CN101638579A - Quantum dot-cyanine dye-folic acid biological probe and preparation method thereof - Google Patents
Quantum dot-cyanine dye-folic acid biological probe and preparation method thereof Download PDFInfo
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- CN101638579A CN101638579A CN200910070179A CN200910070179A CN101638579A CN 101638579 A CN101638579 A CN 101638579A CN 200910070179 A CN200910070179 A CN 200910070179A CN 200910070179 A CN200910070179 A CN 200910070179A CN 101638579 A CN101638579 A CN 101638579A
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- 239000000523 sample Substances 0.000 title claims abstract description 66
- 239000011724 folic acid Substances 0.000 title claims abstract description 57
- 229960000304 folic acid Drugs 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 45
- 239000002096 quantum dot Substances 0.000 claims abstract description 73
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 claims abstract description 26
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 23
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims abstract description 22
- 235000019152 folic acid Nutrition 0.000 claims abstract description 15
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 53
- 239000000975 dye Substances 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 229910052980 cadmium sulfide Inorganic materials 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 19
- UHYPYGJEEGLRJD-UHFFFAOYSA-N cadmium(2+);selenium(2-) Chemical compound [Se-2].[Cd+2] UHYPYGJEEGLRJD-UHFFFAOYSA-N 0.000 claims description 18
- 239000007850 fluorescent dye Substances 0.000 claims description 18
- 238000002866 fluorescence resonance energy transfer Methods 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 239000011701 zinc Substances 0.000 claims description 16
- 239000011258 core-shell material Substances 0.000 claims description 15
- WUPHOULIZUERAE-UHFFFAOYSA-N 3-(oxolan-2-yl)propanoic acid Chemical compound OC(=O)CCC1CCCO1 WUPHOULIZUERAE-UHFFFAOYSA-N 0.000 claims description 14
- 229940116367 cadmium sulfide Drugs 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 11
- 239000002243 precursor Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000008367 deionised water Substances 0.000 claims description 9
- 229910021641 deionized water Inorganic materials 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical class C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 238000001228 spectrum Methods 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- YKYOUMDCQGMQQO-UHFFFAOYSA-L cadmium dichloride Chemical compound Cl[Cd]Cl YKYOUMDCQGMQQO-UHFFFAOYSA-L 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- SBIBMFFZSBJNJF-UHFFFAOYSA-N selenium;zinc Chemical compound [Se]=[Zn] SBIBMFFZSBJNJF-UHFFFAOYSA-N 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 claims description 5
- IJVLVRYLIMQVDD-UHFFFAOYSA-N 1,3-thiazole-2-carboxylic acid Chemical compound OC(=O)C1=NC=CS1 IJVLVRYLIMQVDD-UHFFFAOYSA-N 0.000 claims description 5
- MONMFXREYOKQTI-UHFFFAOYSA-N 2-bromopropanoic acid Chemical class CC(Br)C(O)=O MONMFXREYOKQTI-UHFFFAOYSA-N 0.000 claims description 5
- 229910004613 CdTe Inorganic materials 0.000 claims description 5
- 229910007709 ZnTe Inorganic materials 0.000 claims description 5
- 229950003476 aminothiazole Drugs 0.000 claims description 5
- MARUHZGHZWCEQU-UHFFFAOYSA-N 5-phenyl-2h-tetrazole Chemical compound C1=CC=CC=C1C1=NNN=N1 MARUHZGHZWCEQU-UHFFFAOYSA-N 0.000 claims description 4
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 claims description 4
- -1 tribromo propylamine bromate Chemical compound 0.000 claims description 4
- PFNQVRZLDWYSCW-UHFFFAOYSA-N (fluoren-9-ylideneamino) n-naphthalen-1-ylcarbamate Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1=NOC(=O)NC1=CC=CC2=CC=CC=C12 PFNQVRZLDWYSCW-UHFFFAOYSA-N 0.000 claims description 3
- IYXZQSNENVTSHP-UHFFFAOYSA-N 3,3,3-tribromopropan-1-amine Chemical compound BrC(CCN)(Br)Br IYXZQSNENVTSHP-UHFFFAOYSA-N 0.000 claims description 3
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000005083 Zinc sulfide Substances 0.000 claims description 3
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- LHQLJMJLROMYRN-UHFFFAOYSA-L cadmium acetate Chemical compound [Cd+2].CC([O-])=O.CC([O-])=O LHQLJMJLROMYRN-UHFFFAOYSA-L 0.000 claims description 3
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 claims description 3
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 3
- YHCVRAUCGVYFQA-UHFFFAOYSA-N ethyl bromate Chemical compound CCOBr(=O)=O YHCVRAUCGVYFQA-UHFFFAOYSA-N 0.000 claims description 3
- 238000002189 fluorescence spectrum Methods 0.000 claims description 3
- 229960003151 mercaptamine Drugs 0.000 claims description 3
- 238000000643 oven drying Methods 0.000 claims description 3
- 230000003252 repetitive effect Effects 0.000 claims description 3
- 230000004044 response Effects 0.000 claims description 3
