CN101073137A - Method and system for desorption electrospray ionization - Google Patents
Method and system for desorption electrospray ionization Download PDFInfo
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- CN101073137A CN101073137A CN 200580010684 CN200580010684A CN101073137A CN 101073137 A CN101073137 A CN 101073137A CN 200580010684 CN200580010684 CN 200580010684 CN 200580010684 A CN200580010684 A CN 200580010684A CN 101073137 A CN101073137 A CN 101073137A
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Abstract
A new method and system for desorption ionization is described and applied to the ionization of various compounds, including peptides and proteins present on metal, polymer, and mineral surfaces. Desorption electrospray ionization (DESI) is carried out by directing charged droplets and/or ions of a liquid onto the surface to be analyzed. The impact of the charged particles on the surface produces gaseous ions of material originally present on the surface. The resulting mass spectra are similar to normal ESI mass spectra in that they show mainly singly or multiply charged molecular ions of the analytes. The DESI phenomenon was observed both in the case of conductive and insulator surfaces and for compounds ranging from nonpolar small molecules such as lycopene, the alkaloid coniceine, and small drugs through polar compounds such as peptides and proteins. Changes in the solution that is sprayed can be used to selectively ionize particular compounds, including those in biological matrices. In vivo analysis is demonstrated.
Description
Related application
The application requires the provisional application No.60/558352 of submission on March 30th, 2004; The provisional application No.60/611934 that on September 21st, 2004 submitted to; The provisional application No.60/612100 that on September 22nd, 2004 submitted to; The provisional application No.60/627526 that on November 12nd, 2004 submitted to; The provisional application No.60/630365 that on November 23rd, 2004 submitted to; Priority with the provisional application No.60/643650 that submitted on January 9th, 2005.
Invention field
Usually the present invention relates to the field of analyte in the ionization of sample material, more specifically, relate under atmospheric pressure under environment or controlled condition the analyte in the ionization of sample material, by chemical analysis discern ionizable analyte and, the source of the ionizable analyte of imaging if desired, (imaging).
Background technology
The development of desorption ionization technology may provide fragile (fragile) non-volatile compound for example to break through the first time in the mass spectral analysis of peptide or carbohydrate.Plasma desorption, a kind of as in the first kind desorption ionization method realized in middle 1970s by Macfarlane, and is successfully used to meticulous (delicate) biochemical for example in the ionization of toxin.After plasma desorption, occurred much even more successful desorption ionization method, comprise secondary ion mass spectroscopy (SIMS), liquid secondary ion mass spectroscopy (LSIMS), quick ion or atom bombardment ionization (FAB) and various laser desorption technology.Substance assistant laser desorpted ionization (MALDI) is that a kind of and electro-spray ionization in the laser desorption technology is together by making the in fact biochemical analysis of any kind of feasible bioanalysis mass spectrum that makes that becomes that thorough variation take place.MALDI still is one of the most widely used ioning method, and the most widely used desorption ionization technology beyond doubt.
Except the analysis of non-volatile material, surface portrayal (surface profiling) has also become the important development direction of desorption ionization method.At present, time of flight secondary ion massspectrometry (TOF-SIMS) is one of instrument the most general in the Surface Science; Modern system provides the submicron resolution imaging capability.Though the TOF-SIMS system optimizes to be used for elementary analysis, also is optimized for organic analysis yet begin them since then.Used MALDI to implement molecular imaging recently, as the soft ionomer surface analysis instrument that can provide about the space distribution information of peptide, protein and other biomolecule in the tissue of special preparation.
Generally speaking, realized desorption ionization (DI) in the past, and be similarly to a certain extent, though their experiment parameter difference by the mass spectrum that distinct methods obtains by the particle or the photon bombardment of sample.Plasma desorption utilizes
252The high energy of Cf nucleic (MeV scope) fission fragment.The FAB experiment is usually by using high energy X e atomic beam to carry out.SIMS or LSIMS method are used 10-35keV Cs usually
+Ion is used for the surface bombardment, though can use the ion of any kind of (to comprise for example C of polyatom organic substance in theory
60).(MCI) ionization of big bunch of impact (massivecluster impact) is the soft type of a kind of extreme of SIMS, uses high energy, multi-charge glycerine cluster ion as the energy primary beam.Different with other SIMS method, the multiple-charged ion that MCI can obtain enriching, and spectrum signature is compared the spectrum signature that is similar to electron spray more with other desorption ionization method.A kind of ion sputtering experiment-chemical sputtering of low-energy type has also been described.Chemical sputtering is very effectively to test, and it uses low energy ion to discharge the molecule of absorption on the surface by electron transfer or chemical reaction incident.The laser desorption method is used UV laser (N for example usually
2Laser), but nearest IR laser, particularly-OH resonance Er:YAG laser (λ=2.94 μ m) is used widely.
For the Ionization Efficiency that strengthens known desorb and ionization techniques or only be in order to make the ionization of some material become feasible, can be with on the surface of sample deposition in the suitable matrix.FAB and LSIMS need sample dissolution at the non-volatile liquid of viscosity, high polarity for example in nitrobenzyl alcohol or the glycerine.Use sample and matrix compounds cocrystallization for MALDI.(single in theory analyte molecule is built in the lattice of matrix compounds.) MALDI matrix absorbs strongly in used Wavelength of Laser, and be easy to take place photochemistry and decompose, this is usually directed to produce the gaseous state micromolecule.
Recent findings, some surface for example silicon of active carbon or chemical etching can directly be used as laser desorption ionization (LDI) substrate, because these surfaces itself (or the absorbates above them) strengthen the LDI that is attached to the molecule above them consumingly.These LDI spectrum is similar to the MALDI spectrum, except the former situation lacks the strong basis mass peak and compares the restriction with lower a little segregant compound with conventional MALDI.
