CN105999309A - Protein biological template-based gadolinium-doped copper sulfide nano-particles and preparation method thereof - Google Patents
Protein biological template-based gadolinium-doped copper sulfide nano-particles and preparation method thereof Download PDFInfo
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- 239000002105 nanoparticle Substances 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 102000004169 proteins and genes Human genes 0.000 title claims abstract description 15
- 108090000623 proteins and genes Proteins 0.000 title claims abstract description 15
- OMZSGWSJDCOLKM-UHFFFAOYSA-N copper(II) sulfide Chemical compound [S-2].[Cu+2] OMZSGWSJDCOLKM-UHFFFAOYSA-N 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 30
- 239000002245 particle Substances 0.000 claims abstract description 17
- 239000000843 powder Substances 0.000 claims abstract description 16
- 238000003384 imaging method Methods 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 10
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000011593 sulfur Substances 0.000 claims abstract description 5
- 238000004108 freeze drying Methods 0.000 claims abstract description 4
- 150000000921 Gadolinium Chemical class 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims abstract description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 claims description 21
- 229940098773 bovine serum albumin Drugs 0.000 claims description 21
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 13
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 13
- 229910003317 GdCl3 Inorganic materials 0.000 claims description 9
- 230000033228 biological regulation Effects 0.000 claims description 9
- 238000000502 dialysis Methods 0.000 claims description 9
- MEANOSLIBWSCIT-UHFFFAOYSA-K gadolinium trichloride Chemical group Cl[Gd](Cl)Cl MEANOSLIBWSCIT-UHFFFAOYSA-K 0.000 claims description 9
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 claims description 9
- 230000002902 bimodal effect Effects 0.000 claims description 5
- 229910052688 Gadolinium Inorganic materials 0.000 claims description 4
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims description 3
- 229910021592 Copper(II) chloride Inorganic materials 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 2
- 238000005538 encapsulation Methods 0.000 claims description 2
- 229910052979 sodium sulfide Inorganic materials 0.000 claims description 2
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical group [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000243 solution Substances 0.000 abstract description 49
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- RJOJUSXNYCILHH-UHFFFAOYSA-N gadolinium(3+) Chemical compound [Gd+3] RJOJUSXNYCILHH-UHFFFAOYSA-N 0.000 description 2
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- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1866—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 the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid
- A61K49/1869—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 the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid coated or functionalised with a protein being an albumin, e.g. HSA, BSA, ovalbumin
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- 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
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/14—Peptides, e.g. proteins
- A61K49/143—Peptides, e.g. proteins the protein being an albumin, e.g. HSA, BSA, ovalbumin
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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
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/225—Microparticles, microcapsules
Abstract
The invention discloses protein biological template-based gadolinium-doped copper sulfide nano-particles and a preparation method thereof. The preparation method comprises the following steps: dissolving a protein template in PBS to prepare a solution having a concentration of 0.5-1.5mM, and stirring with copper salt and gadolinium salt solutions; then adding a sodium hydroxide solution, regulating the pH value to be 8-12, and injecting a sulfur source to react at 25-50 DEG C; and dialyzing and freeze-drying to obtain GdCuS nano-particle powder. The prepared GdCuS nano-particles have a particle size of 6-10nm, are externally coated with protein, and have photothermal conversion efficiency of 20-30 percent and a longitudinal relaxation rate r1 being 10-18mM/s. The nano-particles can generate relatively high heat under near infrared ray irradiation, and are an ideal photothermal conversion agent and photoacoustic imaging contrast agent. The preparation method is simple in preparation steps, is easy for large-scale preparation, has mild reaction conditions to reduce energy consumption, has good environment compatibility, and is a green synthesizing process.
Description
Technical field
Copper sulfide (GdCuS) nano-particle that the present invention relates to Gd2 O3 and preparation method thereof, belongs to inorganic nano material synthesis technical field, and specifically a kind of is that biological template biomimetic control synthesizes GdCuS nano-particle based on bovine serum albumin.
