CN100559166C - Quantum dots namo fluorescence probe combined with biochip is sought the method for Chinese medicine target spot - Google Patents
Quantum dots namo fluorescence probe combined with biochip is sought the method for Chinese medicine target spot Download PDFInfo
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- CN100559166C CN100559166C CNB2006100245663A CN200610024566A CN100559166C CN 100559166 C CN100559166 C CN 100559166C CN B2006100245663 A CNB2006100245663 A CN B2006100245663A CN 200610024566 A CN200610024566 A CN 200610024566A CN 100559166 C CN100559166 C CN 100559166C
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Abstract
The invention provides the method for a kind of quantum dot nano technology, belong to material, chemical industry, pharmacy and biological crossing domain in conjunction with pharmaceutically active ingredient action target spot in the biochip technology searching.The present invention is connected quantum dot with middle pharmaceutically active ingredient, form a kind of " quantum dot-middle pharmaceutically active ingredient " fluorescence probe, then with this fluorescence probe directly and biochip hatch altogether, after washing, determine specific binding site (being target spot) between the known protein matter fixing on medicine and the chip according to the fluorescence that quantum dot on the biochip is sent by optical excitation, and then pass through the albumen of these binding sites of computer software analysis.The pharmaceutically active ingredient pair cell produced the target protein of drug effect during the present invention can seek easy, apace, can be research herbal pharmacology and high flux ground screening new Chinese medicine technological means efficiently is provided.
Description
Technical field
The invention belongs to material, chemical industry, pharmacy and biological crossing domain, relate to a kind of combining and seek the method for Chinese medicine action target spot, the method for the target protein of pharmaceutically active ingredient effect in especially on biochip, seeking by the fluorescence of quantum dot nano particle by nanometer technology and biochip technology.
Background technology
Chinese medicine has long history in China, and she has condensed traditional culture of the Chinese nation in several thousand, for the Chinese nation and even the people of the world's health and civilization makes a great contribution.Various Chinese herbal medicines that medical literature such as the Huangdi's Internal Classics that was handed down in 1,100, " thousand sides through ", Compendium of Material Medica are put down in writing and prescription thereof still have very precious reference value highly developed today at medical sci-tech.
Yet the Chinese medicine of China is faced with the severe challenge of international community, and Chinese medicine is more weak in competitiveness in the international market, and the international market occupation rate is only about 4%, and this is very unbecoming with China's traditional Chinese medicine long history in several thousand.One of key factor that restriction Chinese medicine moves towards the international market is that the mechanism of treatment by Chinese herbs disease is unclear, and the action target spot of a lot of middle pharmaceutically active ingredients is still known nothing so far.Chinese medical extract is the potpourri of a complexity often, and is subjected to the influence in the place of production and season, and these all cause it to become a kind of not enough accurate science.Want the molecule mechanism of clear and definite treatment by Chinese herbs disease, just advanced person's science and technology and means must be introduced China's traditional Chinese medicine, make the modernization of Chinese medicine.
People studies show that for many years, and most drug is to realize its drug effect by the enzyme in the interference cell or the function of acceptor.Enzyme or acceptor all are protein, and the room that can be occupied by micromolecule is arranged on their surface a lot, and when micromolecule was combined in room on enzyme or the acceptor as the key of lock, these micromolecule promptly claimed part.When a kind of medicine and part have same or analogous shape, then this medicine just can be incorporated on enzyme or the acceptor, and the enzyme of bound drug or acceptor will send a signal to cell, make cell that a series of physiological reaction take place.The enzyme of bound drug or acceptor are this pharmaceutically-active direct target spot (target protein).When medicine can in conjunction with target spot when being a plurality of, this medicine may just have spinoff.The process that said medicine is had an effect is equally applicable to middle pharmaceutically active ingredient.Pharmaceutically active ingredient action target spot in the research can be illustrated pharmaceutically-active mechanism and bio signal Transduction Mechanism, and then can be new Chinese medicine screening foundation is provided.
