WO2007094570A1 - Nanocomposites auto-assemblés comportant des peptides bioactifs hydrophiles et des matières hydrophobes - Google Patents
Nanocomposites auto-assemblés comportant des peptides bioactifs hydrophiles et des matières hydrophobes Download PDFInfo
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- WO2007094570A1 WO2007094570A1 PCT/KR2007/000336 KR2007000336W WO2007094570A1 WO 2007094570 A1 WO2007094570 A1 WO 2007094570A1 KR 2007000336 W KR2007000336 W KR 2007000336W WO 2007094570 A1 WO2007094570 A1 WO 2007094570A1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01D—HARVESTING; MOWING
- A01D90/00—Vehicles for carrying harvested crops with means for selfloading or unloading
-
- A—HUMAN NECESSITIES
- A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
- A47C—CHAIRS; SOFAS; BEDS
- A47C4/00—Foldable, collapsible or dismountable chairs
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B60—VEHICLES IN GENERAL
- B60P—VEHICLES ADAPTED FOR LOAD TRANSPORTATION OR TO TRANSPORT, TO CARRY, OR TO COMPRISE SPECIAL LOADS OR OBJECTS
- B60P1/00—Vehicles predominantly for transporting loads and modified to facilitate loading, consolidating the load, or unloading
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B62—LAND VEHICLES FOR TRAVELLING OTHERWISE THAN ON RAILS
- B62B—HAND-PROPELLED VEHICLES, e.g. HAND CARTS OR PERAMBULATORS; SLEDGES
- B62B3/00—Hand carts having more than one axis carrying transport wheels; Steering devices therefor; Equipment therefor
Definitions
- the present invention relates to self-assembled nanostructures, comprising hydrophilic bioactive peptides and hydrophobic materials, and more particularly to nanostructures, in which conjugates of hydrophilic bioactive peptides (e.g., cell adhesion-inducing peptides, tissue growth factor-derived peptides and cell permeating peptides) and hydrophobic substances are self-assembled and which can be used for the surface treatment of biomaterials and can also be applied directly for tissue regeneration therapy.
- hydrophilic bioactive peptides e.g., cell adhesion-inducing peptides, tissue growth factor-derived peptides and cell permeating peptides
- extracellular matrixes e.g., fibronectin
- specific tissue growth factors e.g., bone morphogenetic protein (BMP)
- BMP bone morphogenetic protein
- tissue engineering techniques which employ biomaterials such as polymers or ceramics, are the improvement and promotion of the biointerface between cells and tissues.
- functional proteins that regulate the adhesion of cells, and growth factor-derived substances that promote the differentiation and proliferation of cells should be labeled on the surface of biomaterials.
- the chemical bonding can be easily achieved if the surface of the raw material of medical devices has amino groups or carboxyl groups (e.g., chitosan or alginic acid); but otherwise, for example, if the surface of implants is made of titanium or a hydrophobic polymer (e.g., polylactic acid or polyurethane), the efficiency of attaching peptides or other bioactive materials through chemical methods will be reduced.
- amino groups or carboxyl groups e.g., chitosan or alginic acid
- a hydrophobic polymer e.g., polylactic acid or polyurethane
- Korean Patent Registration No. 52909 discloses a method of polymerizing hydrophilic monomers on the surface of a support by modifying the surface of a porous polymer support for tissue engineering using a low-temperature plasma system.
- this method has a shortcoming in that a separate low-temperature plasma discharge system is required to modify the surface.
- Korean Patent Publication No. 10-2005-0040187 discloses a bioniimic composite support of nanofiber/microf ⁇ ber for inducing tissue regeneration and a manufacturing method thereof, but the technology disclosed therein has a shortcoming in that a specific 3D structure should always be kept in order to maintain the activity of high-molecular- weight proteins for inducing tissue regeneration. Also, in existing studies on regeneration effects in tissue regeneration therapy, regeneration effects were measured using histological methods by staining after transplantation into animals, but it was difficult to determine whether the regeneration effects were induced by applied materials themselves or interactions with the surrounding tissues or cells.
- self-assembly refers to a fundamental technology of nanotechnology, which spontaneously forms reproducible nanostructures by artificially manipulating a repulsive or an attractive force between molecules.
- This self-assembly technology can be applied in the field of electronic material and new materials, including biochips for disease diagnosis and nanotubes, and in the manufacture of nanostructures required for the manufacture of highly integrated semiconductors, and is expected to be highly developed through combination with other technologies.
