KR101789563B1 - Micelle that encapsulate hyrophobic indocyanine green and preparation method thereof - Google Patents
Micelle that encapsulate hyrophobic indocyanine green and preparation method thereof Download PDFInfo
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- KR101789563B1 KR101789563B1 KR1020160025534A KR20160025534A KR101789563B1 KR 101789563 B1 KR101789563 B1 KR 101789563B1 KR 1020160025534 A KR1020160025534 A KR 1020160025534A KR 20160025534 A KR20160025534 A KR 20160025534A KR 101789563 B1 KR101789563 B1 KR 101789563B1
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- indocyanine green
- hyaluronic acid
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- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 title claims abstract description 87
- 229960004657 indocyanine green Drugs 0.000 title claims abstract description 86
- 239000000693 micelle Substances 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title description 6
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 61
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 61
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 61
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 57
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 34
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- 150000001412 amines Chemical class 0.000 claims description 7
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- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
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- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 2
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- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 2
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
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- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
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- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 108010003272 Hyaluronate lyase Proteins 0.000 description 2
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- 235000000177 Indigofera tinctoria Nutrition 0.000 description 2
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- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 2
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 2
- 238000003917 TEM image Methods 0.000 description 2
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- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 2
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- 229940097275 indigo Drugs 0.000 description 2
- COHYTHOBJLSHDF-UHFFFAOYSA-N indigo powder Natural products N1C2=CC=CC=C2C(=O)C1=C1C(=O)C2=CC=CC=C2N1 COHYTHOBJLSHDF-UHFFFAOYSA-N 0.000 description 2
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- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 2
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 1
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- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
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- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1806—Suspensions, emulsions, colloids, dispersions
- A61K49/1809—Micelles, e.g. phospholipidic or polymeric micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
- A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0076—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
- A61K49/0082—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion micelle, e.g. phospholipidic micelle and polymeric micelle
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
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- A61K49/1851—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
- A61K49/1863—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being a polysaccharide or derivative thereof, e.g. chitosan, chitin, cellulose, pectin, starch
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Abstract
The present invention relates to a nano-micelle which is formed of amphiphilic hyaluronic acid and which is hydrophobic indocyanine green and which has excellent in-vivo stability and is easy to control indocyanine concentration. The present invention relates to a nano- It is possible to visualize the cancer tissue.
Description
The present invention relates to micelles encapsulating hydrophobic indocyanine green, a method for producing the micelles, and a near infrared ray and photoacoustic dual image application techniques using micelles.
Recently, development of imaging technology for treatment of diseases using nanotechnology and diagnosis and prevention of diseases is actively being carried out. For example, a polymer nanoparticle system with a contrast agent has been applied to imaging techniques of cancer tissues through optical imaging and magnetic resonance imaging.
Among near-infrared imaging techniques, near-infrared fluorescence imaging is attracting attention as a non-invasive disease diagnosis and monitoring technology. In the near infrared region of 700 to 900 nm, background fluorescence is low and light scattering is small. Can be performed. Among the fluorescent dyes for fluorescence imaging, indocyanine green (ICG) is a near-infrared fluorescent dyestuff approved for use in clinical practice. It is mainly used for hepatic vein and heart staining and has been applied to various diagnostic and imaging technologies. However, near-infrared dyes have a low quantum yield due to self-quenching, which may impair optical activity. In particular, indocyanine green forms strong bonds with plasma proteins in the body, There is a disadvantage that it is rapidly discharged into the urine. In addition, since the indigo cyan green itself has a polarity, it is difficult to carry it on particles such as micelles, and it is difficult to transmit indocyanine green to a desired position in the living body without deformation.
