JP2016509007A - 骨のための生体特異的な薬剤 - Google Patents
骨のための生体特異的な薬剤 Download PDFInfo
- Publication number
- JP2016509007A JP2016509007A JP2015556563A JP2015556563A JP2016509007A JP 2016509007 A JP2016509007 A JP 2016509007A JP 2015556563 A JP2015556563 A JP 2015556563A JP 2015556563 A JP2015556563 A JP 2015556563A JP 2016509007 A JP2016509007 A JP 2016509007A
- Authority
- JP
- Japan
- Prior art keywords
- bone
- biospecific
- agent
- peptide
- agent according
- 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.)
- Granted
Links
- 210000000988 bone and bone Anatomy 0.000 title claims abstract description 131
- 239000003814 drug Substances 0.000 title claims description 45
- 229940079593 drug Drugs 0.000 title claims description 42
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 144
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 104
- 239000002872 contrast media Substances 0.000 claims abstract description 62
- 229920000642 polymer Polymers 0.000 claims abstract description 50
- 238000000034 method Methods 0.000 claims abstract description 38
- 238000002595 magnetic resonance imaging Methods 0.000 claims abstract description 37
- 230000000694 effects Effects 0.000 claims abstract description 35
- 238000002591 computed tomography Methods 0.000 claims abstract description 25
- 238000011282 treatment Methods 0.000 claims abstract description 23
- 208000020084 Bone disease Diseases 0.000 claims abstract description 16
- 238000003745 diagnosis Methods 0.000 claims abstract description 13
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 claims abstract description 6
- 229920001661 Chitosan Polymers 0.000 claims description 52
- 210000002997 osteoclast Anatomy 0.000 claims description 50
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 45
- 210000004027 cell Anatomy 0.000 claims description 27
- 210000000963 osteoblast Anatomy 0.000 claims description 20
- 208000001132 Osteoporosis Diseases 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims description 17
- 229910052688 Gadolinium Inorganic materials 0.000 claims description 15
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 14
- 102000004169 proteins and genes Human genes 0.000 claims description 14
- 108090000623 proteins and genes Proteins 0.000 claims description 14
- 229940014800 succinic anhydride Drugs 0.000 claims description 14
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 13
- 239000002616 MRI contrast agent Substances 0.000 claims description 12
- 210000002449 bone cell Anatomy 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 11
- 238000013170 computed tomography imaging Methods 0.000 claims description 10
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims description 10
- 201000008968 osteosarcoma Diseases 0.000 claims description 10
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 10
- 208000006386 Bone Resorption Diseases 0.000 claims description 9
- 230000024279 bone resorption Effects 0.000 claims description 9
- 239000000090 biomarker Substances 0.000 claims description 8
- 230000000975 bioactive effect Effects 0.000 claims description 7
- 230000004069 differentiation Effects 0.000 claims description 7
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 7
- 230000002188 osteogenic effect Effects 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 150000004676 glycans Chemical class 0.000 claims description 5
- 229910052737 gold Inorganic materials 0.000 claims description 5
- 239000010931 gold Substances 0.000 claims description 5
- 229920001282 polysaccharide Polymers 0.000 claims description 5
- 239000005017 polysaccharide Substances 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 208000018084 Bone neoplasm Diseases 0.000 claims description 4
- 108010010803 Gelatin Proteins 0.000 claims description 4
- 208000029725 Metabolic bone disease Diseases 0.000 claims description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- 239000008273 gelatin Substances 0.000 claims description 4
- 229920000159 gelatin Polymers 0.000 claims description 4
- 235000019322 gelatine Nutrition 0.000 claims description 4
- 235000011852 gelatine desserts Nutrition 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 230000000010 osteolytic effect Effects 0.000 claims description 4
- 229920001059 synthetic polymer Polymers 0.000 claims description 4
- 208000010191 Osteitis Deformans Diseases 0.000 claims description 3
- 206010049088 Osteopenia Diseases 0.000 claims description 3
- 208000027868 Paget disease Diseases 0.000 claims description 3
- 229910052742 iron Inorganic materials 0.000 claims description 3
- 239000000696 magnetic material Substances 0.000 claims description 3
- 208000027202 mammary Paget disease Diseases 0.000 claims description 3
- 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 2
- 102000008186 Collagen Human genes 0.000 claims description 2
- 108010035532 Collagen Proteins 0.000 claims description 2
- 229910052692 Dysprosium Inorganic materials 0.000 claims description 2
- 108090000790 Enzymes Proteins 0.000 claims description 2
- 102000004190 Enzymes Human genes 0.000 claims description 2