- 238000005201 scrubbing Methods 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 239000004246 zinc acetate Substances 0.000 claims description 3
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims description 3
- 229960001763 zinc sulfate Drugs 0.000 claims description 3
- 229910000368 zinc sulfate Inorganic materials 0.000 claims description 3
- DRDVZXDWVBGGMH-UHFFFAOYSA-N zinc;sulfide Chemical compound [S-2].[Zn+2] DRDVZXDWVBGGMH-UHFFFAOYSA-N 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 230000005284 excitation Effects 0.000 claims description 2
- 238000000695 excitation spectrum Methods 0.000 claims description 2
- 150000002466 imines Chemical class 0.000 claims description 2
- 229910052979 sodium sulfide Inorganic materials 0.000 claims description 2
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 abstract description 19
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- 210000004027 cell Anatomy 0.000 description 21
- 230000008859 change Effects 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 10
- 229940064302 folacin Drugs 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 235000010265 sodium sulphite Nutrition 0.000 description 5
- 238000001514 detection method Methods 0.000 description 3
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- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
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- SMWDFEZZVXVKRB-UHFFFAOYSA-O hydron;quinoline Chemical compound [NH+]1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-O 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
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- OALHHIHQOFIMEF-UHFFFAOYSA-N 3',6'-dihydroxy-2',4',5',7'-tetraiodo-3h-spiro[2-benzofuran-1,9'-xanthene]-3-one Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(I)C(O)=C(I)C=C21 OALHHIHQOFIMEF-UHFFFAOYSA-N 0.000 description 1
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- XJHABGPPCLHLLV-UHFFFAOYSA-N benzo[de]isoquinoline-1,3-dione Chemical compound C1=CC(C(=O)NC2=O)=C3C2=CC=CC3=C1 XJHABGPPCLHLLV-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
Abstract
The invention provides a quantum dot-cyanine dye-folic acid biological probe. The probe structure comprises a probe which is formed by the quantum dot is bonded with the cyanine dye, and the cyanine dye is bonded with the folic acid. The invention further provides a preparation method of the quantum dot-cyanine dye-folic acid biological probe. The invention has the advantages of convenient preparation method and easy inducing quantum dot of the dye. The biological probe has the characteristics of targeted identifying tumor tissue and transferring fluorescence resonance energy, thereby not being capable of targeted identifying cancer cell and being capable of identifying the space location and the space structure of the cancer cell by the characteristic of transferring fluorescence resonance energy. The biological probe has the dual advantages of the quantum dot and the cyanine dye probe, and has simple preparation method, thereby being high-stability and high-efficiency targeted fluorescence mark. The probe has high sensitivity and less usage amount.
Description
Technical field
The present invention relates to chemistry, physics and Measurement for Biochemistry interdisciplinary field, particularly a kind of quantum dot-cyanine dye bioprobe and preparation method thereof.
Background technology
Cancer now has been first killer who threatens human health, and early diagnosis and the effective identification of carrying out cancer can effectively must improve treatment for cancer.The form of cell is not of uniform size, compares with normal cell, and it is big that the cancer cells volume is wanted, the nuclear-cytoplasmic ratio height, and metabolism is vigorous, and DNA and rna polymerase activity are all high, and the higher and nucleic acid decomposition course of the content of DNA and RNA is starkly lower than normal cell.Folacin receptor is expressed at most of malignant tumor tissue surface elevation, as mammary cancer, cancer of the stomach, ovarian cancer, carcinoma of endometrium, colorectal carcinoma, nasopharyngeal carcinoma, laryngocarcinoma, lung cancer etc., and expresses high conservative in normal cell.
Traditional cancer cells identification and diagnosis mainly detect by oncofetal protein, the enzyme mark, and tumour antigen detects, and plasma proteins detects and the isotope detection method is determined.But all there are shortcomings such as efficient is low, recognition rate is low in traditional method.In recent years, along with the continuous development of molecular biosciences labeling technique, the molecular biosciences labeling technique is used in medical field, especially is being subjected to people's attention gradually aspect the EARLY RECOGNITION of malignant cell and the diagnosis.