Electrospray ionization mass spectrum grows up as the alternative approach of DI, is used for being present in solution non-volatile, high polar compound mutually and comprises the macromolecular analysis of biogenetic derivation.The electro-spray ionization (ESI) or the ion-transfer that will exist already from solution are perhaps carried out ionization during bulk solution (bulksolution) is dispersed into highly charged drop subtly to gas phase.Final gas ion forms from these multi-charge drops by direct ion evaporation (situation of low molecular weight ions) or by carrying out from the complete evaporating solvent of drop (situation of macroion).A major advantage comparing ESI with other DI method is that ESI can be easily and for example liquid chromatogram or Capillary Electrophoresis coupling of separation method.Another advantage is that it is significantly softer than other any DI method.ESI needing to have avoided drying sample maybe to need specimen material and matrix cocrystallization.An ESI further favorable characteristics is to make the multi-charge species from big minute subsample.This phenomenon makes big molecule mass spectrum can use the in fact mass analyzer of any kind, comprises four utmost point filtering medium instrument, quadrupole ion trap, ICR and sector magnetic field instrument.This multi-charge phenomenon also has shortcoming, and particularly in analysis of mixtures, because a kind of signal of analyte is divided into the multi-charge state, this may make spectrum analysis become complicated.Comparing the important disadvantages of ESI with MALDI is the limited success of this method automation.Though the maldi analysis time for a sample average may be less than 1 second, for ESI, for single origin system, because the problem in implementing, each analyzes the shortest time in the cards is 20-40 second.
Though making progress to some extent aspect the ionization of mass spectral analysis material recently, still having some problems not overcome in the road of wide range of commercial use more in these technology.For example, needing can be in certain environment rather than need the low energy desorption ionization method used in the vacuum of type at SIMS.If such desorption ionization method is at atmospheric pressure and for example can play a role in those environment of laboratory or production equipment under environment (the not adding control) condition and at more controlled environment, it will address that need so.Also require such method that sample is not had to destroy substantially, result accurately is provided fast, can come ionization and desorb sample and needing avoid using for example host material pretreatment sample from kinds of surface.In addition, need be enough gentle can be used in animal tissue, plant tissue and biomaterial based on the check of desorption ionization, for example combine with drug metabolism object build-in test and the test of residue of pesticide thing.Also need to be used for not add control at atmospheric pressure with the surface, laboratory on quick, accurate and court nondestructive definite trace materials basically check.In manufacture process, comprise and existing in the manufacture process of pharmaceutical industries accurately, fast and minimize the demand of destructive quality control inspection.To for for example clinical examination quick and precisely carried out of the component of blood, urine, blood plasma and saliva of body fluid, and to for example there are demand in gel chromatography or part in conjunction with the improvement check that the sample of handling carries out for being prepared isolation technics.Also there is demand in quick test to microbe and bacterium.
Summary of the invention
The present invention is commonly referred to as desorption electrospray ionization (DESI) and satisfies these and other needs.One aspect of the present invention is the method for the analyte in desorb and the ionization of sample, comprises producing the active spraying of DESI-and guiding the active spraying of this DESI-to contact with the desorb analyte with sample analytes.The active spraying of DESI-is defined as pneumatic auxiliary fluid drop spraying herein.The active spraying of DESI-can for example form by the electro-spray ionization device, wherein gas flow by fluid from the capillary end that wherein flows to produce the charged drop of this fluid, this charged drop desorb and ionization analyte are to produce analyte ions.Selectable, can apply high-tension metal needle and with charged before analyte contacts by for example using at the fluid drop of capillary end manufacturing.The material of desorb also can by to described spraying and the surface apply identical high voltage (by between described surface and counterelectrode (for example mass spectrometric inlet), producing electrical potential difference) and desorption process after charged with the generation ion.Described spraying can comprise neutral molecule, spray gas (nebulizing gas), gas ion and the charged or not charged fluid drop of atmosphere.Show that the spraying and the interaction of analyte cause the desorb of analyte and ionization with the generation secondary ion.(secondary) ion that is produced can be analyzed to obtain the information about analyte.For example, they can carry out quality analysis in mass spectrometer.Perhaps, the ion that is produced can separate (IMS) by the ion migration, and by detecting the gained ion flow, by the species that separate are carried out quality analysis, perhaps above-mentioned these two kinds of methods are analyzed under atmospheric pressure or decompression then.The ion that is produced also can be analyzed by other known ion analysis system, for example flame spectrophotometer.Beat all, the ion that can be used for these analyses analyte manufacturing from be present in the sample on conduction and insulating surface and at atmospheric pressure under environmental condition at random, manufacturing under setting from the live organism surface and in the laboratory.
In yet another aspect, the present invention is the device of desorb and ionization analyte, comprises the mechanism that produces the active spraying of DESI-and guide it to contact with analyte.
In yet another aspect, the present invention includes the ion of analyzing ionization like this and desorb.Randomly, the present invention can also comprise the gatherer that promotes that maldi ion is collected, and this gatherer comprises through adjustment and is suitable for the pipe of moving iron to the mass spectrometer air interface, is sometimes referred to as the ion-transfer pipeline.This ion-transfer pipeline also can combine with the active spraying of DESI-source, thereby this DESI-active spraying source and this ion-transfer pipeline are operated as unitary element.
In yet another aspect, the present invention is the method that a kind of structure can be used for the database of imaging surface, described method comprises the steps: in a plurality of positions the active spraying of surface and DESI-to be contacted, and analyzes the ion of so making and the position of analysis result and desorb and the described ion of ionization is connected.The present invention includes the operational analysis result and produce the image that is present in lip-deep a kind of analyte or multiple analytes distribution.In addition, the present invention includes the method that is used for producing the 3-D view that the structure analyte distributes, comprise the layer of the described structure of ablation successively and produce the image of each layer successively.
In yet another aspect, the present invention is a method and apparatus of finishing between analyte and the reactant (reagent) reaction, comprises making analyte and the active step of spraying and contacting of DESI-that additionally comprises with the reactant of described analyte response.
In yet another aspect, the present invention is used for bound analyte or is used for the surface of part functionalization and modification that combination is used for the reactant of analyte supporting the sample holder of analyte, this sample holder to be included at least one position with DESI spraying period of contact a kind of being used for.
In yet another aspect, the present invention is a kind of sample supportive device, and the capillary interface location that is used for contiguous mass-synchrometer during DESI analyzes is used for the sample of this analysis.Described sample supportive device is normally adjustable, can fully move so that can scanning samples with respect to DESI spraying being used for imaging applications, and can regulate and be used to support disposable specimen slide or sample holder.
