AU2021106295A4 - A hyaluronic acid-astaxanthin self-assembled nano system and the preparation method and its application - Google Patents
A hyaluronic acid-astaxanthin self-assembled nano system and the preparation method and its application Download PDFInfo
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- AU2021106295A4 AU2021106295A4 AU2021106295A AU2021106295A AU2021106295A4 AU 2021106295 A4 AU2021106295 A4 AU 2021106295A4 AU 2021106295 A AU2021106295 A AU 2021106295A AU 2021106295 A AU2021106295 A AU 2021106295A AU 2021106295 A4 AU2021106295 A4 AU 2021106295A4
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- hyaluronic acid
- astaxanthin
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- ethylenediamine
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- 229940022405 astaxanthin Drugs 0.000 title claims abstract description 62
- 239000001168 astaxanthin Substances 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 46
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 46
- 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 36
- JEBFVOLFMLUKLF-IFPLVEIFSA-N Astaxanthin Natural products CC(=C/C=C/C(=C/C=C/C1=C(C)C(=O)C(O)CC1(C)C)/C)C=CC=C(/C)C=CC=C(/C)C=CC2=C(C)C(=O)C(O)CC2(C)C JEBFVOLFMLUKLF-IFPLVEIFSA-N 0.000 claims abstract description 33
- 235000013793 astaxanthin Nutrition 0.000 claims abstract description 33
- MQZIGYBFDRPAKN-ZWAPEEGVSA-N astaxanthin Chemical compound C([C@H](O)C(=O)C=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)C(=O)[C@@H](O)CC1(C)C MQZIGYBFDRPAKN-ZWAPEEGVSA-N 0.000 claims abstract description 32
- 239000002114 nanocomposite Substances 0.000 claims abstract description 32
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 6
- 229940079593 drug Drugs 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 5
- 239000008367 deionised water Substances 0.000 claims description 3
- 229910021641 deionized water Inorganic materials 0.000 claims description 3
- 230000002757 inflammatory effect Effects 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000008351 acetate buffer Substances 0.000 claims description 2
- 239000008346 aqueous phase Substances 0.000 claims description 2
- 239000002537 cosmetic Substances 0.000 claims description 2
- 238000004132 cross linking Methods 0.000 claims description 2
- 238000009360 aquaculture Methods 0.000 claims 1
- 244000144974 aquaculture Species 0.000 claims 1
- 206010009887 colitis Diseases 0.000 claims 1
- 239000002778 food additive Substances 0.000 claims 1
- 235000013373 food additive Nutrition 0.000 claims 1
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 claims 1
- 201000008482 osteoarthritis Diseases 0.000 claims 1
- 239000000047 product Substances 0.000 claims 1
- 206010061218 Inflammation Diseases 0.000 abstract description 7
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- 235000013376 functional food Nutrition 0.000 abstract 1
- 238000000502 dialysis Methods 0.000 description 7
- 206010018910 Haemolysis Diseases 0.000 description 5
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- 210000004027 cell Anatomy 0.000 description 5
- 230000008588 hemolysis Effects 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000002949 hemolytic effect Effects 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 238000001338 self-assembly Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- -1 amino, carboxyl Chemical group 0.000 description 2
- 230000003064 anti-oxidating effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
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- 210000002540 macrophage Anatomy 0.000 description 2
- 239000002086 nanomaterial Substances 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 241000238557 Decapoda Species 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002929 anti-fatigue Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 235000021466 carotenoid Nutrition 0.000 description 1
- 150000001747 carotenoids Chemical class 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000000385 dialysis solution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 210000003746 feather Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000001878 scanning electron micrograph Methods 0.000 description 1
- 238000004626 scanning electron microscopy Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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Classifications
-
- 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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/56—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 an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—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 an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/6931—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 the material constituting the nanoparticle being a polymer
