JP6063627B2 - 診断イメージング用のナノ粒子造影剤 - Google Patents
診断イメージング用のナノ粒子造影剤 Download PDFInfo
- Publication number
- JP6063627B2 JP6063627B2 JP2011542782A JP2011542782A JP6063627B2 JP 6063627 B2 JP6063627 B2 JP 6063627B2 JP 2011542782 A JP2011542782 A JP 2011542782A JP 2011542782 A JP2011542782 A JP 2011542782A JP 6063627 B2 JP6063627 B2 JP 6063627B2
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- JP
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- Prior art keywords
- trimethoxysilyl
- core
- nanoparticles
- silane
- propane
- 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.)
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- 239000002105 nanoparticle Substances 0.000 title claims description 139
- 239000002872 contrast media Substances 0.000 title description 21
- 238000002059 diagnostic imaging Methods 0.000 title description 6
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 80
- 239000000203 mixture Substances 0.000 claims description 76
- 239000002245 particle Substances 0.000 claims description 58
- 229910000077 silane Inorganic materials 0.000 claims description 50
- 239000000463 material Substances 0.000 claims description 46
- 239000002243 precursor Substances 0.000 claims description 35
- 239000000032 diagnostic agent Substances 0.000 claims description 31
- 229940039227 diagnostic agent Drugs 0.000 claims description 31
- -1 methyl (3- (trimethoxysilyl) propyl) amino Chemical group 0.000 claims description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 26
- BPUBBGLMJRNUCC-UHFFFAOYSA-N oxygen(2-);tantalum(5+) Chemical compound [O-2].[O-2].[O-2].[O-2].[O-2].[Ta+5].[Ta+5] BPUBBGLMJRNUCC-UHFFFAOYSA-N 0.000 claims description 21
- 229910052723 transition metal Inorganic materials 0.000 claims description 20
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- 239000000377 silicon dioxide Substances 0.000 claims description 13
- 150000003624 transition metals Chemical class 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 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 claims description 10
- BHNQVXFIWQMDDV-UHFFFAOYSA-N 3-[dimethyl(3-trimethoxysilylpropyl)azaniumyl]propane-1-sulfonate Chemical group CO[Si](OC)(OC)CCC[N+](C)(C)CCCS([O-])(=O)=O BHNQVXFIWQMDDV-UHFFFAOYSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 125000006850 spacer group Chemical group 0.000 claims description 8