In yet another aspect, the present invention is a kind of fluid that is suitable for forming the active spraying of DESI-, contain the fluid or the fluid mixture that do not contain analyte, and randomly contain at least a ionization promoter, and also randomly contain the reactant (reactant) that is useful on analyte.
In yet another aspect, the present invention is court (forensic) device, being included in atmospheric pressure makes the surface be sprayed at the device that contacts under the external environmental condition with the DESI-activity, demonstration about resulting by the device of the information of maldi ion and more shown information and device about the contrast information of analyte.
Generally, thus the invention provides under atmospheric pressure desorb and ionization analyte provides the method that can be used for obtaining about the secondary ion through desorb (secondaryions) of the information of analyte.
The accompanying drawing summary
Can be expressly understood aforementioned and other target of the present invention more from accompanying drawing and this specification.Parts among the figure are not proportionally drawn, but focus on explanation principle of the present invention.
Fig. 1 schematically provides and is used for producing and sprayer unit that guiding DESI-activity is sprayed to specimen material (analyte) and is used for the resulting ion through desorb of Collection and analysis;
Fig. 2 (a) schematically provides and comprises sample preparation sprayer unit capillaceous or bar;
Fig. 2 (b) schematically provides the sprayer unit of the large sample area that is used to spray;
Fig. 3 (a) provides and is identified under atmospheric pressure and the environmental condition spectrogram that generates from the DESI of the RDX (a kind of explosive) of leather glove surface desorption;
Fig. 3 (b) provides and is identified under atmospheric pressure and the environmental condition spectrogram that generates from the DESI of the chemical warfare stimulant residue of washing nitrile gloves desorb;
Fig. 4 (a) provides the spectrogram that alkaloidal DESI generates in the identification vegetable seeds;
Fig. 4 (b) provides the collection of illustrative plates of the DESI generation that is produced by the single imaging type scanning of crossing over plant stem;
Fig. 4 (c) provides the collection of illustrative plates of the DESI generation that is produced by the single imaging type scanning of crossing over the tomato surface;
Fig. 5 provides the spectrogram of the DESI generation of the wound of bleeding among the people testee, and confirms the existence of desired components;
Fig. 6 (a-c) provides the collection of illustrative plates that generates from the DESI of the typical amino acid of surface desorption and protein;
Fig. 7 provides the collection of illustrative plates that generates from the DESI of the Ionized ox cromoci of the surface of solids;
Fig. 8 provides the purposes of the present invention in the identification enantiomer is formed;
Fig. 9 (a-c) provides the collection of illustrative plates that generates from the DESI of the ion of tablet surface desorption;
Figure 10 provides the confirmation DESI spectrogram that drug metabolite exists on experimenter's skin;
Figure 11 provides by the present invention and detects urine Chinese traditional medicine and drug metabolite;
Figure 12 (a-c) provides by bacterium finger-print of the present invention or drawing; With
Figure 13 provides the another embodiment of device constructed in accordance, is suitable for meticulousr details imaging sample surfaces.
DESCRIPTION OF THE PREFERRED
The present invention relates to the system and method for ionization and desorb material (analyte) under environmental condition at atmospheric pressure or decompression.Described system comprises the device that is used for producing to spray gas by the delivering liquid drop the active spraying of DESI-.Described system comprises that also the described DESI-activity of guiding is sprayed to lip-deep device.It should be understood that at the point that contacts with the surface the active spraying of described DESI-can comprise molecule charged or uncharged liquid drop (or the both comprises), gas ion, spray gas molecule and near atmosphere.Described pneumatic auxiliary spraying is directed into the specimen material surface, and itself and one or more analyte (if being present in the sample) interacts there, and produces the ion through desorb of described one or more analytes.Described ion through desorb may be directed to mass-synchrometer and carries out quality analysis, is directed to the IMS device and is used for also measuring the change in voltage that is produced by size separation, and be directed to flame spectrophotometer and be used for spectrum analysis, or the like.
Fig. 1 schematically illustrates an embodiment putting into practice system 10 of the present invention.Spraying 11 produces by conventional electrospray device 12 in this system.Device 12 comprises spray capillary 13, by these capillary 13 feed liquid solvents 14.Form annular spaces around nebulizer capillary 15, by this annular space spray gas nitrogen (N for example
2) to be admitted at a high speed.In one embodiment, liquid is water/carbinol mixture, and gas is nitrogen.By metal connection parts high voltage is applied to described liquid flux by power supply 17.The spray gas that flows fast is to form the active spraying 11 of the DESI-that contains liquid drop with the liquid results of interaction of leaving capillary 13.The active spraying 11 of DESI-can also comprise neutral atmospheric molecules, spray gas and gas ion.Though described electrospray device 12, any device that can produce the liquid drop stream that is delivered by the spray gas jet may be used to form the active spraying 11 of DESI-.
Spraying 11 is directed on the specimen material 21, and specimen material 21 is carried on the surface 22 in this embodiment.That leaves sample is collected and is incorporated into mass spectrometric atmospheric connection or interface 23 analyzing through the ion 25 of desorb by ion-transfer pipeline 24, and the position of wherein said ion-transfer pipeline 24 and sample are enough near to collect the ion through desorb.Surface 22 can be a platform or can be installed on the transportable platform movably, wherein said transportable platform can move with at different regional desorbs and ionization of sample 21 at x, y or z direction by known driving means, uses distribution map or the image that generates sample composition sometimes.The electromotive force of platform and temperature also can be controlled by any means known.Usually any air interface of finding in mass spectrometer all is suitable for the present invention.Use typical heated capillary air interface to obtain good result.Use has also obtained good result by the air interface of the soft ion-transfer pipeline sampling of the extension of being made by metal or insulator.