Bioluminescence probe dye method compares with traditional isotope detection method that to have speed fast, and good reproducibility is few with the sample amount, advantage such as radiationless.Be widely used at aspects such as DNA automatic sequencing, antibody immunoassay, medical diagnosis on disease, cancer therapy drug analyses.The bioluminescence pigment probe that is used for cell marking at present mainly contains acridine, phenanthridines class, fluoresceins, two fluothane boron classes, diphenylethylene, naphthalimide, cyanine dyes class etc.Has only the cyanine dyes class, a little less than fluorescence background disturbs.Therefore in cell marking, be used widely.But the Cyanine Dyes Fluorescence life-span is short, and photobleaching easily takes place.
The quantum dot probe has the absorb light spectrum width, emmission spectrum is narrow and symmetrical, the overlapping degree of fluorescence emission spectrum and acceptor molecule absorption spectrum can be regulated according to the quantum dot size, the fluorescence quantum efficiency height, emitting fluorescence is that 20 times of organic fluorescent dye emission light intensity, stability are strong more than 100 times, and fluorescence lifetime is long, and advantages such as photobleaching can not take place.Therefore in Photobiology, be used widely.These advantages of quantum dot have remedied the shortcoming of cyanine dyes class.
Research about biological fluorescent labeling both at home and abroad mainly concentrates on several aspects: 1. the design of fluorescence probe dye, synthetic and modification, and to improve the optics sensitivity of probe molecule and DNA or cell interaction.2. strengthen the target sex modification of fluorescence probe dye molecule and cancer cells mark.
This probe has the double properties of organic dye and quantum dot, has solved the shortcoming of single fluorescent probe.Can be applicable to the identification of cancer cells.And this probe also has the character of FRET, therefore can detect variation less than the nanometer distance, can be used to study albumen structure picture, protein-interacting, be applicable to each quasi-molecule of viable cell and fixed cell, highly sensitive and can blur-free imaging, the location and the quantitative information of protein interaction can be provided the most intuitively.The range information that reflects two molecular groupings by the efficiency information of the FRET (fluorescence resonance energy transfer) that is easy to detect.It is close by but interaction or conformational change take place between the enhancing detection molecules of FRET efficient; The weakening of FRET efficient can be used for proving two molecules away from and lose interaction, prove between two parts of a molecule be cut off because of molecule or conformational change mutually away from.Therefore can be used for studying the folacin receptor hypotype space structure phenomenon of cancer cells.
Summary of the invention
For solving the problem that exists in the above-mentioned technology, the purpose of this invention is to provide a kind of quantum dot-cyanine dye-folic acid biological probe and preparation method thereof, help solving the shortcoming of single fluorescent probe, demonstrate fully the double properties of organic dye and quantum dot, can precisely discern cancer cells, and have the characteristic of FRET, can be used for studying the folacin receptor hypotype space structure phenomenon of cancer cells.
For achieving the above object, the technical solution used in the present invention provides a kind of quantum dot-cyanine dye-folic acid biological probe, and wherein: this bioprobe structure includes carboxyl or amino quantum dot bonding cyanine dye bonding folic acid and the probe that forms again.A kind of preparation method of quantum dot-cyanine dye-folic acid biological probe also is provided simultaneously.
Effect of the present invention is:
1, the preparation method of bioprobe of the present invention is simple, and dyestuff is easy to introduce quantum dot.
2, bioprobe of the present invention has the characteristic of FRET, and the target identification that promptly can be used for cancer cells can utilize the characteristic of FRET cancer cells to be carried out the identification of spatial positioning and space structure again.
3, bioprobe of the present invention has the two-fold advantage of quantum dot and cyanine dye probe, and the preparation method is simple, is the fluorescent mark of high stability, high-level efficiency target.
4, probe is highly sensitive, and usage quantity is few.
Embodiment
In conjunction with the embodiments quantum dot of the present invention-cyanine dye bioprobe and preparation method thereof is illustrated.
The double properties with organic dye and quantum dot of quantum dot of the present invention-cyanine dye bioprobe and have the character of FRET (fluorescence resonance energy transfer).Be the fluorescence labeling probe of high stability, high-level efficiency target, novel probe structure of the present invention is on the basis of quantum dot, and the connection carboxyl connects cyanine dye again and then introduces folic acid formation probe on carboxyl.By study this probe and cancer cells surface folacin receptor hypotype bonded conformation, the variable density of mutual edge distance and interfacial state and energy level distribution etc. influence rule mutually, can and obtain the characteristic information of more cancer cells from the 3-d modelling of the cognitive cancerous tumor cell of microscopic scale surface folacin receptor hypotype, be to improve selectivity target tumor imaging results and sensing cancer cells characteristic information, accumulation is to the cognition of cancer essence.Has certain meaning for fluorescent probe in the practical application of life science.
