CN105259229A - Single-molecule analysis method for detecting medicine - Google Patents
Single-molecule analysis method for detecting medicine Download PDFInfo
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- CN105259229A CN105259229A CN201510696153.9A CN201510696153A CN105259229A CN 105259229 A CN105259229 A CN 105259229A CN 201510696153 A CN201510696153 A CN 201510696153A CN 105259229 A CN105259229 A CN 105259229A
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Abstract
A single-molecule analysis method for detecting medicine includes the steps of establishing a medicine nano-pore sensor through natural alpha-hemolysin, sequentially adding target nucleic acid samples and medicine molecules to an electrolytic tank, and recording and analyzing the changes of nano-pore current blockage signals before and after medicine is added. Before medicine is added, current blockage signals can be produced when the target nucleic acid samples penetrate through nano-pores; after nucleic acid is combined with medicine and penetrates through the nano-pores, through the combination of products, characteristic current blockage signals are triggered, and the blockage time, the blockage current and other parameters of the characteristic current blockage signals are remarkably different compared with signals of existing nucleic acid substrates; by monitoring the pore penetrating frequency of the characteristic blockage signals and establishing the relation between the pore penetrating frequency and the concentration of medicine, target medicine can be quantitatively analyzed. In-vitro screening, analyzing and detecting of medicine molecules are achieved, and the method has the advantages of being simple, rapid and high in sensitivity.
Description
Technical field
The present invention relates to nanometer pore single-molecule analytical technology and biosensor technique field, be specifically related to a kind of single molecule analysis method of detection of drugs.
Background technology
In pharmacy and medical diagnostic field, usually to carry out the concentration of medicine, the quick detection of content, as the detection to active constituent content in pharmaceutical preparation, to the detection etc. of patients serum's drug concentration.Nucleic acid, as 26S Proteasome Structure and Function material important in biosome, is the target molecules of much anticancer and antiviral drugs at present.
The classic method of drug test mainly comprises: chromatographic technique, as vapor-phase chromatography, high performance liquid chromatography; Spectral analysis technique, as UV-VIS spectrophotometry, infrared spectrophotometer, fluorescent spectrometry; Electrochemical method; Surface plasma body resonant vibration (SPR) method etc.But in actual sample is analyzed, these methods need complicated sample pretreatment process usually, and with duration, cost is high.In addition, the most sensitivity of spectrographic technique is low, and analysis speed is slow, and is limited to the spectral absorption property of drug molecule in detecting, or needs fluorescence labeling.And electrochemical method and SPR method need the chemical modification carrying out nucleic acid probe at electrode or chip interface mostly, treatment step is comparatively loaded down with trivial details.Above-mentioned classic method has been difficult to the demand meeting drug screening and medical diagnosis on disease, needs the highly sensitive drug test means that development is fast and convenient badly.
Nano-pore as a kind of single molecule analysis technology, possess highly sensitive, without the need to mark, the advantage such as simple, cheap, quick.Directly signal can be read continuously, without the need to carrying out increasing, cloning and the sample preparation of complexity in testing process.Natural alpha hemolysin protein nano hole has unique unimolecule yardstick, can in unimolecule hierarch recognition multiple nucleic acids structure.The small-molecule drug of target nucleic acids can cause the change of nucleic acid size, structure usually, these change easily identify by alpha hemolysin protein nano hole.
Summary of the invention
In order to overcome the shortcoming of above-mentioned prior art, the object of this invention is to provide a kind of single molecule analysis method of detection of drugs, realizing the in-vitro screening of drug molecule and analyzing detection, there is simple, quick, high-sensitive advantage.