The accurate interaction of the generation sample ions that takes place between active spraying 11 of DESI-and sample 21 is not also made clear fully, but it seems not only to relate to single ionic mechanism.The data that obtain so far make us believe that at least three kinds of ions of existence form mechanism.A kind of mechanism relates to charged nanometer droplet to lip-deep " splash ", and lip-deep molecule is impacted drop and picks up in this process.It may be the reason that the collection of illustrative plates of the similar ESI of the protein seen in the DESI collection of illustrative plates of insulating surface record produces that this drop picks up mechanism.The evidence of this mechanism is included in observed state of charge distribution and the strong similitude of same protein by the state of charge distribution of conventional ESI detection in these collection of illustrative plates.The extra evidence of this mechanism is the formation of enzyme/substrate complex, and it needs described composition to spend the minimum time period together in solution.Second mechanism may relate to and has enough momentum transfer and shift with the gaseous ion that causes the surface ion desorb and the electric charge between the lip-deep molecular species.Electric charge shifts may comprise electronics, proton or other ion-exchange.This process is that the research of ion/surface collision phenomenon is learnt under the vacuum.The ionization of fruit surface carotenoid or metallic substrates cholesterol may be the example of this mechanism.The evidence of this mechanism is indirect.The not ionization under the situation of ESI of these compounds, this has got rid of drop and has picked up mechanism, and the irrelevant fact of the pH of result and spray solution has been got rid of the third mechanism (face as follows).Multiple non-volatile compound (for example heavy terpenoid, carbohydrate, peptide) demonstrates macroion efficient in the surface temperature that is significantly higher than by the spraying solvent boiling point.In these cases because the direct contact of Leifenfrost effect surface-drop is unlikely.Do not demonstrate the multiple-charged ion feature of SIMS at the resulting mass spectrum of this temperature range, this provides the circumstantial evidence of the 3rd mechanism.
The 3rd contemplated mechanism is the volatilization/desorb of neutral substance from the surface, is the gaseous ionization of being undertaken by proton translocation or the reaction of other ion then.When with 1M NH
3Some high alkalinity was supported this mechanism with the signal strength signal intensity (comparing with the signal strength signal intensity when using 0.1% acetate) that volatile alkaloid (for example coniine or conicein) increases when solution was sprayed together.It is believed that formed mass spectrum is formed by more than one mechanism in the great majority experiment; But the composition of the chemical nature of analyte, electron spray solvent and Surface Physical/geometric properties may determine to cause the dominant mechanism of ion formation.
We have found that the carrying sample the surface can be the conduction or the insulation.Sample can be liquid or freeze form.When material ionization from glass, metal, polymer, biofluid, paper, leather, clothes, cotton swab, skin, the vegetable material of cutting open and plant surface and plant and animal tissue and desorb material, the DESI method has produced useful results.In being provided with, the laboratory has been found that polytetrafluoroethylene (PTFE), polymethyl methacrylate (PMMA) and glass can be used for carrying dry sample or fluid sample, this shows that various polymeric materials all are operable, and covered in the scope of appended claim.It should be understood that not to be that all useful materials that are used to carry sample in check are all characterized fully.
Because its electrical characteristics and because it comprise by easily functionalized for example to extract the ester of interested analyte the biofluid from complex mixture, so PMMA makes us highly interested at present.Though the DESI of having been found that as described below can discern the component in the whole blood sample, but when making through functionalized when cultivating with the slide that combines with interested analyte and sample, the quality of the checkability of specific analyte and gained data all is improved before using the DESI technical Analysis.It is functionalized that sample holder can comprise that aptamers, acceptor, lectin (lectin), nucleic acid, antibody or antibody fragment, chelate or the like carry out with any useful bond material or part.Single specimen slide plate can carry out the functionalized position array that is used for the detection of DESI method with generation with multiple different part.Similarly, the DESI technology can be used for by the mass spectrum ionization and analyze separated already analyte, and described separation is for example undertaken by TLC or gel chromatography, thereby avoids and need pass through wet-chemical technique elution analysis thing from gel or thin layer surface.The efficient of the running gel analysis of being undertaken by DESI can be improved, described improvement be by utilize draw the analyte that will separate from gel transfer to rigidity more the surface and by DESI analyze this latter surface or by during analyzing or before machinery scraping gel realize.
In using the simple experiment of electrospray device as mentioned above, the insulating surface that known being used to is carried specific sample contacts with the active spraying of DESI-.Confirm to comprise the ion of sample through mass spectrum from the ion of collecting near this surface.In improvement experiment, system of the present invention is contacted with the known liquid that contains specific analyte to this experiment.Confirm to comprise the ion of known sample through mass spectrum from the ion of collecting near this liquid surface.
As in the above-mentioned experiment, can be directed into mass spectrometer analysis from the gas ion of sample manufacturing.Have been found that the specimen material that spectrogram is provided equally when by the ESI ionization, similar spectrogram is provided by the ionization of DESI method the time.For example, the DESI spectrogram of lysozyme is found and contains a series of proton corresponding to different numbers and add to multiple-charged ion on the molecule.Still not general feature, and or even observed state of charge all similar to observed state of charge in the electro-spray ionization.
In one embodiment, make up in soft ion-transfer pipeline and the active spraying of DESI-source in rod tool.The combination of this bar/transfer line can be taked various ways, comprise keep gatherer pipeline 25 and DESI-active system 10 orientation basically with the identical layout of orientation of the parts that separate shown in Fig. 1.An embodiment of suitable bar 31 is shown among Fig. 2 a.Described bar 31 can comprise DESI system 10 and the capillary ion collecting pipe or the ion-transfer pipeline 32 that carry by anchor clamps 33.The active spraying 11 of DESI-is directed on the small size or zone of sample 36, is picked up to transfer to mass analyzer by ion-transfer pipeline 32 from the desorb and the Ionized analyte of this small size.This allows carriage release lever 31 so that the zones of different of spraying and desorb and ionization of sample 36 to be provided.
Though the bar of Fig. 2 a is suitable for having single DESI system 10 and single collection embodiment capillaceous, they can easily be adjusted into and be used to take a sample for example structure of suitcase and clothes of big relatively surface.Fig. 2 b has provided the schematic top view of this type of embodiment, and wherein a plurality of DESI system 10 provides active spraying of DESI-and desorb and Ionized analyte to be collected device 37 to wide zone and collects and be used for analyzing.