Background technology
Cancer the most always threatens human health and " public enemy number one " of life, and currently the traditional treatment means for cancer mainly have three kinds: excision, radiotherapy, chemotherapy.But every kind of therapeutic modality is respectively provided with defect, such as excision only can eliminate Partial tumors cell, easily recurs；The easy normal tissue of radiation and chemotherapy causes damage, and toxic and side effects is relatively big, and tumor cell is lacked specific treatment.The most emerging phototherapy means such as photo-thermal therapies etc. start, by the most studied report, to be based primarily upon following two aspect advantages: (1) realizes the magnetic target therapy to tumor tissues, reduce the damage of normal tissue.(2) the effective killing to tumor cell is realized by the local excitation of outside near infrared light.
Photo-thermal therapy refer to utilize heat that light thermit powder produces after absorbing near infrared light to kill tumor cell, and if simultaneously by means of Imaging Technology, tumor can be accurately positioned analysis, thus improve therapeutic efficiency further.In current Imaging Technology, nuclear magnetic resonance have non-radiative, the characteristics such as soft tissue resolution is high are widely used in medical diagnosis on disease, but its shortcoming that there is also sensitivity difference；And photoacoustic imaging is as a kind of imaging technique of latest development, there is non-radiative, penetration depth length, highly sensitive, without features such as ambient interferences, therefore the conjunctive use of optoacoustic/nuclear magnetic resonance, is just provided simultaneously with high sensitivity and high-resolution, to highly beneficial in early diagnosis of tumor.
In view of nanotechnology is in biological potential application, preparation has the nanoparticle of optoacoustic/nuclear magnetic resonance and photo-thermal therapy function and just becomes the most urgent.In numerous light thermit powders, nano copper sulfate particle has the characteristics such as stability high, cheap, good biocompatibility, near infrared absorption notable (900-1000nm), can be widely used in the diagnosis and treatment research of tumor simultaneously as photoacoustic imaging contrast medium and light thermit powder.Preparation about nano copper sulfate particle at present mainly has high temperature thermal decomposition method and aqueous phase to control nucleation process two kinds, the former not only participates at needs organic solvent, and need to prepare in high temperature (180 DEG C), atmosphere of inert gases, it is necessary to carry out hydrophilically modified just to carry out subsequent bio medical application；The latter the most also needs comparative high temperature (90 DEG C), and the biological safety of the surface ligand of obtained nano copper sulfate particle needs to be considered.It addition, CuS nano-particle own does not possess magnetic resonance radiography ability, and gadolinium element outermost layer has 7 unpaired electrons, fully can act on water proton, is preferable magnetic resonance imaging suite.The most in sum, need a kind of simple, synthesis strategy of green, low cost, good biocompatibility of development at present badly to carry out mass preparation and there is the nano copper sulfate particle of magnetic resonance function, the photo-thermal therapy under optoacoustic/nuclear magnetic resonance bimodal imaging guiding of tumor.
Summary of the invention
It is an object of the invention to provide in a kind of based on the GdCuS nano-particle that bovine serum albumin is biological template biomimetic control synthesis in situ, it is utilized to absorb the characteristics such as strong, photothermal conversion excellent in efficiency, relaxivity are high, biological safety is good near infrared region, simultaneously as optoacoustic/magnetic resonance bimodal imaging contrast and and light thermit powder, the Clinics and Practices to tumor at cellular level and the realization of animal level.
Biomimetic mineralization refers to by organic macromolecule (such as albumen, polypeptide etc.) and the inorganic ions interaction in interface, under mild conditions, the in-situ preparation of inorganic particle is controlled so that it is there is certain shape, size and orientation so that prepared granule has special multilevel hierarchy and assembling mode from molecular level.Bovine serum albumin is as the biological template of a kind of classics; it is widely used in the preparation of nano material; the present invention utilizes its biomimetic mineralization technology mediated can be implemented under physiological temp, aqueous phase realizes the green preparation to Gd2 O3 nano copper sulfate particle; not only enormously simplify the synthesis step of conventional vulcanized copper nano particles, simultaneously because the protection of albumen can give the biological safety that it is high.Gadolinium ion is incorporated in nano copper sulfate particle with the form of doping, the GdCuS formed, and has size uniformity, good dispersion, stability and relaxation rate high, and can produce the characteristics such as higher heat rapidly under near infrared light.The GdCuS nano-particle that the present invention utilizes bovine serum albumin to be biological templated synthesis is repeatable strong, easily realizes being prepared on a large scale, and has potential huge applications prospect in the optoacoustic/field such as nuclear magnetic resonance, photo-thermal therapy of tumor.
