How to cast a "magic bullet"?
Targeted drug delivery
Maxim Abakumov, Candidate of Chemical Sciences, Head of the Laboratory "Biomedical Nanomaterials" of NUST MISIS
Post -science
In our age, it is difficult to find a person who has never taken medication. If you are attentive to health, you probably found a piece of paper with full information about the drug in the box and saw an item with contraindications or side effects. In some medicines they do not cause horror and fear, in other drugs you can find quite terrible consequences, such as anaphylactic shock, brain swelling or coma.
The drugs that we take achieve their goal and work. But the percentage of the drug that reaches the target is very small – on average about 1%. And all the remaining mass is distributed throughout our body and does not benefit, which puts an additional burden on the body and causes non-specific effects. This is one of the modern problems of medical chemistry and pharmacology – to make drugs more effective, lower their dose and eliminate side effects.
At the beginning of the XX century, professor and pharmacologist Paul Ehrlich formulated a concept called "magic bullet": the ideal medicine would hit exactly the target, exactly where it should be, and would not affect any other tissues of the body. This is an idealized concept. And it is still not possible to achieve it to the extent that Ehrlich saw it. But a huge number of attempts are now being made to improve these drug indicators. And this has become especially achievable with the development of advances in biotechnology, genetic engineering, combinatorial chemistry.
Today, the main approach in the implementation of this strategy can be called targeted drug delivery. This direction is to create smart molecules that by themselves are able to find a target in our body. They are created by scientists in such a way that, when ingested, they are not just randomly distributed throughout the body, but find their own target and interact only with it. Such medications, firstly, can significantly reduce side effects. Secondly, if you inject a drug and it all reaches the goal, then the amount of the drug itself is greatly reduced, and this allows you to reduce the cost of the drug.
If you look at the current state of the market and the problems, you can conditionally divide these drugs into several main classes. The first and largest class that has appeared is monoclonal antibodies, that is, molecules that are normally found in our body. They are part of the immune system, and their main task is to interact with molecules with high specificity.
With the creation in the mid-1980s of the technology for producing monoclonal antibodies, it was possible to significantly expand and obtain completely new classes of these molecules. Humanity has learned to obtain antibodies to certain specified molecules that can be obtained earlier in the research process. These may be some specific markers - for example, oncological diseases, there may be some autoimmune diseases. Antibodies can be isolated artificially and then injected into a sick patient. Since these are antibodies that are in our body, they do not cause side effects, they are the same as in normal people. When injected into the body, they circulate through the bloodstream for a long time and bind to their targets.
One example of such drugs is a drug called bevacizumab, or avastin. This is a fairly well-known drug that is used for the treatment of tumor diseases. When a tumor develops, it actively grows and recruits a large amount of nutrients that are delivered by blood vessels. In order to provide itself with nutrition, the tumor produces growth factors, in particular vascular endothelial growth factor, which actively produces the growth of these new vessels and helps the tumor develop. Therapeutic antibodies bind this drug, mask it. Other cells – vascular cells that need to grow, do not receive a signal to develop. They do not allow the vessels to germinate. And the tumor "suffocates" from lack of oxygen and nutrients.
In addition to monoclonal antibodies, there are low-molecular, artificially constructed or synthesized molecules. These are substances that can be analogues of metabolites in the body, or they can be artificial for our body. They are united by the ability to bind highly specifically to certain areas of receptors or cell surfaces.
The most successful and well–known low molecular weight ligand is called PSMA - ligand to prostate-specific membrane antigen. It is a small molecule consisting of several amino acid residues. It has shown high specificity in binding to the membranes of prostate cancer cells and is used for diagnosis. This molecule can be bound to a dye that glows at a certain wavelength and injected into the patient's bloodstream. During surgery or when examined in the light of a lamp, cells that have caught a highly specific ligand will glow. The doctor will be able to see exactly where the foci of the malignant disease are located and prescribe the necessary treatment.
The molecule may be associated with radiopharmaceuticals. These are radioactive isotopes with radiation toxic to cells. When they are introduced into the composition of this molecule – chemical binding – a hybrid system is obtained in which the PSMA ligand serves as something like a postman or delivery. That is, it delivers the poisonous radiopharmaceutical only to the cells where it should be. This is very important because, for example, prostate cancer often metastasizes. And if the primary focus is relatively easy to remove at an early stage, then in the later stages metastasis spreads throughout the body: bones, lungs, liver, and it is almost impossible to remove these metastases. But since these are still prostate cancer cells that carry a signal, then with intravenous administration, the ligand will spread throughout the body, automatically find metastases and remove them. You can find really impressive pictures where you can see how metastasis completely disappears after therapy, and the person remains completely clean and healthy.
The third direction in targeted drug delivery is the use of nanostructured particles, nanoparticles or nanocontainers. The point is that the drug is delivered not in the form of a free molecule, but inside a container that is designed in a certain way and has a large capacity. It carries tens, hundreds, thousands of drug molecules. The advantage of binding it to an addressable ligand is that you significantly reduce the amount of addressable ligand. That is, in the case of the PSMA ligand, you had one drug particle, one radioisotope per molecule. If you connect it to a nanocontainer, then there will be tens, hundreds, thousands of molecules inside it. So you can significantly reduce the amount of targeted ligand, while delivering a much larger amount of substance.
Of course, the method of using nanocontainers has its advantages, but there are also disadvantages. They are special for each class. If we are talking about antibodies, then you can get a specific molecule to almost any target. This is not a problem, but the cost of antibodies is quite high. Thus, the course of treatment with avastin significantly exceeds the average prices for drugs.
If we talk about low-molecular substances, then the problem is precisely in the creation of a molecule. Finding a highly effective specific molecule that is easy to synthesize is to some extent a matter of luck. Not all molecules can be selected for all purposes, they are not so easy to obtain, and their use is limited. It is not possible to find such an effective molecule for all types of cancers or other diseases.
By itself, the targeted delivery system based on nanoparticles is quite difficult to create, and the path from the idea to the clinic takes decades. If you add an addressable molecule there, it complicates the creation of this system. This means that you need to conduct new tests. And it also takes time and requires some strength.
If we talk about the prospects, it seems to me that this direction will develop actively. I think the breakthrough is in what is called Big Data, bioinformatics. Large amounts of data on the structures of molecules, on the proteome of tumors or diseases, on more complex relationships between proteins, gene structures allow us to identify patterns and fundamental differences between healthy tissue and a pathological focus. Improving the methods of three-dimensional analysis and computer modeling will allow you to select a molecule and give them a place to work.
The array of existing data, it seems to me, is still not enough, despite the huge developing field of bioinformatics. But, of course, a breakthrough will be made. Perhaps it will be quantum computing, when you can choose a target, download a program and get a three-dimensional structure with which you will come to a chemical laboratory, order it, and you will be given a powder that will work. It sounds like science fiction, but we're talking about perspective.
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