- Such self-assembly nanostructures are based on the phenomenon in which a number of molecules, each having both a hydrophilic moiety and a hydrophobic moiety, are self-assembled into a specific shape in an aqueous system.
- These self-assembly structures can significantly increase interactions with initial cells, because unit nanostructures contain peptides in an amount significantly larger than that attainable by other surface treatment methods.
- it is possible to simultaneously achieve cell differentiation potential, and diagnostic and therapeutic effects by applied materials by introducing nanoparticles directly into cells through self-assembly nanostructures containing cell-recognizing and intracellular differentiation protein-recognizing peptides to diagnose.
- tissue regeneration therapy the discovery of bioactive peptides and functional peptides and the development of structures using the same allow biomaterial-cell interactions to be fundamentally maximized, thus leading to a significant increase in diagnostic and therapeutic efficiencies.
- peptides are more advantageous over the use of proteins such as tissue growth factors in terms of immunogenity, stability and the like, but the development of relevant peptides is not yet actively studied. Furthermore, a technique of binding peptides to other materials while maintaining the structural stability of the peptides is not yet reported.
- the present inventors have made many efforts to solve the above- described problems occurring in the prior art and to develop a peptide-containing structure, which can be not only applied for the immobilization of peptides but also applied directly for tissue regeneration therapy.
- the present inventors have found that self-assembled nanostructures formed by applying conjugates of hydrophilic peptides and hydrophobic materials to an aqueous system at concentrations higher than the critical micelle concentration are stably attached to the surface of biomaterials and, at the same time, bioactive peptides contained in the nanostructures effectively permeate in vivo to show excellent tissue regeneration effects, thereby completing the present invention.
- the present invention provides a nanostructure in which a conjugate of a hydrophilic bioactive peptide and a hydrophobic material is self-assembled.
- the hydrophobic bioactive peptide is preferably a cell adhesion-inducing peptide, a tissue growth factor-derived peptide or a cell- permeating peptide.
- the hydrophobic material is preferably at least one selected from the group consisting of hydrocarbons, hydrophobic polymers, hydrophobic peptides and silanes
- the hydrophilic bioactive peptide and the hydrophobic material are preferably linked by amide bond, and the hydrophobic material is modified with a carboxyl group or amine group for amide bond with the hydrophilic bioactive peptide.
- the self-assembly nanostructures according to the present invention can be preferably obtained by applying hydrophilic bioactive peptide-hydrophobic material conjugates to an aqueous system at concentrations higher than the critical micell concentration (CMC).
- CMC critical micell concentration
- FIG. l(a) and FIG. l(c) show the structures of hydrophilic bioactive peptides
- FIG. l(b) and FIG. l(d) show the 3D structures of conjugates of hydrophilic bioactive peptides and hydrophobic materials.
- FIG. 2 is a graph showing the critical micelle concentration at which fluorescence intensity rapidly decreases, in which the micelle concentration is determined using a pyrene technique in order to examine whether the hydrophilic peptide- hydrophobic material conjugates are self-assembled.
- FIG. 3(a) shows the results of Western blot analysis for the activation of FAK and ERK, conducted to examine which intracellular signaling system is activated by the nanostructures according to the present invention
- FIG. 3(b) is a graphic diagram showing the Western blot analysis results.
- FIG. 4 shows the results of confocal microscopy performed to examine the cell adhesion ability of the nanostructures according to the present invention.
- FIG. 5 shows the osteoblast differentiation potential of the nanostructures according to the present invention.
- FIG. 6 shows the gene expression level of the nanostructures according to the present invention.
- FIG. 7 shows the results of confocal microscopy performed to examine the cell permeability of the nanostructures according to the present invention.
- the present invention relates to a nanostructure in which a conjugate of a hydrophilic bioactive peptide and a hydrophobic material is self- assembled.
- the self-assembly nanostructures according to the present invention can be easily obtained by applying hydrophilic bioactive peptide-hydrophobic material conjugates to an aqueous system at concentrations higher than the critical micell concentration (CMC).
- CMC critical micell concentration
- the hydrophobic bioactive peptide is preferably a cell adhesion-inducing peptide, a tissue growth factor-derived peptide or a cell- permeating peptide.
- the cell adhesion-inducing peptide it is preferable to use a peptide having an amino acid sequence of RGD. More preferably, the cell adhesion-inducing peptide may be a peptide that essentially contains any one of CGGRGDS (SEQ ID NO: 1) and CGGVACDCRGDCFC (SEQ ID NO: 2) designed to structurally stably maintain the amino acid sequence of RGD.
