Biocompatible agent for dispersing nanoparticles in water medium with application of polymer imitating adhesive protein of mussel

FIELD: chemistry.

SUBSTANCE: invention relates to grafted polymer, imitating adhesive protein of mussel, to method of obtaining grafted polymer, to nanoparticles dispersed in water medium, colloid solution and contrast agent. Grafted polymer represents polyethyleneimine, grafted with polyethyleneglycol and polydihydroxyphenylalanine (PEI-graft-(PEG; PDOPA)). Polydihydroxyphenylalanine represents condensation polymer of 3,4-dihydroxyphenylalanine (DOPA). Method of obtaining grafted polymer includes several stages. At the first stage grafted copolymerisation of polyethyeleneglycol with polyethyleneamine is carried out. At the second stage after protection of hydroxyl groups of 3,4-dihydroxyphenylalanine synthesis of N-carboxyanhydride of 3,4-dihydroxyphenylalanine is performed in presence of triphosgene as catalyst. After that, reaction of polymer, obtained at the first stage, and N-carboxyanhydride of 3,4-dihydroxyphenylalanine in organic solvent is carried out. Colloid solution contains nanoparticles dispersed in water medium, with said grafted polymer being used as dispersion stabiliser. Contrast agent for magnetic-resonance tomography (MRT) includes said colloid solution.

EFFECT: invention makes it possible to obtain biocompatible stabiliser, providing stable dispersion of nanoparticles in water medium, as well as to obtain highly effective nanoparticles as contrast agent for MRT.

25 cl, 8 dwg, 2 tbl, 6 ex

 

The technical field to which the invention relates.

In the present invention are described imitating the adhesive protein of the mussel stabilizing the dispersion agent ("stabilizer") for dispersion of nanoparticles in the aquatic environment, a colloidal solution including nanoparticles, dispersed and stable stabilizing the dispersion agent, and a contrast agent comprising a colloidal solution. More specifically, imitating the adhesive protein of the mussel, the dispersion stabilizer is polyethylenimine grafted with polyethylene glycol and policyidreference (PEI-graft-(PEG; PDOPA)). Grafted polymer consists of two parts, one is polyethylenimine grafted biocompatible polymer based on polyethylene glycol, which has an affinity to the aquatic environment (sometimes known in short as "polyethylene glycol grafted polyethylenimine"), and the other is policyidreference (pDOPA), which has an affinity to the surface of the nanoparticles. Because of these characteristics, the regulator provides a stable dispersion of nanoparticles in the aquatic environment.

The level of technology

Nanoparticles are used in various applications such as nanoelectronic convergent technology scan of a living organism, medical applications, and so on

In particular, nanocast is subjected to super-paramagnetic iron oxide is widely used in various biomedical applications, such as, for example, contrast agents for magnetic resonance imaging (MRI), cell therapy, hyperthermia, drug delivery, separation of cells, preparation of nucleic acids, etc.

The most important requirement for use in biomedical applications represents, primarily, the provision of high quality nanoparticles and, in addition, providing nanoparticles having an excellent ability to dispersion and dispersion stability in an aqueous environment. Here the nanoparticles of high quality can mean the nanoparticles having the following features: (i) uniformity of particle size, (ii) easy control of particle size, (iii) the crystallinity of the particles, (iv) the ability to control the morphology of the particles and so on

However, the known technique, the nanoparticles, which are commercially available, in most cases, are synthesized in an aqueous system, or they can be obtained by synthesis in the gas phase. During the synthesis of nanoparticles in the ways described, it is difficult to obtain particles of uniform shape, and, as a rule, they have violated the crystallinity. In addition, it is difficult to produce nanoparticles having a uniform size, and to control the particle size.

Recently conducted numerous studies for the development of a new method of manufacturing the organic si is the subject of nanoparticles of metal oxides, which have a relatively high quality, that is, uniform in size and favorable crystallinity, compared with nanoparticles synthesized in an aqueous system according to methods of prior art.

Essentially, in the case where the nanoparticles are synthesized in an organic solvent, controlling the uniformity and size of the nanoparticles can sometimes be achieved by their stabilization using organic additive in the synthesis process. In this regard, as on surface of the nanoparticles influences the hydrophobic portion of the organic additives, nanoparticles of metal oxides can be easily atomized in a hydrophobic organic solvent. However, when mixed with water, they do not have sufficient stability.

In the case of such nanoparticles produced in an organic solvent, a hydrophobic surface properties of the nanoparticles can prevent stable dispersion of nanoparticles in water, thus creating a problem for use in biomedical applications. Thus, when using nanoparticles in the aforementioned applications, there is a need to develop biocompatible dispersion stabilizer, which converts (or modifies) the surface of the nanoparticles to make them hydrophilic properties and provides appropriate status is e, so they were homogeneous dispersed in the aquatic environment. In addition, you must also develop a stabilizer dispersion of the nanoparticles, which are produced using the above biocompatible dispersion stabilizer, in which the state of stable dispersion in the aqueous system.

Among the ways of dispersing the nanoparticles in the aqueous system in accordance with the relevant field of technology using a thin layer of silicon dioxide, which has recently described in the article (Journal of American Chemical Society, 2005, 127 so, S. 4990). According to the above article, polyoxyethyleneglycol ether is injected in cyclohexane solution, and mix with it, getting drops microminerals emulsion. After that induce the Sol-gel reaction of tetraethylorthosilicate (TEOS), and the nanoparticles are covered with a layer of silicon dioxide and is dispersed in water. In the above described method of coating the outside of the nanoparticles hydrophilic layer of silicon dioxide dispersion of the nanoparticles in water, in which the nanoparticles produced in an organic solvent. In this case, the method of coating the silicon dioxide using microemulsions arises the problem that, as the number of nanoparticles that are covered at one time is very small, the amount of dispersion of the nanoparticles in the aqueous system, manufactured in one about the essays, also greatly reduced. In addition, according to the number of colloids nanoparticles produced in the same process, or the number polyoxyethyleneglycol ether, changes the state of the microemulsion. Thus, there are difficulties in the fine regulation of the desired thickness of the layer of silicon dioxide and achieving uniformity of coated particles, because you are changing the number of nanoparticles contained in the layer of silicon dioxide. In the case where the nanoparticles are stabilized by a layer of silicon dioxide, the above mentioned methods the relevant field of technology cause problems in that the silane functional groups on the surface of the silicon dioxide are not sufficiently stable, but react with each other; thus, the nanoparticles coated with silica and dispersed in water, are combined and glomerida over time. The result was difficult to ensure the stability of the dispersion during storage over an extended period of time.

In recent years, the method of dispersing the nanoparticles in water using a polymer consisting of phosphine oxide and polyethylene glycol, as described in the article (Journal of American Chemical Society, 2005, 127 so, S. 4556). More specifically, in the above article describes how the dispersion of the nanoparticles, in which, after reaction polietilene the Kohl and 1,2-bis(dichlorophosphino)ethane for the synthesis of the polymer, in which parts of polyethylene glycol linked to each other, the polymer reacts exchange ligands with nanoparticles, dispergirovannykh in a hydrophobic solvent, resulting in stabilization of a dispersion of nanoparticles that are uniformly dispersed in water. The described method of production is simple, and it uses the exchange of ligands for dispersing the nanoparticles in water. However, since the phosphorus atom (P) is prone to oxidation and becoming a phosphoryl group, covering the polymer should be synthesized in an inert atmosphere using nitrogen or argon. In addition, since the polymer is crosslinked state, still remains the problem of introducing a functional group for binding in vivo functional ligands such as DNA, RNA, monoclonal antibody or other functional proteins.

Recently, scientists conducted a series of studies of mussels as a possible source of biological adhesives. Mussels produce and secrete an adhesive material that is functionally differentiated, allowing the mussels to remain in a fixed or snapped in the water, in the marine environment, which is characterized by salinity, humidity, tidal currents, eddy currents, waves, etc. mussel firmly attached to the surface of the material in water, is using threads, consisting of bundles of fibers discharged from the legs mussels. At the end of each fiber is present in a plaque containing a water-resistant binder material, which allows the mussels to attach to wet the solid surface. Protein this thread contains a large amount of 3,4-dihydroxyphenyl-L-alanine (DOPA), which is an amino acid formed by the hydroxylation of tyrosine groups using polyphenoloxidase. Catechin (3,4-dihydroxyphenyl) on the side branch DOPA can form very strong hydrogen bonds with hydrophilic surface and/or tightly bind metal ions, metal oxides (Fe3+, Mn3+), semimetals (silicon), etc.

