06 April 2016

Nanotechnology against cancer

Irina Tereshkova, Rosnauka

Russian scientists have managed to develop a unique method of cancer diagnosis – a magnetite-based nano-device that will help detect the disease at an early stage using MRI and immediately begin effective treatment. How the innovative drug works and when it will be possible not only to diagnose, but also to treat cancer,"Rosnauka.ru " the project manager, head of the NUST MISIS laboratory Alexander Mazhuga told.


Dossier. Alexander Georgievich Mazhuga
Doctor of Chemical Sciences. Professor, Deputy Dean of the Faculty of Chemistry of Lomonosov Moscow State University, Head of the Laboratory "Biomedical Nanomaterials" at NUST MISIS.
Research interests: synthesis of nanohybrid functional materials, bioorganic chemistry, medical chemistry, nanochemistry, development of new approaches to the synthesis and research of biologically active substances.

– Alexander Georgievich, what is the fundamental difference between the diagnosis of cancer by MRI using a new nano-device from the traditionally used methods?

First of all, it is worth telling about what methods of diagnosis of oncopathology exist – ultrasound diagnostics, computed tomography, MRI. Half of these methods are MRI, and in about 70% of cases magnetic resonance imaging is used without contrast media. However, if we are talking about brain cancer or spinal cord lesions, other pathologies, they cannot be detected without using a contrast agent that allows better visualization of the lesion and determine the size of the tumor. To do this, gadolinium-based drugs and magnetic particles are used as contrast agents all over the world.

Gadolinium–based drugs have two disadvantages: firstly, high toxicity, because gadolinium is a heavy metal, and secondly, the elimination period from the body is too fast. Therefore, MRI should be performed very quickly – in the period from 5 to 10 minutes, while the drug has not yet been removed from the patient's body, which is not always possible.

The second type of contrast agents is magnetic particles, this is the direction that our laboratory is developing. In clinical practice, there were 5 contrast agents based on magnetic particles for the diagnosis of liver cancer. They were captured by liver cells or macrophages circulating in human blood and sent directly to the liver. The contrast effect was very impressive, but unfortunately, due to the large size - more than 100 nanometers, the contrast agent had a high toxicity. 3 out of 5 similar drugs had to be withdrawn from clinical practice. Now 2 of them are used – for the gastrointestinal tract and sentinel lymph nodes.

In our opinion, the problem was not only in the large size, but also in the fact that the technology itself for producing magnetic particles was incorrect – the aggregates were obtained in an uncontrolled manner.

Magnetic particles can be made small, for example, we manage to obtain materials with a particle size of 10 nanometers. However, if the synthesis technology is incorrect, these magnetic particles will form an aggregate of too large size, which threatens, for example, to block blood vessels.

When we started implementing this project, we were looking for an answer to the question of how to make particles stable and non-alien to our body. To do this, a team of scientists from NUST MISIS, the Pirogov RNIMU and Lomonosov Moscow State University synthesized particles coated with human serum albumin, which is one of the blood proteins that is not foreign to our body. With the help of chemical synthesis, we have achieved that the particles have a size of 40 to 60 nanometers and are absolutely stable.

How particles behave inside the animal body was studied using a rat model – glioblastoma multiforme, this is brain cancer.

The real discovery was the proof that particles accumulate not only in liver cells, but also in the brain. At the same time, unlike gadolinium-based drugs, they are inside the body not for a few minutes, but for about an hour, after which they are excreted through the liver.

We will be able to talk about this with confidence after appropriate research. Preclinical trials of the innovative nanopreparation have now begun, the purpose of which is to confirm its safety and effectiveness. It remains to be checked whether the drug will adversely affect the immune system, cause allergies and even affect the condition of the next generation. We plan to start clinical trials in 2018.

– Why is it so important that magnetic particles have a certain size and are stable?

(Timur Nizamov, Engineer of the first category of the laboratory "Biomedical Nanomaterials" of NUST MISIS answers)

This is very important, otherwise, they can cause various side effects – thrombosis, immune response of the body and other negative consequences. The correct choice of polymer helps to ensure stability. We can chemically modify it or load a smaller amount of medicine, which also affects the stability properties.

In order for the nanoparticle to have certain magnetic properties and behave in the way we need, we synthesize magnetite or other iron oxides that demonstrate superparamagnetism or pheremagnetism, depending on the tasks. At the same time, we solve another problem – we cover magnetite with polymer stabilizers. In a magnetic field, a particle can heat up or rotate and thereby perform the task assigned to it.

– An innovative drug can be used to diagnose brain tumors, what studies should be conducted in order to use it to detect other types of cancer?

(A.M.)In the project of preclinical trials, it is also planned to test the drug for the diagnosis of breast cancer. If it is confirmed that our technology works correctly, it will be possible to diagnose different types of oncopathology with its help – magnetic particles will penetrate into any affected focus.

– And how do magnetic particles "choose" a target for themselves and accumulate in tumor cells?

Everything is simple. The walls of our vessels are lined with endothelium, which has certain pores. In vessels lining healthy tissue, the pores do not exceed 10 nanometers. The pores in the vessels feeding the malignant tumor increase by 60 times. And it's also easy to explain. Tumor cells actively multiply, they require oxygen, nutrients and vitamins in large quantities. Therefore, the tumor grows an extensive network of vessels around itself and the pores increase tenfold so that it is easier for nutrients to penetrate through them. That is, magnetic particles cannot fall into healthy tissue, and they quietly accumulate in tumors.

– What needs to be done in order to use the technology in the future not only for diagnosis, but also for the treatment of oncological diseases?

We are actively working on this now. In order to use magnetic particles not only to diagnose, but also to treat cancer, you need to load medicine into them. We use the clinically approved drug doxorubicin, intended for chemotherapy. Doxorubicin is added to the shell into which magnetic particles are sewn, whose task is to kill malignant cells.

In order for this technique to be used in cancer therapy, it is necessary to conduct a lot of preclinical tests on cells, choose the right concentration, it is very important to properly synthesize so that the particles are stable, the optimal dose of the drug is loaded.

An important task is to ensure that the medicine flows from the surface of the particles at a certain time and in a strictly defined place under the influence of external factors. To do this, a magnetic field is used: it turns on, and the particles begin to flow out.

– You plan to conduct clinical trials in 2018. And what forecasts can be made already now?

It's no secret that scientists don't like to guess. So far, so good. We have selected the optimal dose of the drug – 5 mg per kg of weight. It is possible to diagnose a tumor almost from the moment of its origin. Now, as part of preclinical tests, a good result has already been obtained: the diagnostic window has been expanded, with the help of a contrast agent, a malignant neoplasm can be observed for 2 hours, not 5-15 minutes. This time is already enough for the shell with magnetic particles to unload a sufficient amount of medicine.

– How was such an idea born to diagnose cancer with the help of magnetite nanoparticles?

It is a product of intellectual work of the collaboration of NUST MISIS together with Lomonosov Moscow State University and N.I. Pirogov RNIMU. Initially, the direction was developed at Moscow State University, where there was a project dedicated to the synthesis of various nanomaterials. We began to cooperate with the N.I. Pirogov RNIMU, where the main specialists in brain tumors in our country work. They provided a model of the brain, so it was decided to develop a diagnosis of this particular type of oncopathology. It is important to correctly characterize the magnetic properties, now we have chemists, biologists, physicists and doctors working in one team.

New drugs, old traditions

The work was built on the path that had already been laid before us. Back in the Soviet Union, they tried to diagnose and treat cancer with the help of magnetic particles loaded with medicine. The created drugs were studied on sheep, but it never reached clinical trials on humans. The use of large magnetic particles entailed a lot of side effects. For example, a cell heated by a magnetic field to 42-44 degrees Celsius died and poisoned the entire body with the products of its decomposition.

The advent of nanotechnology has breathed new life into this technique.

- Will the new drug be expensive?

Absolutely not, because it is based on ordinary iron oxide. The only expensive component is human serum albumin, which covers magnetite. But I can say with confidence that if everything goes well, the new medicine will be quite affordable for Russians. In addition, the drug will have practically no contraindications, except for diseases associated with an increased iron content, since magnetite is an iron oxide.

– What other research in the field of cancer diagnosis and therapy is carried out in your laboratory?

Our laboratory "Biomedical Nanomaterials", formed at NUST MISIS, is still very young, it was established in 2014. At the level of research work, we are now also studying the effect of a low-frequency magnetic field on biochemical reactions inside cells with magnetic particles. This is a non-invasive way of influencing malignant cells. There is nothing like this in the world yet.

NUST MISIS is also developing a method of photodynamic therapy, when tumor cells are loaded with special substances, after which they are shone with a laser with a certain wavelength, resulting in the formation of reactive oxygen species that literally kill the tumor from the inside. In the future, it will be able to replace surgical intervention, which is fraught with the fact that the tumor releases a large number of metastases into the bloodstream during the operation and the patient has to take special drugs to kill them in the blood and prevent them from "sticking" to the walls of blood vessels.

– Cancer is spreading all over the world with a speed that causes great anxiety and at the same time is getting much younger. Are there any precedents for a complete cure today?

Yes, there are such cases and they are not so rare anymore. Every year new effective chemotherapeutic agents appear, if earlier there were only 30-40 such drugs in the arsenal of oncologists, today their number has already exceeded 300. The future belongs to a combination of methods: if previously they were limited to monotherapy, now the tumor is being treated with chemotherapy and irradiated or something else.

The main thing is to identify a dangerous disease at an early stage. The earlier the diagnosis is made, the higher the chances of a cure. In this regard, the development of new diagnostic methods is of great importance.

Portal "Eternal youth" http://vechnayamolodost.ru  06.04.2016

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