The complicacy that has the effective constituent of drug effect in the Chinese medical extract makes herbal pharmacology research more more complex than the synthetic drug that has only single component.Study the target spot that each effective constituent in the mix ingredients of prodrug complex acts on cell, its workload is huge, or even can not realize.What have the honor is that biochip technology and nanometer technology make the difficult problem in this field soluble dawn occur.
Biochip has the characteristics of high throughput analysis, can show huge superiority aspect the pharmaceutically-active molecule mechanism of announcement.As protein-chip, it is that protein probe is fixed on the chip to high-density, but these protein high degree of specificity ground combine with target molecule.When medicine directly with chip on protein have an effect, can reach high flux and analyze pharmaceutically-active target spot apace, this is the most direct method of analysis drug target.For the system of middle prodrug complex, can on chip, fix a large amount of protein relevant (comprise acceptor, antibody, etc.) with the traditional Chinese medicine ingredients effect, hatch with traditional Chinese medicine ingredients then, thus tentatively definite traditional Chinese medicine ingredients action target spot.But when utilizing biochip research mechanism of drug action, what current use was more is genetic chip, as the domestic people of the having regulating action of Chinese medicine compound prescription to mouse kidney gene expression of MRL/lpr lupus and Th1/TH2 cell factor ratio that adopted mouse 8192 point gene chip researches, experiment adopts organic fluorescent dye Cy3 and Cy5 to detect results of hybridization.Experiment shows that this Chinese medicine compound prescription can be regulated the gene expression of a plurality of systems of nephridial tissue, can correct the proportional imbalance of Th1/Th2 cell factor.(Li Fei, Deng. utilize genetic chip to inquire into the regulating action of Chinese medicine compound prescription to mouse kidney gene expression of MRL/lpr lupus and Th1/TH2 cell factor ratio. Chinese combination of Chinese tradiational and Western medicine magazine .2003,23 (3): 198-206) method of this employing genetic chip research mechanism of drug action all has more bibliographical information at home and abroad, but this method can not the direct acting acceptor of clear and definite medicine.
In addition, on the current chip detection of hybridization signal be mostly by evaluation of markers on probe Cy3 and the fluorescence of Cy5 realize that especially genetic chip extensively adopts this fluorescence signal to detect.Yet this fluorescent dye has big defective, and is low as fluorescence quantum yield; Optical stability is poor; Opticator to detection system is strict; Excitation spectrum and emission spectrum have more overlapping, bring difficulty to detection; Be difficult to the same excitation of different fluorescence probes, etc.
Though protein biochip technology relatively be successfully used to high-throughout drug screening (
China's protein core Chip technology is successfully applied to high-flux medicaments sifting.http: //www.ebiotrade.com/newsf/2005-4/2005421100624.htm), but do not see that the experiment report of quantum dot nano technology conjugated protein chip technology being sought the Chinese medicine target spot is arranged.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, the short-cut method of pharmaceutically active ingredient action target spot in a kind of the searching is provided.The invention discloses the method for pharmaceutically active ingredient action target spot in the above-mentioned searching, especially disclose quantum dot and be connected a kind of to form " quantum dot-middle pharmaceutically active ingredient " namo fluorescence probe with middle pharmaceutically active ingredient, and this probe has been used for biochip to seek the method for drug target.
The present invention is achieved by the following technical solutions: the present invention is connected the quantum dot nano particle with middle pharmaceutically active ingredient, form a kind of " quantum dot-middle pharmaceutically active ingredient " fluorescence probe, then with this fluorescence probe directly and biochip hatch altogether, after washing, determine specific binding site (being target spot) between the known organism fixing on medicine and the chip according to the fluorescence that the quantum dot on the biochip is sent by optical excitation, and then pass through the albumen of these binding sites of computer software analysis.