- 108091034117 Oligonucleotide Proteins 0.000 claims description 2
- 229920000954 Polyglycolide Polymers 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- 239000000956 alloy Substances 0.000 claims description 2
- 229910045601 alloy Inorganic materials 0.000 claims description 2
- 150000001718 carbodiimides Chemical class 0.000 claims description 2
- 239000010941 cobalt Substances 0.000 claims description 2
- 229910017052 cobalt Inorganic materials 0.000 claims description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 2
- 229920001436 collagen Polymers 0.000 claims description 2
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 claims description 2
- 229920002674 hyaluronan Polymers 0.000 claims description 2
- 229960003160 hyaluronic acid Drugs 0.000 claims description 2
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 claims description 2
- 239000007769 metal material Substances 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 108020004707 nucleic acids Proteins 0.000 claims description 2
- 102000039446 nucleic acids Human genes 0.000 claims description 2
- 150000007523 nucleic acids Chemical class 0.000 claims description 2
- 201000008482 osteoarthritis Diseases 0.000 claims description 2
- 210000004663 osteoprogenitor cell Anatomy 0.000 claims description 2
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 2
- 229920001610 polycaprolactone Polymers 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229920001184 polypeptide Polymers 0.000 claims description 2
- 239000002243 precursor Substances 0.000 claims description 2
- 150000003384 small molecules Chemical class 0.000 claims description 2
- 206010027452 Metastases to bone Diseases 0.000 claims 1
- 102000014128 RANK Ligand Human genes 0.000 claims 1
- 108010025832 RANK Ligand Proteins 0.000 claims 1
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 108010091748 peptide A Proteins 0.000 claims 1
- 238000003384 imaging method Methods 0.000 abstract description 15
- 230000010072 bone remodeling Effects 0.000 abstract description 7
- 230000003902 lesion Effects 0.000 abstract description 5
- 206010061728 Bone lesion Diseases 0.000 abstract description 2
- 238000002059 diagnostic imaging Methods 0.000 abstract description 2
- 230000001575 pathological effect Effects 0.000 abstract description 2
- 230000008439 repair process Effects 0.000 abstract description 2
- 239000002105 nanoparticle Substances 0.000 description 55
- 239000002245 particle Substances 0.000 description 24
- 150000001413 amino acids Chemical group 0.000 description 21
- 230000015572 biosynthetic process Effects 0.000 description 21
- RYHQMKVRYNEBNJ-BMWGJIJESA-K gadoterate meglumine Chemical compound [Gd+3].CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 RYHQMKVRYNEBNJ-BMWGJIJESA-K 0.000 description 19
- 239000000463 material Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 239000003981 vehicle Substances 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 108010071466 OP3-4 peptide Proteins 0.000 description 13
- 102100032236 Tumor necrosis factor receptor superfamily member 11B Human genes 0.000 description 13
- 235000001014 amino acid Nutrition 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- 201000010099 disease Diseases 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 230000005291 magnetic effect Effects 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- 239000011324 bead Substances 0.000 description 9
- 238000001212 derivatisation Methods 0.000 description 9
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 9
- 239000002953 phosphate buffered saline Substances 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 108010075254 C-Peptide Proteins 0.000 description 8
- -1 9-fluorenylmethyloxycarbonyl (Fmoc) Chemical class 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 102000010498 Receptor Activator of Nuclear Factor-kappa B Human genes 0.000 description 7
- 108010038036 Receptor Activator of Nuclear Factor-kappa B Proteins 0.000 description 7
- 238000000576 coating method Methods 0.000 description 7
- 230000003993 interaction Effects 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 6
- 102100028123 Macrophage colony-stimulating factor 1 Human genes 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 6
- 238000004132 cross linking Methods 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 239000013642 negative control Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 5
- 206010065687 Bone loss Diseases 0.000 description 5
- 108010069241 Connexin 43 Proteins 0.000 description 5
- 102000001045 Connexin 43 Human genes 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 230000037182 bone density Effects 0.000 description 5
- 239000013522 chelant Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000001802 infusion Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 210000005088 multinucleated cell Anatomy 0.000 description 5
- 238000010647 peptide synthesis reaction Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 206010017076 Fracture Diseases 0.000 description 4
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 230000009920 chelation Effects 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 239000000975 dye Substances 0.000 description 4
