Nanotechnology in medicine and pharmacy

M.A.FINGERS, Academician of the Russian Academy of Sciences and the Russian Academy of Medical Sciences
"Remedium" No. 9-2008.

The term "nanotechnology" was first used by Norio Taniguchi, an engineer from the University of Tokyo, in 1974 in an article devoted to the processing of materials. It took another 20 years before the term was introduced into wide scientific circulation. Today, nanotechnology is one of the most intensively developing fields of science in a variety of industries, including medicine and pharmacy.

Today, not only the leading industrial powers, but also developing countries, in particular in the Asia-Pacific region, are striving to develop nanotechnology. The largest state research programs in the field of nanotechnology are implemented by the United States and Japan, investments in these programs amount to more than $1 billion per year. Since 1997, the volume of investments in these technologies in the world has increased by an order of magnitude and in 2004 amounted to $ 4.6 billion.

In the USA, for example, the development of biotechnologies is considered as the main engine of innovation, which should contribute to the competitiveness of North American products on the world market. Private investment in biotechnology in the United States exceeds public investment, and this indicates both a sufficient level of maturity of nanoscale developments and their high economic potential.

Nanomedicine has also been developing rapidly in recent years, which attracts universal attention not only for its purely scientific achievements, but also for its social significance. Today, this term is understood as 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 (Wagner V., Wechsler D., 2004).

The importance of nanomedicine is evidenced by the progressive growth of publications on this topic in international scientific journals (Fig. 2). Within 10 years, the number of scientific publications on nanomedicine in the world has increased 4 times. The number of patent applications for inventions is also growing, and this indicates the increasing commercialization of this area. The undisputed leader in both scientific publications and the number of patent applications is the USA – 32% of publications and 53% of applications come from there annually, followed by Germany (8% of publications and 10% of applications) and Japan (9 and 6%, respectively).

The driving force behind many nanomedical innovations are start-up companies that build their strategy on the introduction and commercialization of innovations.

The interest of the pharmaceutical and medical industry in nanotechnology has increased significantly in recent years, so we should expect significant investments in this area. In the near future, nanotechnology will play a leading role as a driving force for innovation in medicine.

Already in 2004, the global turnover of nanomedical drugs was estimated by experts at $6 billion. However, in these calculations, experts refer to any medical technologies that use nanomaterials or nanotechnology as nanomedical. Thus, the use of gold nanoparticles in rapid diagnostics is only one of the components of the diagnostic test, but their presence gives experts reason to classify this diagnostic method as nanotechnology.

More than 50% of pharmaceutical manufacturing companies that are actively working in the field of nanomedicine use nanotechnology to develop systems for delivering active drugs to target organs and tissues. These drugs account for 80% of the turnover in the global nanomedicine today. One of the leading areas of application of such systems is oncology. The use of delivery systems is aimed at reducing the adverse side effects of drugs. Among these nanopreparations, there are already two blockbusters, not counting other successful drugs, together their turnover is $ 5 billion.

The share of enterprises producing nanotechnology-based implants (19%) and in vitro diagnostic tools (17%) is significantly lower. The most difficult problems – the development of methods and means of treatment based on fundamentally new therapeutic concepts - are dealt with by only 3% of companies (Fig. 3).

Active substance delivery systemsIn the 60s of the last century, liposomes capable of delivering a medicinal substance to the target organ were obtained.

There are two types of liposomes: multilamellar liposomes, whose diameter can be up to 10 µm, and consisting of a single lamella (plate) with a diameter of approximately 20 to 50 nm. The latter are used as a means of delivering the active drug.

Polymer nanoparticles were proposed to be used as delivery systems in the 70s of the twentieth century (Ravi Kumar, 2000, 2003). The starting material for them can be various natural or bioinert synthetic polymers, for example, polysaccharides, polylactic acid, polylactides, polyacrylates, acrylic polymers, etc. The term "polymer nanoparticles" refers to two morphologically different types of particles: nanospheres and nanocapsules. Nanospheres are solid polymer matrices on which the active substance is distributed. Nanocapsules consist of a polymer shell covering a liquid-filled cavity. These types of nanoparticles differ in the release of the active drug substance: from nanospheres, the release proceeds exponentially, and from nanocapsules - for a long time constant.

Another type of drug active substance delivery systems is due to advances in the development of defined polyvalent and dendritic polymers. Examples here are polyanionic polymers – inhibitors of cellular bonds with viruses, polycationic complexes with DNA or RNA (so-called polyplexes) and dendritic particles (Haag R., Kratz F., 2006).

