WO2015133703A1 - 바이오마커 특이적 양친성 나노입자 - Google Patents
바이오마커 특이적 양친성 나노입자 Download PDFInfo
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/66—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/34—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from hydroxy compounds or their metallic derivatives
- C08G65/48—Polymers modified by chemical after-treatment
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
- C08L71/08—Polyethers derived from hydroxy compounds or from their metallic derivatives
- C08L71/10—Polyethers derived from hydroxy compounds or from their metallic derivatives from phenols
- C08L71/12—Polyphenylene oxides
- C08L71/126—Polyphenylene oxides modified by chemical after-treatment
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L87/00—Compositions of unspecified macromolecular compounds, obtained otherwise than by polymerisation reactions only involving unsaturated carbon-to-carbon bonds
- C08L87/005—Block or graft polymers not provided for in groups C08L1/00 - C08L85/04
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
- C08G83/008—Supramolecular polymers
Definitions
- the present invention relates to amphipathic nanoparticles as polyamino acid based nanoplatforms with target directivity specific to biomarkers.
- drug or gene-nanotransfers are formed to carry drugs or genes through amphiphilic polymer synthesis, spacer binding to enhance the stability of the formed nano-carrier and target-directed molecular binding, and After the spacer is bonded to the polymer nanocarrier and subjected to the target-directed molecular binding process (see Figure 1).
- the present invention has been made to solve the drawbacks of the prior art, to provide amphipathic nanoparticles in a poly amino acid based nano platform having a specific target directivity to the biomarker without a spacer configuration through a single process.
- Another object of the present invention is to provide a pharmaceutical use of the amphiphilic nanoparticles.
- the present invention is a hydrophilic and hydrophobic polymer-containing block copolymer (A); And an amphiphilic nanoparticle comprising a peptide and a hydrophobic polymer-containing block copolymer (B) degraded by proteolytic enzymes.
- the present invention also provides a method for preparing amphiphilic nanoparticles of the present invention comprising reacting a hydrophilic polymer and a hydrophobic polymer-containing block copolymer (A) with a peptide and a hydrophobic polymer-containing block copolymer (B) which are degraded by proteolytic enzymes. It provides a manufacturing method.
- the present invention also provides a composition for the activity or quantitative analysis of proteolytic enzymes comprising the amphiphilic nanoparticles of the present invention.
- the invention also relates to amphiphilic nanoparticles of the invention; And a pharmaceutically acceptable carrier.
- the invention also relates to amphiphilic nanoparticles of the invention; And it provides a contrast diagnostic or therapeutic contrast composition comprising a pharmaceutically acceptable carrier.
- the invention also relates to amphiphilic nanoparticles of the invention; And a diagnostic probe for image reading.
- the present invention is a poly amino acid based amphiphilic nanoparticles having a specific target directivity to the biomarker and selectively recognize and bind proteolytic enzymes specifically expressed on specific cell membranes, thereby efficiently incorporating into cells and selective degradation. Can be used as a diagnostic or therapeutic drug or gene carrier.
- amphiphilic nanoparticles of the present invention can be selectively diagnosed or treated because a peptide specific for the biomarker is bound.
- Figure 1 illustrates the mechanism of operation of the amphiphilic nanoparticles of the present invention and the nanocarriers of the prior art for the diagnosis or treatment of conventional cancer.
- Figure 2 shows the amphipathic block copolymer (top) and intracellular influx and selective degradation (bottom) of the amphiphilic nanoparticles of the present invention in the tumor microenvironment of the amphiphilic nanoparticles.
- Figure 3 is a FT-IR in the process (mPEG-OH ⁇ mPEG-TsCl ⁇ mPEG-N 3 ⁇ mPEG-NH 2) to modify (modification) of mPEG-OH used in the amphiphilic block copolymer synthesized in the mPEG-NH 2 Confirmation results are shown.
- the graph indicated by the top arrow is mPEG
- the graph indicated by the right arrow is mPEG-TsCl
- the graph indicated by the next arrow is mPEG-N 3
- the graph at the bottom is mPEG-NH 2.
- the peak at 2850 cm -1 represents CH 3 of mPEG (arrows shown in the left figure), the peak at 560 cm -1 represents SO of mPEG-TsCl (arrows shown in the middle figure), and the peak at 2103 cm -1 It represents a mPEG-N 3 N in 3 (shown to the right of the figure arrows).