- 238000002296 dynamic light scattering Methods 0.000 description 4
- 238000007306 functionalization reaction Methods 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 230000003278 mimic effect Effects 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- 210000005087 mononuclear cell Anatomy 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 235000019832 sodium triphosphate Nutrition 0.000 description 4
- 239000007790 solid phase Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 102000007469 Actins Human genes 0.000 description 3
- 108010085238 Actins Proteins 0.000 description 3
- FZHXIRIBWMQPQF-UHFFFAOYSA-N Glc-NH2 Natural products O=CC(N)C(O)C(O)C(O)CO FZHXIRIBWMQPQF-UHFFFAOYSA-N 0.000 description 3
- 239000007987 MES buffer Substances 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- 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 3
- 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 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 108010035042 Osteoprotegerin Proteins 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000007942 carboxylates Chemical group 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000002738 chelating agent Substances 0.000 description 3
- 239000007771 core particle Substances 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- GFSTXYOTEVLASN-UHFFFAOYSA-K gadoteric acid Chemical compound [Gd+3].OC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 GFSTXYOTEVLASN-UHFFFAOYSA-K 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000003760 magnetic stirring Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000013508 migration Methods 0.000 description 3
- 230000005012 migration Effects 0.000 description 3
- 229920005615 natural polymer Polymers 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- XXUPLYBCNPLTIW-UHFFFAOYSA-N octadec-7-ynoic acid Chemical compound CCCCCCCCCCC#CCCCCCC(O)=O XXUPLYBCNPLTIW-UHFFFAOYSA-N 0.000 description 3
- 230000011164 ossification Effects 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 125000006850 spacer group Chemical group 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 239000008174 sterile solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000002730 succinyl group Chemical group C(CCC(=O)*)(=O)* 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000017423 tissue regeneration Effects 0.000 description 3
- 238000004448 titration Methods 0.000 description 3
- UNXRWKVEANCORM-UHFFFAOYSA-I triphosphate(5-) Chemical compound [O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O UNXRWKVEANCORM-UHFFFAOYSA-I 0.000 description 3
- SXRAPDIXXYFGJG-MDAHIHQXSA-N (2s,3s)-2-[[(2s,3s)-2-[[(2s)-2-[[(2s,3s)-2-[[(2s,3r)-2-[[(2s)-6-amino-2-[[(2s)-2-[[(2s,3r)-2-[[(2s)-1-[(2s)-2-[[(2s)-2-amino-3-hydroxypropanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoyl]amino]-4-carboxybut Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(O)=O)[C@@H](C)CC)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CO)[C@@H](C)O)[C@@H](C)O)[C@@H](C)CC)C1=CC=CC=C1 SXRAPDIXXYFGJG-MDAHIHQXSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000010392 Bone Fractures Diseases 0.000 description 2
- 102000010970 Connexin Human genes 0.000 description 2
- 108050001175 Connexin Proteins 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- 102000004310 Ion Channels Human genes 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 102000013275 Somatomedins Human genes 0.000 description 2
- 101800001707 Spacer peptide Proteins 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000000919 ceramic Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000003501 co-culture Methods 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 230000001054 cortical effect Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000012137 double-staining Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 229960003823 gadoteric acid Drugs 0.000 description 2
- 210000003976 gap junction Anatomy 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000000534 ion trap mass spectrometry Methods 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000002122 magnetic nanoparticle Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000009245 menopause Effects 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 238000000386 microscopy Methods 0.000 description 2
- 108091005601 modified peptides Proteins 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000001582 osteoblastic effect Effects 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 108010016184 phenylalanyl-histidyl-arginyl-arginyl-isoleucyl-lysyl-alanine Proteins 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 108700038288 rhodamine-phalloidin Proteins 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 238000006557 surface reaction Methods 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- MWOGMBZGFFZBMK-LJZWMIMPSA-N (2s)-2-[[(2s)-2-[[2-[[(2s,3s)-2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MWOGMBZGFFZBMK-LJZWMIMPSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- SXGZJKUKBWWHRA-UHFFFAOYSA-N 2-(N-morpholiniumyl)ethanesulfonate Chemical compound [O-]S(=O)(=O)CC[NH+]1CCOCC1 SXGZJKUKBWWHRA-UHFFFAOYSA-N 0.000 description 1
