Nanoparticles in medicine and pharmaceuticals

Medicine and pharmacy in the nanomirThe editorial staff of STRF continues to publish materials on nanotechnology.

This time we will talk about nanomedicine, which has been developing exceptionally rapidly in recent years and attracts everyone's attention not only with purely real achievements, but also with its social contribution.

Nanotechnology is an interdisciplinary field of fundamental and applied science and technology, which is a set of theoretical justification, techniques and methods used in the study, design, production and use of nanostructures, devices and systems, including targeted control and modification of the shape, size, interaction and integration of their constituent nanoscale elements (about 1-100 nm), to obtain objects with new chemical, physical, and biological properties.

In principle, nanotechnology will allow you to create absolutely any objects by manipulating individual atoms of matter. Replacing other technologies, it will not only defeat aging and diseases, but also provide humanity with fantastic material wealth. Practically, nanotechnology in medicine, pharmaceuticals and related fields solves the following main tasks today:

• Creation of solids and surfaces with modified molecular structure. In practice, this will give metals, inorganic and organic compounds, nanotubes, biologically compatible polymers (plastics) and other materials imitating the tissues of living organisms that serve as drug delivery vehicles or implants.
• Development of nanocontainer technologies for vector drug delivery.
• Synthesis of new chemical compounds by forming molecules without chemical reactions. In the next 10-20 years, this will lead to the creation of fundamentally new drugs that synthetics, pharmacists and doctors will "design" based on a specific disease, and even a specific patient.
• Development of self–replicating (self-multiplying) systems based on biosimilars - bacteria, viruses, protozoa.
• Creation of precise medical nanomanipulators and diagnostic devices.

Considering a single atom as a part, nanotechnologists develop methods for constructing materials with specified characteristics from these parts. Many companies are already able to assemble atoms and molecules into certain structures. In the future, any molecules will be assembled, like a children's constructor, since any chemically stable structure that can be described by an appropriate formula can be built.

Development of nanomedicineAccording to the canonical definition of the leading scientist in this field, R. Freitas, nanomedicine is: "tracking, correction, construction and control of human biological systems at the molecular level using developed nanodevices and nanostructures."

Thus, in medicine, the prospect of using nanotechnology lies, ultimately, in the need to change the structure of the cell at the molecular level with the help of nanorobots or other nanotechnologies

Nanomedicine has been developing at an exceptionally rapid pace in recent years and attracts everyone's attention not only with purely real achievements, but also with its social contribution. Under this term (reflecting and perspective) today, they understand the use of nanotechnology in the diagnosis, monitoring and treatment of diseases.

The development of nanomedicine is closely connected with the revolutionary achievements of genomics and proteomics, which allowed scientists to get closer to understanding the molecular foundations of diseases. Nanomedicine is developing where genomics and proteomics data are combined with the capabilities to create materials with new properties at the nanometric level.

There are 5 main areas of application of nanotechnology in medicine: delivery of active drugs, new methods and means of treatment at the nanometer level, in vivo diagnostics, in vitro diagnostics, medical implants.

The place of drugs and bioactive molecules in the nanometer worldIn 1959, the famous American theoretical physicist R. Feynman said that there is "an amazingly complex world of small forms, and someday (for example, in 2000) people will be surprised that until 1960 no one took seriously the research of this world."

Medicine and pharmacy are one of the most important practical applications of the work of nanotechnologists, because the world described above is the world of these scientific disciplines. It is these sizes that are characteristic of the main biological structures – cells, their constituent parts (organelles) and molecules. For the first time, the idea of using microscopic devices (which should include nanoparticles) in medicine was expressed by R. Feynman in his famous lecture "There is a lot of space down there". But only in recent years, Feynman's proposals have come closer to reality, although, we note, they are still far from the micro robot he proposed, capable of penetrating into the heart through the circulatory system, performing valve surgery there, as well as performing a whole set of similar procedures that amaze the imagination.

