CN113402628A - 一种两亲性高生物活性改性透明质酸 - Google Patents
一种两亲性高生物活性改性透明质酸 Download PDFInfo
- Publication number
- CN113402628A CN113402628A CN202110631000.1A CN202110631000A CN113402628A CN 113402628 A CN113402628 A CN 113402628A CN 202110631000 A CN202110631000 A CN 202110631000A CN 113402628 A CN113402628 A CN 113402628A
- Authority
- CN
- China
- Prior art keywords
- hyaluronic acid
- group
- short peptide
- modified hyaluronic
- amphiphilic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 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 class 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 title claims abstract description 94
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 53
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 53
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 34
- 230000001737 promoting effect Effects 0.000 claims abstract description 11
- 230000000975 bioactive effect Effects 0.000 claims abstract description 7
- -1 polyoxypropylene group Polymers 0.000 claims description 4
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 2
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 230000006870 function Effects 0.000 abstract description 13
- 239000000463 material Substances 0.000 abstract description 12
- 230000017423 tissue regeneration Effects 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 5
- 150000004676 glycans Chemical class 0.000 abstract description 4
- 229920001282 polysaccharide Polymers 0.000 abstract description 4
- 239000005017 polysaccharide Substances 0.000 abstract description 4
- 238000011069 regeneration method Methods 0.000 abstract description 4
- 239000012620 biological material Substances 0.000 abstract description 3
- 239000002537 cosmetic Substances 0.000 abstract description 3
- 230000004048 modification Effects 0.000 abstract description 3
- 238000012986 modification Methods 0.000 abstract description 3
- 230000008929 regeneration Effects 0.000 abstract description 3
- 102000008186 Collagen Human genes 0.000 abstract description 2
- 108010035532 Collagen Proteins 0.000 abstract description 2
- 230000004071 biological effect Effects 0.000 abstract description 2
- 229920001436 collagen Polymers 0.000 abstract description 2
- 230000007547 defect Effects 0.000 abstract description 2
- 238000011049 filling Methods 0.000 abstract description 2
- 238000002347 injection Methods 0.000 abstract description 2
