CN105343903A - Silicon dioxide-coated prussian blue analogue nano-particles and preparation method and application thereof - Google Patents
Silicon dioxide-coated prussian blue analogue nano-particles and preparation method and application thereof Download PDFInfo
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- CN105343903A CN105343903A CN201510856286.8A CN201510856286A CN105343903A CN 105343903 A CN105343903 A CN 105343903A CN 201510856286 A CN201510856286 A CN 201510856286A CN 105343903 A CN105343903 A CN 105343903A
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- prussian blue
- particle
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- blue analogue
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- DCYOBGZUOMKFPA-UHFFFAOYSA-N iron(2+);iron(3+);octadecacyanide Chemical class [Fe+2].[Fe+2].[Fe+2].[Fe+3].[Fe+3].[Fe+3].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] DCYOBGZUOMKFPA-UHFFFAOYSA-N 0.000 title claims abstract description 161
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 156
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 title claims abstract description 132
- 239000000377 silicon dioxide Substances 0.000 title claims abstract description 66
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- 235000012239 silicon dioxide Nutrition 0.000 title abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 150000003751 zinc Chemical class 0.000 claims abstract description 8
- 239000002872 contrast media Substances 0.000 claims abstract description 7
- 125000003396 thiol group Chemical group [H]S* 0.000 claims abstract description 7
- UETZVSHORCDDTH-UHFFFAOYSA-N iron(2+);hexacyanide Chemical compound [Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] UETZVSHORCDDTH-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 46
- 239000002356 single layer Substances 0.000 claims description 41
- 238000013019 agitation Methods 0.000 claims description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 238000002156 mixing Methods 0.000 claims description 17
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 claims description 16
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 16
- -1 siloxanes Chemical class 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- BMFMTNROJASFBW-UHFFFAOYSA-N 2-(furan-2-ylmethylsulfinyl)acetic acid Chemical group OC(=O)CS(=O)CC1=CC=CO1 BMFMTNROJASFBW-UHFFFAOYSA-N 0.000 claims description 14
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical class [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- WYGWHHGCAGTUCH-UHFFFAOYSA-N 2-[(2-cyano-4-methylpentan-2-yl)diazenyl]-2,4-dimethylpentanenitrile Chemical compound CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C WYGWHHGCAGTUCH-UHFFFAOYSA-N 0.000 claims description 10
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims description 9
- 229910021529 ammonia Inorganic materials 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- FWDBOZPQNFPOLF-UHFFFAOYSA-N ethenyl(triethoxy)silane Chemical compound CCO[Si](OCC)(OCC)C=C FWDBOZPQNFPOLF-UHFFFAOYSA-N 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 8
- 239000003999 initiator Substances 0.000 claims description 7
- 239000000178 monomer Substances 0.000 claims description 7
- 125000005401 siloxanyl group Chemical group 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- WYTZZXDRDKSJID-UHFFFAOYSA-N (3-aminopropyl)triethoxysilane Chemical compound CCO[Si](OCC)(OCC)CCCN WYTZZXDRDKSJID-UHFFFAOYSA-N 0.000 claims description 6
- 235000015165 citric acid Nutrition 0.000 claims description 6
- 150000007524 organic acids Chemical class 0.000 claims description 6
- QQQSFSZALRVCSZ-UHFFFAOYSA-N triethoxysilane Chemical compound CCO[SiH](OCC)OCC QQQSFSZALRVCSZ-UHFFFAOYSA-N 0.000 claims description 6
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 4
- SJECZPVISLOESU-UHFFFAOYSA-N 3-trimethoxysilylpropan-1-amine Chemical compound CO[Si](OC)(OC)CCCN SJECZPVISLOESU-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
- ICAIHGOJRDCMHE-UHFFFAOYSA-O ammonium cyanide Chemical compound [NH4+].N#[C-] ICAIHGOJRDCMHE-UHFFFAOYSA-O 0.000 claims description 4
- NKSJNEHGWDZZQF-UHFFFAOYSA-N ethenyl(trimethoxy)silane Chemical compound CO[Si](OC)(OC)C=C NKSJNEHGWDZZQF-UHFFFAOYSA-N 0.000 claims description 4
- 239000001630 malic acid Substances 0.000 claims description 4
- 235000011090 malic acid Nutrition 0.000 claims description 4
- 229960003330 pentetic acid Drugs 0.000 claims description 4
- GTSHREYGKSITGK-UHFFFAOYSA-N sodium ferrocyanide Chemical compound [Na+].[Na+].[Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] GTSHREYGKSITGK-UHFFFAOYSA-N 0.000 claims description 4
- 239000000264 sodium ferrocyanide Substances 0.000 claims description 4
- 235000012247 sodium ferrocyanide Nutrition 0.000 claims description 4
- 239000001384 succinic acid Substances 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- UMFJXASDGBJDEB-UHFFFAOYSA-N triethoxy(prop-2-enyl)silane Chemical compound CCO[Si](CC=C)(OCC)OCC UMFJXASDGBJDEB-UHFFFAOYSA-N 0.000 claims description 4
- YUYCVXFAYWRXLS-UHFFFAOYSA-N trimethoxysilane Chemical compound CO[SiH](OC)OC YUYCVXFAYWRXLS-UHFFFAOYSA-N 0.000 claims description 4
- DCXPBOFGQPCWJY-UHFFFAOYSA-N trisodium;iron(3+);hexacyanide Chemical compound [Na+].[Na+].[Na+].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] DCXPBOFGQPCWJY-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- 208000012826 adjustment disease Diseases 0.000 claims description 2
- 239000000276 potassium ferrocyanide Substances 0.000 claims description 2
- 235000011044 succinic acid Nutrition 0.000 claims description 2
- XOGGUFAVLNCTRS-UHFFFAOYSA-N tetrapotassium;iron(2+);hexacyanide Chemical compound [K+].[K+].[K+].[K+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] XOGGUFAVLNCTRS-UHFFFAOYSA-N 0.000 claims description 2
- 238000003384 imaging method Methods 0.000 abstract description 7
- 239000006227 byproduct Substances 0.000 abstract description 5
- 231100000614 poison Toxicity 0.000 abstract description 5
- 230000007096 poisonous effect Effects 0.000 abstract description 5
- 125000000524 functional group Chemical group 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 125000003277 amino group Chemical group 0.000 abstract description 2
- 238000006068 polycondensation reaction Methods 0.000 abstract description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract 1
- OBNDGIHQAIXEAO-UHFFFAOYSA-N [O].[Si] Chemical compound [O].[Si] OBNDGIHQAIXEAO-UHFFFAOYSA-N 0.000 abstract 1