- A61K47/6939—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 the material constituting the nanoparticle being a polymer the polymer being a polysaccharide, e.g. starch, chitosan, chitin, cellulose or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/24—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by six-membered non-aromatic rings, e.g. beta-carotene
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Nanotechnology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Pain & Pain Management (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Rheumatology (AREA)
- Biophysics (AREA)
- Biotechnology (AREA)
- Immunology (AREA)
- Medical Informatics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses the hyaluronic acid-astaxanthin self-assembled
nanocomposites and the preparation method and their application thereof, which
belongs to the field of marine medicines. The preparation method of the hyaluronic
acid-astaxanthin self-assembled nanocomposite comprises the following steps: firstly,
hyaluronic acid reacts with ethylenediamine to generate ethylenediamine hyaluronic
acid. Then, the ethylenediamine hyaluronic acid reacts with astaxanthin to produce
hyaluronic acid-ethylenediamine-astaxanthin compound. Finally, due to the
hydrophilicity of hyaluronic acid and the hydrophobicity of astaxanthin, the hyaluronic
acid-ethylenediamine-astaxanthin compound self-assembled in aqueous solution to
form hyaluronic acid-astaxanthin nanocomposites. The hyaluronic acid-astaxanthin
nanocomposite prepared by the invention has a good dispersibility in aqueous solution
and good biocompatibility in vitro, which improves its efficiency of entering body
tissues and cells, and the method provided by this invention can be developed into
drugs or functional foods for preventing and treating various inflammations.
Description
A hyaluronic acid-astaxanthin self-assembled nano system and the preparation method and its application
TECHNICAL FIELD The invention relates to marine nanometer medicines, in particular to nanometer self-assembly system, and its preparation method, and its application in prevention and treatment of various inflammatory related diseases.
BACKGROUND Astaxanthin (AST) is a kind of red solid powder, which is fat soluble, and insoluble in water, but soluble in organic solvents. It widely exists in the biological world, especially in aquatic animals such as shrimp, crab, fish and the feathers of birds, and it plays a important role in color effect. Astaxanthin, as a kind of carotenoid, is the strongest antioxidant found in nature so far, and has the functions of anti-oxidation, anti-aging, anti-tumor, anti-inflammation, anti-fatigue and so on. However, AST has poor water solubility, and is sensitive to light, heat, oxygen and other factors, so it is easy to be destroyed in a short time, which is not conducive to storage and makes it difficult to develop and utilize. Therefore, the research on the modification of astaxanthin to enhance its stability is of great significance to promote the development and utilization of astaxanthin. Hyaluronic acid contains polyglucuronic acid and is an acidic mucopolysaccharide, it lubricates and nourishes the cells and cellular organs of the body. Hyaluronic acid is also widely used in nano field because of its good biocompatibility and dispersibility, especially it can improve the dispersibility of hydrophobic nano materials in water, and the prepared composite nano materials are used in many fields, including the protection of food functional factors, cancer suppression, bacteriostasis and so on. The amino, carboxyl and hydroxyl functional groups of hyaluronic acid can be chemically cross-linked to obtain derivatives with different characteristics, including improving water solubility and other new functions. Because of its excellent properties, hyaluronic acid and its derivatives are widely used and studied in food, cosmetics, chemical industry, biochemistry, medicine and biomedicine.
The purpose of this invention is used hyaluronic acid and astaxanthin as the raw materials to prepare the hyaluronic acid-astaxanthin nanocomposite by covalent bonding with ethylenediamine. In aqueous system, the hydrophobic astaxanthin was wraped into the hydrophilic hyaluronic acid, and the hyaluronic acid-astaxanthin nanocomposite was constructed by self-assembly,. The invention solves the problems that astaxanthin is easy to oxidize, poor in water solubility, and unstable under heating and acidic conditions, and it improves the bioavailability of astaxanthin in vivo. At the same time, it takes advantage of the good water solubility and biological activity of hyaluronic acid to play a synergistic role. Hyaluronic acid has anti-inflammatory and antibacterial activities, while astaxanthin has anti-oxidation and anti-inflammatory activities. The nanocomposite has good biocompatibility and no cytotoxicity, so it can be used for the prevention and treatment of inflammatory -related diseases. The nano drug delivery system has the characteristics of high drug efficacy, small toxic and side effects.