- Figure 4 shows the NMR results in the process of transforming mPEG-OH used in the synthesis of the amphiphilic block copolymer mPEG-NH 2 (mPEG-OH ⁇ mPEG-TsCl ⁇ mPEG-N 3 ⁇ mPEG-NH 2 ) .
- the top graph is mPEG
- the graph indicated by the arrow below is mPEG-TsCl
- the graph immediately below is mPEG-N 3
- the graph indicated by the bottom arrow is mPEG-NH 2 .
- Peaks at 7.79 and 7.49 ppm represent 2H of TsCl (indicated by arrows in the middle figure), and peaks at 2.90 ppm represent CH 2 -NH 2 of mPEG-NH 2 (indicated by arrows in the right).
- Figure 5 shows the FT-IR confirmation of the amphipathic block copolymer mPEG-b-pLeu.
- the top graph is mPEG
- the four graphs immediately below are all mPEG-b-pLeu
- the bottom graph is the FT-IR result of DL-leucine.
- the peak at 1660 cm ⁇ 1 indicates amide I binding of mPEG-b-pLeu (indicated by arrow in the right figure).
- Figure 6 shows the NMR results of the amphiphilic block copolymer mPEG-b-pLeu.
- the top graph is mPEG
- the four graphs immediately below are all mPEG-b-pLeu
- the bottom graph is a 1 H NMR result of DL-leucine.
- the peak at 0.9 ppm represents the methyl proton of polyleucine (indicated by arrow in the right figure).
- Figure 7 shows the NMR results of the amphipathic block copolymer MT1-MMP-b-pLeu.
- a) represents the chemical formula of MT1-MMP
- the peak (arrow) at 7.55 ppm in the upper left graph of b) represents 2CH 2 of MT1-MMP and the peak at 0.87 ppm in the lower right graph of b) (Arrow) represents 2CH 3 of polyleucine.
- a) represents the chemical formula of MT1-MMP, and in the five graphs in the figure of b), the top graph is mPEG, the graph immediately below is Leu-NCA, the next graph is polyleucine, and the next graph is MT1-b-pLeu, bottom graph shows NMR results of MT1-MMP.
- the peak (arrow) at 7.55 ppm indicates 2CH 2 of MT1-MMP
- the peak (arrow) at 4.3 ppm indicates 2CH 3 of polyleucine
- the peak at 1.77 ppm indicates CH of DL-leucine (arrow). ).
- Figure 9 shows the NMR results confirming that the Fmoc of MT1-MMP-b-pLeu used in the synthesis of the amphipathic block copolymer MT1-MMP-b-pLeu was removed through a deprotection process.
- a) shows the chemical formula of MT1-MMP
- the upper graph shows MT1-b-pLeu
- the lower graph shows NMR results of MT1-b-pLeu (Dep.).
- CLSM confocal laser scanning microscopy
- FIG. 12 shows intracellular cells of micelles formed of mPEG-b-pLeu and mPEG-b-pLeu, which are formed only of amphiphilic block copolymers mPEG-b-pLeu and MT1-MMP-b-pLeu, through HT-1080 cell lines expressing MT1-MMP. This is the result of checking the inflow degree
- FIG. 13 shows HT-1080 (MT1-MMP ++, overexpression), MDA-MB-231 (MT1-MMP +, slightly expressed) and MCF-7 (MT1-MMP-, little expression) cell lines expressing MT1-MMP.
- FIG. 14 shows the results of cell influx of pepti-polymersomes formed of mPEG-b-pLeu and MT1-MMP-b-pLeu loaded with calcein in a HT-1080 cell line with a controlled MT1-MMP expression rate. .
- the present invention provides a hydrophilic and hydrophobic polymer-containing block copolymer (A); And an amphiphilic nanoparticle comprising a peptide and a hydrophobic polymer-containing block copolymer (B) degraded by proteolytic enzymes.
- the present invention provides a preparation of the amphiphilic nanoparticles comprising the step of reacting a hydrophilic polymer and a hydrophobic polymer-containing block copolymer (A) and a peptide and hydrophobic polymer-containing block copolymer (B) that is degraded by a protease Provide a method.
- Amphiphilic nanoparticles of the present invention form a self-assembly or self-aggregate through a balance of hydrophobic and hydrophilic molecules, and are degraded by a biomarker specific peptide, ie, protease.