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- DMJDTPSHLITYJR-UHFFFAOYSA-N 2-[dimethyl(3-trimethoxysilylpropyl)azaniumyl]acetate Chemical compound CO[Si](OC)(OC)CCC[N+](C)(C)CC([O-])=O DMJDTPSHLITYJR-UHFFFAOYSA-N 0.000 claims description 3
- XPYBQYZWVCEVAA-UHFFFAOYSA-N 3-[dimethyl(3-trimethoxysilylpropyl)azaniumyl]propanoate Chemical compound CO[Si](OC)(OC)CCC[N+](C)(C)CCC([O-])=O XPYBQYZWVCEVAA-UHFFFAOYSA-N 0.000 claims description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 3
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- TYBKDTWXECWXCZ-UHFFFAOYSA-N 2-(3-trimethoxysilylpropylamino)acetic acid Chemical compound CO[Si](OC)(OC)CCCNCC(O)=O TYBKDTWXECWXCZ-UHFFFAOYSA-N 0.000 claims description 2
- GBTBTPNYDKDQLP-UHFFFAOYSA-N 2-[4-(3-trimethoxysilylpropylcarbamoyl)piperazin-1-yl]acetic acid Chemical compound CO[Si](OC)(OC)CCCNC(=O)N1CCN(CC(O)=O)CC1 GBTBTPNYDKDQLP-UHFFFAOYSA-N 0.000 claims description 2
- AYOPFHNOHGVFPO-UHFFFAOYSA-N 2-[methyl(3-trimethoxysilylpropyl)amino]acetic acid Chemical compound CO[Si](OC)(OC)CCCN(C)CC(O)=O AYOPFHNOHGVFPO-UHFFFAOYSA-N 0.000 claims description 2
- KGQYLNHGPMFUOI-UHFFFAOYSA-N 3-(3-trimethoxysilylpropylamino)propane-1-sulfonic acid Chemical compound CO[Si](OC)(OC)CCCNCCCS(O)(=O)=O KGQYLNHGPMFUOI-UHFFFAOYSA-N 0.000 claims description 2
- GQPIODMOXXRZMN-UHFFFAOYSA-N 3-(3-trimethoxysilylpropylamino)propanoic acid Chemical compound CO[Si](OC)(OC)CCCNCCC(O)=O GQPIODMOXXRZMN-UHFFFAOYSA-N 0.000 claims description 2
- PFAREDCBFWUTIJ-UHFFFAOYSA-N 3-[methyl(3-trimethoxysilylpropyl)amino]propane-1-sulfonic acid Chemical compound CO[Si](OC)(OC)CCCN(C)CCCS(O)(=O)=O PFAREDCBFWUTIJ-UHFFFAOYSA-N 0.000 claims description 2
- JMCNLEIXOSEEHN-UHFFFAOYSA-N CO[Si](OC)(OC)CCP([O-])(=O)OCC[N+](C)(C)C Chemical compound CO[Si](OC)(OC)CCP([O-])(=O)OCC[N+](C)(C)C JMCNLEIXOSEEHN-UHFFFAOYSA-N 0.000 claims description 2
- RCMQIVQSXHMFFV-UHFFFAOYSA-N C[N+](C)(C)CCOP([O-])(=O)OCC[Si](C)(C)C Chemical compound C[N+](C)(C)CCOP([O-])(=O)OCC[Si](C)(C)C RCMQIVQSXHMFFV-UHFFFAOYSA-N 0.000 claims description 2
- PJBWTTLEYQLSJG-UHFFFAOYSA-N dimethyl-(2h-tetrazol-5-ylmethyl)-(3-trimethoxysilylpropyl)azanium Chemical compound CO[Si](OC)(OC)CCC[N+](C)(C)CC=1N=NNN=1 PJBWTTLEYQLSJG-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 150000003460 sulfonic acids Chemical class 0.000 claims description 2
- AUNLZSWIGFADBN-UHFFFAOYSA-O trimethyl-[3-(3-trimethoxysilylpropanoylsulfamoyl)propyl]azanium Chemical compound CO[Si](OC)(OC)CCC(=O)NS(=O)(=O)CCC[N+](C)(C)C AUNLZSWIGFADBN-UHFFFAOYSA-O 0.000 claims description 2