SUMMARY The purpose of this invention is to provide hyaluronic acid-astaxanthin self assembled nanocomposite and the preparation method and its application thereof. Another purpose of the present invention is to use astaxanthin-hyaluronic acid self-assembled nanocomposites in the prevention and treatment of inflammation related diseases. The further purpose of the present invention is that the prepared astaxanthin hyaluronic acid nanocomposite has no hemolytic toxicity in vitro, its nanometer particle size is 157.9±2.lnm, and Zeta potential is -10.61.OmV, and the nanocomposite has good dispersibility and stability in physiological state. A further object of the present invention is to provide preparation method of the self-assembled astaxanthin-hyaluronic acid nanocomposite, which can effectively stabilize astaxanthin and improve its bioavailability and targeted delivery efficiency in vivo. The preparation method comprises the following steps: Step, Hyaluronic acid was dissolved in dimethyl sulfoxide solution, and crosslinking with ethylenediamine through crosslinking agent to prepare ethylenediamine-modified hyaluronic acid, wherein the mass ratio of hyaluronic acid to ethylenediamine in the mixed solution is 20: 1-10: 1. Step 2: The mixed solution of ethylenediamine-modified hyaluronic acid and astaxanthin is stirred and reacted at 30-80 °C for 2 ~ 5 d, and the reaction process should be kept away from light and protected by nitrogen. Step 3, The reacted mixed solution was dialyzed against deionized water in a dialysis bag with a molecular weight cut-off of 3500 Da for 3-5 d. Further, the organic solvent for dissolving astaxanthin is ethanol, dioxane and tetrahydrofuran. The application of the hyaluronic acid-astaxanthin self-assembled nanocomposite in inflammation-related diseases. The invention has the beneficial effects that: (1) Hyaluronic acid and astaxanthin react under mild conditions to generate hyaluronic acid-astaxanthin compound, which has mild reaction conditions and simple reaction operation. (2) In the aqueous phase system, the hyaluronic acid-astaxanthin compound is self-assembled to construct a hyaluronic acid-astaxanthin nanocomposite, with astaxanthin as the core and hyaluronic acid as the shell, and the easily oxidized and unstable astaxanthin is wrapped inside hyaluronic acid. (3) The particle size of the prepared hyaluronic acid-astaxanthin nanocomposite is between 160-220 nm, which has a good biocompatibility with no hemolytic toxicity, and exihibits the synergistic effect of hyaluronic acid and astaxanthin. (4) An application of the self-assembled nanocomposite of hyaluronic acid and astaxanthin in the prevention and treatment of inflammation-related diseases is provided. BRIEF DESCRIPTION OF THE FIGURES In order to explain the embodiment of the present invention or the technical scheme in the prior art more clearly, the following drawings will be briefly introduced. Fig. 1 is an infrared spectrum of hyaluronic acid-astaxanthin compound. Fig. 2 is a scanning electron micrograph of hyaluronic acid-astaxanthin self assembled nanocomposite.
Fig. 3 is a hemolytic toxicity diagram of hyaluronic acid-astaxanthin self assembled nanocomposite. Wherein, 1. negative control: saline, 2. positive control: purified water, 3.HA-AST, without blood cells, 4. 1000 tg/mL HA-AST, 5. 800 tg/mL HA-AST, 6. 600 pg/mL HA AST. Fig. 4 is an anti-inflammatory activity diagram of hyaluronic acid-astaxanthin self assembled nanocomposite.
