Science in Siberia: Nanobiotechnology for Medicine
Drug development is an important branch of nanobiotechnologyT.G. Tolstikova, head.
Laboratory of Pharmacological Research of NIOH SB RAS, Doctor of Biological Sciences, Professor
"Science in Siberia" No. 14-2009
Nanotechnology as an interdisciplinary field of knowledge has become a powerful engine of technological progress in the coming century. By 2015, the global costs for the development of nanotechnology will reach one trillion dollars. According to government plans, the volume of production of nanoindustry products in Russia by 2015 should exceed 900 billion rubles.
Describing nanotechnology in a somewhat exalted spirit, I would like to say that on its mighty multi-branched tree, one of the most powerful branches bearing more and more fruit is the science of nanobiotechnology.
The scope of its coverage includes problems, without the solution of which it is impossible not only to improve the quality of human life, but also its very existence. These problems include:
– development of food production technologies that contribute to the maximum extent to guarantee a person the normal performance of all vital functions and the prevention of diseases;
– creation of diagnostic tools;
– development of drugs, the specific activity of which would ensure a constant increase in the level of quality of treatment.
The title of this article is actually a brief conclusion from numerous foreign printed materials devoted to the characteristics of the components of modern nanotechnology. In the Siberian Branch of the Russian Academy of Sciences, along with the recognition of the extremely important role of nanomaterials as the basis of the most important industries, more and more attention is being paid to nanobiotechnology.
If we turn to such a section as diagnostic tools, it is necessary to emphasize the high scientific level of research conducted at the Institute of Chemical Biology and Fundamental Medicine under the leadership of Academician V. V. Vlasov. A remarkable feature of these studies, as well as works in the field of medical genetics, is the entry into practice at the optimal time.
The process of drug development includes inextricably linked stages of design and synthesis of new compounds, the creation of dosage forms and, finally, all phases (from primary to clinical) pharmacological study.
Researchers of the Siberian Branch, headed by Academician V. V. Boldyrev, were among the first in the world to understand the special importance of obtaining nanostructured forms of medicines, which, as is commonly believed, provide targeted delivery to the target organ of the active part of the drug. This widespread concept should probably imply the protection of the active substance (DV) from premature metabolism in a living body, as well as the functioning of DV in the form of nanostructured formations exhibiting specific pharmacological activity. Solid-phase mechanochemical synthesis has proved to be a unique approach to obtaining nanostructured forms of drugs. The priority of Siberians in this direction is recognized in the world.
Quite ordinary, at first glance, the event of the Presidium of the SB RAS on the organization of the Department of Chemistry of Natural and Biologically Active Substances within the Novosibirsk Institute of Organic Chemistry contributed to the expansion of research in the section of nanobiotechnology, which is addressed to the development of new, especially nanostructured drugs.
The result of the Department's work is the implementation of large research cycles in cooperation with institutes of SB RAS, SB RAMS, SSC of the World Bank "Vector" and universities in the field of chemistry and pharmacology of natural and synthetic compounds. This led to the identification of candidate substances promising as antiviral, cardiotropic, organoprotective, psychotropic, hypocholesterolemic, psychotropic, anti-inflammatory, anti-ulcer, analgesic and other agents. The fundamental research of the department turns into developments that allow us to count on the creation of original domestic medicines and technologies for their production. And here the most ready for implementation are cardiotropic, hypocholesterolemic agents, correctors of toxic effects of cytostatics, antiviral and anti-inflammatory drugs.
In connection with the main subject of this article, I want to focus only on some of the new approaches we use to develop nanostructured drugs.
It was shown for the first time that vegetable carbohydrate-containing metabolites (glycosides and polysaccharides) form complexes with active drugs (hereinafter referred to as pharmacones), which are typical nanostructures. We obtained reliable evidence of their formation from experiments conducted on animals, the main result of which was the discovery of absolutely indisputable advantages of complexly linked pharmacones over pharmacones administered in pure form. These advantages consist, firstly, in reducing the therapeutically active dose of the pharmacon by 10-150 times; secondly, in a significant decrease (up to complete disappearance in some cases) of the harmful side effects of the pharmacon; thirdly, in strengthening the atypical, so-called pleiotropic properties of the pharmacon of a positive nature.
We have come to the conclusion that a pharmacone complexly associated with a carbohydrate-containing metabolite in a living organism functions as a nanoscale structure interacting with receptors as a new modified pharmacone.
We were supported in this belief by the staff of the Institute of Chemical Kinetics and Gorenje, led by prof. T. V. Leshina and Ph.D. M. B. Taraban. Their research led to the obtaining of data indisputably testifying to the complexation (clathering) of pharmacones with one of the most interesting of the complexing plant metabolites found by us – glycyrrhizic acid. Produced by such multi-tonnage plants of the flora of Russia, Kazakhstan and Central Asia as licorice naked and licorice Ural, glycyrrhizic acid is a kind of unique in the world of plant metabolites. Its uniqueness lies in the combination of high availability with a variety of useful pharmacological properties.
We are convinced that the most promising direction of application of the licorice metabolite is the clathering of pharmacones. The ability to form clathrates (complexes) in glycyrrhizic acid surprises not only with the breadth of coverage of pharmacones, but also with the inevitable appearance of the advantages of the complexes that were discussed.