Concretizing the views expressed, today's specific tasks of nanotechnology in medicine can be divided into several groups: nanostructured materials, including surfaces with nanorelief, membranes with nanoholes; nanoparticles (including fullerenes and dendrimers); micro- and nanocapsules; nanotechnological sensors and analyzers; medical applications of scanning probe microscopes; nano tools and nanomanipulators; micro- and nanodevices varying degrees of autonomy.That is, "nano" (Greek.

– billionth part) when applied to the described objects implies that their sizes are within 10-9 ^{m, which corresponds to the levels of biological organization from atomic to subcellular. Thus, under the definition of "nanoparticles", almost any supramolecular (supramolecular) complexes fall, that is, the formation of both "small" and huge organic molecules (in modern terminology – "host") with ionic or covalently constructed molecules ("guest"). However, according to the already established tradition in the biological and medical literature, nanoparticles mean quite specific (and, above all, artificially created) molecular structures.}

These ideas today require extreme concretization.

In their review published just a few days ago (September 13, journal Nature Nanotechnology, 2009, DOI:10.1038/nnano.2009.242), researchers from the USA and France insist on revising the term "nanoparticle". They believe that there is a need for a more accurate systematization of these particles for further research and practical application in various fields. It is impossible not to be in solidarity with this point of view, although similar proposals, we note, have been heard quite often before.

Here, for example, the dimensions (Table. 1) molecules of some substances (molecules, particles) in nanometers:

Table 1.Substance

Experts express the most important idea that the attribution of new objects to nanomaterials should not be built "blindly by their size" – and based on whether this size leads to the appearance of new properties of such objects.

Despite the fact that in many countries nanomaterials have already found wide application even in cosmetics and sunscreens, in these same countries there are no clear rules regulating the safe use of nanoparticles, while it is obvious that without a clear definition of the concept of "nanoparticle", the appearance of such rules is hardly appropriate to expect at all. Although there is an opinion that any object whose size is less than 100 nm in at least one of their measurements should be considered a nanoobject, in a review published in Nature Nanotechnology, the researchers insist on introducing a stricter classification.

The authors of the review note that it is impossible to simply classify nanoparticles, "rowing them all under one comb," however, they add that not everything that is "small" – certainly represents nanomaterials. The question arises, what criteria should be used in the systematization of nanomaterials? The review examines various physico-chemical characteristics that can form the basis of the proposed new classification. For example, the size of a nanosystem affects the structure of its crystal structure, which, in turn, determines the reactivity of nanoparticles and the features of their interaction with the environment. It has been found, for example, that the properties of nanoparticles having a size of 10-30 nm differ significantly from larger formations.

What is nanotechnology in pharmaceuticals?

The industry of targeted design of new drugs, or, drag design (drug - drug, design – design, construction) is directly related to the subject of nanotechnology, since the interacting drug and target objects are molecular objects. The main concepts used in drag design are the target and the medicine. A target is a macromolecular biological structure, presumably associated with a certain function, the violation of which leads to a disease and on which it is necessary to make a certain impact. The most common targets are receptors and enzymes. A drug is a chemical compound (usually low molecular weight) that specifically interacts with the target and in one way or another modifies the cellular response created by the target. If a receptor acts as a target, then the drug will most likely be its ligand, that is, a compound that interacts in a specific way with the active site of the receptor. For example, F1-adenosine triphosphatase (F1-ATPase), which belongs to a group of enzymes that provide energy synthesis in all organisms, including the process of photosynthesis in plant cells. The diameter of the enzyme molecule is 10-12 nm.Supramolecules are associates of two or more chemical particles connected by intermolecular non–covalent bonds from fragments having geometric and chemical correspondence (complementarity).

Rearrangement of molecules leads to a variety of their combinations. Such systems are the subject of the study of supramolecular chemistry (this term was proposed by the Nobel laureate J.M. Len) and "host-guest" chemistry, and have not been studied much yet, although new materials with unique properties have already been created on their basis. For example, the use of a porous structure that plays the role of a "host" (and in other cases, this role is usually performed by an organic ligand) makes it possible to reversibly place a nanoscale "guest" for selective transport and isolation of medicinal substances. Undoubtedly, supramolecular structures are the next promising object of detailed study after nanocrystals.

