CN102323412A - A kind of purposes of Raman coding microball and utilize the Raman coding microball to detect the method for tumor markers - Google Patents
A kind of purposes of Raman coding microball and utilize the Raman coding microball to detect the method for tumor markers Download PDFInfo
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Abstract
The invention discloses a kind of purposes of Raman coding microball and utilize the Raman coding microball to detect the method for tumor markers, wherein the purposes of Raman coding microball is the application in tumor markers detects; The method of utilizing the Raman coding microball to detect tumor markers is the Raman coding microball to be distributed in the phosphate buffer and to add the detection antibody response obtain nano-probe, obtains the nano-probe of Raman coded markings again with bovine serum albumin(BSA) sealing nano-probe surface vacancy; The serum that will contain tumor markers adds in the insolubilized antibody, and the reaction back adds the nano-probe of Raman coded markings, obtains immune complex, carries out the detection of SERS spectrum after the enrichment of immune complex process externally-applied magnetic field.The Raman coding microball that the present invention uses has superpower SERS effect, can be used for polycomponent ultratrace target analytes is carried out quantitative analysis, and the molecule that can select a large amount of different surfaces to strengthen the raman signatures vibration thing that serves as a mark detects multiple determinand simultaneously.
Description
One, technical field
The present invention relates to a kind of purposes of Raman coding microball and utilize the Raman coding microball to detect the method for tumor markers.
Two, background technology
Malignant tumour is one of healthy important diseases of current harm humans, and the whole world has more than 1,000 ten thousand new cases and more than 600 ten thousand people dead every year.In recent years, under physician, biologist's effort, the human analysis that has got into the microcosmic level for the understanding of self, thus the mechanism that takes place, develops for tumour has also had more understanding.On DNA, RNA, protein, chromosome and cellular level, observe a series of variations relevant with cell carcinogenesis, the variation that these are unusual is exactly in fact the sign of cell carcinogenesis different phase., detect as tumor markers with tumor associated antigen, be expected to realize early diagnosis tumour through immuno analytical method.
At present, the detection of tumor markers mainly is to realize through enzyme immunoassay (EIA), radiommunoassay, fluoroimmunoassay, chemiluminescence immune assay and electrochemiluminescence immunoassay.These method major parts all have very high precision and sensitivity, can select a certain method to measure according to the survey Properties of Objects.Shortcomings such as but they all exist complicated operation in various degree, waste time and energy, cost height.For example, the enzyme immunoassay technology needs special import reagent box, and biology enzyme obtain difficulty, cost is higher, experiment condition is harshness etc. comparatively also; The fluoroscopic examination meeting receives interference and photobleaching effect of sample autofluorescence etc.In addition, often there is identical tumor markers in different types of tumors, and also there is the kinds of tumors mark in the tumour of same kind, and single index detection specificity is not strong, sensitivity is low.
Three, summary of the invention
The present invention aims to provide a kind of purposes of Raman coding microball and utilizes the Raman coding microball to detect the method for tumor markers, and that this method has is highly sensitive, selectivity is high and characteristics fast.
Technical solution problem of the present invention adopts following technical scheme:
The characteristics of the purposes of Raman coding microball of the present invention are: the application of said Raman coding microball in tumor markers detects.
The characteristics of the purposes of Raman coding microball of the present invention also are: said tumor markers is carcinomebryonic antigen (CEA); Alpha-fetoprotein (AFP); PSA (PSA); Ferritin; Cytokeratin; Squamous cell carcinoma antigen (SCC); Acid phosphatase (ACP); Alkaline phosphatase (ALP); Neuronspecific enolase (NSE); Sugar antigen 125 (CA125); Sugar antigen 199 (CA199); Sugar antigen 50 (CA50); Sugar antigen 153 (CA153); Sugar antigen 724 (CA724); Carbohydrate antigen 242 (CA242) or human chorionic gonadotrophin (HCG).
