JP6800984B2 - 軟骨傷害の検出及び処置のためのマイクロ並びにナノデバイス - Google Patents
軟骨傷害の検出及び処置のためのマイクロ並びにナノデバイス Download PDFInfo
- Publication number
- JP6800984B2 JP6800984B2 JP2018536714A JP2018536714A JP6800984B2 JP 6800984 B2 JP6800984 B2 JP 6800984B2 JP 2018536714 A JP2018536714 A JP 2018536714A JP 2018536714 A JP2018536714 A JP 2018536714A JP 6800984 B2 JP6800984 B2 JP 6800984B2
- Authority
- JP
- Japan
- Prior art keywords
- cartilage
- hyaluronic acid
- injured
- biocompatible
- probe
- 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.)
- Active
Links
- 206010007710 Cartilage injury Diseases 0.000 title claims description 27
- 238000001514 detection method Methods 0.000 title claims description 9
- 238000011282 treatment Methods 0.000 title description 20
- 239000000523 sample Substances 0.000 claims description 240
- 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 description 205
- 210000000845 cartilage Anatomy 0.000 claims description 197
- 229920002674 hyaluronan Polymers 0.000 claims description 187
- 229960003160 hyaluronic acid Drugs 0.000 claims description 187
- 230000008685 targeting Effects 0.000 claims description 97
- 239000002245 particle Substances 0.000 claims description 90
- 229920000642 polymer Polymers 0.000 claims description 80
- 210000001612 chondrocyte Anatomy 0.000 claims description 72
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 claims description 68
- 229920001222 biopolymer Polymers 0.000 claims description 66
- 235000019152 folic acid Nutrition 0.000 claims description 60
- 239000011724 folic acid Substances 0.000 claims description 60
- 239000003446 ligand Substances 0.000 claims description 58
- 210000004027 cell Anatomy 0.000 claims description 56
- 230000002917 arthritic effect Effects 0.000 claims description 42
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 42
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 claims description 39
- 208000014674 injury Diseases 0.000 claims description 35
- 230000005012 migration Effects 0.000 claims description 34
- 238000013508 migration Methods 0.000 claims description 34
- 230000006378 damage Effects 0.000 claims description 31
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 claims description 29
- 108010012236 Chemokines Proteins 0.000 claims description 26
- 102000019034 Chemokines Human genes 0.000 claims description 26
- 239000002105 nanoparticle Substances 0.000 claims description 26
- 239000004971 Cross linker Substances 0.000 claims description 25
- 208000027418 Wounds and injury Diseases 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 25
- 230000004069 differentiation Effects 0.000 claims description 22
- 239000003431 cross linking reagent Substances 0.000 claims description 21
- 238000003384 imaging method Methods 0.000 claims description 20
- 102000006815 folate receptor Human genes 0.000 claims description 18
- 108020005243 folate receptor Proteins 0.000 claims description 18
- 239000013543 active substance Substances 0.000 claims description 17
- 210000004271 bone marrow stromal cell Anatomy 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 15
- 229960000304 folic acid Drugs 0.000 claims description 15
- 239000007850 fluorescent dye Substances 0.000 claims description 10
- 230000008733 trauma Effects 0.000 claims description 10
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 claims description 9
