CN103834740B - The apoptotic HSV1-TK molecular image probe of a kind of detection - Google Patents

The apoptotic HSV1-TK molecular image probe of a kind of detection Download PDF

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CN103834740B
CN103834740B CN201410098159.1A CN201410098159A CN103834740B CN 103834740 B CN103834740 B CN 103834740B CN 201410098159 A CN201410098159 A CN 201410098159A CN 103834740 B CN103834740 B CN 103834740B
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hsv1
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CN103834740A (en
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王福
王琰
武文娇
夏玉琼
曾琦
梁继民
田捷
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Xidian University
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Abstract

The invention discloses a kind of detect apoptotic HSV1-TK molecular image probe and construction method and application. The preparation method of HSV1-TK probe provided by the invention, its step comprises: (1) cuts carrier pcDNA3.1 with restriction enzyme HindIII and XhoI enzyme, makes its linearisation; (2) C of pcr amplification DnaE end, the C end of TK gene, DEVD sequence, the N end of TK gene, the N end of albumen introne DnaE. (3) by gene recombination technology, each fragment is recombinated with linearizing pcDNA3.1 carrier in certain sequence; (4) recombinant vector is cut qualification through conversion, extraction plasmid, enzyme, obtains HSV1-TK probe. Molecular image probe of the present invention can be monitored apoptotic development by live body, and having overcome the technology such as electron microscope or flow cytometry can only be in the shortcoming of in vitro horizontal observation of cell apoptosis, for live body monitoring provides a tool.