The characteristics that the present invention utilizes the Raman coding microball to detect the method for tumor markers are to operate according to the following steps:
A, 25mg Raman coding microball is distributed in the phosphate buffer (PBS) that 10mL pH value is 7.4 0.01M; Add 125 μ g and detect antibody; Reaction obtained nano-probe in 12 hours under 4 ℃; In said nano-probe, add mass concentration and be 1% bovine serum albumin(BSA) (BSA) sealing nano-probe surface vacancy, obtain the nano-probe of Raman coded markings after centrifugal, the washing, be distributed to preserve among the PBS subsequent use;
B, the magnetic nano-particle of 15mg coated with silica is distributed in the polyethyleneimine: amine aqueous solution of 50mL 2mg/mL; Stir the nano particle that obtained polyethylene imine beautify in 30 minutes under the room temperature; It is reaction 1 hour in 2.5% the glutaraldehyde solution that the nano particle of said polyethylene imine beautify is distributed to mass concentration, centrifugal, with the PBS washing, adds 75 μ g then and detects the corresponding coated antibody of antibody; Reaction is 12 hours under 4 ℃ of environment; Add mass concentration at last and be 1% the unreacted aldehyde radical of bovine serum albumin(BSA) (BSA) sealing room, obtain insolubilized antibody after centrifugal, the washing, be distributed to preserve among the PBS subsequent use;
Be added with NaCl in the said polyethyleneimine: amine aqueous solution, the concentration of NaCl is 0.5M;
C, the serum that 50 μ L are contained tumor markers join in the insolubilized antibody that step b obtains; Reaction is 1 hour under 37 ℃ of conditions; The nano-probe of the Raman coded markings that magnetic resolution, washing back adding step a obtain; Reacted 1 hour down at 37 ℃, obtain immune complex after magnetic resolution, the washing, be distributed among the PBS subsequent use;
D, the immune complex that step c is obtained suck in the kapillary, utilize the detection of carrying out SERS spectrum after the externally-applied magnetic field enrichment.
The characteristics that the present invention utilizes the Raman coding microball to detect the method for tumor markers also are: described magnetic nano-particle is Fe
3O
4Or γ-Fe
2O
3Deng nano particle with superparamagnetism.
The Raman coding microball that the present invention uses prepares according to following method:
A, 0.2g kernel nano particle is joined in the polyelectrolyte solution of 50mL 2mg/mL; Stirred 30 minutes under the room temperature; Obtain the nano particle that polyelectrolyte is modified after centrifugal, the washing; The nano particle that said polyelectrolyte is modified is distributed in the 50mL metal nanoparticle colloidal sol; Stir under the room temperature and obtained the core-shell nano that the single-layer metal nano particle coats in 30 minutes, the core-shell nano that said single-layer metal nano particle is coated repeats to add successively in polyelectrolyte solution and the metal nanoparticle colloidal sol, obtains the core-shell nano microballoon that the multiple layer metal nano particle coats;
Add NaCl in the said polyelectrolyte solution, the concentration of NaCl is 0.5M.
B, the raman-active species of 1mL 5mM is joined in the core-shell nano microballoon that multiple layer metal nano particle that step a obtains coats, stirred 6-12 hour under the room temperature, obtain the core-shell nano microballoon of raman-active species mark after centrifugal, the washing;
It is in 2.5% the glutaraldehyde solution that the core-shell nano microballoon of c, raman-active species mark that step b is obtained joins massfraction; React and wash with ultrapure water after 1 hour; The core-shell nano microballoon of the raman-active species mark that obtains encapsulating is scattered in the ultrapure water, and is subsequent use.
Said kernel nano particle is Nano particles of silicon dioxide, polymer nano-particle or magnetic nano-particle, and particle diameter is 100-800nm.
Said metal nanoparticle is the metal nanoparticle that golden nanometer particle, Nano silver grain or copper nano-particle etc. have remarkable plasma resonance character, and particle diameter is 5-15nm.
Said raman-active species is to contain the material that aromatic ring, heterocycle, amino, carboxylic acid group, phosphorus atoms or sulphur atom etc. have Raman active.
Said polyelectrolyte is the water-soluble polymers that polyethyleneimine, poly diallyldimethylammonium chloride, PDDA, gelatin or shitosan etc. contain a large amount of amido functional groups.
The present invention detects in the tumor markers method and carries out mark with raman active molecule, and the characteristic spectrum peak of the different raman active molecules of foundation carries out the Raman coding, through the immune nano probe of antibody coupling technology preparation Raman coding; Select for use magnetic nano-particle as insolubilized antibody, design is based on polycomponent " insolubilized antibody-determined antigen-labelled immune probe " the sandwich immune detection structure of magnetic solid phase particles Selective Separation effect; Raman signal output through Raman coding microball superpower SERS effect in surface and coding molecule realizes the synchronous detection to multi-tumor marker.
Compared with prior art, the present invention has following outstanding advantage and technique effect:
1, the Raman coding microball of the present invention's use has superpower SERS effect, can be used for polycomponent ultratrace target analytes is carried out quantitative analysis.
2, the present invention selects for use magnetic nano-particle as insolubilized antibody, can realize quick separation and enrichment to target analytes.
3, the invention enables SERS technical application scope to widen; The molecule that can select a large amount of different surfaces to strengthen the raman signatures vibration thing that serves as a mark detects multiple determinand simultaneously, lays the foundation for this highly sensitive detection technique of SERS is widely used in medical diagnosis and the research.