Quantum dot of the present invention-cyanine dye-folic acid biological probe structure includes quantum dot bonding cyanine dye bonding folic acid and the probe that forms again.The end of described bioprobe is a folic acid, and the fluorescence emission spectrum of carboxyl or amino quantum dot and the fluorescence excitation spectrum of cyanine dye have overlapping, and described probe can target identification tumor tissues and FRET (fluorescence resonance energy transfer).The quantum dot of described bioprobe is a core-shell structure, and this structure includes: ZnS or CdS are the shell of quantum dot, and CdSe or ZnSe or CdTe or ZnTe or CdS are the nuclear of quantum dot.
The cyanine dye of described bioprobe includes: aminothiazole orange, carboxyl thiazole orange, amino Cyn analog derivative n=3 or 5, carboxyl Cyn analog derivative n=3 or 5.
Quantum dot of the present invention-cyanine dye bioprobe preparation method includes following steps:
1) preparation of quantum dot:
Carboxyl or amino quantum dot are synthetic: will contain Zn
2+Or Cd
2+Salt be dissolved in the deionized water wiring solution-forming, control Zn
2+Or Cd
2+Concentration is 1.0～2.0 * 10
-2Mol/L and to Zn
2+Or Cd
2+Dripping an amount of Thiovanic acid or mercaptoethylamine in the solution and transferring to pH with NaOH or HCl solution is 10～11 or 3～6, drips fresh transparent precursor liquid under the nitrogen protection condition, when making zinc selenide or CdSe quantum dots, drips Na
2SeSO
3Or NaHSe solution, when making zinc telluridse or cadmium telluride quantum dot, drip Na
2TeSO
3Or NaHTe solution, dripping NaS solution when making zinc sulphide or cadmiumsulfide quantum dot, back flow reaction obtains transparent quantum dot nuclear solution;
The preparation of quantum dot core-shell structure: under 30 ℃～40 ℃ conditions, with sodium sulfide solution with contain Cd
2+Or Zn
2+Solution dropwise be added drop-wise in the above-mentioned quantum dot nuclear solution shell of parcel ZnS or CdS, the S that drips by control
2+And Cd
2+Or Zn
2+Amount control the ratio of amount of substance of the shell of quantum dot and nuclear at 1: 1～3: 1, under nitrogen protection, controlled temperature is 50 ℃～100 ℃ back flow reaction, question response finishes postcooling, uses acetone and anhydrous diethyl ether to wash in beaker 2～3 times the quantum dot aqueous solution of this core-shell structure, and is centrifugal with the rotating speed of 3000r/min through whizzer, time is 10min, oven drying 1～2h, and be ground to 300～500 orders with crucible, obtain the quantum dot pressed powder of water miscible core-shell structure;
2) preparation of amino or carboxyl quinoline salt:
Take the consoluet tribromo propylamine of ethanol bromate and be placed in the single port flask, under the lucifuge condition, add the 4-toluquinoline, the ratio of the amount of substance of control tribromo propylamine bromate and 4-toluquinoline is 1: 1～1.5: 1.In temperature is 60 ℃～80 ℃ reflux 2～3 days, and the adularescent solid generates, with the ethanol repetitive scrubbing for several times, and the dry quinolylamine salt that gets;
Take consoluet three bromo-propionic acids of acetone and be placed in the flask, get the 4-toluquinoline after the lucifuge, the ratio of controlling the amount of substance of three bromo-propionic acids and 4-toluquinoline is 1: 1～1.5: 1.In temperature is reflux 2～3 days under 40 ℃～60 ℃ conditions, obtains containing the product of carboxyl quinoline salt, product is dripped methyl alcohol dissolve reflux fully, separates out white solid behind the cool to room temperature, after filtration carboxyl quinoline salt;
3) preparation of quantum dot-cyanine dyes fluorescent probe:
Cyanine dye joined be dissolved with a certain amount of N, stirring and dissolving in N '-dicyclohexyl carbimide and the N-maloyl imines methanol solution, with above-mentioned system the quantum dot of core-shell structure join wherein, stir, after in 20 ℃～45 ℃ water-baths, reacting 2～3 days, filter; Obtain quantum dot-cyanine dye solution; This solution is dry at ambient temperature, obtain quantum dot-cyanine dye dry product, quantum dot comprises that ZnSe or CdSe superscribe ZnS or CdS; CdS superscribes CdS or ZnS; ZnTe or CdTe superscribe ZnS or CdS; Cyanine dye includes: aminothiazole orange, carboxyl thiazole orange, amino Cyn analog derivative n=3 or 5, carboxyl Cyn analog derivative n=3 or 5; The fluorescent emission wave spectrum of control quantum dot fluorescence excitation wave spectrum and cyanine dye will have overlapping;
4) preparation of quantum dot-cyanine dye-folic acid fluorescent probe:
Is to be dissolved in dimethyl sulphoxide solution at 2: 1 above-mentioned quantum dot-cyanine dye dry product and pteroylmonoglutamic acid by the amount of substance ratio, adds ether in stirring reaction under the room temperature after 12～24 hours, produces precipitation, after filtration; Resultant precipitation is 25～35 ℃ of following vacuum-dryings in temperature after washing with ether, promptly gets quantum dot-cyanine dye-folic acid FRET fluorescent probe dry product.