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 claims description 9
- 102000056172 Transforming growth factor beta-3 Human genes 0.000 claims description 9
- 108090000097 Transforming growth factor beta-3 Proteins 0.000 claims description 9
- 230000001965 increasing effect Effects 0.000 claims description 9
- -1 radioactive tags Substances 0.000 claims description 9
- 102100023700 C-C motif chemokine 16 Human genes 0.000 claims description 8
- 101000978375 Homo sapiens C-C motif chemokine 16 Proteins 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 230000002285 radioactive effect Effects 0.000 claims description 8
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 7
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 7
- 230000001483 mobilizing effect Effects 0.000 claims description 7
- 238000004132 cross linking Methods 0.000 claims description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
- 230000002757 inflammatory effect Effects 0.000 claims description 5
- 229920002554 vinyl polymer Polymers 0.000 claims description 5
- 239000011148 porous material Substances 0.000 claims description 4
- 102000003951 Erythropoietin Human genes 0.000 claims description 2
- 108090000394 Erythropoietin Proteins 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 229940105423 erythropoietin Drugs 0.000 claims description 2
- 150000002739 metals Chemical class 0.000 claims 4
- 239000003795 chemical substances by application Substances 0.000 claims 3
- 101001054921 Homo sapiens Lymphatic vessel endothelial hyaluronic acid receptor 1 Proteins 0.000 claims 1
- 102100026849 Lymphatic vessel endothelial hyaluronic acid receptor 1 Human genes 0.000 claims 1
- 241000549556 Nanos Species 0.000 claims 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims 1
- 210000001519 tissue Anatomy 0.000 description 68
- 102100032912 CD44 antigen Human genes 0.000 description 48
- 229940014144 folate Drugs 0.000 description 45
- 102000005962 receptors Human genes 0.000 description 35
- 108020003175 receptors Proteins 0.000 description 35
- 210000000130 stem cell Anatomy 0.000 description 34
- 108010092408 Eosinophil Peroxidase Proteins 0.000 description 27
- 102100031939 Erythropoietin Human genes 0.000 description 27
- 206010003246 arthritis Diseases 0.000 description 22
- 210000002540 macrophage Anatomy 0.000 description 19
- 229920000249 biocompatible polymer Polymers 0.000 description 17
- 238000000338 in vitro Methods 0.000 description 17
- 239000000975 dye Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 238000004445 quantitative analysis Methods 0.000 description 11
- 238000009825 accumulation Methods 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 9
- 230000012292 cell migration Effects 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 230000021615 conjugation Effects 0.000 description 8
- 238000003745 diagnosis Methods 0.000 description 8
- 210000004969 inflammatory cell Anatomy 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 6
- 102000006573 Chemokine CXCL12 Human genes 0.000 description 6
- 108010008951 Chemokine CXCL12 Proteins 0.000 description 6
- 101150002621 EPO gene Proteins 0.000 description 6
- 101000897480 Homo sapiens C-C motif chemokine 2 Proteins 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 238000011503 in vivo imaging Methods 0.000 description 6