Continuing these arguments, we recall that the therapeutic nanoscale effect of a targeted drug on a biomishen can be carried out only if a supramolecular nanosystem "ligand-biomishen" is formed and only during the existence of the latter.

That is, the development of targeted drugs falls under the definition of nanotechnology given above, since the mechanism of their action is based on purposeful interaction with the biomishen responsible for the disease. It is this interaction at the nanoscale, realized through a non-covalent (and coordination, including hydrogen) chemical bond between the drug (ligand) and the protein (target), which is studied during development, and determines the selectivity, effectiveness and lower toxicity of targeted drugs compared to the previous generation of drugs, that is, improves consumer properties.

Moreover, during its existence, the ligand-biomishen system is a biomachine in all its characteristics, and the result of its work will be a modification of the disease (complete or partial cure). Thus, K. P. the efficiency of the nanobiomachine depends on the strength and duration of binding of the components of the complex under discussion, which, for a permanent target, depends solely on the properties of an innovative targeted drug-ligand.

Then, formalizing the concepts, it can be argued that nanotechnology in pharmaceuticals is a set of methods and techniques of study, design, production and use, the main stages of which should be considered:

• biological screening, i.e., the search for active molecules (1-10 nm) interacting with a biomishen (protein or protein system, up to 100 nm in size).
• study of the mechanism of action (search for a biomishen and identification of the mechanism of interaction of an active molecule with it).
• computer design of potentially active compounds by calculating the interaction energies of candidate molecules and biomishen (protein) at a distance of several nanometers, that is, the calculation of possible structures and positions of molecules corresponding to the minimum energy of such interaction (dynamic modeling of which takes about 24 hours on a supercomputer with a capacity of about 200 teraflops).
• targeted control and modification of the shape, size, interaction and integration of the components of nanoscale elements ("ligand-biomishen", about 1-100 nm), which leads to an improvement or the appearance of additional operational and /or consumer characteristics and properties of the resulting products (increased efficiency, bioavailability, reduction of toxicity and side effects of the resulting innovative drugs).
• production of nanoscale finished dosage forms (liposomal forms, biodegradable polymers, nanoparticles for directional transport, etc.).
• the use of targeted innovative drugs, providing a nanoscale effect on the biomishen, which leads to a therapeutic effect.

I would like to recall the words said by Academician V. L. Ginzburg: "At the same time, biology, using mostly more and more advanced physical methods, progressed rapidly and, after deciphering the genetic code in 1953, began to develop especially rapidly. Today it is biology, especially molecular biology, that has taken the place of the leading science. One can disagree with such terminology and the essentially unimportant distribution of "places" in science. I just want to emphasize the facts, not by all physicists, especially in Russia, understood. For us, physics remains a matter of life, young and beautiful, but biology has taken the place of physics for human society and its development."

Biologically active substances delivery systemsOne of the simplest and most effective ways to deliver drug molecules to the human body is transdermal (through the skin).

Precisely because of its simplicity, there are no theoretical prohibitions on the delivery of most of the known biologically active compounds in this way, regardless of its molecular weight (size) or physico-chemical properties. Nevertheless, for the nanotransporters described below, the transdermal method is considered as one of the possible ways to transport nanoobjects. (The figure shows nanoparticles used to deliver therapeutic molecules: 1 – liposome and adenovirus; 2 – polymer nanostructure; 3 – dendrimer; 4 – carbon nanotube

Various single-component and multicomponent liposomes formed in lipid solutions have long been known. Liposomes of no more than 20-50 nm in size may be of interest for practical purposes, which are used as a means of delivering a drug to a biological target. In addition, nature itself has prepared in advance a large set of nano-carriers, for example, viruses. Adenoviruses treated in a certain way can be effectively used for vaccination through the skin. In addition to liposomes, artificial biogenic nanoparticles capable of targeted delivery also include lipid nanotubes, nanoparticles and nanoemulsions of lipid origin, some cyclic peptides, chitosans, nanoparticles from nucleic acids.