Above-mentioned steps 1) contains Cd in
2+Or Zn
2+Solution be cadmium acetate, Cadmium chloride fine powder or zinc acetate, solution of zinc sulfate.
Quantum dot of the present invention-cyanine dye bioprobe preparation method further specifies implementation procedure by following examples, but is not limited to this.
Embodiment 1: quantum dot-cyanine dye-folic acid biological probe I number preparation
1) preparation of quantum dot:
The carboxyl quantum dot is synthetic: with 5.14gCd Cl
22.5H
2O is dissolved in the 200mL deionized water, and to drip the 2mL Thiovanic acid and transfer to pH with NaOH solution in this solution be 10～11, the fresh transparent 0.00627molNa that contains of dropping under the nitrogen protection condition
2SeSO
3Precursor liquid, back flow reaction obtains transparent CdSe quantum dot nuclear solution;
The preparation of quantum dot core-shell structure: under 30 ℃～40 ℃ conditions, with 2.21g sodium sulphite and 0.24gCd Cl
22.5H
2The O wiring solution-forming dropwise is added drop-wise in the above-mentioned CdSe quantum dot solution, and the ratio of shell and nuclear is 3: 1.Under nitrogen protection, controlled temperature is 100 ℃ of back flow reaction, question response finishes postcooling, the quantum dot aqueous solution of this core-shell structure is washed 3 times with acetone and anhydrous diethyl ether in beaker, through whizzer with the centrifugal 10min of the rotating speed of 3000r/min, oven drying 2h, and be ground to 500 orders with crucible, obtain the water-soluble good quantum dot pressed powder of core-shell structure Cadmium Sulfide parcel selenizing;
2) preparation of quinolylamine salt:
Take the consoluet tribromo propylamine of ethanol bromate 14.45g and be placed in the 250mL single port flask, add 4-toluquinoline 43.15g, under the lucifuge condition, in temperature is 80 ℃ of reflux 3 days, the adularescent solid generates, with the ethanol repetitive scrubbing for several times, and the dry 3.28g quinolylamine salt that gets;
3) preparation of quantum dot-cyanine dyes fluorescent probe:
Above-mentioned Cadmium Sulfide parcel CdSe quantum dots 0.77g joined be dissolved with 0.47g N, N '-two cyclohexyl carbimide, 0.39g N-maloyl imines, 2.50mL in the 100mL methanol solution of triethylamine and 1.00g quinolylamine salt, stir, reaction was filtered after 3 days in 45 ℃ of water-baths; Obtain the green solution of quantum dot-quinolinium;
Be dissolved in the 1.50g thiazole salt in the methyl alcohol and join in above-mentioned quantum dot-quinolinium solution, drip several triethylamines, induction stirring obtains containing the red solution of quantum dot-cyanine dyes fluorescent probe;
4) preparation of quantum dot-cyanine dye-folic acid fluorescent probe:
Above-mentioned quantum dot-cyanine dye dry product 0.01mmol and 0.02mmol pteroylmonoglutamic acid are dissolved in the 10ml dimethyl sulphoxide solution, add ether after 10 hours, produce precipitation, after filtration in stirring reaction under the room temperature; Resultant precipitation is 35 ℃ of following vacuum-dryings in temperature after washing with ether, promptly gets quantum dot-cyanine dye-folic acid fluorescent probe dry product.This probe claims again quantum dot-cyanine dye-folic acid biological probe I number.