- 238000011835 investigation Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- 210000003321 cartilage cell Anatomy 0.000 description 5
- 230000003848 cartilage regeneration Effects 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 5
- 238000006731 degradation reaction Methods 0.000 description 5
- 239000003102 growth factor Substances 0.000 description 5
- 239000007943 implant Substances 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- BBMCTIGTTCKYKF-UHFFFAOYSA-N 1-heptanol Chemical compound CCCCCCCO BBMCTIGTTCKYKF-UHFFFAOYSA-N 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 101000617130 Homo sapiens Stromal cell-derived factor 1 Proteins 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 102100021669 Stromal cell-derived factor 1 Human genes 0.000 description 4
- 210000001188 articular cartilage Anatomy 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 238000002296 dynamic light scattering Methods 0.000 description 4
- 238000002073 fluorescence micrograph Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 210000003127 knee Anatomy 0.000 description 4
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 4
- 239000011859 microparticle Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 238000011002 quantification Methods 0.000 description 4
- 230000007115 recruitment Effects 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 208000037816 tissue injury Diseases 0.000 description 4
- 230000017423 tissue regeneration Effects 0.000 description 4
- 230000005945 translocation Effects 0.000 description 4
- 210000002417 xiphoid bone Anatomy 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000010799 Receptor Interactions Effects 0.000 description 3
- 230000000763 evoking effect Effects 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000004530 micro-emulsion Substances 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 238000001878 scanning electron micrograph Methods 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 210000001179 synovial fluid Anatomy 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 108010003272 Hyaluronate lyase Proteins 0.000 description 2
- 102000001974 Hyaluronidases Human genes 0.000 description 2
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 2
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000008355 cartilage degradation Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 210000003855 cell nucleus Anatomy 0.000 description 2
- 230000006041 cell recruitment Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229960002773 hyaluronidase Drugs 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 230000002262 irrigation Effects 0.000 description 2
- 238000003973 irrigation Methods 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000010232 migration assay Methods 0.000 description 2
- 231100000324 minimal toxicity Toxicity 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- OARRHUQTFTUEOS-UHFFFAOYSA-N safranin Chemical compound [Cl-].C=12C=C(N)C(C)=CC2=NC2=CC(C)=C(N)C=C2[N+]=1C1=CC=CC=C1 OARRHUQTFTUEOS-UHFFFAOYSA-N 0.000 description 2
- 238000004626 scanning electron microscopy Methods 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 210000002437 synoviocyte Anatomy 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000003827 upregulation Effects 0.000 description 2