Four, description of drawings
Fig. 1 utilizes the Raman coding microball to detect the method synoptic diagram of tumor markers.
Fig. 2 is the SERS spectrogram that embodiment 1 detects tumor markers CEA.The excitation source wavelength of SERS spectral detection is 532nm.Among Fig. 2 1079,1142,1390,1434,1578cm
-1Vibration peak be the characteristic feature vibration of p-Mercaptoaniline, and the intensity of signal increases and increases along with the concentration of CEA, so from the SERS signal of detected p-Mercaptoaniline, can judge and contain tumor markers CEA in the testing sample.The accompanying drawing in the upper right corner is raman scattering intensity ratio (I
CEA/ I
Blank) with the linear relationship of tumor markers CEA concentration, can find out in 0.1pg/mL～1.0ng/mL concentration range linear, R=0.994 (R representes linearly dependent coefficient).
Fig. 3 detects the SERS spectrogram of tumor markers AFP, PSA and CA125 simultaneously for embodiment 2.The excitation source wavelength of SERS spectral detection is 532nm.The Raman spectrogram that on behalf of the Raman encoded particles of 3-methoxybenzenethiol mark, curve a AFP is detected, wherein 992cm
-1The peak is the characteristic spectrum peak of 3-methoxybenzenethiol.The Raman spectrogram that on behalf of the Raman encoded particles of 2-methoxybenzenethiol mark, curve b PSA is detected, wherein 1039cm
-1The peak is the characteristic spectrum peak of 2-methoxybenzenethiol.The Raman spectrogram that on behalf of the Raman encoded particles of 2-thionaphthol mark, curve c CA125 is detected, wherein 1380cm
-1The peak is the characteristic spectrum peak of 2-thionaphthol.Curve d represents this 3 kinds of Raman spectrograms that the Raman encoded particles detects AFP, PSA and CA125 simultaneously, and 992,1039 and 1380cm
-1The signal at peak all can be detected.This result shows the immunoassay that can be applied to multi-tumor marker based on the immunologic detection method of Raman coding microball.
Five, embodiment
Embodiment 1:
Present embodiment is an example with tumor markers CEA, sets forth the method for utilizing the Raman coding microball to detect tumor markers CEA.
(1) preparation of Raman coding microball
A, get the 95mL ultrapure water; Add 1mL 30mM sodium citrate solution and 2mL 5mM liquor argenti nitratis ophthalmicus successively; Inject 1mL 50mM sodium borohydride solution then rapidly, stir under the room temperature after 30 seconds, add 1mL 5mg/mL polyvinylpyrrolidone; Solution gradually becomes buff, and promptly getting diameter is the Nano silver grain colloidal sol of 5-15nm.
B, positive tetraethyl orthosilicate of 3.6mL and 88.1mL ethanol are mixed to join the 250mL round-bottomed flask, stirring condition adds 11.9mL ammoniacal liquor down rapidly, makes its complete reaction at ambient temperature, promptly gets the Nano particles of silicon dioxide that diameter is about 200nm.
C, get the Nano particles of silicon dioxide of 25mL step b preparation, centrifugal and be scattered in the polyethyleneimine: amine aqueous solution of 50mL 2mg/mL, be added with NaCl in the polyethyleneimine: amine aqueous solution; The concentration of NaCl is 0.5M; Stirred 30 minutes under the room temperature, centrifuge washing is distributed in the silver sol of step a preparation again then; Stir under the room temperature and obtained the silicon dioxide nanosphere that single-layer silver nanoparticle coats in 30 minutes; The silicon dioxide nanosphere that the single-layer silver nanoparticle that obtains is coated repeats to add successively in polyethyleneimine: amine aqueous solution and the Nano silver grain colloidal sol, and alternating deposit polyethyleneimine and silver sol promptly obtain the different nucleocapsid silicon dioxide nanospheres of assembling the numbers of plies.
D, the p-Mercaptoaniline of 1mL 5mM is joined in the 5mg nucleocapsid silicon dioxide nanosphere, stirred 6 hours under the room temperature, centrifugal then, washing promptly makes the core-shell nano microballoon of p-Mercaptoaniline mark.
E, the core-shell nano microballoon of p-Mercaptoaniline mark was immersed in the glutaraldehyde solution of mass concentration 2.5% reaction 1 hour; Using pH value is the abundant drip washing of phosphate buffer (PBS) of 7.4 0.01M; Remove unreacted glutaraldehyde; Promptly get the core-shell nano microballoon of the p-Mercaptoaniline mark that encapsulates, i.e. the Raman coding microball.
