CN108543082A - The preparation method and product of the extra small ferric oxide nano particles assembly of pH response types and application - Google Patents
The preparation method and product of the extra small ferric oxide nano particles assembly of pH response types and application Download PDFInfo
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- CN108543082A CN108543082A CN201810225852.9A CN201810225852A CN108543082A CN 108543082 A CN108543082 A CN 108543082A CN 201810225852 A CN201810225852 A CN 201810225852A CN 108543082 A CN108543082 A CN 108543082A
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- oxide nano
- ferric oxide
- nano particles
- extra small
- small ferric
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- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 title claims abstract description 130
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 116
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 title claims abstract description 116
- 230000004044 response Effects 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 39
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims abstract description 36
- 230000004048 modification Effects 0.000 claims abstract description 23
- 238000012986 modification Methods 0.000 claims abstract description 23
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims abstract description 21
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims abstract description 21
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000005642 Oleic acid Substances 0.000 claims abstract description 21
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims abstract description 21
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims abstract description 21
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 150000003384 small molecules Chemical class 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 239000003446 ligand Substances 0.000 claims abstract description 10
- 238000011938 amidation process Methods 0.000 claims abstract description 7
- 150000004705 aldimines Chemical class 0.000 claims abstract description 6
- 238000009833 condensation Methods 0.000 claims abstract description 4
- 230000005494 condensation Effects 0.000 claims abstract description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 238000005660 chlorination reaction Methods 0.000 claims description 3
- 239000002872 contrast media Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 2
- KBIWNQVZKHSHTI-UHFFFAOYSA-N 4-n,4-n-dimethylbenzene-1,4-diamine;oxalic acid Chemical compound OC(=O)C(O)=O.CN(C)C1=CC=C(N)C=C1 KBIWNQVZKHSHTI-UHFFFAOYSA-N 0.000 claims description 2
- UMHJEEQLYBKSAN-UHFFFAOYSA-N Adipaldehyde Chemical compound O=CCCCCC=O UMHJEEQLYBKSAN-UHFFFAOYSA-N 0.000 claims description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 claims description 2
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims description 2
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- PCSMJKASWLYICJ-UHFFFAOYSA-N Succinic aldehyde Chemical compound O=CCCC=O PCSMJKASWLYICJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- IBVAQQYNSHJXBV-UHFFFAOYSA-N adipic acid dihydrazide Chemical compound NNC(=O)CCCCC(=O)NN IBVAQQYNSHJXBV-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- QQHJDPROMQRDLA-UHFFFAOYSA-N hexadecanedioic acid Chemical compound OC(=O)CCCCCCCCCCCCCCC(O)=O QQHJDPROMQRDLA-UHFFFAOYSA-N 0.000 claims description 2
- 229960004502 levodopa Drugs 0.000 claims description 2
- 125000003431 oxalo group Chemical group 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- NXUBVBMQRSLBHQ-UHFFFAOYSA-N O1OOCC=C1.C1=CC=CC=C1 Chemical compound O1OOCC=C1.C1=CC=CC=C1 NXUBVBMQRSLBHQ-UHFFFAOYSA-N 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 claims 1
- 239000011943 nanocatalyst Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 8
- 230000000712 assembly Effects 0.000 abstract description 4
- 238000000429 assembly Methods 0.000 abstract description 4
- 238000003384 imaging method Methods 0.000 abstract description 4
- 238000010382 chemical cross-linking Methods 0.000 abstract description 3
- 230000005540 biological transmission Effects 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 230000008859 change Effects 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 6
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- 150000002505 iron Chemical class 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 238000000502 dialysis Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 description 3
- 238000002595 magnetic resonance imaging Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 229940055577 oleyl alcohol Drugs 0.000 description 3
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- -1 o-dichlorohenzene Substances 0.000 description 2
- 235000021313 oleic acid Nutrition 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 241000549556 Nanos Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- XEVRDFDBXJMZFG-UHFFFAOYSA-N carbonyl dihydrazine Chemical compound NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000003809 water extraction Methods 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
- A61K49/18—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
-
- 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
- A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Nanotechnology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Radiology & Medical Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention relates to a kind of preparation methods of the extra small ferric oxide nano particles assembly of pH response types and product and application, preparation method to include the following steps：1) the extra small ferric oxide nano particles of Coated with Oleic Acid and the small molecule with carboxyl are subjected to ligand exchange reaction, obtain the extra small ferric oxide nano particles of carboxyl modified；2) the extra small ferric oxide nano particles of carboxyl modified carry out amidation process with the small molecule with hydrazino, obtain the extra small ferric oxide nano particles of hydrazino modification；3) the extra small ferric oxide nano particles of hydrazino modification are reacted with the compound progress aldimine condensation with more aldehyde radicals, obtain the extra small ferric oxide nano particles assembly of pH response types.The preparation method introduces hydrophilic smaller ligand, makes extra small ferric oxide nano particles chemical crosslinking at pH response type nano assemblies, it is made to have good bioavilability and imaging effect.