Below preparation method of the present invention and application are further specified, specific as follows:
The present invention by in covalent bond, coordination bond, hydrogen bond, the Electrostatic Absorption any one or arbitrarily several compound actions quantum dot is connected with middle pharmaceutically active ingredient.The product that obtains, is hatched the probe and the biochip that obtain to remove free middle pharmaceutically active ingredient then by separation and purification.
Perhaps adopt silane coupling agent molecule that quantum dot is connected with middle pharmaceutically active ingredient, then the probe and the biochip that obtain are hatched.Described silane coupling agent comprises CH
2=CHSi (OC
2H
5)
3, CH
2=CHSi (OCH
3)
2, CH
2=CHSi (OC
2H
4OCH
3)
3, CH
2=C (CH
3) COOC
3H
6Si (OCH
3)
3, HSC
3H
6Si (OCH
3)
3, H
2NC
3H
6Si (OC
2H
5)
3, H
2NC
2H
4NHC
3H
6Si (OCH
3)
3, H
2NCONHC
3H
6Si (OC
2H
5)
3, CH
3Si (OC
2H
5)
3, (CH
3)
3SiNHSi (CH
3)
3, H
2NC
2H
5Si (OC
2H
5)
3In any one;
The compounds a kind of or any several combination groups that quantum dot of the present invention, its surface are contained in sulfydryl, carboxyl, amino, shin base, hydroxyl, the sulfonic group are modified.The compound of modifying when quantum dot contains carboxyl, when pharmaceutically active ingredient contains amino simultaneously, perhaps the compound of modifying when quantum dot contains amino, when pharmaceutically active ingredient contains carboxyl simultaneously, adopt 1-ethyl-3 (3-dimethyl amido propyl group) carbodiimide hydrochloride (1-ethyl-3 (3-dimethylamino propyl)-carbodiimide earlier, EDC) activated carboxyl is connected quantum dot by the reaction of carboxyl with amino then with middle pharmaceutically active ingredient.The probe and the biochip that obtain are hatched.
Above-mentioned connection procedure is to carry out in the mixed liquor of water, organic phase or water and organic solvent.
Described protein-chip, the protein in its point sample district is acceptor, antibody or specific protein, refers in particular to acceptor, antibody or the specific protein relevant with drug mechanism to be measured.
Described quantum dot is meant semiconductor nano material, refers in particular to ZnS, CdS, HgS, ZnSe, CdSe, HgSe, CdTe, ZnTe, ZnO, PbSe, HgTe, CaAs, InP, InAs, InCaAs, CdS/ZnS, CdS/Ag
2S, CdS/PbS, CdS/Cd (OH)
2, CdS/HgS, CdS/HgS/CdS, ZnS/CdS, ZnS/CdS/ZnS, ZnS/HgS/ZnS/CdS, CdSe/CdS, CdSe/ZnS, CdSe/ZnSe, CdSe/CuSe, CdSe/HgTe, CdSe/HgSe, CdSe/HgSe/CdSe, CdTe/HgS, CdTe/HgTe, InAs/InP, InAs/CdSe, InAs/ZnSe, MgS, MgSe, MgTe, CaS, CaSe, CaTe, SrS, SrSe, SeTe, BaS, BaSe, BaTe, CdS:Mn, ZnS:Mn, CdS:Cu, ZnS:Cu, CdS:Tb, the combination of any one among the ZnS:Tb or any several nano particles; And by above-mentioned any one quantum dot be nuclear, silicon dioxide is the core-shell type nano-complex particle of shell.
Pharmaceutically active ingredient in described is meant any simplification compound that extracts or the potpourri of two or more compounds arbitrarily from animal, plant or mineral.These compounds have anticancer or antihepatitic activity, the effect of cardiovascular and cerebrovascular pharmacology, AIDS resisting, anti-ageing, treatment diabetes, treatment prostatic disorders, anti-senile dementia, antibiotic, treatment disease of digestive tract, antirheumatic or rheumatism, treatment osteoporosis or climacteric syndrome active any one or any several effect.