In order to overcome the disadvantages of such indocyanine green, it is required to develop a technique of delivering indocyanine green by using polymer nanoparticles. Korean Patent Laid-Open Publication No. 2015-0095108 discloses a technology capable of binding indocyanine green to hyaluronic acid to improve in vivo stability and to exhibit fluorescence specifically according to hyaluronidase activity. However, when the indocyanine green is bonded to a polymer or the like, it may be difficult to control the amount of indocyanine green, and there may be a difficulty in approval for sale as a medicinal product because chemical modification such as modification of a bonding moiety is accompanied.
The present invention provides a hydrophobic indocyanine green-encapsulated nano-micelle which is stable in vivo and capable of imaging cancer tissues through near-infrared and photoacoustic dual images, and a method for producing the same.
The present invention provides nano-micelles formed of amphiphilic hyaluronic acid and encapsulated with hydrophobic indocyanine green.
The present invention provides compositions capable of near-infrared and photoacoustic dual imaging, including nanomyelites formed with amphiphilic hyaluronic acid and encapsulated with hydrophobic indocyanine green.
The present invention relates to a method for preparing an amphipathic hyaluronic acid by replacing a carboxy group of hyaluronic acid with an amine and bonding an alkyl group to the substituted amine to prepare an aqueous solution containing amphiphilic hyaluronic acid, And dropping the hydrophobic indocyanine green into an aqueous solution containing the amphipathic hyaluronic acid. The present invention also provides a method for preparing a hydrophobic indocyanine green encapsulated nanomyelite.
The amphipathic hyaluronic acid nanomyelite encapsulated with the hydrophobic indocyanine green of the present invention can be specifically internalized into cancer cells and can be subjected to near infrared fluorescence imaging and photoacoustic imaging, Cancer New blood vessels can be monitored in real time.
In addition, the hydrophobic indocyanine green of the present invention is not bound to hyaluronic acid but encapsulated in a micelle formed of amphiphilic hyaluronic acid, so that the activity of indocyanine green and the imaging effect using the same are excellent.
Figure 1 shows the preparation process of HA-C18 which is amphiphilic hyaluronic acid.
FIG. 2 shows 1 H-NMR of amphiphilic hyaluronic acid, HA-C18, in which one of the peaks represents an acetamido moiety in N-acetyl-D-glucosamine of hyaluronic acid and 2 represents an acetamido moiety of C18 Terminal methyl group (CH2CH3), and 3 represents a methylene group (CH2CH2CH2) of C18.
FIG. 3 shows the size of HA-ICG, which is a nanomyelite encapsulated with hydrophobic indocyanine, according to the degree of encapsulation of lead-free green.
Fig. 4 shows the zeta potential of HA-ICG, a nanomyelite encapsulated with hydrophobic indocyanine, according to the degree of encapsulation of indocyanine green.
Figure 5 shows the critical micelle concentration of HA-C18.
6 shows TEM images of HA-IC18 prepared by dropwise addition of 10% by weight of indocyanine green in TEM image of HA-C18 micelle and (B) in (A).
Figure 7 shows the absorbance spectra of HA-ICG prepared by dropping different indocyanine greens in (A) and the fluorescence emission spectra in (B).
Figure 8 shows cytotoxicity results of SCC-7 according to MTT assay and cytotoxicity results of NIH-3T3 according to MTT assay in (B) in (A).
Figure 9 shows that HA-ICG nanomyelocytes in SCC-7 overexpressing CD44 and not blocking the CD44 receptor are cell-mediated into CD44 receptor-mediated SCC-7 cells.
Fig. 10 quantitatively shows cellular uptake of HA-ICG in SCC-7 overexpressing CD44, SCC-7 in which CD44 receptor was blocked, and NIH-3T3 in which CD44 was not expressed in (A) SCC-7, CD44 receptor-blocked SCC-7, and CD44-expressing NIH-3T3 overexpressed CD44.
FIG. 11 shows in vivo distribution of NIRF after HA-ICG injection into mice.
12 shows the NIRF images of the main organs extracted from the mouse injected with HA-ICG in (A) and the quantitative intensity of NIRF in (B).