- Peptides are bound to selectively recognize protease specifically expressed on the cell membrane of a particular cell, then bound and introduced into the cell, selectively degraded by the protease to carry a supporting material such as a diagnostic reagent, drug or It can be used as a diagnostic or therapeutic drug or gene carrier by delivering a gene into a cell.
- Figure 1 shows the operating mechanism of the prior art nanocarriers and nanocarriers of the present invention for the diagnosis or treatment of cancer
- Figure 2 is an amphiphilic block copolymer (top) for producing the amphiphilic nanoparticles of the present invention
- It is a nanocarrier that selectively recognizes -MMP, and then binds and efficiently enters and selectively degrades cells.
- a "peptide-polymersome” refers to a polymersome having biomarker-specific peptides selectively targeted to a biomarker expressed in a particular cell or tissue while the peptide is bound within a block copolymer to form a polymersome. Refers to. In particular, when the amphiphilic nanoparticles of the present invention form a polymersome structure, it is called a pepti-polymersome.
- the term “pepti-micel” is used when the amphiphilic nanoparticles of the present invention form a micelle structure.
- Amphiphilic nanoparticles of the present invention are characterized in that they contain a peptide that is specifically degraded by proteolytic enzymes in the block copolymer, and thus have a target directing ability against proteolytic enzymes without spacer composition. Therefore, there is an advantage that can reduce the production cost through a single process. In addition, since it has a target directivity for the protease specifically expressed in the cell membrane of the lesion site cells in relation to cancer, osteoarthritis, rheumatoid arthritis, dementia or atherosclerosis, etc., it is useful to diagnose or treat these diseases. Can be.
- the block copolymer (A) may be an amphipathic block copolymer prepared through chemical bonding of a hydrophilic polymer and a hydrophobic polymer.
- the hydrophilic polymer is polyalkylene glycol, polyethylene oxide, polyoxazoline, poly (N-vinylpyrrolidone), polyvinyl alcohol, polyhydroxyethyl methacrylate, dextran, polyserine, polythreonine, polytyrosine , Polylysine, polyarginine, polyhistidine, polyaspartic acid or polyglutamic acid and the like can be used alone or in combination of two or more.
- polyalkylene glycol having a molecular weight of 1000 to 5000 or a derivative thereof and the like can be used. More preferably, methoxy amino polyethylene glycol having a molecular weight of 1000 to 5000 can be used.
- the hydrophilic polymer may be appropriately modified using a known technique for bonding with the hydrophobic polymer. According to one embodiment, after the deformation process of the mPEG-OH ⁇ mPEG-TsCl ⁇ mPEG-N 3 ⁇ mPEG-NH 2 may be used in the form of mPEG-NH 2.
- hydrophilic nanoparticles may have a mass fraction of 25 to 40 calculated according to Equation 1 below to form amphiphilic nanoparticles of the present invention:
- Mass fraction molecular weight of hydrophilic polymer or peptide / (molecular weight of hydrophilic polymer or peptide + molecular weight of hydrophobic polymer)
- the hydrophilic nanoparticles may have a mass fraction greater than 40 and less than or equal to 70, calculated according to Equation 1, to form an micelle of the amphiphilic nanoparticles of the present invention.
- the hydrophobic polymer may be a homo poly amino acid represented by Formula 1 below:
- M is leucine, isoleucine, valine, phenylalanine, proline, glycine or methionine,
- n 10-100.
- an amphiphilic block copolymer (A) mPEG-b-polyleucine (mPEG-b-pLeu) may be synthesized through the peptide bond of the modified hydrophilic polymer and hydrophobic polyleucine.
- block copolymer (B) may be synthesized as an amphipathic block copolymer through a peptide bond of a hydrophobic polymer and a peptide decomposed by a protease.
- the hydrophobic polymer As the hydrophobic polymer, the above-mentioned homopolyamino amino acid can be used.
- the peptides degraded by the protease are matrix metals including MMP-2 / 9, MMP-7, MMP-13, MT1-MMP (membrane type 1 matrix metalloproteinase, membrane-type 1 matrix metalloproteinase), and the like.
- polystyrene resin may be represented by any one of the amino acid sequences set forth in SEQ ID NOS: 1 to 13. More specifically, it may be represented by the amino acid sequence set forth in SEQ ID NO: 1 which is specifically degraded by membrane-type 1 matrix metalloproteinase.
- the target protease-related diseases of the peptides degraded by the protease are shown in Table 1 below.