- UPMGJEMWPQOACJ-UHFFFAOYSA-N 2-[4-[(2,4-dimethoxyphenyl)-(9h-fluoren-9-ylmethoxycarbonylamino)methyl]phenoxy]acetic acid Chemical compound COC1=CC(OC)=CC=C1C(C=1C=CC(OCC(O)=O)=CC=1)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 UPMGJEMWPQOACJ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- VOUAQYXWVJDEQY-QENPJCQMSA-N 33017-11-7 Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)NCC(=O)NCC(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)CCC1 VOUAQYXWVJDEQY-QENPJCQMSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- 208000000103 Anorexia Nervosa Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 101100329834 Danio rerio gja1 gene Proteins 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 102000055008 Matrilin Proteins Human genes 0.000 description 1
- 108010072582 Matrilin Proteins Proteins 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000003076 Osteolysis Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000013201 Stress fracture Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 206010047623 Vitamin C deficiency Diseases 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- MSWZFWKMSRAUBD-QZABAPFNSA-N beta-D-glucosamine Chemical compound N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-QZABAPFNSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000012984 biological imaging Methods 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000033558 biomineral tissue development Effects 0.000 description 1
- 238000007470 bone biopsy Methods 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 108010009896 bone resorption factor Proteins 0.000 description 1
- 210000003557 bones of lower extremity Anatomy 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 210000003010 carpal bone Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229940124447 delivery agent Drugs 0.000 description 1
- 238000000326 densiometry Methods 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 235000006694 eating habits Nutrition 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000001317 epifluorescence microscopy Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 108010044046 gap 27 peptide Proteins 0.000 description 1
- 230000007661 gastrointestinal function Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000035992 intercellular communication Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 150000002497 iodine compounds Chemical class 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 238000004969 ion scattering spectroscopy Methods 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- DCYOBGZUOMKFPA-UHFFFAOYSA-N iron(2+);iron(3+);octadecacyanide Chemical compound [Fe+2].[Fe+2].[Fe+2].[Fe+3].[Fe+3].[Fe+3].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] DCYOBGZUOMKFPA-UHFFFAOYSA-N 0.000 description 1
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical group [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 239000002102 nanobead Substances 0.000 description 1
- 229940031182 nanoparticles iron oxide Drugs 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000004072 osteoblast differentiation Effects 0.000 description 1
- 230000001599 osteoclastic effect Effects 0.000 description 1
- 230000001009 osteoporotic effect Effects 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000005298 paramagnetic effect Effects 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 238000004375 physisorption Methods 0.000 description 1
- INAAIJLSXJJHOZ-UHFFFAOYSA-N pibenzimol Chemical compound C1CN(C)CCN1C1=CC=C(N=C(N2)C=3C=C4NC(=NC4=CC=3)C=3C=CC(O)=CC=3)C2=C1 INAAIJLSXJJHOZ-UHFFFAOYSA-N 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 235000017924 poor diet Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000003918 potentiometric titration Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000007425 progressive decline Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229960003351 prussian blue Drugs 0.000 description 1
- 239000013225 prussian blue Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 108091006084 receptor activators Proteins 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000001878 scanning electron micrograph Methods 0.000 description 1
- 208000010233 scurvy Diseases 0.000 description 1
- 150000003334 secondary amides Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 229950004959 sorbitan oleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000012421 spiking Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 206010062261 spinal cord neoplasm Diseases 0.000 description 1
- 206010041569 spinal fracture Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical compound O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 230000010415 tropism Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 108010052768 tyrosyl-isoleucyl-glycyl-seryl-arginine Proteins 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 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
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/14—Peptides, e.g. proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