Description of the invention

Technical problem

Thus, as a result of extensive studies for solving the above problems in the related technical field the present invention has been biocompatible dispersion stabilizer, which may cause the surface of the nanoparticles in the hydrophilic state to dispersing the nanoparticles in the aqueous system, and found that when using this stabilizer can provide dispersion and stabilization of nanoparticles stabilization of a dispersion in an aqueous system, as a result it can be effectively used for biomedical applications. In addition, pilotage detected, the nanoparticles, dispersed and stabilized biocompatible dispersion stabilizer according to the present invention may be applicable in the field of nanoelectronic technology for melting quantum dot (Q-dot) light-emitting device, the scanning area of biological objects as a contrast agent for MRI, the field of textile technology for cell therapy, Biomedicine concerning hyperthermia, drug delivery, and so forth.

The present invention is to provide a dispersion stabilizer, which simulates protein mussels and converts the surface of a variety of nanoparticles in the hydrophilic state through a simple process in such a way as to stabilize the dispersion of the nanoparticles in the aquatic environment that ensures their application in Biomedicine.

Another objective of the present invention is to provide biocompatible dispersion stabilizer, which simulates protein mussels and includes branched polymer type policyidreference, in which the stabilizer can stably connect with nanoparticles during the formation of many links.

Another objective of the present invention is to provide polyethylenimine grafted polietilene the MCPFE and policyidreference (PEI-graft-(PEG; PDOPA)), including the formation of polyethylenimine grafted biocompatible polymer based on polyethylene glycol, which has an affinity to the aquatic environment (sometimes known in short as "polyethylene glycol grafted polyethylenimine"), and policyidreference, which has an affinity to the surface of the nanoparticles.

Another objective of the present invention is to provide a method of obtaining a biocompatible dispersion stabilizer comprising simulating protein mussels polymer, i.e. polyethylenimine grafted with polyethylene glycol and policyidreference.

Another objective of the present invention is to provide dispersed in the aqueous environment of the nanoparticles using a dispersion stabilizer.

Another objective of the present invention is to provide a colloidal solution containing nanoparticles, dispersed and stabilized in an aqueous medium by using a dispersion stabilizer.

Another objective of the present invention is to offer a contrast agent comprising a colloidal solution, which is described above.

Solution

In a General aspect the present invention provides imitating the adhesive protein of the mussel, the dispersion stabilizer for the dispersion of nanoparticles in the aquatic environment, Collot the command solution containing nanoparticles, dispersed and stabilized by the above-mentioned dispersion stabilizer, and a contrast agent comprising a colloidal solution, which is described above. More specifically, imitating the adhesive protein of the mussel, the dispersion stabilizer is polyethylenimine grafted with polyethylene glycol and policyidreference (PEI-graft-(PEG; PDOPA)) comprising a polymer of polyethylenimine grafted biocompatible polymer based on polyethylene glycol, which has an affinity to the aquatic environment (sometimes abbreviated called "polyethylenimine grafted by polyethylene glycol"), and policyidreference, which has an affinity to the surface of the nanoparticles.

The present invention also provides a method of obtaining polyethylenimine grafted with polyethylene glycol and policyidreference, comprising: (a) connection of polyethylene glycol as a hydrophilic polymer with polyethylenimine through the formation of covalent bonds with obtaining polyethylenimine grafted polyethylene glycol; (b) after protection of the hydroxyl groups of DOPA synthesis of N-carboxyanhydride (NCA) DOPA in the presence of triphosgene as a catalyst; and (c) reaction covalently linked polyethylene glycol and polyethylenimine from stage (a) and N-carboxyanhydride (NCA) DOPA, obtained in stage (b), in organic solvents is e, obtaining in this way polyethylenimine grafted with polyethylene glycol and policyidreference.

In addition, the present invention provides dispersed in the aqueous environment of the nanoparticles using polyethylenimine grafted with polyethylene glycol and policyidreference as a stabilizer dispersion containing a colloidal solution. In addition, the present invention provides a contrast agent comprising a colloidal solution.

Hereinafter the present invention will be described in more detail.

Simulating the adhesive protein of the mussel, the dispersion stabilizer according to the present invention is polyethylenimine grafted with polyethylene glycol and policyidreference comprising a polymer of polyethylenimine grafted biocompatible polymer based on polyethylene glycol, which has an affinity to the aquatic environment (sometimes abbreviated called "polyethylenimine grafted by polyethylene glycol"), and policyidreference that has affinity to the surface of the nanoparticles, which contains the adhesive amino acid mussels, i.e. DOPA.

To get polyethylenimine grafted with polyethylene glycol and policyidreference according to the present invention, polyethylene glycol and polyethylenimine first joining through education Kowal is ntih links, forming polyethylenimine grafted polyethylene glycol. The obtained product is used as biocompatible macroinitiator.

The polyethylene glycol used in the present invention, may be a polyethylene glycol having srednecenovogo molecular weight of from 300 to 50,000, a hydroxyl group or carboxyl group on the end. According to one variant of implementation of the present invention, the polyethylene glycol is methoxypolyethyleneglycol containing as substituents metaxylene group on one end and a carboxyl group at the other end.

Polyethylenimine used in the present invention, may be a branched polyethylenimine, non-toxic, which Brednikova molecular weight is from 100 to 10100, preferably from 100 to 2000. If Brednikova molecular weight branched polyethylenimine is less than 100, the resulting copolymer according to the present invention will not be able to properly combined with a physiologically active material suitable for this purpose. On the other hand, when Brednikova molecular weight is 10100 or more, you may experience difficulty in removing the above-mentioned material from the body through the kidneys. Accordingly, in the present izobreteny which should preferably be used polyethylenimine, which Brednikova molecular weight is in the above range.

Policyidreference used in the present invention, may be a condensation polymer, for which 3,4-dihydroxyphenylalanine (DOPA) is used as the monomer. The repeating units are linked by amide bonds. The number of repeating units is from 1 to 100. Policyidreference you can polimerizuet by solid-phase synthesis and liquid phase synthesis using a variety of methods of education relations, including the reaction via carbodiimide, symmetric anhydrite way, anhydrite mixed method, active ester method, azide method, acylchlorides way and N-carboxyanhydrides way. Such approximate methods, which are described above, are proposed to ensure a clear understanding of policyidreference. However, policyidreference not limited to polymers, which are synthesized by the above methods. Policyidreference used in the present invention, can be synthesized in several ways, described above, preferably N-carboxyanhydrides way.

Polyethylenimine grafted with polyethylene glycol and policyidreference according to the present invention may include polietilen the school link represented by the following structure (A), the link polyethylenimine, represented by the following structure (B), and the link policyidreference, represented by the following structure (C):

where a is from 2 to 1200,

where A represents a branched polyethylenimine and x is from 1 to 100,

where d is from 1 to 100.

The above link polyethylenimine (B) may, in particular, to provide the following structure.

where each number of b and c independently range from 1 to 100, preferably from 1 to 30.

Policyidreference according to the present invention are synthesized from N-carboxyanhydride (NCA) DOPA, where DOPA is one of the adhesive amino acids mussels and preferably at least one substance selected from L-DOPA (L-3,4-dihydroxyphenylalanine) and D-DOPA (D-3,4-dihydroxyphenylalanine). Policyidreference can be selected from the group comprising L-policyidreference synthesized from N-carboxyanhydride (NCA) L-3,4-dihydroxyphenylalanine (L-DOPA), D-policyidreference synthesized from N-carboxyanhydride (NCA) D-3,4-dihydroxyphenylalanine (D-DOPA) and L,D-policyidreference synthesized from N-carboxyanhydride (NCA) L,D-3,4-dihyd is oxyphenisatin (L,D-DOPA, a mixture of L-DOPA and D-DOPA).

Stage (a) is the process of obtaining biocompatible macroinitiator used in the synthesis of simulating protein mussels polymer to stabilize the nanoparticles. At stage (a) can be done in the formation of covalent bonds between polyethylene glycol and polyethylenimine using dicyclohexylcarbodiimide (DCC)/N-hydroxysuccinimide (NHS) or, alternatively, hexamethylenediisocyanate (HMDI). Here DCC and NHS activate the carboxyl group of the polyethylene glycol containing at the ends as metaxylene and carboxyl group to interact with the primary amino group of polyethylenimine forming peptide covalent bond. Alternatively, HMDI activates the hydroxyl group of polyethylene glycol containing at the end metaxylene group, and is used for connection with the primary amino group of polyethylenimine. The formation of covalent bonds between polyethylene glycol and polyethylenimine, which is activated HMDI, may include any reaction with the formation of covalent bonds between the two above mentioned polymers. In one embodiment of the present invention after the dissolution of the polyethylene glycol and activation polyethylenimine DCC/NHS in chloroform, respectively, a solution of polyethylene glycol is added in drops to a solution of polyethylenimine, ensure achiwa, thus, the formation of covalent bonds between the two polymers. After completion of the reaction, the reaction solution was concentrated, and diethyl ether precipitated the product quality covalent copolymer of polyethylene glycol and polyethylenimine. Structure of polyethylene glycol, activated DCC/NHS, and the structure containing the covalent bond of the activated polyethylene glycol and polyethylenimine branched type (PEI) is illustrated as follows:

(where a is from 2 to 1200.)

