Carbon nanotubes for diagnosis and treatment
Nanotubes in medicine
V.V. Utochnikova, "Nanometer"
based on the article by K. Kostarelos, A. Bianco & M. Prato:
Promises, facts and challenges for carbon nanotubes in imaging and therapeutics
Nature Nanotechnology 4, 627-633 (2009)
One of the key capabilities of nanotubes in biology and medicine is that they can be easily absorbed by cells and therefore can act as carriers of various molecules necessary for treatment and diagnosis. Moreover, their unique electrical, spectral and thermal properties within the framework of biological applications create new opportunities for the detection and treatment of diseases. Many educational and production laboratories around the world are intensively investigating not only the therapeutic and diagnostic applications of nanotubes, but also their toxicity and possible pathologies caused by them. The balance of risk and advantages of this material is estimated in all these applications and will answer the question of further use of this material.
The synthesized nanotubes are insoluble in most organic and aqueous solvents and, thus, the surface of the nanotubes must be pre-modified for any biological applications. Thus, it has been shown that chemically modified nanotubes are unique carriers of nucleic acids. They were used for the directed transfer of small organic molecules (for example, cancer drugs), as a platform for the directed transfer of antibiotics and for the transfer of protein and carbohydrate substitutes, vaccines were developed on their basis. However, carbon nanotubes are still at an early stage of medical development, the effectiveness and limitations in their use have yet to be thoroughly studied. The possible toxicity of these materials is being actively discussed. It is necessary to carefully study the effect of the introduction of nanotubes on biocomponents at the cellular (and physiological) level.
A further problem is the lack of an approved method for determining the purity of nanotubes. Standard chromatography – for example, thin film chromatography and high–pressure liquid chromatography - have achieved only small success. In order to move to large-scale clinical trials, these and other technical problems must be solved and standard procedures for the production, purification and modification of nanotubes must be created.
Once these problems are solved, it is necessary to demonstrate the undeniable advantage of nanotubes over existing alternative solutions in order to continue investments in the pharmaceutical industry in this area. Demonstrating the benefits of nanotubes in medicine is also necessary to eliminate inflated expectations, which may be unconstructive and cause real harm to development in this area. We will try to consider the current state of affairs in this area, referring only to in vivo experiments.
Carbon nanotubes in observation and treatmentNanotubes can be single- and multi-walled, and are now being produced in sufficient quantities for various commercial applications.
Their diameter varies in the nanometer range, and their length can reach several microns. In bio-application, the first problem was their insolubility in most solvents, and especially in biologically compatible buffers. Many studies have been undertaken to ensure the compatibility of nanotubes with the biological environment. The two main techniques are non-covalent attachment of amphiphilic molecules (lipids or polymers) to nanotubes, as well as covalent modification of the surface of nanotubes by sewing various groups directly to the carbon skeleton.
Figure 1 shows which types of nanotubes have been studied in biological applications using in vivo models.
The three groups shown have different structures and surfaces, which greatly affects their bioactivity. The initial nanotubes (Fig. 1a) are already prototypes, but are difficult to use in biology, since they are poorly soluble in aqueous solutions and have a strong tendency to aggregation. Interestingly, the original nanotubes – mostly poorly soluble in aqueous solutions – were the first to be used in almost all toxicological studies. Their solubility was significantly increased when amphiphilic macromolecules, for example, lipid-PEG conjugate (Fig. 1b), copolymers, surfactants (Fig. 1c) and even single-chiral DNA (Fig. 1d) were applied to the surface of the nanotube. Covalently modified nanotubes used for biomedical purposes are made of a starting material with a surface modified either by a cyclopric coupling reaction to sew on ammonium groups (Fig. 1e), or by treatment with strong acid to form carboxyl groups (Fig. 1f). Both methods of chemical treatment significantly improve solubility in water, and also provide a basis for further modification. After conducting all the research in this area, it becomes clear that the degree of aggregation of nanotubes in the biological environment plays an important role in pharmaceutical applications.
Lessons learned from preclinical researchAll the experiments with nanotubes in vivo known to date used one of the methods described above (Fig. 1), and preclinical trials were mainly focused on oncology, which makes cancer one of the first diseases for which the first clinical results will probably be obtained.
Nanotubes have a number of advantages for cancer therapy. For example, covalently modified nanotubes are able to avoid the preosmic region, getting directly into the cytoplasm of different cell types. Moreover, their unique physical properties allow for effective electromagnetic stimulation and high-precision detection. A large surface area and the presence of an internal volume allow for the "loading" of drugs and other small molecules. Nanotubes can be used to prevent tumor growth as part of the use of chemotherapy and hyperthermia. Targeted treatment of tumors using both non-covalently and covalently modified nanotubes has also been studied in vivo. Despite the results achieved, however, there are no results of comparison with other agents with proven biological efficacy. All studies published to date in this area are classified in Table 1.
The Dai group was the first to cover the surface of nanotubes with polymers, and then they studied their activity against cancer. The peripheral end of PG is usually used to bind other molecules, for example, target agents, radionucleides, drugs. The treatment of tumors can be carried out using nanotubes with nanotube-PEG-RGD conjugate (arginine-glycine-aspatrtam peptide), and observation was carried out using Raman spectroscopy. The therapeutic effect has been investigated using the Paclitaxel drug attached to the end of the RGD chain, but a direct comparison of the results obtained with approved drugs (for example, with Doxil) has yet to be carried out.
Another way to use nanotubes to fight cancer is their ability to convert electromagnetic field energy into heat. Nanotube-based hyperthermia with radio wave activation was performed using nanotubes coated with Kentera (a polymer based on polyphenylene-ethinylene).
Chemical modification of nanotubes suggests that after further modification by therapeutic agents, functional groups remain rigidly fixed on the carbon frame. Table 1 presents therapeutic models in which covalently and non-covalently modified nanotubes are compared.
The use of nanotubes in medicine, which was first discussed a few years ago, has already led to some results in vivo. New results focused on the treatment of specific diseases are expected in the near future. There are other medical applications whose development has just begun – mainly engineering (electrodes for neurology), orthopedic and dental implants, biosensors – which lie outside the scope of this article. Such applications, especially those that will not be in direct contact with living organisms, can be developed faster.
Unwanted side effects of nanotubes, despite the constant interest of researchers to the issue of safety hitherto could not be detected (table. 2).
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