A single molecule analysis method for detection of drugs, comprises the following steps:
The structure of a, nanopore sensor:
Nanopore sensor is built based on natural alpha hemolysin, insulating polymeric material is selected to make sample cell, sample cell is divided into positive pond, anti-pond, separated by insulating polymeric material film, center membrane position has a diameter to be 150 micrometer pores, the electrolyte solution that volumetric molar concentration is not more than 1 mole often liter is added respectively on sample cell both sides, the aperture of diameter 150 microns builds phospholipid bilayer, when adding natural alpha hemolysin albumen, natural alpha hemolysin albumen spontaneously inserts in phospholipid bilayer and forms single nano-pore, two silver/silver chloride electrode is just being inserted, in the electrolyte solution in anti-pond, electrode in positive pond is connected with current detecting system, electrode ground connection in anti-pond, apply to be not more than 200mV current potential between electrode after, record the electrolyte solution single channel current signal by nano-pore,
The analysis of b, medicine detects:
Nucleic acid samples and drug molecule is added successively in the anti-pond of electrolytic cell, record adds the change of the single channel current signal before and after drug molecule respectively, nucleic acid samples molecule, with negative charge, through nano-pore under the driving of electromotive force, obtains the disabling signal S of gas current; After adding medicine, medicine and nucleic acid molecules generation specificity interact, and medicine causes corresponding gas current disabling signal S to nucleic acid in conjunction with product
drug, Medicine small molecule is less because of size, is difficult to detect signal in nanopore sensor,
Because drug specificity is in conjunction with target nucleic acids substrate, this medicine-nucleic acid is in conjunction with product compared to target nucleic acids molecule, and its size, structure all change, the S caused
drugblocking-up electric current, the Xining of signal have remarkable difference compared to S signal, therefore, it is possible to judge drug molecule whether bind nucleic acid substrate under unimolecule level, when after the medicine of variable concentrations and the nucleic acid primer specific binding of 10nM concentration, and its S produced
drugthe frequency f of signal can change with drug concentration c, by making f-c typical curve, realizes highly sensitive, the high selectivity quantitative test of drug molecule.
Described insulating polymeric material is teflon or polystyrene.
Described electrolyte solution is potassium chloride, sodium chloride or tetramethyl ammonium chloride buffer solution.
Described drug molecule is organic molecule, comprises and the interactional natural drug of nucleic acid (DNA, RNA) fragment and synthetic drug.
Described medicine comprises microbiotic, antiviral agent, Comprecin or antineoplastic.
Advantage of the present invention and good effect:
The single molecule analysis method of a kind of detection of drugs that the present invention proposes, be different from traditional drug test method, as spectroscopic analysis methods such as high performance liquid chromatography isochromatic spectrum analytic approach, UV-VIS spectrophotometry, its detection sensitivity is higher, without the need to the sample pretreatment process such as separation, purification of complexity, modify without the need to fluorescence labeling and surface chemistry, easy, economical, quick; The present invention is not limited to the spectral absorption property of drug molecule in the detection, and universality is strong; The detection method that the present invention proposes can be analyzed in the biological sample of complexity, and be not subject to the large molecule of other biological as the impact of albumen, nucleic acid etc., antijamming capability is strong, and selectivity is good.
Accompanying drawing explanation
Fig. 1 is the nanometer pore single-molecule analysis schematic diagram that embodiment detects target nucleic acids drug molecule.
Fig. 2 is that embodiment adds before and after PDS medicine, before nanopore sensor adds PDS medicine to the response signal of nucleic acid: a., and the nano-pore perforation current signal of nucleic acid, Xining, blocking-up electric current statistics histogram; B., after adding PDS medicine, medicine-DNA in conjunction with the nano-pore perforation current signal of product, and current signal " stage-1 " and " stage-2 " respective Xining, blocks electric current and adds up histogram.
Fig. 3 is the feature disabling signal (S in conjunction with product of embodiment medicine and nucleic acid
drug) frequency and the graph of a relation of drug concentration.
Embodiment
Below in conjunction with embodiment and accompanying drawing, the present invention is described in detail.
With representative nucleic acid G-tetrad target agent Pyridostatin (PDS) for embodiment, the single molecule analysis testing process of medicine and nucleic acid interaction is described.PDS is a kind of organic drug molecule of Prof. Du Yucang, and structural formula as shown in Figure 1.Correlative study finds, PDS possesses anticancer property.In cell, telomeric DNA sequence contains repetitive (TTAGGG)
n, a large amount of G-tetrad structure can be formed.The G-tetrad of PDS medicine to DNA has higher selectivity and binding ability, the G-tetrad structure in cancer cell telomere can be stablized well, inhibition cancer cell telomerase is to the prolongation effect of telomere, thus the apoptosis of priming cancer cell, reach anticancer object.
The detecting instrument related in the present invention is highly sensitive current detector, comprises current amplifier, low-pass filter etc.The reagent material etc. used in experiment, without specified otherwise, all can obtain from commercial channels.