<Activation of polyethylene glycol (PEG-NHS)>

(where, a is from 2 to 1200.)

<Polyethylenimine grafted polyethylene glycol (PEI-graft-PEG)>

Synthesis of N-carboxyanhydride (NCA) DOPA at the stage (b) can be carried out using at least one substance selected from adhesive amino acids mussels, that is, L-3,4-dihydroxyphenylalanine (L-DOPA) and D-3,4-dihydroxyphenylalanine (D-DOPA) as a starting material, and any method of obtaining N-carboxyanhydride (NCA) amino acids, which is known in the relevant field of technology. Preferably the above-mentioned substance (NCA) is obtained by reaction of the adhesive amino acids mussels (D-DOPA or L-DOPA or L,D-DOPA) in an appropriate solvent in the presence of triphosgene as a catalyst.

According to gnome variant implementation of the present invention, as illustrated below, L-DOPA dissolved in acetic acid using acetic anhydride and hydrochloric acid, then acetimidoyl hydroxyl group of L-DOPA to synthesize (AC)2DOPA, while protecting a hydroxyl group. Then, using triphosgene in an organic solvent, which is a tetrahydrofuran (THF), synthesize N-carboxyanhydride (NCA) L-DOPA (see below).

<a reaction Scheme N-carboxyanhydride (NCA) DOPA>

Getting polyethylenimine grafted with polyethylene glycol and policyidreference at the stage (c) can be done in multiple initiating polyethylenimine grafted polyethylene glycol obtained in stage (a) and N-carboxyanhydride (NCA) DOPA, synthesized at the stage (b), in an organic solvent that provides the appropriate polymerization. Policyidreference synthesized by inducing polymerization of N-carboxyanhydride DOPA, using the primary amino group present in polyethylenimine grafted polyethylene glycol, as multiple initiator. According to the above processes, the synthesized policyidreference connected with polyethylenimine grafted polyethylene glycol, to form the final product, i.e. polyethylenimine grafted polietileno Olam and policyidreference.

At the stage (c) by adjusting the added amount of N-carboxyanhydride (NCA) DOPA, which is used as a simulator of biological binding centre, you can give the polymer according to the present invention an adjustable binding capacity and hydrophobic properties (hydrophobicity). Preferably the molar ratio of polyethylenimine grafted peg to the N-carboxyanhydride (NCA) DOPA is from 1:1 to 1:50. If the molar ratio is outside the above interval, problems can occur increasing the hydrophobicity or reduce the binding ability of simulating biological protein stabilizer dispersion.

The organic solvent used in stage (c) may include at least one substance selected from dimethyl sulfoxide (DMSO), tetrahydrofuran (THF) and chloroform (CHCl3).

After completion of the polymerization in stage (c) can further include a stage (d), which is a process to unprotect a protected hydroxyl group policyidreference. According to one variant of implementation of the present invention, after completion of the polymerization of polyethylenimine grafted with polyethylene glycol and policyidreference product was dispersed in dimethylformamide (DMF). After that, by adding to the mixture appropriate to the number of hydroxyl piperidine group DOPA, protected by acetyl group, can be deacetylate, receiving, in turn, polyethylenimine grafted with polyethylene glycol and policyidreference PEI-graft-(PEG; PDOPA), represented by the following structure:

(where a is from 2 to 1200, and each of the numbers d and d' independently is from 1 to 100).

<Polyethylenimine grafted with polyethylene glycol and policyidreference PEI-graft-(PEG; PDOPA)>

In addition, the proposed dispersed in the aqueous environment of the nanoparticles, which are used stabilizing the dispersion agent, and a colloidal solution comprising the nanoparticles.

Polyethylenimine grafted with polyethylene glycol and policyidreference used in the present invention, may be a biocompatible dispersion stabilizer branched type, including simulating the adhesive protein of the mussel biocompatible polymer and containing policyidreference, which is useful for dispersion and stabilization of nanoparticles in the aquatic environment.

These nanoparticles can include one or more inorganic nanoparticles selected from the group comprising metal, chalcogenide metal, oxide metal, magnetic material, magnetic alloys, semiconductor materials or multicomponent composite structure.

More specifically, the metal can is about to select from the group composed of Pd, Pt, Au, Cu and Ag; chalcogenide metal can represent MxEy(M=Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zr, Mo, Ru, Rh, Ag, W, Re, Ta, Hf, Zn or Cd; E=O, S or Se; 0<x≤3; 0<y≤5); and the metal oxide can be selected from the group which consists of titanium oxide, vanadium oxide, chromium oxide, manganese oxide, iron oxide, cobalt oxide, Nickel oxide, copper oxide, zirconium oxide, molybdenum oxide, ruthenium oxide, rhodium oxide, silver oxide, tungsten oxide, rhenium oxide, tantalum oxide, hafnium oxide and zinc oxide. More preferably, the iron oxide can be selected from FeO, Fe3O4(magnetite), α-Fe2O3, β-Fe2O3, γ-Fe2O3(maghemite), ε-Fe2O3, Fe(OH)2, Fe(OH)3α-FeOOH, β-FeOOH, γ-FeOOH, δ-FeOOH, Fe5HO8•4H2O, 5Fe2O3•9H2O, FeOOH•4H2O, Fe8O8(OH)6(SO)•nH2O, Fe16O16(OH•SO4)12-13•10-12H2O and a mixture of Fe3O4(magnetite) and γ-Fe2O3(maghemite). Alternatively, the magnetic substance is preferably chosen from the group comprising Co, Mn, Fe, Ni, Gd, MM'2O4and MxOy(M or M'= Co, Fe, Ni, Mn, Zn, Gd, Cr; 0<x≤3; 0<y≤5, respectively); magnetic alloys are preferably chosen from the group which consists of CoCu, CoPt, FePt, CoSm, NiFe and NiFeCo. When this semiconductor material can be selected from the group that SOS is ablaut semiconductors, including elements selected from group 2 and group 6, respectively; semiconductors comprising elements selected from the group 3 and group 5, respectively; semiconductors comprising elements of group 4; semiconductors comprising elements selected from group 4 and group 6, respectively; and semiconductors comprising elements selected from the group 5 and group 6, respectively. Multi-component composite structure may include at least two materials selected from the group comprising metal, chalcogenide metal, magnetic material, magnetic alloys and semiconductor materials, also included are materials having a structure with a core and shell or heterophony structure. More preferably it is possible to use at least one material selected from the group consisting of the following combinations of compounds that form the structure of the core/sheath, respectively: cadmium selenide/zinc sulfide (CdSe/ZnS), cadmium selenide/zinc selenide (CdSe/ZnSe), cadmium selenide/cadmium sulfide (CdSe/CdS), cadmium telluride/zinc sulfide (CdTe/ZnS), cadmium telluride/selenide zinc (CdTe/ZnSe), cadmium telluride/cadmium sulfide (CdTe/CdS) the cadmium telluride/cadmium selenide (CdTe/CdSe), zinc sulfide (ZnS), cadmium sulfide (CdS), indium arsenide (InAs), indium phosphide (InP), indium arsenide/indium phosphide (InAs/InP), gallium indium/cadmium selenide (InAs/Cde), gallium indium/zinc sulfide (InAs/ZnS), gallium indium/zinc selenide (InAs/ZnSe), indium phosphide/cadmium selenide (InP/CdSe), indium phosphide/zinc sulfide (InP/ZnS), indium phosphide/zinc selenide (InP/ZnSe), etc.

In addition, a contrast agent comprising a colloidal solution.

Useful effects of the invention

According to the present invention, it is possible to synthesize imitating the adhesive protein of the mussel biocompatible dispersion stabilizer, which is able to modify the surface of nanoparticles and stably dispersing them in an aqueous environment. The stabilizer dispersion obtained according to the present invention contains policyidreference synthesized by mnogonatsionalnoi polymerization and containing, in turn, at least one link DOPA molecule, i.e. representing repeatedly interacting ligand (MIL) and having a high strength of bonding with the hydrophilic surface. Since the stabilizer dispersion obtained according to the present invention, has a positive charge, this can further enhance the electrostatic attraction to the surface of the nanoparticles with a negative charge. In addition, since many molecules of polyethylene glycol having hydrophilic properties, connected with the branches of polyethylenimine branched tee is a, it is possible to provide a high degree of stabilization of aqueous dispersions due to the hydrophilic properties and stereoscopic effects. Accordingly, biocompatible stabilizer dispersion obtained according to the above description, can provide a stable dispersion of nanoparticles in the aquatic environment, therefore it is applicable in a variety of fields, including, for example, nanoelectronic convergent technologies, such as quantum dot (Q-Dot light-emitting devices, contrast agents for use in imaging of biological objects, such as magnetic resonance imaging (MRI); the application of cellular technologies, such as cell therapy; biomedical applications such as hyperthermia, drug delivery, and so on in Addition, compared with nanoparticles, dispergirovannykh stabilizers dispersions obtained according to conventional technologies, it becomes possible to achieve excellent stability of dispersion.