- 238000012800 visualization Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- GAKUNXBDVGLOFS-DUZKARGPSA-N (1-acetyloxy-3-hexadecanoyloxypropan-2-yl) (9z,12z)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COC(C)=O)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC GAKUNXBDVGLOFS-DUZKARGPSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000005422 Foreign-Body reaction Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 102000055008 Matrilin Proteins Human genes 0.000 description 1
- 108010072582 Matrilin Proteins Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 108010067787 Proteoglycans Proteins 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241001433070 Xiphoides Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000003349 alamar blue assay Methods 0.000 description 1
- 229940030225 antihemorrhagics Drugs 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000001217 buttock Anatomy 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229920006237 degradable polymer Polymers 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- IWBOPFCKHIJFMS-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl) ether Chemical compound NCCOCCOCCN IWBOPFCKHIJFMS-UHFFFAOYSA-N 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 239000002874 hemostatic agent Substances 0.000 description 1
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 210000005067 joint tissue Anatomy 0.000 description 1
- 238000013150 knee replacement Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 238000003333 near-infrared imaging Methods 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000004417 patella Anatomy 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 238000004375 physisorption Methods 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 229950003937 tolonium Drugs 0.000 description 1
- HNONEKILPDHFOL-UHFFFAOYSA-M tolonium chloride Chemical compound [Cl-].C1=C(C)C(N)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 HNONEKILPDHFOL-UHFFFAOYSA-M 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6872—Intracellular protein regulatory factors and their receptors, e.g. including ion channels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1841—Transforming growth factor [TGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/195—Chemokines, e.g. RANTES
-
- 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
- A61K47/54—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 compound
- A61K47/55—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 compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
- A61K47/551—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 compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0052—Small organic molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0089—Particulate, powder, adsorbate, bead, sphere
- A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0089—Particulate, powder, adsorbate, bead, sphere
- A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
- A61K49/0093—Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/82—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving vitamins or their receptors
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/70585—CD44
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/10—Musculoskeletal or connective tissue disorders