In the typical laboratory operation of Fig. 1 equipment, sample solution (1-5 μ l) is at PTFE surface settlement and dry.Methanol-water (contain at 1: 1 1% acetate or 0.1% acetic acid aqueous solution) is sprayed with the flow velocity of 0.1-15 μ l/min under the influence of 4kV voltage.The nominal linear of spray gas is set at about 350m/s.These parameters are mentioned below among several embodiment of Fig. 1 equipment and being used.
Relatively being undertaken by the check of lysozyme of DESI method and MALDI sensitivity, DESI analyzes and uses Finnigan LTQ, MALDI to use Bruker Reflex III equipment.Use these concrete equipment, the lysozyme detectable limit of two kinds of technology all is in the scope of 10-50pg.
Reserpine, bradykinin and lysozyme have been measured the sensitivity of DESI under the present state of development of DESI, all these three kinds of materials all are deposited on the PTFE surface.Be present in the zone that is exposed to the active spraying of DESI-, detectable limit (LOD ' s) (corresponding to 3: 1 signal to noise ratios) is respectively 200pg, 110pg and 10pg.In these experiments, 0.2 μ l sample aqueous solution deposits and the dry point that obtains the 1.1mm diameter from the teeth outwards.In this case, the sampling area is～3mm
2, comprise the point of deposition fully.Spraying liquid is the methanol 1: 1 that contains 0.1% acetate.Other condition is shown in Table 1.
Think that at present influencing the factor of DESI Ionization Efficiency and spectrum signature is that spray condition (i.e. Pen Wu liquid, its pH, the voltage that applies and gas flow rate), spraying are most advanced and sophisticated to surperficial distance to the angle of attack and the spraying on surface.The condition of having found to be summarized in the table 1 is effective initial setting, and it has nothing to do with specimen material (analyte) to a great extent and can finely tune.Can predict, the technical staff will find to be used for the multiple setting that various DESI use.
Table 1
The useful operating condition of record DESI spectrogram
| Parameter | Optimize and set |
| Sample-MS enter the mouth (AP interface) | 30cm length |
| Electron spray voltage | ＞3kV |
| The electron spray flow velocity | 5μl/min |
| The spray gas linear velocity | 350m/s |
| MS inlet-surface distance | 2mm |
| Tip-surface distance | 5mm |
| Incident angle (α among Fig. 1) | 50 degree |
| Collection angle (β) | 10 degree |
As mentioned above, after testing multiple analytes, the monamino acid of on kinds of surface, conforming to the principle of simplicity to drug molecule to protein.Described detection confirms that the DESI technology comprises use practicality dry or aspects such as fluid sample is studied, clinical chemistry, point-of care (point-of-care) test on the array in kinds of surface.Be to use the DESI system to be used to analyze the embodiment of multiple analytes below.
The DESI apparatus and method are used for for example prospect of the lip-deep explosive of testing environment (not adding control) and chemical reagent of court and public safety applications, are described by two experiments at this.Explosive RDX obtains 1ng/mm from tan leather (pig) surface desorption of insulation in an experiment
2The anion DESI of RDX spectrum (Fig. 3 (a)) uses acetonitrile (CAN)/methyl alcohol (MeOH)/trifluoroacetic acid (TFA) 1: 1: 0.1% as solvent.The existence of this explosive is confirmed by polyphone MS (illustration) in the spectrogram.
In second experiment, the nitrile gloves were exposed to dimethyl methyl phosphonate steam (DMMP is the chemical weapons stimulants) less than one second, washed then and drying, provided mass spectrum, were shown among Fig. 3 (b) existence of clear and definite demonstration trace DMMP.Use acetonitrile (ACN)/methyl alcohol (MeOH)/trifluoroacetic acid (TFA) as solvent to obtain the cation DESI spectrogram of DMMP at 1: 1: 0.1%. Embodiment 1 and 2 also show the active spraying of DESI-comprise can with the material of example reaction, wherein said material is to form and the mode and the sample of the ionic species measured of desorb product react.
Hemlock (Conium maculatum) seed is broken away and is positioned under environmental condition in the device among Fig. 1.Methanol is used to produce the active spraying of the DESI-that is sprayed onto on the seed, and the ion of desorb is transferred to ion and captures mass spectrometer.Fig. 4 (a) shows the positive DESI ion spectrogram that obtains.Corresponding to protonated γ-conicein (coniceine) (molecular weight 125), this is a kind of alkaloid that is present in the plant at the signal of m/z126.Active spraying of DESI-and the material that is used for moving ironization and desorb are scanned to mass spectrometric shaft-like ion collection pipeline and pass one section hemlock stem.Fig. 4 (b) has shown the intensity distributions of the m/z126 of the transversal part of whole stem.The active spraying of DESI-also is scanned passes a part of tomato epidermis, and the ionised species that is produced is collected and the ion transport pipe by metal is incorporated into ion and captures MS.Resulting spectrogram is shown among Fig. 4 (c).
In experiment by using suitable interior mark can obtain quantitative result, wherein sample by pre-deposition to target surface; But it all is difficult carrying out quantitative nature in the analysis of self-faced by any method.For the plant tissue surface of piercing through, produce semiquantitative result (the relative standard deviation value is～30%) as interior target atomization compound.
The result of embodiment 3 proves the purposes of the present invention in the naturally occurring organic substance of non-destructive detection plant surface.These results also prove the purposes of the present invention in obtaining to be used for the data of species distribution on the imaging surface or biomolecule, and representative instance is the seed of opening.
The tissue of prepared fresh is placed in the active spraying of DESI-, go out as shown in fig. 1 like that, make tissue be exposed to the spraying of 1: 1 solution of ethanol/water, obtain the spectrogram of Fig. 5.Though this spectrogram comprises a lot of rich ions that produce, the MS/MS product ion spectrogram of these ions of m/z162 and m/z204 clearly proves the existence of carnitine and acetylcarnitine in the tissue.The purposes of disclosed digital proof the present invention in the analysis of body fluid, tissue etc. among the embodiment 4.
Tested multiple analytes, the monamino acid of conforming to the principle of simplicity is to drug molecule to protein, and these analytes are present in the different sample of complexity.Some representational DESI spectrograms are shown among Fig. 6 (a-c).The stenosis at viewed state of charge distribution and peak makes and can draw such conclusion: when analyte was dissolved in the same dicyandiamide solution and sprays then, the DESI spectrogram of institute's detection compound was very similar to the ESI spectrogram that is write down.