Brief description of drawings

The above and other objectives, features and advantages of the present invention become apparent from the following description of preferred embodiments given in conjunction with the accompanying drawings, of which:

Fig.1 illustrer is no chemical structure mimics the adhesive protein of the mussel biocompatible stabilizer dispersion and stabilization of the nanoparticles, used in the present invention;

Fig.2 illustrates the results of the analysis by the method of NMR spectroscopy1H (in DMSO) polymer PEI-graft-(PEG; PDOPA5) obtained in example <1-6>;

Fig.3 illustrates the results of the analysis by the method of NMR spectroscopy1H (CDCl3) polymer PEI-graft-(PEG; PDOPA5) obtained in example <1-6>;

Fig.4 illustrates the results of the analysis by the method of NMR spectroscopy1H (in DMSO) polymer PEI-graft-(PEG; PDOPA15) obtained in example <1-6>;

Fig.5 illustrates the results of the analysis by the method of NMR spectroscopy1H (CDCl3) polymer PEI-graft-(PEG; PDOPA15) obtained in example <1-6>;

Fig.6 illustrates obtained by the method of transmission electron microscopy (TEM) images of the nanoparticles (a: 11 nm Fe3O4b: 13 nm MnO, c: 5 nm Au, d: 3 nm CdSe/ZnS), dispersed before stabilization, and nanoparticles (e: 11 nm Fe3O4, f: 13 nm MnO, g: 5 nm Au, h: 3 nm CdSe/ZnS), which was dispersible in the water after stabilization using mimic the adhesive protein of the mussel biocompatible dispersion stabilizer (MIL2); and received from the device dynamic light scattering (DLS) particle sizes for a variety of nanoparticles, which was stable dispersible in water using mimic the adhesive protein of the mussel biocompatible dispersion stabilizer (i: Fe3O4j:MnO, k: Au, l: CdSe/ZnS);

Fig.7 illustrates the results of experimental studies of the stability of the nanoparticles of iron oxide (Fe3O4before stabilization, and after they were dispersively and stabilized in water, using mimic the adhesive protein of the mussel stabilizer dispersions at different pH values (Fig.7 (a)) and ion concentration (Fig.7 (b)), where the hydrodynamic diameter (HD) was measured using DLS device, and then compared the results of measurements (MIL0 (♦), MIL1 (▲) and MIL2 (○0)); and

Fig.8 illustrate the obtained in vivo by the method of magnetic resonance imaging (MRI) image stabilization of iron oxide imitating the adhesive protein of the mussel biocompatible dispersion stabilizer (MIL2), including image based on the measurement results before the introduction of the stabilizer (Fig.8 (a)) and after its introduction after 24 hours (Fig.8 (C)) and 48 hours (Fig.8 (C)).

Embodiments of the inventions

Advantages, features and aspects of the present invention become apparent from the following description of embodiments when considering the accompanying drawings, which are given after it. However, these embodiments of the above, to provide a clearer understanding of the present invention, and the amount of technical configurations of the present invention should not and shall Talkonaut as limited herein options for implementation. On the contrary, various modifications or changes to the underlying concepts of the present invention and its implementation will be able to easily produce the usual experts in the relevant field of technology.

L-3,4-dihydroxyphenylalanine (DOPA), PEG-OH (5000 Da), dimethylformamide (DMF), N-hydroxysuccinimide (NHS), N,N'-dicyclohexylcarbodiimide (DCC), acetic anhydride, glacial acetic acid, methylene chloride (MC) and chloroform were purchased from the company Sigma Chemical Company (St. Louis, Missouri), and PEI (1800 Yes; PEI 1800) was purchased from Alfa Aesar. Within 48 hours before using these materials were dried at 40°C in vacuum.

[Example 1] Synthesis of simulating the adhesive protein of the mussel biocompatible dispersion stabilizer

<1-1> Activation of polyethylene glycol

<1-1-1> dicyclohexylcarbodiimide/N-hydroxysuccinimide (DCC/NHS)

After installing the dephlegmator methoxypolyethyleneglycol acid (PEG-COOH, 5000) (10 g) was dissolved in methylene chloride (CH2Cl2(50 ml) in a flask with a volume of 250 ml and Then the solution was added N-hydroxysuccinimide (NHS) (0.52 g) and dicyclohexylcarbodiimide (DCC) (0.74 g) and the reaction was performed at room temperature for 20 hours. After separation of dicyclohexylamine by filtering this material was besieged in diethyl ether, olucha the polyethylene glycol is in the activated state (PEG-NHS) (yield 87%). An NMR spectrum1H (300 MHz, CDCl3):1H NMR(300 MHz, CDCl3):δ4,1 (b, -CO-CH2-CH2-CH2-0-), 3.5 to 3.8 (m, -CH2CH2O-), and 2.8 (b, -CO-CH2-CH2-CO-), and 1.8 (b, -CO-CH2-CH2-CH2-CH2-CH2-O-), 1,2 (b, -CO-CH2-CH2-CH2-CH2-CH2-O-).

<1-1-2> Use of hexamethylenediisocyanate (HDMI)

After installing the dephlegmator methoxypolyethyleneglycol (PEG-OH) (15,23 g) was dissolved in chloroform (CHCl3) (15 ml) in a flask with a volume of 100 ml. and Then the solution was added hexamethylenediisocyanate (HMDI) (60 ml) and reaction was performed for 24 hours to obtain a polymer. After completion of the reaction the polymer was besieged in petroleum ether for purification and after three times washing with petroleum ether (400 ml) washed material was again dissolved in chloroform (CHCl3) (20 ml). After that permeate again besieged in petroleum ether (500 ml) for purification. The above procedure was repeated 10 times, and then were dried in vacuum, obtaining the polyethylene glycol is in the activated state (yield 80%).

<1-2> Getting polyethylenimine grafted polyethylene glycol (PEI-graft-PEG)

The activated polyethylene glycol (PEG-NHS) (2 g) obtained in example <1-1>, was dissolved in chloroform (200 ml). Then after the dissolution of the polyethylene is mine (Alfa Aesar, 1800 Yes, 0.5 g) in chloroform (50 ml), was added in drops a solution of polyethylene glycol to the reaction with the formation of covalent bonds between polyethylene glycol and polyethylenimine. This reaction was carried out for 24 hours, and after completion of the reaction the resulting product was concentrated to achieve a total volume of 30 ml using a vacuum concentrator. After this concentrated material was besieged in diethyl ether, receiving polyethylenimine grafted polyethylene glycol (PEI-graft-PEG) (yield 85%). An NMR spectrum1H (300 MHz, D2O). In the result of measurement of the peaks-CH2CH2O - PEG at 3.5 to 3.8 M. D. and CH2CH2NH - PEI with 2,5-3,2 memorial plaques was calculated Mn PEI-graft-PEG, which amounted to approximately 41800 Yes. The assumption was made that on one link in PEI grafted copolymer was approximately 8 units of PEG (hereinafter designated as PEI1-graft-PEG8). An NMR spectrum1H (300 MHz, D2O):δ3.5 to 3.8 (m, -CH2CH2O-), 3.5 to 3.8 (m, -CH2CH2O-), and 3.3 (s, CH3O-), 2,5-3,2 (m, -CH2CH2NH-).

<1-3> protection of the hydroxyl group of the amino acid DOPA

L-DOPA (3 g) suspended in glacial acetic acid (100 ml), and then blew dried gaseous hydrogen chloride at room temperature for 5 hours. After added the acetic anhydride (3 ml) and the reaction at room temperature for 90 minutes was added 3 ml of acetic anhydride, and the reaction was carried out at an oil bath at 60°C for 30 minutes. The reaction product was concentrated using a vacuum concentrator, and unreacted acetic anhydride was separated by adding ethanol. After that, the remaining product was besieged in diethyl ether, obtaining the amino acid DOPA-protected hydroxyl group (DOPA(Ac)2) (yield 80%). An NMR spectrum1H (300 MHz, D2O):δ6,7-6,9 (m, -C6H3(OH)2), 4,0 (m, C6H3(OH)2-CH2-CH(N-)-C(O)N-), 3,2 (m, C6H3(OH)2-CH2-CH-), and 2.4 (s, CH3(CO)-).