Technical scheme is as follows:
A kind of Gd2 O3 nano copper sulfate particle based on protein biology template, prepared GdCuS nano particle diameter 6-10nm, outside is protein encapsulation, and photo-thermal conversion efficiency reaches 20%-30%, longitudinal relaxation rate r1=10mM s-1-18mM·s-1。
A kind of based on protein biology template the Gd2 O3 nano copper sulfate particle preparation method of the present invention, protein template is dissolved in PBS, it is configured to the solution that concentration is 0.5～1.5mM, mantoquita and gadolinium saline solution, sodium hydroxide solution is added after stirring, regulation pH is 8～12, is subsequently injected into sulfur source, reacts under the conditions of 25 DEG C-50 DEG C；Through dialysis and lyophilizing, i.e. obtain GdCuS powder of nanometric particles.
Protein template used is preferably bovine serum albumin, and molecular weight is 68kDa.
Described mantoquita is preferably CuCl2·2H2O, and solution concentration scope is 5～10mM.
Described gadolinium salt is preferably GdCl3·6H2O, and solution concentration scope is 1～10mmol/mL.
Described sulfur source is preferably Na2S·9H2O。
Preferably at 25 DEG C-50 DEG C, preferably react 3-12h.
Described freeze-drying time is 48h-96h.
Gd2 O3 nano copper sulfate particle is as the optoacoustic/magnetic resonance bimodal imaging contrast of tumor or light thermit powder.
The present invention utilizes the GdCuS nano-particle relaxivity prepared by biomimetic mineralization technology high, and utilize it to absorb the characteristics such as strong, photothermal conversion efficiency is high near infrared region (780-1100nm), such that it is able to the photo-thermal therapy of the tumor realized under tumor locus optoacoustic/magnetic resonance bimodal imaging technique guides.This technology is ease of Use simultaneously, favorable repeatability, environmental protection, and bovine serum albumin can give the biological safety that prepared GdCuS nano-particle is high, reduces the toxic damages to histoorgan as far as possible.The GdCuS nano-particle that the present invention utilizes albumen to be biological templated synthesis has huge potential application foreground in the field such as diagnosis and treatment of tumor.
Compared with existing synthetic technology, the invention have the advantages that
(1) reaction condition of the present invention more relaxes, and whole building-up process is to carry out in room temperature or physiological temp (～37) DEG C water-bath.Avoid practicality and high temperature, the protection of noble gas of organic solvent simultaneously, decrease the consumption of the energy.
(2) course of reaction related in the present invention is all dependent on albumen self structure and specific aminoacid fabricated in situ, and without the use of strong reductant, Environmental compatibility is more preferable, is a kind of green synthesis method.
(3) present invention operates height simple, repeatable, it is simple to be prepared on a large scale, and is prone to concentrate by lyophilization and collects.
(4) the GdCuS nanoparticle size prepared by the present invention is homogeneous, good stability, and photo-thermal conversion efficiency is high, good dispersion, does not reunites static half a year.
(5) present invention has certain universality, it is possible to use albuminoid control to synthesize other have different-shape, size, function nano-particle for biomedical sector.
Accompanying drawing explanation
The transmission electron microscope photo of GdCuS nano-particle prepared by Fig. 1: biomimetic mineralization.
The energy spectrogram of GdCuS nano-particle prepared by Fig. 2: biomimetic mineralization.
GdCuS nano-particle prepared by Fig. 3: the biomimetic mineralization ultra-violet absorption spectrum under variable concentrations.
GdCuS nano-particle prepared by Fig. 4: the biomimetic mineralization heating curve under variable concentrations.
The longitudinal relaxation efficiency of GdCuS nano-particle prepared by Fig. 5: biomimetic mineralization.
The transverse relaxation efficiency of GdCuS nano-particle prepared by Fig. 6: biomimetic mineralization.
Detailed description of the invention
It is further elaborated based on the preparation that albumen is biological template bio-mimetic syntheses GdCuS nano-particle in situ of the present invention below by embodiment, but the invention is not restricted to this.