With the 0.00627mol Na in embodiment 1 step 1)
2SeSO
3Precursor liquid change the precursor liquid of 0.00627molNaHSe into, other step is constant, can get quantum dot-cyanine dye-folic acid biological probe I number;
With in embodiment 1 step 1) with 5.14gCd Cl
22.5H
2O is dissolved in the 200mL deionized water, changes (the CH with 5.99gCd into
3COOOH)
2Be dissolved in that other step is constant in the 200mL deionized water gets quantum dot-cyanine dye-folic acid biological probe I number.
Embodiment 2: quantum dot-cyanine dye-folic acid biological probe II number preparation
0.00627mol Na with embodiment 1 step 1)
2SeSO
3Precursor liquid change 0.00627molNa into
2TeSO
3Precursor liquid, 3) in change above-mentioned Cadmium Sulfide parcel cadmium selenide into Cadmium Sulfide parcel cadmium telluride, other step is constant to be got quantum dot-cyanine dye-folic acid biological probe II number;
0.00627mol Na with embodiment 1 step 1)
2SeSO
3Precursor liquid change the precursor liquid of 0.00627molNaHTe into, change above-mentioned Cadmium Sulfide parcel cadmium selenide into Cadmium Sulfide parcel cadmium telluride in the step 3), other step is constant to be got quantum dot-cyanine dye-folic acid biological probe II number.
Embodiment 3: quantum dot-cyanine dye-folic acid biological probe III number preparation
0.00627mol Na with embodiment 1 step 1)
2SeSO
3Precursor liquid change 0.00627molNa into
2The precursor liquid of S changes above-mentioned Cadmium Sulfide parcel cadmium selenide into other constant the getting quantum dot-cyanine dye-folic acid biological probe III number of step of Cadmium Sulfide parcel Cadmium Sulfide in the step 3).
Embodiment 4: quantum dot-cyanine dye-folic acid biological probe IV number preparation
With in embodiment 1 step 1) with 5.14gCd Cl
22.5H
2O is dissolved in the 200mL deionized water, and back flow reaction obtains transparent CdSe quantum dot nuclear solution, the preparation of quantum dot core-shell structure: under 30 ℃～40 ℃ conditions, with 2.21g sodium sulphite and 0.24gCd Cl
22.5H
2The O wiring solution-forming dropwise is added drop-wise in the above-mentioned CdSe quantum dot solution.Above-mentioned Cadmium Sulfide parcel CdSe quantum dots is changed into 6.23gZnSO in embodiment 1 step 3)
47H
2O is dissolved in the 200mL deionized water, and back flow reaction obtains transparent ZnSe quantum dot nuclear solution; The preparation of quantum dot core-shell structure: under 30 ℃～40 ℃ conditions, with 2.21g sodium sulphite and 0.29gZnSO
47H
2The O wiring solution-forming dropwise is added drop-wise in the sputtering ZnS e quantum dot solution.In embodiment 1 step 3) with above-mentioned zinc sulphide parcel zinc selenide quantum dot, other step is constant to be got quantum dot-cyanine dye-folic acid biological probe IV number;
To go up 6.23gZnSO in the example
47H
2O is dissolved in the 200mL deionized water, with 2.21g sodium sulphite and 0.29gZnSO
47H
2The O wiring solution-forming.Change (CH into 4.73Zn
3COOOH)
2Be dissolved in the 200mL deionized water, with 2.21g sodium sulphite and 0.28g Zn (CH
3COOOH)
2Wiring solution-forming.Other step is constant, can get quantum dot-cyanine dye-folic acid biological probe IV number.
Embodiment 5: quantum dot-cyanine dye-folic acid biological probe V number preparation
With embodiment 1 step 2) to remove, the preparation of step 3) quantum dot-cyanine dyes fluorescent probe changes into:
Above-mentioned Cadmium Sulfide parcel CdSe quantum dots 0.77g joined be dissolved with 0.47g N, N '-two cyclohexyl carbimide, 0.39g N-maloyl imines, 2.50mL in the 100mL methanol solution of the amino Cy3 of triethylamine and 2.00g, stir, reaction was filtered after 3 days in 45 ℃ of water-baths; Obtain the solution of quantum dot-Cy3; Other step is constant, can get quantum dot-cyanine dye-folic acid biological probe V number.
Embodiment 6: quantum dot-cyanine dye-folic acid biological probe V number preparation
It is constant to change the amino Cy3 of the 2.00g among the embodiment 5 into the amino Cy5 of 2.00g other step, can get quantum dot-cyanine dye-folic acid biological probe VI number.