<1-4> Synthesis of N-carboxyanhydride (NCA) amino acid DOPA

In THF (50 ml) was dispersively 0.5 g of the amino acid DOPA-protected hydroxyl group, synthesized in example <1-3>, and 0.5 g of triphosgene, and carried out the reaction in an oil bath at 60°C. thereafter, the reaction product was besieged in hexane (800 ml) was dissolved in THF (50 ml) and again besieged in hexane. The above procedure was repeated three times. After purification the product was dried using a vacuum dryer, and received N-carboxyanhydride DOPA (DOPA(AC2)-NCA) (yield 65%). An NMR spectrum1H (300 MHz, DMSO):δa 6.2 to 6.9 (m, -C6H3(OH)2), 4,3 (t,-NHCH CO-), and 3.7 (m, C6H3(OH)2-CH2-CH(N-)-C(O)N-), 3,3 (m, C6 H3(OH)2-CH2-CH-), and 2.4 (s, CH3(CO)-).

<1-5> Synthesis of polyethylenimine grafted with polyethylene glycol and policyidreference (PEI-graft-(PEG; PDOPA))

Used 0.5 g of polyethylenimine grafted polyethylene glycol (PEI-graft-PEG) obtained in example <1-2>, and N-carboxyanhydride DOPA (DOPA(AC2)-NCA) obtained in example <1-4>, at different molar ratios (1:5 and 1:15, respectively), which are reacted in a solvent THF, the resulting synthesized polyethylenimine grafted with polyethylene glycol and policyidreference (yield 85% at a molar ratio of 1:5 and 87% at a molar ratio of 1:15.

<1-6> unprotect polyethylenimine grafted with polyethylene glycol and policyidreference

After dissolving 0.5 g of polyethylenimine grafted with polyethylene glycol and policyidreference synthesized in example <1-5> in DMF (30 ml), the solution was added 8 ml of piperidine. 15 minutes after the reaction the reaction product was besieged in diethyl ether, receiving polyethylenimine grafted with polyethylene glycol and policyidreference, which removed the protection from the protected hydroxyl group DOPA (yield 80% at a molar ratio of 1:5 (Fig.2 and 3) and 81% at a molar ratio of 1:15 (Fig.4 and 5)).

The following table 1 represents the results of the structure imitating the adhesive b is Lok mussels biocompatible dispersion stabilizer according to the present invention and its characteristics, where the polymer structure and its characteristics were investigated by NMR1H and spectroscopy in the ultraviolet and visible range, using fluorescent tag.

Table 1
Analysis of the structure and characteristics simulating the adhesive protein of the mussel biocompatible dispersion stabilizer
The code samplePolymerPEG
Mn
PEIMnThe molar ratio of the individual materialsandMnaCMC (g/l)b
PEGPEIDOPA
MIL0PEI-graft-PEG5000180081-41800-
MIL1 PEI-graft(PEG;
PDOPA)
50001800815428000,015
MIL2PEI-graft(PEG;
PDOPA)
500018008115448000,005
aMnrepresents srednecenovogo molecular weight, which is determined using NMR methods1H and spectroscopy in the ultraviolet and visible range.
bCMC is the critical micellization concentration, which was determined using the fluorescent label (Hoechst 33342)

[Example 2] the Synthesis of nanoparticles of iron oxide, stabilized mimic the adhesive protein of the mussel biocompatible dispersion stabilizer

Magnetic nanoparticles (Fe3O4, 10 mg) synthesized in an organic solvent and stabilized by oleic acid and 60 mg imitating the adhesive protein of the mussel biocompatible dispersion stabilizer (MIL1 and MIL2, respectively) were dispersible in 10 ml of chloroform (CHCl 3) and was stirred at room temperature for 30 minutes. After evaporation of chloroform (CHCl3and adding to the residue distilled water dispersed product was filtered through a syringe filter 200 nm (filter MCE syringe from Fisher Scientific company). After centrifugation to separate the unreacted stabilizer filtering was repeated 3 to 5 times using a centrifugal filter (Millipore, NMWL 10000, speed 3000 rpm, 10 minutes). The resulting product was dispersible in an aqueous system having a pH of 7.

[Example 3] the Synthesis of nanoparticles of manganese oxide, stabilized mimic the adhesive protein of the mussel biocompatible dispersion stabilizer

Nanoparticles of manganese oxide (MnO, 10 mg) synthesized in an organic solvent in the same manner as described in example 2, stabilized using mimic the adhesive protein of the mussel biocompatible stabilizers dispersion (MIL1 and MIL2, respectively), and then dispersible in the water.

[Example 4] Synthesis of gold nanoparticles stabilized mimic the adhesive protein of the mussel biocompatible dispersion stabilizer

Gold nanoparticles (Au, 10 mg) synthesized in an organic solvent in the same manner as described in example 2, stabilized using mimic the adhesive protein of the mussel biocompatible stabilizer, the dispersion (MIL1 and MIL2, respectively), and then dispersible in the water.

[Example 5] Synthesis of quantum dot nanoparticles, stabilized mimic the adhesive protein of the mussel biocompatible dispersion stabilizer

Quantum dot nanoparticles (CdSe/ZnS, 10 mg) synthesized in an organic solvent in the same manner as described in example 2, stabilized using mimic the adhesive protein of the mussel biocompatible stabilizers dispersion (MIL1 and MIL2, respectively), and then dispersible in the water.

[Example 6] the Synthesis of other inorganic nanoparticles, stabilized mimic the adhesive protein of the mussel biocompatible dispersion stabilizer

These inorganic nanoparticles synthesized in an organic solvent in the same manner as described in example 2, stabilized using mimic the adhesive protein of the mussel biocompatible stabilizers dispersion (MIL1 and MIL2, respectively), and then dispersible in the water.

Table 2
Inorganic nanoparticlesMIL1MIL2
The size of nanoparticles (nm)Hydrodynamic diameter* (nm) The size of nanoparticles (nm)Hydrodynamic diameter* (nm)
ZnO20282029
CdS69611

CoFeO412151218
FePt10141018
GdO25342536
*Hydrodynamic diameter is srednetsenovoj size determined by DLS method in dispergirovannom state in the aqueous system.

Fig.6 illustrates obtained by the method of transmission electron microscopy (TEM) images of the nanoparticles (a: 11 nm Fe3O4b: 13 nm MnO, c: 5 nm Au, d: 3 nm CdSe/ZnS), dispersed before stabilization, and nanoparticles (e: 11 n the Fe 3O4, f: 13 nm MnO, g: 5 nm Au, h: 3 nm CdSe/ZnS), which was dispersible in the water after stabilization using mimic the adhesive protein of the mussel biocompatible dispersion stabilizer (MIL2) obtained by the method according to the present invention.

According to the obtained by the method of TEM images in Fig.6, it can be understood that a variety of nanoparticles, which was stable dispersible in water using mimic the adhesive protein of the mussel biocompatible dispersion stabilizer obtained by the method described in the present invention are practically such a morphology and dimensions, which have different types of nanoparticles dissolved in a hydrophobic solvent before adding the above-mentioned polymer. In addition, it was found that these results are virtually unchanged even after adding a dispersion stabilizer.

In this case, the quantities i, j, k and l in Fig.6 illustrate certain method DLS particle size for a variety of nanoparticles (i: Fe3O4j: MnO, k: Au, l: CdSe/ZnS), which was stable dispersible in water using mimic the adhesive protein of the mussel biocompatible dispersion stabilizer (MIL2). It was demonstrated that the above-mentioned nanoparticles have a uniform and stable amount of 11 nm, 13 nm, 5 nm and 3 nm, respectively.

Fig.7 shows nanoparticles (Fe3O4 ), which was dispersively and stabilized in an aqueous system using mimic the adhesive protein of the mussel stabilizer dispersion obtained by the method according to the present invention, at different pH values (Fig.7 (a)) and ion concentration (Fig.7 (b)). More specifically, it can be seen that, compared with nanoparticles, dispergirovannykh and stable does not contain DOPA stabilizer dispersion (Fig.7 (a, b), MIL0 (♦)), nanoparticles, which were dispersively and stabilized using biocompatible stabilizer dispersion obtained according to the present invention (Fig.7 (a, b), MIL1 (▲) and MIL2 (○)), are more stable at different pH values (Fig.7 (a)) and ion concentration (Fig.7 (b)).

Fig.8 illustrate the obtained in vivo by the method of magnetic resonance imaging (MRI) image of nanoparticles of Fe3O4dispersed and stabilizedsimulating the adhesive protein of the mussel biocompatible dispersion stabilizer (MIL2), as a contrast agent in MRI device. In this regard, the image obtained before the introduction of the stabilizer (Fig.8, (A)) and after its introduction after 24 hours (Fig.8, (B) and 48 hours (Fig.8, (C)) demonstrate a favorable stability in the blood stream and a longer half-life (i.e. increased longevity) in the blood. In addition, NAS the particles of Fe 3O4dispersed stabilizing the dispersion agent, showed good efficacy as a contrast agent for MRI. Concerning obtained by means of MRI images in Fig.8 (a-C), confirmed that the bodies of the mouse was obscured after the introduction of nanoparticles of Fe3O4that have been modified MIL2. Accordingly, it is confirmed that the above-mentioned nanoparticles can be used as a contrast agent for medical use according to the present invention.