For overcoming the deficiencies in the prior art, the present invention substitutes traditional fluorescent dye (as Cy3 and Cy5) with the quantum dot nano particle and comes pharmaceutically active ingredient in the mark, and then hatches altogether with biochip, to obtain pharmaceutically-active direct target spot.Quantum dot is meant the semiconductor nano crystallite, and yardstick is tens nanometers, a few nanometer or littler.Compare with the fluorescent dye that Cy3 and Cy5 etc. are traditional, quantum dot has very high quantum yield and light stability, and emission spectrum is narrow, and the excitation wave length and width can use the exciting light of same wavelength to carry out multi-channel detection simultaneously.In theory, thousands of kinds can be had thousands of different middle pharmaceutically active ingredients of quantum dot difference mark of different fluorescence colors and fluorescence signal intensity, and on same biochip, hatch simultaneously.Replace the conventional fluorescent molecule to combine quantum dot, then can not only significantly improve the stability of hybridization signal, strengthen intensity of hybridization signal, but also can reach the effect of two high throughput testing with biochip technology.The present invention screens for pharmaceutically active ingredient action target spot in illustrating with to new Chinese medicine has important and practical meanings.
The present invention has substantive distinguishing features and marked improvement, the superior optical property of quantum dot nano particle has overcome the deficiency of traditional organic fluorescent dye, quantum dot is connected with middle pharmaceutically active ingredient, and hatch altogether with protein-chip, the target spot of pharmaceutically active ingredient effect in can directly obtaining, medicine pharmacology and screening new Chinese medicine aspect have broad application prospects under study for action.
Embodiment
Embodiment 1:
CdSe (590) (self-control) (590 are meant that the peak position of the emission spectrum of CdSe is arranged in 590nm) the nano particle aqueous solution that is about 10nM to 50ml concentration adds mixed liquor and the 20 μ l ammoniacal liquor that 300 μ l contain the ethyl orthosilicate (purchasing in chemical reagents corporation of Chinese Medicine group) of 27% (v/v) absolute ethyl alcohol (purchasing in the virtuous chemical reagents corporation in east, Shanghai), react after 2-3 days, obtain the still solution of clear, analyze through X-ray diffraction (XRD) and X-ray energy spectrum (XPS) after getting the sample segment freeze drying, the result shows that the CdSe surface wrapped by silicon dioxide, has promptly formed CdSe/SiO
2(at preparation CdSe/SiO
2The time should control the consumption of ethyl orthosilicate, absolute ethyl alcohol and ammoniacal liquor, otherwise can cause that particle assembles.)
With CdSe/SiO
2Join absolute ethyl alcohol and silane coupling agent H
2NC
2H
5Si (OC
2H
5)
3In (purchasing in chemical reagents corporation of Chinese Medicine group) solution (in the reaction system, CdSe/KH550=10: 1.5, absolute ethyl alcohol/water=10),, obtain the CdSe/SiO that the surface connects the silane coupling agent in 60 reaction 2h
2Nano particle.Add an amount of glutaraldehyde then, and under room temperature stirring reaction 3-4h, add trichosanthin (mol ratio of CdSe and trichosanthin is about 1: 10) then, spend the night in 4 ℃ of reactions.The albumen of separated free promptly obtains " the CdSe/SiO that is obtained by covalently bound method
2-albumen " nano-complex particle.Infrared spectrum and ultra-violet absorption spectrum detect and show, the infrared spectrum of the sample that reaction obtains and the characteristic peak that ultra-violet absorption spectrum all has albumen, but peak-to-average force ratio a little less than, show CdSe/SiO
2The surface has connected a certain amount of protein drug.The control of this reaction conditions is harsh, otherwise can cause that particle obviously assembles.
