CN114716581A - Multiple modified hyaluronic acid derivative and application thereof - Google Patents
Multiple modified hyaluronic acid derivative and application thereof Download PDFInfo
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- CN114716581A CN114716581A CN202210306737.0A CN202210306737A CN114716581A CN 114716581 A CN114716581 A CN 114716581A CN 202210306737 A CN202210306737 A CN 202210306737A CN 114716581 A CN114716581 A CN 114716581A
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- hyaluronic acid
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- 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 90
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 44
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 44
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 18
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 25
- 125000003277 amino group Chemical group 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 9
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 125000001033 ether group Chemical group 0.000 claims description 4
- 229920000570 polyether Polymers 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 239000000463 material Substances 0.000 claims 2
- 239000007858 starting material Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 20
- 238000005859 coupling reaction Methods 0.000 abstract description 16
- 230000000694 effects Effects 0.000 abstract description 12
- 230000008878 coupling Effects 0.000 abstract description 10
- 238000010168 coupling process Methods 0.000 abstract description 10
- 239000003431 cross linking reagent Substances 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 10
- 239000000017 hydrogel Substances 0.000 abstract description 6
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 238000000502 dialysis Methods 0.000 description 14
- 230000009257 reactivity Effects 0.000 description 14
- 239000002246 antineoplastic agent Substances 0.000 description 9
- 229940041181 antineoplastic drug Drugs 0.000 description 9
- 239000012153 distilled water Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 8
- 125000000524 functional group Chemical group 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000007344 nucleophilic reaction Methods 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229920002385 Sodium hyaluronate Polymers 0.000 description 4
- 238000007385 chemical modification Methods 0.000 description 4
- 230000000269 nucleophilic effect Effects 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 229940010747 sodium hyaluronate Drugs 0.000 description 4
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(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- Chemical compound [Na+].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 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 3
- PBVAJRFEEOIAGW-UHFFFAOYSA-N 3-[bis(2-carboxyethyl)phosphanyl]propanoic acid;hydrochloride Chemical compound Cl.OC(=O)CCP(CCC(O)=O)CCC(O)=O PBVAJRFEEOIAGW-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 229960002685 biotin Drugs 0.000 description 3
- 239000011616 biotin Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 210000002744 extracellular matrix Anatomy 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- HQSMEHLVLOGBCK-UHFFFAOYSA-N 1-ethenylsulfinylethene Chemical compound C=CS(=O)C=C HQSMEHLVLOGBCK-UHFFFAOYSA-N 0.000 description 2
- RFSLCYMUNOEIFF-UHFFFAOYSA-N 2-(3-nitropyridin-2-yl)sulfanylethanamine Chemical compound NCCSC1=NC=CC=C1[N+]([O-])=O RFSLCYMUNOEIFF-UHFFFAOYSA-N 0.000 description 2
- UDPCXVIKHFVPSZ-HOIFWPIMSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-n-[2-[2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethoxy]ethyl]pentanamide Chemical compound C([C@H]1[C@H]2NC(=O)N[C@H]2CS1)CCCC(=O)NCCOCCOCCNC(=O)CCN1C(=O)C=CC1=O UDPCXVIKHFVPSZ-HOIFWPIMSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 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
- 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
- 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 2
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- HCOMFAYPHBFMKU-UHFFFAOYSA-N butanedihydrazide Chemical compound NNC(=O)CCC(=O)NN HCOMFAYPHBFMKU-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004737 colorimetric analysis Methods 0.000 description 2
- 238000011033 desalting Methods 0.000 description 2
- 125000000600 disaccharide group Chemical group 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 229940097043 glucuronic acid Drugs 0.000 description 2
- 150000002463 imidates Chemical class 0.000 description 2
- -1 pentafluorophenyl ester Chemical class 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- DTLVBHCSSNJCMJ-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-[2-[2-[2-[2-[5-(2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl)pentanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]propanoate Chemical compound S1CC2NC(=O)NC2C1CCCCC(=O)NCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O DTLVBHCSSNJCMJ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 102100032912 CD44 antigen Human genes 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 1
- 102100027735 Hyaluronan mediated motility receptor Human genes 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- OVRNDRQMDRJTHS-RTRLPJTCSA-N N-acetyl-D-glucosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-RTRLPJTCSA-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
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 108010003425 hyaluronan-mediated motility receptor Proteins 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- RDBMUARQWLPMNW-UHFFFAOYSA-N phosphanylmethanol Chemical compound OCP RDBMUARQWLPMNW-UHFFFAOYSA-N 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- GWIKYPMLNBTJHR-UHFFFAOYSA-M thiosulfonate group Chemical group S(=S)(=O)[O-] GWIKYPMLNBTJHR-UHFFFAOYSA-M 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000003954 umbilical cord Anatomy 0.000 description 1
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
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
The multiple modified hyaluronic acid derivative can be flexibly and efficiently used for preparing a hyaluronic acid-drug conjugate due to the fact that the multiple modified hyaluronic acid derivative simultaneously has amino and sulfydryl, can realize the coupling of various drugs and hyaluronic acid through sulfydryl and amino, and can also be used for preparing (double) crosslinked hydrogel with a crosslinking agent with sulfydryl reaction activity and/or a crosslinking agent with amino reaction activity. The multiple modified hyaluronic acid derivative has positive prospect in medical application such as targeted antitumor treatment.