- tissue growth factor-derived peptide it is possible to use a peptide that is identified from the active region of a tissue growth factor to chemically synthesize.
- a tissue growth factor-derived peptide it is possible to use at least one selected from among the following peptides, and more preferably, cysteine or a spacer, such as CGG, CGGGGG or CEEEEEEE, is added to the N-terminal end of the selected peptide in order to make it easy to immobilize the peptide: (a) an amino acid sequence of positions 2-18 of bone morphogenetic protein (BMP)-2 (SEQ ID NO: 3), an amino acid sequence of positions 2-18 of BMP-4 (SEQ ID NO: 4), an amino acid sequence of positions 2-18 of bone morphogenetic protein (BMP)-6 (SEQ ID NO: 5), an amino acid sequence of positions 16-34 of BMP-2 (SEQ ID NO: 6), an amino acid sequence of positions 41-71 of BMP-2 (SEQ ID NO: 7); an amino acid sequence of positions
- a peptide essentially containing an amino acid sequence of SEQ ID NO: 70 (VSRRRRRRGGRRRR) or SEQ ID NO: 71 (YGRKKRRQRRR). More preferably, cysteine or a spacer, such as CGG or CGGGGG, CEEEEEEE, is added to the N-terminal end of this peptide in order to make it easy to immobilize the peptide.
- the hydrophobic material is at least one selected from the group consisting of hydrocarbons, hydrophobic polymers (e.g., polycaprolactone), hydrophobic peptides and silanes, but the scope of the present invention is not limited thereto.
- the hydrophilic bioactive peptide and the hydrophobic material are preferably linked by amide bonds, and the hydrophobic material is modified with a carboxyl group or amine group for amide bond with the hydrophilic bioactive peptide.
- amino acid sequences were isolated and extracted from the active regions of antibodies binding to bioactive cytokine or marker proteins of intracellular differentiation, the three-dimensional structures thereof were analyzed, domains binding to cells were screened, and tissue growth factor- derived peptides were designed from the domains.
- tissue growth factor- derived peptides were designed from the domains.
- amino acid sequences of all tissue growth factors 5-15 amino acid sequences were synthesized, and they were used to study cell adhesion and to test activity, differentiation potential and the like, thus selecting amino acid sequences having the highest activity. Also, the terminal ends of these peptides were chemically modified.
- hydrophilic peptides were linked with hydrophobic materials, including synthetic polymers such as polycaprolactone (molecular weight: 2000), peptides, such as alanine, glycine and hydrophobic amino acids, saturated hydrocarbon materials, and silanes, thus preparing hydrophobic peptide-hydrophobic material conjugates.
- synthetic polymers such as polycaprolactone (molecular weight: 2000)
- peptides such as alanine, glycine and hydrophobic amino acids
- saturated hydrocarbon materials such as silanes
- the prepared peptide-hydrophobic material conjugates were applied to an aqueous system, and analyzed through the pyrene probe technique and an electron microscope. As a result, it was seen that self-assembled nanostructures in the form of micells and nanofibers were formed. Because the nanostructures according to the present invention are formed through the process in which molecules, each having a hydrophobic moiety and a hydrophilic moiety, are self-assembled into a specific form in an aqueous system, it is possible to enable a unit nanostructure to contain peptides in an amount much larger than that attainable by other surface treatment methods.
- the nanostructures according to the present invention can markedly increase interactions with initial cells and can efficiently attach cell-recognizing and intracellular differentiation protein-recognizing peptides to the surface of biomaterials, and thus they can promote the adhesion, proliferation and differentiation of cells in injured tissue.
- the nanostructures according to the present invention are introduced into cells, it is possible to image, diagnose and measure intracellular differentiation and the like, thus optimizing tissue regeneration and repair efficiency.
- Example 1 Synthesis of cell-recognizing and cell-activating peptides Peptides of SEQ ID NOs: 6, 17, 70 and 71, each having the ability to recognize and activate cells, were synthesized using a solid phase synthesis method with an automatic peptide synthesizer (see Table 1). Specifically, for the synthesis of the peptides, Rink resin (0.075 mmol/g, 100-200 mesh, 1% DVB crosslinking) having Fmoc-(9-Fluorenylmethoxycarbonyl) as a blocking group linked thereto was used.