Description

The apoptotic HSV1-TK molecular image probe of a kind of detection
Technical field
The present invention relates to biological technical field, in particular the apoptotic HSV1-TK molecular image of a kind of detectionProbe and construction method thereof and application.
Background technology
Apoptosis, is a kind of physiological apoptosis process in organism, is the one spy of cell deathDifferent directions or tendencies formula (another kind is meronecrosis) is cell for the specific change of environmental factor of living in and replying of producing. ConventionalMethod of cell apoptosis is all vitro detection method, such as electron microscope morphological observation, DNA electrophoresis, flow cytometry, enzymeConnection immunoabsorption etc., but how much all there is limitation in these methods self. Such as, sample disposal process complexity, can only be qualitative,Can not be quantitative, and all have traumaticly, conventionally can only, at a certain particular point in time research Apoptosis, can not dynamically supervise continuouslySurvey apoptosis generation and evolution in vivo.
Molecular imaging can without wound, repeat live body, real-time, dynamic, visual molecule or gene information be provided, simultaneouslyCarry out quantitative study, the data comparison that the data that obtain and conventional study means obtain, approaches the true feelings of body moreCondition. In recent years, along with the development of molecular image technology, people are applied to apoptosis research by molecular imaging gradually,This method has overcome the limitation of cell in vitro apoptosis detection method, for apoptotic basic and clinic studies is in vivo openedCreate a brand-new non-invasive research means. Molecular imaging technology mainly comprises positron emission computerized tomography(PositronEmissionTomography, PET), single photon emission computerized tomography (SinglePhotonEmissionComputedTomography, SPECT), magnetic resonance imaging (MagneticResonanceImaging,MRI), optical imagery and ultrasound molecular imaging etc. But MRI and ultrasonic imaging are because sensitivity is lower, optical imagery is owing to wearingPower and fault resolution are lower thoroughly, and its application is subject to certain limitation. SPECT is owing to having low resolution, and its application is also subject toCertain limitation. Compared with other molecular imaging technology, it is short that PET has high sensitivity and fault resolution, labeled drug half-lifeAnd do not change the remarkable advantages such as the pharmacologically active of former medicine, in vivo detect apoptotic best-of-breed technology thereby be called.
Herpes simplex virus 1 thymidine kinase (herpessimplexvirus1-thymidinekinase, HSV1-TK) reporter gene is the molecular probe of applying wider PET imaging. Its principle is substantially, the ucleosides of positron radionuclide markLike thing as18The fluoro-3-of F-9-[4-(methylol)-butyl] guanine (18F-9-[4-F-3-hydroxymethybuty]-guanine,18F-FHBG) after active transport is passed through HSV1-TK transfectional cell, by the sweet kinases of coded product chest of this gene(thymidinekinase, TK) phosphoric acid turns to 5 '-phosphoric acid nucleoside, and 5 '-phosphoric acid nucleoside can not be absorbed in through cell membrane againIn transfected cell. Thereby intracellular radioactive activity has reflected the expression of TK gene. Therefore, by building HSV1-TK'sMolecular image probe, can in vivo monitor apoptotic development by PET imaging.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of new molecular image probe based on HSV1-TK and structure thereofConstruction method, monitors apoptotic development for live body.
Technical scheme of the present invention is as follows:
A construction method that detects apoptotic HSV1-TK molecular image probe, comprises the following steps: (1) is with limittingProperty restriction endonuclease HindIII processed and XhoI enzyme are cut carrier pcDNA3.1, make its linearisation; (2) pcr amplification albumen introne DnaEThe N end DnaEn of the C end TKc of C end DnaEc, TK gene, N end TKn, the DnaE of TK gene, and the chemical synthesis DEVD of company orderRow, its sequence is 5 '-gatgaagtcgac-3 '; (3) by gene recombination technology by above-mentioned each fragment DnaEc, TKc,DEVD, TKn, DnaEn recombinate with linearizing pcDNA3.1 carrier successively; (4) recombinant vector is through transforming, extract plasmid, enzymeCut qualification, obtain HSV1-TK probe.
The apoptotic HSV1-TK molecular image probe of detection that described construction method builds, it comprises promoter, eggThe C end of white introne DnaE, the C end of TK gene, DEVD sequence, the N end of TK gene, the N end of albumen introne DnaE, its nucleosidesAcid sequence is as shown in SEQIDNO:1.
Described HSV1-TK molecular image probe is monitored the developing application of apoptotic generation at live body.
The principle of this molecular probe is as follows: shown in Fig. 1, and in vivo first through transcribing, being translated as a linear peptide chain,Thereby then carry out the TK of a cyclisation of montage formation under the effect of DnaE, at this moment the N of TK end and C end link together, butNot active. In the situation that cell is subject to environmental stimuli and causes apoptosis, thereby caspase-3 enzyme can cut DEVD siteForm a linear TK, but now TK still do not have activity. Form correct three-dimensional finally by the albumen autofolding of crossing in bodyStructure, TK has activity, thereby can be captured signal by PET imaging, apoptosis situation in antimer. Molecular image of the present invention is visitedPin can be monitored apoptotic development by live body, and having overcome the technology such as electron microscope or flow cytometry can only be in vitroThe shortcoming of horizontal observation of cell apoptosis, for live body monitoring provides a tool.
Brief description of the drawings
Fig. 1 is the fundamental diagram of this HSV1-TK molecular image probe;
Fig. 2 is the structure schematic diagram of HSV1-TK molecular image probe;
The determination of activity result of HSV1-TK when Fig. 3 is Apoptosis;
Fig. 4 is the protein conformation result of westernblot detection molecules image probe;
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in detail.
Embodiment 1 builds HSV1-TK molecular image probe, shown in Fig. 2:
1. linearized vector: pcDNA3.1 is after restriction enzyme HindIII and XhoI digestion, and enzyme is cut product and used1% agarose gel electrophoresis cuts target DNA fragment under ultraviolet light. Object band reclaims kit with glue and reclaims purifying.
2. obtain Insert Fragment:
The acquisition of DEVD sequence: utilize conventional chemical synthetic method to synthesize DEVD sequence, its sequence from Shanghai Sheng Gong companyBe 5 '-gatgaagtcgac-3 ';
The acquisition of TKn and TKc sequence: the N end of pcr amplification HSV1-TK fragment and C end respectively. In order to reduce TK in vivoToxicity, its N end above 45 amino acid sequences does not increase, but since the 46th amino acid. Through bioinformaticsAnalyses and prediction have 3 potential sites, can interrupt in these 3 sites, thereby insert DEVD sequence. These three sites are TKThe 76th, 266 and 276 amino acids sites. Therefore the TKn of amplification is respectively from 46-76,46-266,46-276 amino acid;TKc is respectively from 77-375,267-375,277-375 amino acid. 3 probes that finally obtain called after cTK76 respectively,CTK266 and cTK276.
The acquisition of DnaEn and DnaEc sequence: the N end of pcr amplification DnaE full length fragment and C end respectively. Amplification DnaEc twoThe primer 1 of end is introduced restriction enzyme site HindIII and BamHI, the primer 2 at amplification DnaEn two ends introduce restriction enzyme site NotI andXhoI. The program of amplification is: in ice bath, in the following order each composition is joined in an aseptic PCR-EP pipe
Adjust response procedures. Be placed on PCR instrument, PCR response parameter is: 94 DEG C 30 seconds; 56 DEG C 30 seconds; 72 DEG C 60Second, circulate 30 times. Last 72 DEG C 5 minutes.
3. the restructuring of Insert Fragment and carrier: fragment DnaEc, TKc that above-mentioned amplification is obtained, DEVD, TKn, DnaEn andLinearized vector pcDNA3.1 is mixed with into the DNA solution of 10ul, then adds isopyknic 10ulT4DNA ligase, fillsDivide and mix, 16 DEG C are reacted 12 hours.
4. transform: get the recombining reaction liquid of 10ul and the escherichia coli DH5a competent cell of 0.1ml mixes, 30 points on iceClock, then 42 degree heat shocks are put rapidly 5 minutes on ice for 90 seconds afterwards. Add afterwards the LB fluid nutrient medium of 800ul, 37 degree shaking tables are hatched1 hour, then to get above-mentioned bacterium liquid and be coated on the LB solid medium flat board that contains ampicillin, the placement half that faces up is littleTime, after being absorbed by culture medium completely, bacterium liquid is inverted plate, and 37 degree incubators are cultivated 16 hours.
5. positive colony qualification: picking list bacterium colony is cultivated, extracts plasmid, adopts the little extraction reagent kit (OMEGA of plasmidPlasmidMiniKit), with HindIII and the XhoI double digestion row agarose gel electrophoresis of going forward side by side. Enzyme cut be accredited as positiveClone is by further checking of order-checking. The DNA sequence dna of order-checking and corresponding amino acid sequence are:
The mensuration (seeing Fig. 3) of embodiment 2 molecular image probes activity in the time of Apoptosis
1. cultivate 22B tumour cell, get the culture dish of 12 orifice plates, add respectively a certain amount of 3x105The training of 22B cell 37 degreeSupport to 70% left and right degree of converging.
2. add respectively the cTK76 of 0.8ug according to the description of Lipofectamine2000, the matter of cTK266 and cTK276Grain DNA.
3. transfection, after 24 hours, adds the adriamycin (Dox) of 5ug/ml with cell death inducing in every porocyte.
4. induction, after 24 hours, adds the radioactive substrates of 10uCi toward every porocyte18F-FHBG, it is little that 37 degree continue cultivation 1Shi Hou, washes away culture medium, then washes 3 times with PBS, every porocyte is carried out to cracking with the each 200ml of NaOH of 0.1M.
5. collect every porocyte lysate, calculate its radioactive activity, represent with %AD, and calculate each probe at cellInterior right18The relative changing value of F-FHBG. Fig. 3 A result shows, when the different probe of transfection is in cell, after 24 hours, adoptsChemotherapeutic Dox (adriamycin) cell death inducing of 5ug/ml final concentration, after 24 hours, collecting cell is surveyed18The radioactivity of F-FHBGActivity, the absolute activity activity of cTK76 probe is the highest, the radioactive activity minimum of cTK76. But work as its value and do not add DOX medicineThe value of thing group is proofreaied and correct, and obtains the relative radioactivity activity (Fig. 3 B) of each probe. Result shows, cTK266 probe relativelyRadioactive activity is the highest, cTK276 secondly, cTK76 minimum.
When embodiment 3 Apoptosis, the protein conformation of molecular image probe is measured (Fig. 4)
1. cultivate 22B tumour cell, get the culture dish of 6 orifice plates, in 2 holes, add a certain amount of 3x10 respectively622B cell37 degree are cultured to 70% left and right degree of converging.
2. add the cTK266 DNA of 1.6ug according to the description of Lipofectamine2000.
3. transfection is after 24 hours, toward wherein adding the adriamycin (Dox) of 5ug/ml with cell death inducing in a porocyte,Another hole does not add dox for contrast.
4. induction is after 24 hours, and collecting cell, is westernblot with TK antibody and detects. Result visible (shown in Fig. 4),In the time there is no dox induction (Dox is 0), molecular probe is mainly the TK band (cyclicTK) of cyclisation in cell, but also canTo see slight linear TK band (linearTK), this is because TK probe is not before Apoptosis produces, mainly with ringIn the protein structure body of shape; Be subject to dox induction at cell and produce after apoptosis, adding dox concentration is 5ug/ml24 hourAfter, because caspase-3 activates after apoptosis, the DEVD site in probe is cut, cause some in probeThe band of cyclisation becomes linear TK band (linearTK), can see and in the time of dox5ug/ml, occur 2 bands(cyclicTK and linearTK). β-actin is as the internal reference of westernblot.
Should be understood that, for those of ordinary skills, can be improved according to the above description or convert,And all these improvement and conversion all should belong to the protection domain of claims of the present invention.

Claims (2)

1. detect an apoptotic HSV1-TK molecular image probe, it is characterized in that, construction method comprises the following steps:(1) cut carrier pcDNA3.1 with restriction enzyme HindIII and XhoI enzyme, make its linearisation; (2) pcr amplification albumen includesThe N end DnaEn of N end TKn, the DnaE of the C end DnaEc of sub-DnaE, the C end TKc of TK gene, TK gene, and company's chemistry closesBecome DEVD sequence, its sequence is 5 '-gatgaagtcgac-3 '; (3) by gene recombination technology by above-mentioned each fragment DnaEc,TKc, DEVD, TKn, DnaEn recombinate with linearizing pcDNA3.1 carrier successively; (4) recombinant vector is through transforming, extract matterGrain, enzyme are cut qualification, obtain HSV1-TK probe; The 76th, 266 of HSV1-TK probe and 276 amino acids sites are for insertingThe site of DEVD; The apoptotic HSV1-TK molecular image probe of described detection, it comprises promoter, albumen introne DnaEC end, the C end of TK gene, DEVD sequence, the N end of TK gene, the N end of albumen introne DnaE, its nucleotide sequence is as SEQShown in IDNO:1.
2. to monitor apoptotic generation at live body developing for HSV1-TK molecular image probe according to claim 1The application of non-diagnostic purpose.
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CN110317806B (en) * 2019-05-06 2021-06-04 西安电子科技大学 Constitutive splicing reporter gene image probe and preparation method thereof
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