Description
Technical Field
The invention relates to the field of medicines, and particularly relates to a multiple modified hyaluronic acid derivative and application thereof.
Background
Hyaluronic Acid (HA), also known as "Hyaluronic Acid", is a linear anionic non-sulfonated mucopolysaccharide formed by alternating beta-1, 4 and beta-1, 3 glycosidic linkages with glucuronic Acid (GlcA) and N-acetylglucosamine (GlcNAc) as disaccharide units, widely distributed in animal and human extracellular matrices, having high content in skin, lung and intestine, and present in synovial fluid, umbilical cord and blood, and is a main component constituting extracellular matrix and mesenchyme, playing important roles in maintaining extracellular matrix structure and regulating intracellular activities. Hyaluronic acid is widely used in the fields of clinical medicine, advanced cosmetics, beauty and plastic, health food and the like due to its unique physicochemical properties and biological functions.
Hyaluronic acid not only has good physicochemical and biological properties such as biocompatibility, degradability, high viscoelasticity, nonimmunity and the like, but also can be combined with receptors (CD44, RHAMM and the like) over-expressed on the surface of tumor cells, so that the capacity of combining with the tumor cells and internalizing the hyaluronic acid is enhanced, and the hyaluronic acid has important regulation effects on the generation of tumor vessels, the tumor metastasis, the tumor invasiveness and the like (Misra and the like, FEBS J, 2011, 278: 1429-1443). Therefore, the hyaluronic acid is used as an anticancer drug delivery carrier in the field of tumor treatment and is continuously one of the hot spots of tumor targeted drug delivery system research (Oh et al, Qiu et al, J Control Release, 2010, 141(1): 2-12; pharmaceutical science report 2013, 48 (9): 1376-.
The hyaluronic acid-drug conjugate is a prodrug prepared by combining a small-molecule antitumor drug with hyaluronic acid through a covalent bond. These covalent bonds are not readily cleavable in blood, but are cleaved by hydrolysis or enzymatic action upon reaching the target site, releasing the drug. The hyaluronic acid-drug conjugate can improve the solubility of the drug, change the distribution and half-life period of the drug in vivo, increase the accumulation in tumor tissues by enhancing the effect of penetration and retention, and better exert the drug effect.
The side chain of the hyaluronic acid has carboxyl and hydroxyl functional groups for coupling reaction, but the hydroxyl group usually needs to have certain nucleophilic reaction activity in a strong alkaline environment, so that not only are the reaction conditions harsh, but also the strong alkaline can cause the hyaluronic acid to undergo significant main chain hydrolysis and fracture; for carboxyl, the coupling reaction with a specific group (such as an amino group) is usually carried out after the carbodiimide is activated, and the reaction is greatly limited; in summary, the research and development of the hyaluronic acid-drug conjugate are restricted by the two functional groups of carboxyl and hydroxyl due to low reaction efficiency, harsh reaction conditions and the like.