- A61B6/02—Arrangements for diagnosis sequentially in different planes; Stereoscopic radiation diagnosis
- A61B6/03—Computed tomography [CT]
- A61B6/032—Transmission computed tomography [CT]
-
- 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
- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
- A61K38/1793—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0409—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
- A61K49/0414—Particles, beads, capsules or spheres
- A61K49/0423—Nanoparticles, nanobeads, nanospheres, nanocapsules, i.e. having a size or diameter smaller than 1 micrometer
- A61K49/0428—Surface-modified nanoparticles, e.g. immuno-nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1866—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1875—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle coated or functionalised with an antibody
-
- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
- G01R33/00—Arrangements or instruments for measuring magnetic variables
- G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
- G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
- G01R33/48—NMR imaging systems
- G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
- G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
- G01R33/5601—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nanotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Immunology (AREA)
- Radiology & Medical Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Physics & Mathematics (AREA)
- Medical Informatics (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- High Energy & Nuclear Physics (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Cell Biology (AREA)
- Biotechnology (AREA)
- Crystallography & Structural Chemistry (AREA)
- General Engineering & Computer Science (AREA)
- Physical Education & Sports Medicine (AREA)
- Signal Processing (AREA)
- Pulmonology (AREA)
- Pathology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Surgery (AREA)
- Theoretical Computer Science (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- General Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Orthopedic Medicine & Surgery (AREA)
Abstract
Description
(i)(KKKK)−(KK)−K−YCLEIEFCY(SEQ ID No.12)。このペプチドは、CペプチドG2PL(すなわち、SEQ ID No.10)に係留したOP3−1ペプチド(すなわち、SEQ ID No.2)を含むであろう。このペプチドは、本明細書で言及する際、G2PL−OP3−1とする。
(j)DOTA−KGG−YCLEIEFCYLIR(SEQ ID No.13)。MRI可視化Gd3+のキレート化のための新規のDOTA−係留OP3−4ペプチドである。このペプチドは、本明細書で言及する際、DOTA−OP3−4とする。
本発明の骨生体特異的な薬剤が、単剤治療で用いられうる、薬剤として使用されうることは明らかであるだろう。また、本発明の薬剤は、添加物として、もしくはそれらの組み合わせとしてまたは骨疾患を治療するための既知の治療との組み合わせとして用いられるであろう。
本発明者らは、改善した装置および診断(例えば、MRIまたはCT画像化のいずれかによる)または骨関連疾患の治療のための方法を提供することに関心を有していた。したがって、本発明者らは、図5Eで示す、骨の細胞(例えば、骨細胞、骨芽細胞)もしくは骨にのみ存在するペプチド(例えばヒドロキシアパタイト特異的ペプチド)を認識する、1以上のペプチドで誘導体化または機能化された、ポリマー6(例えば、キトサン)で覆われた、造影剤コア4(例えば、鉄酸化またはゴールドメタリックコア)を含む、新規の骨特異的な薬剤2(例えば、微粒子、サブミクロン粒子、および原子または分子要素)を設計し、発展させている。コア4、アウターシェル6を形成するポリマーコーティング、ポリマーアウターシェル6に結合する骨−特異的な機能化ペプチド8における材料の厳選により、ナノ粒子2などは、診断または治療で用いられうる。例えば、前記粒子2は、骨リモデリング活性の画像化、病態の検出および/または組織修復プロセスの検出で用いられうる。下記実施例は、これらの研究の結果を記載する。
本発明者らは、キトサン(CS)、造影剤または薬剤の他の活性成分をコートするために用いられうる多糖は、無水コハク酸に結合しうることを明らかにしている。キトサンコハク酸エステル複合体は、タブレットで用いられうる生体適合性および生分解性ドラッグデリバリー薬剤であるとして、当技術分野で公知である。
(i)キトサン(CS)誘導体化
CSは、既知の開環反応(Yan et al.,2006,Yakugaku Zasshi,126,789−793)を用いて無水コハク酸により誘導体化された(Suc−Chi)。1%(W/V)CS溶液(1%v/v酢酸中)は、0.8μm細孔膜(Millipore)を通してろ過され、メタノールで希釈された(1:4)。無水コハク酸(≧99%GC、Sigma Aldrich)は、4%(w/v)の5mlアセトンに溶解され、磁気攪拌下、液滴で加えられ、室温で攪拌しながら一晩置かれた。形成されたゲルは、過剰な溶液が除かれ、メタノールで2倍希釈され、3日間超純水で透析された。水は1日2回交換され、その後、得られた沈殿物は、遠心分離により回収し、凍結乾燥された。
Suc−Chiビーズは、確立したイオンゲル法(Agnihotri,et al.,2004)を用いて製造された。簡潔には、トリポリリン酸ナトリウム(TPP)溶液(1mg/ml)は、1mg/mlのSuc−CS溶液(上記)に体積比1:5、磁気攪拌下液滴で加えられ、室温で45分、反応させた。核磁気共鳴影像法(MRI)またはCT画像化生体特異的造影剤(すなわち、本発明のナノ粒子2)を製造するために、酸化鉄コア4粒子(Fe3O4、10nm平均直径)または金コア4粒子(<20nm平均直径)はまず、Suc−CS溶液に添加する前、超音波処理を用いてTPP溶液に分散された。加えられたコア粒子4の重量は、溶解ポリマー6の半分であった。その後、コア4粒子は、(滅菌するために)エタノールを用いて遠心分離により洗浄され、その後超純水で洗浄され、滅菌PBSに戻された。
表1に記載されたペプチド8およびそれらに対応するアミノ酸配列は、合成され、その後コア粒子4を機能化するために用いられた。
上記ペプチド2は、本発明のナノ粒子2を作製するためにカルボジイミドの化学的性質によりコア4粒子に共有結合された。非誘導化粒子は、まず、2mlの2−(N−モルフォリノ)エタンスルホン酸(MES)バッファー(0.1M MES、0.3M NaCl、pH6.5)に分散され、1mg/mlのビーズ濃度が得られた。その後、コア4粒子のカルボキシル基は、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド(EDC、4mM)およびN−ヒドロキシスクシンイミド(NHS、10mM)の添加により活性化された。活性化反応は、室温で30分間、進められた。過剰なEDCは、β−メルカプトエタノール(2.8μl)の添加により不活化され、コア4粒子は、脱塩メンブレンにより洗浄された。その後、表1から選択されたペプチド(例えば、YCEIEFCYLIR配列を有するOP3−4ペプチド)が1mg/mlであるMESバッファー溶液は、体積比1:1でコア4粒子の溶液に加えられた。抱合反応は、室温で3時間、磁気攪拌下で進められた。当該反応は、その後、5〜10mMの最終濃度を得るためにヒドロキシアミンの添加によりクエンチされた。
CSおよびSuc−Chiの1H NMRスペクトルを図2に示す。簡潔に、シグナルは、下記のように割り当てられる:2.50〜2.70ppm(H−Ac)は、GlcNAcモノマーのアセチルタンパク質に割り当てられた;2.50−2.75ppm(H2D)は、GlcNモノマーのプロトン2に割り当てられた;3.95〜4.65ppm(H2−2)は、GlcNAcおよびGlcNモノマー両方のプロトン2〜6に割り当てられた;4.65〜4.90ppm(HOD)は、溶媒(HOD)に対応する;5.10〜5.30ppm(H1−A)は、GlcNAcモノマーのプロトン1に対応する;5.30〜5.65ppm(H1−D)は、GlcNモノマーのプロトン1に対応する。CSのスペクトルと対比すると、Suc−Chiのスペクトルは、無水コハク酸のCSへの結合が成功していることを裏付けている。ここでは、5.00〜5.70ppm(図2B、矢印、最初の2つを参照)およびH2Dの3.6〜3.9ppmの範囲でのH1(D)、H1−AおよびH2Dの分解能の悪いまたは消失したシグナルが見られる。CSのスペクトルでは見られないがSuc−Chiのスペクトルで見られる、2.34〜2.57ppmの範囲での新たなシグナルは、スクシニル基の2つのメタン水素基(−COCH2CH2COOH)に帰し、他の報告(Liang,et al.,2012,Xiangyang,et al.,2007)と一致する。