Bacteria are like nanobiomachines delivering drugs. It has already been proven that bacteria can be used as a means of targeted drug delivery to diseased tissues. Experts have launched MC–1 bacteria into the rat's blood system. These bacteria are able to move quickly due to the rotation of their flagella, but in addition, they contain magnetic nanoparticles, which makes them sensitive to the magnetic field and makes them move along the lines of force. Such power lines can be created, for example, by a magnetic resonance device. Researchers believe that before trying to create artificial nanomachines capable of moving through the human body, you should pay attention to the already existing creations of nature.

Nanospheres and nanocapsules belong to the family of polymer nanoparticles. If nanospheres are solid matrices on the polymer surface of which the active substance is distributed, then in nanocapsules the polymer shell forms a cavity filled with liquid. As a result, the active substance is released into the body by various mechanisms – from nanospheres the release is exponential, and from nanocapsules it occurs at a constant rate for a long time. Polymer nanoparticles can be obtained from natural or synthetic polymers, which are polysaccharides, polylactic and polyglycolic acids, polylactides, polyacrylates, acrylic polymers, polyethylene glycol (PEG) and its analogues, etc. Polymer materials are characterized by a set of valuable properties for drug transport, such as biocompatibility, biodegradation ability, and functional compatibility.

Dendrimers are of particular interest. They represent a new type of polymers that have not the usual linear, but "branching" structure. The first sample was obtained back in the 50s, and the main methods of their synthesis were developed in the 80s. The term "dendrimers" appeared earlier than "nanotechnology", and at first they were not associated with each other. However, recently, dendrimers are increasingly mentioned precisely in the context of their nanotechnological and nanomedical applications. Dendrimers are a unique class of polymers because their size and shape can be very precisely specified during chemical synthesis, which is extremely important for nanotransferers. Dendrimers are obtained from monomers by conducting successive convergent and divergent polymerizations (including using methods of peptide synthesis), thus setting the nature of branching. Typical monomers used in synthesis are polyamidoamine and the amino acid lysine. The "target" molecules bind to dendrimers either by forming complexes with their surface or by embedding deeply between their individual chains. In addition, it is possible to stereospecifically arrange the necessary functional groups on the surface of dendrimers, which will interact with viruses and cells with maximum effect. An example of creating an active substance based on a dendrimer is Vivigel, a gel that can protect against HIV infection.

Among carbon nanoparticles formed only by carbon atoms, the most widely distributed are fullerenes and nanotubes, which can be obtained using a variety of chemical or physico-chemical methods. For example, on an industrial scale, fullerenes are obtained by thermal spraying of carbon-containing soot in an inert gas atmosphere, at reduced pressure, in the presence of a catalyst. Fullerenes, according to experts, can become the basis not only for delivery systems, but also for a new class of medicines. The main feature is their skeleton shape: the molecules look like closed, hollow inside the "shell". The most famous of the carbon frame structures is fullerene C ₆₀, the absolutely unexpected discovery of which in 1985 caused a boom in research in this field (the Nobel Prize in Chemistry for 1996 was awarded to the discoverers of fullerenes). After the development of a technique for obtaining fullerenes in macro quantities, many other, lighter or heavier fullerenes were discovered: ranging from ₂₀ to ₇₀, ₈₂, ₉₆ and above. On the basis of fullerenes, drug delivery systems for the treatment of HIV-infected patients and cancer patients are being developed.

In 1991, again – quite unexpectedly (theorists did not predict their existence), long, cylindrical carbon formations, called nanotubes, were discovered. They are characterized by a variety of shapes: large and small, single-layer and multi-layer, straight and spiral; unique strength, demonstrate a whole range of the most unexpected electrical, magnetic, optical properties. In fact, nanotubes can be used as microscopic containers for the transport of many chemically or biologically active substances: proteins, toxic gases, fuel components and even molten metals. For the needs of medicine, nanotubes have an important increased affinity for lipid structures, they are able to form stable complexes with peptides and DNA oligonucleotides and even encapsulate these molecules. The combination of these properties determines their use in the form of effective delivery systems for vaccines and genetic material.