Fig. 6 (a) provides with 10ng/cm
2Average surface concentration be present in the DESI mass spectrum of the lip-deep peptide-bradykinin of PTFE.The ion that methanol is directed onto upward surperficial and desorb uses Thermo Finnigan LTQ mass spectrometer to take a sample.The m/z531 ion is represented the double charge molecular ion of bradykinin, and the m/z1061 ion is single electric charge molecular ion.
Fig. 6 (b) provides from the DESI spectrogram of the reserpine ion of PTFE surface desorption, and wherein average surface concentration is 20ng/cm
2
Fig. 6 (c) provides from the DESI spectrogram of the lysozyme of PTFE surface desorption, and wherein average surface concentration is 50ng/cm
2Have 1301,1431,1590 and the ion of 1789m/z ratio be lysozyme+11 ,+10 ,+9 and+8 state of charge.
The potential value that DESI is used to discern biologic artifact shows by the mass spectrum by the ox cromoci of trypsinization, is shown among Fig. 7.In this spectrogram, observe and surpass 60% possible trypsase fragment, this feasible identification that can implement protein by database retrieval.Fig. 7 has provided the trypsinization thing (1mg/cm of the ox cromoci that the device by Fig. 1 obtains
2) cation DESI spectrogram.
Embodiment 7
Applicability to non-covalent complex compound and other fine structure is represented that by the DESI spectrogram of L-serine it has produced this amino acid whose protonated magic number eight aggressiveness.The interaction that also can keep enzyme/substrate, enzyme/inhibitor or antigen/antibody for example is sprayed onto the acetyl group chitohexaose solution that is present on the lip-deep lysozyme of PTFE and has produced zymolyte complex compound in m/z1944 and 2220.Analyte from the teeth outwards and be incorporated between the part in the spray solution and also can generate specific complex compound.This has a lot of purposes, comprises the experiment that the wherein original enantiomer composition (chirality) that is present in lip-deep specific compound is measured.The cationic complex ions of the bond of gaseous state (it contains reference compound molecule and an analyte molecule of two enantiomer-pures) be formed, carry out quality is selected and dissociate (CID) that cause by collision by fragmentation.The enantiomer composition is measured by the intensity of main fragment ion in the dynamic method step.Use phenylalanine as analyte, the L-tryptophan is as reference, and Cu (II) is as metal center, can see between the percentage of the L-phenylalanine that (Fig. 8) exists having linear relationship (Fig. 8) that this makes and can carry out quantitatively determining to the chirality of the alanine sample of unknown enantiomeric purity in the natural logrithm of main fragment ion strength ratio and sample.This particular experiment has very wide potential application, from archaeology (age determine) to pharmaceutical applications (quality control) to asstrobiology.
The ability of a large amount of samples of DESI fast detecting is tested by directly analyzing drug molecule (Loratadine) from tablet.The typical spectrum of Claritine (Schering-Plough) tablet is illustrated in Fig. 9 (a).Be less than 0.1mg in the loss in weight that is exposed to methanol spraying tablet after 1 second, do not have visible analysis vestige.The spectrogram that is shown in the chromatogram of Fig. 9 (b) and 9 (c) and obtains shows that can be low to moderate 0.05 second the analysis time of a sample.
Embodiment 9
Charged methanol-water stream of liquid droplets is sprayed on experimenter's finger taking back 50 minutes of 10mg OTC antihistamine Loratadine (m/z383/385).Extreme care is to avoid staying this medicine of trace when taking this antihistamine on experimenter's finger.As shown in figure 10, when material by from experimenter's finger ionization, be collected in ion trap MS and when measuring, in the DESI spectrogram, observe the existence of Loratadine.Described Loratadine ion is considered to stem from the metabolin of the antihistamine of taking.Also by this way skin has been carried out test with the metabolin of finding other medicines molecule and their metabolin and food component for example caffeine, theobromine, menthol or the like.Comprise urea, amino acid, aliphatic acid, uric acid, kreatinin, glucose and other organic compound being controlled the material of on experimenter's skin, finding under the less condition.The tables of data of Miao Shuing understands that the present invention is used for the purposes of drug disposition dose monitoring, drug abuse test or the like in this embodiment.
In another metabolin check, a urine of collecting in 40 minutes after the experimenter takes two tablets of Alka-Seltzer Plus Flu medicines is placed from the teeth outwards and is subjected to the effect of charged methanol stream of liquid droplets.Capture the ion produced and obtain being shown in spectrogram among Figure 11 by mass spectral analysis.Described spectrogram comprises known peak (272.76) and the metabolite O of dextromethorphan or the peak (257.64) of N-demethyl dextromethorphan that is present in the dextromethorphan in the medicine.Kreatinin (a kind of conventional ingredient of urine) peak (114.41) is also identified.
The present invention's drafting or " finger-printization " interesting target for example purposes of the component of bacterium obtain proof in the following way: in dry about 1mg bacterial cell on the PTFE surface (growth is 24 hours on LB agar), the cell with drying places under the effect of charged methanol stream of liquid droplets then.The collect Ionized material of self-desiccation bacterial cell and in Thermo FinniganLTQ mass spectrometer, analyzing." finger-print " that so prepared Escherichia coli (Escherchia coli), Arthrobacter (Arthrobacter sp.) and Pseudomonas aeruginosa (Pseudomonas aeruginosa) also is shown in respectively among Figure 12 a, 12b and the 12c.
DESI is applied to mass spectral field comes from so simple sample making course.In fact, with respect to the standard mass spectrometry method, process analysis procedure analysis and other high throughput experimentation are greatly simplified, and show the analysis speed that can reach for 20 sample/seconds at the preliminary experiment of medicine.