Industrial applicability

According to the present invention, it is possible to synthesize imitating the adhesive protein of the mussel biocompatible dispersion stabilizer, is able to modify the surface of nanoparticles and stably dispersing them in an aqueous environment. The stabilizer dispersion obtained according to the present invention contains policyidreference obtained in the process mnogonatsionalnoi polymerization, in turn, contains at least one link DOPA molecule, that is, by repeatedly interacting ligands (MIL), and having a high strength of bonding with the hydrophilic surface. Since the stabilizer dispersion obtained according to the present invention, has a positive charge, it can give additional force to the electrostatic attraction to p. the surface of the nanoparticles, possessing a negative charge. In addition, since many molecules of polyethylene glycol having hydrophilic properties, connected with the branches of polyethylenimine branched type, high stabilization of aqueous dispersions can be achieved with hydrophilic properties and stereoscopic effects. Accordingly, biocompatible stabilizer dispersion obtained according to the above description, can provide a stable dispersion of nanoparticles in the aquatic environment, therefore it is applicable in a variety of fields, including, for example, nanoelectronic convergent technologies, such as quantum dot (Q-Dot light-emitting devices, contrast agents for use in imaging of biological objects, such as magnetic resonance imaging (MRI); the application of cellular technologies, such as cell therapy; biomedical applications such as hyperthermia, drug delivery, and so on in Addition, compared with nanoparticles, dispergirovannykh stabilizers dispersions obtained according to conventional technologies, it becomes possible to achieve excellent stability of dispersion.

1. Polyethylenimine, grafted with polyethylene glycol and policyidreference (PEI-graft-(PEG; PDOPA)), including polietileno is l, polyethylenimine and policyidreference in which policyidreference is a condensation polymer of 3,4-dihydroxyphenylalanine (DOPA).

2. PEI-graft-(PEG; PDOPA) under item 1, in which the grafted polyethylene glycol is a polyethylene glycol having srednecenovogo molecular weight of from 300 to 50,000, a hydroxyl group or a carboxyl group at one end.

3. PEI-graft-(PEG; PDOPA) under item 2, in which one end of the polyethylene glycol is a hydroxyl group or carboxyl group and at the other end is metaxalona group.

4. PEI-graft-(PEG; PDOPA) under item 1, in which polyethylenimine is polyethylenimine branched type, having srednecenovogo molecular weight of from 100 to 10100.

5. PEI-graft-(PEG; PDOPA) under item 1, in which policyidreference synthesized from N-carboxyanhydride DOPA.

6. PEI-graft-(PEG; PDOPA) under item 5, in which DOPA is at least one substance selected from L-DOPA and D-DOPA.

7. PEI-graft-(PEG; PDOPA) under item 5, in which policyidreference selected from polyL-DOPA, synthesized from N-carboxyanhydride L-DOPA, and polyD-DOPA, synthesized from N-carboxyanhydride D-DOPA, and polyL,D-DOPA, synthesized from N-carboxyanhydride L,D-DOPA.

8. PEI-graft-(PEG; PDOPA) under item 1, which includes;
link polyethylene glycol represented by structure A,
link polyethylenimine presented structure is dependent on B, and
link policyidreference represented by structure C:

where a is from 2 to 1200,

where A represents a branched polyethylenimine and x is from 1 to 100,

where d is from 1 to 100.

9. PEI-graft-(PEG; PDOPA) under item 8, in which the link polyethylenimine represents the following structure:

where each number of b and c is from 1 to 100.

10. PEI-graft-(PEG; PDOPA) under item 5, in which the molar ratio of polyethylenimine grafted polyethylene glycol, and N-carboxyanhydride DOPA is from 1:1 to 1:50.

11. The method of obtaining polyethylenimine, grafted with polyethylene glycol and policyidreference (PEI-graft-(PEG; PDOPA)), including:
(a) graft copolymerization of polyethylene glycol with polyethylenimine through the formation of covalent bonds with obtaining polyethylenimine grafted polyethylene glycol;
(b) after protection of the hydroxyl groups of DOPA synthesis of N-carboxyanhydride DOPA in the presence of triphosgene as a catalyst; and
(c) reaction of polyethylenimine grafted polyethylene glycol obtained in stage (a), and N-carboxyanhydride DOPA, synthesized at the stage (b), in an organic solvent to obtain PEI-graft-(PEG; PDOPA).

12. The method according to p. 11, in which the grafted copolymerization with the adiya's (a) carry out, using dicyclohexylcarbodiimide and N-hydroxysuccinimide or, alternatively, using hexamethylenediisocyanate.

13. The method according to p. 11, in which DOPA at the stage (b) is at least one substance selected from L-DOPA and D-DOPA.

14. The method according to p. 11, in which the organic solvent at the stage (c) is at least one substance selected from dimethyl sulfoxide, tetrahydrofuran and chloroform.

15. The method according to p. 11, in which the molar ratio of polyethylenimine grafted polyethylene glycol, and N-carboxyanhydride DOPA at the stage (c) is from 1:1 to 1:50.

16. The method according to p. 11, further including:
(d) removing the protective group of hydroxyl group in policyidreference.

17. Dispersed in the aqueous environment of the nanoparticles, using as a dispersion stabilizer PEI-graft-(PEG; PDOPA) according to any one of paragraphs.1-10.

18. Nanoparticles under item 17, which are nanoparticles of one, two or more of the materials selected from the group comprising metal, chalcogenide metal, a metal oxide, a magnetic substance, a magnetic alloy, semiconductor material and heterophony material.

19. Nanoparticles under item 18 in which the metal is a one, two or more metals selected from the group comprising Pd, Pt, Au, Cu and Ag; chalcogenide metal you submitted the a M xEy(M=Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zr, Mo, Ru, Rh, Ag, W, Re, Ta, Hf, Zn or Cd; E=O, S or Se; 0<x≤3; 0<y≤5); the metal oxide is one or two or more oxides selected from the group which consists of titanium oxide, vanadium oxide, chromium oxide, manganese oxide, iron oxide, the cobalt oxide, Nickel oxide, copper oxide, zirconium oxide, molybdenum oxide, ruthenium oxide, rhodium oxide, silver oxide, tungsten oxide, rhenium oxide, tantalum oxide, hafnium oxide and zinc oxide; magnetic substance is one, two or more substances selected from the group comprising Co, Mn, Fe, Ni, Gd, MM'2O4and MxOy(M or M'=Co, Fe, Ni, Mn, Zn, Gd, Cr; x is from 1 to 3 and y is from 1 to 5, respectively); the magnetic alloy is a one, two or more alloys selected from the group which consists of CoCu, CoPt, FePt, CoSm, NiFe and NiFeCo; semiconductor material is a one, two or more of the materials selected from the group which consists of semiconductors comprising elements selected from group 2 and group 6, respectively; semiconductors, including elements selected from the group 3 and group 5, respectively; semiconductors comprising elements of group 4; semiconductors comprising elements selected from group 4 and group 6, respectively; and semiconductors comprising elements selected from the group 5 and group 6, meet the but.

20. Nanoparticles under item 18, in which heterophony material has a structure with a core and shell.

21. Nanoparticles on p. 19 in which the metal oxide is an oxide of iron.

22. Nanoparticles on p. 21, in which the metal oxide is one or two or more oxides selected from the group which consists of FeO, Fe3O4(magnetite), α-Fe2O3, β-Fe2O3, γ-Fe2O3(maghemite), ε-Fe2O3, Fe(OH)2, Fe(OH)3α-FeOOH, β-FeOOH, γ-FeOOH, δ-FeOOH, Fe5HO8•4H2O, 5Fe2O3•9H2O, FeOOH•4H2O, Fe8O8(OH)6(SO)•nH2O, Fe16O16(OH•SO4)12-13•10-12H2O and a mixture of Fe3O4(magnetite) and γ-Fe2O3(maghemite).

23. Nanoparticles on p. 22, in which the iron oxide is one, two or more oxides selected from Fe3O4(magnetite), γ-Fe2O3(maghemite) and mixtures thereof.

24. A colloidal solution containing dispersed in the aqueous environment of the nanoparticles under item 17.

25. Contrast agent for magnetic resonance imaging (MRI), comprising a colloidal solution containing nanoparticles dispersed in an aqueous medium p. 24.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to amphiphilic water-soluble alkoxylated polyalkylene imines and can be used as a detergent additive. The amphiphilic water-soluble alkoxylated polyalkylene imines have an internal polyethylene oxide block containing 10-50 polyethylene oxide units, and especially such alkoxylated polyalkylene imines in which the ratio of polyethylene oxide units to polypropylene oxide units is proportional to the square root of the number of polyalkylene imine units present in the skeleton.