Embodiment 7: quantum dot-cyanine dye-folic acid biological probe VII number preparation
With dripping the 2mL Thiovanic acid in embodiment 1 step 1) and transferring to pH with NaOH solution is 10～11, change that to add the 3.36g mercaptoethylamine and regulate pH with HCl solution be 3～6 steps 2 among the embodiment 1 just also into) preparation of quinolylamine salt becomes the step 2 of embodiment 7) be the preparation of carboxyl base quinolinium: take the consoluet three bromo-propionic acid 16.22g of acetone and be placed in the 250mL flask, getting 5mL 4-toluquinoline after the lucifuge is reflux 3 days under 60 ℃ of conditions in temperature, obtain containing the product of carboxyl quinoline salt, product is dripped methyl alcohol dissolve reflux fully, separate out white solid behind the cool to room temperature, get carboxyl base quinolinium after filtration;
And in the 100mL methanol solution with the 1.00g quinolylamine salt in embodiment 1 step 3), become the step 3) that becomes embodiment 7 in the 100mL methanol solution of 1.00g carboxyl quinoline salt, other step remains unchanged, and can get quantum dot-cyanine dye-folic acid biological probe VII number.
Embodiment 8: quantum dot-cyanine dye-folic acid biological probe VIII number preparation
Step 2 with embodiment 7) removes, the step 3) of embodiment 7 is become the preparation of quantum dot-cyanine dyes fluorescent probe: above-mentioned Cadmium Sulfide parcel CdSe quantum dots 0.77g is joined be dissolved with 0.47g N, N '-dicyclohexyl carbimide, 0.39g N-maloyl imines, 2.50mL in the 100mL methanol solution of triethylamine and 2.00g carboxyl Cy3, stir, reaction was filtered after 3 days in 45 ℃ of water-baths; Obtain the solution of quantum dot-Cy3; Other step is constant, can get quantum dot-cyanine dye-folic acid biological probe VIII number.
Embodiment 9: quantum dot-cyanine dye-folic acid biological probe IX number preparation
Change the 2.00g carboxyl Cy3 in the last example into 2.00g carboxyl Cy5 other constant the getting quantum dot-cyanine dye-folic acid biological probe IX number of step.
By conversion Cd
2+Or Zn
2+Solution be cadmium acetate, Cadmium chloride fine powder or zinc acetate, solution of zinc sulfate, the shell of conversion quantum dot is ZnS or CdS, the nuclear of conversion quantum dot is CdSe or ZnSe or CdTe or ZnTe or CdS, and the conversion cyanine dye is aminothiazole orange, carboxyl thiazole orange, amino Cyn analog derivative n=3 or 5, carboxyl Cyn analog derivative n=3 or 5.Can obtain quantum dot-cyanine dye-folic acid biological probe I to VIII number as above-mentioned embodiment; The cyanine dye of probe I, II, III, IV, VII number is a thiazole orange, and probe V, VI, VIII, IX number cyanine dye is the Cyn analog derivative.
Conditions such as the concentration control quantum dot reaction of the time by the foregoing description, temperature, pressure, particle, regulate the emission spectrum of quantum dot, make itself and cyanine dye to excite wave spectrum to have overlapping, thereby impel this probe to have the characteristic of FRET (fluorescence resonance energy transfer).
Claims (6)
1, a kind of quantum dot-cyanine dye-folic acid biological probe is characterized in that: this bioprobe structure includes carboxyl or amino quantum dot bonding cyanine dye bonding folic acid and the probe that forms again.
2, according to the described quantum dot-cyanine dye-folic acid biological probe of claim 1, it is characterized in that: the end of described bioprobe is a folic acid, the fluorescence emission spectrum of carboxyl or amino quantum dot and the fluorescence excitation spectrum of cyanine dye have overlapping, described probe have can target the characteristic of identification tumor tissues and FRET (fluorescence resonance energy transfer).
3, according to the described quantum dot-cyanine dye-folic acid biological probe of claim 1, it is characterized in that: the quantum dot of described bioprobe is a core-shell structure, this structure includes: ZnS or CdS are the shell of quantum dot, and CdSe or ZnSe or CdTe or ZnTe or CdS are the nuclear of quantum dot.
4, according to the described quantum dot-cyanine dye-folic acid biological probe of claim 1, it is characterized in that: the cyanine dye of described bioprobe includes: aminothiazole orange, carboxyl thiazole orange, amino Cyn analog derivative n=3 or 5, carboxyl Cyn analog derivative n=3 or 5.