(2) preparation of the nano-probe of Raman coded markings
In the 25mg of above-mentioned preparation Raman coding microball, add 125 μ g CEA antibody; Reaction is 12 hours under 4 ℃ of environment; Use mass concentration to seal unreacted aldehyde radical room at last as 1%BSA; Obtain the nano-probe of Raman coded markings after centrifugal, the washing, with the nano-probe of the Raman coded markings that obtains be dispersed in preserve among the PBS for use.
(3) preparation of magnetic insolubilized antibody
A, take by weighing 1.35g FeCl
36H
2O adds 40mL monoethylene glycol, 0.5g polyglycol and 3.6g anhydrous sodium acetate successively, stirs under the room temperature and obtains uniform solution in 12 hours, then it is transferred in the 50mL agitated reactor, and reaction promptly got the Fe that diameter is about 300nm in 24 hours under 200 ℃ of conditions
3O
4Nano particle.
B, get 0.1g Fe
3O
4Nano particle; Place 50mL 0.1M HCl ultrasonic 10 minutes, and be scattered in then in 100mL ethanol/water (volume ratio of second alcohol and water=4: the 1) solution, add 1mL ammoniacal liquor and the positive tetraethyl orthosilicate of 30 μ L more successively; Stirred under the room temperature 6 hours, and obtained the Fe of coated with silica after centrifugal
3O
4Nano particle is with the Fe of 15mg coated with silica
3O
4Nano particle is scattered in the polyethyleneimine: amine aqueous solution of 50mL 2mg/mL, contains the NaCl of 0.5M in the polyethyleneimine: amine aqueous solution, stirs 30 minutes under the room temperature; Be immersed in the glutaraldehyde solution of mass concentration 2.5% reaction after centrifugal, the washing 1 hour; With the abundant drip washing of PBS, remove unreacted glutaraldehyde, add 75 μ g CEA coated antibodies then; Reaction is 12 hours under 4 ℃ of environment; Using mass concentration at last is that 1% BSA seals unreacted aldehyde radical room, obtains insolubilized antibody after centrifugal, the washing, with the gained insolubilized antibody be dispersed in preserve among the PBS for use.
(4) the Raman coding microball is to the SERS immune detection of tumor markers CEA
A, the serum that 50 μ L are contained tumor markers CEA join in the insolubilized antibody of step (three) preparation; Reacted 1 hour down at 37 ℃; The nano-probe of the Raman coded markings that magnetic resolution, washing back adding step (two) obtain; Reacted 1 hour down at 37 ℃, obtain immune complex after magnetic resolution, the washing, be distributed among the PBS immune complex subsequent use.
B, the immune complex that step a is obtained suck in the kapillary, carry out the detection of SERS spectrum behind the magnetite gathering.Testing result is seen Fig. 2.
Embodiment 2: a kind of Raman coding microball detects to tumor markers AFP, PSA and CA125 the time
(1) preparation of Raman coding microball
The preparation method of Raman coding microball is with embodiment 1 in the present embodiment; Different is replaces p-Mercaptoaniline as raman-active species with 3-methoxybenzenethiol, 2-methoxybenzenethiol and 2-thionaphthol respectively, the core-shell nano microballoon of the core-shell nano microballoon of the core-shell nano microballoon of the 3-methoxybenzenethiol mark that obtains respectively encapsulating, the 2-methoxybenzenethiol mark of encapsulation and the 2-thionaphthol mark of encapsulation.
(2) preparation of the nano-probe of Raman coded markings
In the core-shell nano microballoon of the 3-methoxybenzenethiol mark that the 25mg of above-mentioned preparation encapsulates, add 125 μ g AFP antibody; Reaction is 12 hours under 4 ℃ of environment; Use mass concentration to seal unreacted aldehyde radical room at last as 1%BSA; Obtain the nano-probe of 3-methoxybenzenethiol mark after centrifugal, the washing, with the nano-probe of the 3-methoxybenzenethiol mark that obtains be dispersed in preserve among the PBS for use.
In the core-shell nano microballoon of the 2-methoxybenzenethiol mark that the 25mg of above-mentioned preparation encapsulates, add 125 μ g PSA antibody; Reaction is 12 hours under 4 ℃ of environment; Use mass concentration to seal unreacted aldehyde radical room at last as 1%BSA; Obtain the nano-probe of 2-methoxybenzenethiol mark after centrifugal, the washing, with the nano-probe of the 2-methoxybenzenethiol mark that obtains be dispersed in preserve among the PBS for use.
