The $140 billion market

How nanomaterials for targeted drug delivery are developing

Mstislav Makeev, Forbes, 22.05.2017

Currently, it is the targeted delivery of medicines from all directions of nanomedicine that is developing especially rapidly. It is these technologies that can allow drugs to work as a "magic bullet", as chemists and biologists expected a hundred years ago.

At the beginning of the XXI century, a new direction in science and technology emerged – nanobiotechnology. She studies the biological use of nanotechnology as a link between living and inanimate nature. Medical applications of nanobiotechnology have led to the emergence of a new industry – nanomedicine. According to the definition of R. Freitas: "Nanomedicine is the correction, construction and control of human biological systems at the molecular level using developed nanodevices and nanostructures."

An important direction in the development of nanomedicine is targeted drug delivery using nanoparticles. In the near future, it will allow for the uninterrupted delivery of drugs inside the body in the required direction without loss of the transported substance.

Targeted delivery excites the minds of Russian scientists as well. One of the directions defined in the Strategy of Scientific and Technological Development of the Russian Federation (approved by Decree of the President of the Russian Federation dated December 1, 2016 No. 642 "On the Strategy of Scientific and Technological Development of the Russian Federation") is the transition to personalized medicine, high-tech healthcare and health-saving technologies, including through the rational use of medicines (primarily total antibacterial).

This speaks in favor of the fact that in Russia in the coming years, much attention will be paid to nanomedicine and, in particular, targeted drug delivery, and, accordingly, large amounts of funding will be allocated for this.

More than a hundred years ago, chemist and biologist Paul Ehrlich introduced the concept of a "magic bullet". That's how he called his dream – a drug that finds and kills the causative agent of the disease itself, without harming the patient. According to legend, it happened like this. Ehrlich listened to Karl Maria von Weber's opera The Free Shooter. The plot there is tied around magic bullets, which always hit the target and which can only be obtained by selling your soul to the devil. It was then that Ehrlich came up with the idea of a drug that could independently find the source of the disease or the focus of the disease and hit them without affecting healthy organs and tissues of the body.

Ehrlich bequeathed his dream to the next generations of scientists. And for many generations they have been struggling to create such a medicine. Ehrlich himself was the first to get such a medicine, in 1909 he created the famous "drug 606" – salvarsan, a cure for syphilis. The rebirth of the idea has occurred in recent years, which is primarily due to the development of nanotechnology.

The fact is that such a "magic bullet" must be very small – have nanoscale dimensions – in order to freely "fly" through the smallest capillaries of the circulatory system. To fulfill its mission, the "magic bullet" must overcome various barriers (walls of the gastrointestinal tract, capillary walls, blood-brain barrier between blood and brain cells, cell membranes and membranes of cellular organelles), deliver the drug into the cell, unload it there, and then self-destruct, disintegrating into non-toxic components, and then leave the cell and the organism. This is ideal. A real system should contain at least the following components: firstly, a nanoscale container for the drug itself; secondly, a shell that prevents nanoparticles from sticking together, providing them with protection from environmental influences, as well as biocompatibility - when the cells of the body's immune system do not perceive these objects as an alien; thirdly, recognition system, "molecular address".

Almost ideal for the implementation of the "magic bullet" is the use of nanoparticles. They have a number of unique features. First of all, it is a developed specific surface area (a large ratio of the surface area to the volume or mass of the particle). This is due to the high adsorption capacity of nanoparticles. Secondly, these are the quantum properties of nanoparticles, due to which they penetrate through cell membranes or the blood-brain barrier, which are an insurmountable barrier to smaller and relatively simpler molecules of medicinal substances. And they do not just penetrate, but also drag these very molecules after them.

Various biocompatible nanomaterials can be used as carriers in drug delivery systems. For example, these can be liposomes, polymers, micelles, dendrimers, silicon or carbon materials, viral, magnetic and composite nanoparticles.

Active substances may be contained in their cavities. For example, liposomes are hollow bubbles formed by phospholipid molecules, micelles are hollow spheres of silicon dioxide or organic polymer, etc., inside which an antibiotic is hidden. Also, the drug can be attached to the surface of a solid nanoparticle, for example, gold, diamond, graphite, fullerene, carbon nanotube, etc. Another option is when the drug itself is a nanoparticle, for example, magnetic iron oxide or the same gold for hyperthermia of cancerous tumors.

In addition, the surface of the particles is modified so that they overcome natural barriers, such as cell membranes, like "Trojan horses", and with the help of biosensors (for example, antibodies) recognize individual cells and tissues, attach to them, and release active substances to the target without damaging the surrounding tissues.

The figure below shows a liposome that can carry various active substances (drugs, DNA, RNA) and ligands (for example, antibodies, proteins, peptides, carbohydrates, etc.), providing directed transport of liposomes to the target cell, and have different surface configurations.

Special attention is paid to the use of such nanomaterials in oncology. They are suitable for this role because they have small size, biocompatibility, resistance to the effects of tissues and body media and at the same time biodegradability, hydrophobic and hydrophilic properties, low toxicity and immunogenicity.

The surface of nanoscale carriers is supplied with antibodies that either react to a lower pH of the tumor compared to the surrounding tissue, or directly recognize tumor cells, penetrate them and secrete active substances directly to their target for a relatively long period of time. One of the specific variants of this method is magnetic targeting of drugs. With passive magnetic targeting, nanoscale metal oxides (iron and gold particles) bind to cytostatics (antitumor drugs that disrupt the growth, development and division mechanisms of all cells of the body, including malignant ones) and are injected into the body. At the same time, they circulate in it and are slightly deposited in the organs of the reticuloendothelial system (spleen, lymph nodes, bone marrow, etc.).

With active magnetic targeting, iron oxide Fe3O4 particles associated with cytostatics are directed to the tumor tissue using magnetic fields and concentrated there. The advantages of this method over traditional chemotherapy, which affects the entire body and in which only a small part of the active substances reaches the tumor tissue, have been demonstrated in animal studies, as well as when used in humans.

In simple words, the release of cytostatics exclusively into the tumor tissue significantly reduces the number of side effects and at the same time it is possible to increase the dose of the active substance into the affected tissue. Thus, one of the key problems of the treatment of malignant neoplasms is solved – ensuring the delivery of antitumor drugs directly into the tumor tissue of the patient to increase the therapeutic activity of drugs and minimize non-specific side effects.

At the moment, a number of drugs targeted for cancer treatment (chemotherapy) are already at the stage of clinical trials. These are MM-302 for the treatment of breast cancer, BIND‑014 for the treatment of lung cancer and prostate cancer, MBP-426 for the treatment of gastric, esophageal and gastro-esophageal adenocarcinoma, Anti-EGFR immunoliposomes filled with doxorubicin for the treatment of solid tumors, CPX‑351 or Vyxeos for the treatment of acute myeloid leukemia and CPX‑1 for the treatment of advanced colorectal cancer.

Recent results of phase III clinical trials of liposomal cytarabine and daunorubicin (Vyxeos, also known as CPX-351) have shown that, compared with the standard treatment regimen for patients with high-risk acute myeloid leukemia, overall survival increases from 5.95 to 9.56 months.

Another option for cancer nanotherapy is the use of particles that accumulate in the tumor tissue, and then are heated by hyperthermia or thermal ablation. Due to this, only the tumor tissue is weakened and destroyed, and the toxicity of chemotherapeutic agents is also reduced. In the treatment of brain tumors, ferrofluids are injected directly into the tumor and heated there using alternating magnetic fields. Roughly speaking, the "magic bullet" delivers a real bomb with napalm directly into the tumor, and under external influence, this bomb explodes, destroying the enemy – that is, the tumor. Clinical studies have shown that this method can be safely used in humans and that promising results can be achieved in combination with radiation therapy.

Currently, it is the targeted delivery of medicines from all directions of nanomedicine that is developing especially rapidly. There are already results that can contribute to the fact that all medications will soon be delivered to the affected areas of the body in this way with the least side effects for the body.

In the next decade, nanotechnology and nanobiotechnology will become increasingly important in medicine and medical technology. This trend is already clearly defined at the present time: in the first half of this decade (2010-2014), 3,438 publications with the keyword "nanomedicine" appeared in the Web of Knowledge (Core Collection) database (as opposed to 857 entries during the previous decade 2000-2009). The total number of works related to "nanoparticles" at PubMed doubled every 2 years between 2000 and 2014.

Nanomedicine can significantly improve the quality of life of patients. At the same time, new opportunities involve risks and raise sociological and ethical issues that will need to be addressed. Nevertheless, nanotechnology has the potential to change medicine in the coming decades.

The volume of the global nanomedicine market in 2016 was estimated at $138.8 billion, while at least $3.8 billion is spent annually on research and development in the field of nanotechnology. In recent years, global funding for new nanotechnology has grown by 45% per year, with product sales exceeding $1 trillion in 2013. According to forecasts, by 2019, the global nanomedicine market will reach a value of $ 177.6 billion, and by 2024 – $ 344.0 billion. As the nanomedicine industry continues its growth, it is expected to have a significant impact on the economy.

Portal "Eternal youth" http://vechnayamolodost.ru  22.05.2017