5, the preparation method of the described quantum dot-cyanine dye-folic acid biological probe of a kind of claim 1, this method includes following steps:
1) preparation of quantum dot:
Carboxyl or amino quantum dot are synthetic: will contain Zn
2+Or Cd
2+Salt be dissolved in the deionized water wiring solution-forming, control Zn
2+Or Cd
2+Concentration is 1.0～2.0 * 10
-2Mol/L and to Zn
2+Or Cd
2+Dripping an amount of Thiovanic acid or mercaptoethylamine in the solution and transferring to pH with NaOH or HCl solution is 10～11 or 3～6, drips fresh transparent precursor liquid under the nitrogen protection condition, when making zinc selenide or CdSe quantum dots, drips Na
2SeSO
3Or NaHSe solution, when making zinc telluridse or cadmium telluride quantum dot, drip Na
2TeSO
3Or NaHTe solution, dripping NaS solution when making zinc sulphide or cadmiumsulfide quantum dot, back flow reaction obtains transparent quantum dot nuclear solution;
The preparation of quantum dot core-shell structure: under 30 ℃～40 ℃ conditions, with sodium sulfide solution with contain Cd
2+Or Zn
2+Solution dropwise be added drop-wise in the above-mentioned quantum dot nuclear solution shell of parcel ZnS or CdS, the S that drips by control
2+And Cd
2+Or Zn
2+Amount control the ratio of amount of substance of the shell of quantum dot and nuclear at 1: 1～3: 1, under nitrogen protection, controlled temperature is 50 ℃～100 ℃ back flow reaction, question response finishes postcooling, uses acetone and anhydrous diethyl ether to wash in beaker 2～3 times the quantum dot aqueous solution of this core-shell structure, and is centrifugal with the rotating speed of 3000r/min through whizzer, time is 10min, oven drying 1～2h, and be ground to 300～500 orders with crucible, obtain the quantum dot pressed powder of water miscible core-shell structure;
2) preparation of amino or carboxyl quinoline salt:
Taking the consoluet tribromo propylamine of ethanol bromate is placed in the single port flask, under the lucifuge condition, add the 4-toluquinoline, the ratio of the amount of substance of control tribromo propylamine bromate and 4-toluquinoline is 1: 1～1.5: 1, in temperature is 60 ℃～80 ℃ reflux 2～3 days, the adularescent solid generates, with the ethanol repetitive scrubbing for several times, and the dry quinolylamine salt that gets;
Taking consoluet three bromo-propionic acids of acetone is placed in the flask, get the 4-toluquinoline after the lucifuge, the ratio of controlling the amount of substance of three bromo-propionic acids and 4-toluquinoline is 1: 1～1.5: 1, in temperature is reflux 2～3 days under 40 ℃～60 ℃ conditions, obtain containing the product of carboxyl quinoline salt, product is dripped methyl alcohol dissolve reflux fully, separate out white solid behind the cool to room temperature, get carboxyl quinoline salt after filtration;
3) preparation of quantum dot-cyanine dyes fluorescent probe:
Cyanine dye joined be dissolved with a certain amount of N, stirring and dissolving in N '-dicyclohexyl carbimide and the N-maloyl imines methanol solution, with above-mentioned system the quantum dot of core-shell structure join wherein, stir, after in 20 ℃～45 ℃ water-baths, reacting 2～3 days, filter; Obtain quantum dot-cyanine dye solution; Quantum dot comprises that ZnSe or CdSe superscribe ZnS or CdS; CdS superscribes CdS or ZnS; ZnTe or CdTe superscribe ZnS or CdS; Cyanine dye includes: aminothiazole orange, carboxyl thiazole orange, amino Cyn analog derivative n=3 or 5, carboxyl Cyn analog derivative n=3 or 5; The fluorescent emission wave spectrum of control quantum dot fluorescence excitation wave spectrum and cyanine dye will have overlapping;
4) preparation of quantum dot-cyanine dye-folic acid fluorescent probe:
Is to be dissolved in dimethyl sulphoxide solution at 2: 1 above-mentioned quantum dot-cyanine dye dry product and pteroylmonoglutamic acid by the amount of substance ratio, adds ether in stirring reaction under the room temperature after 12～24 hours, produces precipitation, after filtration; Resultant precipitation is 25～35 ℃ of following vacuum-dryings in temperature after washing with ether, promptly gets quantum dot-cyanine dye-folic acid fluorescent probe dry product.
6, according to the preparation method of the described quantum dot of claim 5-cyanine dye bioprobe, it is characterized in that: contain Cd described in the step 1)
2+Or Zn
2+Solution be cadmium acetate, Cadmium chloride fine powder or zinc acetate, solution of zinc sulfate.
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