- CIVHTCJTZBUOBF-UHFFFAOYSA-N 3-[4-(3-trimethoxysilylpropylcarbamoyl)piperazin-1-yl]propanoic acid Chemical compound CO[Si](OC)(OC)CCCNC(=O)N1CCN(CCC(O)=O)CC1 CIVHTCJTZBUOBF-UHFFFAOYSA-N 0.000 claims 1
- CRFWAJMPCWBSPA-UHFFFAOYSA-N CO[Si](CCCNC(NCCC(C(=O)O)N)=O)(OC)OC Chemical compound CO[Si](CCCNC(NCCC(C(=O)O)N)=O)(OC)OC CRFWAJMPCWBSPA-UHFFFAOYSA-N 0.000 claims 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 1
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- UQMRAFJOBWOFNS-UHFFFAOYSA-N butyl 2-(2,4-dichlorophenoxy)acetate Chemical compound CCCCOC(=O)COC1=CC=C(Cl)C=C1Cl UQMRAFJOBWOFNS-UHFFFAOYSA-N 0.000 description 8
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 8
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- ATUOYWHBWRKTHZ-UHFFFAOYSA-N dimethylmethane Natural products CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- VBJZVLUMGGDVMO-UHFFFAOYSA-N hafnium atom Chemical compound [Hf] VBJZVLUMGGDVMO-UHFFFAOYSA-N 0.000 description 1
- 229910000449 hafnium oxide Inorganic materials 0.000 description 1
- WIHZLLGSGQNAGK-UHFFFAOYSA-N hafnium(4+);oxygen(2-) Chemical compound [O-2].[O-2].[Hf+4] WIHZLLGSGQNAGK-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- LZKLAOYSENRNKR-LNTINUHCSA-N iron;(z)-4-oxoniumylidenepent-2-en-2-olate Chemical compound [Fe].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O LZKLAOYSENRNKR-LNTINUHCSA-N 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 238000011694 lewis rat Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 231100001252 long-term toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- AMWRITDGCCNYAT-UHFFFAOYSA-L manganese oxide Inorganic materials [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- PPNAOCWZXJOHFK-UHFFFAOYSA-N manganese(2+);oxygen(2-) Chemical class [O-2].[Mn+2] PPNAOCWZXJOHFK-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 150000001247 metal acetylides Chemical class 0.000 description 1
- 239000013580 millipore water Substances 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- RHOUWZMGYYQBEY-UHFFFAOYSA-N n-methyl-n-trimethoxysilylmethanamine Chemical compound CO[Si](OC)(OC)N(C)C RHOUWZMGYYQBEY-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000005408 paramagnetism Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical class O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 238000012643 polycondensation polymerization Methods 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 229960005335 propanol Drugs 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 231100001251 short-term toxicity Toxicity 0.000 description 1