Therefore, it is a problem to be solved to improve the coupling reactivity of hyaluronic acid with drugs. The sodium hyaluronate is modified, and a functional group with higher reactivity is introduced, so that the coupling reaction efficiency of hyaluronic acid and a medicament can be effectively improved. The multiple modified hyaluronic acid derivative with various functional groups with high reactivity can perform specific coupling reaction with various medicines, and particularly has advantages. In addition, the multiple modified hyaluronic acid derivatives having various high reactive functional groups are also advantageous in the preparation of hyaluronic acid crosslinked hydrogels. However, at present, no multiple modified hyaluronic acid derivative having a plurality of highly reactive functional groups such as amino groups and thiol groups has been reported.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a multiple modified hyaluronic acid derivative, which simultaneously has side chains containing amino and sulfydryl, has high reactivity, can be simultaneously coupled with various small-molecule antitumor drugs, can be coupled with specific small-molecule antitumor drugs according to requirements, and can be used as a carrier of various antitumor drugs; meanwhile, the derivative can be better applied to preparing hyaluronic acid cross-linked hydrogel.
In order to solve the technical problems, the multiple modified hyaluronic acid derivative provided by the invention simultaneously comprises a sulfydryl-containing side chain and an amino-containing side chain. Compared with the side chain carboxyl and hydroxyl of hyaluronic acid, the amino and the sulfhydryl in the side chain of the hyaluronic acid derivative have better nucleophilic reaction activity, can be directly coupled with various groups, have high reaction efficiency, and can obviously reduce the dosage of expensive micromolecular antitumor drugs; in addition, the reaction of the two functional groups requires mild conditions, and can be carried out in a neutral or weakly alkaline aqueous environment. The side chain containing amino group of the derivative can be generally coupled with N-hydroxysuccinimide ester (NHS ester), aldehyde group, imido ester, pentafluorophenyl ester, hydroxymethyl phosphine and other groups, when the side chain is reacted with NHS ester, a coupling structure of amido bond can be generated, and when the side chain is reacted with imido ester, a coupling structure of amidine bond can be generated. The side chain containing sulfydryl of the derivative can be generally coupled with groups such as maleimide, halogenated acetyl (bromine-, chlorine-or iodine-), pyridine disulfide, thiosulfonate, vinyl sulfone and the like, when the side chain containing sulfydryl is reacted with maleimide and halogenated acetyl to generate a coupling structure of thioether bond, and is reacted with pyridine disulfide to generate a coupling structure of exchange disulfide bond; therefore, the derivative provided by the invention can realize simultaneous coupling of drug molecules with reactivity with amino and drug molecules with reactivity with sulfydryl, and realize combined targeted therapy of various antitumor drugs. Understandably, the antitumor drug can be independently coupled with amino or sulfhydryl according to the requirement to realize the preparation of the specific antitumor drug.
In addition, the derivative has both amino-containing side chains and mercapto-containing side chains, so that the derivative can be simultaneously crosslinked with a crosslinking agent with mercapto reactivity and a crosslinking agent with amino reactivity to prepare a double-crosslinked hydrogel which is more stable and has a flexibly adjustable crosslinking structure; understandably, the crosslinking hydrogel can be prepared by selectively crosslinking by selecting a crosslinking agent reactive with a mercapto group or a crosslinking agent reactive with an amino group according to requirements.
It should be noted that the multiple modified hyaluronic acid derivatives provided by the present application are prepared by chemically modifying the side chain of hyaluronic acid, and the molecular weight of the adopted hyaluronic acid raw material is 1 ten thousand to 1000 ten thousand daltons; preferably, the molecular weight of the hyaluronic acid raw material used is 10-300 ten thousand daltons; more preferably, the molecular weight of the adopted hyaluronic acid raw material is 20-100 ten thousand daltons, and the molecules of the hyaluronic acid raw material have enough disaccharide units (500-2500 units) for chemical modification and cannot cause reduction of chemical modification efficiency due to overhigh molecular weight; and the multiple modified hyaluronic acid derivative provided by the application has the same linear structure with hyaluronic acid.