Description
Technical field
The present invention relates to the preparation fields of iron oxide assembly, and in particular to a kind of extra small iron oxide nano-granule of pH response types
The preparation method and product of sub- assembly and application.
Background technology
Cancer is to threaten one of the maximum killer of global human life, is the weight that Medical research field is faced
Big challenge.According to statistics, cancer has become first cause of death of Chinese Urban Residents.Effectively diagnosis early-stage cancer has been science
The task of top priority in research.
Magnetic resonance imaging (MRI) technology is widely used in cancer diagnosis.In order to improve tumor region with it is normal
The contrast in region generally requires to introduce contrast agent.The response type iron oxide assembling physical efficiency studied extensively at present makes tumor region
Magnetic resonance signal weaken and achieve the purpose that comparison, but it is easy mutually to obscure with other dark areas pathological tissues.
The extra small ferric oxide nano particles of recent research report can significantly improve magnetic resonance signal value.However, traditional hand
Section is often made with high molecular polymer and wraps up extra small ferric oxide nano particles formation biotic environment response type nano micellar carrier,
Since thicker macromolecule layer is to the factors such as unstable, imaging effect in vivo under the obstruction and extremely low concentration of penetration by water
It is greatly limited with bioavilability.
Invention content
In view of the above-mentioned deficiencies in the prior art, it is an object of the present invention to provide a kind of extra small ferric oxide nano particles of pH response types
The preparation method of assembly, being introduced primarily into hydrophilic smaller ligand makes extra small ferric oxide nano particles chemical crosslinking at pH
Response type nano assembly makes it have good bioavilability and imaging effect.
Technical solution provided by the present invention is：
A kind of preparation method of the extra small ferric oxide nano particles assembly of pH response types, includes the following steps：
1) the extra small ferric oxide nano particles of Coated with Oleic Acid and the small molecule with carboxyl are subjected to ligand exchange reaction, obtained
To the extra small ferric oxide nano particles of carboxyl modified；
2) the extra small ferric oxide nano particles of carboxyl modified carry out amidation process with the small molecule with hydrazino, obtain
The extra small ferric oxide nano particles of hydrazino modification；
3) the extra small ferric oxide nano particles of hydrazino modification are reacted with the compound progress aldimine condensation with more aldehyde radicals,
Obtain the extra small ferric oxide nano particles assembly of pH response types.
The extra small ferric oxide nano particles of Coated with Oleic Acid pass through ligand exchange reaction and amidation process respectively in the present invention,
Make its end that there is-CO-NH-NH2Structure, the compound with more aldehyde radicals continue the extra small ferric oxide nano with hydrazino modification
Particle carries out aldimine condensation reaction, the extra small ferric oxide nano particles assembly of pH response types is formed by chemical crosslinking, wherein having
There is the compound of more aldehyde radicals to play crosslinked action so that mutual formation-NH-N=CH- structures, and-NH-N=CH- structures
It is the key that assembly is responded with pH.
The extra small ferric oxide nano particles assembling physical efficiency of pH response types of formation is chemically crosslinked in the present invention at much lower concentrations
It is stabilized, is not limited by critical micelle concentration, higher magnetic resonance signal enhancing is obtained in acid tumor locus.Secondly,
By its unique nano-grade size, tumor tissues targeting may be implemented by high-permeability and retention effect (EPR effects).Enter
After born of the same parents, extra small ferric oxide nano particles assembly solution is stimulated to scatter under acidic environment for many super-small ferric oxide nanos
Particle so that tumor locus signal value is improved；Compared to tumor locus, it is trapped in the extra small oxygen of pH response types of normal structure
Change that the Fe nanometer particles assembling scale of construction is seldom, therefore the signal value of normal structure is basically unchanged, to reach tumor locus targeting at
The purpose of picture.