13 is to (A) at 750nm wavelength using the HA-ICG-injected mice in the (B) represents the photoacoustic signal strength of the HA-ICG concentration on the in-vitro treatment shows a photoacoustic image on the in- vivo .
Figure 14 shows the UV absorption spectra of nano-micelles encapsulated with indocyanine green hydrophobized with doxorubicin.
Hereinafter, the present invention will be described in detail. The terms used in the present specification should be construed as generally understood by a person having ordinary skill in the art unless otherwise defined. It is to be understood that the drawings and embodiments are not intended to limit the scope of the present invention, which is not intended to limit the scope of the present invention. It is not.
The present invention provides a nanometer micelle formed of amphipathic hyaluronic acid and encapsulated with hydrophobic indocyanine green. In addition, the present invention can provide a composition for a near infrared ray and a photoacoustic image including the nano-micelle of the present invention. Hyaluronic acid is a linear polymer of natural structure existing in nature where D-glucuronic acid and N-acetyl-D-glucosamine are alternately repeated, and biodegradability and bio- It is a substance with excellent compatibility and extremely low immunoreactivity. According to one embodiment of the present invention, an amphiphilic hyaluronic acid formed by introducing an amine group into a carboxyl group of D-glucuronic acid contained in hyaluronic acid and binding an alkyl group to hyaluronic acid through an amine group, You can enclose non-greens.
In the present invention, amphiphatic hyaluronic acid can be prepared by binding a compound having hydrophobic properties to hyaluronic acid, and preferably, by binding an alkyl group to hyaluronic acid. When an amphiphilic hyaluronic acid is prepared by bonding an alkyl group to hyaluronic acid, an hyaluronic acid is bound to an alkyl group to have an amphiphilic property, and amphiphilic hyaluronic acid is self-assembled. It is possible to form a nano-micelle. The alkyl group bonded to hyaluronic acid is not limited to C8 to C20, C12 to C20, preferably C16 to C20 alkyl groups. As the chain length of the alkyl group bonded to hyaluronic acid is increased, hydrophobicity increases and amphiphilic hyaluronic acid can be easily formed into a small amount of amphiphilic hyaluronic acid. However, the micelle may not be dense and the chain length of the alkyl group bonded to hyaluronic acid is short It is necessary to increase the amount of amphiphilic hyaluronic acid to form nano-micelles, so it may be necessary to control the number of carbon atoms of the alkyl group bonded to hyaluronic acid. According to one embodiment of the present invention, an octadecyl group bonded to an alkyl group bonded to hyaluronic acid is bound to the carboxy group through an amine at an average of 100 residues in the hyaluronic acid polymer.
The inside of the nanomicell formed of amphiphilic hyaluronic acid can be encapsulated with a hydrophobic environment formed by the alkyl group and hydrophobic indocyanine green. The nanomyelite formed of the amphipathic hyaluronic acid of the present invention can specifically bind to CD44 receptor overexpressed in tumor tissue cells, and thus it is possible to specifically induce cancer cell mediated by the CD44 receptor. Through such specific cell internalization, the indocyanine green encapsulated in the nano-micelles of the present invention can be selectively delivered to cancer cells, thereby enabling near-infrared imaging of tumor tissue and tumor blood vessels as well as double imaging through photoacoustic imaging It is possible.
In the present invention, the hydrophobic indocyanine green (ICG) encapsulated in nano-micelles formed of amphiphilic hyaluronic acid is prepared by hydrophobic treatment of indocyanine green. Hydrophobic Indocyanine Green Hydrophobic salts can be prepared by mixing indocyanine green and preferred hydrophobic salts are tetrabutylammonium iodide (TBAI), but not limited thereto. Indocyanine green can also be incorporated into nano-micelles by the formation of indocyanine green in the form of hydrophobic salts by hydrophobic anticancer agents. Hydrophobic anti-cancer agents for forming hydrophobic indocyanine green include doxorubicin, cisplatin or melphalan, but are not limited thereto.
In the present invention, the hydrophobic indocyanine green is encapsulated in nanomicelles formed of amphiphilic hyaluronic acid. In this case, the amphiphilic hyaluronic acid does not undergo specific chemical bonding such as covalent bonding with the amphiphilic hyaluronic acid, As shown in FIG. This feature does not require specific binding with the polymer such as indocyanine green, which forms the micelle, and it does not require chemical modification such as the modification of indocyanine green, and thus the drug such as anticancer drug used for hydrophobizing indocyanine and indocyanine The intrinsic property can be maintained as it is. Specifically, since the indocyanine green does not form a specific bond with the polymer or the like, the optical characteristics of the indigo cyan green are maintained. When the indocyanine green hydrophobicized by the anticancer agent is encapsulated in the nanomicell, not only the characteristic optical characteristic of the indocyanine green itself is maintained, but also the intrinsic fluorescence characteristic of the anticancer agent and the effect of the anticancer agent are maintained, Specific < / RTI > In addition, the indocyanine green can be enclosed in a self-formed nano-micelle without binding to a polymer material or the like, so that the concentration of indocyanine green can be effectively controlled and sealed in the nano-micelle. This feature may not be evident in photoacoustic and fluorescence image imaging if indocyanine green accumulates at a low concentration in the target tumor tissue, and may be due to the effect of self-quencing when accumulating at too high a concentration It is possible to easily solve the phenomenon in which the optical activity is impaired due to the increase in fluorescence, and clear photoacoustic and fluorescence image imaging may not appear.
The drug such as the hydrophobic indocyanine green or the anti-cancer agent encapsulated in the nano-micelles of the present invention can be used for the treatment of nano-micelle injected into the living body, which is specifically distributed in the tumor tissue or tumor blood vessels, It is released upon decomposition.
According to the present invention, since the hydrophobic indocyanine green does not bind to the hyaluronic acid constituting the nanomyelite but is located at the inner center of the nanomyelite, the effect is distinguished from the conventional method of binding and transferring the fluorescent dye to the polymer have. In particular, it is possible to prevent hyaluronic acid from being degraded by enzymes such as hyaluronidase, so that the delivery of indocyanine to the tumor tissue is minimized to be released or decomposed before accumulation in cancer cells Can be accumulated a lot.
The present invention provides a method for the preparation of nanomyelites comprising amphiphilic hyaluronic acid and including hydrophobic indocyanine green. According to the present invention, there is provided a method for preparing a nanomyelol, comprising the steps of: replacing a carboxy group of hyaluronic acid with an amine; and bonding an alkyl group to the substituted amine to prepare an aqueous solution containing amphiphilic hyaluronic acid; Treating the indocyanine green with a hydrophobic salt to prepare a hydrophobic indocyanine green; And dropping the hydrophobic indocyanine green into an aqueous solution containing the amphipathic hyaluronic acid. The present invention also provides a method for preparing a hydrophobic indocyanine green encapsulated nanomyelite.
In the step of adding the hydrophobic indocyanine green to the aqueous solution containing amphiphilic hyaluronic acid in the production method of the present invention, the amount of the hydrophobic indocyanine green added is 30% by weight or less, preferably 10 to 30% by weight, Is 5 to 15% by weight, but is not limited thereto. According to an embodiment of the present invention, when the amount of the nano-particles exceeds 30% by weight, nanoparticles may not be formed due to agglomeration phenomenon. In addition, as the amount of hydrophobic indocyanine green added is increased, the hydrophobic indocyanine green contained in the nanomicell increases, thereby increasing the signal intensity of photoacoustic and fluorescence images. However, the size of the nanomicell is also increased, The effect can be reduced.
Hereinafter, the present invention will be described in more detail with reference to the following examples, but the present invention is not construed as being limited thereto.
Hydrophobic Indocyanine Green Enclosed Micelle Produce
1-1. Amphipathic Preparation of hyaluronic acid
A solution of 6 mM hyaluronic acid (3 mM) in anhydrous formamide (5 mL) was prepared and dissolved at room temperature. After cooling the solution, 96 mg of EDC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide) and 58 mg of NHS (N-hydroxysuccinimide) were added to react with the carboxy group of hyaluronic acid. After 2 hours, 3 mM of C18 dissolved in DMF (NN dimethyl formamide) was added and reacted for 5 hours in a nitrogen atmosphere. The temperature was maintained at 60 캜 during the reaction (FIG. 1). Subsequently, the mixed solution was further stirred at room temperature for 24 hours, and then dialyzed sequentially for 24 hours in ethanol, 48 hours in an ethanol-water mixed solution and for 24 hours in water. After completion of the dialysis, the resulting final solution was purified by filtration and freeze-drying to obtain amphiphilic hyaluronic acid HA-C18 and confirmed by 1 H-NMR using an NMR spectrophotometer (300 Hz; Bruker, Billerica, MA) (Fig. 2).
1-2. Hydrophobicity India's non-green Preparation and Michelle Encapsulation
TBAI (tetrabutylammonium iodide) salt (6 mM) was added to 1 mM aqueous solution of indocyanine green in chloroform, followed by ultrasonic treatment for about 30 minutes to prepare hydrophobic indocyanine green Indocyanine-TBAI. HA-C18 micellar solution, which is an amphiphilic hyaluronic acid, prepared by adding hydrophobic indocyanine green to 10, 20, and 30 wt%, respectively, and added HA-
1-3. Cytotoxicity check
The cytotoxicity of HA-C18 micelles (HA-ICG) encapsulated with hydrophobic indocyanine green (ICG) in vitro was evaluated by squamous cell carcinoma (SCC) cell line SCC-7 and mouse embryonic fibroblast, MTT assay was performed by treating HA-ICG, a micelle containing hydrophobic indocyanine green, at 0.2, 0.4, 0.8, 1.5, 3, 6.25, and 12.5 μg / ml in NIH-3T3 cell line NIH-3T3. Cytotoxicity was calculated as the percentage of cells treated with Triton-X-100 (triton-X-100) as a negative control, and cells treated with HA-ICG as a positive control. Five different samples The mean ± standard deviation. As a result, both NIH-3T3 and SCC-7 showed high cell survival rate (> 90%) (FIG. 8).
Hydrophobicity Indy Cyan Green Enclosed Of Michel (HA-ICG) in vitro Intracellular Confirm internalization
SCC-7 cells to 37 ℃, 5% CO 2 conditions, and 10% (v / v) FBS and 1% (v / v) antibiotic-division inhibitor solution (GibcoVR / Invitrogen / Thermo Fisher Scientific ) RMPI 1640 containing the (GibcoVR ≪ / RTI > Thermo Fisher Scientific, Waltham, Mass.). SCC-7 cells were seeded at 1 × 10 5 cells / well on a Lab-Tek chamber slide to confirm the cellular uptake of HA-ICG micelles. After 24 hours, HA-ICG micelles were added to SCC-7 cells, For 4 hours. After incubation, cells in the medium were washed three times with PBS (phosphate buffer saline) and fixed with 4% paraformaldehyde. After cell fixation, nuclei were stained with gold antifade reagent and DAPI (20 mM) for 20 minutes, and cell fluorescence was confirmed by confocal laser microscopy. In order to confirm the cellular uptake of HA-ICG micelles by CD44-mediated SCC-7 cell culture medium, SCC-7 cells in which 8 mg / ml hyaluronic acid polymer was treated to block the CD44 receptor and NIH-3T3 cells not expressing CD44 Intracellular internalization confirmation was performed. As a result, fluorescence due to intracellular internalization of HA-ICG was confirmed in SCC-7 cells overexpressing CD44 (FIG. 9). After cell culture, the cells were washed three times with PBS, harvested, and subjected to flow cytometric analysis with a flow cytometer (FACScan). The results were similar to those confirmed by confocal laser microscopy (Fig. 10). These results indicate that HA-ICG micelles are internalized into cancer cells via endocytosis by CD44 receptor mediated by cancer cells.
Hydrophobicity Indy Cyan Green Enclosed Of Michel (HA-ICG) in- vivo And ex- vivo Intracellular Confirm internalization
Mice transplanted with CD44-expressing SCC-7 were prepared by subcutaneously injecting cells into a nearby Balb / c nude mouse (5 weeks, male; Orient Bio Inc., Seongnam-si, South Korea). HA-ICG was administered intravenously to mice when the tumor size grew to about 100 mm 3 . The tumor specificity and bio-distribution analysis of HA-ICG after intravenous administration was performed at different specific times using Fluorescencelabeled Organism Bio-imaging Instrument (FOBI, NEO science, Gyeonggi, Korea) ). Twenty-four hours after administration of HA-ICG, liver, lung, spleen, heart, kidney and tumor tissues were removed from the main organs and tumor accumulation of HA-ICG was measured by near-infrared fluorescence (NIRF) (Fig. 12). NIRF results showed the NIRF intensity higher in tumor tissue and liver, is shown the NIRF strength high in the liver even shown a high intensity between the NIRF because by HARE receptor and sepia reticular system (reticuloendothelial system), fluorescence measured at in- vivo And it was confirmed that the tumor tissue can be confirmed.
Hydrophobicity Indy Cyan Green Enclosed To Michel (HA-ICG) by Photoacoustic Imaging Measure
Photoacoustic imaging (PAI) for identifying tumor tissues and tumor vessels by HA-ICG administration was performed using a photoacoustic CT scanner (Nexus 128; Endra Inc., Ann Arbor, Mich.) At 680, . The photoacoustic intensity was dependent on the concentration of HA-ICG, and tumor tissue and tumor blood vessels were confirmed by photoacoustic imaging (FIG. 13).
To doxorubicin Hydrophobicized by Indy Cyan Green Enclosed Of Michel (HA-ICG / DOX) Produce
Doxorubicin (DOX) and indocyanine green (ICG) were dissolved in DMSO for 1 hour in dark condition and mixed at a ratio of 1: 1. After that, the mixture containing doxorubicin and indocyanine green was dropped into a MES buffer of pH 5.5, and the precipitated doxorubicin and indocyanine were precipitated with stirring. After precipitation of doxorubicin and indocyanine bound to the salt phase, the precipitate was obtained by centrifugation at 15,000 rpm for 15 minutes. The obtained precipitate was washed well with PBS and then lyophilized to prepare indocyanine green (DOX-ICG) hydrophobicized by doxorubicin. The DOX-ICG was dissolved in DMSO together with the HA-C18 prepared in Example 1, and dropped into distilled water while stirring to obtain an aqueous solution containing HA-C18 nano-micelle HA-ICG / DOX encapsulated with DOX-ICG . HA-ICG / DOX solution was dialyzed with MWCO 3,500 Da dialysis membrane to remove powdered HA-ICG / DOX by removing DMSO, doxorubicin and indocyanine green, which were not in salt form, and lyophilized. HA-ICG / DOX, which is a nano-micelle produced, was confirmed to be nano-micelle encapsulated with indocyanine green hydrophobicized by doxorubicin through UV absorption spectrum (FIG. 14).
Claims (8)
The hydrophobic indocyanine green is hydrophobicized by tetrabutylammonium iodide.
The hydrophobic indocyanine green is nano-micelles hydrophobized with doxorubicin, cisplatin or melphalan.
And dropwise adding the hydrophobic indocyanine green to an aqueous solution containing the amphiphilic hyaluronic acid in an amount of 10 to 30% by weight.
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