- 150000004756 silanes Chemical class 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 150000003455 sulfinic acids Chemical class 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- FAWYJKSBSAKOFP-UHFFFAOYSA-N tantalum(iv) sulfide Chemical compound S=[Ta]=S FAWYJKSBSAKOFP-UHFFFAOYSA-N 0.000 description 1
- XSOKHXFFCGXDJZ-UHFFFAOYSA-N telluride(2-) Chemical compound [Te-2] XSOKHXFFCGXDJZ-UHFFFAOYSA-N 0.000 description 1
- 150000004772 tellurides Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229910000314 transition metal oxide Inorganic materials 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052726 zirconium Inorganic materials 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
- A61K49/04—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
- A61K49/1833—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 a small organic molecule
- A61K49/1848—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 a small organic molecule the small organic molecule being a silane
-
- 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
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nanotechnology (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Radiology & Medical Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Crystallography & Structural Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Apparatus For Radiation Diagnosis (AREA)
- Magnetic Resonance Imaging Apparatus (AREA)
- Compounds Of Iron (AREA)
- Inorganic Compounds Of Heavy Metals (AREA)
Description
以上のシェルで被覆することができる。個々のシェルは同一の材料からなっていてもよいし、或いは2種以上の材料からなっていてもよい。コアを2以上のシェルで被覆し得る実施形態では、シェルは同一の材料又は異種の材料からなり得る。
又はこれらの組合せの使用を含み得る。別の実施形態では、本方法はさらに精製ナノ粒子の単離を含む。
酸化タンタル系ナノ粒子の合成
段階1:N,N−ジメチル−3−スルホ−N−(3−(トリメトキシシリル)プロピル)プロパン−1−アミニウムの合成
撹拌棒を含む500mL丸底フラスコに、トルエン(無水、250mL)、N,N−ジメチルアミノトリメトキシシラン(25g、121mmol)及び1,3−プロパンスルトン(13.4g、110mmol)を添加した。混合物を室温で4日間撹拌した。次いで、混合物を濾過して沈殿した生成物を単離し、続いてこれを新鮮な無水トルエン(2×60mL)で洗浄した。真空下で乾燥した後の白色粉末の収集は23.6gであった。
方法1:溶媒として1−プロパノール
撹拌棒を含む250mL三つ口丸底フラスコに1−プロパノール(73mL)を仕込み、次いでイソ酪酸(1.16mL、12.51mmol、Taに対して1.27eq)及びDI水(1.08mL、59.95mmol、Taに対して6.09eq)を添加して反応混合物を形成した。反応混合物中に窒素を20分間吹き込み、次いで撹拌しながら反応混合物にタンタルエトキシド(Ta(OEt)5)(2.55mL、4g、9.84mmol)を室温で15分かけて滴下した。Ta(OEt)5の添加中、反応混合物中への窒素の吹込みを続けた。Ta(OEt)5の添加が完了した後、上述した反応混合物を窒素下において室温で16時間撹拌した。
