RUDN University bioengineers have created nanocontainers for targeted drug delivery
One of the main problems of pharmaceuticals are their side effects, which often occur because the active substance of drugs enters healthy organs. That is why, for example, chemotherapy is so hard for patients in the treatment of cancer: toxic drugs affect not only tumor cells, but also the entire body. Targeted drug delivery systems solve this problem. Many potential “carriers” have been proposed in recent years: microcapsules with a shell of polyelectrolytes, artificial liposomes of micro- and nanoscale, protein nanoparticles. Several dozen drugs packed in such containers are already used in practice or are undergoing clinical trials.
However, there are still many problems that prevent the widespread use of “smart” carriers. One of them is the dependence of the biodistribution of drugs in tissues on the size of containers. The smaller the size, the greater the likelihood that the drug will reach the diseased organ, and the less the dose of the drug is needed and the less the toxic effect is. Another problem is the lack of information about toxicity, effects on the body and distribution in living tissues. Both of these problems have been successfully solved by the RUDN University biochemists in collaboration with colleagues from Russia and the UK.
Researcher of the Surface Engineering Laboratory of RUDN University Olga Sindeeva and her co-authors created submicron magnetic-sensitive containers –particles of 400-600 nanometers, with a shell of several layers of bovine serum albumin (BSA) with a fluorescent tag Cy7™, and tannic acid (TA).
The novelty of the study is in the method of obtaining containers, in which nanoparticles of magnetite (MNPs), mixed iron oxide (II, III) were first adsorbed on the surface of porous granules of calcium carbonate, which were then coated sequentially with several layers of BSA-Cy7 and TA. Then, сalcium carbonate was washed out of the containers with an aqueous solution with a chelating agent.
“With this method, it was possible to double the amount of magnetite in containers compared to what is obtained by adsorption and co-deposition methods. Thus, it is possible to increase the magnetic moment of nanocontainers and increase the speed of their movement in the vascular system”, Olga Sindeeva explained.
RUDN University bioengineers expect the submicron size of the containers to increase the bioavailability of the drug that is loaded into the MNPs (BSA-Cy7-TA) container.
Preliminary experiments on two cell lines, HeLa and fibroblasts, have shown that the containers do not affect cell viability and can be used in vivo.
The drug-free containers were then tested on live BALB/c mice of both sexes weighing about 20 grams, 10 individuals per group. Containers in the form of a suspension in saline solution were injected into the tail vein of anesthetized mice. A suspension of magnetite-free containers (BSA-Cy7-TA) was used as a control. Then, one of the hind legs of the mice was exposed to a magnetic field for an hour, and the other was left free for comparison. The distribution of nanocontainers in the tissues of living mice was observed using magnetic resonance imaging (MRI) and fluorescent tomography. Magnetometric analysis and histological examination of post mortem mice tissues were also performed one hour after removal of the magnet.
RUDN University biologists have shown that in the peripheral vessels of the hind limbs at rest at a low blood flow rate, MNPs(BSA-Cy7-TA) particles move in the first hour after intravenous injection in the direction of the limb to which the magnet is attached.
MRI showed that the concentration of magnetite in the muscle near the magnet passes through the maximum. The magnetite amount at this time is 70 percent higher than in the free limb. Then, the magnetite signal drops to background values.
According to the results of histological studies and magnetometry, researchers found that MNPs (BSA-Cy7-TA) concentrated mainly in the lungs, and, to a lesser degree, in the liver and spleen, moreover their concentration in the lungs was 4-5 times higher. A small amount of the carrier was also found in other internal organs and muscles, but concentration was significantly lower than in the lungs. Thus, biochemists concluded that the distribution of intravenous containers depends on the blood supply to the organs, that is, on the speed of blood flow, but is sensitive to the localization of the magnetic field.
Particular attention was paid to the study of the toxicity of intravenous containers and their effects on the body. Preliminary tests have shown that in vitro in plasma or blood a significant part of the containers is subjected to destruction during the day. The results of studies suggest that the containers have time to achieve the goal with intravenous injection. Then, by changing the fluorescence signal, it can be seen that the carrier particles gradually degrade and are excreted from the body. The particles are non-toxic and hemocompatible, their size allows them to penetrate various tissues of the body, but in working doses, they do not harm the respiratory and circulatory system, kidneys and liver functions. The activation of the complement system that is necessary for the biodegradation of the protein membrane of the containers does not affect the level of leukocytes, and therefore does not lead to a noticeable systematic inflammation.
Thus, the RUDN University researchers were able to get containers with a high amount of magnetite and effectively manage their distribution in the body using a magnetic field.
In the future, the project participants intend to create “smart” nanocapsules that can bring the drug to the diseased organ and "open up" only there to release the active substance. This method of drug delivery would help to avoid the side effects of treatment. In addition, the problem of treating patients with a whole bunch of diseases, as well as children or elderly people with poor health can be solved, when the consulting physician is forced to refuse to prescribe the necessary therapy because of the risk of declining the patient's condition.
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