JP5701408B2 - 親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法、及び酸化鉄ナノ粒子を含む磁気共鳴画像造影剤 - Google Patents
親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法、及び酸化鉄ナノ粒子を含む磁気共鳴画像造影剤 Download PDFInfo
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- JP5701408B2 JP5701408B2 JP2013553345A JP2013553345A JP5701408B2 JP 5701408 B2 JP5701408 B2 JP 5701408B2 JP 2013553345 A JP2013553345 A JP 2013553345A JP 2013553345 A JP2013553345 A JP 2013553345A JP 5701408 B2 JP5701408 B2 JP 5701408B2
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- iron oxide
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- 229940031182 nanoparticles iron oxide Drugs 0.000 title claims description 122
- 239000000126 substance Substances 0.000 title claims description 66
- 238000000034 method Methods 0.000 title claims description 51
- 239000002405 nuclear magnetic resonance imaging agent Substances 0.000 title description 2
- 239000002245 particle Substances 0.000 claims description 46
- 229920002307 Dextran Polymers 0.000 claims description 42
- 229960002086 dextran Drugs 0.000 claims description 42
- 238000000137 annealing Methods 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 39
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 28
- 238000000576 coating method Methods 0.000 claims description 24
- 229960000633 dextran sulfate Drugs 0.000 claims description 20
- 239000011248 coating agent Substances 0.000 claims description 19
- 229920001223 polyethylene glycol Polymers 0.000 claims description 17
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 15
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 14
- 239000000194 fatty acid Substances 0.000 claims description 14
- 229930195729 fatty acid Natural products 0.000 claims description 14
- 150000004665 fatty acids Chemical class 0.000 claims description 14
- 239000011780 sodium chloride Substances 0.000 claims description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims description 12
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 9
- 230000002209 hydrophobic effect Effects 0.000 claims description 9
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 238000005119 centrifugation Methods 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- -1 KHCO 3 ) Chemical compound 0.000 claims description 7
- 229920002125 Sokalan® Polymers 0.000 claims description 7
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- HOIQWTMREPWSJY-GNOQXXQHSA-K iron(3+);(z)-octadec-9-enoate Chemical group [Fe+3].CCCCCCCC\C=C/CCCCCCCC([O-])=O.CCCCCCCC\C=C/CCCCCCCC([O-])=O.CCCCCCCC\C=C/CCCCCCCC([O-])=O HOIQWTMREPWSJY-GNOQXXQHSA-K 0.000 claims description 7
- 239000004584 polyacrylic acid Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 229910052742 iron Inorganic materials 0.000 claims description 6
- 150000004698 iron complex Chemical class 0.000 claims description 6
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 5
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 5
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 5
- 239000005642 Oleic acid Substances 0.000 claims description 5
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 5
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 5
- 239000003446 ligand Substances 0.000 claims description 5
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 5
- 239000011368 organic material Substances 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 150000007942 carboxylates Chemical group 0.000 claims description 4
