging, MPQ (magnetic particle quantification) and MPI (magnetic particle imaging). At the same time, in order to receive such signals, only a few tens of picograms of specially designed nanoparticles are enough.
The work was published in the journal Nanoscale (Nikitin et al., Ultrasensitive detection enabled by nonlinear magnetization of nanomagnetic labels). The development was carried out by an international group of scientists from MIPT, IOF RAS, MISIS and Argon National Laboratory (USA). The research was made possible thanks to grants from the Russian Academy of Sciences, the Ministry of Education and Science of Russia and the US Department of Energy.
The researchers were able to demonstrate record sensitivity of registration of specially prepared magnetic nanostructures promising for a variety of applications. To do this, they used objects of a special shape – iron-nickel microdisks of nanometer thicknesses. This geometric shape leads to a vortex-like structure of the magnetic moments of the particles, as a result of which they acquire special properties. In particular, such disks have no residual magnetization, do not aggregate in solutions, and have a strong nonlinear dependence of magnetization on the magnitude of a weak magnetic field. This circumstance allowed the authors, due to the previously proposed MPQ magnetic nanoparticle detection method, to confidently detect from 39 picograms of magnetic material ("pico-" is 1000 times smaller than "nano-") in a wide linear sensitivity range of 7 orders of magnitude. Experiments conducted on remote registration of such nanostructures in the body by laboratory animals in vivo and ex vivo confirmed the prospects of using this approach in biology and medicine.
The results were commented on by the first author of this work, head of the Laboratory of Nanobiotechnology at MIPT Maxim Nikitin:
"Earlier, our American colleagues from the Argon National Laboratory in the USA in in vitro experiments showed the possibility of suppressing human glioma tumor cells using microdisks when exposed to weak (non-maturing) low-frequency magnetic fields. This aroused intense interest in the diverse biomedical applications of such nanostructures and a large number of important publications. In the current work, we have demonstrated another interesting feature of such nanostructures, namely the possibility of their registration and topography by induction methods, including in animals, with ultra-high sensitivity using portable devices with relatively small exciting magnetic fields. This is also important for the metrological support of biomedical research using magnetic nanoobjects."
In the near future, nanomaterials will significantly expand the capabilities of medicine in the diagnosis and treatment of various diseases. And some of them, for example, magnetic nanoparticles, have already been approved in many leading countries for intravenous injections to humans – to improve image quality and contrast tumors with magnetic resonance imaging (MRI), to make up for iron deficiency in anemia, etc. Also, these particles, due to their sensitivity to the effects of magnetic fields, are considered one of the most promising for the development of new biomedical technologies for imaging various neoplasms inside the body, targeted drug delivery or tumor treatment.
As part of the study, the scientists combined a previously developed highly sensitive method for detecting MPQ nanoparticles and a new magnetic material. The MPQ method is based on the exposure of nanoparticles to an external alternating field at two different frequencies, followed by the detection of a signal at combinatorial frequencies (which are a linear combination of these frequencies). The method allows registering from 60 zeptomoles (the prefix "zepto-" means 10 to minus twenty-first degree) of ordinary colloidal magnetic nanoparticles. This is comparable to the threshold of registration of nanoparticles based on radioactive isotopes of iron by concomitant gamma radiation.
Scientists obtained and studied magnetic nanoparticles in the form of microdisks made of permalloy, an alloy of nickel and iron. In order to make such microdisks with a diameter of 1.5 microns, but with different thicknesses from 10 nm to 40 nm, the researchers used the method of optical lithography (Fig.1). Due to their unusual shape, their physical properties differ significantly from those for spherical nanoparticles: the magnetic moments of microdisks form vortex-like structures with zero total residual magnetization. With an increase in the external magnetic field, such a structure is transformed and the magnetic moments are oriented in the direction of the field. When the magnetic field decreases, the initial distribution is restored, and when the direction of the magnetic field changes, it changes to the opposite.
Figure 1. In the absence of a magnetic field, the residual magnetization is zero due to the vortex-like distribution of magnetic moments (central image), when the magnetization is saturated, a single-domain structure is formed (images on the left and right with negative and positive magnetic field directions, respectively) / MIPT Press Service
The presence of such a transition, which leads to greater nonlinearity of magnetization in relatively weak fields, significantly increases the detection limit by the MPQ method, which was the key result of the work. The researchers obtained an unprecedented sensitivity that allows inductively registering 39 picograms of magnetic material in a relatively large volume. It should be noted that the detected signals significantly depend on the orientation of the microdisks. This property, called anisotropy, is associated with their special geometry. If the direction of the magnetic field is parallel to the plane of the disks, then the value of MPQ signals is maximum. An increase in the angle between the direction of the magnetic field and the plane of the disks leads to a monotonous decrease in the signal when 90 o is reached.
Scientists also conducted a number of biophysical experiments to study the dynamics of the obtained nanoparticles in the bloodstream of laboratory mice in vivo and their behavior in the tissues of various organs ex vivo. Previously, the microdisks were transferred to a saline solution. To study the rate of their removal from the bloodstream, a solution of microdisks was introduced systemically, and their detection took place in the tail vein and artery of the mouse when the tail was placed in the measuring coil of the MPQ device (see Fig.2).
Figure 2. Illustration of the experiment: a mouse (under anesthesia) was placed in an external coil generating a constant magnetic field when switched on, while the mouse tail was placed in the measuring coil of the MPQ device / Photo by the authors of the study
The circulation time of nanoparticles is usually about 10 minutes. The inclusion of an external magnetic field of small amplitude 15 Oersted (large coil in Fig. 2) dramatically increased the MPQ signal, which showed an interesting possibility of modulating the response of microdisks and their reorientation in a living organism. For comparison, the researchers used magnetic microspheres – for them, the MPQ signal did not depend on the external field. In addition, the bio-distribution of magnetic microdisks was studied. The results of the experiments showed that the accumulation occurred in the liver, spleen and lungs, which is a characteristic property of nanoparticles. The researchers also observed an interesting relationship: when exposed to an external field on disks in different organs, they received a different degree of increase in the MPQ signal. Scientists have suggested that this is due to the dissimilarity of the properties of different tissues (viscosity, density, stiffness), which in turn can be used, for example, for the induction detection of tumors in animals.
An explanation was made by the co-author of the article and one of the inventors of the MPQ method, head of the laboratory of the IOF RAS Pyotr Nikitin (1979 graduate of MIPT): "The experiments have shown very interesting and informative features of the dependence of signals on the ratio of diameter to thickness of disks, their spatial orientation, etc. For example, it turned out that with weak exciting fields it is much easier to register very thin disks (with a smaller mass of magnetic material) than thick ones. This is due to the different magnitudes of the demagnetization fields of the structures. Magnetic nanoobjects registered with high sensitivity are of great interest for applications as nanometrics in DNA and immunoassays, biosensorics, anti-counterfeit protection of important drugs, etc. In addition, currently the use of MPQ and MPI methods for biomedical research is limited to experiments on small laboratory animals. The proposed approach to the transition from traditional colloidal nanoparticles to specially designed nanostructures may prove promising for increasing the size of the sensitivity zones of MPQ and MRI methods for human clinical studies."
Thus, scientists have developed an ultra-sensitive method for detecting constructed magnetic nanostructures with strong dependencies of disk properties on size and composition, which will allow creating nanoagents with the most advantageous properties. In addition, these objects can be remotely detected in a complex biological environment (in the bloodstream and tissues). The synergy of nanotechnology and medicine underlying the approach seems promising for creating unique tools for solving specific problems of theranostics and treatment of diseases.
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