07 December 2010

Returnees: Alexander Kabanov, nanomedicine specialist

Nanomedicine against cancerAbout nanomedicine – one of the most effective ways to treat complex cancers – "Newspaper.

Ru" said Alexander Kabanov, director of the first drug nanodelivery center in the USA and the only winner of the "megagrant" in chemistry. He shared his plans for organizing a laboratory in Russia, spoke about the problems of introducing innovative technologies in medicine and China's experience in reviving science.

What is nanodelivery of medicines?To begin with, what is a medicine?

We know that various chemical compounds – both small molecules and biopolymers – can have an effect on the human body. This ability is used to create drugs, including those used in the chemotherapeutic treatment of cancer. But when these molecules are introduced into the body, there are a lot of problems directly with their delivery to the point where they should work. Among such problems are high toxicity, low penetration ability to cells that need to be killed or treated. Low penetration, for example, may be due to the fact that the drug is "sprayed", penetrates non-selectively into ordinary tissues and is excreted from the body. Another reason is that the target cell may be separated by a barrier (for example, the blood–brain barrier that separates our brain from the circulatory system). Then the medicine simply cannot pass through this barrier. How to solve this problem? It would seem that you just need to change the chemical structure of the drug to make it more selective and "teach" how to overcome cellular barriers. However, it turned out to be almost impossible to do this, or very difficult. Because as soon as we begin to modify the structure of a small molecule, replace functional groups, its biological activity and all its medicinal properties also change.

Then an elegant solution was proposed – you need to take this small molecule and combine it with a polymer. These can be polymer micelles, liposomes, simply soluble polymers to which an insoluble drug molecule can be "sewn" (chemically attached) (this is how the problem of drug solubility can be solved). As a result of such inclusion of a drug molecule in the "delivery vehicle", its properties can change dramatically – the insoluble molecule becomes soluble, it does not go to the "wrong" cells, it goes to the "right" cells, and so on.

This science appeared in the 80s, the work on liposomal nanodelivery was a little earlier. It slowly evolved, moving towards understanding that a polymer carrier can be designed to perform important functions of drug delivery. These delivery systems work like a car in which we load a passenger, bring him to the right place, and drop him off at the right point. It turned out that these polymer systems are very small: their size is from 10 to 100 nanometers (nm). Hence the term "nanomedicine".

When we started doing this ourselves, we didn't know yet that this was "nanotechnology": I called my first work on polymer micelles for drug delivery "Micellar Microcontainer". And after 15 years I changed the name, I started calling it "micellar nanocontainer" – and everyone began to use this term: it correctly reflects what we are working with.

The same applies to protein delivery. Proteins are unstable – they often do not reach the place where they should function, they do not penetrate the same blood-brain barrier, they do not penetrate the target cells. And by changing not the structure of the protein itself, but its packaging in such a "spaceship", it is possible in some cases to solve the problem of its effective delivery. The same applies to DNA molecules and other biopolymers that we want to use as medicines.

We use polymers that contain soluble and insoluble parts. The insoluble parts self-assemble around the insoluble drug into so-called micelles, and soluble groups remain on the surface, which ensure the solubility of the entire particle, the so-called polymer micelle. One of the works that made me famous, done back in 1989, was that we started using such polymer micelles to deliver medicines. Medicines are often insoluble, then they are included in this polymer micelle, as in a small container.

This micelle has a distinct core and outer shell. The medicine is located in the core – it is hidden from the environment until the micelle crumbles and releases the medicine. The shell plays the role of a masking barrier that prevents the drug from interacting with the body ahead of time and provides the properties necessary for delivery, such as solubility.

The micelle is somewhat similar to a nut with a shell and a core, the size of which is 20-30 nm. This allows such particles to effectively penetrate into the cells, and already inside they crumble.

Nanodrugs today and tomorrowNanodrugs are already available on the pharmaceutical market.

So far, these are liposomal drugs, but these are really real nanodrugs. They have a size of less than 100 nm and are more effective (or less toxic – this is very important) due to the fact that the active drug is somehow packaged, in this case in a liposome. A good example of a liposomal drug is doxil, a liposomal form of doxorubicin, which is now used to treat metastatic ovarian cancer and AIDS–associated Kaposi's sarcoma. The original idea of doxil was that when doxorubicin – a very toxic drug – was packed into a liposomal container, it became much less cardiotoxic. But then it turned out that doxil also increases the effectiveness of the treatment of a number of cancers.

Now another nano-drug, the so-called abraxane, has entered the market (several years ago). This medicine is paclitaxel (its dosage form is taxol). Abraxane is a nanoform of paclitaxel, an analogue of taxol, only much better designed. There is much more drug per unit of formulation in it.