The side chain hydroxyl of hyaluronic acid generally needs to have certain nucleophilic reactivity in a strong alkaline environment, so that not only are the reaction conditions harsh, but also the strong alkaline can cause the hyaluronic acid to undergo significant backbone hydrolysis and fracture; the chemical modification of the side chain carboxyl groups of hyaluronic acid can be performed under relatively mild conditions. Therefore, preferably, the side chain containing sulfhydryl group of the derivative of the invention is connected with sulfhydryl group through chemical connecting structure via carboxyl of the side chain; the side chain containing amino of the derivative is connected with amino through a chemical connecting structure through carboxyl of the side chain. Understandably, the side chain hydroxyl and carboxyl of the hyaluronic acid can be subjected to various chemical modifications under specific conditions, and the side chain carboxyl is preferably modified by the invention, and various functional groups such as sulfydryl or amino are introduced; and the form of the chemical linking structure is not limited.
Preferably, the thiol-containing side chain of the derivative is of formula I and/or formula II:
wherein HA is a hyaluronic acid residue; r1And R2Each independently selected from one of substituted or unsubstituted alkylene, aromatic group and polyether group; when present, the substituent is selected from an alkyl group, an amide group, an ester group, or an ether group. More preferably, said R1And R2Each independently selected from-CH2CH2-or-CH2CH2CH2-. In the preferred embodiment, the chemical linking structure is preferably an amide bond, such as formula I and formula II, wherein formula II is an amide bond linking structure including a hydrazide structure, it is understood that the amide bond structure is generally stable, and the amide bond has an electron-withdrawing effect, and can enhance the nucleophilic reaction activity of the thiol group to a certain extent, when the amide bond includes the hydrazide structure, the amino group of the hydrazide structure has a better affinity reaction activity, and in addition, the preparation efficiency of the hydrazide linking structure is higher than that of the amide bondThe connection structure is higher; for R1And R2When different structures are chosen, the reactivity of the nucleophilic reaction differs, for example for formula II, when R2＝CH2CH2When the pKa of the mercapto group is 8.87, when R is2＝CH2CH2CH2The pKa of the mercapto group is 9.01. Understandably, the derivative can simultaneously have a plurality of sulfydryl-containing side chains with different chemical structure connection forms, and the nucleophilic reactivity of each side chain is different, so that the derivative has different potential applications.
Preferably, the side chain containing amino group of the derivative is shown as formula III and/or formula IV:
wherein HA is a hyaluronic acid residue; r3And R4Each independently selected from one of substituted or unsubstituted alkylene, aromatic group and polyether group; when present, the substituent is selected from an alkyl group, an amide group, an ester group, or an ether group. More preferably, said R3And R4Each independently selected from-CH2CH2-or-CH2CH2CH2-. In the preferred scheme, the chemical linking structure is preferably an amide bond, such as formula III and formula IV, wherein the formula IV is an amide bond linking structure containing a hydrazide structure; for R3And R4The nucleophilic activity of the compound(s) is different when different structures are selected, for example, the electron donating effect of the nitrogen adjacent to the amide bond results in an amino group (-C (O) NHNH) in the hydrazide functional group2) (pKa usually 3-4) is higher than that of a conventional amino group (-NH)2) (pKa is usually>8) Has higher nucleophilic reaction activity. Understandably, the derivative can simultaneously have a plurality of amino-containing side chains in different chemical structure connection forms, and the nucleophilic reactivity of each side chain is different, so that the derivative has different potential applications.
The multiple modified hyaluronic acid derivative provided by the invention has both amino and sulfydryl, can be flexibly and efficiently used for preparing a hyaluronic acid-drug conjugate, can realize the coupling of various drugs and hyaluronic acid through sulfydryl and amino, and can also prepare (dual) crosslinked hydrogel with a crosslinking agent with reactivity of sulfydryl and/or a crosslinking agent with reactivity of amino. The multiple modified hyaluronic acid derivative has positive prospect in medical application such as targeted antitumor treatment.