Embodiment 1:
(1) accurately weighing 0.05mmol bovine serum albumin powder with electronic balance and pour in 50mL single port bottle, add 10mL phosphate buffer (0.01M), ultrasonic vibration dissolves, and obtains the bovine serum albumin solution of clear.
(2) CuCl of 3mmol is taken respectively2·2H2O and 5mmol GdCl3·6H2O joins in the solution in (1), continuously stirred 5min under room temperature.
(3) having configured the sodium hydroxide solution that concentration is 1M, joined in reaction bulb, regulation system pH is 8.
(4) Na that concentration is 4mmol/mL has been configured2S·9H2O solution, takes out 0.4mL and joins in above-mentioned reaction system, sustained response 12h under the conditions of 25 DEG C.
(5) being taken out by solution after reaction terminates, add in the bag filter that molecular cut off is 8,000 14000, be put in the beaker filling secondary water, dialyse 24h, and period changes water three times.
(6) solution after dialysis is collected, after being put in 80 DEG C of preservation 3h, put into and lyophilizing bottle carries out lyophilizing concentration, finally obtain the GdCuS nano-particle after lyophilizing.
Embodiment 2:
(1) accurately weighing 0.1mmol bovine serum albumin powder with electronic balance and pour in 50mL single port bottle, add 10mL phosphate buffer (0.01M), ultrasonic vibration dissolves, and obtains the bovine serum albumin solution of clear.
(2) CuCl of 4.5mmol is taken respectively2·2H2O and 5mmol GdCl3·6H2O joins in the solution in (1), continuously stirred 5min under room temperature.
(3) having configured the sodium hydroxide solution that concentration is 1M, joined in reaction bulb, regulation system pH is 12.
(4) Na that concentration is 4mmol/mL has been configured2S·9H2O solution, takes out 0.4mL and joins in above-mentioned reaction system, sustained response 4h under the conditions of 37 DEG C.
(5) being taken out by solution after reaction terminates, add in the bag filter that molecular cut off is 8,000 14000, be put in the beaker filling secondary water, dialyse 24h, and period changes water three times.
(6) solution after dialysis is collected, after being put in 80 DEG C of preservation 3h, put into and lyophilizing bottle carries out lyophilizing concentration, finally obtain the GdCuS nano-particle after lyophilizing.Fig. 1 is the transmission electron microscope photo of the GdCuS nano-particle prepared by the present invention, it can be seen that particle diameter is 9nm.Fig. 2 is the energy spectrogram of corresponding GdCuS nano-particle, it can be seen that this nano-particle exists tri-kinds of elements of Gd, Cu, S really.
Embodiment 3:
(1) accurately weighing 0.15mmol bovine serum albumin powder with electronic balance and pour in 50mL single port bottle, add 10mL phosphate buffer (0.01M), ultrasonic vibration dissolves, and obtains the bovine serum albumin solution of clear.
(2) CuCl of 6mmol is taken respectively2·2H2O and 5mmol GdCl3·6H2O joins in the solution in (1), continuously stirred 5min under room temperature.
(3) having configured the sodium hydroxide solution that concentration is 1M, joined in reaction bulb, regulation system pH is 10.
(4) Na that concentration is 4mmol/mL has been configured2S·9H2O solution, takes out 0.4mL and joins in above-mentioned reaction system, sustained response 12h under the conditions of 50 DEG C.
(5) being taken out by solution after reaction terminates, add in the bag filter that molecular cut off is 8,000 14000, be put in the beaker filling secondary water, dialyse 48h, and period changes water three times.
(6) solution after dialysis is collected, after being put in 80 DEG C of preservation 3h, put into and lyophilizing bottle carries out lyophilizing concentration, finally obtain the GdCuS nano-particle after lyophilizing.Fig. 3 is the ultra-violet absorption spectrum under variable concentrations of the GdCuS nano-particle prepared by the present invention.It can be seen that improving constantly along with concentration, GdCuS nano-particle absorbs near infrared region increasingly stronger, presents significant linear relationship.
Embodiment 4:
(1) accurately weighing 0.05mmol bovine serum albumin powder with electronic balance and pour in 50mL single port bottle, add 10mL phosphate buffer (0.01M), ultrasonic vibration dissolves, and obtains the bovine serum albumin solution of clear.