A lot of nanopreparations are being developed now. This field actually exploded about five years ago – chemists, physicists, and pharmacists began to deal with it. Enormous funding has been allocated and continues to be allocated.

In 2004, at our University in Nebraska, we founded the Center for Nanomedicine and Drug Delivery. As I understand it, it was the first academic nanomedical center in America and in the world. Since then, we have been working in two main areas: one is related to the treatment of cancer, and the other is related to the delivery of substances through the blood–brain barrier. Both tasks are very big and serious.

In the field of cancer treatment, perhaps the work in which we have shown that certain polymers dramatically increase the effectiveness of drugs against resistant cancers has gone the furthest.

Resistant cancers are cancers that mutate in response to chemotherapy. And it turns out to be impossible to treat them: they, for example, "spit out" the medicine from themselves. We found that polymers interact with resistant cancer cells, depriving them of the ability to resist the drug. By a lucky coincidence, these polymers are able to deprive cancer cells of a power source – ATP. In order to throw medicine out of themselves, resistant cells must consume a lot of energy, they need it. And these polymers, penetrating into such a cell, deprive it of the ability to produce energy. Therefore, in fact, the strength of resistant cells turned out to be their weakness.

This work led to the creation of a clinical drug, for which we have already completed the second phase of clinical trials. We have shown that such a polymer micelle, consisting of the drug doxyrubicin and polymer, has a high efficiency in treating patients with resistant cancers who had no therapeutic options left.

A newer development concerns increasing the content of the medicinal substance in the formulation. If you want to increase the effectiveness of the drug, you need to design it so that it contains as much as possible of what you directly deliver, and as little ballast, auxiliary substances as possible. It is desirable that the active substance itself is at least 10% of the weight of the drug. Rarely has anyone managed to do more using containers of polymer micelles. Recently, we have discovered certain polymer materials that allow for 1 g of the same paclitaxel to use only 1 g of polymer carrier. Due to this, we repeatedly reduce the load on the body. The fact is that in the dosage form – taxol – the dose-limiting toxicity is determined by the presence of what is required to dissolve such an insoluble substance as paclitaxel. And we use 100 times less polymer-ballast than in taxol, which is necessary for dissolution (and 10 times less than in abraxane). Therefore, our toxicity is much less, therefore, we can increase the dose and treat cancer better. In principle, such simple solutions are most effective in pharmaceutical sciences. Interestingly, we are doing this work with the support of the American National Cancer Institute together with colleagues from the Technical University of Dresden, Germany. So modern science is international and knows no borders: we have a common cause – to help people in all countries.

There are two ways to improve the drug – to reduce toxicity or increase activity. In the first case, we have increased activity – and we can kill cancer better. In the second case, we have reduced the toxicity, so we can increase the dose – and again kill cancer better.

The second area is the transport of medicines through barriers. There are organs in the human body that are separated by very serious barriers, and this is no coincidence. One of them is the blood–brain barrier, which separates our brain from the blood. It's an amazing barrier. Firstly, it is of enormous length: in every person, the length of the capillaries of the brain separated by this barrier is equal to the length of the Great Wall of China. Its area is also large, up to 20 sq. m. When we inject medicine into the blood, it begins to flow through the circulatory system and usually penetrates to the organs through the walls of blood vessels. But the vessels of the brain are unique: their cells form so-called dense joints, and these cells also contain different transport systems that "spit out" drugs back into the blood. As a result, it is very difficult for an alien body to get into the brain. Therefore, in cases of brain diseases – such as tumors, injuries, strokes, Parkinson's and Alzheimer's diseases – it turns out to be almost impossible to get the medicine to the place where it needs to be treated.

About 20 years ago, my colleague, now academician of the Russian Academy of Medical Sciences, Vladimir Pavlovich Chekhov and I began to design various polymer systems that could deceive these blood-brain barrier protection systems and penetrate into the brain. These works have progressed a lot, expanded in our center. Now, in this way, we are already able to deliver enzymes to the brain that destroy harmful oxidative particles – free radicals, which are produced in the brain in response to many degenerative processes. Degenerative processes are very often associated with the formation of free radicals, inflammation associated with their formation, and the subsequent destruction of neurons – nerve cells of the brain, neurodegeneration. This is the general pattern of development of Parkinson's disease, Alzheimer's disease, strokes, and a fairly wide range of other degenerative processes in the brain. Of course, it would be ideal to inject so-called antioxidants into the brain, but this is difficult to do due to the presence of a blood-brain barrier. And we decided to "throw" complex antioxidants through it into the brain at once – quite large molecules called enzymes.