撹拌棒を含む100mL三つ口丸底フラスコにトリフルオロエタノール(42mL)を仕込んだ。溶媒に窒素を吹き込みながら、注射器を用いてイソ酪酸(0.53mL、5.7mmol)を添加し、次いで水(0.13mL、7.4mmol)を添加した。連続的に窒素を吹き込みながら、溶液をさらに15分間撹拌した。注射器を用いてタンタルエトキシド(Ta(OEt)5)(2g、4.9mmol)を滴下した。僅かに濁った溶液を窒素下において室温で17時間撹拌した。N,N−ジメチル−3−スルホ−N−(3−(トリメトキシシリル)プロピル)プロパン−1−アミニウム(実施例1、3.2g、9.8mmol)を水(15mL)に溶解した。この均質で無色の溶液を撹拌しながら空気下でタンタル含有反応混合物に手早く滴下した。フラスコに凝縮器を取り付け、次いで78℃に予熱した油浴中に配置した。この温度で6時間撹拌した後、無色で均質の反応混合物を室温に冷却した。水(20mL)を添加した後、回転蒸発器でトリフルオロエタノールを実質的に除去した。濃水酸化アンモニウムを用いて水溶液を中和し、次いで200nm、100nm及び20nmフィルターで順次に濾過した。次いで、3500MWカットオフの再生セルローススネークスキン透析チューブを用いて溶液を4回透析した。最初の透析は、50:50のDI水:pH7.0リン酸塩緩衝液中で実施した。以後の透析はDI水中で実施した。精製ナノ粒子生成物は水から単離しなかった。アリコートに関する%固形分試験を用いて、被覆ナノ粒子の収量が1.55gであることを決定した。平均粒度は動的光散乱によって1.6nmと測定された。
酸化タンタル系ナノ粒子の合成
段階1:2−(4−(3−(トリメトキシシリル)プロピルカルバモイル)ピペラジン−1−イル)酢酸エチルの合成
エチルアセトキシピペラジン(3.789g)の塩化メチレン(20mL)に(3−イソシアナトプロピル)トリメトキシシラン(4.106g)を添加した。溶液を16時間撹拌し、次いで溶媒を減圧下で除去して8.37gの物質を得、これをそれ以上精製せずに使用した。
500mL丸底フラスコに、n−プロパノール(99mL)、イソ酪酸(1.4mL)及び水(1.2mL)を仕込んだ。溶液を5分間撹拌し、次いでTa(OEt)5(5.37g)を溶液に滴下した。溶液を窒素下において室温で18時間撹拌した。次いで、全部で60mLのこの溶液を2−(4−(3−(トリメトキシシリル)プロピルカルバモイル)ピペラジン−1−イル)酢酸エチル(6.37g)に添加し、溶液を窒素下において100℃で2時間撹拌した。次いで、混合物を室温に冷却し、水(20mL)に添加し、混合物を室温で18時間撹拌した。次いで、全部で75mLの0.33N塩酸水溶液を添加し、溶液を60℃で6時間加熱した。次いで、混合物を室温に冷却し、250mLの28%アンモニア水を添加し、混合物を5日間撹拌した。アンモニア及びプロパノールを減圧下で除去し、次いで材料を3000MWカットオフの再生セルロース透析チューブに注入し、透析緩衝液を12時間ごとに交換しながら蒸留水に対して48時間透析した。次いで、溶液を30000MWカットオフの遠心フィルターで濾過することで、DLSにより測定して4.5nmの粒度を有する粒子を得た。
酸化鉄系ナノ粒子の合成
超常磁性酸化鉄ナノ粒子の合成
100mL三つ口丸底フラスコに706mgのFe(acac)3及び20mLの無水ベンジルアルコールを仕込んだ。溶液中に窒素を吹き込み、次いで窒素雰囲気下において165℃で2時間加熱した。次いで、溶液を室温に冷却し、その温度で貯蔵した。
ベンジルアルコール中の超常磁性酸化鉄ナノ粒子(5.58mg Fe/mL)の10mLアリコートを50mLのテトラヒドロフランで希釈した。2.00gの2−(4−(3−(トリメトキシシリル)プロピルカルバモイル)ピペラジン−1−イル)酢酸エチルを添加し、混合物を撹拌しながら60℃で2時間加熱し、次いで室温に冷却した。50mLの1.0M炭酸カリウム水溶液を添加した後、フラスコを密封し、撹拌しながら60℃で18時間加熱した。次いで、混合物を冷却して遠心分離し、水性層を10000MWカットオフの再生セルロース透析チューブに注入し、透析緩衝液を12時間ごとに交換しながら4リットルの10mMクエン酸ナトリウムに対して48時間透析した。最終容量は94mLであり、溶液1mL当たり全部で0.416mgの鉄を含んでいた。かかる物質は、動的光散乱により150mM塩化ナトリウム水溶液中で測定して8.4nmの平均粒度を有していた。
ベンジルアルコール中の超常磁性酸化鉄ナノ粒子(5.58mg Fe/mL)の16.75mLアリコートをテトラヒドロフランに添加して全容量を94.5mLにした。次いで、この溶液を3.1gのN,N−ジメチル−3−スルホ−N−(3−(トリメトキシシリル)プロピル)プロパン−1−アミニウムと共に耐圧フラスコに添加し、混合物を撹拌しながら50℃で2時間加熱した。室温に冷却した後、全部で31mLのイソプロパノール及び76mLの濃水酸化アンモニウム水溶液(水中28%NH3)を添加し、次いでフラスコをを密封し、撹拌しながら50℃で18時間加熱した。混合物を冷却し、ヘキサン(100mL×3)で洗浄した。水性層を10000MWカットオフの再生セルロース透析チューブに注入し、4リットルの10mMクエン酸ナトリウムに対して18時間透析した。最終溶液は、溶液1mL当たり全部で0.67mgの鉄を含んでいた。かかる物質は9.2nmの粒度を有していた。