- 235000011114 ammonium hydroxide Nutrition 0.000 abstract 1
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 238000010526 radical polymerization reaction Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 91
- 239000013225 prussian blue Substances 0.000 description 20
- 229960003351 prussian blue Drugs 0.000 description 19
- 239000010410 layer Substances 0.000 description 13
- 230000001105 regulatory effect Effects 0.000 description 9
- 239000008187 granular material Substances 0.000 description 7
- 239000002086 nanomaterial Substances 0.000 description 7
- 230000031700 light absorption Effects 0.000 description 5
- 229920000936 Agarose Polymers 0.000 description 4
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 4
- 230000004962 physiological condition Effects 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229910001385 heavy metal Inorganic materials 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910021645 metal ion Inorganic materials 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000002616 MRI contrast agent Substances 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000005518 electrochemistry Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 229910001428 transition metal ion Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 1
- 229910000859 α-Fe 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
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/225—Microparticles, microcapsules
-
- 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
- A61K49/183—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 inorganic material or being composed of an inorganic material entrapping the MRI-active nucleus, e.g. silica core doped with a MRI-active nucleus
-
- 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
-
- 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
Abstract
The invention provides silicon dioxide-coated prussian blue analogue nano-particles and a preparation method thereof. The preparation method comprises the steps that prussian blue analogue nano-particles with double bonds on the surfaces are synthesized by taking hexacyanoferrate acid substances and zinc salt as raw materials, then the surfaces of the nano-particles are coated with organosilicone monolayers through a free radical polymerization reaction, silicon dioxide layers are formed through an ammonia water catalytic polycondensation reaction, and then the silicon dioxide-coated prussian blue analogue nano-particles are prepared. The invention further provides clinical application of the nano-particles in magnetic resonance and photoacoustic dual-function imaging as a contrast agent. The preparation method is mild in reaction condition, and no other poisonous or harmful by-product exists; the inner nuclear layers and the shell layers of the prepared nano-particles are connected through silicon-oxygen covalent bonds, the prepared nano-particles are very stable under physical conditions, and the biocompatibility and the imaging signal stability are improved; in addition, the surfaces of the nano-particles are provided with functional groups such as amino groups or sulfhydryl groups, so that very beneficial conditions are supplied to further surface modifying and antibody grafting.
Description
Technical field
The invention belongs to biomedical materials field, Prussian blue analogue nano-particle being specifically related to a kind of Silica-coated and preparation method thereof, and it is as magnetic resonance and the application clinically of the difunctional image-forming contrast medium of optoacoustic.
Background technology
The application of nano material in biomedical sector especially medical diagnosis and treatment more and more receives much concern, and nano material is expected to the limitation solving traditional biological medical procedures.But the research of current nano material is only limitted in vitro tests, its biological safety in human body can not get ensureing, seriously limits it and further develops.Solve the biological safety of nano material and become the key issue that nano material applies at biomedical sector.
Prussian blue is a kind of ancient dyestuff, and low price, because of performances such as its excellent optical physics, magnetic, electrochemistry and structures, is widely used in every field.Prussian blue preparation method is very simple, mild condition, and most importantly Prussian blue is a kind of clinical application, is the routine deposit medicine of hospital.Prussian blue long-term clinical application demonstrates its reliable biological safety and metabolic pathway in human body.Structurally, Prussian blue is six cyanogen network ferrites of a kind of ferrous iron and ferric iron mixed valence, and in prussian blue nano particle structure, ferrous iron is connected with carbon atom, it is low spin, ferric iron is connected with nitrogen-atoms, is high-spin, in each ferrous iron-carbon-nitrogen-ferric construction unit, have 5 unpaired electronics, due to Prussian blue this special construction, it can shorten transverse direction or the longitudinal relaxation time of water proton, thus for nuclear magnetic resonance.In addition, owing to there are some unpaired vacant ferric iron sites in prussian blue nano particle structure, therefore hydrone can enter in particle structure and ferric iron coordination, thus realizes a kind of inside nanoparticles Relaxation Mechanism, effective enhancing nuclear magnetic resonance effect.Metal ion simultaneously in prussian blue nano particle is with cyano group owing to being connected by coordinate bond, and therefore very firm, not easily toxigenous free metal ion and hydrocyanic acid, also not easily produce the harmful substances such as oxygen-derived free radicals, therefore safety is very high.In addition, compared with Conventional nano material, as gold nanorods, CNT etc., the photo-thermal conversion efficiency of prussian blue nano particle is higher, and photo and thermal stability is strong, has advantage clearly in photoacoustic imaging application.Existing research confirms the Prussian blue imaging applications as MRI contrast agent (J.Mater.Chem., 2010,20,5251-5259; InorganicChemistryCommunications, 2010,13,58-61; ) and imaging applications (Chem.Commun., 2013,49, the 11029-11031 of photoacoustic contrast agent; Biomaterials, 2014,35,9844-9852.).