The principle of PDS medicine and DNA interaction single molecule analysis is shown in Fig. 1, and wherein the sequence of DNA substrate is 5 '-A
25 tAGGGTTAGGGTTAGGGTTAGGGTTa
25-3 ', underscore is one section of telomeric DNA sequence, containing repetitive (TTAGGG)
n, this DNA sequence dna forms stable G-tetrad structure under excessive potassium ion exists.These sequence two ends respectively connect one section of sequence containing 25 A bases, are guiding chain, make DNA molecular enter the frequency of nano-pore higher.Because the aperture at the natural the narrowest place of alpha hemolysin is only 1.4nm, be less than the size of G-tetrad structure, when therefore this G-tetrad nucleic acid is through nano-pore, will unwind as straight chain DNA.
Embodiment, a kind of single molecule analysis method of detection of drugs, comprises the following steps:
The structure of a, nanopore sensor:
Nanopore sensor is built based on natural alpha hemolysin, select the sample cell that insulating polymeric material polystyrene is made, sample cell is divided into positive pond, anti-pond, separated by the insulating polymeric material film of band diameter 150 micrometer pores, electrolyte solution is added respectively on sample cell both sides, phospholipid bilayer can be built on the aperture of diameter 150 microns, electrolyte solution is for containing 0.5M tetramethyl ammonium chloride (TMACl), 0.1MKCl, the aqueous solution of 5mMTris, pH is 7.4, when adding natural alpha hemolysin albumen, after forming single nano-pore in natural alpha hemolysin albumen spontaneous insertion phospholipid bilayer, two silver/silver chloride electrode is just being inserted, in the electrolyte solution in anti-pond, electrode in positive pond is connected with current detecting system, electrode ground connection in anti-pond, apply+200mV current potential between electrode after, record the electrolyte solution single channel current signal by nano-pore,
The analysis of b, medicine detects:
When only there is 100nMDNA in solution, its perforation current signal is as Fig. 2 a, and the signal of each molecule blocks in " separate unit stepwise ", and average Xining is 0.30 ± 0.08s, and average blocking-up electric current is (89.09 ± 2.04) %, after add 1 μM of PDS medicine in the solution containing 100nMDNA, as shown in accompanying drawing 2b, perforation current signal occurs that " dual stage stepwise " blocks, each current signal has two levelling benches, be defined as respectively " stage-1 " and " stage-2 ", the average Xining in " stage-1 " and " stage-2 " is respectively 1.16 ± 0.61s, 4.30 ± 1.51s, average blocking-up electric current is respectively (88.70 ± 1.92) %, (95.11 ± 0.76) %, the appearance of " dual stage stepwise " disabling signal, demonstrate the formation of medicine bind nucleic acid product, the prolongation of its Xining, also demonstrate the stabilization of PDS medicine to telomere, after DNA is combined with medicine, characteristic " dual stage stepwise " disabling signal produced and " separate unit stepwise " disabling signal of nucleic acid primer have marked difference, Drugs can be applied to further.
Using 10nMDNA as target substrate, in target substrate solution, add the PDS drug molecule of variable concentrations respectively, after reacting 30min under normal temperature, carry out nano-pore testing current.Feature disabling signal (the S in conjunction with product of PDS medicine and nucleic acid is shown with reference to Fig. 3, Fig. 3
drug) frequency and the graph of a relation of PDS drug concentration, this typical curve presents good linear relationship under log-log coordinate, and the range of linearity reaches four order of magnitude spans, and from 1pM to 10nM, detectability reaches 1pM.
After adding the supernatant of human serum in the sample to which, do not affect signal to noise ratio (S/N ratio) and the sensitivity of nano-pore testing current.The drug-induced S of PDS of 10nM
drugsignal frequency is 3.90 ± 0.48min
-1, the check sample result 4.03 ± 0.56min of this testing result and not increase serum
-1close, demonstrating the present invention has good anti-interference to non-specific biological composition, can be used for complex biological sample analysis.
More than describe and be only exemplary implementation example of the present invention, according to basic skills of the present invention, the drug molecule of research comprises and the interactional natural drug of nucleic acid (DNA, RNA) fragment and synthetic drug.