The grain size of the extra small ferric oxide nano particles of Coated with Oleic Acid is 3~4nm in the present invention, since surface is coated with oleic acid
It can only be dissolved in oil phase solvent, the preparation of the extra small ferric oxide nano particles of Coated with Oleic Acid has been proposed in
J.Am.Chem.Soc.2011,133,12624–12631。
Preferably, the preparation method of the extra small ferric oxide nano particles of the Coated with Oleic Acid includes：
(1) enuatrol and Iron(III) chloride hexahydrate are dissolved in the mixed solution of water, ethyl alcohol and hexane, at 50~80 DEG C
Under the conditions of stir 2~6 hours, oil phase partial extraction and dry obtain oily iron complexes；
(2) oily iron complexes in step (1) are dissolved in the mixed solution of oleyl alcohol, oleic acid and diphenyl ether, argon gas protection
Under stirred at 200~280 DEG C, precipitated through poor solvent, obtain the extra small ferric oxide nano particles of Coated with Oleic Acid.
Preferably, enuatrol in the step (1), Iron(III) chloride hexahydrate, water, ethyl alcohol and hexane rate of charge be 30
~80g:10~20g:50~150mL:50~200mL:100~300mL.
Preferably, oily iron complexes in the step (2), oleyl alcohol, oleic acid and diphenyl ether rate of charge be 0.5~2g:
0.5~2g:0.3~0.6g:5~15g.
Preferably, poor solvent is selected from methanol, ethyl alcohol, acetone, n,N-Dimethylformamide, second in the step (2)
It is one or more in ether and dimethyl sulfoxide.
Preferably, ligand exchange reaction includes in the step 1)：By the extra small ferric oxide nano particles of Coated with Oleic Acid
It is added in the mixed solvent, the small molecule with carboxyl is added, is reacted at 80-120 DEG C, obtains the extra small iron oxide of carboxyl modified
Nano-particle；The mixed solvent is made of good solvent and poor solvent.Ligand exchange reaction will be primarily to will be coated on super
The oleic acid on small ferric oxide nano particles surface replaces with the small molecule with carboxyl so that repaiies on extra small ferric oxide nano particles surface
It is decorated with carboxyl, water phase is converted by oil phase.Small molecule with carboxyl refers to that molecular weight contains carboxyl less than 1000 dalton
Compound.
Preferably, the extra small ferric oxide nano particles of Coated with Oleic Acid and the small molecule with carboxyl in the step 1)
Rate of charge is 10~120mg:100mg~250mg.
Preferably, in the step 1) after ligand exchange reaction, the extra small ferric oxide nano particles of product carboxyl modified
It precipitates to obtain through poor solvent.
Preferably, good solvent is chloroform, n-hexane, o-dichlorohenzene, petroleum ether, tetrahydrochysene furan in the step 1)
It mutters, is one or more in toluene, benzene；The poor solvent is N,N-dimethylformamide, dimethyl sulfoxide (DMSO), ethyl alcohol, ether, third
It is one or more in ketone, methanol.
Preferably, in the step 1) with carboxyl small molecule be citric acid, levodopa, ethanedioic acid, succinic acid,
One or more of thapsic acid.
Preferably, amidation process includes in the step 2)：By the extra small ferric oxide nano particles of carboxyl modified with
Catalyst is added in good solvent, and the small molecule with hydrazino is added, is reacted under room temperature, obtains the extra small oxygen of hydrazino modification
Change Fe nanometer particles.The carboxyl of small molecule and extra small ferric oxide nano particles surface modification with hydrazino is anti-by amidation
It answers, obtains-CO-NH-NH2Structure.Small molecule with hydrazino refers to that molecular weight is multiple less than containing for 1000 dalton
The compound of amino includes at least two hydrazinos.
Preferably, the extra small ferric oxide nano particles of carboxyl modified and the small molecule with hydrazino in the step 2)
Rate of charge be 20~100mg:1~5g.
Preferably, the small molecule with hydrazino is hydrazine hydrate, two hydrazine of oxalyl, two acyl of adipic acid in the step 2)
It is one or more in hydrazine, carbamyl hydrazine, carbohydrazide.
Preferably, in the step 2) catalyst be 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides,
It is one or more in n-hydroxysuccinimide, dicyclohexylcarbodiimide.