方法1からのナノ粒子(36.2mg)を2mLのDI水に溶解した。溶液を20nm濾過膜で濾過した。濾過段階の直後に、平均粒度を動的光散乱(DLS)により流体力学的半径として測定した。DLSによって定期的にモニターしながら、試料を37℃で15日間貯蔵した。結果を表1に示す。
ナノ粒子の生体分布試験
体重150〜500グラムの範囲内のサイズを有する雄Lewisラットを用いてインビボ試験を実施した。ラットは標準的なハウジング内に収容し、食物及び水を随意に与えると共に、12時間昼夜照明サイクル下に置いた。生体分布試験のために使用したすべての動物は、他の点では未処置の健常被験体であった。
20 コア
30 コア表面
40 シェル
Claims (13)
- 複数のナノ粒子を含んでなる診断剤組成物であって、1以上のナノ粒子が、
a)本質的にシリカを含まないコア表面(30)を有するコア(20)と
b)コア表面(30)に結合したシェル(40)であって、1以上のシラン官能化双性イオン性部分を含むシェル(40)と
を含んでなるナノ粒子(10)であって、ナノ粒子が標的化リガンドを含んでおらず、前記シラン官能化双性イオン性部分が前駆体トリアルコキシシランの加水分解生成物を含んでいる、ナノ粒子(10)である、診断剤組成物。 - 前記コア(20)が遷移金属又は遷移金属化合物を含む、請求項1記載の診断剤組成物。
- 前記コア(20)が酸化タンタルを含む、請求項2記載の診断剤組成物。
- 前記コア(20)が超常磁性材料を含む、請求項1記載の診断剤組成物。
- 前記コア(20)が超常磁性酸化鉄を含む、請求項4記載の診断剤組成物。
- 前記シラン官能化双性イオン性部分が、正に帯電した部分、負に帯電した部分、及び正に帯電した部分と負に帯電した部分との間に位置する第1のスペーサー基を含み、任意には前記スペーサー基がアルキル基である、請求項1乃至請求項5のいずれか1項記載の診断剤組成物。
- 前記正に帯電した部分が第四アルキルアミンを含む、請求項6記載の診断剤組成物。
- 前記負に帯電した部分が脱プロトン化カルボン酸又は脱プロトン化スルホン酸を含む、請求項6又は請求項7記載の診断剤組成物。
- 前記シラン官能化双性イオン性部分のケイ素原子が、第2のスペーサー基を介して正又は負に帯電した部分に連結されており、任意には前記スペーサー基がアルキル基である、請求項6乃至請求項8のいずれか1項記載の診断剤組成物。
- 複数のナノ粒子を含んでなる診断剤組成物であって、1以上のナノ粒子が、
a)本質的にシリカを含まないコア表面(30)を有するコア(20)と
b)コア表面(30)に結合したシェル(40)であって、1以上のシラン官能化双性イオン性部分を含むシェル(40)と
を含んでなるナノ粒子(10)であって、前記シラン官能化双性イオン性部分が、前駆体トリアルコキシシランの加水分解生成物を含んでおり、前駆体トリアルコキシシランが、N,N−ジメチル−3−スルホ−N−(3−(トリメトキシシリル)プロピル)プロパン−1−アミニウム、3−(メチル(3−(トリメトキシシリル)プロピル)アミノ)プロパン−1−スルホン酸、3−(3−(トリメトキシシリル)プロピルアミノ)プロパン−1−スルホン酸、2−(2−(トリメチルシリル)エトキシ(ヒドロキシ)ホスホリルオキシ)−N,N,N−トリメチルエタンアミニウム、2−(2−(トリメトキシシリル)エチル(ヒドロキシ)ホスホリルオキシ)−N,N,N−トリメチルエタンアミニウム、N,N,N−トリメチル−3−(N−3−(トリメトキシシリル)プロピオニルスルファモイル)プロパン−1−アミニウム、N−((2H−テトラゾール−5−イル)メチル)−N,N−ジメチル−3−(トリメトキシシリル)プロパン−1−アミニウム、N−(2−カルボキシエチル)−N,N−ジメチル−3−(トリメトキシシリル)プロパン−1−アミニウム、3−(メチル(3−(トリメトキシシリル)プロピル)アミノ)プロピオン酸、3−(3−(トリメトキシシリル)プロピルアミノ)プロピオン酸、N−(カルボキシメチル)−N,N−ジメチル−3−(トリメトキシシリル)プロパン−1−アミニウム、2−(メチル(3−(トリメトキシシリル)プロピル)アミノ)酢酸、2−(3−(トリメトキシシリル)プロピルアミノ)酢酸、2−(4−(3−(トリメトキシシリル)プロピルカルバモイル)ピペラジン−1−イル)酢酸、3−(4−(3−(トリメトキシシリル)プロピルカルバモイル)ピペラジン−1−イル)プロピオン酸、2−(メチル(2−(3−(トリメトキシシリル)プロピルウレイド)エチル)アミノ)酢酸、2−(2−(3−(トリメトキシシリル)プロピルウレイド)エチル)アミノ酢酸又はこれらの組合せからなる、診断剤組成物。 - 前駆体トリアルコキシシランが、N,N−ジメチル−3−スルホ−N−(3−(トリメトキシシリル)プロピル)プロパン−1−アミニウム、N−(2−カルボキシエチル)−N,N−ジメチル−3−(トリメトキシシリル)プロパン−1−アミニウム、N−(カルボキシメチル)−N,N−ジメチル−3−(トリメトキシシリル)プロパン−1−アミニウム又は2−(4−(3−(トリメトキシシリル)プロピルカルバモイル)ピペラジン−1−イル)酢酸からなる、請求項10記載の診断剤組成物。
- 前記コアが酸化タンタルを含む、請求項10又は請求項11記載の診断剤組成物。
- ナノ粒子(10)が50nm以下の粒度を有する、請求項1乃至請求項12のいずれか1項記載の診断剤組成物。
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