- 150000007524 organic acids Chemical group 0.000 claims description 4
- 239000001103 potassium chloride Substances 0.000 claims description 4
- 235000011164 potassium chloride Nutrition 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 3
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 claims description 3
- 229910000020 calcium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 2
- 239000011812 mixed powder Substances 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 229920002491 Diethylaminoethyl-dextran Polymers 0.000 claims 2
- 239000001110 calcium chloride Substances 0.000 claims 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 239000002105 nanoparticle Substances 0.000 description 63
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 20
- 239000007864 aqueous solution Substances 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 238000002441 X-ray diffraction Methods 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- 230000008569 process Effects 0.000 description 12
- 238000002595 magnetic resonance imaging Methods 0.000 description 10
- 239000002872 contrast media Substances 0.000 description 8
- 230000005389 magnetism Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000002616 MRI contrast agent Substances 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 230000002776 aggregation Effects 0.000 description 5
- 238000004220 aggregation Methods 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 238000002296 dynamic light scattering Methods 0.000 description 4
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 4
- 239000002122 magnetic nanoparticle Substances 0.000 description 4
- 230000005415 magnetization Effects 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229910052595 hematite Inorganic materials 0.000 description 3
- 239000011019 hematite Substances 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- LIKBJVNGSGBSGK-UHFFFAOYSA-N iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Fe+3].[Fe+3] LIKBJVNGSGBSGK-UHFFFAOYSA-N 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 2
- CMHKGULXIWIGBU-UHFFFAOYSA-N [Fe].[Pt] Chemical compound [Fe].[Pt] CMHKGULXIWIGBU-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 231100000263 cytotoxicity test Toxicity 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 229940044631 ferric chloride hexahydrate Drugs 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 description 2
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- CCCMONHAUSKTEQ-UHFFFAOYSA-N octadec-1-ene Chemical compound CCCCCCCCCCCCCCCCC=C CCCMONHAUSKTEQ-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229910000859 α-Fe Inorganic materials 0.000 description 2
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- QGLWBTPVKHMVHM-KTKRTIGZSA-N (z)-octadec-9-en-1-amine Chemical compound CCCCCCCC\C=C/CCCCCCCCN QGLWBTPVKHMVHM-KTKRTIGZSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 239000012692 Fe precursor Substances 0.000 description 1
- 206010020843 Hyperthermia Diseases 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 230000004931 aggregating effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 229910001566 austenite Inorganic materials 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- RKTYLMNFRDHKIL-UHFFFAOYSA-N copper;5,10,15,20-tetraphenylporphyrin-22,24-diide Chemical compound [Cu+2].C1=CC(C(=C2C=CC([N-]2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3[N-]2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 RKTYLMNFRDHKIL-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 238000012258 culturing Methods 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