EFFECT: invention improves removal of dirt even at low washing temperature.

13 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: described is a method of obtaining polyphenylene ether ketone oxymate, consisting in the interaction of dioxymate anions of 4,4'-diacetyldiphenyloxide with 4,4'-dihalogenbenzophenone at higher temperatures in the aprotonic dipolar solvent dimethylsulphoxide, characterised by the fact that the synthesis of polyphenylene ether ketone oxymate is carried out in two stages: at the first stage with the reaction of potassium dioxymate of 4,4'-diacetyldiphenyloxide with 4,4'-dichlorobenzophenone with a molar ratio of 1:0.5 and the concentration of a solution C=1 mol/l in terms of dioxymate for 1 hour at a temperature of 165°C in the presence of a solid powder-like KOH obtained is a dioxymate anion of the following structure -O-N=C(CH3)-C6H4-O-C6H4-C(CH3)=N-O-C6H4-CO-C6H4-O-N=C(CH3)-C6H4-O-C6H4-C(CH3)=N-O-, at the second terminating stage of the process a mixture of 4,4'-difluorobenzophenone, 4,4'-dichlorobenzophenone and crushed and annealed K2CO3 in molar ratios of 0.5:0.005:0.15, counted per 1 mol of the initial diketoxime of 4,4'-diacetyldiphenyloxide, in a water-free DMSO, with an additional volume of the water-free DMSO being taken in such an amount that the concentration of the solution by each of the monomers at the second oligopolymer stage of the synthesis becomes equal to 0.5 mol/l, the total time of carrying out the reaction is 6 hours at a temperature of 165°C.

EFFECT: intensification, optimisation and cheapening of the process of obtaining polyphenylene ether ketone oxymate.

3 ex

FIELD: chemistry.

SUBSTANCE: group of inventions relates to cyanate ester-based polymer compositions which are modified with polysulphones, reinforced with fibrous filler and are used for producing structural polymer composite materials with operating temperature of up to 200°C and articles from said materials, which can be used in aviation, aerospace, motorcar, ship-building and other industries. Disclosed is a cyanate ester-based polymer composition for polymer composite materials, which comprises a thermoplastic modifier and a curing agent, wherein the modifier used is a thermoplastic selected from polysulphone, polyestersulphone, polyarylsulphone or mixtures thereof, and the curing agent used is an amine catalyst. The invention also discloses a prepreg which includes said polymer composition and fibrous filler, and an article made from said prepreg by moulding.

EFFECT: producing a thermoplastic-modified cyanate ester-based polymer composition which is characterised by homogeneity of the composition, which enables prepreg processing thereof and enables to obtain moisture-proof articles from polymer composite materials made therefrom, with improved thermomechanical properties, a coefficient of variation of physical and mechanical properties and good retention of strength properties at high temperatures.

7 cl, 12 dwg, 3 tbl

FIELD: chemistry.

SUBSTANCE: described are compositions for hair care, containing a β-aminoether compound in a cosmetically acceptable carrier, such as a spray or cream. Described is a compound of formula

:

in which n represents an integer number from 1 to 100; Z and Z′ together with atoms, which they are bound to, represent acrylate, methacrylate or amino-terminal groups; R2 represents C1-C20alkyl, possibly substituted with: hydroxyl, siloxyl, C1-C20alkoxygroup, substituted with hydroxyl, amino-C1-C20alkyl, substituted with from one to two hydroxyl groups, C6-C10aryl, substituted with C1-C20alkoxygroup, or C5-C10heteroaryl, containing one nitrogen heteroatom; and A contains a rubber fragment, which has a molecular weight in the range from approximately 1000 g/mol to approximately 10000 g/mol, selected from the group, consisting of butadiene and isoprene units. Also described is a cosmetic composition for hair, containing the said compound and cosmetically acceptable carrier. The application of the said cosmetic composition for scalp care is described.

EFFECT: obtaining the cosmetic composition for hair, increasing adhesion of hairs to each other, adding volume, texture and shape to the hair.

10 cl, 4 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compositions, containing an active substance. Described is a composition for the active substance delivery, which contains: a) at least, one block-copolymer, containing, at least, one poly(2-oxazoline) block A, consisting of repeating units of formula where RA stands for a hydrocarbon group, which can be optionally substituted with -OH, -SH, -COOH, -NR'2, -COOR', -CONR', -CHO, where R' stands for H or C1-3 alkyl, and RA is selected in such a way that a repeating link of formula (I) is hydrophilic; and at least one poly(2-oxazoline) block B, consisting of repeating units of formula (II), where RB stands for a hydrocarbon group, which can be optionally substituted with halogen, -OH, -SH, -COOH, -NR''2, -COOR'', -CONR'', -CHO, where R'' stands for H, alkyl or alkenyl, and RB is selected in such a way that a repeating link of formula is more hydrophobic than the repeating link of formula (I); and (b) one or more active substances. Also described is application of a copolymer for solubilisation of the active substance in water or a water solution.

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12 cl, 6 dwg

FIELD: chemistry.

SUBSTANCE: described is a method of producing a highly purified disinfectant which contains polyhexamethylene guanidine hydrochloride, characterised by that flush water from production of polyhexamethylene guanidine hydrochloride in solid form is used. The flush water is mixed with 25% NaCl solution in ratio of 1:1 (polyhexamethylene guanidine hydrochloride solution with impurities: NaCl solution) while stirring constantly for 1 hour at temperature in the range of 50-60°C. Stirring is stopped and the mixture is cooled to 5°C, thereby dividing the mixture into two parts; the bottom part is drained, neutralised and sent for recycling and the top part containing up to 60-70% polyhexamethylene guanidine hydrochloride is further diluted to 50% with an aqueous solution of quaternary ammonium salts (QAS) to QAS concentration of not higher than 5%.

EFFECT: extracting highly purified, concentrated high-molecular weight polyhexamethylene guanidine hydrochloride from flush water, reducing the amount and toxicity of waste water, improving disinfecting properties and increasing output of the commercial-grade product when producing polyhexamethylene guanidine hydrochloride in solid form, reducing cost.

1 cl, 1 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: method of producing a disinfectant involves first carrying out polycondensation of hexamethylenediamine and guanidine hydrochloride. Polycondensation starts with preparation of a reaction mass in form of a suspension of crystalline guanidine hydrochloride in molten hexamethylenediamine, taken in ratio of 1:(1-1.5). The suspension is obtained by gradually adding crystalline guanidine hydrochloride, preheated to temperature of 90-120°C, to molten hexamethylenediamine and then stirring. The reaction mass is then heated in steps: holding for 4 hours at 120°C, then for 8 hours at 160°C and then for 3 hours at 180°C. Temperature is then gradually raised to 210°C at a rate of 3-4°C/h. The reaction mass is then subjected to vacuum treatment and cooled.

EFFECT: method enables to reduce toxicity of the end product and obtain a polymer with the required molecular weight and sufficient purity without washing steps.

2 tbl

FIELD: chemistry.

SUBSTANCE: described is a method of producing polyguanidines by polycondensation of a guanidine salt with a diamine while heating, characterised by that polycondensation is carried out in the presence of an organic acid or a mixture of organic acids and heating is carried out in steps as follows: at the first step at 120-130°C for 0.5-1 hour; at the second step at 150-160°C for 3.5-4 hours; at the third step at 170-180°C for 0.5-1.5 hours.

EFFECT: improved method.

11 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to polyphenylene ether ketone oximates, as well as a method for production thereof. An elementary unit of said polyphenylene ether ketone oximate has the formula: [-O-N=C(CH3)-C6H4-O-C6H4-C(CH3)=N-O-C6H4-CO-C6H4]n. The polyphenylene ether ketone oximate has reduced viscosity of 0.4-0.5 dl/g and molecular weight ranging from 40800 to 51000. Polyphenylene ether ketone oximate are obtained by non-equilibrium nucleophilic polycondensation of difluorodiphenyl ketone with diacetyl diphenyl oxide diketoxime. The reaction is carried out in dimethyl sulphoxide for 6 hours at 165°C, with reaction of equimolar amounts of potassium diacetyl diphenyl oxide dioximate with 4,4'-difluorobenzophenone. The molar ratio 4,4'-difluorobenzophenone: 4,4'-diacetyl diphenyl oxide diketoxime: KOH: K2CO3 is equal to 1:1:2:0.15.

EFFECT: obtained polymer has improved mechanical properties, heat-resistance, and also has a system of properties which are characteristic for both polyether formal oximates and polyether ketones.

