Nanomedicine: apply, but check

Dualism of nanoparticlesPublished on the website STRF.ru
The material was provided by the editorial board of the journal "Russian Nanotechnologies"

The changes brought to life by the development of nanotechnology are comparable in depth to the consequences of the discovery of radioactivity or the computer revolution. Experience suggests that changes of this magnitude can have not only positive, but also negative consequences. However, experience is not enough here, experiments are needed. How evidence of the benefits and harms of nanoparticles is collected, says Alexander Danilov, Candidate of Physical and Mathematical Sciences.

The side is lightExisting concerns about the safety of nanotechnology come to the fore when it comes to their medical applications — the area where nanoparticles purposefully affect the human body.

The promising fields of application of medical nanotechnology currently being discussed are very diverse, and there is not even a generally accepted classification of them. It is possible, apparently, to distinguish three general directions (European Technology Platform on NanoMedicine, Vision Paper and Basis for a Strategic Research Agenda for NanoMedicine. 2005).

The first is the diagnosis of diseases at an early stage, in the future — at the level of single cells. As an example, diagnostics using magnetic nanoparticles can be given. When a suspension of such particles is introduced into the body, they are captured by macrophages. If there is a tumor or an inflammatory process somewhere, "labeled" macrophages rush there and can be easily detected using a magnetic tomograph. Another example is quantum dots, which, like atoms, have a discrete radiation spectrum. Treated in a certain way, they can mark cancer cells, which has already been confirmed by experiments on mice. Alternatively, a suspension of green quantum dots can be injected into vessels to visualize the circulatory system. If a small vessel or capillary is damaged in some place, it will be clearly visible, since there is no green color in the tissues of the human body.

The second direction is targeted delivery of drugs, and in the longer term — and genes, to the affected cells. This greatly increases the possibility of treating oncological and some other diseases with potent drugs with pronounced side effects.

The third direction is regenerative medicine. Its goal is to mobilize the body's own capabilities to fight diseases such as diabetes, osteoarthritis, lesions of the heart muscle and central nervous system. Regenerative medicine is based on the delivery of biocompatible materials, stem cells, and signaling molecules that initiate regenerative processes at the cellular level to the affected areas of the body.

Of course, the use of nanotechnology should be strictly controlled from the very beginning. After all, in addition to unacceptable harm to human health and the environment, the possible negative reaction of society should be taken into account.

Nanomedical drugs, like all other medicines and medical materials, are strictly tested. In particular, in our country, the testing of nanomaterials is regulated by Resolution No. 79 of the Chief State Sanitary Doctor of the Russian Federation dated October 31, 2007 "On approval of the Concept of Toxicological studies, Risk Assessment Methodology, methods of identification and quantitative determination of nanomaterials", which also applies to medical materials.

In the world since 2005, 130 nanotechnological drugs and delivery systems, as well as 125 devices or diagnostic tests have entered preclinical, clinical or commercial development. There is a lot of difficult work to be done, since ensuring the safety of nanopreparations may require unique risk assessments, given the novelty and variety of products, the high mobility and reactivity of the designed nanoparticles and the blurring of diagnostic and therapeutic classifications "medicine" and "therapeutic device" (Faunce T.A. // Nanoterapeutecs: New challenges for safety and cost-effectiveness regulation in Australia, MJA. 2007. V. 186. № 4.).

The dark side

The main risk factor for the use of medical nanotechnology is the lack of information about the interaction of specific nanoparticles with the human body. Scientists today have a better understanding of how nanoparticles are absorbed by vertebrates and invertebrates, but do not know how they affect an individual organism or even a colony of microorganisms.

Currently published literature reviews (Lyssov V. N., Murzin N. V. // Problems of nanotechnology safety. M.: MEPhI. 2007. G. Oberdorster, V. Stone, K. Donaldson // Toxicology of nanoparticles: A historical perspective, Nanotoxicology. 2007. V.1. № 16; Buzea C., Blandino I.I.P., Robbie K. // Nanomaterials and nanoparticles: Sources and toxicity, Biointerphases. 2007. V. 2. No. 4.) on the negative impact of nanoparticles on human health contain only the first data concerning their possible toxicity. There are observations describing the relationship between nanoscale particles circulating in the atmosphere and morbidity, especially in the elderly and people with reduced immunity. Given the similar properties of atmospheric and artificial nanoparticles, it can be assumed that the latter are also capable of causing various diseases, including those with a long latency period (Samsonova M. V. // Nanomedicine: modern approaches to the diagnosis and treatment of diseases, safety issues. Pulmonology. 2008. № 5.).

Not only fullerenes and nanotubes are suspected of toxicity, but also titanium dioxide nanoparticles already widely used in cosmetics, as well as silver particles and quantum dots that are promising from the point of view of medical applications. Even biocompatible materials such as ceramics and aluminum, when used for implantation and prosthetics, can serve as sources of nanoparticles that accumulate in internal organs and cause allergic reactions and vasculitis.

If the toxicity test is carried out only on healthy organisms (animal experiments or clinical studies), adverse effects may occur in sensitive parts of the population, and verification of this requires separate tests. Experts from the US National Institutes of Health note the possibility of unforeseen reactions in vivo.