- 239000007924 injection Substances 0.000 abstract description 2
- 238000005461 lubrication Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 230000008827 biological function Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- 102000004196 processed proteins & peptides Human genes 0.000 description 10
- 229920001184 polypeptide Polymers 0.000 description 8
- 210000002950 fibroblast Anatomy 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- 150000001718 carbodiimides Chemical class 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical class NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- 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 1
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 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 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003519 biomedical and dental material Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- ACBQROXDOHKANW-UHFFFAOYSA-N bis(4-nitrophenyl) carbonate Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)OC1=CC=C([N+]([O-])=O)C=C1 ACBQROXDOHKANW-UHFFFAOYSA-N 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 125000000600 disaccharide group Chemical group 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000013376 functional food Nutrition 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000010837 receptor-mediated endocytosis Effects 0.000 description 1
- 230000037384 skin absorption Effects 0.000 description 1
- 231100000274 skin absorption Toxicity 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/20—Polysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/23—Carbohydrates
- A61L2300/236—Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Birds (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
本发明公开了一种两亲性高生物活性改性透明质酸。本发明以透明质酸为主链，以具有促进组织修复和再生功能的高活性短肽为生物活性接枝基团，以亲脂基团为促进透皮能力的接枝基团。通过接枝改性，制备同时具有亲水及亲脂的两亲性和高生物活性的透明质酸材料。通过用不同分子量的透明质酸主链，制备不同用途的透明质酸衍生物生物材料，小分子量改性透明质酸可作为化妆品功能性原料，通过涂抹透皮吸收。大分子量的改性多糖材料可通过注射用于医美材料或组织再生或关节腔润滑。本发明克服了透明质酸材料单一的物理填充作用的缺陷，在透明质酸材料固有的高保湿特性上，增加了多糖类生物材料透明质酸促进细胞再生、胶原再生等生物学功能。
Description
技术领域
本发明涉及一种两亲性高生物活性改性透明质酸，属于生物医用材料技术领域。
背景技术
透明质酸(Hyaluronic acid,HA)又叫玻尿酸，是一种重要的天然多糖高分子生物医用材料，其基本结构是由双糖单位D-葡萄糖醛酸及N-乙酰葡糖胺组成的多糖类高分子，具有优异的保水性、润滑性、黏弹性、生物相容性等特性，在医药、化妆品及功能性食品领域应用广泛，特别是作为组织填充剂、关节润滑剂及功能保湿成分时，HA尚无天然可替代品。目前常规HA使用中面临的挑战包括：(1)半衰期短，易被机体内HA酶降解；(2)功能单一，缺乏细胞粘附和增殖位点。虽通过交联、共混改性(与生长因子、胶原、壳聚糖等混合和交联)等手段可提高HA的抗酶解能力并赋予其功能性，但这些方法极易引起免疫排异、透皮吸收难等问题。