本発明者らは、次に、タンパク質、破骨細胞や骨芽細胞のような、骨の細胞で特異的に発現した、オステオプロテゲリン(osteoprogetrin)3(OP3)が、ガドリニウムを含む、さまざまな造影剤をコートするために用いられうるキレート剤である、ドタレム(Dotarem)(DOTA)に結合しうるかどうかを決定することに着手した。ドタレムは、ガドテル酸、既知の巨大環状構造のGD系MRI造影剤である。それは、キレート剤として有機酸DOTAからなる。
新規DOTA−OP3−4複合タンパク質は、OP3−1およびOP3−2の合成で記載したFmocを用いて固相ペプチド合成法により合成された。しかし、この場合、最初にリジンコアアミノ酸を加え、次に、DOTAとMttで保護されたNH2基とをカップリングした。その後、2つのグリシンアミノ酸は、OP3−4ペプチドのその後の集合に続くスペーサーを形成するためにカップリングされた。DOTA分子とOP3−4配列間のリジン−グリシン−グリシンスペーサーの導入は、合成中の潜在的な立体障害およびペプチドのポテンシーへの影響を避けるために重要であると考えられる。DOTA−OP3−4の構造は、図7に示される。
図9および11は、直鎖状(図9)および分岐(図11)OP3−4ペプチドの代表的な質量分析スペクトルを示す。これらは、コア4粒子への安定した結合と当該粒子の機能化の形成に必要なそれらのペプチドの合成に成功したことを示す。95%を超える純度が精製後に得られた。
本発明者らは、次に、ガドリニウム(Gd)系造影剤がDOTA被覆と骨特異的なタンパク質オステオプロゲトリン3(OP3)との結合により本発明のナノ粒子2を形成するために生成されうるかどうかを決定することに着手した。期待は、それらがまたMRIおよび/またはCT画像化技術で使用されうることであった。
新規ペプチドは、MRIおよびCTのための生体特異的な造影剤(すなわち、機能化ナノ粒子2)を製造するために用いられた(表1参照)。コア4粒子、Gd3+のキレート化は、15時間、バッファーシステムにおいて、GdCl3とDOTA−OP3−4とをインキュベートすることによりなされた。DOTA部分は、多座配位子として働き、Gd3+を複合体にする場合、MRI−可視化ペプチドとするために金属カチオンをエンベロープした。複合体でのDOTAリガンドと金属イオンとの配位は、リガンドの配座および金属カチオンの幾何学的傾向に依存する。DOTAは、それ自体で、8配位のリガンドとして働き、4つのアミノ基および4つのカルボキシレート基と金属とを結合する。本研究では、カルボキシレート基の一つがペプチドとの共有結合に用いられるため、DOTA分子は、7配位として働く。しかし、アミノ酸結合DOTAのカルボキシレート基およびペプチドは、8配位子をもたらし、そして8配位の状態に戻り、安定性の高い配位複合体を形成する(Viola−Villegas,et al.,2009)。
Gd3+のキレート化の成功は、LC−MSにより確認され、DOTA−OP3−4のm/zの694.1のピークがGd3+のキレート化後の[M+3H]3+に対応するm/zの714.8のピークに置き換わっていた。アミノ酸分析は、OP3−4のガドリニウム(Gd)系ナノ粒子2への結合の成功を裏付けた(図12)。加水分解後、ポリマー中に存在するグルコサミンユニットの量およびアミノ酸の量が決定された。ナノ粒子2に結合したペプチド8の量は、ピークエリアの積分により算出した。OP3−4ペプチド8で機能化されたGdナノ粒子2の加水分解生成物の代表的なLCプロファイルは、図12に示される。材料のマイクログラムあたりのグルコサミンユニットは、キトサン系ナノ粒子(CNB)で1.92ナノモル、Gdコア4粒子(そのまま)で1.40ナノモルならびにOP3−4ペプチド8で機能化されたGdナノ粒子2およびGdナノ粒子−DOTA−Gd−OP3−4で1.40ナノモルと算出された。
本発明者らは、次に、T1およびT2モードでのポジティブMRIシグナリングのための生体特異的なペプチド−機能化ナノ粒子2を試験した。生体特異的なナノ粒子2は、Gdコア4を誘導化ペプチド8で覆い、あらかじめ生物活性ペプチドで機能化したナノ粒子にグラフトすることで得られた。
ペプチド(DOTA−OP3−4およびDOTA−Gd−OP3−4)のPBSバッファー溶液は、まず最少量のDMSOにペプチドを溶解して調製され、次に希釈して20μg/mlペプチドのPBS(1%DMSO)原液とし、0.1M HClでpHを7.2に調整した。さまざまなナノ粒子2(すなわち、コア4粒子のみ、ナノ粒子−OP3−4複合体、ナノ粒子−DOTA−Gd−OP3−4複合体)は、同じPBSバッファー溶液に懸濁された。DOTA−Gd3+(20μg/ml)およびFe3O4ナノ粒子(10nm、20μg/ml)の原液は、調製され、ガドリニウム系およびFe3O4系造影剤それぞれのポジティブコントロールとして用いられた。
図13は、リン酸緩衝生理食塩水(PBS)に浸したネガティブコントロールフィルター、造影剤コア4を含まないDOTA−OP3−4ペプチド8からなるネガティブコントロールおよびガドリニウム−キレートDOTA−OP3−4ナノ粒子2の代表的なMRIスキャンを示す。前記スキャンは、ネガティブコントロールがノイズシグナルのみを示す一方、ガドリニウムコア4をキレートしたペプチド8が明らかなポジティブシグナルを示すことを明確に表している。ガドリニウム−キレートDOTA−OP3−4およびペプチド−機能化磁性ナノ粒子2のいずれかに浸したフィルターの比較分析では、検出の選択モードでの2つの造影剤から期待される典型的な明暗画像を示した。
本発明者は、次に、オステオプロテゲリン(osteoprogetrin)3または4(OP3またはOP4)ペプチドと結合したDOTA−被覆ガドリニウムコア4を含むナノ粒子が、インビトロでの破骨細胞形成および破骨細胞活性を阻害するかどうかを決定した。
破骨細胞は、RNAKおよびM−CSFを有する細胞の添加(spiking)またはM−CSFを添加した骨芽細胞の単核細胞共培養システムに基づく一般的な方法により、健康なヒトドナーからの末梢血から単離した新鮮な単核細胞から得られた。ペプチドおよびペプチド−係留ナノ粒子2(すなわち、ナノ粒子−OP3−4、磁性ナノ粒子−OP3−4、ナノ粒子−OP3−DOTAおよびナノ粒子−OP3−4−Gd−DOTA)は、アミノ酸分析により決定された50μMのペプチド当量濃度で細胞に添加された。ネガティブコントロールは、試験材料を添加されず、ポジティブコントロールは、rh OPG(50ng/ml)を添加された。添加(spiking)は、単核細胞の破骨細胞への分化の前後のいずれかに行われた。
破骨細胞形成でのOP3−4およびそのGd3+キレート化誘導体により機能化されたナノ粒子2の影響に関する研究の結果は、図15に示される。すべての薬剤において、ナノ粒子2およびガドリニウムに結合しないならびに結合した修飾ペプチド8は、コントロールとは著しく異なるレベルで破骨細胞の形成を減少したが、有効性の度合いは異なっていた(図15)。
薬剤の局所注入による骨病理学の診断および治療は、広く支持されている。本発明者らは現在、MRIおよびCT画像化で用いる新規の造影剤を発展させ、薬剤は、石灰化した骨細胞外マトリクスと同様に、骨の細胞、骨芽細胞および破骨細胞を認識できる。これらの生物学的認識特性は、さまざまな骨の細胞および骨のミネラル相に特異的な新規誘導化ペプチドの合成により得られた。誘導化は、画像化特性に影響を与えることなくナノ粒子またはイオン組成物の造影剤と安定した結合を有利にするために設計された。磁化ポリマービーズ、主にキトサンナノビーズの形態での造影剤の特定のタイプは、磁性コアを被覆するもしくはガドリニウム−修飾ペプチドをグラフトする方法、またはペプチドの架橋マトリクスでのイオン散在のいずれかにより得られた。骨の細胞および構造成分を認識する能力は、細胞の挙動を制御する能力と結び付けられた。分化した破骨細胞の活性を認識および阻害するだけではなく、破骨細胞への分化プロセスの間に単核細胞をも認識できる生体特異的な造影剤は、骨芽細胞移動を有利にできる薬剤とともに得ることができた。
1.ヒドロキシアパタイト−特異的ペプチドを有し、骨芽細胞−および破骨細胞−特異的ペプチドも有する、Fe3O4ナノ粒子(すなわち、MRI造影剤)および金ナノ粒子(すなわち、CT造影剤)のようなサブミクロン粒子の表面機能化が好ましい。
Claims (35)
- 核磁気共鳴影像法(MRI)またはコンピューター断層撮影法(CT)を用いて可視化される、造影剤のコアを含む骨生体特異的な薬剤であって、前記造影剤のコアが、骨−標的ペプチドで機能化された、ポリマーシェルによって囲まれ、前記ペプチドが、使用時、骨への前記生体特異的な薬剤を標的とする、骨生体特異的な薬剤。
- 前記造影剤のコアの平均直径が5nm〜30nmである、請求項1に記載の生体特異的な薬剤。
- 前記造影剤のコアが金属材料を含む、請求項1または2に記載の生体特異的な薬剤。
- 前記造影剤のコアが、磁性材料を含み、およびMRI造影剤である、請求項3に記載の生体特異的な薬剤。
- 前記造影剤のコアが、鉄、ニッケル、コバルトもしくはジスプロシウムまたは1以上のこれらの元素を含む、酸化物もしくは合金のような化合物である、請求項3または4に記載の生体特異的な薬剤。
- 前記造影剤が、マグネタイト(Fe3O4)を含む、請求項1〜5のいずれか1項に記載の生体特異的な薬剤。
- 前記造影剤のコアが、非磁性材料を含み、ならびにMRI造影剤およびCT造影剤の両方である、請求項1〜3のいずれか1項に記載の生体特異的な薬剤。
- 前記造影剤のコアが、ガドリニウム、金、ヨウ素またはボロサルフェート(boro−sulphate)を含む、請求項7に記載の生体特異的な薬剤。
- 前記造影剤が、ガドリニウムを含む、請求項8に記載の生体特異的な薬剤。
- 前記骨生体特異的な薬剤のポリマーシェルが、ポリペプチド、荷電タンパク質、多糖または核酸を含む、請求項1〜9のいずれか1項に記載の生体特異的な薬剤。
- 前記ポリマーシェルが、キトサン、コラーゲン、ゼラチン、ヒアルロン酸、ポリ(エチレングリコール)ポリ(乳酸)、ポリ(グルコール酸)、ポリ(ε−カプロラクトン)およびポリ(アクリル酸)を含む生体適合性の天然または合成ポリマーを含む、請求項1〜10のいずれか1項に記載の生体特異的な薬剤。
- 前記ポリマーシェルがキトサンを含む、請求項1〜11のいずれか1項に記載の生体特異的な薬剤。
- 前記ポリマーシェルが無水コハク酸で誘導体化されている、請求項1〜12のいずれか1項に記載の生体特異的な薬剤。
- 前記ポリマーシェルが、骨への生体特異的な薬剤を標的とする、1種または2種以上の骨−標的ペプチドで機能化される、請求項1〜13のいずれか1項に記載の生体特異的な薬剤。
- 前記骨−標的ペプチドが、例えば骨芽細胞、骨細胞、破骨細胞、骨前駆細胞、破骨前駆細胞または骨ライニング細胞のような、排他的に骨に存在する細胞への生体特異的な薬剤を標的とする、請求項1〜14のいずれか1項に記載の生体特異的な薬剤。
- 前記骨−標的ペプチドが、骨芽細胞または破骨細胞への生体特異的な薬剤を標的とする、請求項1〜15のいずれか1項に記載の生体特異的な薬剤。
- 前記骨−標的ペプチドが、例えばヒドロキシアパタイトのような、骨ミネラル相への生体特異的な薬剤を標的とする、請求項1〜16のいずれか1項に記載の生体特異的な薬剤。
- 前記骨−標的ペプチドが、RANKL−誘導破骨細胞分化および活性を減少または抑制するために、RANKに結合することによりOPGをミミックするアミノ酸配列を含む、請求項1〜17のいずれか1項に記載の生体特異的な薬剤。
- 前記骨−標的ペプチドが配列番号1〜15を含む、請求項1〜18のいずれか1項に記載の生体特異的な薬剤。
- 前記骨−標的ペプチドが環化している、請求項1〜19のいずれか1項に記載の生体特異的な薬剤。