(2) CuCl of 4.5mmol is taken respectively2·2H2O and 5mmol GdCl3·6H2O joins in the solution in (1), continuously stirred 5min under room temperature.
(3) having configured the sodium hydroxide solution that concentration is 1M, joined in reaction bulb, regulation system pH is 12.
(4) Na that concentration is 4mmol/mL has been configured2S·9H2O solution, takes out 0.4mL and joins in above-mentioned reaction system, sustained response 12h under the conditions of 37 DEG C.
(5) being taken out by solution after reaction terminates, add in the bag filter that molecular cut off is 8,000 14000, be put in the beaker filling secondary water, dialyse 36h, and period changes water three times.
(6) solution after dialysis is collected, after being put in 80 DEG C of preservation 3h, put into and lyophilizing bottle carries out lyophilizing concentration, finally obtain the GdCuS nano-particle after lyophilizing.
Fig. 4 is GdCuS nano-particle heating curve figure under laser irradiates: the aqueous solution taking 800uL variable concentrations GdCuS nano-particle respectively joins in cuvette, start the most above it, by the laser illumination (power: 0.6W/cm2) of 980nm, to utilize infrared thermography monitoring sample temperature with the change of irradiation time.The GdCuS nano-particle of variable concentrations heating curve under laser irradiates as shown in Figure 4, in the irradiation time of 5min, contrasts with water, and GdCuS nano-particle temperature rise effect is obvious, and improving constantly along with granule density, and increasing extent of temperature constantly becomes big.This phenomenon explanation GdCuS nano-particle prepared by the present invention can effectively absorb the light of 980nm, and it can be converted into heat efficiently, can be used for photoacoustic imaging and the photo-thermal therapy of tumor.
Embodiment 5:
(1) accurately weighing 0.1mmol bovine serum albumin powder with electronic balance and pour in 50mL single port bottle, add 10mL phosphate buffer (0.01M), ultrasonic vibration dissolves, and obtains the bovine serum albumin solution of clear.
(2) CuCl of 3mmol is taken respectively2·2H2O and 5mmol GdCl3·6H2O joins in the solution in (1), continuously stirred 5min under room temperature.
(3) having configured the sodium hydroxide solution that concentration is 1M, joined in reaction bulb, regulation system pH is 10.
(4) Na that concentration is 4mmol/mL has been configured2S·9H2O solution, takes out 0.4mL and joins in above-mentioned reaction system, sustained response 3h under the conditions of 37 DEG C.
(5) being taken out by solution after reaction terminates, add in the bag filter that molecular cut off is 8,000 14000, be put in the beaker filling secondary water, dialyse 48h, and period changes water three times.
(6) solution after dialysis is collected, after being put in 80 DEG C of preservation 3h, put into and lyophilizing bottle carries out lyophilizing concentration, finally obtain the GdCuS nano-particle after lyophilizing.
Embodiment 6:
(1) accurately weighing 0.05mmol bovine serum albumin powder with electronic balance and pour in 50mL single port bottle, add 10mL phosphate buffer (0.01M), ultrasonic vibration dissolves, and obtains the bovine serum albumin solution of clear.
(2) CuCl of 6mmol is taken respectively2·2H2O and 5mmol GdCl3·6H2O joins in the solution in (1), continuously stirred 5min under room temperature.
(3) having configured the sodium hydroxide solution that concentration is 1M, joined in reaction bulb, regulation system pH is 10.
(4) Na that concentration is 4mmol/mL has been configured2S·9H2O solution, takes out 0.4mL and joins in above-mentioned reaction system, sustained response 8h under the conditions of 50 DEG C.
(5) being taken out by solution after reaction terminates, add in the bag filter that molecular cut off is 8,000 14000, be put in the beaker filling secondary water, dialyse 48h, and period changes water three times.
(6) solution after dialysis is collected, after being put in 80 DEG C of preservation 3h, put into and lyophilizing bottle carries out lyophilizing concentration, finally obtain the GdCuS nano-particle after lyophilizing.