Preferably, good solvent is water, dimethyl sulfoxide (DMSO), n,N-Dimethylformamide, ethyl alcohol, acetonitrile in the step 2)
In it is one or more.
Preferably, in the step 2) after amidation process, the extra small ferric oxide nano particles of product hydrazino modification
It is obtained through dialysis.
Preferably, aldimine condensation reaction includes in the step 3)：The extra small iron oxide nano-granule that hydrazino is modified
Son, catalyst and the compound with more aldehyde radicals are added in good solvent, and reaction response at 70-90 DEG C obtains pH response types
Extra small ferric oxide nano particles assembly.Wherein the compound with more aldehyde radicals refers to the organic molecule containing multiple aldehyde radicals, until
Include less 2 aldehyde radicals, passes through the crosslinked action of the compound with more aldehyde radicals, formation-NH-N=CH- structures.
Preferably, the extra small ferric oxide nano particles that hydrazino is modified in the step 3) and the chemical combination with more aldehyde radicals
The rate of charge of object is 1~60mg:1~100mg.
Preferably, the compound with more aldehyde radicals is glutaraldehyde, butanedial, hexandial, equal benzene three in the step 3)
Formaldehyde, 1,3,5- tri- (4- benzaldehydes) benzene, chlorination 4,4 ', 4 "-(1,3,5- triazines -2,4,6- three) three -1- (4- benzaldehydes) pyrrole
It is one or more in pyridine, 2,4,6- tri- (4- aldehyde radicals phenyl) -1,3,5- triazines, three aldehyde radical phloroglucins.
Preferably, catalyst is one or more of in trifluoroacetic acid, hydrochloric acid, sulfuric acid, acetic acid in the step 3).
Preferably, good solvent is one or more of in water, acetonitrile, acetone, ethyl alcohol, methanol in the step 3).
The present invention also provides a kind of extra small ferric oxide nano particles of pH response types being prepared such as above-mentioned preparation method
Assembly.The extra small ferric oxide nano particles assembly of pH response types has good bioavilability and imaging effect, significantly carries
The magnetic resonance signal value of peracidity tumor region.
The present invention also provides a kind of as the above-mentioned extra small ferric oxide nano particles assembly of pH response types is preparing tumour magnetic
Application in resonance image-forming contrast agent.
Compared with the existing technology, beneficial effects of the present invention are embodied in：
(1) reaction system in the present invention is mild, and condition is controllable, and prepared material all has good biocompatibility
And availability, there is good clinical conversion possibility.
(2) the extra small ferric oxide nano particles assembly of pH response types in the present invention, stimulation, which mediates, under acidic environment surpasses
Small ferric oxide nano particles assembly solution is scattered for many super-small ferric oxide nano particles so that tumor locus signal value
It is improved.
(3) the extra small ferric oxide nano particles assembly of pH response types in the present invention is not limited by critical micelle concentration,
Safety and stability presence is remained at much lower concentrations.
Description of the drawings
Fig. 1 is the transmission electron microscope picture of the extra small ferric oxide nano particles of Coated with Oleic Acid in embodiment 1；
Fig. 2 is the transmission electron microscope picture of the extra small ferric oxide nano particles of carboxyl modified in embodiment 2；
Fig. 3 is the transmission electron microscope picture of the extra small ferric oxide nano particles of carboxyl modified in embodiment 3；
Fig. 4 is the transmission electron microscope picture of the extra small ferric oxide nano particles of carboxyl modified in embodiment 4；
Fig. 5 is the transmission electron microscope picture for the extra small ferric oxide nano particles that hydrazino is modified in embodiment 5；
Fig. 6 is the transmission electron microscope picture for the extra small ferric oxide nano particles that hydrazino is modified in embodiment 6；
Fig. 7 is the transmission electron microscope picture for the extra small ferric oxide nano particles that hydrazino is modified in embodiment 7；
Fig. 8 is transmission of the extra small ferric oxide nano particles assembly of pH response types in pH 7.4 and pH5.5 in embodiment 8
Electron microscope；
Fig. 9 is dynamic of the extra small ferric oxide nano particles assembly of pH response types in pH 7.4 and pH5.5 in embodiment 8
Light scattering particle size distribution map；
Figure 10 is aquation grain size in embodiment 8 with the reduction variation diagram of concentration；
Figure 11 is reversible change figure of the magnetic resonance signal under pH variations in embodiment 8；
Figure 12 is transmission electron microscope of the extra small ferric oxide nano particles assembly of pH response types in pH 7.4 in embodiment 9
Figure；
Figure 13 is transmission electron microscope of the extra small ferric oxide nano particles assembly of pH response types in pH 7.4 in embodiment 10
Figure；
Figure 14 is tumor region magnetic resonance signal in application examples with time variation diagram.