- G01N2800/105—Osteoarthritis, e.g. cartilage alteration, hypertrophy of bone
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Pharmacology & Pharmacy (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Cell Biology (AREA)
- Nanotechnology (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Microbiology (AREA)
- Physics & Mathematics (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Food Science & Technology (AREA)
- Biotechnology (AREA)
- Analytical Chemistry (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Materials Engineering (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Physical Education & Sports Medicine (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
Claims (14)
- 損傷/傷害軟骨標的用プローブを含む、関節炎軟骨を標的とする及び/又は処置するための医薬であって、
前記損傷/傷害軟骨標的用プローブが、
ビニルスルホン架橋剤によって架橋されて架橋バイオポリマーを形成する生体適合性ヒアルロン酸ポリマーであって、前記生体適合性ヒアルロン酸ポリマーが、10K〜1.5Mの分子量を有し、前記生体適合性ヒアルロン酸ポリマーと前記ビニルスルホン架橋剤とのモル比が、4:1〜1:4の間であり、前記架橋バイオポリマーが、内部移行を調節するために150超〜500nmの直径を有する、前記生体適合性ヒアルロン酸ポリマー;
前記架橋バイオポリマーと接触するリガンドであって、CD44受容体と相互作用するヒアルロン酸、葉酸受容体と相互作用する葉酸、又は両方である、前記リガンド;並びに
前記ビニルスルホン架橋剤、前記生体適合性ヒアルロン酸ポリマー、前記リガンド、又はそれらの組合せと接触する、蛍光色素、放射性タグ、金属、ナノ粒子、又はそれらの組合せである、検出可能なタグ;
を含む、前記医薬。 - 損傷/傷害軟骨標的用プローブが、
ビニルスルホン架橋剤によって架橋されて架橋バイオポリマーを形成する生体適合性ヒアルロン酸ポリマーであって、前記生体適合性ヒアルロン酸ポリマーが、10K〜1.5Mの分子量を有し、前記生体適合性ヒアルロン酸ポリマーと前記ビニルスルホン架橋剤とのモル比が、4:1〜1:4の間であり、前記架橋バイオポリマーが、内部移行を調節するために150超〜500nmの直径を有する、前記生体適合性ヒアルロン酸ポリマー;
前記架橋バイオポリマーと接触するリガンドであって、1又は2以上の細胞表面標的と相互作用し、CD44受容体と相互作用するヒアルロン酸、葉酸受容体と相互作用する葉酸、又は両方である、前記リガンド;並びに
前記ビニルスルホン架橋剤、前記生体適合性ヒアルロン酸ポリマー、前記リガンド、又はそれらの組合せと接触する、蛍光色素、放射性タグ、金属、ナノ粒子、又はそれらの組合せである、検出可能なタグ;
を含む、請求項1に記載の医薬。 - 以下のステップを含む方法において使用される、請求項1又は2に記載の医薬。
ビニルスルホン架橋剤によって架橋されて架橋バイオポリマーを形成する生体適合性ヒアルロン酸ポリマーを含む損傷/傷害軟骨標的用プローブを用意するステップであって、前記生体適合性ヒアルロン酸ポリマーが、10K〜1.5Mの分子量を有し、前記生体適合性ヒアルロン酸ポリマーと前記ビニルスルホン架橋剤とのモル比が、4:1〜1:4の間であり、前記架橋バイオポリマーが、内部移行を調節するために150超〜500nmの直径を有し、かつ、前記架橋バイオポリマーと接触するリガンドであって、1又は2以上の細胞表面標的と相互作用し、CD44受容体と相互作用するヒアルロン酸、葉酸受容体と相互作用する葉酸、又は両方である前記リガンド;並びに、前記ビニルスルホン架橋剤、前記生体適合性ヒアルロン酸ポリマー、前記リガンド、又はそれらの組合せと接触する、蛍光色素、放射性タグ、金属、ナノ粒子、又はそれらの組合せである、検出可能なタグ;を有する、前記ステップ;
損傷していることが疑われる軟骨を前記損傷/傷害軟骨標的用プローブと接触させるステップ;並びに
前記損傷/傷害軟骨を検出するステップ; - 損傷/傷害軟骨標的用プローブが、
ビニルスルホン架橋剤によって架橋されて架橋バイオポリマーを形成する生体適合性ヒアルロン酸ポリマーであって、前記生体適合性ヒアルロン酸ポリマーが、10K〜1.5Mの分子量を有し、前記生体適合性ヒアルロン酸ポリマーと前記ビニルスルホン架橋剤とのモル比が、4:1〜1:4の間であり、前記架橋バイオポリマーが、内部移行を調節するために150超〜500nmの直径を有する、前記生体適合性ヒアルロン酸ポリマー;
前記架橋バイオポリマーと接触するリガンドであって、1又は2以上の細胞表面標的と相互作用し、CD44受容体と相互作用するヒアルロン酸、葉酸受容体と相互作用する葉酸、又は両方である前記リガンド;
CCL2、SDF、エリスロポエチン、VEGF及びCCL16から選択され、前記損傷/傷害軟骨標的用プローブに結合する、1又は2以上のケモカインであって、骨髄ストローマ細胞を動員するために放出される、前記1又は2以上のケモカイン;並びに
前記ビニルスルホン架橋剤、前記生体適合性ヒアルロン酸ポリマー、前記リガンド、又はそれらの組合せと接触する、蛍光色素、放射性タグ、金属、ナノ粒子、又はそれらの組合せである、検出可能なタグ;
を含む、損傷/傷害軟骨に骨髄ストローマ細胞を動員するための請求項1〜3のいずれかに記載の医薬。 - 損傷/傷害軟骨標的用プローブが、
ビニルスルホン架橋剤によって架橋されて架橋バイオポリマーを形成する生体適合性ヒアルロン酸ポリマーであって、前記生体適合性ヒアルロン酸ポリマーが、10K〜1.5Mの分子量を有し、前記生体適合性ヒアルロン酸ポリマーと前記ビニルスルホン架橋剤とのモル比が、4:1〜1:4の間であり、前記架橋バイオポリマーが、内部移行を調節するために150超〜500nmの直径を有する、前記生体適合性ヒアルロン酸ポリマー;
前記架橋バイオポリマーと接触するリガンドであって、1又は2以上の細胞表面標的と相互作用し、CD44受容体と相互作用するヒアルロン酸、葉酸受容体と相互作用する葉酸、又は両方である前記リガンド;
TGF−β1及びTGF−β3から選択され、前記損傷/傷害軟骨標的用プローブに結合する、1又は2以上のTGF活性薬剤であって、より高い軟骨細胞への分化を惹起するために放出される、前記1又は2以上のTGF活性薬剤;並びに
前記ビニルスルホン架橋剤、前記生体適合性ヒアルロン酸ポリマー、前記リガンド、又はそれらの組合せと接触する、蛍光色素、放射性タグ、金属、ナノ粒子、又はそれらの組合せである、検出可能なタグ;
を含む、軟骨細胞への分化を増加させるための請求項1〜4のいずれかに記載の医薬。 - 損傷/傷害軟骨が、機械的な外傷、物理的な外傷、圧迫性外傷、関節炎性損傷、炎症性損傷、又はそれらの組合せに由来する、請求項2〜5のいずれかに記載の医薬。
- 損傷/傷害軟骨標的用プローブの分子量が、10K、60K、700k、又は1.5Mである、請求項1〜6のいずれかに記載の医薬。