Thus, recent studies (Salonen E., Lin S., Reid M. L., Allegood M., Xi Wang, Rao A.M., Vattulainen I., Pu Chun Ke // Real-Time Translocation of Fullerene Reveals Cell Contraction, Small. V. 4, No. 11. 2008) show that some cell cultures, when exposed to fullerenes, they are intact and even not affected in any way. Cells are also unaffected in the presence of gallic acid nanoparticles, which is found in almost all plants (for example, tea, oak bark, tannic extracts, etc.). However, when fullerenes and gallic acid are present in cell culture together, they form compounds that attach to the cell surface and cause its death. The given example shows how difficult it is to isolate the effects of nanoparticles on the body and how "targeted" it should be if we count on its therapeutic effect.

Once in the body, nanoparticles can damage biomembranes, disrupt the functions of biomolecules, including molecules of the genetic apparatus of the cell and cellular organelles (mitochondria), leading to disruption of regulatory processes and cell death. The mechanism of the impact of nanoobjects on living structures is associated with the formation of free radicals in their presence, including perhydrates, as well as with the appearance of complexes with nucleic acids. The effect on a living organism is manifested in the occurrence of inflammatory processes in individual organs and tissues and a decrease in immunity.

It is confirmed that the toxicity depends on the concentration of nanoparticles, their surface area, as well as the environment in which they are located, but not on the total mass and volume. The toxicity increases with decreasing particle sizes. Thus, nanoparticles from materials that are not toxic in their usual form may also exhibit toxicity.

It should be emphasized that most of these conclusions are based on experiments on animals and cell cultures, and their direct extrapolation to the human body is not correct. In addition, further research may suggest ways to combat the side effects of exposure to nanoparticles on the human body. For example, quantum dots from CdSe can be made non-toxic due to their surface coating or replaced with photoluminescent nanodiamonds with colored centers (Faklaris O., Garrot D., Treussart F., Joshi V., Curmi P., Boudou J., Sauvage T. // Comparison of the photoluminescence properties of semiconductor quantum dots and non-blinking diamond nanoparticles. Observation of the diffusion of diamond nanoparticles in living cells, arXiv:0904.2648v1. 2009). However, the data provided in the reviews confirm that the problem exists. Therefore, the new scientific discipline — nanotoxicology — faces the task of not only identifying possible harmful effects of nanoobjects on the human body, but also purposefully modifying the properties of particles in order to prevent this harm while preserving their useful properties.

Risk listsThe scientific community is fully aware of the risks of using nanoparticles for therapeutic purposes.

This is evidenced by the recently published first general overview of scientific and applied research in the field of nanotechnology security — Emergnano. The authors of the review — the Safenano initiative group, created by the Institute of Occupational Medicine of the City of Edinburgh (a large independent center for scientific research in the field of occupational safety and the environment, currently operating under the auspices of the World Health Organization) and the Ministry of Food Industry and Agriculture of the United Kingdom — conducted a quantitative and qualitative assessment of nanotechnology safety research. In addition, they tried to give a comprehensive assessment of the risks associated with the use of nanotechnology, investigated the environmental legislation of different countries, as well as the availability of safety regulations when working with nanomaterials and their use. Safenano project manager Rob Aitken notes the relevance of such a "snapshot" of the state of affairs in a large branch of science around the world.

Of the 358 projects selected for research in 13 countries, 260 have been completed or are close to completion. However, the researchers were able to make significant progress only on a very limited range of problems.

The authors of the review note that the largest number of research projects in the field of nanotechnology security were launched in the United States (165 projects), followed by the United Kingdom, Switzerland and the European Union (19 projects). In terms of spending on these studies, the United States and the European Union are leading (about 37 million pounds and 26 million pounds, respectively), which is only one to three percent of the scientific budget of developed countries.

A new major project of integrated risk assessment associated with the use of artificial nanoparticles ENPRA (Engineered NanoParticle Risk Assessment), initiated by the participants of the 7th EU Framework Program, should close some significant gaps in the field of nanotechnology safety research. Its launch was announced in Paris on May 14, 2009. The total cost of the project will be 3.7 billion euros, the expected duration is 3.5 years. ENPRA employs specialists and equipment from 15 European and six American partners, including three US federal agencies. The project will be led by Dr. Liang Tran, Director of the Computational Toxicology Laboratory at the Institute of Occupational Medicine in Edinburgh.

Within the framework of the ENPRA project, several tasks are expected to be solved. In particular, scientists will have to identify the physicochemical characteristics of artificial nanoparticles responsible for their toxicity, and develop methods for predicting the potential toxicity of nanoparticles; investigate the mechanisms of interaction between nanoparticles and living organisms at the cellular and molecular level. In addition, they will have to develop test systems that will determine the toxicity of nanoparticles without animal experiments and expensive and lengthy clinical trials. Such tests, if their results can be extrapolated to real situations that consumers of products containing nanoparticles may encounter, will allow for the faster introduction of new safe technologies and materials.

Attention is drawn to the absence of Russian scientists in the expert groups developing and implementing these projects. Of course, our country also understands the seriousness of the problem, which is confirmed by the adoption of the aforementioned resolution of the Chief State Sanitary Doctor of the Russian Federation. However, it seems appropriate for Russian specialists to participate more widely in international cooperation in the field of nanotechnology security.

Nanotechnology opens up unprecedented prospects for medicine, as well as for other fields of activity, but at the same time their safe and effective application poses challenges to researchers, technologists and managers of a completely new level of complexity.

Portal "Eternal youth" http://vechnayamolodost.ru07.09.2009