Embodiment 2:
(Jiangxi book on Chinese herbal medicine work of nature Science and Technology Ltd.) is dissolved in the PBS damping fluid of pH7 with tanshin polyphenolic acid B, add 1-ethyl-3 (3-dimethyl amido propyl group) carbodiimide hydrochloride (EDC) (purchasing) in chemical reagents corporation of Chinese Medicine group, room temperature reaction 1h, quantum dot CdSe/ZnS (590) (self-control) the nano particle aqueous solution that adds the finishing mercaptoethylmaine then, room temperature reaction spends the night, and quantum dot is connected with medicine with the covalent reaction of carboxyl by amino.In the reactant liquor, CdSe/ZnS is about 50nM, and the mol ratio of CdSe/ZnS, tanshin polyphenolic acid B and EDC is about 1: 100: 120.Remove free tanshin polyphenolic acid B and EDC by the gel column separation, promptly obtain the connection product of " CdSe/ZnS-tanshin polyphenolic acid B ".This product is launched the fluorescence identical with CdSe/ZnS, i.e. red fluorescence under the optical excitation of 488nm wavelength.The Capillary Electrophoresis experiment shows that the electrophoretic velocity of " CdSe/ZnS-tanshin polyphenolic acid B " shows that than the slow approximately 1min of the electrophoretic velocity of CdSe/ZnS tanshin polyphenolic acid B is connected on the CdSe/ZnS.
Embodiment 3:
" quantum dot-tanshin polyphenolic acid B " nano-probe and protein-chip are hatched altogether: the protein-chip (number health Bioisystech Co., Ltd) in the kit is selected in this work for use, though this chip is not specially designed at this experiment, but its fixing multiple specific antigen in surface, especially the tumor cell surface expression level is higher at normal cell and tumor cell surface for they.The kit method operation is pressed in experiment, and " quantum dot-danshensuan B " nano-probe solution and chip wash the laser confocal scanning analysis after hatching 30-40min under 37 ℃.Found that a small amount of phosphor dot is arranged on the chip, illustrate that tanshin polyphenolic acid B might act on the kinds of tumor cells surface antigen.
Claims (8)
1, a kind of quantum dots namo fluorescence probe combined with biochip is sought the method for Chinese medicine target spot, it is characterized in that adopting following steps: quantum dot is connected with middle pharmaceutically active ingredient, form a kind of " quantum dot-middle pharmaceutically active ingredient " fluorescence probe, then with this fluorescence probe directly and biochip hatch altogether, after washing, determine specific binding site between the known organism fixing on medicine and the chip according to the fluorescence that the quantum dot on the biochip is sent by optical excitation, and then pass through the albumen of these binding sites of computer software analysis; Pharmaceutically active ingredient is trichosanthin or tanshin polyphenolic acid B in described.
2, method according to claim 1 is characterized in that: by in covalent bond, coordination bond, hydrogen bond, the Electrostatic Absorption any one or arbitrarily several compound actions quantum dot is connected with middle pharmaceutically active ingredient; The product that obtains to remove free middle pharmaceutically active ingredient, promptly obtains " quantum dot-middle pharmaceutically active ingredient " namo fluorescence probe by separation and purification, then this probe and biochip is hatched.
3, method according to claim 1 is characterized in that: adopt silane coupling agent molecule that quantum dot is connected with middle pharmaceutically active ingredient, then the probe and the biochip that obtain are hatched; Described silane coupling agent comprises CH
2=CHSi (OC
2H
5)
3, CH
2=CHSi (OCH
3)
2, CH
2=CHSi (OC
2H
4OCH
3)
3, CH
2=C (CH
3) COOC
3H
6Si (OCH
3)
3HSC
3H
6Si (OCH
3)
3, H
2NC
3H
6Si (OC
2H
5)
3, H
2NC
2H
4NHC
3H
6Si (OCH
3)
3, H
2NCONHC
3H
6Si (OC
2H
5)
3, CH
3Si (OC
2H
5)
3, (CH
3)
3SiNHSi (CH
3)
3, H
2NC
2H
5Si (OC
2H
5)
3In any one.