- 損傷/傷害軟骨標的用プローブのモル比が、1:4、1:3、1:2、1:1、1:3.9、1:3.5、1:2.3、4:1、3:1、又は2:1である、請求項1〜7のいずれかに記載の医薬。
- 損傷/傷害軟骨標的用プローブが、生分解性である、請求項1〜8のいずれかに記載の医薬。
- 1若しくは2以上のケモカイン又は1若しくは2以上のTGF活性薬剤が、架橋バイオポリマーに結合している、放出可能に結合している、架橋バイオポリマー中に配置している、架橋バイオポリマー上にスプレー被覆されている、又はそれらの組合せである、請求項4又は5に記載の医薬。
- 架橋バイオポリマーが1又は2以上の孔を含み、前記1又は2以上の孔に、1若しくは2以上のケモカイン又は1若しくは2以上のTGF活性薬剤が、時間と共に持続放出するように配置されており、前記1又は2以上の孔が、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29nm、又は1nm未満の直径、若しくは29nmを超える直径を有する、請求項4又は5に記載の医薬。
- 損傷/傷害軟骨標的用プローブが、15分未満で1又は2以上の標的と接触して、15分以内での迅速な検出を可能にする、請求項1〜11のいずれかに記載の医薬。
- 損傷/傷害軟骨標的用プローブが、
ビニルスルホン架橋剤によって架橋されて架橋バイオポリマーを形成する生体適合性ヒアルロン酸ポリマーであって、前記生体適合性ヒアルロン酸ポリマーが、10K〜1.5Mの分子量を有し、前記生体適合性ヒアルロン酸ポリマーと前記ビニルスルホン架橋剤とのモル比が、4:1〜1:4の間であり、前記架橋バイオポリマーが、内部移行を調節するために150超〜500nmの直径を有する、前記生体適合性ヒアルロン酸ポリマー;
前記架橋バイオポリマーと接触するリガンドであって、CD44受容体と相互作用するヒアルロン酸、葉酸受容体と相互作用する葉酸、又は両方である、前記リガンド;並びに
前記ビニルスルホン架橋剤、前記生体適合性ヒアルロン酸ポリマー、前記リガンド、又はそれらの組合せと接触する、検出可能なタグであって、前記損傷/傷害軟骨で検出することができ、前記損傷/傷害軟骨の画像を生成するために使用することができる、蛍光色素、放射性タグ、金属、ナノ粒子、又はそれらの組合せである、前記検出可能なタグ;
を含む、請求項1〜12のいずれかに記載の医薬。 - 損傷/傷害軟骨標的用プローブが、
損傷/傷害軟骨を識別するための軟骨損傷イメージングプローブであって、前記軟骨損傷イメージングプローブが、ビニルスルホン架橋剤によって架橋されて架橋バイオポリマーを形成する生体適合性ヒアルロン酸ポリマーを含み、前記生体適合性ヒアルロン酸ポリマーが、10K〜1.5Mの分子量を有し、前記生体適合性ヒアルロン酸ポリマーと前記ビニルスルホン架橋剤とのモル比が、4:1〜1:4の間であり、前記架橋バイオポリマーが、内部移行を調節するために150超〜500nmの直径を有し、前記架橋バイオポリマーと接触するリガンドであって、CD44受容体と相互作用するヒアルロン酸、葉酸受容体と相互作用する葉酸、又は両方である、前記リガンド;並びに前記ビニルスルホン架橋剤、前記生体適合性ヒアルロン酸ポリマー、前記リガンド、又はそれらの組合せと接触する、検出可能なタグであって、損傷/傷害軟骨で検出することができ、前記損傷/傷害軟骨の画像を生成するために使用することができる、蛍光色素、放射性タグ、金属、ナノ粒子、又はそれらの組合せである、前記検出可能なタグ;を有する、前記軟骨損傷イメージングプローブ;並びに
前記損傷/傷害軟骨に骨髄ストローマ細胞を動員することによって損傷/傷害軟骨を処置する医薬として使用するための軟骨標的用プローブであって、前記軟骨標的用プローブが、ビニルスルホン架橋剤によって架橋されて架橋バイオポリマーを形成する生体適合性ヒアルロン酸ポリマーを含み、前記生体適合性ヒアルロン酸ポリマーが、10K〜1.5Mの分子量を有し、前記生体適合性ヒアルロン酸ポリマーと前記ビニルスルホン架橋剤とのモル比が、4:1〜1:4の間であり、前記架橋バイオポリマーが、内部移行を調節するために150超〜500nmの直径を有し、かつ、前記架橋バイオポリマーと接触するリガンドであって、1又は2以上の細胞表面標的と相互作用し、CD44受容体と相互作用するヒアルロン酸、葉酸受容体と相互作用する葉酸、又は両方である前記リガンド;CCL2、SDF、エリスロポエチン、VEGF及びCCL16から選択され、前記損傷/傷害軟骨標的用プローブに結合する、1又は2以上のケモカインであって、骨髄ストローマ細胞を動員するために放出される、前記1又は2以上のケモカイン;を有し、かつ、任意で、前記ビニルスルホン架橋剤、前記生体適合性ヒアルロン酸ポリマー、前記リガンド、又はそれらの組合せと接触する第2の検出可能なタグを有する、前記軟骨標的用プローブ;
を含み、かつ
任意で、軟骨細胞への分化を増加させることによって前記損傷/傷害軟骨を処置する医薬として使用するための軟骨分化プローブを含み、前記軟骨分化プローブが、ビニルスルホン架橋剤によって架橋されて架橋バイオポリマーを形成する生体適合性ヒアルロン酸ポリマーを含み、前記生体適合性ヒアルロン酸ポリマーが、10K〜1.5Mの分子量を有し、前記生体適合性ヒアルロン酸ポリマーと前記ビニルスルホン架橋剤とのモル比が、4:1〜1:4の間であり、前記架橋バイオポリマーが、内部移行を調節するために150超〜500nmの直径を有し、かつ、前記架橋バイオポリマーと接触するリガンドであって、1又は2以上の細胞表面標的と相互作用し、CD44受容体と相互作用するヒアルロン酸、葉酸受容体と相互作用する葉酸、又は両方である前記リガンド;TGF−β1及びTGF−β3から選択され、損傷/傷害軟骨標的用プローブに結合する、1又は2以上のTGF活性薬剤であって、より高い軟骨細胞への分化を惹起するために放出される、前記1又は2以上のTGF活性薬剤;並びに、前記ビニルスルホン架橋剤、前記生体適合性ヒアルロン酸ポリマー、前記リガンド、又はそれらの組合せと接触する、第3の検出可能なタグを有する、請求項1〜13のいずれかに記載の医薬。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562237217P | 2015-10-05 | 2015-10-05 | |
US62/237,217 | 2015-10-05 | ||
PCT/US2016/055552 WO2017062493A1 (en) | 2015-10-05 | 2016-10-05 | Micro-and nano-device for cartilage injury detection and treatment |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2018530607A JP2018530607A (ja) | 2018-10-18 |
JP6800984B2 true JP6800984B2 (ja) | 2020-12-16 |
Family
ID=58488515
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018536714A Active JP6800984B2 (ja) | 2015-10-05 | 2016-10-05 | 軟骨傷害の検出及び処置のためのマイクロ並びにナノデバイス |
Country Status (5)
Country | Link |
---|---|
US (1) | US20180296706A1 (ja) |
EP (1) | EP3359200B1 (ja) |