Detailed Description
The technical solutions in the present invention will be described clearly and completely below, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
The first embodiment is as follows: preparation of multiple modified hyaluronic acid derivative (thiol having amide bond linkage structure and amino having amide bond linkage structure)
Sodium hyaluronate (molecular weight 100 kilodalton) 1g (2.5mmol) is dissolved in 250ml of distilled water at room temperature, 1-hydroxybenzotriazole 0.667g (5.0mmol) is added, 3-Nitro-2-pyridinedithioethylamine (3-Nitro-2-pyridinesulfenylethyl amine)1g (3.74mmol) is added, and the mixture is stirred and dissolved. Then, the pH of the solution was adjusted to 4.75 with 0.5mol/L hydrochloric acid, 1.43g (7.48mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the pH of the solution was maintained at 4.75 by adding 0.5mol/L hydrochloric acid. After reacting at room temperature for 2 hours, the above reaction solution was put into a dialysis tube (molecular weight cut off 3500), dialyzed with a large amount of 0.2 mol/l sodium chloride solution for 2 days, then dialyzed with a large amount of distilled water for 1 day, and finally the solution in the dialysis tube was collected and freeze-dried to obtain a flocculent solid.
The yellow flocculent solid obtained by the freeze-drying was dissolved in 250ml of distilled water at room temperature, 0.667g (5.0mmol) of 1-hydroxybenzotriazole was added, 1.2g (20mmol) of ethylenediamine was added, and the mixture was stirred and dissolved. Then, the pH of the solution was adjusted to 4.75 with 0.5mol/L hydrochloric acid, and 0.715g (3.74mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added to maintain the pH of the solution at 4.75 with 0.5mol/L hydrochloric acid. After 2 hours of reaction at room temperature, the above reaction solution was put into a dialysis tube (molecular weight cut off 3500), dialyzed with a large amount of 0.2 mol/l sodium chloride solution for 2 days, then dialyzed with a large amount of distilled water for 1 day, and finally the solution in the dialysis tube was collected.
To the dialyzed solution, 3g (10.5mmol) of tris (2-carboxyethyl) phosphine hydrochloride was added, and the mixture was stirred and reacted for 4 hours. The above solution was put into a dialysis tube (molecular weight cut off 3500), dialyzed with a large amount of 0.001 mol/l hydrochloric acid and 0.2 mol/l sodium chloride solution for 2 days, and then dialyzed with a large amount of 0.001 mol/l hydrochloric acid solution for 1 day. And finally, collecting the solution in the dialysis tube, and freeze-drying to obtain flocculent solid, namely the multiple modified hyaluronic acid derivative.
The side chain sulfhydryl content of the multiple modified hyaluronic acid derivative of the invention can be detected by an improved Ellman reagent method (Shu et al, Biomacromolecules 2002,3:1304-1311) or hydrogen nuclear magnetic resonance (H-NMR)1H-NMR) (D2O is solvent), and the content is 223 mu mol/g (taking the characteristic methyl absorption peak of acetyl of hyaluronic acid as an internal standard); the content of amino groups in the side chains can be detected by conventional ninhydrin colorimetry (Chen et al, J. Pharma. Anal., 2005, 25: 526-1H-NMR)(D2O as a solvent), and the like (characteristic methyl absorption peak of acetyl group of hyaluronic acid is taken as an internal standard), and the content thereof is 98 μmol/g.
The side chain mercapto group and the side chain amino group of the multiple modified hyaluronic acid derivative of the invention have the following chemical connection structures respectively:
wherein HA is the hyaluronic acid residue in the multiple modified hyaluronic acid derivative.
Example 2: preparation of multiple modified hyaluronic acid derivative (sulfhydryl containing amide bond connecting structure and hydrazide amino containing amide bond connecting structure)
Sodium hyaluronate (molecular weight 50 kilodaltons) 1g (2.5mmol) was dissolved in 250ml of distilled water at room temperature, and 0.667g (5.0mmol) of 1-hydroxybenzotriazole was added, and 3-Nitro-2-pyridinedithioethylamine (3-Nitro-2-pyridinesulfenylethyl amine)1g (3.74mmol) was added, followed by stirring and dissolution. Then, the pH of the solution was adjusted to 4.75 with 0.5mol/L hydrochloric acid, 1.43g (7.48mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the pH of the solution was maintained at 4.75 by adding 0.5mol/L hydrochloric acid. After reacting at room temperature for 2 hours, the above reaction solution was put into a dialysis tube (molecular weight cut off 3500), dialyzed with a large amount of 0.2 mol/l sodium chloride solution for 2 days, then dialyzed with a large amount of distilled water for 1 day, and finally the solution in the dialysis tube was collected and freeze-dried to obtain a flocculent solid.