Specific implementation mode
It is described further with reference to specific embodiment and attached drawing.
Embodiment 1：The synthesis of the extra small ferric oxide nano particles of Coated with Oleic Acid
(1) enuatrol of the Iron(III) chloride hexahydrate of 10g and 36g 80mL ethyl alcohol, 60mL water and 140mL hexanes is dissolved in mix
It closes in solution, 70 DEG C of 4 hours of stirring.After reaction, oil phase part lease making water extraction obtains and dries to obtain oily iron complexes.
(2) oily iron complexes 1.8g is taken to be dissolved in 0.6g oleic acid, 1.6g oleyl alcohol and 10g diphenyl ether mixed solutions, argon gas is protected
It is warming up to 250 DEG C under shield, and the temperature is kept to stir 30 minutes, acetone precipitation is added after reaction is cooling and centrifugation obtains oil phase
Extra small ferric oxide nano particles, nanometer particle size is in 3~4nm.
Transmission electron microscope is carried out to the extra small ferric oxide nano particles for the Coated with Oleic Acid being prepared and carries out pattern table
Sign, as shown in Figure 1.
Embodiment 2：The synthesis of the extra small ferric oxide nano particles of carboxyl modified
The extra small ferric oxide nano particles of the oleic acid modified of 100mg are dissolved in the o-dichlorohenzene of 7.5ml, 100mg is added
Citric acid and 7.5ml N,N-dimethylformamides.Under the guard mode of argon gas, 100 degree are stirred 24 hours.Reaction terminates
Afterwards, ether is added and acetone is precipitated, centrifugation obtains the extra small ferric oxide nano particles of carboxyl modified.
Transmission electron microscope is carried out to the extra small ferric oxide nano particles for the carboxyl modified being prepared and carries out pattern table
Sign, as shown in Figure 2.
Embodiment 3：The synthesis of the extra small ferric oxide nano particles of carboxyl modified
It is synthesized with reference to the preparation process of embodiment 2, the difference is that, the extra small oxidation for the oleic acid modified being added
Fe nanometer particles are changed to 20mg, are similarly obtained the extra small ferric oxide nano particles of carboxyl modified.
The extra small ferric oxide nano particles for the carboxyl modified that change method is prepared carry out transmission electron microscope into
Row morphology characterization, as shown in Figure 3.
Embodiment 4：The synthesis of the extra small ferric oxide nano particles of carboxyl modified
It is synthesized with reference to the preparation process of embodiment 2, the difference is that, the good solvent being added in reaction process changes
For chloroform, it is similarly obtained the extra small ferric oxide nano particles of carboxyl modified.
The extra small ferric oxide nano particles for the carboxyl modified that change method is prepared carry out transmission electron microscope into
Row morphology characterization, as shown in Figure 4.
Embodiment 5：The synthesis of the extra small ferric oxide nano particles of hydrazino modification
Weigh 250mg 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides and 200mg N- hydroxysuccinimidyl acyls
Imines is dissolved in 2- (N- morpholines) ethanesulfonic acid buffer of 20ml, and the extra small ferric oxide nano particles of 20mg carboxyl modifieds are added.
4g hydrazine hydrates are added afterwards, the extra small ferric oxide nano particles of hydrazino modification are obtained through dialysis centrifugation.
Transmission electron microscope is carried out to the extra small ferric oxide nano particles for the hydrazino modification being prepared and carries out pattern
Characterization, as shown in Figure 5.
Embodiment 6：The synthesis of the extra small ferric oxide nano particles of hydrazino modification
It is synthesized with reference to the preparation process of embodiment 5, the difference is that, the extra small iron oxide of carboxyl modified be added
Nano-particle is changed to 50mg, is similarly obtained the extra small ferric oxide nano particles of carboxyl modified.
Transmission electron microscope is carried out to the extra small ferric oxide nano particles for the hydrazino modification being prepared and carries out pattern
Characterization, as shown in Figure 6.