Claims (5)
1. a single molecule analysis method for detection of drugs, is characterized in that, comprise the following steps:
The structure of a, nanopore sensor:
Nanopore sensor is built based on natural alpha hemolysin, insulating polymeric material is selected to make sample cell, sample cell is divided into positive pond, anti-pond, separated by insulating polymeric material film, center membrane position has a diameter to be 150 micrometer pores, the electrolyte solution that volumetric molar concentration is not more than 1 mole often liter is added respectively on sample cell both sides, phospholipid bilayer can be built on the aperture of diameter 150 microns, when adding natural alpha hemolysin albumen, natural alpha hemolysin albumen spontaneously inserts in phospholipid bilayer and forms single nano-pore, two silver/silver chloride electrode is just being inserted, in the electrolyte solution in anti-pond, electrode in positive pond is connected with current detecting system, electrode ground connection in anti-pond, apply to be not more than 200mV current potential between electrode after, record the electrolyte solution single channel current signal by nano-pore,
The analysis of b, medicine detects:
Nucleic acid samples and drug molecule is added successively in the anti-pond of electrolytic cell, record adds the change of the single channel current signal before and after drug molecule respectively, nucleic acid samples molecule, with negative charge, through nano-pore under the driving of electromotive force, obtains the disabling signal S of gas current; After adding medicine, medicine and nucleic acid molecules generation specificity interact, and medicine causes corresponding gas current disabling signal S to nucleic acid in conjunction with product
drug, Medicine small molecule is less because of size, is difficult to detect signal in nanopore sensor,
Because drug specificity is in conjunction with target nucleic acids substrate, this medicine-nucleic acid is in conjunction with product compared to target nucleic acids molecule, and its size, structure all change, the S caused
drugblocking-up electric current, the Xining of signal have remarkable difference compared to S signal, therefore, it is possible to judge drug molecule whether bind nucleic acid substrate under unimolecule level, when after the medicine of variable concentrations and the nucleic acid primer specific binding of 10nM concentration, and its S produced
drugthe frequency f of signal can change with drug concentration c, by making f-c typical curve, realizes highly sensitive, the high selectivity quantitative test of drug molecule.
2. the single molecule analysis method of a kind of detection of drugs according to claim 1, is characterized in that: described insulating polymeric material is teflon or polystyrene.
3. the single molecule analysis method of a kind of detection of drugs according to claim 1, is characterized in that: described electrolyte solution is potassium chloride, sodium chloride or tetramethyl ammonium chloride buffer solution.
4. the single molecule analysis method of a kind of detection of drugs according to claim 1, is characterized in that: described drug molecule is organic molecule, comprises and the interactional natural drug of nucleic acid (DNA, RNA) fragment and synthetic drug.
5. the single molecule analysis method of a kind of detection of drugs according to claim 1, is characterized in that: described medicine comprises microbiotic, antiviral agent, Comprecin or antineoplastic.
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| CN115728353A (en) * | 2022-08-05 | 2023-03-03 | 四川大学华西医院 | Application of MscCG in preparation of kit for detecting valproic acid drugs |
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| CN107860752A (en) * | 2017-10-23 | 2018-03-30 | 清华大学 | Nanometer pore single-molecule fluoroscopic imaging device and method under a kind of exchange power mode |
| CN107860752B (en) * | 2017-10-23 | 2020-06-23 | 清华大学 | Nanopore monomolecular fluorescence imaging device and method in alternating current mode |
| CN108181358A (en) * | 2017-11-15 | 2018-06-19 | 华东理工大学 | Method based on aerolysin nanochannel detection amino acid |
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| CN111323469A (en) * | 2020-02-14 | 2020-06-23 | 中国科学院重庆绿色智能技术研究院 | Immunoglobulin M detection method based on nanopore hydrolysis reaction |
| CN113138223A (en) * | 2021-04-23 | 2021-07-20 | 华东理工大学 | Single-molecule detection method for perfluoro and polyfluoroalkyl pollutants |
| CN113138223B (en) * | 2021-04-23 | 2022-10-28 | 华东理工大学 | Single-molecule detection method for perfluoro and polyfluoroalkyl pollutants |
| CN115728353A (en) * | 2022-08-05 | 2023-03-03 | 四川大学华西医院 | Application of MscCG in preparation of kit for detecting valproic acid drugs |
| CN115728353B (en) * | 2022-08-05 | 2023-08-11 | 四川大学华西医院 | Application of MscCG in preparation of kit for detecting valproic acid medicines |
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