Due in Prussian blue structure cell, transition metal ions occupies two different positions, and these two positions can substitute with other different transition metal, causes the great variety diversity of Prussian blue analogue particle.Therefore other most biological safety of nano-material of potential solution can not get ensureing and expensive difficult medical problem by Prussian blue analogue nano-particle, its investigation and application Huge value.
Also there are some defects in existing prussian blue nano granule, such as: water miscible KFe [Fe (CN)
6] owing to having potassium ion, intravenous injection application has limitation; And Fe
4[Fe (CN)
6]
3water insoluble again.Protection for the granule of prussian blue nano is modified the current major part of research and is utilized non-water-soluble Organic substance; and the prussian blue nano granule of water miscible Organic substance parcel adopts is the method for Electrostatic Absorption; the product obtained is in vivo under physiological condition; organic layer is easily destroyed; form exposed prussian blue nano granule; the exposed water insoluble environment of prussian blue nano granule; easily removed by body; metal ion simultaneously in physiology salt and exposed Prussian blue easy generation displacement reaction, have potential toxic action to organism.
Summary of the invention
In order to solve the technical problem of above-mentioned existence, Prussian blue analogue nano-particle that the object of the present invention is to provide a kind of Silica-coated and preparation method thereof, the method adopts the Prussian blue analogue nano-particle of three-step approach synthetic silica parcel.
The present invention also aims to the Prussian blue analogue nano-particle of the Silica-coated providing a kind of above-mentioned preparation method to prepare.
The present invention also aims to provide a kind of Prussian blue analogue nano-particle of above-mentioned Silica-coated as magnetic resonance and the application clinically of the difunctional image-forming contrast medium of optoacoustic.
Object of the present invention is achieved by the following technical programs:
A preparation method for the Prussian blue analogue nano-particle of Silica-coated, comprises the following steps:
Step one: prepare Prussian blue analogue nano-particle
(1) six cyanogen network ferrum acids, organic acid are dissolved in solvent, after mixing and stirring, are mixed with solution A, wherein contain six cyanogen network ferrum acid 0.002-0.02g, organic acid 0.002-0.04g in every milliliter of solution A;
(2) zinc salt is dissolved in solvent, after mixing and stirring, is mixed with B solution, wherein contain zinc salt 0.002-0.04g in every milliliter of B solution;
(3) by even for B solution magnetic agitation, be heated to 70-100 DEG C and the 0.5-3h that refluxes, and then dropwise add solution A, adjustment reaction temperature is 20-100 DEG C, magnetic agitation reaction 0.5-4h, centrifugalize, obtains Prussian blue analogue nano-particle C, be dissolved in dissolving completely in ethanol, thus obtained the solution of Prussian blue analogue nano-particle C; Wherein, the volume ratio of solution A and B solution is 1:0.5-1:3.
Step 2: the Prussian blue analogue nano-particle preparing organosilicon monolayer parcel
To join in the solution of the Prussian blue analogue nano-particle C obtained in step one with the siloxanyl monomers of double bond and initiator, be heated to 60-80 DEG C, magnetic agitation reaction 20-60min, cool to room temperature, centrifugalize is purified, obtaining the Prussian blue analogue nano-particle D of organosilicon monolayer parcel, being dissolved in dissolving completely in ethanol, thus obtain the solution of the Prussian blue analogue nano-particle D of organosilicon monolayer parcel; Wherein, Prussian blue analogue nano-particle C, be (0.08-0.1) with the siloxanyl monomers of double bond, the mass ratio of initiator: (0.221-0.663): (0.032-0.05).
Step 3: the Prussian blue analogue nano-particle preparing Silica-coated
In the solution of the Prussian blue analogue nano-particle D of the organosilicon monolayer parcel obtained in step 2, add ethyl orthosilicate, and to add ammonia adjust ph be 7-8, add the siloxanes with amino or mercapto functional group again, stirred at ambient temperature, separating-purifying, thus the Prussian blue analogue nano-particle obtaining Silica-coated; Wherein, the mass ratio of the siloxanes of the amino or mercapto functional group of the Prussian blue analogue nano-particle of organosilicon monolayer parcel, ethyl orthosilicate, band is (0.04-0.06): (0.1-0.2): (0.01-0.05).
In above-mentioned preparation method, have employed sol-gel chemistries reaction, the polyreaction of free radical initiation and the polycondensation reaction of ammonia-catalyzed respectively.Will from synthetic method, sol-gel chemistries reaction is that the solution of six cyanogen network ferrum acids and zinc salt is reacted, form Prussian blue analogue nano-particle, then the siloxanyl monomers containing double bond and initiator is added, add thermal-initiated polymerization, form organic silicon single-layer in nanoparticle surface, then add other siloxanes and ammonia, under room temperature, hydrolysis forms silicon dioxide layer.The reaction condition of whole synthesis is very gentle, close to room temperature, and does not produce poisonous and hazardous side-product.
In above-mentioned preparation method, the thickness of silicon dioxide layer can be regulated by the concentration of control raw material, response time, and reaction is at room temperature carried out, and without other poisonous and harmful by-products, energy-conserving and environment-protective, operation is simple.
In above-mentioned preparation method, described six cyanogen network ferrum acids can comprise the one in potassium ferrocyanide, the potassium ferricyanide, sodium ferrocyanide, sodium ferricyanide, ferrous ammonium cyanide and ammonium-cu hexacyanoferrate etc.
In above-mentioned preparation method, described organic acid can comprise the one in citric acid, tartaric acid, malic acid, succinic acid and diethyl pentetic acid etc.
In above-mentioned preparation method, described solvent can comprise the one in water, ethanol and ethylene glycol etc.
In above-mentioned preparation method, described zinc salt can be zinc methacrylate.Zinc and ferrum are all micro elements needed by human, and two kinds of elements are absorbed with the pay-as-you-go operation mutually restricted in vivo, without other heavy metals, have increased substantially biocompatibility.
In above-mentioned preparation method, the described siloxanyl monomers with double bond can comprise the one in VTES, vinyltrimethoxy silane, allyltriethoxysilane and allyltrimethoxysilanis etc.
In above-mentioned preparation method, described initiator can comprise the one in azodiisobutyronitrile, azo-bis-iso-dimethyl and 2,2'-Azobis(2,4-dimethylvaleronitrile) etc.
In above-mentioned preparation method, described one or more the combination that can comprise with siloxanes that is amino or mercapto functional group in 3-aminopropyl triethoxysilane, 3-aminopropyl trimethoxysilane, (3-mercaptopropyi) triethoxysilane and (3-mercaptopropyi) trimethoxy silane etc.Nano grain surface has amino or sulfydryl, can provide very favorable condition for further finishing and antibody grafting.
Present invention also offers a kind of Prussian blue analogue nano-particle of the Silica-coated utilizing above-mentioned preparation method to prepare.The kernel of the Prussian blue analogue nano-particle of the Silica-coated that preparation method of the present invention obtains is Prussian blue analogue nano-particle, shell is silicon dioxide layer, kernel is connected by silica covalent bond with shell, and surface, with hydrophilic group, can be cross-linked with biomolecule.The absorbing wavelength of this nano-particle is between 700-730 nanometer, and photo and thermal stability is better, and can at water, stable existence in phosphate buffer and cell culture medium.
Present invention also offers the Prussian blue analogue nano-particle of above-mentioned Silica-coated as magnetic resonance and the application clinically of the difunctional image-forming contrast medium of optoacoustic.The inner nuclear layer of the Prussian blue analogue nano-particle of the Silica-coated that preparation method of the present invention obtains is Prussian blue analogue nano-particle; it can produce magnetic resonance signal and photoacoustic signal; skin is silicon dioxide layer; outer covalently cross-linked by silica with inner nuclear layer; effective protection Prussian blue analogue nano-particle is not destroyed, and has surface amino groups, the hydrophilic functional groups such as sulfydryl; add water solublity and the biocompatibility of nano-particle, can further grafting or modification be carried out.The ultraviolet and visible absorption peak of this nano-particle drops between 700 nanometers to 730 nanometers, and inner nuclear layer and outer shell are connected by silica covalent bond, highly stable in physiological conditions, improves biocompatibility and reduction of contrast signal stability.It is as magnetic resonance and the difunctional image-forming contrast medium of optoacoustic, in conjunction with two kinds of imaging advantages, for medical diagnosis provides effective information more comprehensively.
Beneficial effect of the present invention:
(1) inner nuclear layer of the Prussian blue analogue nano-particle of Silica-coated of the present invention is be connected by silica covalent bond with outer shell, highly stable in physiological conditions, improves the stability of biocompatibility and reduction of contrast signal;
(2) surface of the Prussian blue analogue nano-particle of Silica-coated of the present invention is with functional groups such as amino or sulfydryls, can modify further or antibody grafting;
(3) thickness of the silicon dioxide layer of the Prussian blue analogue nano-particle of Silica-coated of the present invention can be regulated by the concentration of control raw material, response time, reaction is at room temperature carried out, without other poisonous and harmful by-products, energy-conserving and environment-protective, operation is simple;
(4) inner nuclear layer of the Prussian blue analogue nano-particle of Silica-coated of the present invention is Prussian blue analogue nano-particle, and it can as light absorption material, and efficiency of light absorption is high, and photo and thermal stability is good;
(5) in the Prussian blue analogue nano-particle of Silica-coated of the present invention, zinc and ferrum are all micro elements needed by human, and two kinds of elements are absorbed with the pay-as-you-go operation mutually restricted in vivo, without other heavy metals, have increased substantially biocompatibility.
Accompanying drawing explanation
Fig. 1 is the UV-vis absorption spectrum figure of the Prussian blue analogue nano-particle of Silica-coated;
Fig. 2 is the photoacoustic signal figure of the Prussian blue analogue nano-particle of Silica-coated.
Detailed description of the invention
In order to there be understanding clearly to technical characteristic of the present invention, object and beneficial effect, existing following detailed description is carried out to technical scheme of the present invention, but can not be interpreted as to of the present invention can the restriction of practical range.
Embodiment 1
Present embodiments provide a kind of preparation method of Prussian blue analogue nano-particle of Silica-coated, comprise the following steps:
Step one: prepare Prussian blue analogue nano-particle
(1) potassium ferricyanide, citric acid are dissolved in ethanol, after mixing and stirring, are mixed with solution A, wherein contain potassium ferricyanide 0.006g, citric acid 0.012g in every milliliter of solution A;
(2) zinc methacrylate is dissolved in solvent, after mixing and stirring, is mixed with B solution, wherein contain zinc methacrylate 0.018g in every milliliter of B solution;
(3) by even for B solution magnetic agitation, be heated to 80 DEG C and the 1h that refluxes, and then dropwise add solution A, reaction temperature is regulated to be 20 DEG C, magnetic agitation reaction 4h, centrifugalize, obtains Prussian blue analogue nano-particle C, be dissolved in dissolving completely in ethanol, thus obtained the solution of Prussian blue analogue nano-particle C; Wherein, the volume ratio of solution A and B solution is 1:1;
Step 2: the Prussian blue analogue nano-particle preparing organosilicon monolayer parcel
VTES and 2,2'-Azobis(2,4-dimethylvaleronitrile) are joined in the solution of the Prussian blue analogue nano-particle C obtained in step one, be heated to 70 DEG C, magnetic agitation reaction 60min, cool to room temperature, centrifugalize is purified, obtaining the Prussian blue analogue nano-particle D of organosilicon monolayer parcel, being dissolved in dissolving completely in ethanol, thus obtain the solution of the Prussian blue analogue nano-particle D of organosilicon monolayer parcel; Wherein, the mass ratio of Prussian blue analogue nano-particle C, VTES, 2,2'-Azobis(2,4-dimethylvaleronitrile) is 0.1:0.45:0.05;
Step 3: the Prussian blue analogue nano-particle preparing Silica-coated
In the solution of the Prussian blue analogue nano-particle D of the organosilicon monolayer parcel obtained in step 2, add ethyl orthosilicate, and to add ammonia adjust ph be 7-8, add 3-aminopropyl triethoxysilane again, stirred at ambient temperature 12h, separating-purifying, thus the Prussian blue analogue nano-particle obtaining Silica-coated; Wherein, organosilicon monolayer parcel Prussian blue analogue nano-particle D, ethyl orthosilicate, 3-aminopropyl triethoxysilane mass ratio be 0.05:0.1:0.02.
Embodiment 2
Present embodiments provide a kind of preparation method of Prussian blue analogue nano-particle of Silica-coated, comprise the following steps:
Step one: prepare Prussian blue analogue nano-particle
(1) ferrous potassium cyanate, tartaric acid is soluble in water, after mixing and stirring, be mixed with solution A, wherein in every milliliter of solution A containing ferrous potassium cyanate 0.008g, tartaric acid 0.016g;
(2) zinc methacrylate is soluble in water, after mixing and stirring, be mixed with B solution, wherein contain zinc methacrylate 0.02g in every milliliter of B solution;
(3) by even for B solution magnetic agitation, be heated to 70 DEG C and the 2h that refluxes, and then dropwise add solution A, reaction temperature is regulated to be 50 DEG C, magnetic agitation reaction 2h, centrifugalize, obtains Prussian blue analogue nano-particle C, be dissolved in dissolving completely in ethanol, thus obtained the solution of Prussian blue analogue nano-particle C; Wherein, the volume ratio of solution A and B solution is 1:2;
Step 2: the Prussian blue analogue nano-particle preparing organosilicon monolayer parcel
Vinyltrimethoxy silane and azo-bis-iso-dimethyl are joined in the solution of the Prussian blue analogue nano-particle C obtained in step one, be heated to 60 DEG C, magnetic agitation reaction 60min, cool to room temperature, centrifugalize is purified, obtaining the Prussian blue analogue nano-particle D of organosilicon monolayer parcel, being dissolved in dissolving completely in ethanol, thus obtain the solution of the Prussian blue analogue nano-particle D of organosilicon monolayer parcel; Wherein, the mass ratio of Prussian blue analogue nano-particle C, vinyltrimethoxy silane, azo-bis-iso-dimethyl is 0.1:0.221:0.032;
Step 3: the Prussian blue analogue nano-particle preparing Silica-coated
In the solution of the Prussian blue analogue nano-particle D of the organosilicon monolayer parcel obtained in step 2, add ethyl orthosilicate, and to add ammonia adjust ph be 7-8, add (3-mercaptopropyi) triethoxysilane again, stirred at ambient temperature 24h, separating-purifying, thus the Prussian blue analogue nano-particle obtaining Silica-coated; Wherein, organosilicon monolayer parcel Prussian blue analogue nano-particle D, ethyl orthosilicate, (3-mercaptopropyi) triethoxysilane mass ratio be 0.04:0.1:0.01.
Embodiment 3
Present embodiments provide a kind of preparation method of Prussian blue analogue nano-particle of Silica-coated, comprise the following steps:
Step one: prepare Prussian blue analogue nano-particle
(1) sodium ferricyanide, malic acid are dissolved in ethylene glycol, after mixing and stirring, are mixed with solution A, wherein contain sodium ferricyanide 0.008g, malic acid 0.02g in every milliliter of solution A;
(2) zinc methacrylate is dissolved in ethylene glycol, after mixing and stirring, is mixed with B solution, wherein contain zinc methacrylate 0.02g in every milliliter of B solution;
(3) by even for B solution magnetic agitation, be heated to 90 DEG C and the 1h that refluxes, and then dropwise add solution A, reaction temperature is regulated to be 100 DEG C, magnetic agitation reaction 4h, centrifugalize, obtains Prussian blue analogue nano-particle C, be dissolved in dissolving completely in ethanol, thus obtained the solution of Prussian blue analogue nano-particle C; Wherein, the volume ratio of solution A and B solution is 1:0.5;
Step 2: the Prussian blue analogue nano-particle preparing organosilicon monolayer parcel
Allyltriethoxysilane and 2,2'-Azobis(2,4-dimethylvaleronitrile) are joined in the solution of the Prussian blue analogue nano-particle C obtained in step one, be heated to 80 DEG C, magnetic agitation reaction 20min, cool to room temperature, centrifugalize is purified, obtaining the Prussian blue analogue nano-particle D of organosilicon monolayer parcel, being dissolved in dissolving completely in ethanol, thus obtain the solution of the Prussian blue analogue nano-particle D of organosilicon monolayer parcel; Wherein, the mass ratio of Prussian blue analogue nano-particle C, allyltriethoxysilane, 2,2'-Azobis(2,4-dimethylvaleronitrile) is 0.08:0.221:0.032;
Step 3: the Prussian blue analogue nano-particle preparing Silica-coated
In the solution of the Prussian blue analogue nano-particle D of the organosilicon monolayer parcel obtained in step 2, add ethyl orthosilicate, and to add ammonia adjust ph be 7-8, add 3-aminopropyl triethoxysilane again, stirred at ambient temperature 24h, separating-purifying, thus the prussian blue nano granule obtaining Silica-coated; Wherein, organosilicon monolayer parcel Prussian blue analogue nano-particle D, ethyl orthosilicate, 3-aminopropyl triethoxysilane mass ratio be 0.05:0.1:0.02.
Embodiment 4
Present embodiments provide a kind of preparation method of Prussian blue analogue nano-particle of Silica-coated, comprise the following steps:
Step one: prepare Prussian blue analogue nano-particle
(1) sodium ferrocyanide, succinic acid are dissolved in ethanol, after mixing and stirring, are mixed with solution A, wherein contain sodium ferrocyanide 0.02g, succinic acid 0.04g in every milliliter of solution A;
(2) zinc methacrylate is dissolved in ethanol, after mixing and stirring, is mixed with B solution, wherein contain zinc methacrylate 0.04g in every milliliter of B solution;
(3) by even for B solution magnetic agitation, be heated to 100 DEG C and the 1h that refluxes, and then dropwise add solution A, reaction temperature is regulated to be 60 DEG C, magnetic agitation reaction 3h, centrifugalize, obtains Prussian blue analogue nano-particle C, be dissolved in dissolving completely in ethanol, thus obtained the solution of Prussian blue analogue nano-particle C; Wherein, the volume ratio of solution A and B solution is 1:3;
Step 2: the Prussian blue analogue nano-particle preparing organosilicon monolayer parcel
Allyltrimethoxysilanis and azodiisobutyronitrile are joined in the solution of the Prussian blue analogue nano-particle C obtained in step one, be heated to 80 DEG C, magnetic agitation reaction 30min, cool to room temperature, centrifugalize is purified, obtaining the Prussian blue analogue nano-particle D of organosilicon monolayer parcel, being dissolved in dissolving completely in ethanol, thus obtain the solution of the Prussian blue analogue nano-particle D of organosilicon monolayer parcel; Wherein, the mass ratio of Prussian blue analogue nano-particle C, allyltrimethoxysilanis, azodiisobutyronitrile is 0.1:0.663:0.05;
Step 3: the Prussian blue analogue nano-particle preparing Silica-coated
In the solution of the Prussian blue analogue nano-particle D of the organosilicon monolayer parcel obtained in step 2, add ethyl orthosilicate, and to add ammonia adjust ph be 7-8, add (3-mercaptopropyi) triethoxysilane again, stirred at ambient temperature 24h, separating-purifying, thus the Prussian blue analogue nano-particle obtaining Silica-coated; Wherein, organosilicon monolayer parcel Prussian blue analogue nano-particle D, ethyl orthosilicate, (3-mercaptopropyi) triethoxysilane mass ratio be 0.04:0.1:0.01.
Embodiment 5
Present embodiments provide a kind of preparation method of Prussian blue analogue nano-particle of Silica-coated, comprise the following steps:
Step one: prepare Prussian blue analogue nano-particle
(1) ammonium-cu hexacyanoferrate, diethyl pentetic acid are dissolved in ethanol, after mixing and stirring, are mixed with solution A, wherein contain ammonium-cu hexacyanoferrate 0.009g, diethyl pentetic acid 0.04g in every milliliter of solution A;
(2) zinc methacrylate is dissolved in ethanol, after mixing and stirring, is mixed with B solution, wherein contain zinc methacrylate 0.04g in every milliliter of B solution;
(3) by even for B solution magnetic agitation, be heated to 70 DEG C and the 3h that refluxes, and then dropwise add solution A, reaction temperature is regulated to be 100 DEG C, magnetic agitation reaction 4h, centrifugalize, obtains Prussian blue analogue nano-particle C, be dissolved in dissolving completely in ethanol, thus obtained the solution of Prussian blue analogue nano-particle C; Wherein, the volume ratio of solution A and B solution is 1:1;
Step 2: the Prussian blue analogue nano-particle preparing organosilicon monolayer parcel
VTES and 2,2'-Azobis(2,4-dimethylvaleronitrile) are joined in the solution of the Prussian blue analogue nano-particle C obtained in step one, be heated to 80 DEG C, magnetic agitation reaction 20min, cool to room temperature, centrifugalize is purified, obtaining the Prussian blue analogue nano-particle D of organosilicon monolayer parcel, being dissolved in dissolving completely in ethanol, thus obtain the solution of the Prussian blue analogue nano-particle D of organosilicon monolayer parcel; Wherein, the mass ratio of Prussian blue analogue nano-particle C, VTES, 2,2'-Azobis(2,4-dimethylvaleronitrile) is 0.1:0.221:0.032;
Step 3: the Prussian blue analogue nano-particle preparing Silica-coated
In the solution of the Prussian blue analogue nano-particle D of the organosilicon monolayer parcel obtained in step 2, add ethyl orthosilicate, and to add ammonia adjust ph be 7-8, add 3-aminopropyl trimethoxysilane again, stirred at ambient temperature 48h, separating-purifying, thus the Prussian blue analogue nano-particle obtaining Silica-coated; Wherein, organosilicon monolayer parcel Prussian blue analogue nano-particle D, ethyl orthosilicate, 3-aminopropyl trimethoxysilane mass ratio be 0.06:0.2:0.05.
Embodiment 6
Present embodiments provide a kind of preparation method of Prussian blue analogue nano-particle of Silica-coated, comprise the following steps:
Step one: prepare Prussian blue analogue nano-particle
(1) ferrous ammonium cyanide, citric acid is soluble in water, after mixing and stirring, be mixed with solution A, wherein in every milliliter of solution A containing ferrous ammonium cyanide 0.01g, citric acid 0.04g;
(2) zinc methacrylate is soluble in water, after mixing and stirring, be mixed with B solution, wherein contain zinc methacrylate 0.04g in every milliliter of B solution;
(3) by even for B solution magnetic agitation, be heated to 80 DEG C and the 1h that refluxes, and then dropwise add solution A, reaction temperature is regulated to be 100 DEG C, magnetic agitation reaction 4h, centrifugalize, obtains Prussian blue analogue nano-particle C, be dissolved in dissolving completely in ethanol, thus obtained the solution of Prussian blue analogue nano-particle C; Wherein, the volume ratio of solution A and B solution is 1:2;
Step 2: the Prussian blue analogue nano-particle preparing organosilicon monolayer parcel
VTES and 2,2'-Azobis(2,4-dimethylvaleronitrile) are joined in the solution of the prussian blue nano granule C with surface double-bond obtained in step one, be heated to 80 DEG C, magnetic agitation reaction 20min, cool to room temperature, centrifugalize is purified, obtaining the Prussian blue analogue nano-particle D of organosilicon monolayer parcel, being dissolved in dissolving completely in ethanol, thus obtain the solution of the Prussian blue analogue nano-particle D of organosilicon monolayer parcel; Wherein, the mass ratio of Prussian blue analogue nano-particle C, VTES, 2,2'-Azobis(2,4-dimethylvaleronitrile) is 0.09:0.54:0.05;
Step 3: the Prussian blue analogue nano-particle preparing Silica-coated
In the solution of the Prussian blue analogue nano-particle D of the organosilicon monolayer parcel obtained in step 2, add ethyl orthosilicate, and to add ammonia adjust ph be 7-8, add (3-mercaptopropyi) trimethoxy silane again, stirred at ambient temperature 48h, separating-purifying, thus the Prussian blue analogue nano-particle obtaining Silica-coated; Wherein, organosilicon monolayer parcel Prussian blue analogue nano-particle D, ethyl orthosilicate, (3-mercaptopropyi) trimethoxy silane mass ratio be 0.05:0.15:0.02.
The Prussian blue analogue nano-particle uv absorption spectra experiment of embodiment 7 Silica-coated
The Prussian blue analogue nano-particle of Silica-coated embodiment 1 prepared carries out uv absorption spectra experiment.The ultra-violet absorption spectrum of the Prussian blue analogue nano-particle of Silica-coated is measured in the interscan of ultraviolet spectra 500-900nm wave-length coverage.Experimental result as shown in Figure 1.
Experimental result shows: the Prussian blue analogue absworption peak red shift of the Silica-coated of gained of the present invention is to about 710-730nm, can make absorption away from the absorption bands scope of biological tissue, wavelength is longer, penetration depth in biological tissue is darker, thus it is higher to obtain signal to noise ratio, deeper photoacoustic signal.
The Prussian blue analogue nano-particle photoacoustic signal experiment of embodiment 8 Silica-coated
A, the Prussian blue analogue nano-particle of Silica-coated embodiment 1 synthesized get 1mg, soluble in water, are mixed with A1, A2, A3, A4 solution that Concentraton gradient is respectively 0.5mg/mL, 0.25mg/mL, 0.125mg/mL, 0.0625mg/mL;
The preparation of b, 2% agarose solution: get 2g agarose and add heating for dissolving in 98g water, preparation obtains the agarose solution that concentration is 2%;
C, A1, A2, A3, A4 solution respectively with 200 μ L concentration of getting 200 μ L are the agarose solution mixing of 2%, in successively in imitative mould four holes of instillation, and cooling curing;
D, the imitative body prepared is placed in photoacoustic imaging system carries out signals collecting, adjusting wavelength is 720nm, and light energy is 0.8mJ, tests its photoacoustic signal, and result as shown in Figure 2.
Experimental result shows: the photoacoustic signal of the Prussian blue analogue nano-particle of Silica-coated of the present invention strengthens clearly, and efficiency of light absorption is higher, and stability is better.
In sum, inner nuclear layer and the outer shell of the Prussian blue analogue nano-particle of Silica-coated provided by the invention are connected by silica covalent bond, highly stable in physiological conditions, improves the stability of biocompatibility and reduction of contrast signal; This nano grain surface, with functional groups such as amino or sulfydryls, can be modified or antibody grafting further; The thickness of this nano particle silica layer can be regulated by the concentration of control raw material, response time, and reaction is at room temperature carried out, without other poisonous and harmful by-products, and energy-conserving and environment-protective, operation is simple; This nano-particle inner nuclear layer is Prussian blue analogue nano-particle, and it can as light absorption material, and efficiency of light absorption is high, good light stability; In this nano-particle, zinc and ferrum are all micro elements needed by human, and two kinds of elements are absorbed with the pay-as-you-go operation mutually restricted in vivo, without other heavy metals, have increased substantially biocompatibility.