The yellow flocculent solid obtained by the freeze-drying was dissolved in 250ml of distilled water at room temperature, 0.667g (5.0mmol) of 1-hydroxybenzotriazole was added, 2.92g (20mmol) of succinic dihydrazide was added, and the mixture was stirred and dissolved. Then, the pH of the solution was adjusted to 4.75 with 0.5mol/L hydrochloric acid, 0.024g (0.125mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the pH of the solution was maintained at 4.75 with the addition of 0.5mol/L hydrochloric acid. After 1 hour of reaction at room temperature, the above reaction solution was put into a dialysis tube (molecular weight cut off 3500), dialyzed with a large amount of 0.2 mol/l sodium chloride solution for 2 days, then dialyzed with a large amount of distilled water for 1 day, and finally the solution in the dialysis tube was collected.
To the dialyzed solution was added 3g (10.5mmol) of tris (2-carboxyethyl) phosphine hydrochloride, and the mixture was stirred and reacted for 4 hours. The above solution was put into a dialysis tube (molecular weight cut off 3500), dialyzed with a large amount of 0.001 mol/l hydrochloric acid and 0.2 mol/l sodium chloride solution for 2 days, and then dialyzed with a large amount of 0.001 mol/l hydrochloric acid solution for 1 day. And finally, collecting the solution in the dialysis tube, and freeze-drying to obtain flocculent solid, namely the multiple modified hyaluronic acid derivative.
The thiol content of the multiple modified hyaluronic acid derivative of the invention can be detected by an improved Ellman reagent method (Shu et al, Biomacromolecules 2002,3:1304-1311) or hydrogen nuclear magnetic resonance (H-NMR) method reported by Shu et al1H-NMR)(D2O is solvent), and the like (taking the characteristic methyl absorption peak of acetyl of hyaluronic acid as an internal standard), and the content of the hyaluronic acid is 246 mu mol/g; the amino group content can be determined according to the standardRegular ninhydrin colorimetric (Chen et al, J. Pharma analysis 2005, 25: 526-1H-NMR)(D2O is a solvent), and the content is 108. mu. mol/g (taking a characteristic methyl absorption peak of acetyl of hyaluronic acid as an internal standard).
The side chain mercapto group and the side chain amino group of the multiple modified hyaluronic acid derivative of the invention have the following chemical connection structures respectively:
wherein HA is the hyaluronic acid residue in the multiple modified hyaluronic acid derivative.
Example 3: preparation of multiple modified hyaluronic acid derivative (sulfhydryl containing two amide bond connecting structures and hydrazide amino containing one amide bond connecting structure)
1g (2.5mmol) of sodium hyaluronate (molecular weight 20 kilodaltons) was dissolved in 250ml of distilled water at room temperature, 0.667g (5.0mmol) of 1-hydroxybenzotriazole was added, and then 4.74g (20mmol) of dithiodipropylhydrazide, 5.32g (20mmol) of dithiodibutylhydrazide and 2.92g (20mmol) of succinic dihydrazide were added and dissolved by stirring. Then, the pH of the solution was adjusted to 4.75 with 0.5mol/L hydrochloric acid, 0.072g (0.375mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the pH of the solution was maintained at 4.75 by adding 0.5mol/L hydrochloric acid. After 1 hour at room temperature, 3g (10.5mmol) of tris (2-carboxyethyl) phosphine hydrochloride was added and the reaction was stirred for 4 hours. The above solution was put into a dialysis tube (molecular weight cut off 3500), dialyzed with a large amount of 0.001 mol/l hydrochloric acid and 0.2 mol/l sodium chloride solution for 2 days, and then dialyzed with a large amount of 0.001 mol/l hydrochloric acid solution for 1 day. And finally, collecting the solution in the dialysis tube, and freeze-drying to obtain flocculent solid, namely the multiple modified hyaluronic acid derivative.
The thiol content of the multiple modified hyaluronic acid derivative of the invention can be detected by an improved Ellman reagent method (Shu et al, Biomacromolecules 2002,3:1304-1311) or hydrogen nuclear magnetic resonance (H-NMR) method reported by Shu et al1H-NMR)(D2O as a solvent), and the like (characteristic of methyl group of acetyl group of hyaluronic acid)Peak collection as internal standard) with a content of 196 mu mol/g; the amino content can be detected by conventional ninhydrin colorimetry (Chen et al, J. Pharma analysis 2005, 25: 526-1H-NMR)(D2O is a solvent), and the content thereof is 112. mu. mol/g (with the characteristic methyl absorption peak of acetyl group of hyaluronic acid as an internal standard).