Embodiment 7：The synthesis of the extra small ferric oxide nano particles of hydrazino modification
It is synthesized with reference to the preparation process of embodiment 5, the difference is that, small point of the hydrazino being added in reaction
Son is changed to adipic dihydrazide, is similarly obtained the extra small ferric oxide nano particles of carboxyl modified.
Transmission electron microscope is carried out to the extra small ferric oxide nano particles for the hydrazino modification being prepared and carries out pattern
Characterization, as shown in Figure 7.
Embodiment 8：The synthesis of the extra small ferric oxide nano particles assembly of pH response types
By chlorination 4,4 ', 4 "-(1,3,5- triazines -2,4,6- three) three-(1- (4- benzaldehydes) pyridines and the 5mg connection of 20mg
Amido modified extra small ferric oxide nano particles are dissolved in 15ml water, and the trifluoroacetic acid of 50 μ l is added.Stirring 8 is small at 70 DEG C
When.After reaction, dialysis obtains the extra small ferric oxide nano particles assembly of pH response types.
Morphology characterization is carried out in pH 7.4 and pH 5.5 to obtained Nanoscale assemblies using transmission electron microscope, as a result
As shown in Figure 8.
Using the size distribution of dynamic scattering analysis its Nanoscale assemblies in pH 7.4 and pH 5.5, as a result such as Fig. 9
It is shown.
The change of size that it is reduced with concentration using dynamic scattering analysis, the results are shown in Figure 10.
Using the reversible change of its Nanoscale assemblies of magnetic resonance image analysis signal value under the variation of pH, as a result such as Figure 11
It is shown.
Result above proves that the extra small ferric oxide nano particles assembly of this kind of pH response type is in condition of different pH lower structure
Apparent reversible change can occur, while can be stabilized in the neutral environment of extremely low concentration.
Embodiment 9：The synthesis of the extra small ferric oxide nano particles assembly of pH response types
It is synthesized with reference to the preparation process of embodiment 8, the difference is that, the extra small oxygen for the hydrazino modification being added
Change Fe nanometer particles and be changed to 20mg, is similarly obtained the extra small ferric oxide nano particles assembly of pH response types.
Transmission electron microscope is carried out to the extra small ferric oxide nano particles assembly of the pH response types being prepared and carries out shape
Looks characterize, as shown in figure 12.
Embodiment 10：The synthesis of the extra small ferric oxide nano particles assembly of pH response types
It is synthesized with reference to the preparation process of embodiment 8, the difference is that, the extra small oxygen for the hydrazino modification being added
Change Fe nanometer particles and be changed to 2mg, is similarly obtained the extra small ferric oxide nano particles assembly of pH response types.
Transmission electron microscope is carried out to the extra small ferric oxide nano particles assembly of the pH response types being prepared and carries out shape
Looks characterize, as shown in figure 13.
Application examples：Application of the extra small ferric oxide nano particles assembly of pH response types for tumor region magnetic resonance imaging
Subcutaneous lung cancer (selected cell strain is A549) model, 5~6mm of tumor size are made with male nude mouse.It is noted by tail vein
The extra small ferric oxide nano particles assembly of pH response types (being made according to 8 method of the present embodiment) is penetrated, observes different time points later
Tumor region signal intensity situation, specific variation are as shown in figure 14.With the extension of time, tumor locus gradually brightens, explanation
The assembling physical efficiency is enriched in tumor locus while having high response to the acidic environment of tumour well, makes it have good
Magnetic resonance imaging effect.
Technical scheme of the present invention and advantageous effect is described in detail in embodiment described above, it should be understood that with
Upper described is only specific embodiments of the present invention, be not intended to restrict the invention, all to be done in the spirit of the present invention
Any modification, supplement and equivalent replacement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of preparation method of the extra small ferric oxide nano particles assembly of pH response types, which is characterized in that include the following steps：
1) the extra small ferric oxide nano particles of Coated with Oleic Acid and the small molecule with carboxyl are subjected to ligand exchange reaction, obtain carboxylic
The extra small ferric oxide nano particles of base modification；
2) the extra small ferric oxide nano particles of carboxyl modified carry out amidation process with the small molecule with hydrazino, obtain hydrazine
The extra small ferric oxide nano particles of base modification；
3) the extra small ferric oxide nano particles of hydrazino modification are reacted with the compound progress aldimine condensation with more aldehyde radicals, are obtained
The extra small ferric oxide nano particles assembly of pH response types.