Unfortunately, despite the high potential for effectiveness, systems for delivering active substances to target organs and tissues are also associated with undesirable side effects. Thus, the pharmaceutical giant Novartis, the Ciba concern, after analyzing the data on the safety of various delivery systems, decided to focus on the development of drugs with cleavable nanocarriers, since the safety of stable nanoparticles is questionable and additional research is needed to confirm it (Feiertaf A., 2007).

The search for alternative systems continues. Along with the improvement of known delivery systems, new ones are being developed - polymer compounds with active substances, polymer micelles, inorganic nanoparticles, solid lipid nanoparticles, fullerenes (Table 1). The latter, according to experts, can become the basis not only for delivery systems, but also for a new class of drugs (Gorman, 2002, Csixty, 2003). On the basis of fullerenes, drugs are being developed – means of drug delivery for the treatment of HIV-infected patients and cancer patients.

Delivery systems are of great importance for drugs based on proteins, the effect of which is often reduced due to the limited time spent in the blood, chemical lability and the ability to provoke an immune reaction. With the help of delivery systems, scientists are trying to improve the application properties of protein preparations. By attaching a polymer chain to the protein, it is possible not only to increase their half-life in the blood, but also to increase their effectiveness. Today, two bestsellers among nanopharmaceuticals are known - polymer-protein conjugate, Pegasys (Pegasys – pegylated alpha2a-interferon) for the treatment of hepatitis C and Neulasta (Neulasta – pegylated hG-CSF) for the treatment of neutropenia (Table 2).

Active substances and new methods of treatmentNanometer molecules can be used directly as active substances.

In particular, an interesting class of molecules from this point of view are dendrimers. These branched, like the crown of a tree, molecules (hence their name) can reach the size of small proteins. Compared with classical polymer molecules, they have the advantage that their synthesis can be controlled with the desired properties, i.e. program for a specific medical application. In addition, specific functional groups can be placed on the surface in a specific way, so that they will interact particularly effectively with viruses and cells. An example of creating an active substance based on a dendrimer is Vivigel, a gel that can protect against HIV infection. Vivigel was developed by the Australian biotech company Starpharma, and is currently undergoing clinical trials.

One of the new principles is the pulverization of active medicinal substances to nanometer sizes. This is how they are trying to solve the problem of insufficient solubility of drugs: 40% of new active substances that are currently in development dissolve poorly and, accordingly, have insufficient bioavailability.

In the 90s, it was possible to obtain nanoparticles of an active medicinal substance, the so-called active nanocrystals, using the processes of pulverization or hyperbaric homogenization (Mueller et al., 2001). These nanoparticles consist of 100% of the 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 the suspension. 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. To improve the application properties of nanocrystalline drugs, the surface of the crystals is modified. Wyeth-Ayers Laboratories (USA), PharmaSol (Germany), SkyePharma (UK), Merck &Co. are working in this direction. (USA) and many others. One of the nanocrystalline drugs introduced into clinical practice in 2000 is Rapamune (Wyeth-Ayers Laboratories), an immunosuppressive drug that is used after organ transplantation. Nano-Crystal® technology (developed by Elan) was used in the production of this drug. And in 2003, pharmaceutical companies Merck &Co. and Johnson & Johnson signed a contract with Elan for the use of this technology in the production of other innovative drugs.

A different concept is the basis of thermotherapy with nanoparticles. This is a new way to treat cancerous tumors. The essence of the method is that nanoparticles are injected into the tumor, and then either due to the influence of a magnetic field or laser irradiation, they are heated, while the tumor cells are destroyed. For the first time this medical technology was proposed more than 15 years ago by scientists from the Charite University Clinic (Berlin) under the guidance of Dr. Jordan. For this development, in 2005, scientists were awarded the Frost&Sullivan Award for Technology Innovation. In 2003, the development was transferred to a commercial nanotechnology company for completion and implementation. At the same time, clinical studies of thermotherapy of brain tumors and prostate cancer began. Today, a number of companies in Europe (for example, Magnamedics, Aachen) and the USA (Nanospectra Bioscience, Houston) are working in this direction.

In vivo diagnosticsRevolutionary advances in genomics and molecular biology have led to a better understanding of the molecular processes that underlie diseases.

Diagnostics based on the transmission of visual information about molecular structures can be called molecular visiography. The same principle is used here as with traditional methods of obtaining images – radiography, echography, ultrasound, etc., only a different contrast agent is required, as well as special medical devices and data processing systems.