Inorganic nanoparticles, one of the most important classes of nanotransporters, include compounds of silicon oxide, as well as various metals (gold, silver, platinum). Often such a nanoparticle has a silicon core and an outer shell formed by metal atoms. The use of metals makes it possible to create carriers with a number of unique properties. Thus, their activity (and, in particular, the release of a therapeutic agent) can be modulated by thermal exposure (infrared radiation), as well as by a change in the magnetic field. In the case of heterogeneous solid-phase composites, for example, metal nanoparticles on the surface of a porous carrier, new properties appear due to their interaction.

Perhaps the most common platform technologies are microcapsulation, as well as technologies for obtaining matrix, multilayer, shell tablets and capsules. For example, platform technologies for creating nanoscale complexes of active substances with biocompatible and biodegradable synthetic and natural polymers have been developed and are currently being patented in Russia. Nanoformulation can lead to an increase in the activity of the drug by 2-4 times, as well as to the appearance of more pronounced therapeutic properties. In some cases, preclinical studies of known drugs in new nanopackages (for example, taxol or nurofen of prolonged action) are already underway. Platform technologies of controlled drug release are relevant for the targeted delivery of highly toxic antitumor drugs. Traditional oncological drugs are evenly distributed throughout the body: they fall into the foci of the disease and into healthy organs. The problem can be solved with the help of targeted drug delivery together with a biodegradable polymer – then the drug is released not immediately, but as the polymer degrades. But there are even more advanced methods of targeted drug delivery using nanoparticles of genetic material, DNA or RNA. Particles about 200 nanometers in size or slightly smaller can exit the bloodstream only in places of inflammation – where the capillaries have enlarged pores.

During the journey through the bloodstream, nanoparticles can become overgrown with plasma proteins, they are absorbed by immune guardians – macrophages. To extend the residence time of nanoparticles in the body, polymer chains are attached to them. Another option is to attach to the nanoparticle antibodies of tumor cells that know the way to the target, and an antibiotic that will destroy the malignant formation. For example, scientists are designing a liposomal anti-cancer drug in which thermosensitive liposomes are wrapped in a polymer and equipped with antibodies that determine the "delivery address".

Numerous vaccinations against all kinds of diseases have become a routine procedure, but the technique itself has not changed much over the last century. In the near future, syringes with a solution of antigens will be replaced by nanotransferers (sizes up to 500 nm) capable of delivering antigens through the skin to the immune cells present there. It has been shown that the use of small nanoparticles (only 40 nm) allows antigens to be delivered directly through the hair follicles.

At the same time, active substance delivery systems today are associated with risks, that is, side effects. It is not for nothing that the pharmaceutical giant Novartis, the Ciba concern and some other large companies have linked their further developments in this direction only with biologically cleavable nanocarriers.

NanotherapyNanometer molecules can also be used as active substances.

One of the new campaigns is the crushing of active medicinal substances to nanometer sizes – about half of the new active substances that are currently in development dissolve poorly, that is, they have insufficient bioavailability.

Crystals of an active medicinal nanomaterial consist of an active substance and are produced in the form of a suspension (nanosuspension), which can be administered intravenously, and for oral administration, granules or tablets can be produced from it. At the same time, a polymer matrix is not needed, the destruction of which, according to some scientists, can have a toxic effect on cells. The usual size of nanocrystals is 200-600 nm. One of the nanocrystalline drugs introduced into clinical practice back in 2000 is Rapamune (Wyeth-Ayers Laboratories), an immunosuppressive agent that is used after organ transplantation. Thermotherapy with nanoparticles, apparently, has a great prospect. It is known that when near-infrared radiation hits nanotubes, the latter begin to vibrate and heat up the substance around them. The effectiveness of such therapy turned out to be very high: in 80 percent of mice that received a dose of a solution of multilayer nanotubes, cancerous tumors in the kidney completely disappeared after a while. Almost all of the mice in this group survived to the end of the study, which lasted about 9 months. Clinical studies of thermotherapy of brain tumors and prostate cancer are being conducted. The researchers found that the contact of nanotubes with damaged bone tissue of mice accelerates the regeneration of bone tissue and reduces the likelihood of inflammatory processes during treatment. Similarly, nanozolot particles kill microbes, recognize and destroy cancer cells.