2. the preparation method of the extra small ferric oxide nano particles assembly of pH response types according to claim 1, feature exist
In ligand exchange reaction includes in the step 1)：
The extra small ferric oxide nano particles of Coated with Oleic Acid are added in the mixed solvent, the small molecule with carboxyl, 80- is added
It is reacted at 120 DEG C, obtains the extra small ferric oxide nano particles of carboxyl modified；The mixed solvent is by good solvent and poor solvent group
At.
3. the preparation method of the extra small ferric oxide nano particles assembly of pH response types according to claim 1, feature exist
In the small molecule with carboxyl is in citric acid, levodopa, ethanedioic acid, succinic acid, thapsic acid in the step 1)
It is one or more of.
4. the preparation method of the extra small ferric oxide nano particles assembly of pH response types according to claim 1, feature exist
In amidation process includes in the step 2)：
The extra small ferric oxide nano particles of carboxyl modified and catalyst are added in good solvent, small point with hydrazino is added
Son reacts under room temperature, obtains the extra small ferric oxide nano particles of hydrazino modification.
5. the preparation method of the extra small ferric oxide nano particles assembly of pH response types according to claim 1, feature exist
In the small molecule with hydrazino is hydrazine hydrate, two hydrazine of oxalyl, adipic dihydrazide, carbamyl hydrazine, carbon in the step 2)
It is one or more in hydrazides.
6. the preparation method of the extra small ferric oxide nano particles assembly of pH response types according to claim 4, feature exist
In catalyst is 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, N- hydroxysuccinimidyls acyl Asia in the step 2)
It is one or more in amine, dicyclohexylcarbodiimide.
7. the preparation method of the extra small ferric oxide nano particles assembly of pH response types according to claim 1, feature exist
In aldimine condensation, which reacts, in the step 3) includes：
The extra small ferric oxide nano particles, catalyst and compound with more aldehyde radicals of hydrazino modification are added to good solvent
In, reaction response at 70-90 DEG C obtains the extra small ferric oxide nano particles assembly of pH response types.
8. the preparation method of the extra small ferric oxide nano particles assembly of pH response types according to claim 1, feature exist
In the compound with more aldehyde radicals is glutaraldehyde, butanedial, hexandial, equal benzene trioxin, 1,3,5- tri- in the step 3)
(4- benzaldehydes) benzene, chlorination 4,4 ', 4 "-(1,3,5- triazines -2,4,6- three) three -1- (4- benzaldehydes) pyridine, tri- (4- of 2,4,6-
Aldehyde radical phenyl) it is -1,3,5- triazines, one or more in three aldehyde radical phloroglucins.
9. the extra small iron oxide nano-granule of pH response types that a kind of preparation method as described in claim 1~8 is any is prepared
Sub- assembly.
10. a kind of extra small ferric oxide nano particles assembly of pH response types as claimed in claim 9 is preparing tumour magnetic resonance
Application in image-forming contrast medium.
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| CN109675062A (en) * | 2018-12-06 | 2019-04-26 | 中山大学 | A kind of High-efficient Water phase inversion of organic phase nano iron oxide |
| CN109675063A (en) * | 2019-02-01 | 2019-04-26 | 复旦大学附属华山医院 | Target the preparation method of the mr contrast agent of Epileptic focus region P- glycoprotein |
| CN112007177A (en) * | 2020-09-09 | 2020-12-01 | 浙江大学 | Preparation method of inorganic nano particle/supermolecule nano targeting compound, product and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109675062A (en) * | 2018-12-06 | 2019-04-26 | 中山大学 | A kind of High-efficient Water phase inversion of organic phase nano iron oxide |
| CN109675062B (en) * | 2018-12-06 | 2021-10-29 | 中山大学 | High-efficiency aqueous phase conversion method of organic phase nano iron oxide |
| CN109675063A (en) * | 2019-02-01 | 2019-04-26 | 复旦大学附属华山医院 | Target the preparation method of the mr contrast agent of Epileptic focus region P- glycoprotein |
| CN112007177A (en) * | 2020-09-09 | 2020-12-01 | 浙江大学 | Preparation method of inorganic nano particle/supermolecule nano targeting compound, product and application |
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