A contrast agent for molecular diagnostics consists of nanoparticles with which imaging components and certain antibodies or some other molecules capable of finding a target are connected. When the contrast agent is injected into the bloodstream, its search components interact with the target structures on the surface of the diseased cell according to the "key-lock" principle, and the imaging components enter the diseased tissues. After that, it remains to "read" the visualized information. The company Kereos (St. Louis) is working on this concept, which develops contrast agents based on perfluorocarbon nanoemulsion, each droplet of which carries several thousand gadolinium atoms. Thus, the contrast increases dramatically. The company develops these drugs in cooperation with global concerns Philips and Bristol-Myers Squibb.

Complex molecular contrast agents created on the basis of nanotechnology are not yet available for clinical practice. But simple contrast agents have already been introduced, which consist of iron oxide nanoparticles. They provide high contrast in the diagnosis of liver diseases. This contrast agent was developed and implemented under the Resovist® trademark by Schering.

In vitro diagnosticsExperts point out that nanotechnology has contributed to the renaissance of biosensory, because they have allowed for completely new sensory concepts.

Nanotechnology in in vitro diagnostics is developing in two directions: 1) the use of nanoparticles as markers of biological molecules; 2) the use of innovative nanotechnological measurement methods.
Nanosphere, an Illinois-based company, has developed new diagnostic tests for detecting cancer, Alzheimer's disease and cystic fibrosis. Moreover, it is stated that a new diagnostic test for cystic fibrosis will cost 10 times cheaper than those available today.

The new nanomedical diagnostic tests also include the Cantilever and SPR (Surface plasma resonance) sensor systems. The Cantilever sensor consists of artificial beams with a length of several 10 to 200 µm and a thickness of nanometers to micrometers. The beams are covered with a layer of DNA molecules or proteins that specifically interact with the target biomolecules in the sample. This interaction leads to the deflection of the beam, the movement of which is detected by the laser detector. Compared to many optical methods, the Cantilever sensor has the advantage that the molecules in the sample do not require labeling, and due to this, the diagnostic procedure is significantly simplified. The SPR sensor allows you to measure the interaction between proteins or proteins and DNA in real time due to a certain arrangement of nanolayers and different intensity of reflected light depending on the mass of biomolecules in the layer. These devices have already found wide application in medical materials science.

It is also worth mentioning the Quicklab diagnostic system, designed for express diagnostics. This is a small-sized electronic device with a biochip with nanometer electrodes. DNA molecules and proteins are determined by the biochemical method. The principle was developed by the Institute of Silicon Technologies (FRG) and implemented by Siemens Corp. Technology. The device is designed to diagnose infectious diseases, blood poisoning, lung inflammation, diseases of the genitourinary tract.

Implants and biomaterialsImplantology has received an impetus for development in recent decades due to the need for methods and means of restoration or replacement of organs and tissues.

A number of companies have been working with nanocrystalline materials and coating the surface of implants with hydroxyapatite for a long time.

Another method is nanocrystalline diamond coating, which also promises to increase the duration of functioning and stability of implants. Experiments have already shown that osteoblasts recognize diamond submicrostructures and can be fixed on them. These results indicate excellent biocompatibility of diamond coatings.

Materials made of nanocrystalline hydroxylapatite are used for the treatment of bone defects, and thanks to the nanocrystalline structure, bone-forming cells can be fixed in such an implant and the process of osteogenesis practically includes artificial material in natural bone.

Recently, another direction of nanotechnological biomaterials has begun to develop - nanofibers, which scientists propose to use in tissue engineering – the creation of artificial tissues (in the future, it is also possible for organs) based on cellular technologies.

ConclusionThus, today the foundation is being laid for the application of nanotechnology in almost all areas of medicine (Table 3). At the same time, nanoparticles are currently mainly used in delivery systems and in vivo diagnostics as carriers of active drugs or contrast agents in the affected organs and target tissues.

In the development of new active substances and treatment methods, first used in the pharmaceutical potential of certain molecular nanosystems (dendrimers, fullerenes), and secondly, you can use nanochastitsy in combination with thermal or mechanical action of the magnetic fields, laser radiation, ultrasound, etc., is rapidly developing nanotechnology diagnosis in vitro: it uses a wide range of possibilities of nanotechnology – from nanoparticles with markers to biochips. In the development of biomaterials researchers ' attention is riveted again to nanoparticles, including nanocrystals, which should take it to a new level of modern implantology, orthopedics, dentistry.

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07.04.2009