Embodiment 7:
(1) accurately weighing 0.1mmol bovine serum albumin powder with electronic balance and pour in 50mL single port bottle, add 10mL phosphate buffer (0.01M), ultrasonic vibration dissolves, and obtains the bovine serum albumin solution of clear.
(2) CuCl of 6mmol is taken respectively2·2H2O and 5mmol GdCl3·6H2O joins in the solution in (1), continuously stirred 5min under room temperature.
(3) having configured the sodium hydroxide solution that concentration is 1M, joined in reaction bulb, regulation system pH is 12.
(4) Na that concentration is 4mmol/mL has been configured2S·9H2O solution, takes out 0.4mL and joins in above-mentioned reaction system, sustained response 3h under the conditions of 25 DEG C.
(5) being taken out by solution after reaction terminates, add in the bag filter that molecular cut off is 8,000 14000, be put in the beaker filling secondary water, dialyse 36h, and period changes water three times.
(6) solution after dialysis is collected, after being put in 80 DEG C of preservation 3h, put into and lyophilizing bottle carries out lyophilizing concentration, finally obtain the GdCuS nano-particle after lyophilizing.
Fig. 5 and Fig. 6 is the test result of the relaxivity of GdCuS nano-particle: is used in conjunction instrument (ICP MS) by inductivity coupled plasma mass spectrometry and accurately measures the concentration of Gd ion in GdCuS.Subsequently by diluted sample 5 times, 10 times, 20 times, 40 times, 80 times, obtain the GdCuS solution of five concentration, take 200uL respectively and load in five nuclear magnetic tubes, and be put in 37 DEG C of water-baths standing 10min.The most successively nuclear magnetic tube is inserted in magnetic resonance analyzer, reads the longitudinal relaxation time (T of 5 samples1) and T2 (T2), then with its (1/T reciprocal1And 1/T2) with corresponding gadolinium ion concentration (Gd3+) be fitted analyzing, gained slope is longitudinal relaxation rate (r1) and transverse relaxation rate and (r2).Shown in Fig. 5 and 6, the r of GdCuS nano-particle1And r2It is respectively 16mM s‐ 1With 29.477mM s‐ 1, illustrate that GdCuS nano-particle has significant T1 contrasting effects, the accuracy of diagnosing tumor can be significantly improved.
Above-described embodiment is the present invention preferably embodiment; but embodiments of the present invention are also not restricted to the described embodiments; the change made under other any spirit without departing from the present invention and principle, modify, substitute, combine, simplify; all should be the substitute mode of equivalence, within being included in protection scope of the present invention.
Claims (9)
1. a Gd2 O3 nano copper sulfate particle based on protein biology template, is characterized in that prepared GdCuS
Nano particle diameter 6-10nm, outside is protein encapsulation, and photo-thermal conversion efficiency reaches 20%-30%, longitudinal relaxation
Rate r1=10mM s-1-18mM·s-1。
2. a kind of based on protein biology template the Gd2 O3 nano copper sulfate particle preparation method of claim 1, its
Be characterised by: protein template is dissolved in PBS, be configured to the solution that concentration is 0.5～1.5mM, mantoquita and
Gadolinium saline solution, adds sodium hydroxide solution after stirring, regulation pH is 8～12, is subsequently injected into sulfur source, 25
React under the conditions of DEG C-50 DEG C；Through dialysis and lyophilizing, i.e. obtain GdCuS powder of nanometric particles.
3. method as claimed in claim 2, is characterized in that protein template used is bovine serum albumin, molecular weight
For 68kDa.
4. method as claimed in claim 2, is characterized in that described mantoquita is CuCl2·2H2O, and solution concentration
Scope is 5～10mM.
5. method as claimed in claim 2, is characterized in that described gadolinium salt is GdCl3·6H2O, and solution concentration
Scope is 1～10mmol/mL.
6. method as claimed in claim 2, is characterized in that described sulfur source is Na2S·9H2O。
7. method as claimed in claim 2, is characterized in that at 25 DEG C-50 DEG C, reacts 3-12h.
8. method as claimed in claim 2, is characterized in that described freeze-drying time is 48h-96h.
9. Gd2 O3 nano copper sulfate particle is as the optoacoustic/magnetic resonance bimodal imaging contrast of tumor or light thermit powder.
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