- Table 1 disease Target protease Peptide Substrate / Cutting Site SEQ ID NO: cancer MT1-MMP GPLPLRSW / GLK One MMP-2 / 9 PLG / LR 2 Arteriosclerosis MMP-7 VPLS / LTM 3 Rheumatoid arthritis MMP-13 PLG / MRG 4 Cathepsin B K / K 5 Cathepsin D PICF / FRL 6 PSA HSSLQ / 7 Cell death Caspase-1 WEHD / 8 Caspase-3 DEVD / 9 Cardiovascular disease Thrombin F (Pip) R / S 10 Fijian NQ / EQVS 11 diabetes DPP-IV GP / GP 12 HSV HIV protease GVSQNY / PIVG 13
- Peptides degraded by the protease can be appropriately synthesized, and such synthesis can use various peptide synthesis methods known to those skilled in the art, such as Fmoc strategy according to solid phase synthesis. have.
- the peptide may have a mass fraction of 25 to 40 calculated according to Equation 1 in order for the amphiphilic nanoparticles of the present invention to form a polymersome.
- the peptide may have a mass fraction of more than 40 and less than or equal to 70, calculated according to Equation 1, to form an micelle of the amphiphilic nanoparticles of the present invention.
- the amphiphilic nanoparticles are mixed with an amphiphilic block copolymer (A) and an amphiphilic block copolymer (B) in an appropriate weight ratio, such as (A) :( B) at 10:90 to 50:50 and dispersed in a solvent. Or by dissolving.
- a method of dispersing a block copolymer (A) and a block copolymer (B) in an aqueous solution and then applying ultrasonic waves a method of dispersing or dissolving in a organic solvent and then extracting or evaporating the organic solvent with an excess of water, and dispersing it in an organic solvent.
- dissolving and dialysis with excess water dispersing or dissolving in an organic solvent, strongly evaporating the solvent using a homogenizer or a high pressure emulsifier, or thin film hydration. have.
- the organic solvent may be chloroform, hexane, heptane, methylene chloride, benzene, toluene, tetrahydrofuran, acetone or mixtures thereof, but is not particularly limited thereto.
- the block copolymer (A) and the block copolymer (B) are dissolved in the organic solvent at a predetermined ratio, and then the organic solvent is evaporated through a rotary vacuum evaporator, and the formed thin film is hydrated for a predetermined time. After stirring can be formed.
- Amphiphilic nanoparticles prepared through the above process may have an average particle diameter of 200 nm or less. Preferably from 50 to 200 nm.
- amphiphilic nanoparticles of the present invention have a micelle structure in the form of a spherical particle having a hydrophobic core and a hydrophilic shell through the amphipathic properties of the block copolymers, or a hollow hydrophilic core is surrounded by a double hydrophobic shell and a hydrophilic shell. It may be a polymersome structure.
- Such structural forms can be prepared by controlling the mass fraction of the hydrophilic polymer (and peptide). For example, a polymersome is formed when the mass fraction of the hydrophilic polymer (and peptide) is 25 to 40, and micelles may be prepared when it is more than 40 but less than 70.
- micellar structure can carry a hydrophobic dye in a hollow hydrophobic core
- the polymersome structure can simultaneously carry a hydrophilic dye in a hollow hydrophilic core and a hydrophobic dye in a hydrophobic shell so that the amphiphilic nanoparticles of the present invention are hydrophilic.
- it has the advantage of using as a drug carrier capable of supporting a hydrophobic drug.
- amphipathic nanoparticles of the present invention may further comprise a fluorescent material for diagnosis.
- the fluorescent material may be physicochemically encapsulated or bound to a hydrophilic region or a hydrophobic region.
- the fluorescent material may be a phosphor that emits fluorescence in the visible region or near infrared rays.
- fluorescein, BODYPY, tetramethylrhodamine, Alexa, cyanine (Cyanine), allopicocyanine (allopicocyanine) or other fluorescence generating fluorescence may be used.
- a fluorescent material having a high quantum yield It may also be a hydrophilic or hydrophobic dye.
- amphipathic nanoparticles of the present invention may further comprise a pharmaceutically active ingredient for the treatment of a disease.
- the pharmaceutical active ingredient may be physicochemically encapsulated or bound to the hydrophilic or hydrophobic region.