JP (1) | JP6800984B2 (ja) |
CN (1) | CN108697804B (ja) |
WO (1) | WO2017062493A1 (ja) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102018102807A1 (de) * | 2018-02-08 | 2019-08-08 | Stefan Eggli | Mittel zum Clustern von Rezeptoren |
CN110006790B (zh) * | 2019-04-09 | 2024-05-07 | 中国人民解放军总医院 | 软骨渗透性测量装置及测量方法 |
CN113440626A (zh) * | 2020-03-30 | 2021-09-28 | 复旦大学附属华山医院 | 一种针对关节软骨损伤的靶向纳米磁共振造影剂及其制备和应用 |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001231401A (ja) * | 2000-02-23 | 2001-08-28 | Japan Science & Technology Corp | 人工的に誘発された変形性関節症モデル齧歯目動物 |
EP1416944B1 (en) * | 2001-08-14 | 2005-12-14 | Medipost, Co., Ltd. | Composition for treatment of articular cartilage damage |
EP2233150B1 (de) * | 2003-12-30 | 2016-09-07 | Augustinus Bader | Erythropoietin zur Anwendung bei der Behandlung von Wunden oder der Transplantation von Zellen |
US8071757B2 (en) * | 2006-03-02 | 2011-12-06 | Novozymes Biopharma Dk A/S | Aryl/alkyl vinyl sulfone hyaluronic acid derivatives |
US7919077B2 (en) * | 2006-07-24 | 2011-04-05 | Yeda Research And Development Co. Ltd. | Pharmaceutical compositions comprising CCL2 and use of same for the treatment of inflammation |
CN101878230B (zh) * | 2007-12-19 | 2012-11-21 | 赢创高施米特有限公司 | 乳液中的交联透明质酸 |
KR20090102552A (ko) * | 2008-03-26 | 2009-09-30 | 한양대학교 산학협력단 | 히알루론산을 포함하는 연골 손상 질환 치료용도의미세천공 부위 도포용 조성물 |
WO2010054321A2 (en) * | 2008-11-07 | 2010-05-14 | The Regents Of The University Of Michigan | Methods of treating autoimmune disorders and/or inflammatory disorders |
CA2769470A1 (en) * | 2009-07-30 | 2011-02-03 | Carbylan Biosurgery, Inc. | Modified hyaluronic acid polymer compositions and related methods |
JP5830882B2 (ja) * | 2010-04-08 | 2015-12-09 | 東ソー株式会社 | 酸化亜鉛系透明導電膜、その製造方法及びその用途 |
US20110256628A1 (en) * | 2010-04-20 | 2011-10-20 | The University Of Washington Through Its Center For Commercialization | Adaptive tissue engineering scaffold |
EP2699274B1 (en) * | 2011-04-20 | 2015-03-04 | Carbylan Therapeutics, Inc. | In-situ gel forming compositions |
US20140213524A1 (en) * | 2011-08-23 | 2014-07-31 | National University Corporation Hokkaido University | Composition for regeneration of cartilage |
CN103690971B (zh) * | 2013-12-20 | 2015-08-19 | 中国科学院过程工程研究所 | 一种具有类风湿性关节炎部位靶向作用的超顺磁性颗粒、制备方法及其用途 |
-
2016
- 2016-10-05 EP EP16854239.7A patent/EP3359200B1/en active Active
- 2016-10-05 US US15/766,039 patent/US20180296706A1/en active Pending
- 2016-10-05 CN CN201680069894.7A patent/CN108697804B/zh active Active
- 2016-10-05 JP JP2018536714A patent/JP6800984B2/ja active Active
- 2016-10-05 WO PCT/US2016/055552 patent/WO2017062493A1/en active Application Filing
Also Published As
Publication number | Publication date |
---|---|
CN108697804A (zh) | 2018-10-23 |
WO2017062493A1 (en) | 2017-04-13 |
CN108697804B (zh) | 2022-11-15 |
EP3359200C0 (en) | 2023-08-02 |
JP2018530607A (ja) | 2018-10-18 |
EP3359200A1 (en) | 2018-08-15 |
EP3359200B1 (en) | 2023-08-02 |
US20180296706A1 (en) | 2018-10-18 |
EP3359200A4 (en) | 2018-10-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Poinard et al. | Polydopamine coating enhances mucopenetration and cell uptake of nanoparticles | |
Li et al. | The effect of a nanofiber-hydrogel composite on neural tissue repair and regeneration in the contused spinal cord | |
Lin et al. | Charge‐guided micro/nano‐hydrogel microsphere for penetrating cartilage matrix | |
Brown et al. | Effects of cartilage-targeting moieties on nanoparticle biodistribution in healthy and osteoarthritic joints | |
Rami et al. | Physicochemical modulation of chitosan‐based hydrogels induces different biological responses: Interest for tissue engineering | |
CN112023060B (zh) | 一种靶向软骨具光热响应特征的双药负载纳米微球及其制备方法和应用 | |
Li et al. | Bioinspired polysaccharide hybrid hydrogel promoted recruitment and chondrogenic differentiation of bone marrow mesenchymal stem cells | |
Zhou et al. | Real time monitoring of biomaterial-mediated inflammatory responses via macrophage-targeting NIR nanoprobes | |
Chen et al. | Adhesive and injectable hydrogel microspheres for inner ear treatment | |
Reineke et al. | Can bioadhesive nanoparticles allow for more effective particle uptake from the small intestine? | |
Xu et al. | An injectable acellular matrix scaffold with absorbable permeable nanoparticles improves the therapeutic effects of docetaxel on glioblastoma | |
JP6800984B2 (ja) | 軟骨傷害の検出及び処置のためのマイクロ並びにナノデバイス | |
Murab et al. | Glucosamine loaded injectable silk-in-silk integrated system modulate mechanical properties in bovine ex-vivo degenerated intervertebral disc model | |
Cheng et al. | A colon‐targeted oral probiotics delivery system using an enzyme‐triggered fuse‐like microcapsule | |
Gan et al. | Mesenchymal stem cell exosomes encapsulated oral microcapsules for acute colitis treatment | |
CN114470223B (zh) | 清除促炎因子和抑制t细胞活化的细胞膜包被纳米诱饵及其制备方法与应用 | |
Sawyer et al. | Nanoparticle-based evaluation of blood–brain barrier leakage during the foreign body response | |
Chen et al. | Kartogenin (KGN)/synthetic melanin nanoparticles (SMNP) loaded theranostic hydrogel scaffold system for multiparametric magnetic resonance imaging guided cartilage regeneration | |
Tao et al. | A novel biocompatible, simvastatin-loaded, bone-targeting lipid nanocarrier for treating osteoporosis more effectively | |
Wang et al. | Bacteria-inspired transformable nanoparticle targets and covers residual tumor against bladder cancer recurrence | |
CN113995891B (zh) | 一种自更新水合润滑载药水凝胶微球及其制备方法与应用 | |
Wang et al. | A bio-orthogonally functionalized chitosan scaffold with esterase-activatable release for nerve regeneration | |
Song et al. | Rod‐Shaped Polymeric Nanoparticles Intervene Neutrophils for Efficient Ischemic Stroke Therapy | |
Liu et al. | Platelet Membrane Fragment Self‐Assembled Oral Hydrogel Microspheres for Restoring Intestinal Microvascular Injury | |
Wang et al. | A ROS-responsive fluorescent probe detecting experimental colitis by functional polymeric nanoparticles |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180629 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180629 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190527 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190730 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20191209 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200309 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200706 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200907 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20201102 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20201125 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6800984 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |