CN109364247A - A kind of protein@Cu2-xO composite nanoparticle and its preparation method and application - Google Patents
A kind of protein@Cu2-xO composite nanoparticle and its preparation method and application Download PDFInfo
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- 239000002105 nanoparticle Substances 0.000 title claims abstract description 67
- 102000004169 proteins and genes Human genes 0.000 title claims abstract description 61
- 108090000623 proteins and genes Proteins 0.000 title claims abstract description 61
- 239000002131 composite material Substances 0.000 title claims abstract description 59
- 229910018271 Cu2-xO Inorganic materials 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims description 23
- 229960003067 cystine Drugs 0.000 claims abstract description 21
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 18
- 238000003384 imaging method Methods 0.000 claims abstract description 12
- 238000007626 photothermal therapy Methods 0.000 claims abstract description 9
- 239000010949 copper Substances 0.000 claims description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 18
- 238000010521 absorption reaction Methods 0.000 claims description 15
- 238000005119 centrifugation Methods 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 102000016943 Muramidase Human genes 0.000 claims description 7
- 108010014251 Muramidase Proteins 0.000 claims description 7
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 claims description 7
- 102000004142 Trypsin Human genes 0.000 claims description 7
- 108090000631 Trypsin Proteins 0.000 claims description 7
- 229960000274 lysozyme Drugs 0.000 claims description 7
- 235000010335 lysozyme Nutrition 0.000 claims description 7
- 239000004325 lysozyme Substances 0.000 claims description 7
- 239000012588 trypsin Substances 0.000 claims description 7
- 229910052802 copper Inorganic materials 0.000 claims description 5
- 230000003595 spectral effect Effects 0.000 claims description 5
- 238000000502 dialysis Methods 0.000 claims description 4
- 150000001879 copper Chemical class 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims description 3
- 239000012266 salt solution Substances 0.000 claims description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 2
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 14
- 239000011149 active material Substances 0.000 abstract description 11
- XOCUXOWLYLLJLV-UHFFFAOYSA-N [O].[S] Chemical compound [O].[S] XOCUXOWLYLLJLV-UHFFFAOYSA-N 0.000 abstract description 10
- 229910052751 metal Inorganic materials 0.000 abstract description 8
- 239000002184 metal Substances 0.000 abstract description 8
- 238000010189 synthetic method Methods 0.000 abstract description 4
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 abstract 2
- 229940098773 bovine serum albumin Drugs 0.000 description 72
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 71
- 238000003786 synthesis reaction Methods 0.000 description 14
- 239000000463 material Substances 0.000 description 12
- 239000000126 substance Substances 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 238000003745 diagnosis Methods 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 238000004998 X ray absorption near edge structure spectroscopy Methods 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000002173 high-resolution transmission electron microscopy Methods 0.000 description 4
- 239000002159 nanocrystal Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000001392 ultraviolet--visible--near infrared spectroscopy Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000004075 alteration Effects 0.000 description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000002253 near-edge X-ray absorption fine structure spectrum Methods 0.000 description 3
- 229910000510 noble metal Inorganic materials 0.000 description 3
- 239000011368 organic material Substances 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 241000209094 Oryza Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 239000000956 alloy Substances 0.000 description 2
- 229910045601 alloy Inorganic materials 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002591 computed tomography Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000011258 core-shell material Substances 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
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- 235000013399 edible fruits Nutrition 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
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- 239000000203 mixture Substances 0.000 description 2
- 239000002086 nanomaterial Substances 0.000 description 2
- 229920000620 organic polymer Polymers 0.000 description 2
- 230000000149 penetrating effect Effects 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 239000010970 precious metal Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 239000004065 semiconductor Substances 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 238000004061 bleaching Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
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- 238000010894 electron beam technology Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011174 green composite Substances 0.000 description 1
- 238000001027 hydrothermal synthesis Methods 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002082 metal nanoparticle Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 239000002057 nanoflower Substances 0.000 description 1
- 239000002064 nanoplatelet Substances 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
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- 238000002560 therapeutic procedure Methods 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 238000000584 ultraviolet--visible--near infrared spectrum Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Physics & Mathematics (AREA)
- Acoustics & Sound (AREA)
- Radiology & Medical Imaging (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to composite nanoparticles, disclose a kind of protein@Cu2‑xO composite nanoparticle, the composed structure of the composite nanoparticle are R-S-Cu2‑xO, wherein the protein group of cystine linkage post-rift formation of the R-S- in the protein containing cystine linkage；Wherein, 0 < X < 1.The present invention overcomes thinks Cu in the prior art2‑xO is not suitable as the prejudice of metal oxygen sulfur family near-infrared active material, and provides a kind of protein@Cu2‑xO composite nanoparticle, which has surface plasma body resonant vibration property, and wavelength is located at biological second window, and tissue resorption is smaller, therefore the low potential quality having applied to photoacoustic imaging and photo-thermal therapy of background signal.And the synthetic method step is simple, reaction condition is mild, and reaction system is simple, it is easy to accomplish.
Description
Technical field
The present invention relates to composite nanoparticles, and in particular, to a kind of protein@Cu2-xO composite nanoparticle and its system
Preparation Method and application.
Background technique
Photoacoustic imaging and the photo-thermal therapy four class photo-thermal diagnosis reagents of main development in previous research: noble metal is closely red
Outer active material, organic polymer near-infrared active material, carbon-based near-infrared active material, semiconductor alloy oxygen sulfur family near-infrared
Active material.But previous material has following characteristics:
Precious metal nano material in the first: it is being very easy to that the change on pattern occurs after laser irradiates repeatedly
Change, so as to cause absorbing wavelength change, and then the light thermal property of material is caused to reduce.And from previous research it can be found that
The optical absorption of precious metal nano material is limited only to biological first window, it is difficult to carry out being located at the deeper of biological second window
((650-950nm wave band is referred to as the first window of biology, near-infrared at the short-wave band of near-infrared for the tumour diagnosis and treatment research of level
(1000-1350nm wave band is referred to as the second window of biology, and the wavelength of in general incident laser is longer, tissue at long wave
Penetration capacity is stronger, is more accessible at tumour, and during penetrating have to biological tissue injure it is smaller, energy attenuation compared with
The features such as few).And though the tumour diagnosis and treatment efficiency of noble metal near-infrared active material is good, manufacturing price valuableness application cost compared with
Height limits its application in clinical medicine.And noble metal nano particles do not allow in vivo it is degradable, it is difficult to body is discharged
Outside, bio-toxicity is larger, this disadvantage equally makes such material be difficult to make further progress.Organic polymer is closely red in second
Outer active material: anti-light bleaching power is poor, easily decomposes after illumination, it is difficult to meet the needs of long-term diagnosis and treatment in clinical medicine.The
In three kinds carbon-based class optical-thermal conversion material there are poorly water-soluble need Hydrophilic modification, the absorption coefficient of light are low, preparation process is complicated,
The defects of preparation condition is harsh.
And semiconductor alloy oxygen sulfur family near-infrared active material has preferable photothermal conversion efficiency and material in the 4th kind
Photo and thermal stability it is also preferable, some metal oxygen sulfur family near-infrared active materials not only photothermal conversion it is functional and have other
Multiple functions, such as photoacoustic imaging, CT scan (CT) and preferable magnetic；There are also some metal oxygen sulphur
Active oxygen can be generated in laser irradiation lower surface in race's near-infrared active material, therefore can be realized optical dynamic therapy and photo-thermal is controlled
The dual treatment of cancer treated.In the prior art, material type that can be for selection is more, such as titanium, tungsten, iron, molybdenum etc..Because having
Surface plasma body resonant vibration property is that have the basis of the potential quality of photo-thermal diagnosis, and copper is not because under study for action because being found Cu2- xO has surface plasmon absorption at near-infrared and is considered being not suitable as metal oxygen sulfur family near-infrared activity material
Material.
Summary of the invention
The object of the present invention is to provide a kind of protein@Cu2-xO composite nanoparticle and its preparation method and application, this hair
It is bright overcome think Cu in the prior art2-xO is not suitable as the prejudice of metal oxygen sulfur family near-infrared active material, and provides one kind
Protein@Cu2-xO composite nanoparticle, protein@Cu2-xO composite nanoparticle can be avoided background signal interference, and should
Synthetic method and synthesis step are simple, and reaction condition is mild, do not need the harsh preparation condition such as high temperature and pressure, and in water phase
Middle completion, reaction system are simple, it is easy to accomplish.Moreover, protein@Cu provided by the invention2-xO composite nanoparticle tool
There is surface plasma body resonant vibration property, therefore there is the potential quality applied to photoacoustic imaging and photo-thermal diagnosis.
To achieve the goals above, the present invention provides a kind of protein@Cu2-xO composite nanoparticle, it is described compound to receive
The composed structure of rice corpuscles is R-S-Cu2-xO, wherein after cystine linkage fracture of the R-S- in the protein containing cystine linkage
Formation protein group；Wherein, 0 < X < 1.
The present invention also provides a kind of preparation method of previously described composite nanoparticle, the preparation method includes following
Step: the solution of the protein containing cystine linkage is mixed with copper salt solution, be added sodium hydroxide adjust mixed liquor pH to
11.3-13 obtains composite nanoparticle mixed liquor then in 50-60 DEG C of standing 6-12h.
Moreover, the present invention also provides a kind of previously described composite nanoparticles in photoacoustic imaging and photo-thermal therapy
Application.
Through the above technical solutions, the present invention overcomes thinks Cu in the prior art2-xIt is close that O is not suitable as metal oxygen sulfur family
The prejudice of infrared active organic material, and a kind of protein@Cu is provided2-xO composite nanoparticle, protein@Cu2-xO composite Nano
Particle can be avoided background signal interference, and the synthetic method and synthesis step are simple, and reaction condition is mild, does not need high temperature height
The harsh preparation conditions such as pressure, and completed in water phase, reaction system is simple, it is easy to accomplish.Moreover, the present invention provides
Protein@Cu2-xO composite nanoparticle has surface plasma body resonant vibration property, and wavelength is located at biological second window, group
Knit absorb it is smaller, therefore background signal it is low have applied to photoacoustic imaging and photo-thermal therapy potential quality.
Other features and advantages of the present invention will the following detailed description will be given in the detailed implementation section.
Detailed description of the invention
The drawings are intended to provide a further understanding of the invention, and constitutes part of specification, with following tool
Body embodiment is used to explain the present invention together, but is not construed as limiting the invention.In the accompanying drawings:
Fig. 1 is BSA@Cu in embodiment 12-xThe detection figure of O NPs: A is BSA@Cu2-xThe TEM of O NPs schemes；B is BSA@
Cu2-xThe HRTEM of O NPs schemes；C is the BSA@Cu of spherical aberration instrument shooting2-xThe shape appearance figure of O NPs；D is BSA@Cu2-xThe electricity of O NPs
Sub- diffraction pattern；E is BSA@Cu2-xThe XRD spectra of O NPs；F is BSA@Cu2-xThe UV-Vis-NIR of O NPs absorbs spectrogram.
Fig. 2 is that the product in product and comparative example 1 in embodiment 1 carries out XPS test chart: A is BSA@in embodiment 1
Cu2-xThe Cu element peak of O NPs；B is BSA@Cu in embodiment 12-xThe peak XPS of the S of O NPs；C is to synthesize in comparative example 1
Cu2-xThe Cu element peak of S NPs；D is the Cu synthesized in comparative example 12-xThe peak of the S element of S NPs.
Fig. 3 is BSA@Cu in embodiment 12-xO NPs structure of matter spectrogram: A is x ray absorption near edge structure (XANES)
Spectrogram；B is Extended X-ray Absorption Fine Structure (EXAFS) spectrogram of Cu.
Fig. 4 is in embodiment 1 to BSA@Cu2-xO NPs has the verifying of surface plasma volume property in the absorption of near-infrared
Figure: B is BSA@Cu2-xWith the increase of solvent refractive index red shift figure occurs for the absorbing wavelength of O NPs；A is that synchrotron radiation surveys BSA@
Cu2-xCu and S the key combination figure of O NPs.
Fig. 5 is protein@Cu in embodiment 4-62-xThe detection figure of O NPs: A, D corresponds to HSA@Cu2-xO NPs；B, E is corresponding
Trypsin@Cu2-xO NPs；C, F corresponds to Lysozym@Cu2-xO NPs。
Specific embodiment
Detailed description of the preferred embodiments below.It should be understood that described herein specific
Embodiment is merely to illustrate and explain the present invention, and is not intended to restrict the invention.
The endpoint of disclosed range and any value are not limited to the accurate range or value herein, these ranges or
Value should be understood as comprising the value close to these ranges or value.For numberical range, between the endpoint value of each range, respectively
It can be combined with each other between the endpoint value of a range and individual point value, and individually between point value and obtain one or more
New numberical range, these numberical ranges should be considered as specific open herein.
The present invention provides a kind of protein@Cu2-xThe composed structure of O composite nanoparticle, the composite nanoparticle is
R-S-Cu2-xO, wherein the protein base of cystine linkage post-rift formation of the R-S- in the protein containing cystine linkage
Group；Wherein, 0 < X < 1.
Through the above technical solutions, the present invention overcomes thinks Cu in the prior art2-xIt is close that O is not suitable as metal oxygen sulfur family
The prejudice of infrared active organic material, and a kind of protein@Cu is provided2-xO composite nanoparticle, protein@Cu2-xO composite Nano
Particle can be avoided background signal interference.Moreover, protein@Cu provided by the invention2-xO composite nanoparticle has table
Surface plasma resonance property, and wavelength is located at biological second window, tissue resorption is smaller, therefore background signal is low with application
In the potential quality of photoacoustic imaging and photo-thermal therapy.
650-950nm wave band at the short-wave band of near-infrared is referred to as the first window of biology, at near-infrared long wave
1000-1350nm wave band is referred to as the second window of biology.In general the wavelength of incident laser is longer, tissue penetration
It is stronger, it is more accessible at tumour, and there are, energy attenuation less equal spies smaller to biological tissue's injury during penetrating
Point.Further, protein@Cu provided by the invention2-xThe spectral absorption peak of O composite nanoparticle is located at biological second window.
The present invention has done a large amount of characterization, such as UV-Vis-NIR absorbs spectrum analysis, further, in the present invention
Protein@Cu2-xThe spectral absorption peak of O composite nanoparticle is located at 1250-1350nm, further explains its spectral absorption
Peak is in biological second window.This and the Cu reported before2-xThe pattern and optical property of O nanoparticle are entirely different.Wang et al.
With the Cu of the synthesis different-shape of Huang et al. report2O, CuO nanocrystal all has good crystal form and UV absorption light
The protein@Cu that the peak position of spectrum is synthesized with us2-xO NPs (protein@Cu2-xO composite nanoparticle) there is very big difference.
The Cu of conventional method synthesis2O, CuO nanocrystal absorbs peak position generally in 400-700nm.And the protein@in the present invention
Cu2-xO NPs spectrum is in 1250-1350nm.
Further, the protein@Cu in the present invention2-xO composite nanoparticle is the unformed core-shell structure of amorphous,
Rather than monocrystalline or polycrystalline.Documents and materials show that undefined structure is more convenient for degrading, and are applied to be easy degradation row in vivo
Out.
Still further, the protein@Cu in the present invention2-xThe particle size range of O composite nanoparticle is 3-10nm.In this way,
Protein@Cu2-xO composite nanoparticle is more advantageous to photoacoustic imaging and photo-thermal diagnosis.
And for protein@Cu2-xThe structure R-S-Cu of O composite nanoparticle2-xO, wherein can be in wider model for R-S-
Enclose it is interior selected, as long as containing cystine linkage in protein, can form a kind of new composite nanoparticle.Of the invention a kind of
In preferred embodiment, the protein containing cystine linkage be BSA (bovine serum albumin), HAS (human serum albumins),
One of Trypsin (trypsase) and Lysozyme (lysozyme) or a variety of.
The present invention also provides a kind of preparation method of previously described composite nanoparticle, the preparation method includes following
Step: the solution of the protein containing cystine linkage is mixed with copper salt solution, be added sodium hydroxide adjust mixed liquor pH to
11.3-13 obtains composite nanoparticle mixed liquor then in 50-60 DEG C of standing 6-12h.
Through the above technical solutions, the present invention overcomes thinks Cu in the prior art2-xIt is close that O is not suitable as metal oxygen sulfur family
The prejudice of infrared active organic material, and a kind of protein@Cu is provided2-xO composite nanoparticle, protein@Cu2-xO composite Nano
Particle can be avoided background signal interference, and the synthetic method and synthesis step are simple, and reaction condition is mild, does not need high temperature height
The harsh preparation conditions such as pressure, and completed in water phase, reaction system is simple, it is easy to accomplish.Moreover, the present invention provides
Protein@Cu2-xO composite nanoparticle has surface plasma body resonant vibration property, and wavelength is located at biological second window, group
Knit absorb it is smaller, therefore background signal it is low have applied to photoacoustic imaging and photo-thermal therapy potential quality.
And the reagent for adjusting pH, the present invention has also carried out a variety of common sense, for example changes sodium hydroxide into potassium hydroxide
Or other buffer solutions, it is to synthesize similar protein@Cu2-xO composite nanoparticle.As it can be seen that sodium hydroxide is in above-mentioned skill
In art scheme, not only play a part of to adjust pH value.
For the additive amount of the protein containing cystine linkage and mantoquita, can be adjusted in a wider range, in order to
To protein@Cu2-xO composite nanoparticle, and preparation and purification cost is saved, in a kind of preferred embodiment of the present invention,
Relative to, containing the protein of cystine linkage, the dosage of mantoquita is 15-25mmol/L described in 200mg.
And for the mass concentration in the solution of the protein containing cystine linkage, it can be adjusted in a wider range, and
Homogeneous reaction system in order to obtain, and it is conducive to the progress of reaction and the purifying of product, in a kind of preferred embodiment party of the present invention
In formula, the mass concentration in the solution of the protein containing cystine linkage is 30-50mg/mL.