- the filtered solution was removed using a vacuum rotary evaporator. Then, cold ether was added, or an excess amount of cold ether was added directly to the
- TFA cocktail solution containing the peptide dissolved therein, so as to crystallize the peptide in a solid phase.
- the crystallized peptide was isolated by centrifugation. At this time, the TFA cocktail was completely removed by washing several times with ether and a centrifugation process.
- the peptides thus obtained were dissolved in distilled water and freeze-dried. The synthesis of the peptides was confirmed by dissolving the peptides in distilled water and measuring the molecular weight of the peptides using MALDI-TOF.
- peptides of SEQ ID NOs: 1-5, 7-16 and 18-69 can also be synthesized in the same manner as described above.
- cysteine was added to the terminal end of each of the peptides (OPDl, OPD2, LMWP, and TAT) prepared in Example 1 (OPDl : CGGYVPKPCCAPTKLNAISVLYF, OPD2: CGGSDVGWNDWIVAPPGYHA).
- OPDl CGGYVPKPCCAPTKLNAISVLYF
- OPD2 CGGSDVGWNDWIVAPPGYHA
- the synthesized active peptides were confirmed through NMR and the like, and the molecular weights thereof were measured using MALDI-TOF or GPC.
- the synthesized peptides were used for linking with hydrophobic materials.
- hydrophilic bioactive peptides OPDl and OPD2 having cysteine (CGG) added to the N-terminal end thereof, which were synthesized in Example 2 a hydrophobic saturated hydrocarbon material having 16 carbon atoms was linked using palmitic acid (alkyl OPDl and alkyl OPD2) (see Reaction Scheme below).
- amide linkage between the terminal end of the hydrophobic saturated hydrocarbon material and the amine group of the N- terminal end of the hydrophilic peptide was induced using palmitic acid having a carboxyl group.
- the linkage was carried out in the same manner as in the amino acid coupling method described in Example 1, except that the reaction time was 3 hours.
- the synthesis of the peptides having a hydrophobic terminal end was confirmed by dissolving the peptides in distilled water and then measuring the molecular weights of the peptides using MALDI-TOF.
- FIG. l(b) and FIG. l(d) show the 3D structure of the hydrophilic bioactive peptides linked with the hydrophobic material.
- Example 4 Formation of nanostructiire by self-assembly of hydrophilic peptide-hydrophobic material conjugates and confirmation thereof
- OPD2 having cysteine (CGG) added to the N-terminal end thereof, prepared in Example 2, and the hydrophilic peptide-hydrophobic material conjugate (alkyl)
- OPD2 OPD2
- Example 3 OPD2
- a 6.Ox 10 "6 M pyrene solution (solvent: distilled water) was serially diluted 10-fold from 1.0 mg/ml to 1.0x l0 ⁇ 5 mg/ml, and the fluorescence intensity of the solution was measured.
- concentration at which the fluorescence intensity rapidly changes shows the minimum concentration at which micelles are formed by self-assembly (see FIG. 2).
- concentration at which micelles began to form was 0.1 mg/ml.
- OPDl showed a slight change
- alkyl OPD2 showed a definite change.
- Example 5 Intracellular signaling of nanostructure consisting of hydrophilic peptide and hydrophobic material
- HOS cells (Korean Cell Line Bank, KCLB No. 21543) were cultured and subjected to starvation for 24 hours. Then, the cells were treated with 1 mg of each of the peptides and conjugates dissolved in distilled water, followed by culture for 30 minutes. The activity of the cultured cells was analyzed by Western blot.
- alkyl OPDl and alkyl OPD2 formed self-assembled nanostructures when they were dissolved in distilled water.
- each of the samples was blocked with 5% skim milk/TBS-T solution for 1 hour, and allowed to react with a primary antibody (a 1 :1000 dilution in 5% BSA/TBS-T) at room temperature for 4 hours. Then, each of the samples was allowed to react with a secondary antibody (a 1 :2000 dilution in 5% skim milk/TBS-T). Then, each of the membranes was allowed to react with ECL solution, and exposed to an X-ray film, followed by development. The thickness of bands shown in the X-ray films was measured, thus comparing the activation between the samples.
- the activation of ERK and FAK was analyzed in the order of a non- treated group, OPDl, alkyl OPDl, OPD2, and alkyl OPD2.
- the activities of the hydrophilic bioactive peptides and the hydrophilic peptide-hydrophobic material conjugates were higher than that of the non-treated group, and the activity of the hydrophilic bioactive peptides and the activity of the hydrophilic peptide-hydrophobic material conjugates were almost similar to each other.