- the pharmaceutically active ingredient is not particularly limited, but anticancer drugs, antibiotics, hormones, hormonal antagonists, interleukin, interferon, growth factor, tumor necrosis factor, endotoxin, lymphokoxy, urokinase, streptokinase, tissue plasminogen activator, protease inhibitor, Alkylphosphocholine, a component labeled with a radioisotope, a cardiovascular drug, a gastrointestinal drug, or a nervous system drug may be used alone or in combination of two or more thereof.
- the invention also relates to a composition for the activity or quantitative analysis of proteolytic enzymes comprising the amphipathic nanoparticles of the invention.
- Amphiphilic nanoparticles of the present invention can easily modify and control the peptides degraded by the protease, so that it can easily control the desired specific protease and the desired wavelength band, it can be designed for a variety of protease, Activity or quantitative analysis of the above-described proteases is possible.
- the invention also relates to amphiphilic nanoparticles of the invention; And a pharmaceutically acceptable carrier.
- Amphiphilic nanoparticles of the present invention are coupled to a peptide specifically cleaved by a specific protease, so that the target can be directed to cells or tissues in which the protease is present, and thus target sites through magnetic resonance and optical imaging devices. Can be used as a contrast medium.
- Such pharmaceutically acceptable carriers include carriers and vehicles commonly used in the pharmaceutical arts, and in particular, ion exchange resins, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum albumin), buffer materials (eg, Various phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids), water, salts or electrolytes (e.g.
- protamine sulfate disodium hydrogen phosphate, carbohydrogen phosphate, sodium chloride and zinc salts
- gelatinous Silica magnesium trisilicate
- polyvinylpyrrolidone polyvinylpyrrolidone
- cellulosic substrates polyethylene glycols, sodium carboxymethylcellulose, polyarylates, waxes, polyethylene glycols or wool, and the like.
- target-oriented contrast agent composition of the present invention may further include a lubricant, a humectant, an emulsifier, a suspending agent, a preservative, and the like, in addition to the above components.
- the target oriented contrast agent composition according to the present invention can be prepared in an aqueous solution for parenteral administration, preferably Hank's solution, Ringer's solution or physically buffered saline. Buffer solutions can be used.
- Aqueous injection suspensions can be added with a substrate that can increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran.
- target directed contrast composition of the present invention may be in the form of sterile injectable preparations of sterile injectable aqueous or oily suspensions.
- Such suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents (eg Tween 80) and suspending agents.
- the sterile injectable preparation may be a sterile injectable solution or suspension (eg, a solution in 1,3-butanediol) in a nontoxic parenterally acceptable diluent or solvent.
- Vehicles and solvents that may be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution.
- sterile, nonvolatile oils are conventionally employed as a solvent or suspending medium. For this purpose any non-irritating non-volatile oil can be used including synthetic mono or diglycerides.
- the target-oriented contrast agent composition of the present invention can be used to obtain an image by detecting a signal emitted from amphiphilic nanoparticles by administering to tissues or cells isolated from a diagnosis target.
- MRI magnetic resonance imaging apparatus
- optical imaging In order to detect a signal emitted by the amphiphilic nanoparticles, it is preferable to use a magnetic resonance imaging apparatus (MRI) and optical imaging.
- MRI magnetic resonance imaging apparatus
- a magnetic resonance imaging apparatus places a living body in a strong magnetic field and irradiates radio waves of a specific frequency to absorb energy into atomic nuclei such as hydrogen in biological tissues to make the energy high, and then stops propagating the atomic nuclei energy such as hydrogen. It is a device that processes the energy by converting this energy into a signal and processing it with a computer. Since magnetism or propagation is not obstructed by bone, clear three-dimensional tomograms can be obtained at longitudinal, transverse, and arbitrary angles around solid bones or tumors of the brain or bone marrow.
- the magnetic resonance imaging apparatus is preferably a T2 spin-spin relaxation magnetic resonance imaging apparatus.
- the invention also relates to amphiphilic nanoparticles of the invention; And a pharmaceutically acceptable carrier.
- Amphiphilic nanoparticles of the present invention can fluoresce in cells or tissues expressing proteolytic enzymes related to the disease through physicochemical encapsulation or binding of the pharmaceutically active ingredient and the fluorescent material through magnetic resonance and optical imaging devices. It can be used for nano probes such as separation, diagnosis or treatment of biological molecules, drugs or gene delivery vehicles.
- amphipathic nanoparticles may be a molecular magnetic resonance imaging diagnosis or a magnetic relaxation sensor.