In the above-mentioned technical solutions, the mantoquita can be adjusted in a wider range, as long as water-soluble mantoquita is equal
The present invention can be achieved.In a kind of preferred embodiment of the present invention, in order to be conducive to the progress of reaction, it is preferable that the mantoquita
For one of copper chloride, copper nitrate and copper sulphate or a variety of.
And for the purifying of composite nanoparticle obtained in above-mentioned preparation method can there are many selections.Such as be centrifuged,
Liquid is removed, the product precipitating to be precipitated.Although these means are conventional, the selection of poor solvent but right and wrong
Often difficult.In this regard, we have attempted 10 kinds or more the solvents such as direct centrifugation (aqueous solution), acetone, ethyl alcohol, methanol, it is only different
Propyl alcohol can be by the protein@Cu in the present invention2-xO composite nanoparticle is precipitated out from mixed liquor, and passes through the side of centrifugation
Formula obtains the precipitating of product formation.
For the protein@Cu further purified2-xO composite nanoparticle obtains the heavy of product formation in centrifugation
Behind shallow lake, the invention also includes be dispersed in water above-mentioned precipitating, dialyse in bag filter.
In a kind of preferred embodiment of the present invention, in order to simplify purification step, and yield is improved, it is preferable that described
Preparation method further includes mixing the composite nanoparticle mixed liquor with volume ratio 1:1.5-2.5 with isopropanol, is then carried out
Centrifuge separation；It will be centrifuged product water-dispersible the step of being placed in dialysis 12-36h in bag filter again.
And for the condition of centrifugation, it can be selected in a wider range, in a kind of preferred embodiment of the present invention,
Centrifugal condition includes: that centrifugation rate is 5000-10000rpm；Centrifugation time is 8-15min.
Moreover, the present invention also provides a kind of previously described composite nanoparticles in photoacoustic imaging and photo-thermal therapy
Application.
Protein@Cu provided by the invention2-xO composite nanoparticle has surface plasma body resonant vibration property, and wavelength position
In biological second window, tissue resorption is smaller, therefore the low potential quality having applied to photoacoustic imaging and photo-thermal therapy of background signal.
The present invention will be described in detail by way of examples below.
Embodiment 1
Take BSA (bovine serum albumin(BSA)) aqueous solution and CuCl of 5mL 40mg/mL2(1mL, 20mmol/L) aqueous solution is mixed
It closes, is stirred at room temperature three minutes.Sodium hydroxide (0.5mol/L, 600 μ L) are added later and adjust pH to 12, at this time mixed liquor
Color become from light blue to purple, stir two minutes；Finally the above solution is placed in 55 DEG C of water-baths and stands 9h, at this time
Solution becomes blackish green and obtains composite nanoparticle mixed liquor.It is proved through subsequent characterization, generates BSA@Cu at this time2-xO NPs
(bovine serum albumin(BSA)@Cu2-xO composite nanoparticle)；
BSA@Cu to be synthesized2-xAfter O NPs mixed liquor is cooled to room temperature, with BSA@Cu2-xO NPs mixed liquor and isopropanol
Volume ratio be 1:2 it is miscible, then in 8000rpm centrifugation 10min it is primary.It is water-dispersible to be centrifuged product, it is saturating with bag filter later
Analysis is for 24 hours.It is stand-by (4 DEG C) to place refrigerator.
Embodiment 2
Take the BSA aqueous solution and CuCl of 4mL 50mg/mL2The mixing of (1mL, 15mmol/L) aqueous solution, is stirred at room temperature
Three minutes.Sodium hydroxide (0.5mol/L, 600 μ L) are added later and adjust pH to 11.3, and the color of mixed liquor is from pale blue at this time
Discoloration is to stir two minutes to purple；Finally the above solution is placed in 50 DEG C of water-baths and stands 12h, solution becomes ink at this time
It is green to obtain composite nanoparticle mixed liquor.It is proved through subsequent characterization, generates BSA@Cu at this time2-xO NPs；
BSA@Cu to be synthesized2-xAfter O NPs mixed liquor is cooled to room temperature, with BSA@Cu2-xO NPs mixed liquor and isopropanol
Volume ratio be 1:1.5 it is miscible, then in 5000rpm centrifugation 15min it is primary.It is water-dispersible to be centrifuged product, uses bag filter later
Dialyse 12h.It is stand-by (4 DEG C) to place refrigerator.