2 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing oligo-3,3-bis(azidomethyl)oxetane which is used as a hydroxyl-containing compound for producing energy-intensive polyurethane thermoplastic elastomers. The method involves cationic polymerisation of 3,3-bis(chloromethyl)oxetane in methylene chloride at 20-35°C in the presence of 1-10 wt % boron trifluoride etherate and a diatomic alcohol in molar ratio of 1:(5-15) to 3,3-bis(chloromethyl)oxetane. Further, the intermediate oligo-3,3-bis(chloromethyl)oxetane is separated in finely dispersed form, for which at the end of polymerisation, an organic solvent is added to the reaction mass, methylene chloride is evaporated and oligo-3,3-bis(chloromethyl)oxetane is precipitated with water. Sodium azide is then added to the obtained finely dispersed oligo-3,3-bis(chloromethyl)oxetane in a medium of an organic solvent at 90-130°C in the presence of 0.5-3 wt % tetrabutylammonium bromide.

EFFECT: highly efficient method of producing oligo-3,3-bis(azidomethyl)oxetane and high output of the end product.

5 cl, 1 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: disclosed are oligomers based on hexamethylene guanidine derivatives of formula (I), where R denotes or , n1, n2 and n3 equal 1-3, z equals 0.15-1.10; with molecular weight distribution Mw/Mn from 5.4 to 9.3, with weight-average molecular weight Mw 3800-6300 and number-average molecular weight Mn 600-1100. Disclosed also is a disinfectant containing disclosed oligomers as an active component, as well as use thereof.

EFFECT: disclosed compounds have improved and steadily reproducible disinfectant properties, low toxicity and corrosiveness.

4 cl, 1 dwg, 6 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: proposed method involves the following stages: (a) reaction of carbon monoxide with hydrogen in Fischer-Tropsch reaction conditions in the presence of Fischer-Tropsch catalyst; (b) separation from products of stage (a), of at least one fraction of hydrocarbons, containing paraffins, with 9 to 17 carbon atoms and olefins, with 9 to 17 carbon atoms, where the hydrocarbon fraction also contains at least 2% alcohols; (c) bringing one or several fractions, obtained at stage (b), into contact with alkylene oxide and (d), extraction of a mixture of alkoxylated alcohols from products of stage (c) reaction.

EFFECT: simpler method of producing a mixture of alkoxylated alcohols, using cheap raw materials.

10 cl, 1 tbl, 1 ex

FIELD: measurement equipment.

SUBSTANCE: cantilever is connected to an exploring needle, the top of which is connected to the sphere made from glass with nanometre pores, filled with quantum points of nucleus - shell structure coated with protective polymeric layer, transparent for the length of external electromagnetic radiation source and the stokes shifted wavelength generated by quantum points of nucleus - shell structure.

EFFECT: possibility of simultaneous combination of electromagnetic effect with measurement of mechanical response to this stimulating effect in one common point of the surface of the diagnosed object without impacting the neighbouring sections.

2 cl, 2 dwg

FIELD: physics.

SUBSTANCE: blue LED flip-chip on nitride heterostructures comprises p-type metal electrodes, a p-type nitride layer, a III-nitride active region, an n-type III-nitride layer, a silicon carbide substrate with a patterned semipolar or nonpolar surface which is in form of nanoformations, the dimensions and distance between which are comparable with the radiation wavelength.

EFFECT: improved properties.

6 cl, 1 dwg

FIELD: chemistry.

SUBSTANCE: composition contains ammonium nitrate brand ZhV, dinitramide guanidinium salt, orthocarborane, di-N-oxide-1,3-dinitrile-2,4,6-triethylbenzene, mixture of microdisperse powder of aluminium brand ASD-6 and ultradisperse aluminium powder, methylpolyvinyltetrazole and mixture plasticiser of methylpolyvinyltetrazole, consisting of 1-ethyl-3-nitro-1,2,4-triazole and 2-ethyl-3-nitro-1,2,4-triazole.

EFFECT: increase of burning velocity, specific impulse and stability of physic-mechanical characteristics of composition, reduction of dependence of its burning velocity on pressure.

1 tbl

FIELD: metallurgy.

SUBSTANCE: device and method versions allow for obtainment of ultradisperse and nanosize metal monopowder. Device includes melting, evaporating and condensation chambers and evaporator. In the first version, evaporator features melting chamber with a floating trap hood in the bottom part. To stabilise temperature mode in evaporation chamber of evaporator, heat insulation screen is mounted at the bottom intake of evaporator, above upper end of multichannel atomiser. Atomiser channels for metal vapour discharge are tilted at 5-12° angle to the atomiser axis and at 90° angle to external conical surface of the atomiser. Condensation chamber is assembled of hollow cylindrical sections with cooling jacket and sight ports. In the second device version, spray shield with 0.8-1.2 mm wide vertical side slots along the perimeter of vertical cylindrical wall is mounted above upper surface of single-channel atomiser coaxially to it. Method versions allow for obtainment of ultradisperse metal powder with average grain size of 0.1-1 mcm and monodisperse metal powders, of nanosize as well, with average grain size under 100 nm.

EFFECT: improved metal powder quality, enhanced efficiency.

6 cl, 5 dwg, 1 ex

FIELD: machine building.

SUBSTANCE: method is performed by addition to the surface layers of the item the alloying chemical elements and by decreasing of size of the particles forming the surface layer during the item surface treatment by the pulse plasma streams with simultaneous action on the surface of the electric current pulses of the acoustic oscillations and magnetic field. To optimise the treatment process the treated surface is by a controlled method connected with the electric circuit by anode or cathode. Control of the connection polarisation is performed upon the combustion gas mixture addition to the plasma generating medium.

EFFECT: modification of chemical composition and structure of surface layer is performed for its hard facing and for improvement of other operation features.

6 cl, 1 tbl, 7 dwg

FIELD: machine building.

SUBSTANCE: products are cleaned in a vacuum chamber in the inert gas medium, with further execution of ionic etching, ion-plasma nitriding alternating with ionic etching and application of nanocomposite coating using the method of physical vapour deposition using magnetrons. The temperature of thin-walled and thick-walled parts of products is levelled during cleaning of products in the medium of inert gas, ionic etching, ion-plasma nitriding alternating with ionic etching and application of nanocomposite coating by placement of products so that the thin-walled part of one product to be located between thick-walled parts of other products. The named application of nanocomposite coating is performed by application of microlayer composed of nanolayers with the thickness 1-100 nm from the titanium and chromium and the subsequent application of microlayer of nanolayers 1-100 nm from titanium and chromium nitrides. In specific applications of the invention the titanium and chromium microlayer is applied with the thickness 0.3-0.8 mcm by consecutive passing of the product in front of magnetrons with targets from the named materials. The microlayer of titanium and chromium nitrides is applied with the thickness 2.5-3 mcm by consecutive passing of the product in front of magnetrons with titanium and chromium targets when feeding into the nitrogen chamber.

EFFECT: increase of coating service life in conditions of erosion, corrosion and high temperatures.

3 cl, 1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention represents an agent for the intracellular delivery of a biologically active high-molecular compound containing a high-molecular compound specified in milk serum protein, peptide fragments of milk serum protein, protein of porcine transmissible gastroenteritis virus, thermally-stable tuberculin protein recovered from the mycobacteria Mycobacterium bovi, M1 protein of influenza virus of the strain PR8, protein of VP1 foot-and-mouth disease virus, nanoparticles - colloidal selenium, distilled water with the ingredients of the agent taken in certain relations, wt %.

EFFECT: creating non-toxic and effective agent for intracellular delivery of biologically active substances.

4 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: material includes chlorosulphonated polyethylene, filling agents (kaolin, titanium dioxide), fire retardant (decabromodiphenyloxide), vulcanising agents (magnesium oxide, zinc oxide) vulcanisation accelerators (thiuram D, 2-metcaptobenzothiazole), additionally contains fluralit (nanopolytetrafluoroethylene), nanoadditive "Cloisite 30B", polychloroprene, chloroparaffin-470, antimony trioxide, rosin, mixture of nefras and ethylacetate in ratio 1:1 and textile base - technical polyether fabric, or cotton-polyether fabric, or fibreglass fabric. Method of manufacturing light-weight rubber-polymer material includes application of rubber-polymer composition on textile base on adhesive spreading machine IVO 3220 with steam pressure in steam stoves of adhesive spreading machines 2.0-2.1 kgf/cm2.

EFFECT: manufacturing light-weight rubber-polymer material, providing protection against impact of toxic, aggressive chemical substances and open fire.

2 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: composition of basic alkali-borosilicate glass includes Fe2O3 and FeO in amount of 20 wt % with respect to Fe2O3. The glass is heat-treated at 550°C for 130-150 hours. After heat treatment, the biphase alkali-borosilicate glass is held in a 3 M solution of inorganic acids at 50-100÷C and washed in distilled water, followed by combined drying in air at 20-120°C. The glass has pore volume of 0.2-0.6 cm3/cm3.

EFFECT: obtaining porous glass in the form of solid articles with thickness of 0,1-2 mm with crystallite size of 5-20 nm.

4 cl, 7 dwg, 1 tbl

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