Claims (10)
1. a preparation method for the Prussian blue analogue nano-particle of Silica-coated, is characterized in that, comprise the following steps:
Step one: prepare Prussian blue analogue nano-particle
(1) six cyanogen network ferrum acids, organic acid are dissolved in solvent, after mixing and stirring, are mixed with solution A, wherein contain six cyanogen network ferrum acid 0.002-0.02g, organic acid 0.002-0.04g in every milliliter of solution A;
(2) zinc salt is dissolved in solvent, after mixing and stirring, is mixed with B solution, wherein contain zinc salt 0.002-0.04g in every milliliter of B solution;
(3) by even for B solution magnetic agitation, be heated to 70-100 DEG C and the 0.5-3h that refluxes, and then dropwise add solution A, adjustment reaction temperature is 20-100 DEG C, magnetic agitation reaction 0.5-4h, centrifugalize, obtains Prussian blue analogue nano-particle C, be dissolved in dissolving completely in ethanol, thus obtained the solution of Prussian blue analogue nano-particle C; Wherein, the volume ratio of solution A and B solution is 1:0.5-1:3;
Step 2: the Prussian blue analogue nano-particle preparing organosilicon monolayer parcel
To join in the solution of the Prussian blue analogue nano-particle C obtained in step one with the siloxanyl monomers of double bond and initiator, be heated to 60-80 DEG C, magnetic agitation reaction 20-60min, cool to room temperature, centrifugalize is purified, obtaining the Prussian blue analogue nano-particle D of organosilicon monolayer parcel, being dissolved in dissolving completely in ethanol, thus obtain the solution of the Prussian blue analogue nano-particle D of organosilicon monolayer parcel; Wherein, Prussian blue analogue nano-particle C, be (0.08-0.1) with the siloxanyl monomers of double bond, the mass ratio of initiator: (0.221-0.663): (0.032-0.05);
Step 3: the Prussian blue analogue nano-particle preparing Silica-coated
In the solution of the Prussian blue analogue nano-particle D of the organosilicon monolayer parcel obtained in step 2, add ethyl orthosilicate, and to add ammonia adjust ph be 7-8, add the siloxanes with amino or mercapto functional group again, stirred at ambient temperature, separating-purifying, thus the Prussian blue analogue nano-particle obtaining Silica-coated; Wherein, the mass ratio of the siloxanes of the amino or mercapto functional group of the Prussian blue analogue nano-particle D of organosilicon monolayer parcel, ethyl orthosilicate, band is (0.04-0.06): (0.1-0.2): (0.01-0.05).
2. preparation method according to claim 1, is characterized in that, described six cyanogen network ferrum acids comprise the one in potassium ferrocyanide, the potassium ferricyanide, sodium ferrocyanide, sodium ferricyanide, ferrous ammonium cyanide and ammonium-cu hexacyanoferrate.
3. preparation method according to claim 1, is characterized in that, described organic acid comprises the one in citric acid, tartaric acid, malic acid, succinic acid and diethyl pentetic acid.
4. preparation method according to claim 1, is characterized in that, described solvent comprises the one in water, ethanol and ethylene glycol.
5. preparation method according to claim 1, is characterized in that, described zinc salt is zinc methacrylate.
6. preparation method according to claim 1, is characterized in that, the described siloxanyl monomers with double bond comprises the one in VTES, vinyltrimethoxy silane, allyltriethoxysilane and allyltrimethoxysilanis.
7. preparation method according to claim 1, is characterized in that, described initiator comprises the one in azodiisobutyronitrile, azo-bis-iso-dimethyl and 2,2'-Azobis(2,4-dimethylvaleronitrile).
8. preparation method according to claim 1, it is characterized in that, described one or more the combination comprised with siloxanes that is amino or mercapto functional group in 3-aminopropyl triethoxysilane, 3-aminopropyl trimethoxysilane, (3-mercaptopropyi) triethoxysilane and (3-mercaptopropyi) trimethoxy silane.
9. the Prussian blue analogue nano-particle of Silica-coated prepared by the preparation method described in a claim 1-8 any one.
10. the Prussian blue analogue nano-particle of Silica-coated according to claim 9 is as magnetic resonance and the application clinically of the difunctional image-forming contrast medium of optoacoustic.
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| CN108836949A (en) * | 2018-07-23 | 2018-11-20 | 西南大学 | The preparation method of Ce6 embedded type erythrocyte membrane package prussian blue nano particle |
| CN109171660A (en) * | 2018-10-09 | 2019-01-11 | 深圳先进技术研究院 | Photoacoustic imaging probe and application |
| CN108598412B (en) * | 2018-04-23 | 2020-06-16 | 中南大学 | Silicon alloy composite negative electrode material based on metal organic matter and preparation method thereof |
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| CN108598412B (en) * | 2018-04-23 | 2020-06-16 | 中南大学 | Silicon alloy composite negative electrode material based on metal organic matter and preparation method thereof |
| CN108836949A (en) * | 2018-07-23 | 2018-11-20 | 西南大学 | The preparation method of Ce6 embedded type erythrocyte membrane package prussian blue nano particle |
| CN108836949B (en) * | 2018-07-23 | 2020-07-24 | 西南大学 | Preparation method of Prussian blue nano-particles wrapped by Ce6 embedded red cell membranes |
| CN109171660A (en) * | 2018-10-09 | 2019-01-11 | 深圳先进技术研究院 | Photoacoustic imaging probe and application |
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