MALDI and SIMS may be used to the imaging biomaterial, are to carry out in a vacuum but be to use the experiment of MALDI and SIMS.Substance assistant laser desorpted ionization of atmospheric pressure (AP-MALDI) and atmospheric pressure laser ablation have been used to the antivacuum imaging of biomaterial; But at all in these two kinds of methods, sample fixed by strictness with respect to ion source and in experimentation can not near and can not handle.Because under environmental condition, work, so DESI can be used to the analysis of self-faced, for example at specific compound imaging plant or animal tissue.This class possibility of its application obtains explanation by the DESI spectrogram of hemlock (Conium maculatum) blade-section, is shown among the embodiment 3.The peak at m/z126 place is that known its is present in this specific floristics owing to conicein among Fig. 4.The possibility of original position imaging is by the cross section that makes the spraying spot scan cross this plant stem be confirmed (Fig. 4 (b)).Similarly, the DESI spectrogram of collecting from tomato (lycopersicon esculentum) epidermis also shows the position (Fig. 4 (c)) of the characterization compound of the lycopene that is included in m/z536.Because DESI carries out in air, so it is obviously to have to allow (in-vivo) sampling in the body and in first kind of mass-spectrometric technique of the tissue surface imaging capability of living, as shown about embodiment 5.
Selectable embodiment shown in Figure 13 all is suitable in most of DESI use, and details changes into decent product surface or the upward application of species distribution of surface but wherein needing to be particularly useful for more subtly.As shown in Figure 13, the spray droplet 11 of charged liquid is directed in gas on the surface of sample 40 to use sprayer unit 10 identical to those shown in Fig. 1 basically and that have same reference numerals to incite somebody to action not.But, do not apply voltage to liquid capillary.Different is that pin 42 is placed on the position of seeking imaging and applies voltage between pin 42 and grounding electrode 43 near sample surfaces 40.Voltage on the pin 42 is lower than breakdown threshold, but but is enough to produce an electric field, and wherein this electric field will soon with before sample surfaces 40 contacts make liquid droplet charged in the spraying solvent droplets.Described charged spray droplet from nebulizer capillary is located immediately at the sample surfaces of the small size under the described pin with contact, makes that can carry out details to the surface changes into picture.Movement of sample makes can form image.
Imaging resolution based on DESI also can be improved by using mask, and the contact area that wherein said mask physically limits between active spraying of DESI-and the sample makes from the regional ion of collecting desorb of the sample surfaces of meticulous qualification.Covering (masking) also can be used for physically the ion limit of collecting being made as those ions that have straight path between sample and mass spectrometer atmospheric pressure interface substantially.Increase based on the selectable layout of the imaging resolution of DESI be to use the plane of approaching sample and be placed in sample and the active spraying of DESI-source between grid between the electric field set up.Polarized the flowing of this electric field with antagonism (resist) DESI-active spraying intermediate ion or charged drop.The conducting element that prolongs, normally lead crosses this electric field, the other end is gone up the zone of interesting imaging near the surface near the position in the active spraying of DESI-source thereby an end is positioned at.Thereby the charged generation of this conducting element tunnel-like electric field parallel with it, it promotes passing through of DESI-active spraying intermediate ion and charged drop.These electric fields play a role together the contact between active spraying of DESI-and the described surface are restricted to little zone, and do not have physics to cover viewedly to compare described little zone and have the active spraying of relative high DESI-concentration of component.
The layout of another kind of useful improvement image resolution ratio comprises that the active spraying of the DESI-that makes surface and energy level be lower than ionization and desorb desired level just contacts, and the laser of the hot spot scanning samples by for example can be enough very little increases enough energy with above ionization and desorb interaction threshold value simultaneously.
Fig. 1 of accompanying drawing schematically and with the cross-sectional view at rising visual angle has provided electrospray device 10, and this electrospray device 10 is found and can be used for making liquid surface and the active spraying 11 of DESI-to contact.In one embodiment, methanol aqueous solution (50%v/v) the electron spray voltage of 5kV by electron spray in spray gas, and the active spraying 11 of the DESI-that is produced is directed and is present in the lip-deep fluid sample that contains bradykinin of PMMA and contacts.The volume flow rate that incidence angle in this specific embodiment (α) is no more than 45 ° and solvent is 1-3 μ L/min.With respect to the atmospheric connection of Thermofinnigan LTQ mass spectrometer 23, angle β approximately is 10 °.As the favorable method in the practice, use relatively low incidence angle to avoid the overcrushing with active 11 fluid samples when contacting of spraying of DESI-.
Generally speaking, use the DESI system of the active spraying of DESI-can be used for interacting with sample, thus the ion that ionization and desorb specimen material (needing not to be this order) and generation are used to analyze through desorb.Ion through desorb can be analyzed by mass spectrometer or other analyzer.The active spraying of described DESI-can be atmospheric pressure basically with the environment that is not adding control in contact specimen material.Specimen material can perhaps can be a natural part that has ground structure with conduction or insulating surface carrying, perhaps can be liquid or the material that freezes.For example, sample can be carried on the common environmental surfaces for example clothes, luggage, paper, furniture, indoor ornament and instrument.Perhaps, described sample can be a part, hair, biological tissue, food, room temperature composition, water body, fluid, waste water, stagnant water, toxic liquid and the seawater of skin.Perhaps, described sample can be in the environment that is controlled.Described specimen material can be in medical research, science or the industry setting.Described specimen material can be attached to specimen slide to form array by one or more parts, acceptor, lectin, antibody, binding partner, chelate or the like.Described specimen material can be food or COF.The active spraying of described DESI-is made up of water and water-alcohol mixture usually.But described spraying can also comprise the reactant of specimen material, thereby makes the active spraying of specimen material and DESI-contact the detectable ion that causes from the specimen material desorb, comprises the ion of the product of reactant and sample.
Described DESI system can comprise that soft transfer line enters mass spectrometer or other analytical instrument to shift sample ions.Thereby can provide the ion map from the different piece of sample at a plurality of positions contact specimen materials.Can mobile example different zones be exposed to the active spraying of DESI-.Coverage, electric field cover (field masking) and other method can be used for spray-guided to certain location.The data that obtain from various reactions can be used for producing image or the map (map) that the component of sample material distributes.
Though various embodiments of the present invention are described, still have more embodiment and execution mode for a person skilled in the art within the scope of the invention.Therefore, the present invention only is subjected to the restriction of accompanying Claim and equivalent thereof.