HA广泛分布于哺乳动物骨髓细胞、眼部玻璃体以及软组织的细胞外基质中，在细胞应答，如增殖、变异、迁移、黏附和基因表达等方面发挥重要作用。相对分子质量高的HA可以保证细胞外基质的含水量和细胞的完整性；低分子量的HA则可以诱发受体介导的细胞内吞作用。高活性短肽(Bioactive Short Peptides,BSP)是一类可模拟体内活性蛋白质生理功能且无免疫源性的小分子肽链，可实现单位密度内有效成份的高表达，如抗菌、促组织再生和免疫调节等。BSP合成路径清晰，具有活性位点丰富、构象稳定、易于合成、方便保存等优势，是当前国际功能生物材料领域的研究与产业热点。目前关于采用生物活性功能的材料对HA进行改性从而获得新型HA材料的相关技术还未见报道。
发明内容
本发明所要解决的技术问题是：如何利用生物活性功能材料BSP对HA进行改性从而获得功能多样性的HA材料。
为了解决上述技术问题，本发明提供了一种两亲性高生物活性改性透明质酸，以透明质酸HA为主链，以活性短肽为生物活性接枝基团，以亲脂基团为促进透皮接枝基团，其化学结构式如式I所示：
其中，式I中的R1为活性短肽、R2为亲脂基团，或者式I中的R1为亲脂基团、R2为活性短肽，n＝1～7000。
优选地，所述的活性短肽包括氨基酸序列为RXDX的短肽，其中，X为E、G、V或S。
优选地，所述亲脂基团包括C4～C20的羰基、聚氧丙烯基、长链全氟烷基、聚硅氧烷基以及含有芳基、酯基、醚基、胺基、酰胺基、环烷基或双键的烃基中的任意一种基团或多种基团的组合。
优选地，所述透明质酸HA主链的分子量为1K-2500KDa。
优选地，所述的如式I所示的改性透明质酸的亲疏水性和生物活性可通过改变活性短肽和亲脂基团的接枝比例来调节，所述活性短肽和亲脂基团的接枝比例之比为1000：1～1：1000。。
优选地，所述活性短肽和透明质酸HA主链之间为直接共价结合或通过短肽链接剂结合。
更优选地，所述的短肽链接剂为WGRGDSP、GWGLGPAGK或CCRR。
与现有技术相比，本发明的有益效果在于：
1.本发明的两亲性高生物活性改性透明质酸利用具有生物活性功能的BSP，接枝于HA表面，赋予HA促组织再生等生物活性功能，同时接枝亲脂疏水基团，增强其透皮吸收效果，并可以通过调节活性短肽和亲脂基团的接枝比例获得功能多样性的改性透明质酸；
2.本发明利用不同分子量的透明质酸主链进行改性后，小分子量改性透明质酸可作为化妆品功能性原料，通过涂抹透皮吸收，其具有的亲脂基团能够大大促进皮肤的吸收；大分子量的改性透明质酸可通过注射用于医美材料或组织再生或关节腔润滑，其具有良好的生物相容性和促进细胞再生的功能，本发明克服了透明质酸材料单一的物理填充功能的缺陷。
附图说明
图1为实施例1的改性透明质酸与普通透明质酸HA对成纤细胞的培养结果；其中，A:普通透明质酸HA对成纤细胞的培养结果，B：实施例1的改性透明质酸对成纤细胞的培养结果；
图2为实施例2的低分子量改性透明质酸和普通透明质酸HA涂抹后透皮吸收对比图；其中，(A)：普通透明质酸HA涂抹后透皮吸收情况；(B)：实施例2的低分子量改性透明质酸涂抹后透皮吸收情况。
具体实施方式
为使本发明更明显易懂，兹以优选实施例，并配合附图作详细说明如下。
实施例1
一种两亲性高生物活性改性透明质酸的制备方法，包括如下步骤：
将大于800KDa的高分子量的HA(n＝6500，或n＝2500)在水浴中加热到80℃，并在该温度下维持1小时。37℃下，在pH＝6.8的含有碳化二亚胺和1-羟基苯并三唑(HOBt)的二甲基亚砜(DMSO)中反应1小时，将多肽RXDX(其中X可以是E或G、V和S，本实施例中的多肽为REDG)通过WGRGDSP(linker)接枝到HA的羧基上。利用十六烷基三甲基溴化铵(CTA)与HA的6位伯醇羟基在37℃下，在二甲基亚砜(DMSO)中反应1小时，生成HA-CTA后，再与二(对硝基苯)碳酸酯(4-NPBC)在pH＝8.0的磷酸盐-DMSO缓冲体系中反应1小时，形成活化酯后，再与苯胺在65℃条件下反应24小时，反应结束后，用乙醚沉淀并洗涤产品，得到一种高分子量的具有促进组织修复生物活性功能的改性透明质酸，为化合物1～2。
所得化合物1中，n＝6500，R1＝WGRGDSPREDG，R2＝C6H5NH；
所得化合物2中，n＝2000，R1＝WGRGDSPREDG，R2＝C6H5NH。
测试上述具有促进组织修复生物活性功能的改性透明质酸中的化合物1或2的生物活性：以普通透明质酸HA为对照组，将成纤细胞加入含透明质酸的培养皿中培养24h，观察成纤细胞的贴附与增殖情况，如图1所示，由图1可知，上述改性透明质酸与成纤细胞之间贴附良好且有效促进成纤细胞的增殖，其具有良好的生物相容性和高生物活性。
实施例2
一种两亲性高生物活性改性透明质酸的制备方法，包括如下步骤：
将分子量为2.5KDa左右的HA(n＝8)在水浴加热到80℃，并在该温度下在pH＝4.6的极性溶剂磷酸盐-DMSO中搅拌1小时。37℃下，在pH＝6.8的含有碳化二亚胺和1-羟基苯并三唑(HOBt)的二甲基亚砜(DMSO)中反应1小时，将多肽RXDX(其中X可以是E或G、V和S，本实施例中的多肽为REDG)接聚到HA的羧基衍生物上。在HA主链的6位伯醇羟基进行修饰(其活性比其他位点的羟基高)，和丁酸酐在pH＝8.0的DMSO中搅拌1小时进行酯化反应，从而引入相应的丁酸酯。得到一种低分子量的具有促进组织修复生物活性功能的改性透明质酸，为化合物3。
所得化合物3中，n＝8，R1＝REDG，R2＝CH3CH2CH2C＝O。
其中，低分子量改性透明质酸中的化合物3可涂抹后透皮吸收，涂抹后可在3秒内完全吸收，而普通透明质酸HA涂抹后在3分钟仍未完全吸收，如图2所示。
实施例3
一种两亲性高生物活性改性透明质酸的制备方法，包括如下步骤：