4, according to arbitrary described method among the claim 1-3, the preparation of " quantum dot-middle pharmaceutically active ingredient " namo fluorescence probe, it is characterized in that: the compounds a kind of or any several combination groups that described quantum dot, its surface are contained in sulfydryl, carboxyl, amino, the shin base are modified; The compound of modifying when quantum dot contains carboxyl, when pharmaceutically active ingredient contains amino simultaneously, perhaps the compound of modifying when quantum dot contains amino, when pharmaceutically active ingredient contains carboxyl simultaneously, adopt 1-ethyl-3 (3-dimethyl amido propyl group) carbodiimide hydrochloride activated carboxyl earlier, by the reaction of carboxyl quantum dot is connected with middle pharmaceutically active ingredient then with amino; The probe and the biochip that obtain are hatched.
5, according to arbitrary described method among the claim 1-3, it is characterized in that: described connection procedure is to carry out in the mixed liquor of water, organic phase or water and organic solvent.
6, according to arbitrary described method in the claim 4, it is characterized in that: described connection procedure is to carry out in the mixed liquor of water, organic phase or water and organic solvent.
7, method according to claim 1, it is characterized in that: described biochip is a protein-chip, the protein in its point sample district is acceptor, antibody or specific protein, refers in particular to acceptor, antibody or the specific protein relevant with drug mechanism to be measured.
8, according to arbitrary described method among the claim 1-7, it is characterized in that: described quantum dot is a semiconductor nano material, comprising: ZnS, CdS, HgS, ZnSe, CdSe, HgSe, CdTe, ZnTe, ZnO, PbSe, HgTe, CaAs, InP, InAs, InCaAs, CdS/ZnS, CdS/Ag
2S, CdS/PbS, CdS/Cd (OH)
2, CdS/HgS, CdS/HgS/CdS, ZnS/CdS, ZnS/CdS/ZnS, ZnS/HgS/ZnS/CdS, CdSe/CdS, CdSe/ZnS, CdSe/ZnSe, CdSe/CuSe, CdSe/HgTe, CdSe/HgSe, CdSe/HgSe/CdSe, CdTe/HgS, CdTe/HgTe, InAs/InP, InAs/CdSe, InAs/ZnSe, MgS, MgSe, MgTe, CaS, CaSe, CaTe, SrS, SrSe, SeTe, BaS, BaSe, BaTe, CdS:Mn, ZnS:Mn, CdS:Cu, ZnS:Cu, CdS:Tb, the combination of any one among the ZnS:Tb or any several nano particles; And be nuclear by above-mentioned any one quantum dot, silicon dioxide is the core-shell type nano-complex particle of shell.
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Families Citing this family (8)
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| CN102539780A (en) * | 2010-12-28 | 2012-07-04 | 盛世泰科生物医药技术(苏州)有限公司 | Method for seeking micromolecule chemical drug target spots by combining quantum dot nanometer fluorescent probe and protein chip |
| CN102221614B (en) * | 2011-03-28 | 2013-07-17 | 山东大学 | Analysis method for identifying effect target of small molecular compound by using gold nanoprobe |
| JP6396297B2 (en) * | 2012-08-29 | 2018-09-26 | ドンジン セミケム カンパニー リミテッド | White light emitting quantum dots |
| CN103033463A (en) * | 2012-12-26 | 2013-04-10 | 江南大学 | Method for simultaneously detecting two pathogenic bacteria by employing quantum dot marked aptamer recognition and flow cytometry |
| CN104280366B (en) * | 2013-07-03 | 2017-10-10 | 复旦大学 | A kind of method of the target proteinses of high flux detection compound |
| CN110384946A (en) * | 2018-04-16 | 2019-10-29 | 杨孟君 | Accurate Chinese medicine frequency modulation is oriented to stew |
| CN108645830A (en) * | 2018-05-15 | 2018-10-12 | 华中科技大学鄂州工业技术研究院 | A kind of method that namo fluorescence probe combined protein chip finds drug target |
| CN112175044B (en) * | 2019-07-05 | 2022-09-20 | 南京大学深圳研究院 | Polypeptide and method for biologically synthesizing near-infrared silver sulfide quantum dots |
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