- Amphipathic nanoparticles show a larger T2 contrast effect as their size increases, which can be used as a sensor to detect biomolecules. That is, when a specific biomolecule induces agglomeration of amphiphilic nanoparticles, the T2 magnetic resonance imaging effect is increased. This difference is used to detect biomolecules.
- amphipathic nanoparticles of the present invention can be used for various diseases associated with tumors, such as squamous cell carcinoma, uterine cancer, cervical cancer, prostate cancer, head and neck cancer, pancreatic cancer, brain tumor, breast cancer, liver cancer, skin cancer, esophageal cancer, testicular cancer, kidney. Cancer, colorectal cancer, rectal cancer, gastric cancer, kidney cancer, bladder cancer, ovarian cancer, cholangiocarcinoma, gallbladder cancer.
- the present invention can be used for imaging proteolytic enzymes in inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and refractory diseases including dementia, stroke, and the like.
- the invention also relates to amphiphilic nanoparticles of the invention; And a diagnostic probe for image reading.
- the diagnostic probe may use a T1 magnetic resonance imaging diagnostic probe, an optical diagnostic probe, a CT diagnostic probe, or a radioisotope.
- the multiple diagnostic probe may simultaneously perform T2 magnetic resonance imaging and T1 magnetic resonance imaging.
- Resonance imaging and optical imaging can be performed at the same time.
- CT diagnostic probe MRI and CT diagnosis can be performed simultaneously.
- radioisotopes magnetic resonance imaging, PET, and SPECT can be simultaneously diagnosed.
- the T1 magnetic resonance imaging diagnostic probe may include a Gd compound or a Mn compound, and the optical diagnostic probe may be an organic fluorescent dye (dye), a quantum dot, or a dye labeled inorganic support (eg SiO 2 , Al 2). O 3 )), CT diagnostic probes include I (iodine) compounds, or gold nanoparticles, and radioisotopes include In, Tc, F, and the like.
- CT diagnostic probes include I (iodine) compounds, or gold nanoparticles, and radioisotopes include In, Tc, F, and the like.
- a block copolymer composed of methoxy amino polyethylene glycol (mPEG-NH 2 , 0.2 mmol) having a molecular weight of 2000 as a hydrophilic polymer and polyleucine (Polyleucine) as a hydrophobic polymer was synthesized.
- Leucine-N-Carboxyanhydride Leucine-N-Carboxyanhydride, Leu-NCA, 6.3 mmol
- triphosgene triphosgene, 11.43 mmol.
- DL-leucine was dissolved in THF at 40 ° C. and nitrogen, and then triphosphene was added.
- Leu-NCA obtained by precipitation in n-haxane was recrystallized from THF / n-haxane.
- Leu-NCA was added to the DMF solution of mPEG-NH 2 to maintain the reaction under 35 ° C. and nitrogen for 24 hours to obtain mPEG-b-polyleucine (mPEG-b-pLeu).
- mPEG-b-polyleucine mPEG-b-pLeu
- Amphiphilic block copolymers prepared above formed pepti-polymersomes through thin film hydration.
- mPEG-b-pLeu and MT1-MMP-b-pLeu which are synthesized amphiphilic block copolymers, were dissolved in an organic solvent in a 50:50 ratio, and then a rotary vacuum depressurizer (Rotary) was prepared to prepare a thin amphiphilic block copolymer film.
- the organic solvent was evaporated through a vacuum evaporator.
- the thin film formed was hydrated for 6 hours and then stirred for 6 hours.
- the formed pepti-micel and pepti-polymersomes were identified through TEM and CLSM in FIGS. 10 and 11 and stored at 4 ° C.
- FIG. 5 and 6 show FT-IR and NMR results of mPEG-b-pLeu, an amphiphilic block copolymer, and amide 1 of mPEG-b-pLeu at 1660 and 1754 cm ⁇ 1 through FT-IR of FIG. 5.
- the binding and the amide 2 binding were confirmed, indicating that the synthesis was made.
- CH 3 of mPEG-b-pLeu was confirmed at 0.9 ppm through NMR of FIG. 6, indicating that the synthesis was performed, and the molecular weights summarized in Table 2 were confirmed.
- FIG. 8 is a result of confirming the NMR characteristics of MT1-MMP-b-pLeu and Leu-NCA, poly leucine, MT1-MMP used in the synthesis thereof
- Figure 9 is deprotection of Fmoc of MT1-MMP-b-pLeu ( Deprotection was removed as a result of the disappearance of the peak of 7-9 ppm.
- FIGS. 10 and 11 show that the mPEG-b-pLeu, an amphiphilic block copolymer, varies in particle form depending on the ratio of the hydrophilic polymer and the polyamino acid, which is a hydrophobic polymer.
- the mass fraction of the hydrophilic polymer (mPEG) is 0.33. , 0.39, 0.54, and 0.64.
- Table 3 summarizes the sizes of amphiphilic nanoparticles of mPEG-b-pLeu and MT1-MMP-b-pLeu.
- the mass fraction of the hydrophilic peptide in the amphiphilic block copolymer MT1-MMP-b-pLeu was also synthesized as 0.34, 0.39, 0.55 and 0.65, and the mass fraction was calculated according to the following formula 1:
- Mass fraction molecular weight of hydrophilic polymer or peptide / (molecular weight of hydrophilic polymer or peptide + molecular weight of hydrophobic polymer)
- the particle shape according to each ratio was confirmed through TEM images, and it was found that micelles were formed at 0.64 and 0.54 and polymersomes were formed at 0.40.
- the hydrophilic dye FITC-Dextran and the hydrophobic dye Nile Red were supported, and it was confirmed that the microsomes were formed in micelles at 0.44 and 0.54 and 0.40 in the particle forms.
- Peptide- micelles consisting of MT1-MMP-b-pLeu and mPEG-b-pLeu were found to be well introduced into cells at 1 and 2 hours of incubation time.
- Figure 13 is a result confirming the degree of cellular influx of the polymersome formed of amphiphilic block copolymers mPEG-b-pLeu and MT1-MMP-b-pLeu in HT-1080, MDA-MB-231 and MCF-7 cell line, Peptide-polymersomes were synthesized using the mass fractions of mPEG and MT1-MMP at 0.40 and 0.39, respectively. Blue was Hoechst 33258, green was FITC-Dextran, and red was Nile Red-peptide. -Represents the polymersome.
- HT1080 MT1-MMP ++: MT1-MMP overexpression (100% reference), MDA-MB-231 (MT1-MMP +): MT1-MMP slight expression (19%), MCF-7 (MT1-MMP -): MT1-MMP Refers to cell line with little expression (0.1%). MT1-MMP expression was confirmed by qRT-PCR based on HT1080 cell line 100.
- Peptide-polymersomes consisting of MT1-MMP-b-pLeu and mPEG-b-pLeu were efficiently introduced into cells.
- HT-1080 cell lines with transfection using MT1-MMP siRNA to control MT1-MMP expression rate were formed of mPEG-b-pLeu and MT1-MMP-b-pLeu loaded with calcein.
- the higher the MT1-MMP expression rate the higher the influx of the pepti-polymersome into the cells was found in the difference in fluorescence intensity (Fig. 14).
- the invention can be used in the field of diagnosis or treatment of a disease.
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Abstract
Description
질환 | 표적 단백질분해효소 | 펩타이드 기질/절단 부위 | 서열번호 |
암 | MT1-MMP | GPLPLRSW/GLK | 1 |
MMP-2/9 | PLG/LR | 2 | |
동맥경화증 | MMP-7 | VPLS/LTM | 3 |
류마티스 관절염 | MMP-13 | PLG/MRG | 4 |
카텝신B | K/K | 5 | |
카텝신D | PICF/FRL | 6 | |
PSA | HSSLQ/ | 7 | |
세포사멸 | 카스파제-1 | WEHD/ | 8 |
카스파제-3 | DEVD/ | 9 | |
심혈관질환 | 트롬빈 | F(Pip)R/S | 10 |
피지안 | NQ/EQVS | 11 | |
당뇨병 | DPP-IV | GP/GP | 12 |
HSV | HIV 프로테아제 | GVSQNY/PIVG | 13 |
명칭 | 수율(%) | 전환 수율(%) | 분자량(g/mol) | |
GPC | 1H-NMR | |||
mPEG2000 | - | 100 | 2000 | - |
mPEG-TsCl | 88 | 93 | 1953 | 2168 |
mPEG-N2 | 84 | 99 | 1988 | 2074 |
mPEG-NH2 | 94 | 98 | 1988 | 2048 |
mPEG 질량 분율 | 크기(nm) |
0.33 | 179.3±4.5 |
0.39 | 133.7±4.8 |
0.54 | 66.0±2.8 |
0.64 | 55.9±3.0 |
Claims (17)
- 친수성 및 소수성 고분자 함유 블록 공중합체(A); 및단백질분해효소에 의해 분해되는 펩타이드 및 소수성 고분자 함유 블록 공중합체(B)를 포함하는 양친성 나노입자.
- 제1항에 있어서,친수성 고분자는 폴리알킬렌글리콜, 폴리에틸렌옥시드, 폴리옥사졸린, 폴리(N-비닐피롤리돈), 폴리비닐알콜, 폴리히드록시에틸메타크릴에이트, 덱스트란, 폴리세린, 폴리트레오닌, 폴리티로신, 폴리 리신, 폴리아르기닌, 폴리히스티딘, 폴리아스파르트산 및 폴리글루탐산으로 이루어진 군으로부터 선택된 하나 이상인 양친성 나노입자.
- 제1항에 있어서,친수성 고분자는 메톡시 아미노 폴리에틸렌글리콜을 포함하는 양친성 나노입자.
- 제1항에 있어서,소수성 고분자는 하기 화학식 1로 표시되는 호모 폴리 아미노산인 양친성 나노입자:[화학식 1](poly-M)n여기서,M은 루신, 이소루신, 발린, 페닐알라닌, 프롤린, 글리신 또는 메틴오닌이고,n은 10 내지 100을 나타낸다.
- 제1항에 있어서,단백질분해효소에 의해 분해되는 펩타이드는 SEQ ID NOS: 1 내지 13에 기재된 아미노산 서열 중 어느 하나로 표시되는 양친성 나노입자.
- 제1항에 있어서,양친성 나노입자는 직경이 평균 입경 50 내지 200 nm인 양친성 나노입자.
- 제1항에 있어서,양친성 나노입자는 폴리머좀(polymersome) 또는 마이셀(micelle) 형태인 양친성 나노입자.
- 제1항에 있어서,양친성 나노입자는 형광물질을 추가로 포함하는 양친성 나노입자.
- 제1항에 있어서,양친성 나노입자는 약제학적 활성성분을 추가로 포함하는 양친성 나노입자.
- 친수성 고분자 및 소수성 고분자 함유 블록 공중합체(A)와 단백질분해효소에 의해 분해되는 펩타이드 및 소수성 고분자 함유 블록 공중합체(B)를 반응시키는 단계를 포함하는 제1항의 양친성 나노입자의 제조방법.
- 제10항에 있어서,양친성 나노입자는 하기 식 1에 따라 계산된 질량 분율(mass fraction)이 25 내지 40인 친수성 고분자 또는 펩타이드를 포함하여 합성된 폴리머좀인 양친성 나노입자의 제조방법:[식 1]질량 분율(mass fraction)=친수성 고분자 또는 펩타이드의 분자량/(친수성 고분자 또는 펩타이드의 분자량 + 소수성 고분자의 분자량)
- 제10항에 있어서,양친성 나노입자는 하기 식 1에 따라 계산된 질량 분율(mass fraction)이 40을 초과하고 70 이하인 친수성 고분자 또는 펩타이드를 포함하여 합성된 마이셀 구조인 양친성 나노입자의 제조방법:[식 1]질량 분율(mass fraction)=친수성 고분자 또는 펩타이드의 분자량/(친수성 고분자 또는 펩타이드의 분자량 + 소수성 고분자의 분자량)
- 제1항의 양친성 나노입자를 포함하는 단백질분해효소의 활성 또는 정량 분석용 조성물.
- 제13항에 있어서,단백질분해효소는 기질 금속단백분해효소(matrix metalloproteinases; MMP), 트롬빈, FXIIIa(factor Xiiia), 카스파제(caspase), 우로키나아제 플라스미노겐 활성제(urokinase plasminogen activator, uPA), 피지안(Fijian), 카텝신(cathepsins), HIV 프로테아제, DPP-IV(dipeptidyl peptidase) 또는 프로테아좀(proteasome)중 어느 하나인 단백질분해효소의 활성 또는 정량 분석용 조성물.
- 제1항의 양친성 나노입자; 및약제학적으로 허용 가능한 담체를 포함하는 표적 지향형 조영제 조성물.
- 제1항의 양친성 나노입자; 및약제학적으로 허용 가능한 담체를 포함하는 동시 진단 또는 치료용 조영제 조성물.
- 제1항의 양친성 나노입자; 및영상 판독을 위한 진단 프로브를 포함하는 다중 진단 프로브.
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