In the core-shell nano microballoon of the 2-thionaphthol mark that the 25mg of above-mentioned preparation encapsulates, add 125 μ g CA125 antibody; Reaction is 12 hours under 4 ℃ of environment; Use mass concentration to seal unreacted aldehyde radical room at last as 1%BSA; Obtain the nano-probe of 2-thionaphthol mark after centrifugal, the washing, with the nano-probe of the 2-thionaphthol mark that obtains be dispersed in preserve among the PBS for use.
With the mixed solution that obtains nano-probe after above-mentioned three kinds of nano-probes mixing, subsequent use.
(3) preparation of magnetic insolubilized antibody
The preparation method of insolubilized antibody is with embodiment 1 in the present embodiment; Different is respectively with AFP coated antibody, PSA coated antibody and CA125 coated antibody replacement CEA coated antibody; Obtain AFP insolubilized antibody, PSA insolubilized antibody and CA125 insolubilized antibody respectively, obtain mixing insolubilized antibody after above-mentioned three kinds of different insolubilized antibodies are mixed.
(4) the Raman coding microball is to the SERS immune detection of tumor markers CEA
A, the serum that will contain tumor markers AFP, PSA and CA125 join and mix in the insolubilized antibody; Reaction is 1 hour under 37 ℃ of conditions; Magnetic resolution, washing back add the mixed solution of nano-probe; Reaction is 1 hour under 37 ℃ of conditions, obtains the mixed immunity compound after magnetic resolution, the washing, is distributed among the PBS gained mixed immunity compound subsequent use.
B, will go on foot the mixed immunity compound that b obtains and suck in the kapillary, carry out the detection of SERS spectrum behind the magnetite gathering.Testing result is seen Fig. 3.
The compound method of the 0.01M phosphate buffer that uses in the embodiment of the invention (pH 7.4) is following:
With 1.22g K
2HPO
4, 0.136g KH
2PO
4Be dissolved in the 100mL ultrapure water with 0.85g NaCl, and then be diluted to 1000mL with ultrapure water and get final product.
Claims (4)
1. the purposes of a Raman coding microball is characterized in that: the application of said Raman coding microball in tumor markers detects.
2. the purposes of Raman coding microball according to claim 1 is characterized in that: said tumor markers is carcinomebryonic antigen, alpha-fetoprotein, PSA, ferritin, cytokeratin, squamous cell carcinoma antigen, acid phosphatase, alkaline phosphatase, neuronspecific enolase, sugar antigen 125, sugar antigen 199, sugar antigen 50, sugar antigen 153, sugar antigen 724, carbohydrate antigen 242 or human chorionic gonadotrophin.
3. utilize the Raman coding microball to detect the method for tumor markers, it is characterized in that operating according to the following steps:
A, 25mg Raman coding microball is distributed in the phosphate buffer that 10mL pH value is 7.4 0.01M; Add 125 μ g and detect antibody; Reaction obtained nano-probe in 12 hours under 4 ℃; In said nano-probe, add mass concentration and be 1% bovine serum albumin(BSA) sealing nano-probe surface vacancy, obtain the nano-probe of Raman coded markings after centrifugal, the washing;
B, the magnetic nano-particle of 15mg coated with silica is distributed in the polyethyleneimine: amine aqueous solution of 50mL 2mg/mL; Stir the nano particle that obtained polyethylene imine beautify in 30 minutes under the room temperature; It is reaction 1 hour in 2.5% the glutaraldehyde solution that the nano particle of said polyethylene imine beautify is distributed to mass concentration; Centrifugal, with PBS washing, add 75 μ g then and detect the corresponding coated antibody of antibody, under 4 ℃ of environment, reacted 12 hours; Add mass concentration at last and be 1% bovine serum albumin(BSA) and seal unreacted aldehyde radical room, obtain insolubilized antibody after centrifugal, the washing;
Be added with NaCl in the said polyethyleneimine: amine aqueous solution, the concentration of NaCl is 0.5M;
C, the serum that 50 μ L are contained tumor markers join in the insolubilized antibody that step b obtains; Reaction is 1 hour under 37 ℃ of conditions; The nano-probe of the Raman coded markings that magnetic resolution, washing back adding step a obtain; Reacted 1 hour down at 37 ℃, obtain immune complex after magnetic resolution, the washing;
D, the immune complex that step c is obtained suck in the kapillary, utilize the detection of carrying out SERS spectrum after the externally-applied magnetic field enrichment.
4. the method for utilizing the Raman coding microball to detect tumor markers according to claim 3, it is characterized in that: described magnetic nano-particle is Fe
3O
4Or γ-Fe
2O
3Nano particle.
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