We have created systems – polymer nanoparticles, very similar to micelles with small molecules, in which there is an inner part where a catalytically active antioxidant molecule "sits", and there is an outer part that is made of a non-toxic polymer. We called such particles nanozymes (enzymes are enzymes), they are absolutely catalytically active, they are full–fledged antioxidants. Only unlike ordinary enzyme molecules, which are very quickly excreted from the body and which are very quickly destroyed either in the blood or in the epithelial cells of the brain, these particles turn out to be stable, circulating for a long time, able to penetrate into the foci of diseases in the brain. Now we have a very large front of work going on, a very large grant specifically dedicated to this topic, $ 11 million. We create such particles and together with our colleagues – biologists and physicians – we study how they can be used to treat Parkinson's disease, Alzheimer's disease, and stroke. Now we have started a project on brain injuries, which is very relevant in the United States: American soldiers serve in Afghanistan and are subject to such injuries – they need treatment.

Work plans in RussiaI work in Russia all the time, despite the fact that I have been living in the USA for many years.

I collaborated with my father (academician Viktor Aleksandrovich Kabanov – approx. "Newspapers.Ru") – with the Department of High–molecular Compounds of the Faculty of Chemistry of Moscow State University; we worked in the field of designing polymer nanomaterials - block-ionomer complexes. Many employees of the department came to me in the USA, defended their dissertations, and returned to Russia. In addition, we cooperate with the Department of Chemical Enzymology, of which I myself am a graduate. Thanks to this cooperation, a common language and methodology has been accumulated, which is applicable to the design of delivery systems. We have learned how to make polymer blocks with important properties, in which we can include a variety of molecules – enzymes, DNA, drugs. During these 15 years of collaboration, we have created a constructor on the basis of which you can work. All this time there was an active exchange between the department and my staff. On the other hand, when we began to seriously study enzymes, in particular redox enzymes, we began to work together with MSU Professor Natalia Lvovna Klyachko, an expert on these issues. She worked with my young guys in Nebraska, they went to Moscow. Here we are talking about the creation of enzyme preparations, nanoparticles. When the question of this grant arose, we looked at what we could do together, and realized that we already had a serious groundwork. We decided to apply for a grant to create various enzyme preparations that can be used for medical purposes.

New direction – magnetic nanoparticlesWith the use of such particles, we can see where the medicine has reached, where it accumulates, and look, "without revealing" the body, using magnetic resonance imaging.

You can see how the medicine is "going", and it is very important to monitor, for example, what dose has hit the target organ. In this case, the nanocarbon combines a therapeutic and diagnostic role.

With the help of Megagrant, I want to organize a full-fledged scientific group in Russia that will work on these and other tasks on an ongoing basis. It will most likely be based at the Department of Chemical Enzymology, but the Department of High–molecular Compounds (there is a good accumulated work experience there) and other MSU employees - chemists, biologists, physicists who can make an important contribution to this work will participate in the work. We plan to expand cooperation with the State Medical University (the group of Academician of the Russian Academy of Medical Sciences Vladimir Pavlovich Chekhov), because our ultimate goal is medicines. In my opinion, a good qualified team is being formed. Last year, our University of Nebraska Medical Center signed agreements on scientific and educational exchange with both MSU and RSMU. At the same time, we will have the opportunity to use scientific resources and biological models of diseases, the instrument base of my center in America, which is certainly useful.

The problem of introducing medical developments in the USA and RussiaThe introduction of the developed drugs into medical practice is not such an easy task.

The mechanism for the introduction of scientific developments is not fully worked out in the United States, so Russia has good opportunities in this area. In order to start using the medicine in practice, it is not enough to show that it works on some models. We need to show that it works on all models, without exception, on which it should work. In addition, you need to show the complete safety of the drug.

In the USA, the issue of drug introduction is one of the most difficult today. Of course, fundamental science is well funded, but this funding, as a rule, is not aimed at creating a commercial product. There are not enough funds to conduct clinical trials of any medicine. The so-called "valley of death" is coming, which not all promising developments overcome. And only at the final stage of testing, pharmaceutical companies and large corporations are involved in financing. Because they are interested in investing in a ready-made product that will definitely work. And there is a big gap between it and promising biomedical development.

Overcoming the "valley of death" in the introduction of innovative products and developments is a colossal scientific and economic problem of the future. And how to solve it, few people understand.

We face the same problem in my center in the USA. Its total funding from grants is about $34 million (almost $8 million per year). This is a lot of money for basic research. But we cannot spend this money on the development of the final product. It's not even that it will be illegal, since the money is allocated for something else. Let's say I can convince the National Institutes of Health that I need to allocate this money. As soon as I start doing this, I will stop new developments, I will stop doing what is necessary to get this money – and I will lose it.