The antihypertensive drug nifedipine, which has been successfully used in the treatment of hypertension for several decades, began to be replaced by its more expensive analogues. However, with the appearance of new dosage forms of nifedipine on the market, the interest of doctors in this inexpensive drug has returned again. The form of nifedipine in the form of a complex with glycyrrhizic acid, proposed by us, should take a special place among cardiotropic drugs. What is the peculiarity of our nanostructured drug? It exhibits the necessary antihypertensive activity with a 10-fold reduced content of nifedipine in it. Clathering with glycyrrhizic acid powerfully enhances the secondary effect of nifedipine – antiarrhythmic effect. In order to stop arrhythmia without affecting blood pressure, it is necessary to introduce clathrate containing a dose of nifedipine 29 times lower than its antihypertensive dose. Its solubility increases several times, and, consequently, the possibility of using intravenous injections in an ambulance. The use of the drug developed by us will significantly reduce the risk of progression of angina and other cardiovascular complications, as well as prevent the development of liver and kidney failure. Thus, the conversion of nifedipine into a nanostructured form makes it a multifunctional drug. And there are not so many multifunctional drugs on the drug market.
Other examples are no less convincing. Widely used nonsteroidal anti–inflammatory drugs (NSAIDs) aspirin, orthophen, indomethacin, analgin and others have a significant drawback - destructive changes in the gastric mucosa. We have shown that their clathering with glycyrrhizic acid leads to an increase in anti-inflammatory, antipyretic and analgesic activity by 3-5 times in doses significantly (2-10 times) reduced. A particularly important consequence of clathering is a sharp decrease in toxicity and the degree of destructive lesions of the gastric mucosa. In addition, the protection of the liver and kidneys increases.
Drugs called statins are effective means of reducing low–density lipoproteins and total cholesterol. The breadth of their use in the treatment of atherosclerosis can be judged by their implementation on the drug market. Thus, the volume of sales of drugs based on the synthetic statin atorvostatin exceeded $ 10 billion per year. In Russia, a one-year course of the drug liprimar costs about 20 thousand rubles. Studies conducted under the leadership of academician Yu. P. Nikitin and Doctor of Chemical Sciences N. F. Salakhutdinov allowed us to establish that the clathering of statins with glycyrrhizic acid can reduce the therapeutic dose of an expensive pharmacon by 3-5 times and significantly reduce the harmful side effects inherent in statins.
As we found out, arabinogalactan, a polysaccharide metabolite of the Siberian larch (Larix sibirica) and Gmelin larch (Larix Gmelinii) endemic to the Siberian forest flora, is no less promising than glycosides. It easily stands out from the wood of these trees. The content of arabinogalactan is about 10% of the weight of dry wood. It should be emphasized that both types of larch are the main components of the forests of Eastern Siberia. Isolation and purification of arabinogalactan is carried out using a simple technology developed at the Irkutsk Institute of Chemistry. To isolate arabinogalactan, waste from logging, sawmilling, pulp and paper industry can be used. Thus, arabinogalactan by its availability has no competitors among natural and biosynthetic polysaccharides.
Chemically, arabinogalactan is a comb-shaped polysaccharide. The main chain consists of galactose links, the side chains consist of arabinose and galactose links. This feature of the structure contributes to the formation of strong complexes of drugs with it.
Its clathrates obtained by solid-phase synthesis with NSAIDs indomethacin, tranquilizers sibazone and mesapam, neuroleptic azaleptin, antiarrhythmic amiodarone, antihypertensive drug nifedipine showed, as noted above, the characteristic properties of nanostructured complexes of pharmacones. Thus, the basic anti-inflammatory activity of indomethacin in clathrates remains high at pharmacone doses reduced by 10 and 20 times, destructive damage to the gastric mucosa is reduced by 2 times. The clathrate formation of sibazone and mesapam leads to an increase in the anxiolytic effect, to a 10-fold reduction in the dose while maintaining the basic pharmacological activity.
Clathrates with nifedipine and amiodarone, allowing in the case of nifedipine to increase the solubility in water by 6.8 times and reduce the dose by 10 times while maintaining its high basic hypotensive activity, and for amiodarone – to increase the solubility in water by 15 times while maintaining the properties.
Thus, with the help of vegetable carbohydrate-containing metabolites, in particular, glycyrrhizic acid and arabinogalactan, which, if properly formulated, will become inexpensive substances obtained from domestic plant raw materials, well-known pharmacones are transformed into new drugs with previously unknown positive properties.
An important area of nanobiotechnology in the SB RAS is the work led by academicians V. V. Boldyrev and V. M. Fomin on the creation and research of nanoaerosols of water-insoluble drugs.
Aerosol forms of traditional drugs, as well as the improvement of devices for their delivery to the patient's lungs, are one of the current trends in the development of pharmaceuticals and pharmacotherapy. Aerosol dosage forms are considered as an alternative for invasive and oral methods of administration into the body, especially for drugs that are slightly soluble in water.
In the development of these works, the laboratory of Doctor of Chemical Sciences A. A. Onishchuk of the Institute of Chemical Kinetics and Gorenje has created unparalleled installations that allowed to begin in-depth toxico-pharmacological studies on animal drugs in the form of nanoaerosols.
The results of toxico-pharmacological studies have led us to believe that the use of drugs in nanoaerosol form is very promising as a new therapeutic approach.
In conclusion, we express the hope that the examples described in this article, covering only part of the research in the field of nanobiotechnology, will allow the reader to judge the serious approach of Siberian scientists to solving important problems and the high scientific level of research typical of SB RAS.
Returning to the high style, we hope that flowers and fruits will appear on the powerful branch of the tree in the wake of our research.
Portal "Eternal youth" www.vechnayamolodost.ru23.04.2009