A package for the brain

Yuri Drize, "Search" No. 48-2015

"Search" continues a series of publications for the scientific session of the General Meeting of the Russian Academy of Sciences devoted to the effectiveness and safety of medicines. The next material tells about vector nanosystems of drug delivery to target cells.

Some years will pass – and doctors will fight the most dangerous diseases in an amazing, even fantastic way: they will send a nanocontainer – a ball with a diameter of about 100 nanometers containing medicine to the diseased organ, or rather to the very cell from where the disease "came from". Such an unusual method of treatment is many times superior to all current ones and, please note, practically does not give side effects. I asked one of its developers, Academician Vladimir Chehonin, head of the Department of Fundamental and Applied Neurobiology of the V.P. Serbsky Federal Medical Research Center for Psychiatry and Narcology, to tell about the promising Search method.

– 110 years ago, the idea of the so–called directional transport, sometimes called the magic bullet, was put forward by the founder of chemotherapy, Nobel Prize winner in 1908 Paul Ehrlich, the author of the discovery of biologically active molecules – antibodies, - says Vladimir Pavlovich. – With their help, he believed, it is possible to deliver drugs to the affected cell. This assumption gave impetus to the appearance of numerous works describing the specificity of certain pathological cells and the ability to distinguish them from healthy ones. Scientists and doctors recognized the new method of treatment as extremely promising, it remains only to put it into practice. 

– But there may be tens, hundreds of thousands of cells in a diseased organ. How to recognize exactly the one that doctors need?

– All normal cells have a certain appearance, but the disease forces them to synthesize pathological molecules. For example, mutations appear in a tumor cell at the genetic level, the product of which may be pathological proteins. That is, there is a noticeable, I emphasize, deviation from the norm. This was confirmed by pioneering research by Soviet scientists: Academician Harry Abelev and Professor Yuri Tatarinov. They were the first to study the phenomenon of synthesis by tumor cells of a specific protein, uncharacteristic for a healthy organism. It was in 1963.

But as soon as scientists understood how to "sew the necessary medicine to the vehicle" (they may be antibodies or some other molecules), another problem arose: when the "package" is formed, the structure of the drug changes dramatically. In fact, a new medicine is being formed, and it is no longer possible to vouch for its medicinal properties. Nothing terrible, of course, will happen, we are sure of it, but we need to check, and very carefully, spending a lot of time on it. And all because we violated the structure of the drug, putting it in unusual conditions, so we must be responsible. To avoid complications, the researchers went the other way: they created special nanocontainers, put drugs in them and "sewed" special delivery molecules to them. Nanoparticles of iron, gold, polymer nanogels, micelles or liposomes can be used as nanocontainers. You won't see them under a conventional microscope: the dimensions of the "parcel" are from 15 to 200 nanometers.

– Is it difficult to make a nanocontainer? 

– No, it's simple enough. For this purpose, fat bubbles are used. A medicine or diagnostic drug is injected into their cavity. Special chemicals bind the nanocontainer and vector molecules (deliverers). Nanocontainer structures appeared in the 60-70s of the last century, and the credit for this also belongs to our scientist, Professor Vladimir Torchilin, who is now working in America. He was the first to use fat emulsions to create nanocontainers.

But our problems didn't end there. It is necessary to introduce the "parcel" into the bloodstream, and it will be doomed to death: the protective blood cells will literally tear it apart. The "package" had to be protected – covered with something resembling armor, for which long polymer molecules were used. The design turned out to be quite complicated, and some of our colleagues doubted that the nanocontainers really reach the diseased target cells and get directly into them. It was possible to convince them only with the help of confocal microscopy with ultra-high resolution. 

So gradually the delivery technology was developed, the safety of nanocontainers was achieved. This immediately made the clinical development of a new breakthrough method real. I would like to note the work of Professor Alexander Kabanov, who heads a center in the USA that develops these technologies. We have known him for 30 years and are working closely together today. 

– The question is probably naive, but how can a drug whose dimensions are measured in nanometers defeat a serious illness?

– From 50 to 100 sufficiently large drug molecules are placed in the nanocontainer. And due to an accurate hit into the target cell, the concentration of the medicinal substance is reduced by tens, even hundreds of times. With this method of treatment, I emphasize this, there are practically no toxic side effects or they decrease hundreds of times. Without exaggeration, the development of a new method will make a revolution in pharmacology. 

– Does the brain react to the package – after all, they didn't ask for permission?

– We introduce such a minuscule amount of substance that the body does not seem to notice it. But the conversation about the brain is special. My co–authors – academicians Alexander Nikolaevich Konovalov and Alexander Alexandrovich Potapov - many years ago proposed to create a system for transporting drugs for the treatment of malignant brain tumors. The task is the most difficult. The statistics of such diseases are terrifying: almost all 100% of patients die. The tumor, we can say, takes root – they are not so easy to find and neutralize. Therefore, operations are not always saved, especially since relapses are possible. And our technologies today are actually the only way to fight tumors. But the difficulty is that the brain is separated from the rest of the body by a kind of barrier that reliably protects it from the invasion of foreign structures, including drugs. And it had to be overcome. It turned out to be extremely difficult to do this, it was necessary to find a non-standard approach. Alexander Kabanov helped develop it by conducting fundamental research, and today, although not very intensively, the "parcels" still pass through the protection, and for the first time we have the opportunity to deliver drugs directly to the target cells of the brain. 

– Have you already been tested?

– Yes, so far only preclinical, we conducted them together with clinicians and were very satisfied: 20% of rats got rid of brain tumors. To begin with, the result is simply wonderful! But in the transition to clinical trials, it is necessary to find an answer to a number of far from simple questions, including ethical ones: what is allowed for us to do for the development of such technologies, and what is not. 

– It is clear that the whole developed world is working in this direction. Who's ahead?

– Similar technologies are already being used abroad, five or six drugs that are at the stage of limited preclinical trials have appeared there. For example, for the treatment of liver and small intestine cancer, and other serious diseases. However, the treatment of brain tumors lends itself to foreign colleagues with great difficulty – and here we are "keeping up". We just need to move as quickly as possible to the next stage – albeit limited, but clinical trials. There is great interest in our work both in Russia and abroad. We publish in prestigious foreign journals such as "Nanomedicine", "Drug Delivery", "Molecular Pharmacology", etc.

– A prosaic question. The method is wonderful, but expensive, requiring the highest qualification of clinic staff. Will it find wide application?

– I am absolutely sure that as soon as the technology passes clinical trials, dozens of pharmaceutical companies will take up its development. And it's not as difficult as it seems. A method for obtaining inexpensive vector molecules has already been developed, and the creation of nanocontainers themselves, as I have already said, is not so difficult. So technical issues can be solved quite simply. Yes, this method will be expensive, but effective. The country has both personnel and the necessary equipment. I am sure that almost all neurosurgical clinics will be able to implement these technologies.

– When do you think they will start working?

– In the next two or three years, it is necessary to solve the issue of clinical trials. We are ready for this, and so are the clinicians. We are united by a good goal: to save at least 20% of patients – and this is already a colossal achievement. The method will undoubtedly become widespread in the diagnosis of the most complex diseases. Contrasting drugs appear that allow you to literally "see" brain tumors. It is enough to introduce a special chemical element into the container instead of the medicine, and it will make the image of the tumor more contrasting, which is very important for tomography.

– Is it possible to expand the scope of your method?

- Yes. The universal vector delivery method can be used not only for the transportation of diagnostic drugs and medicines, but also, for example, for the delivery of genetic material to target cells, which is important in the treatment of a variety of genetic diseases and mutations. The "right" DNA will be integrated into the current gene system and, hitting the target, will begin to correct the "mistakes of nature" and acquired disorders. Such work is already actively underway in the world. 

I would compare the method of drug delivery using nanocontainers... with the launch of the rocket. It does not matter what kind of "filling" it has, it is important that the "parcel" gets to the addressee at the right place and time.

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02.12.2015