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- 238000013461 design Methods 0.000 description 1
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- 125000005313 fatty acid group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000036031 hyperthermia Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
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- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002103 nanocoating Substances 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 229910052754 neon Inorganic materials 0.000 description 1
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920000314 poly p-methyl styrene Polymers 0.000 description 1
- 206010063401 primary progressive multiple sclerosis Diseases 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
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- 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
- A61K49/1851—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 having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
- A61K49/1857—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 having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA
- A61K49/186—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 having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA the organic macromolecular compound being polyethyleneglycol [PEG]
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- 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
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- 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
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Description
酸化鉄ナノ粒子の合成
「J.Park et al.Nat.Mater.2004,4, 891」に記載の方法により100Lのパイロットプラントでオレイン酸鉄錯体(Iron oleate complex)を合成し、これを用いて酸化鉄ナノ粒子を合成した。オレイン酸鉄錯体は、オレイン酸ナトリウム(sodium oleate)と塩化第二鉄六水和物(FeCl36H2O)とを反応させることで調製したものを用いた。より詳細には、塩化第二鉄六水和物1.08kg及びオレイン酸ナトリウム3.65kgを水6L、エタノール8L及びヘキサン14Lからなる混合溶媒と混合した後、強く撹拌しながら60℃程度で1時間反応させる。2つの層に分離された生成物のうち透明な下層を除去した後、残りの茶色の有機層に水を混合し、さらに水層を除去して、残りの水溶性塩を除去する。このような水洗過程を3回繰り返す。精製された錯体溶液のヘキサン溶媒を蒸発させることで、オレイン酸鉄錯体を得る。
酸化鉄ナノ粒子と塩粒子を含む混合物のアニーリング処理による有機物が除去された酸化鉄ナノ粒子の調製、及び有機物が除去された酸化鉄ナノ粒子の磁性及び流体力学的径の測定
前記調製された酸化鉄ナノ粒子50mg と硫酸ナトリウム(Sodium sulfate、Na2SO4)(平均粒子サイズ150μm)25gを1:500の重量比でヘキサン(hexane)で撹拌する。温度を高めてヘキサンを徐々に蒸発させる。ヘキサンを蒸発させた後、ナノ粒子と上記塩が混合された粉末を空気条件下で500℃で5時間加熱する。熱処理後、過剰量の塩は蒸溜水に溶かして13,000rpmで30分間遠心分離することで除去する。塩を十分に除去するために、蒸溜水を用いた洗浄及び遠心分離を数回繰り返す。
酸化鉄ナノ粒子と塩粒子を含む混合物のアニーリング処理による親水性物質でコーティングされた酸化鉄ナノ粒子の調製、及び親水性物質でコーティングされた酸化鉄ナノ粒子の流体力学的径及び安定性の測定
親水性物質がコーティングされる工程を除き、実施例1と同様の工程で酸化鉄ナノ粒子と塩の混合物をアニールした。親水性物質(表2)1g を蒸溜水250mlに溶かした。親水性物質水溶液を撹拌しながら1:12.5の重量比でアニールした酸化鉄ナノ粒子12.5gと塩の粉末を徐々に添加する。親水性物質でコーティングされた酸化鉄ナノ粒子は、13,000rpmで30分間遠心分離することで分離する。親水性物質水溶液を用いた追加的な洗浄及び遠心分離をさらに2回繰り返す。
小さいサイズの塩粒子を用いたアニーリング処理によるデキストラン硫酸でコーティングされた酸化鉄ナノ粒子の調製
塩粒子のサイズが13μmであることを除き、実施例2と同様の過程でDSでコーティングされた酸化鉄ナノ粒子を調製した。DSでコーティングされた酸化鉄ナノ粒子の流体力学的径は31.03nmであった(表3)。
デキストラン誘導体でコーティングされた酸化鉄ナノ粒子の細胞毒性試験
DSとCM‐デキストランでコーティングされた酸化鉄ナノ粒子に対してMTT方法により測定した。様々な濃度の酸化鉄ナノ粒子を48時間細胞と培養した後、細胞の生存率を測定した結果、200μg[Fe]/mlの濃度以下で全ての細胞が生きていることを確認することができた(図15)。
デキストラン誘導体でコーティングされた酸化鉄ナノ粒子の磁気共鳴画像(magnetic resonance imaging、MRI)造影剤としての応用可能性試験