Embodiment 3
Take the BSA aqueous solution and CuCl of 6.5mL 30mg/mL2The mixing of (1mL, 25mmol/L) aqueous solution, is stirred at room temperature
It mixes three minutes.Sodium hydroxide is added later and adjusts pH to 13, and the color of mixed liquor becomes from light blue to purple, stirring at this time
Two minutes；Finally the above solution is placed in 60 DEG C of water-baths and stands 6h, solution becomes blackish green composite nanoparticle at this time
Mixed liquor.It is proved through subsequent characterization, generates BSA@Cu at this time2-xO NPs；
BSA@Cu to be synthesized2-xAfter O NPs mixed liquor is cooled to room temperature, with BSA@Cu2-xO NPs mixed liquor and isopropanol
Volume ratio be 1:2.5 it is miscible, then in 10000rpm centrifugation 8min it is primary.It is water-dispersible to be centrifuged product, uses bag filter later
Dialyse 36h.It is stand-by (4 DEG C) to place refrigerator.
Embodiment 4
Protein@Cu is prepared according to the method in embodiment 12-xO NPs is obtained the difference is that BSA is replaced with HAS
HAS@Cu2-xO NPs。
Embodiment 5
Protein@Cu is prepared according to the method in embodiment 12-xO NPs is obtained the difference is that BSA is replaced with Trypsin
To Trypsin@Cu2-xO NPs。
Embodiment 6
Protein@Cu is prepared according to the method in embodiment 12-xO NPs, the difference is that BSA is replaced with into Lysozyme,
Obtain Lysozyme@Cu2-xO NPs。
Comparative example 1
It is prepared according to the method in embodiment 1, unlike, the mixed liquor after adjustment pH is placed in 120 DEG C of water-baths
9h is stood in pot.
Detect example 1
Respectively using TEM, HRTEM, spherical aberration Electronic Speculum, electronic diffraction, XRD, UV-Vis-NIR absorption spectra in embodiment 1
BSA@Cu after dialysis purification2-xO NPs is analyzed, the result is shown in Figure 1, as shown in Figure 1, A is BSA@Cu in Fig. 12-xO NPs's
TEM, as we can see from the figure BSA@Cu2-xThe size of O NPs is 5nm or so, and spherical and size is presented than more uniform.It inserts thereon
Figure is the BSA@Cu2-xO NPs solution of synthesis, is blackish green under daylight and can in high volume synthesize.
B is BSA@Cu in Fig. 12-xThe HRTEM of O NPs schemes, and the lattice of BSA@Cu2-xO NPs is unknown as we can see from the figure
Aobvious, color is deeper among each particle, and more fuzzy state is but presented in edge.In this regard, it is presumed that this may be due to material
Layer side edge coats the organic matter (protein groups) of upper unformed state, therefore has to the expression of the electron beam of transmission electron microscope certain
Interference effect, so that the data of detection are not very clear, presentation light gray.But generally we may determine that, synthesis
BSA@Cu2-xO NPs is core-shell structure (Core-Shell).
In order to more confirm, we have taken BSA@Cu shown in C as shown in figure 1 using spherical aberration instrument2-xThe pattern of O NPs, knot
Identical, BSA@Cu is obtained on fruit and HRTEM2-xO NPs is non crystalline structure.
Pass through BSA@Cu in D in Fig. 12-xO NPs diffraction pattern can be seen that BSA@Cu2-xO NPs is not monocrystalline or more
Crystalline substance, it is a kind of unformed nanoparticle.
And E is the XRD spectra of BSA@Cu2-xO NPs in Fig. 1, it can be seen that without obvious crystal face peak, we equally can be true
The fixed nanoparticle is the undefined structure of amorphous.
It is found by literature reading, undefined structure is more convenient for degrading, and is applied to be easy degradation discharge in vivo.
F is that the UV-Vis-NIR of the substance absorbs spectrogram in Fig. 1, it can be seen that its peak shape is in 1300nm or so.This is therewith
The Cu of preceding report2-xThe pattern and optical property of O NPs is entirely different.Wang et al. and Huang et al. such as Liu Q, Liu H,
Liang Y,et al.Large-scale synthesis of single-crystalline CuO nanoplatelets
by a hydrothermal process[J].Materials Research Bulletin,2006,41(4):697-702；
Wang H,Xu J Z,Zhu J J,et al.Preparation of CuO nanoparticles by microwave
irradiation[J].Journal of Crystal Growth,2002,244(1):88-94.Duan Y,Liu X,Han
L,et al.Optically active chiral CuO“nanoflowers”[J].Journal of the American
Chemical Society, 2014,136 (20): 7193-7196.) that reports synthesizes the Cu of different-shape2O, CuO nanocrystal
All with good crystal form and BSA@Cu that the peak position of ultra-violet absorption spectrum is synthesized with us2-xO NPs has very big difference
Not.The Cu of conventional method synthesis2O, CuO nanocrystal absorbs peak position generally in 400-700nm.And synthesized in this experiment
BSA@Cu2-xO NPs spectrum is in 1300nm.
Through detecting, the testing result of the product in embodiment 2-3 is similar in embodiment 1, and details are not described herein.
Detect example 2
XPS test (X-ray photoelectron spectroscopic analysis) is carried out to the product in the product and comparative example 1 in embodiment 1, knot
Fruit sees Fig. 2.From Figure 2 it can be seen that A is BSA@Cu in embodiment 1 in Fig. 22-xThe Cu element peak of O NPs.According to photoelectric absorption peak position
(electron binding energy) is set it can be seen that peak position is respectively belonging to Cu in 935eV, 932eV2+、Cu+Cu2p3/2Peak, and peak area
Than for 1:2.5.It and is Cu at 938-945eV2+Typical satellites.Cu2p1/2Locate peak position to distinguish in 954.1eV and 952.8eV
Belong to CuO and Cu2The Cu of O2p1/2Peak.
B is BSA@Cu in embodiment 1 in Fig. 22-xThe peak XPS of the S of O NPs.163.3eV is S2p1/2Peak, it is a large amount of by investigating
Document discovery 163.3 is sulfydryl peak (- S-H) or is the peak Cu-S-H.And S does not belong to SO in 169.5eV, 168.3eV4 2-With
SO3 2-Peak, peak S in the BSA is oxidized to form SO in a humid environment4 2-With SO3 2。
C is the Cu synthesized in comparative example 1 in Fig. 22-xThe Cu element peak of S NPs.It can be seen that peak position 935eV,
932eV is respectively belonging to Cu2+、Cu+Cu2p3/2Peak, and peak area ratio is 1:2.3.It is Cu at 938-945eV2+Typically defend
Star peak, peak position belong to Cu in 952.5eV2S, the Cu of CuS2p1/2Peak.
D is the Cu of (120 DEG C) synthesis under 1 high temperature of comparative example in Fig. 22-xThe peak of the S element of S NPs.Position exists
162.5eV, 161.8eV are belonging respectively to CuS, Cu2The peak of S.And from the XPS of S still it can be seen that 163.3eV from peak,
Illustrate still to contain a small amount of BSA@Cu in the substance of high―temperature nuclei2-xO NPs.Same S does not belong in 169.5eV, 168.3eV
SO4 2-With SO3 2Peak.
Detect example 3
The connection type between composition and each element in order to further prove BSA@Cu2-xO NPs, we utilize synchronous spoke
It penetrates and is measured, as a result see Fig. 3, if A is x ray absorption near edge structure (XANES) spectrogram in Fig. 3, be observed that from figure
BSA, CuS and BSA@Cu2-xThe K-edge of S absorbs in O NPs.BSA@Cu2-xIn O NPs the ABSORPTION EDGE of S be located at BSA and CuS it
Between, show BSA@Cu2-xType comprising S in BSA and CuS in O NPs.The XANES spectrum of BSA includes two main peaks, respectively
For 2472.8eV and 2474eV, S -- S and S-R key are respectively corresponded.The XANES spectrum of CuS has a main peaks, is
2473.6eV shows that CuS contains Cu-S key.And BSA@Cu2-xThe XANES spectrum of O NPs is shown containing there are two main peaks, difference
For 2472.8eV and 2473.8eV, show to contain S-S, S-Cu, S-R key in sample.Speculate that our sample is likely to above
The structure of R-S-Cu.
If B is Extended X-ray Absorption Fine Structure (EXAFS) spectrogram of Cu in Fig. 3, wherein including Cu2O, CuO and
The K-edge of BSA@Cu2-xO NPs absorbs.It is located at Cu from can see BSA@Cu2-xO NPs sample peak in Fig. 3 in B2O、CuO
Between, show BSA@Cu2-xO NPs is positively charged, contains+1 ,+divalent, is Cu2The mixture of O and CuO.
Based on above we determined that the composed structure of substance is R-S-Cu2-xO, wherein double sulphur of the R-S- in BSA
The BSA protein group that key is broken to form.
Detect example 4
Due to the nanoparticle with surface plasma volume property in different solvents due to the difference of solvent refractive index, receive
The absorbing wavelength of rice corpuscles can move.There is surface plasma in order to verify product of the invention in the absorption of near-infrared
Property, We conducted next verifyings.
Therefore we are BSA@Cu2-xO NPs is dispersed in water, ethylene glycol (ethylene glycol), dimethyl sulfoxide respectively
(DMSO) in, as a result as shown in figure 4, B is observed that BSA@Cu in Fig. 42-xThe absorbing wavelength of O NPs is with solvent refractive index
Increase occur red shift.BSA@Cu is surveyed by synchrotron radiation2-xA in Cu and S the key combination such as Fig. 4 of O NPs, in contrast
We construct the model of our synthesized substances are as follows: and BSA cystine linkage under basic conditions can occur fracture and expose sulfydryl,
Cu2-xU is in conjunction with the S in BSA for O NPs surface C.Being in the Systems Theory can be by commercial Comsol
Multiphysics calculates wavelength:
It solves Maxwell wave equation using finite element method (FEM) (finite element method, FEM).K0It is
The wave number of incidence wave with transverse electric field E.Relative permeability μrIt is respectively 1 and 0 with conductivityσ's value, and the opposite of material is situated between
Electric constant εrFrom variable-angle spectroscopic ellipsometers (variable angle spectroscopy, VASE) in the electricity of COMSOL
Experimental result in magnetic wave optical module.Defined using spherical symmetry perfect domination set (perfect matching layer,
PML) and the physical domain of model, usually with free tetrahedron structure block gridding.From the point of view of absorption spectrum, it is evident that we
Analog result greatly support our experimental work.
Detect example 5
In order to which the method for proving us has universality.We in embodiment 4-6 BSA change into HSA, Trypsin or
Person Lysozyme is as presoma, with synthesis BSA@Cu2-xO NPs step is identical, we, which have synthesized, equally has in UV-Vis-NIR
The substance absorbed strongly, as shown in Figure 5.The substance of the corresponding HSA synthesis of A, D in Fig. 5, size is in 5nm or so.B, E in Fig. 5
The substance of corresponding Trypsin synthesis, size is also in 5nm or so.C, F are the substance of Lysozyme synthesis in same Fig. 5,
Its size is in 5nm or so.
The preferred embodiment of the present invention has been described above in detail, still, during present invention is not limited to the embodiments described above
Detail within the scope of the technical concept of the present invention can be with various simple variants of the technical solution of the present invention are made, this
A little simple variants all belong to the scope of protection of the present invention.
It is further to note that specific technical features described in the above specific embodiments, in not lance
In the case where shield, can be combined in any appropriate way, in order to avoid unnecessary repetition, the present invention to it is various can
No further explanation will be given for the combination of energy.
In addition, various embodiments of the present invention can be combined randomly, as long as it is without prejudice to originally
The thought of invention, it should also be regarded as the disclosure of the present invention.
Claims (10)
1. a kind of protein@Cu2-xO composite nanoparticle, which is characterized in that the composed structure of the composite nanoparticle is R-
S-Cu2-xO, wherein the protein group of cystine linkage post-rift formation of the R-S- in the protein containing cystine linkage；
Wherein, 0 < X < 1.
2. composite nanoparticle according to claim 1, wherein the spectral absorption peak of the nanoparticle is located at biology the
Two windows；
Preferably, the spectral absorption peak of the nanoparticle is located at 1250-1350nm.
3. composite nanoparticle according to claim 2, wherein the composite nanoparticle is the unformed nucleocapsid of amorphous
Structure；
Preferably, the particle size range of the composite nanoparticle is 3-10nm.
4. composite nanoparticle according to claim 1-3, wherein the protein containing cystine linkage is
One of BSA, HSA, Trypsin and Lysozyme or a variety of.
5. a kind of preparation method of the described in any item composite nanoparticles of claim 1-4, which is characterized in that the preparation side
Method the following steps are included:
The solution of protein containing cystine linkage is mixed with copper salt solution, be added sodium hydroxide adjust mixed liquor pH to
11.3-13 obtains composite nanoparticle mixed liquor then in 50-60 DEG C of standing 6-12h.
6. preparation method according to claim 5, wherein relative to containing the protein of cystine linkage, copper described in 200mg
The dosage of salt is 15-25mmol/L.
7. preparation method according to claim 6, wherein contain double sulphur described in the solution of the protein containing cystine linkage
The mass concentration of the protein of key is 30-50mg/mL.
8. preparation method according to claim 5, wherein the mantoquita is one in copper chloride, copper nitrate and copper sulphate
Kind is a variety of.
9. according to the described in any item preparation methods of claim 5-8, wherein further include by the composite nanoparticle mixed liquor
It is mixed with isopropanol with volume ratio 1:1.5-2.5, is then centrifuged；It will be centrifuged that product is water-dispersible to be placed in dialysis again
In bag the step of dialysis 12-36h；
Preferably, it is 5000-10000rpm that centrifugal condition, which includes: centrifugation rate,；Centrifugation time is 8-15min.
10. a kind of application of described in any item composite nanoparticles of claim 1-4 in photoacoustic imaging and photo-thermal therapy.
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