The side chain sulfhydryl and the side chain amino of the multiple modified hyaluronic acid derivative respectively have the following chemical connection structures:
wherein HA is the hyaluronic acid residue in the multiple modified hyaluronic acid derivative.
Example 4: coupling reaction of multiple modified hyaluronic acid derivative and thiol-reactive model compound
2mg of the multiple modified hyaluronic acid derivative prepared in example 1 was dissolved in 2ml of a phosphate buffer (pH7.0), and 1mg of Maleimide-PEG2-Biotin (EZ-Link Maleimide-PEG2-Biotin) (ThermoFisher) was added thereto, followed by stirring for reaction overnight. And purifying the solution after the reaction by a desalting column to remove unreacted reagents, thus obtaining the biotin coupling hyaluronic acid derivative.
Example 5: coupling reaction of multiple modified hyaluronic acid derivative and amino reactive model compound
2mg of the multiple modified hyaluronic acid derivative prepared in example 2 was dissolved in 2ml of a phosphate buffer solution (pH7.0), and 1.5mg of succinimide-PEG 4-Biotin (EZ-Link NHS-PEG4-Biotin) (ThermoFisher) was added thereto, followed by stirring and reacting for 30 minutes. And purifying the solution after the reaction by a desalting column to remove unreacted reagents, thus obtaining the biotin coupling hyaluronic acid derivative.
Example 6: preparation of double-crosslinked hyaluronic acid gel
Polyethylene glycol divinyl sulfoxide (MW3400) (avadin) 33.32mg and N-hydroxysuccinimide-polyethylene glycol-N-hydroxysuccinimide (MW3400) (avadin) 20mg were dissolved in 5ml of phosphate buffer (pH7.4) to obtain a crosslinking agent solution. 100mg of the multiple modified hyaluronic acid derivative prepared in example 3 was dissolved in 5ml of phosphate buffer (pH7.4), and 5ml of the above-mentioned crosslinking agent solution was added thereto, followed by uniform mixing, whereby the solution gradually lost fluidity and formed a double-crosslinked gel.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A multiple modified hyaluronic acid derivative, wherein the derivative comprises both a thiol-containing side chain and an amino-containing side chain.
2. The derivative of claim 1, wherein the thiol-containing side chain of the derivative is linked to the thiol group through a chemical linking structure via the carboxyl group of the side chain;
the side chain containing amino of the derivative is connected with amino through a chemical connecting structure through carboxyl of the side chain.
3. The derivative of claim 2, wherein the thiol-containing side chain of the derivative is of formula I and/or formula II:
wherein HA is a hyaluronic acid residue; r1And R2Each independently selected from one of substituted or unsubstituted alkylene, aromatic group and polyether group; when present, the substituent is selected from an alkyl group, an amide group, an ester group, or an ether group.
4. The derivative of claim 3, wherein R is1And R2Each independently selected from-CH2CH2-or-CH2CH2CH2-。
5. The derivative of claim 2, wherein the side chain containing an amino group of the derivative is of formula III and/or formula IV:
wherein HA is a hyaluronic acid residue; r is3And R4Each independently selected from one of substituted or unsubstituted alkylene, aromatic group and polyether group; when present, the substituent is selected from an alkyl group, an amide group, an ester group, or an ether group.
6. The derivative of claim 5, wherein R is3And R4Each independently selected from-CH2CH2-or-CH2CH2CH2-。
7. The derivative of claim 1, wherein the hyaluronic acid starting material used to synthesize the derivative has a molecular weight of 1-1000 kilodaltons.
8. The derivative of claim 7, wherein the hyaluronic acid material has a molecular weight of 10-300 kilodaltons.
9. Use of a derivative according to any one of claims 1 to 8 for the preparation of hyaluronic acid-drug conjugates in the medical field.
10. Use of a derivative according to any one of claims 1 to 8 for the preparation of a cross-linked hyaluronic acid material.
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