Claims (47)
1. the method for the analyte in desorb and the ionization of sample material comprises the active spray droplet of DESI-is directed on the surface of specimen material to take place to interact and the described analyte of desorb with described surface.
2. the process of claim 1 wherein that the spraying that contacts with the surface has charged drop.
3. the process of claim 1 wherein that the analyte of desorb is with after desorb powers on.
4. the method for claim 2, wherein said drop is with when they form and is powered on.
5. claim 1,2 or 3 method, wherein the active spraying of described DESI-contacts with specimen material under the pressure that is atmospheric pressure basically.
6. the process of claim 1 wherein that described DESI-activity is sprayed under the external environmental condition contacts with specimen material.
7. the process of claim 1 wherein and produce the active spray droplet of described DESI-in the spray gas by inserting the liquid into.
8. the method for claim 4, the active spray droplet of wherein said DESI-produces by electrospray device.
9. claim 1,2,3 or 5 method, wherein said drop are selected from water, pure and mild their mixture.
10. the method for claim 8, wherein said liquid contains a spot of ionization promoter.
11. the method for claim 8, wherein said liquid contains the reactant of specimen material, thereby make the analyte ions that causes detectable desorb that contacts of specimen material and DESI-activity spraying, described analyte ions comprises the product of described reactant and specimen material.
12. the method for claim 6 wherein joins reactant in the described liquid ion with the desorb of the product that produces described specimen material and described reactant.
13. the method for claim 8, wherein said sample are biomaterial and described reactant be and the biomaterial of described biomaterial reaction with the analyte ions of the desorb that forms described chemical reaction.
14. the method for claim 8, its intermediate ion be introduced in the described liquid with and specimen material take place to interact and produce the ion of the desorb of the complex compound between specimen material and the described ion.
15. the process of claim 1 wherein that the active spraying of described DESI-is provided in a point of spraying on the sample and scans this ion with desorb that the representative sample different piece is provided.
16. the method for claim 15, wherein said sample relatively moves relevant with the position of described point with the ion that produces the ion of analyte the specimen material from the diverse location of specimen material and produced with point mutually.
17. the method for claim 16, the position of wherein said point is used to form the image of analyte ions on the sample.
18. the method for claim 15, wherein said point is set by covering.
19. the method for claim 15 is wherein saidly set by the drop that moves towards the described liquid of specimen material surface spray, and described drop applies charged being with electric field by the position at described point to described drop and powers on.
20. the method for claim 15, wherein saidly be lower than just by the guiding energy level that the DESI-activity of analyte desorption and ionization desired level is sprayed to the specimen material surface in the specimen material, and increase enough energy at described point and set to surpass analyte desorption and ionization threshold value.
21. the method for claim 20, wherein said energy provides by laser.
22. the process of claim 1 wherein that described DESI-activity is sprayed at the described specimen material of contact in the environment that is controlled.
23. the process of claim 1 wherein that described DESI-activity is sprayed at the described specimen material of contact in the environment that does not add control.
24. the process of claim 1 wherein that described sample is positioned on solid or the soft-surface.
25. the process of claim 1 wherein that described sample is a liquid.
26. the process of claim 1 wherein that described specimen material freezes.
27. the process of claim 1 wherein that described specimen material is carried on the specimen slide.
28. the method for claim 27, wherein said specimen material as arranged in arrays on specimen slide.
29. the method for analyte wherein is attached to one or more samples on the specimen slide by one or more parts, acceptor, lectin, antibody, binding partner, chelate etc. in the ionization of claim 1 or 15 and the desorb sample.
30. the process of claim 1 wherein that described specimen material is a biogenetic derivation.
31. the process of claim 1 wherein that described specimen material is industrial workpiece or drug products or composition.
32. the process of claim 1 wherein that described specimen material is selected from food or COF, toxin, medicine, explosive, bacterium or biological tissue.
33. the method for an analytic sample material, it comprises desorb according to claim 1 and ionization analyte and the described analyte ions of Collection and analysis then.
34. the method for claim 33, wherein said analyte ions is analyzed by mass spectrometer.
35. the method for claim 33, wherein said analyte ions is transferred to mass spectrometer by the ion-transfer pipeline near the specimen material.
36. the method for claim 33 is included in spray described specimen material and described analyte ions is carried out quality analysis in each position of a plurality of positions.
37. the method for claim 36 is included in the distributed image of each position service quality analysis with the analyte quality of development sample surfaces.
38. the system of an analytic sample material comprises:
Produce the active spraying of DESI-and it is directed to sample surfaces to take place to interact with described surface and to produce the device of the ion of analyte in the sample;
Mass-synchrometer; With
The ion that is produced is transferred to the ion-transfer pipeline of mass-synchrometer from specimen material.
39. the system of claim 38, wherein said mass-synchrometer is a mass spectrometer.
40. the system of claim 38, the active spraying of wherein said DESI-produces by electron spray equipment.
41. an analysis is positioned at the device of suprabasil analyte, comprising:
Can be directed into the source of the active spraying of DESI-of substrate; With
Analyzer has the input port, and this input port can be positioned in apart from the ion product of the enough near position of substrate with the desorb of the analyte collecting the active spraying of DESI-and produce.
42. the device of claim 41 also comprises the spectrometer that is connected with the analyzer input port.
43. the device of claim 42, wherein said spectrometer comprises mass spectrometer.
44. the device of claim 41, active spraying source of wherein said DESI-and described analyzer input port interconnect.
45. the device of claim 41 also comprises the platform of supporting described substrate.
46. the device of claim 45, wherein said substrate remains on controlled temperature.
47. the device of claim 41 also comprises the heater that is connected with the analyzer input port.
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| Application Number | Priority Date | Filing Date | Title |
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| US55835204P | 2004-03-30 | 2004-03-30 | |
| US60/558,352 | 2004-03-30 | ||
| US60/611,934 | 2004-09-21 | ||
| US60/612,100 | 2004-09-22 | ||
| US60/627,526 | 2004-11-12 | ||
| US60/630,365 | 2004-11-23 | ||
| US60/643,650 | 2005-01-13 | ||
| US11/090,455 | 2005-03-25 |
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