I need to come up with a mechanism by which I can direct a certain amount of investment to the development of the final product. And which product to choose? Just last year our center made patent applications in the USA for 30 new innovative technologies and products – this is half of all patents of our medical university. And right away I can't say which of their developments can really be commercially successful. I need to choose 10-15 best technologies, invest some small amount of money in them to conduct a so-called "proof of principles", shift them towards products, see which ones will work. Then, with this new information, choose three of them and invest serious money to overcome the "valley of death". This kind of path has begun to take shape for me, and I hope that soon there will be results of this work. We are organizing a so–called Translational Nanomedicine Institute in Omaha - and there will be a transition from an idea to a practical product.

I have changed the way I communicate with my students. Very often people engaged in basic research say: "I will work with these molecules, and then it will be put into practice somehow." As a result, a good science is created, but it is often impossible to apply it, since this possibility is not inherent in it initially. The scientific process itself does not contain a certain gene aimed at the final practical application. Therefore, in order to increase the likelihood of promising implementation of developments, the creation of such a gene in our science, I began to play – we have such "funny shelves".

I tell the guys at the very first stage of development, when we have an idea: imagine that we have already created a product. What parameters will this product have based on this idea in order to effectively treat the disease? And in general, what kind of disease will it be? Here we say: we will treat cancer. But cancer is too general, it is a huge spectrum of various diseases, and approaches to the treatment of different types of cancer are different, so we need to decide where we can really have a breakthrough and where we can have a concrete advantage over existing and currently being developed methods of treatment. There are other important issues: how we will conduct clinical trials, how the production of the product will be arranged. Being a fundamental group that has achieved a lot in understanding the processes of nano-delivery in cells, we simultaneously began to think about such practical things. We began to invite businessmen and clinical research specialists to our negotiations. And I hope that this allows us to make the right choice very early in our fundamental research. For example, not to work with a certain polymer, because it is not biocompatible, but to work with another – biocompatible. Otherwise, we will stay on developments on non-biocompatible polymer all our lives, which cannot be implemented: in order to get a new grant, we need to give previous results, and they are already fixated on the wrong path. Therefore, it seems to me that such business games play a big role in the fate of developments, in the effectiveness of the entire process.

When I was young, this field of science was very new. We were creating a new science, making discoveries – and that was enough. Now dozens of groups are engaged in polymer micelles, thousands of works have been published, this no longer distinguishes us. But the fact that we have reached the third stage of clinical trials is valuable and important. I myself was the chairman of the Grant Distribution Council of the US National Institutes of Health for several years. And I watched people bring ideas – one, another; but these are ideas that will never be realized. And I decided that, working in the field of healthcare, it is wrong not to focus my activities on creating a real medicine. Since then, we have changed the approach to our work and always focus on the final product.

I can't say that we are completely ahead of the whole planet, but we are one of the strongest bands in America that does this. That is, scientists in Russia should realize that the problem of introducing fundamental scientific developments is very serious and it has not been solved either in the USA or in Europe. Therefore, the Russians have a chance to seriously participate in solving these problems. Today we are having a conversation with practitioners and clinicians here in Russia, quite seriously, and I hope that we will be able to solve these issues together. Together we can create a good drug and try it on a serious clinical basis.

The Revival of Science: China's ExperienceRussia has a chance to succeed in science, but it is connected with the global strategic tasks that the country sets for itself.

China made its global strategic choice several decades ago. They decided that they needed to develop technology. As a result of thirty years of pouring finances and efforts into science, China "suddenly" turned into a world scientific power. Now I go to China often, every year, we have contacts and cooperation there. It happened to them, and for me this is a very important example. It shows you what to do when you find yourself in a difficult situation. And they were in a situation much worse than Russia is now. You need to understand that in the 60s they just closed all the universities.

There is not the slightest doubt that Russian, Soviet science went through a terrible crushing period of perestroika, the 90s, but China really was in a worse situation. I specifically studied the steps they took to revive science. They also had mega–grants - both larger and smaller ones for professors who temporarily came to give lectures. And now they have their own good scientists, and students who want to study, do science, because there are companies where you can apply your knowledge. If Russia follows this path, the result will be.

This is the most important question – where Russia will go. And it is much more important than the question of whether the grant recipients will finally return or not. The experience of China, which I was interested in, showed that the greatest benefit for the revival of science was played by major scientists of Chinese origin who did not return back to China. They remained American citizens or Green Card holders, they received "mega grants", but did not move to live in China permanently. However, they worked there, created a scientific environment, educated students and postgraduates. As a result, now promising young people from China, receiving a degree or work experience as a postdoc in the United States, return home, become professors there and do science in China. It is developing, despite the fact that the biggest "stars" from the United States could not be "permanently" returned; it is developing because the country has made a strategic choice. Time will tell what choice Russia will make.

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