優れた安定性のため、DSの代わりにCM‐デキストランでコーティングされた酸化鉄ナノ粒子を選択した。水溶液に分散されたナノ粒子のT2 MRIイメージは、鉄イオンの濃度が増加するほどシグナルが減少することを示す(図16)。造影効果を評価するために、r2弛緩率(relaxivity)値を計算した。r2弛緩率は、造影剤濃度に対するT2弛緩時間の逆数の勾配値である。これは、造影剤の濃度変化に応じてT2弛緩時間がどれくらい敏感に変化するかを示す指標である。r2弛緩率値を計算するにあたり、1/T2=1/T2o+r2*Cの式を用い、この際、T2はT2弛緩時間、T20は初期T2弛緩時間、Cは造影剤の濃度を示す。親水性物質でコーティングされた酸化鉄ナノ粒子を含む造影剤の濃度をx軸変数とし、前記濃度で測定された1/T2の値をy軸変数とすると、グラフプロットで勾配値からr2を誘導することができ、r2はr2弛緩率値を示す。アニーリング処理せずにPEG‐phospholipidでコーティングした酸化鉄ナノ粒子の場合、124.46mM‐1s‐1であったが、アニーリング処理後にCM‐デキストランでコーティングした酸化鉄ナノ粒子は358.9mM‐1s‐1であって、2.9倍向上された値を示した。このような高い弛緩率は、アニーリング処理過程で結晶性が向上されたことと、CM‐デキストランのコーティング過程で多くの粒子が1つのデキストランシェルでコーティングされたことによる結果である。実施例1で上述したように、アニーリング処理後の飽和磁化値は追加的な結晶化により増加した。また、CM‐デキストランでコーティングした後にも、アニーリング処理後の飽和磁化値と類似の値(106emu/g[Fe])を有することを確認した(図17)。また、分散された超常磁性ナノ粒子の凝集時にr2弛緩率が増加することは、「magnetic relaxation switch」という概念として報告されている(J.M.Perez,et.al.Chem.Bio.Chem.2004,5,261)。また、このように造影効果が高い物質を用いると、ナノ粒子の体内注入量を減少させることができるため、毒性効果を低めることができるという長所も有する。このような結果に基いて、CM‐デキストランでコーティングされた酸化鉄ナノ粒子は造影効果が高い生体適合性MRI造影剤として用いられることができると判断される。
Claims (18)
- a)疎水性有機物質で表面処理された磁性酸化鉄ナノ粒子と塩粒子とを含む混合粉末をアニーリングすることで、有機物質がない酸化鉄ナノ粒子を得ること、及び
b)前記有機物質がない酸化鉄ナノ粒子の表面を親水性物質でコーティングすることを含む、親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法。 - 前記a)の酸化鉄ナノ粒子に付着されている疎水性有機物質は、C4〜C25の脂肪酸、C4〜C25の脂肪族アルコール、及びC4〜C25の脂肪族アミンからなる群から選択される少なくとも1つであることを特徴とする、請求項1に記載の親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法。
- 前記a)の酸化鉄ナノ粒子に付着されている脂肪酸はオレイン酸(oleic acid)であることを特徴とする、請求項2に記載の親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法。
- 前記a)の塩粒子は、硫酸ナトリウム(Sodium sulfate、Na2SO4)、炭酸水素ナトリウム(Sodium bicarbonate、NaHCO3)、炭酸水素カリウム(Potassium bicarbonate、KHCO3)、炭酸水素カルシウム(Calcium bicarbonate、Ca(HCO3)2)、塩化ナトリウム(Sodium chloride、NaCl)、塩化カリウム(Potassium chloride、KCl)、及び塩化カルシウム(Calcium chloride、CaCl2)から選択される少なくとも1つであることを特徴とする、請求項1乃至3の何れか一項に記載の親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法。
- 前記a)の塩粒子は1〜500μmの直径を有することを特徴とする、請求項1乃至4の何れか一項に記載の親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法。
- 前記a)の酸化鉄ナノ粒子は、中心原子として鉄と、配位子としてそれに付着したC4〜C25の有機酸基(カルボキシラート)とを含む鉄錯体と、C4〜C25の脂肪酸とを反応させることで得ることを特徴とする、請求項1乃至5の何れか一項に記載の親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法。
- 前記鉄錯体はオレイン酸鉄錯体(iron oleate)であることを特徴とする、請求項6に記載の親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法。
- 前記脂肪酸はオレイン酸であることを特徴とする、請求項6又は7に記載の親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法。
- 前記a)の酸化鉄ナノ粒子の直径が1〜100nmであることを特徴とする、請求項1乃至8の何れか一項に記載の親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法。
- 前記a)の酸化鉄ナノ粒子と塩粒子は、1:10〜1:1000の範囲の重量比を有することを特徴とする、請求項1乃至9の何れか一項に記載の親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法。
- 前記a)のアニーリングは、空気雰囲気下で400〜600℃で1〜10時間加熱することで行われることを特徴とする、請求項1乃至10の何れか一項に記載の親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法。
- 前記a)のアニーリング後、さらに塩粒子を除去することを特徴とする、請求項1乃至11の何れか一項に記載の親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法。
- 前記a)の塩粒子を除去することは遠心分離により行われることを特徴とする、請求項12に記載の親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法。
- 前記a)のアニーリング後、塩を除去する前に温度を室温に低下させることを特徴とする、請求項12又は13に記載の親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法。
- 前記b)の親水性物質は、デキストラン誘導体(Dextran derivatives)、ポリアクリル酸(Polyacrylic acid)、澱粉(Starch)、シリカ(Silica)、ポリエチレングリコール(PEG)、またはリン酸‐ポリエチレングリコール(PEG‐Phosphate、PO‐PEGs)であることを特徴とする、請求項1乃至14の何れか一項に記載の親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法。
- 前記b)の親水性物質であるデキストラン誘導体は、ジエチルアミノエチル‐デキストラン(diethylaminoethyl‐dextran、DEAE‐ デキストラン)、デキストラン硫酸(dextran sulfate、DS)、またはカルボキシメチルデキストラン(Carboxymethyl dextran、CM‐デキストラン)であることを特徴とする、請求項15に記載の親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法。
- 前記b)で、親水性物質のコーティングと塩の除去が同時に行われることを特徴とする、請求項1乃至16の何れか一項に記載の親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法。
- 調製される親水性物質でコーティングされた酸化鉄ナノ粒子が、磁性及び造影効果を有することを特徴とする、請求項1に記載の親水性物質でコーティングされた酸化鉄ナノ粒子の調製方法。
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