DESCRIPTION OF THE INVENTION The following will clearly and completely describe the technical scheme in the embodiment of the present invention with reference to the drawings in the embodiment of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without creative labor belong to the scope of protection of the present invention. In the following examples, various processes and methods that are not described in detail are conventional methods known in the field, and the reagents used without marked source and specifications are commercially available analytically or chemically pure. Embodiment 1 The method for preparing astaxanthin-hyaluronic acid self-assembled nanocomposite comprises the following steps: (1) 80 pM hyaluronic acid and 40 pM NHS were added into 5 mL dimethyl sulfoxide, and heated at 50 °C to assist dissolution. 140 pM EDC was added and stirred at room temperature for 10 min. Then 5 pM ethylenediamine was added and stirred at room temperature under the protection of nitrogen for 12 hthen the reaction was stopped., The reaction solution was dialyzed with dialysis bag (molecular weight cut-off of 3500 Da) to remove the impurities. The dialysis solvents are as follows: 0.01M NaOH dialysis for 3-8h, acetonitrile: water (1:1, VN) dialysis for 10-24 h, distilled water dialysis for 24-72 h. The dialysis solution in the dialysis bag was concentrated and freeze-dried to obtain ethylenediamineized hyaluronic acid.
(2) 1.0 mM ethylenediamine hyaluronic acid was dissolved in 10 mL acetate buffer solution (pH 5.0), and 1.0 mM astaxanthin was added. The solutions was stirred and reacted at 50 °C for 3 d in the dark under the protection of nitrogen. The reaction solution was dialyzed with deionized water for 5 d, and concentrated, then freeze-dried to obtain the hyaluronic acid-astaxanthin compound. (3) The hyaluronic acid-astaxanthin compoundwas dispersed in saline by ultrasound, and the hydrophobic astaxanthin was wraped inner the hydrophilic hyaluronic acid , so the self-assembly occurs, and the uniformly dispersed self assembled hyaluronic acid-astaxanthin nanocomposite is obtained. Hyaluronic acid, astaxanthin and astaxanthin-hyaluronic acid compound were dried under vacuum and reduced pressure, then tabletted by KBr, and analyzed by infrared spectroscopy. Infrared spectra of hyaluronic acid, astaxanthin and astaxanthin hyaluronic acid compound are shown in Fig.1. It can be seen from the figure that in astaxanthin-hyaluronic acid compound, the hydroxyl peak of hyaluronic acid decreases obviously at 3500-3400cm- 1, and the peak intensity at 1700-1600 cm-1 increases obviously, that indicating the new amide bond and hydrazone bond are formed. The astaxanthin-hyaluronic acid nanocomposite was placed on a silicon wafer for scanning electron microscopy analysis. It can be seen from Fig.2 that the astaxanthin hyaluronic acid nanocomposite is smooth and spherical, with a particle size of 157.9±2.1nm. Astaxanthin-hyaluronic acid nanocomposite was dissolved in phosphate buffer solution, and its stability was studied by nano-particle size analyzer. The Zeta potential of astaxanthin-hyaluronic acid nanocomposite is -10.6±1.0 mV, which indicates that the astaxanthin-hyaluronic acid nanocomposite has a good stability in phosphate buffer solution. Measurement of hemolysis equivalent: 0.5mL of samples in a certain concentration was added into a tube, and then 0.5mL of 2% red blood cell suspension was added. The positive control and negative control was 0.5 mL distilled water and 0.5mL normal saline, respectively. The experiment was determined with 3 parallel tubes. The solutions in the tube was mixed evenly, and keeped them in the water bath at 37 °C for 2 h. Then the reaction was stopped by taking them into the ice bath immediately. The reaction solution was centrifuged, and 200pL of the supernatant was taken by mixing with 5ml methanol, then measured at 415 nm.. The hemolysis rate was calculated according to the formula as follows: hemolysis rate = (Asample -Anegative) /(Apositive -Anegative)x 100%. The hemolysis curve of each sample was obtained by plotting the hemolysis rate of the sample against the concentration of the sample. Anti-inflammatory activity experiment in vitro: The anti-inflammatory activity of astaxanthin-hyaluronic acid self-assembled nanocomposites was determined by enzyme-linked immunosorbent assay. Macrophages RAW264.7 in logarithmic growth phase were inoculated into a 96-well culture plate with a cell density of 10000 cells per well and cultured overnight. The cells were stimulated with LPS at 5 pg/mL to induce inflammatory reaction, and then astaxanthin-hyaluronic acid self-assembled nanocomposites (2, 4, 8pg/mL) with different concentrations were added and cultured for 24 hours. The cell supernatants were collected, and the levels of TNF-a and IL-6 in supernatants were measured by ELISA to evaluate the effect of hyaluronic acid astaxanthin self-assembled nanocomposites on macrophage inflammation reaction.
Claims (6)
- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. Hyaluronic acid-astaxanthin self-assembled nano system and preparation method is characterized in comprising the following steps: (1) Hyaluronic acid was dissolved in dimethyl sulfoxide solution, and NHS and EDC were added, which can be heated and ultrasonicated for assisting dissolving. Then ethylenediamine was added for crosslinking reaction under the protection of nitrogen. The reaction solution was dialyzed with sodium hydroxide, acetonitrile: water and deionized water in turn, and then were freeze-dried to obtain ethylenediamineized hyaluronic acid. (2) Ethylenediamine hyaluronic acid was dissolved in acetate buffer solution with pH5.0, and a certain amount of astaxanthin was added. The reaction was heated and stirred under the protection of nitrogen. Then the reaction solution was dialyzed and freeze-dried to obtain the hyaluronic acid-astaxanthin compound. (3) The hyaluronic acid-astaxanthin compound was dispersed in an aqueous phase system, and the uniformly dispersed hyaluronic acid-astaxanthin self-assembled nanocomposite was obtained by ultrasonic.
- 2. The preparation method according to claim 1, is characterized in that the astaxanthin in the step (1) is firstly dissolved in an organic solvent, and then added dropwise to the ethylenediamineized hyaluronic acid solution.
- 3. The preparation method, according to claim 1, is characterized in that step (1), the reaction is carried out at 40-80 °C for 2-5 d without light and under the protection of nitrogen.
- 4. The preparation method, according to claim 1, is characterized in that the molar ratio of hyaluronic acid to astaxanthin in the step is 0.5:1-5:1.
- 5. The hyaluronic acid-astaxanthin self-assembled nanocomposite is prepared by the method of this invention including any one of claims 1-4, and its application in prevention and treatment of inflammatory related diseases (such as colitis, osteoarthritis, etc.).
- 6. The hyaluronic acid-astaxanthin nanocomposite prepared by the preparation method of any one of claims 1-4 can be applied to health products, medicines, cosmetics, food additives, aquaculture and the like.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114106216A (en) * | 2021-12-20 | 2022-03-01 | 青岛科技大学 | Hyaluronic acid-astaxanthin nano-composite and preparation method and application thereof |
| CN115645367A (en) * | 2022-09-22 | 2023-01-31 | 江南大学 | Preparation method and application of astaxanthin hyaluronic acid ester and micelle |
| CN116251037A (en) * | 2021-12-09 | 2023-06-13 | 华熙生物科技股份有限公司 | Hydrolysis sodium hyaluronate self-assembled structure, and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116251037A (en) * | 2021-12-09 | 2023-06-13 | 华熙生物科技股份有限公司 | Hydrolysis sodium hyaluronate self-assembled structure, and preparation method and application thereof |
| CN114106216A (en) * | 2021-12-20 | 2022-03-01 | 青岛科技大学 | Hyaluronic acid-astaxanthin nano-composite and preparation method and application thereof |
| CN115645367A (en) * | 2022-09-22 | 2023-01-31 | 江南大学 | Preparation method and application of astaxanthin hyaluronic acid ester and micelle |
| CN115645367B (en) * | 2022-09-22 | 2023-07-18 | 江南大学 | Astaxanthin hyaluronic acid ester, preparation method of micelle and application of astaxanthin hyaluronic acid ester and micelle |
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