- Example 6 Cell adhesion test of nanostructure consisting of hydrophilic peptide and hydrophobic material
- Example 7 Test of osteoblast differentiation potential of hvdrophilic peptide-hydrophobic material conjugates
- alkyl OPDl showed osteoblast differentiation potential higher than that of OPDl
- OPD2 showed osteoblast differentiation potential similar to that of alkyl OPD2.
- the hydrophilic bioactive peptides and the conjugates all showed excellent osteoblast differentiation potential compared to that of the non-treated group (NT).
- the extracted RNA was subjected to PCR using a primer of collagen type I, a characteristic protein that is expressed with the differentiation of osetoblasts.
- a primer of collagen type I a characteristic protein that is expressed with the differentiation of osetoblasts.
- the PCR products were electrophoresed on 2% agarose gel and stained with EtBr, and the expression of the protein was examined using UV (see FIG. 6).
- Example 9 Cell permeability of nanostructures for intracellular diagnosis
- the peptides (LMWP: SEQ ID NO: 70; TAT: SEQ ID NO: 71) prepared in Example 1 were labeled with fluorescent material FITC, and hydrophilic peptide- hydrophobic material conjugates were prepared from the peptides in the same manner as in Examples 2 and 3. Then, the labeled conjugates in aqueous solution were added to HOS cell culture media. Herein, the conjugates were self-assembled in aqueous solution to form nanostructures. After 60 minutes, the cells were immobilized, and the cell permeability of the nanostructures was observed using confocal microscopy (see FIG. 7).
- LMWP showed excellent cell permeability compared to TAT, and in the case of NT treated with fluorescent material FITC solution alone, nuclei were observed. This suggests that LMWP and TAT facilitated cell permeation.
- the present invention provides the nanostructures, in which the hydrophilic bioactive peptide-hydrophobic material conjugates are self-assembled.
- the nanostructures according to the present invention are formed through the process in which molecules, each having a hydrophilic moiety and a hydrophobic moiety, are self-assembled into a specific shape in an aqueous system. Accordingly, unit nanostructures can contain peptides in an amount much larger than that attainable by other surface treatment methods, and thus the nanostructures can considerably increase interactions with initial cells. Also, they can efficiently attach cell-recognizing and intracellular differentiation protein-recognizing peptides to the surface of biomaterials, and thus the nanostructures can promote the adhesion, proliferation and differentiation of cells in injured tissue.
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Abstract
La présente invention concerne des nanostructures auto-assemblées, comportant des peptides bioactifs hydrophobes et des matières hydrophobes, et de manière plus spécifique, des nanostructures, dans lesquelles des conjugués de peptides bioactifs hydrophobes (par exemple, des peptides induisant une adhérence cellulaire, des peptides dérivés du facteur de croissance tissulaire, des peptides de perméation cellulaire, et autres) et des matières hydrophobes sont auto-assemblés et qui peuvent être utilisées non seulement pour le traitement superficiel de matières vivantes mais peuvent également être appliquées directement pour la thérapie de régénération tissulaire. Les nanostructures selon l'invention sont formées par le procédé selon lequel des molécules, chacune ayant une fraction hydrophile et une fraction hydrophobe, sont auto-assemblées en une forme spécifique dans un système aqueux. Par conséquent, des nanostructures unitaires peuvent contenir des peptides en une quantité supérieure que celle susceptible d'être obtenue par d'autres procédés de traitement superficiel, et donc les nanostructures peuvent accroître considérablement des interactions avec des cellules de départ. En outre, étant donné que les nanostructures peuvent fixer efficacement des peptides, qui peuvent reconnaître des cellules et des protéines de différenciation intracellulaire, à la surface de matières vivantes, les nanostructures peuvent favoriser l'adhérence, la prolifération et la différenciation des cellules dans un tissu abîmé.
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WO2017009490A1 (fr) * | 2015-07-16 | 2017-01-19 | Nuritas Limited | Peptides favorisant la croissance et leurs utilisations |
WO2017032856A3 (fr) * | 2015-08-25 | 2017-06-22 | Histide Ag | Composés destinés à induire une formation de tissu et utilisations de ces composés |
US10463591B2 (en) | 2015-07-16 | 2019-11-05 | Nuritas Limited | Anti-inflammatory peptides, and uses thereof |
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US11779531B2 (en) | 2015-07-16 | 2023-10-10 | Nuritas Limited | Anti-inflammatory peptides, and uses thereof |
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