- 前記骨−標的ペプチドが、共有結合により前記骨生体特異的な薬剤の前記ポリマーシェルに結合している、請求項1〜20のいずれか1項に記載の生体特異的な薬剤。
- 前記ペプチドがカルボジイミドの化学的性質を用いて前記ポリマーシェルに共有結合している、請求項1〜21のいずれか1項に記載の生体特異的な薬剤。
- 前記生体特異的な薬剤が、前記骨−標的ペプチドの存在により骨へと運ばれる、生体活性化合物を含む、請求項1〜22のいずれか1項に記載の生体特異的な薬剤。
- 前記生体活性化合物が、色素、電気化学メディエータ、タンパク質、ペプチド、化学化合物(例えば、薬)、遺伝物質(例えば、オリゴヌクレオチド、DNA、RNA)、小分子、抗体、または酵素から構成される分子の群から選択される、請求項24に記載の生体特異的な薬剤。
- 前記生体特異的な薬剤の平均直径が1000nm未満である、請求項1〜24のいずれか1項に記載の生体特異的な薬剤。
- 前記生体特異的な薬剤の平均直径が100〜450nmである、請求項1〜25のいずれか1項に記載の生体特異的な薬剤。
- 診断に用いられる、請求項1〜26のいずれか1項に記載の骨生体特異的な薬剤。
- MRI生体標識としてのまたはCT生体標識としての、請求項1〜26のいずれか1項に記載の骨生体特異的な薬剤の使用。
- 請求項1〜26のいずれか1項に記載の骨生体特異的な薬剤を含む、生体標識。
- 請求項1〜26のいずれか1項に記載の骨生体特異的な薬剤の使用を含む、MRIまたはCT画像検査法。
- 治療に用いられる、好ましくは薬剤として用いられる、請求項1〜26のいずれか1項に記載の骨生体特異的な薬剤。
- 骨疾患を治療する、予防するまたは改善することに用いられる、請求項1〜26のいずれか1項に記載の骨生体特異的な薬剤。
- 前記骨疾患が、骨吸収、骨腫瘍の治療、パジェット病、変形性関節症、骨粗しょう症、骨肉腫、骨減少症ならびに溶骨性および造骨性の表現型などを含む骨転移を含む、請求項32に記載の骨生体特異的な薬剤。
- 請求項1〜26のいずれか1項に記載の骨生体特異的な薬剤、および薬学的に許容されるベヒクルを含む、薬剤組成物。
- 請求項1〜26のいずれか1項に記載の治療上有効な量の骨生体特異的な薬剤と、薬学的に許容されるベヒクルとを接触させることを有する、請求項34に記載の組成物の製造方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1302199.3 | 2013-02-07 | ||
GB1302199.3A GB2510587B (en) | 2013-02-07 | 2013-02-07 | Biospecific agents for bone |
PCT/GB2014/050265 WO2014122431A1 (en) | 2013-02-07 | 2014-01-31 | Biospecific agents for bone |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018153482A Division JP6683773B2 (ja) | 2013-02-07 | 2018-08-17 | 骨のための生体特異的な薬剤 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2016509007A true JP2016509007A (ja) | 2016-03-24 |
JP2016509007A5 JP2016509007A5 (ja) | 2017-02-23 |
JP6400026B2 JP6400026B2 (ja) | 2018-10-03 |
Family
ID=47998779
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015556563A Active JP6400026B2 (ja) | 2013-02-07 | 2014-01-31 | 骨のための生体特異的な薬剤 |
JP2018153482A Active JP6683773B2 (ja) | 2013-02-07 | 2018-08-17 | 骨のための生体特異的な薬剤 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018153482A Active JP6683773B2 (ja) | 2013-02-07 | 2018-08-17 | 骨のための生体特異的な薬剤 |
Country Status (10)
Country | Link |
---|---|
US (2) | US20150367000A1 (ja) |
EP (1) | EP2953682B1 (ja) |
JP (2) | JP6400026B2 (ja) |
CN (1) | CN105142729A (ja) |
CA (1) | CA2898366C (ja) |
ES (1) | ES2904260T3 (ja) |
GB (1) | GB2510587B (ja) |
HK (1) | HK1217910A1 (ja) |
NZ (1) | NZ710436A (ja) |
WO (1) | WO2014122431A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2019001783A (ja) * | 2017-06-13 | 2019-01-10 | 国立研究開発法人量子科学技術研究開発機構 | 医薬、並びにその製造方法 |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2974611C (en) * | 2014-02-27 | 2022-07-12 | Pharmalink Ab | Conjugates of hyaluronan hemiesters with pharmaceutically active substances |
CN108187143A (zh) * | 2018-02-09 | 2018-06-22 | 福州大学 | 一种兼具磁热效应和原位诱导成骨的多功能复合材料及其制备方法 |
CN109289119B (zh) * | 2018-09-16 | 2022-05-17 | 华北理工大学 | 一种用于脊柱康复系统的磁性纳米粒子球混合物 |
US11944982B2 (en) * | 2019-06-05 | 2024-04-02 | Battelle Memorial Institute | Polymer-functionalized magnetic particle embodiments for solute separation, and devices and systems for using the same |
CN111558041A (zh) * | 2020-04-30 | 2020-08-21 | 浙江理工大学 | 羟基磷灰石包裹磁性载药纳米颗粒及其制备方法和在制备骨肉瘤光疗药物中的应用 |
WO2023041639A2 (fr) * | 2021-09-15 | 2023-03-23 | Centre National De La Recherche Scientifique | Nanoparticules hybrides |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008533203A (ja) * | 2005-03-21 | 2008-08-21 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 官能基化された磁性ナノ粒子およびその使用法 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH694935A5 (de) * | 2000-07-26 | 2005-09-30 | Straumann Holding Ag | Oberflaechenmodifizierte Implantate. |
US7323542B2 (en) * | 2002-02-21 | 2008-01-29 | University Of Virginia Patent Foundation | Bone targeting peptides |
EP1715971A4 (en) * | 2004-01-28 | 2010-10-13 | Cytimmune Sciences Inc | FUNCTIONALIZED COLLOIDAL METAL COMPOSITIONS AND METHODS |
AU2012204100B2 (en) * | 2005-03-21 | 2014-03-06 | The Regents Of The University Of California | Functionalized magnetic nanoparticles and methods of use thereof |
EP2510935B1 (en) * | 2005-09-28 | 2016-03-23 | The Regents of the University of California | Calcium binding peptides |
US20100028387A1 (en) * | 2007-06-12 | 2010-02-04 | Ganesan Balasundaram | Biocompatible Coated Nanostructured Titanium Surfaces |
US8063636B2 (en) * | 2009-05-29 | 2011-11-22 | The Invention Science Fund I, Llc | Systems, devices, methods, and compositions including targeted ferromagnetic structures |
US9316645B2 (en) * | 2011-10-07 | 2016-04-19 | Brown University | Methods, compositions and kits for imaging cells and tissues using nanoparticles and spatial frequency heterodyne imaging |
-
2013
- 2013-02-07 GB GB1302199.3A patent/GB2510587B/en active Active
-
2014
- 2014-01-31 ES ES14702931T patent/ES2904260T3/es active Active
- 2014-01-31 CA CA2898366A patent/CA2898366C/en active Active
- 2014-01-31 US US14/765,508 patent/US20150367000A1/en not_active Abandoned
- 2014-01-31 NZ NZ710436A patent/NZ710436A/en unknown
- 2014-01-31 CN CN201480007874.8A patent/CN105142729A/zh active Pending
- 2014-01-31 WO PCT/GB2014/050265 patent/WO2014122431A1/en active Application Filing
- 2014-01-31 JP JP2015556563A patent/JP6400026B2/ja active Active