将分子量为80kDa左右的HA(n＝250)在水浴中加热到80℃，并在该温度下维持1小时。37℃下，在pH＝6.8的含有碳化二亚胺和1-羟基苯并三唑(HOBt)的二甲基亚砜(DMSO)中反应1小时，将多肽RXDX(其中X可以是E或G、V和S，本实施例中的多肽为REDG)通过GWGLGPAGK(linker)接枝到HA的羧基上。将此改性HA溶解在含棕榈酸的pH为6.0的磷酸盐-DMSO环境中，室温下搅拌24小时，得到一种中分子量的具有促进组织修复生物活性功能的改性透明质酸，为化合物4。
所得化合物4中，n＝250，R1＝GWGLGPAGKREDG，R2＝CH3(CH2)14C＝O。
实施例4
一种两亲性高生物活性改性透明质酸的制备方法，包括如下步骤：
将分子量为10kDa左右的HA(n＝30)在水浴中加热到80℃，并在该温度下维持1小时。将多肽RXDX(其中X可以是E或G、V和S，本实施例中的多肽为REDG)通过CCRR(linker)接枝到制备的HA的羧基上(接枝方法同实施例3)。在HA主链的6位伯醇羟基进行修饰(其活性比其他位点的羟基高)，具体地，采用棕榈酸与HA分子上的OH在pH＝8.0的DMSO中搅拌1小时进行酯化反应，生成酯，从而引入亲脂基团，得到一种具有促进组织修复生物活性功能的改性透明质酸，为化合物5。
所得化合物5中，n＝30，R1＝CCRRREDG，R2＝CH3(CH2)14C＝O。
上述实施例仅为本发明的优选实施例，并非对本发明任何形式上和实质上的限制，应当指出，对于本技术领域的普通技术人员，在不脱离本发明的前提下，还将可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。
Claims (7)
1.一种两亲性高生物活性改性透明质酸，其特征在于，以透明质酸HA为主链，以活性短肽为生物活性接枝基团，以亲脂基团为促进透皮接枝基团，其化学结构式如式I所示：
其中，式I中的R1为活性短肽、R2为亲脂基团，或者式I中的R1为亲脂基团、R2为活性短肽，n＝1～7000。
2.如权利要求1所述的两亲性高生物活性改性透明质酸，其特征在于，所述的活性短肽包括氨基酸序列为RXDX的短肽，其中，X为E、G、V或S。
3.如权利要求1所述的两亲性高生物活性改性透明质酸，其特征在于，所述亲脂基团包括C4～C20的羰基、聚氧丙烯基、长链全氟烷基、聚硅氧烷基以及含有芳基、酯基、醚基、胺基、酰胺基、环烷基或双键的烃基中的任意一种基团或多种基团的组合。
4.如权利要求1所述的两亲性高生物活性改性透明质酸，其特征在于，所述透明质酸HA主链的分子量为1K-2500KDa。
5.如权利要求1所述的两亲性高生物活性改性透明质酸，其特征在于，所述的如式I所示的改性透明质酸的亲疏水性和生物活性可通过改变活性短肽和亲脂基团的接枝比例来调节，所述活性短肽和亲脂基团的接枝比例之比为1000：1～1：1000。
6.如权利要求1所述的两亲性高生物活性改性透明质酸，其特征在于，所述活性短肽和透明质酸HA主链之间为直接共价结合或通过短肽链接剂结合。
7.如权利要求6所述的两亲性高生物活性改性透明质酸，其特征在于，所述的短肽链接剂为WGRGDSP、GWGLGPAGK或CCRR。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110631000.1A CN113402628A (zh) | 2021-06-07 | 2021-06-07 | 一种两亲性高生物活性改性透明质酸 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110631000.1A CN113402628A (zh) | 2021-06-07 | 2021-06-07 | 一种两亲性高生物活性改性透明质酸 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113402628A true CN113402628A (zh) | 2021-09-17 |
Family
ID=77676688
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110631000.1A Pending CN113402628A (zh) | 2021-06-07 | 2021-06-07 | 一种两亲性高生物活性改性透明质酸 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113402628A (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106474486A (zh) * | 2016-10-17 | 2017-03-08 | 浙江大学 | 一种聚合物胶束及其应用 |
| US20180296631A1 (en) * | 2017-04-12 | 2018-10-18 | University Of Toronto | Hydrogel composition and associated method of use |
| CN110713517A (zh) * | 2019-10-11 | 2020-01-21 | 润辉生物技术（威海）有限公司 | 一种乙酰透明质酸寡肽及其制备与应用方法 |
-
2021
- 2021-06-07 CN CN202110631000.1A patent/CN113402628A/zh active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106474486A (zh) * | 2016-10-17 | 2017-03-08 | 浙江大学 | 一种聚合物胶束及其应用 |
| US20180296631A1 (en) * | 2017-04-12 | 2018-10-18 | University Of Toronto | Hydrogel composition and associated method of use |
| CN110713517A (zh) * | 2019-10-11 | 2020-01-21 | 润辉生物技术（威海）有限公司 | 一种乙酰透明质酸寡肽及其制备与应用方法 |
Non-Patent Citations (1)
| Title |
|---|
| 侯琳: "载药传递体的构建及其透皮释药的研究", 《中国优秀博硕士学位论文全文数据库(硕士) 工程科技Ⅰ辑》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100674177B1 (ko) | 교차 결합된 히알루론산과 그것의 의학적 용도 | |
| Dahlmann et al. | Fully defined in situ cross-linkable alginate and hyaluronic acid hydrogels for myocardial tissue engineering | |
| AU2002223995B2 (en) | Cross-linked hyaluronic acid-laminin gels and use thereof in cell culture and medical implants | |
| US6642363B1 (en) | Polymers containing polysaccharides such as alginates or modified alginates | |
| AU2005257078B2 (en) | Hydrogels of hyaluronic acid and alpha, beta-polyaspartylhydrazide and their biomedical and pharmaceutical uses | |
| AU2002223995A1 (en) | Cross-linked hyaluronic acid-laminin gels and use thereof in cell culture and medical implants | |
| US20060110426A1 (en) | Cohesive coprecipitates of sulfated polysaccharide and fibrillar protein and use thereof | |
| CN112535766B (zh) | 基于人间充质干细胞细胞外基质来源复合胶原蛋白提取液水凝胶及其制备方法 | |
| Chopra et al. | Biopolymer-based scaffolds for tissue engineering applications | |
| US20100278893A1 (en) | Implantable material comprising cellulose and the glycopeptide xyloglucan-grgds | |
| EP1806367A2 (en) | Polymers containing polysaccharides such as alginates or modified alginates | |
| CN113402628A (zh) | 一种两亲性高生物活性改性透明质酸 | |
| US8507659B2 (en) | Method for chemically modifying biopolymer and polypeptide | |
| KR20170075723A (ko) | 글리코사미노글리칸 및 단백질을 함유하는 조성물 | |
| Hayashi | Fish Collagen: Characteristics and Application | |
| Schenke-Layland et al. | Use of Extracellular Matrix Proteins and Natural Materials in Bioengineering | |
| Tronci | Synthesis, characterization, and biological evaluation of gelatin-based scaffolds | |
| CN117229430A (zh) | 一种活性短肽改性几丁质及其制备方法 | |
| CN117500535A (zh) | 用丝心蛋白交联多糖以及所获得材料的用途 | |
| CN115838478A (zh) | 一种透明质酸衍生物或其盐及其制备方法和应用 | |
| JP2023001803A (ja) | 架橋コラーゲン | |
| CN109337082A (zh) | 一种玻尿酸-聚乳酸改性材料的制备方法 | |
| Bartoli | DESIGN AND PREPARATIONS OF NEW POLYMERIC MATERIALS OF SYNTHETIC AND NATURAL ORIGIN FOR BIOMEDICAL AND ENVIRONMENTAL APPLICATIONS |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210917 |
|
| RJ01 | Rejection of invention patent application after publication |