Nanoparticles can also be used to stimulate innate regeneration mechanisms. The main focus here is on the artificial activation and management of adult stem cells. Here are a few achievements: amphiphilic proteins that support cell growth to repair damaged spinal cord; coatings of brain tumor areas from magnetic nanoparticles and enzyme-sensitive particles; nanoparticle probes for intracellular drug delivery and gene expression, quantum dots that detect and determine the number of biomarkers of human breast cancer.

Nanoantibodies are the smallest protein antigen-recognizing molecules known today (measuring 2-4 nm). They are fragments (variable domains) of special single–domain antibodies - they consist of a dimer of only one shortened heavy chain of immunoglobulin and are fully functional in the absence of a light chain. After synthesis, the nanoantibodies are already functional and do not require any post-translational modifications. This makes it possible to immediately develop them in bacterial cells or in yeast, which makes the way of creating these proteins significantly more economical. It is quite easy to carry out all kinds of genetic engineering manipulations with nanoantibodies, for example, to create more effective combined structures that include two or more nanoantibodies, as well as other protein domains or functional groups. Such antibodies do not exist in the human body, and therefore there is no adaptation to them. Thus, it becomes possible to bypass the tricks of abnormal, pathological cells and microorganisms that have managed to adapt to the human immune system and find a weak link in their defense.

Biologically active additives (dietary supplements) developed with the use of nanotechnology, the so-called nanoceuticals (nanoceuticals), are aimed at a powerful enhancement of the body's capabilities: from enhancing the digestibility of active food components to improving mental activity and the ability to concentrate, are the highlight of the modern market. However, consumer rights societies insist on stricter state control of the actual safety and effectiveness of products that end up on store shelves.

About the safety of nanotechnology in healthcareThe general opinion of experts is that researchers have not yet created the tools necessary for a 100% assessment of the risks associated with nanotechnology in healthcare.

Such developments are 3-5 years behind the actual creation of the most important medical nanomaterials, and, according to some estimates, even more. Nanomaterials belong to an absolutely new class of products, and the characterization of their potential danger to human health and the state of the environment is mandatory in all cases. Nanoparticles and nanomaterials have a complex of physical, chemical properties and biological effects (including toxic), which often radically differ from the properties of the same substance in the form of solid phases or macroscopic dispersions (Table 2).

So, in 2000, The National Nanotechnology Initiative (The National Nanotechnology Initiative – NNI) was formed in the USA, coordinating the work of 26 federal agencies. This is an interdepartmental program for the assessment of chemical agents dangerous to human health based on the results of modern toxicological tests. In 2008, the NNI received a budget of $1.44 billion, which is more than 3 times higher than the costs of the starting 2001 ($464 million) and 13 percent higher than the 2007 budget.

The US Food and Drug Administration (FDA) is responsible for ensuring the safety, effectiveness and reliability of medicines, medical devices, biotechnological products, tissue products, vaccines, cosmetics and medicines created for humans and animals using nanotechnology. In 2006, the FDA Commission on Nanotechnology (FDA Nanotechnology Task Force) was formed. So far, the FDA does not impose additional requirements on the safety of nanotechnology products, since their status has not been established and there is no list of data provided by manufacturers, that is, the evaluation of new products is similar to conventional drugs. The FDA stated that taking into account the speed of development and the huge potential of nanotechnology in the pharmaceutical field, the legislative framework for their regulation should be created as soon as possible.

Ethical problems of nanomedicineThe ethical issues of nanomedicine lie outside the safety problem: patient consent based on complete information, risk assessment, toxicity and human wellness are just some of the existing ethical issues discussed by specialists.

Experts warn that discussing the ethics of nanomedicine will bring many difficult questions for society. "Genetic testing, for example, could become much easier and widely available," they explain. "But then the problem of aborting defective embryos will affect a large number of people."

Nanomedicine will raise a whole layer of social issues. According to the experts of the Ethics in Science and New Technologies group of the European Commission, when using nanomedicine, the issue of patient (doctor) consent based on complete information is very difficult. "Consent based on complete information requires that the information be understood. Is it realistic to provide information about the consequences and conduct a risk assessment in a rapidly developing field of research, against the background of many unknown factors and the level of complexity?" – answers to these questions cannot be given today, and possibly in the foreseeable future.

Another problem is the connection between medical and non–medical uses of nanotechnology for diagnostic, therapeutic and preventive purposes. The good news is that these questions are being asked, but there is also a bad one – there is still a lot of work in this direction.

New things and changes in the usual way of life can lead to the loosening of the foundations of society, the emergence of a number of ethical problems. This applies, for example, to medications and devices that make it relatively easy to modify the structure of the brain or to stimulate certain parts of it to obtain effects that mimic any form of mental activity.

Despite the huge potential of nanomedicine and significant funding, research on the ethical, legal and social implications of nanomedicine applications is small. "Science is rushing forward, ethics is lagging behind." As with nanotechnology in general, there is a danger of the collapse of nanomedicine if the study of ethical, legal and social values critically lags behind scientific development.

Expected risks of nanopreparationsNanomedicine and nanotechnology in general are new fields, and there is little experimental evidence of unintended and adverse effects.

The lack of knowledge about how nanoparticles will be "integrated" into biochemical processes in the human body is of particular concern. A recent article in the Medical Journal of Australia states that the safety rule for nanopreparations may require unique risk assessments, given the novelty and variety of products, the high mobility and reactivity of the designed nanoparticles, as well as the blurring of diagnostic and therapeutic classifications of "medicine" and "therapeutic device".

Polyamidoamindendrimers (PAMAMs) nanoparticles used as drug delivery agents have been found to cause cellular damage in lung tissues, the results are published in the Journal of Molecular Cell Biology. In a series of experiments conducted at the Chinese Academy of Medical Sciences on mice, it was found that PAMAMs nanoparticles trigger a "cell death" program known as autophagy. The project managers immediately called on the scientific community to pay special attention to the safety of using nanotechnology in medicine.

The most widely used, both in pure form and as part of nanomaterials, is titanium oxide (TiO ₂). Toxicological studies of ultra-thin (20 nm) particles of _TiO2 when inhaled to rats have shown that the particles are able to accumulate in lymphoid tissues, have a damaging effect on the DNA of lymphocytes and brain cells. The main mechanism of toxic action of TiO ₂ nanoparticles was the induction of reactive oxygen species. Aluminum nanoparticles have strong toxic properties, which are capable of suppressing the synthesis of MRNA, causing cell proliferation, inducing proatherogenic inflammation, mitochondrial dysfunction, etc.

Fullerenes were intravenously administered to rats at doses of 15 and 25 mg/kg. Injection of 25 mg/kg for 5 minutes resulted in the death of two out of twenty rats. Fullerenes almost completely bound to plasma proteins and inactivated hepatic glutathione-S-transferases, glutathione peroxidases and glutathione reductases, inducing oxidative damage to rat hepatocytes. Both fullerenes and carbon nanotubes are characterized by a high affinity for the DNA molecule, which makes them potentially dangerous mutagens. However, the main cause of the damaging effect of carbon nanostructures is the induction of reactive oxygen species and the oxidation of biological molecules.

Polystyrene-based nanoparticles (30 nm) with oral administration are able to penetrate the liver and spleen. Injections of poly-(isobutyl cyanoacrylate) nanoparticles with a size of 200 nm, at a dose of 40 ml/ kg, led to the death of 50 percent of mice.
Nanoparticles based on organic polymers and dendrimers are actively captured by macrophages, and polyamidoamine dendrimer in concentrations of 10-100 nmol increased the pores in the cell membrane.

The presented data on the toxic properties of some nanomaterials are far from exhaustive. It has been shown that toxicity depends not only on the physical nature, method of production, size, structure of nanoclusters and nanoparticles, but also on the biological model on which the tests are carried out. Target organs and mechanisms of toxic effect development are diverse. Some nanomaterials, due to their physical nature, are able to induce reactive oxygen species, while others are able to penetrate tissue barriers into cells and interact with intracellular components. Still others – dendrimers of varying degrees of generation, some other types of nanomaterials, can disrupt membrane structures, making them permeable. Considering the accumulated experimental material, it can be found that not always and not everywhere nanomaterials have a toxic or other damaging effect. So, some researchers have definitely discovered the cytotoxic effect of magnetic particles based on iron oxide, while others, on the contrary, have shown that they are harmless. And there are enough such examples. This shows how unique and diverse nanomaterials are in their properties, even if they consist of the same chemical substance.

Experts point out that the field of nanotechnology may be considered risky, dangerous and questionable for investment if important safety and health issues are not taken into account when conducting research. Nanomaterials, as a rule, enter into chemical transformations more easily than larger objects of the same composition, so they are able to form complex compounds with previously unknown properties. Nanoparticles, due to their small size, easily penetrate into the human body and animals through protective barriers (epithelium, mucous membranes, etc.), respiratory system and gastrointestinal tract. The absorbing properties of nanoelements are significantly higher than those of other molecules.

One of the leading experts in the field of health and the environment, Professor E. Seaton (University of Edinburgh, UK) believes that nanoparticles of pharmaceutical products can cause problems with the respiratory organs, heart, immune system, etc. in humans, but tests of such products have not been conducted. Professor G. Oberderster (University of Rochester, USA) has shown that carbon nanoparticles with a diameter of 35 nm are able to penetrate into the brain directly through sensitive nerve fibers. Specialists of the US National Aerospace Agency report that nanotubes, when inhaled in large quantities, lead to pneumonia. It was revealed that the nanotube, which is a compound of ultrathin needles, has a structure similar to asbestos, and this material causes lung damage when inhaled. Inhalation of polystyrene nanoparticles also causes inflammation of the lung tissue and, moreover, provokes thrombosis of blood vessels. There is evidence that carbon nanoparticles can cause cardiac disorders and suppress the activity of the immune system.

In addition, scientists pay attention to a very important fact of possible changes in the properties of nanoparticles after their penetration into the body, for example, coating with proteins when they get into physiological fluids (blood, plasma). Depending on the properties and concentration of the nanoparticles used, when they enter the body, we can get a wide range of intracellular changes.

In conclusion, it should be noted that the need for a detailed study of all aspects of the effect of nanodrugs on living systems does not seem dramatic and in no way reduces the huge interest in the drugs of the future. Recall that the pharmaceutical industry of "classic" medicines had to go through a similar stage at the time of its creation and formation, and this path cost humanity considerable losses. Gradually, rules were developed for the introduction of new medicines to the market, including strictly observed safe production standards, long-term and comprehensive clinical trials, etc.

Similarly, the study of nanoprocesses and their mechanisms, the development of norms, requirements, methodologies, standards, and the subsequent, on their basis, the study of chemical, pharmaceutical properties of candidate nanocarriages, their toxicology, ecology and other properties will allow us to create new rules, the totality of which we today conditionally call GNP (good nanotechnological practice). From this moment, undoubtedly, the countdown of a new era in global healthcare will begin.

The material was prepared by TSVT "HIMRAR" specifically for STRF.ruPortal "Eternal youth" http://vechnayamolodost.ru

05.10.2009