- 2014-01-31 EP EP14702931.8A patent/EP2953682B1/en active Active
-
2016
- 2016-05-24 HK HK16105926.0A patent/HK1217910A1/zh unknown
-
2018
- 2018-08-17 JP JP2018153482A patent/JP6683773B2/ja active Active
-
2019
- 2019-11-25 US US16/693,780 patent/US11464878B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008533203A (ja) * | 2005-03-21 | 2008-08-21 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 官能基化された磁性ナノ粒子およびその使用法 |
Non-Patent Citations (6)
Title |
---|
ACS NANO, vol. 5, no. 5, JPN6017015514, 2011, pages 3905 - 3916, ISSN: 0003549333 * |
ADVANCED DRUG DELIVERY REVIEWS, vol. 64, no. 12, JPN6017015504, 2012, pages 1220 - 1238, ISSN: 0003549329 * |
CELL, vol. 107, no. 4, JPN6017015517, 2001, pages 513 - 523, ISSN: 0003549334 * |
NANOTECHNOLOGY, vol. Vol.22,No.3,035102, JPN6017015506, 2011, pages 1 - 11, ISSN: 0003549330 * |
PHARMACEUTICAL RESEARCH, vol. 29, no. 4, JPN6017015511, 2012, pages 953 - 960, ISSN: 0003549332 * |
WORLD NEUROSURGERY, vol. [online], JPN6017015508, 5 January 2013 (2013-01-05), pages 10 - 1016, ISSN: 0003549331 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2019001783A (ja) * | 2017-06-13 | 2019-01-10 | 国立研究開発法人量子科学技術研究開発機構 | 医薬、並びにその製造方法 |
JP7156665B2 (ja) | 2017-06-13 | 2022-10-19 | 国立研究開発法人量子科学技術研究開発機構 | 医薬、並びにその製造方法 |
Also Published As
Publication number | Publication date |
---|---|
CA2898366A1 (en) | 2014-08-14 |
US11464878B2 (en) | 2022-10-11 |
EP2953682B1 (en) | 2021-10-13 |
JP6400026B2 (ja) | 2018-10-03 |
CN105142729A (zh) | 2015-12-09 |
CA2898366C (en) | 2021-05-04 |
GB2510587A (en) | 2014-08-13 |
GB201302199D0 (en) | 2013-03-27 |
NZ710436A (en) | 2020-07-31 |
JP2018199693A (ja) | 2018-12-20 |
US20200215207A1 (en) | 2020-07-09 |
GB2510587B (en) | 2020-05-20 |
WO2014122431A1 (en) | 2014-08-14 |
JP6683773B2 (ja) | 2020-04-22 |
ES2904260T3 (es) | 2022-04-04 |
HK1217910A1 (zh) | 2017-01-27 |
EP2953682A1 (en) | 2015-12-16 |
US20150367000A1 (en) | 2015-12-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6683773B2 (ja) | 骨のための生体特異的な薬剤 | |
Qi et al. | Self‐assembled peptide‐based nanomaterials for biomedical imaging and therapy | |
Feng et al. | Engineering of bone-and CD44-dual-targeting redox-sensitive liposomes for the treatment of orthotopic osteosarcoma | |
Lee et al. | Prostate cancer-targeted imaging using magnetofluorescent polymeric nanoparticles functionalized with bombesin | |
Qi et al. | Folate receptor-targeted dendrimer-methotrexate conjugate for inflammatory arthritis | |
US8945526B2 (en) | Amphiphilic substance, and drug delivery system and molecular imaging system using the same | |
Park et al. | A new atherosclerotic lesion probe based on hydrophobically modified chitosan nanoparticles functionalized by the atherosclerotic plaque targeted peptides | |
CN102105157B (zh) | 聚合物、抗血管生成剂和靶向部分的缀合物及其在制备用于治疗骨相关血管生成状况的药物中的用途 | |
US20120107229A1 (en) | Novel nano-probes for molecular imaging and targeted therapy of diseases | |
AU2006200363B2 (en) | Glycopeptide compositions | |
Tao et al. | A novel biocompatible, simvastatin-loaded, bone-targeting lipid nanocarrier for treating osteoporosis more effectively | |
CA2345932C (en) | Peptide-based carrier devices for stellate cells | |
WO2018103660A1 (zh) | Vap多肽及其在制备靶向诊疗肿瘤药物中的应用 | |
Cherri et al. | Biodegradable dendritic polyglycerol sulfate for the delivery and tumor accumulation of cytostatic anticancer drugs | |
US20130302255A1 (en) | Novel targeted paramagnetic contrast agent | |
KR101093549B1 (ko) | 질환의 진단을 위한 표적 펩타이드가 결합된 양친성 키토산나노입자 조영제 | |
KR20200060666A (ko) | 플라그 표적화 펩타이드 및 키토산이 결합된 플루로닉 고분자를 포함하는 플라그 표적화 나노전달체 | |
JP2002504927A (ja) | デキストラン担持白金化合物を使用する腫瘍のx線造影 | |
Rasouli et al. | 99mTc-anionic linear globular dendrimer-G2-phenylalanine conjugate: Novel brain tumor SPECT imaging | |
KR101675948B1 (ko) | 동맥경화 진단용 키토산 나노입자 복합체, 이의 제조방법 및 이를 포함하는 조영제 조성물 | |
KR102358116B1 (ko) | 기체 발포형 마이셀 및 이의 제조방법 | |
Jirátová et al. | Biological characterization of a novel hybrid copolymer carrier system based on glycogen | |
KR20210109812A (ko) | 부갑상선 호르몬 약제의 경구전달용 나노 복합체 | |
Tao et al. | A Biocompatible, Simvastatin-Loaded, Bone-Targeting Lipid Nanocarrier: Breaking the'Traditional Shackle'to Treat Osteoporosis More Effectively | |
CN117563012A (zh) | 一种多肽偶联物及制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170119 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20170119 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20170421 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20170509 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170804 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20171205 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180404 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20180525 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20180517 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20180710 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180817 |
|
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: 20180828 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20180904 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6400026 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |