CN106018572A - HPLC-TOF-MS/MS method for simultaneous determination of 10 nucleosides and application - Google Patents
HPLC-TOF-MS/MS method for simultaneous determination of 10 nucleosides and application Download PDFInfo
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
Belonging to the technical field of small molecule metabolite analysis, the invention relates to an HPLC-TOF-MS/MS method for simultaneous determination of 10 nucleosides. The method specifically includes the steps of: mixing of 10 nucleosides to prepare solutions with different concentrations; HPLC-TOF-MS/MS analysis and identification of the10 nucleosides; HPLC-TOF-MS analysis and stability, precision, detection limit and quantification limit analysis of nucleoside mixed solutions with different solutions; drawing of a standard curve of the 10 nucleosides; HPLC-TOF-MS and HPLC-TOF-MS/MS analysis of biological samples; and qualitative and quantitative analysis of several specific nucleosides in the biological samples according to the HPLC-TOF-MS/MS data of each nucleoside and the standard curve. The method has the characteristics of rapid and simple analysis process, reliable detection result and high sensitivity, and is suitable for qualitative and quantitative analysis of nucleosides in blood samples, urine samples, saliva and other biological samples.
Description
Technical field
The present invention relates to analytical chemistry and life science, particularly belong to small molecule metabolites and divide folding technical field.Relate to one
Based on HPLC-TOF-MS/MS, 10 kinds of nucleosides materials are carried out qualitative analysis, and based on HPLC-TOF-MS result to it
The method carrying out quantitative analysis, and it is applied to the analysis of such material in urine the most at last.
Background technology
Modified nucleoside in human urine and serum is mainly transfer RNA (Transfer Ribonucleic Acid, tRNA) metabolism
Product, its content reflects the metaboilic level of human body to a certain extent, and existing many reports disclose nucleosides material and tumor
And the dependency of some Inflammations reaction.When tumor occurs, tumor cell needs more nutrition supply to ensure that self is not
Disconnected breeding.Now, a large amount of synthetic protein of body, and tRNA is as the important medium in from DNA to protein building-up process,
Play key player in this process, can not be present in body steadily in the long term due to it again, therefore its metabolite obtains greatly
Accumulation.Owing to lacking the enzyme that can reuse modified nucleoside in human body, substantial amounts of modified nucleoside is caused to be arranged eventually through urine
Go out external, therefore substance in vivo metabolic process can be monitored by the content of modified nucleoside in detection urine, blood.In a word, modify
Nucleoside qualitative, quantitatively for medical diagnosis on disease and Observation On The Prognosis, all there is great meaning.
Quantitative analysis for nucleoside in urine class material preferably gathers twenty-four-hour urine liquid, but considers for feasibility, and we use
The method of Gehrke and Borek, replaces such thing in twenty-four-hour urine sample with the ratio of modified nucleoside in random urine and creatinine
The content of matter.
Existing LC-MS method there is no a kind of analysis method of simple universal for multiple nucleosides material, in view of modification
The importance of nucleoside, the present invention attempts detecting multiple nucleoside and modified nucleoside material simultaneously, finally lists second order ms figure and standard
Curve is respectively used to qualitative and quantitative study, and its analysis result, through statistical analysis, is found out material to be analyzed and deposited with tumor
Relation.
Summary of the invention
Goal of the invention
It is an object of the invention to for 10 kinds of common nucleosides materials (cytidine, guanosine, inosine, uridnine, pseudouridine, 1-
Methyladenosine, 5-methylcytidine, 5-methyl-uridin, 2-thiocytidine, N-4-acetyl group cytidine) provide a kind of simple, fast
Qualitative and quantitative analysis method, in particular to a kind of HPLC-TOF-MS/MS measuring 10 kinds of common nucleosides materials simultaneously
Method, and it is applied to the qualitative and quantitative analysis of nucleosides material in biological specimen, final result is analyzed by statistical software
After, decide the relation that the diseases such as such material and tumor exist.
Technical scheme
For achieving the above object, the technical solution used in the present invention is as follows:
1, ten kinds of mixture of nucleosides standard substance (hereinafter referred to as mixed mark), by the titer of gradient dilution six kinds of concentration of preparation, are chosen mother
Liquid carries out HPLC-TOF-MS and HPLC-TOF-MS/MS and analyzes, and HPLC-TOF-MS/MS data are used for qualitative analysis,
HPLC-TOF-MS data are used for quantitative analysis.The mixed mark of variable concentrations carries out HPLC-TOF-MS analysis successively, with
The a height of vertical coordinate of HPLC-TOF-MS mass spectra peak, the concentration of every kind of material is that abscissa draws standard curve.
2, taking mixed mark mother solution and place 0,4,12,24h, sample introduction carries out HPLC-TOF-MS analysis respectively, different according to same substance
The stability of institute's method for building up is investigated in the peak height change of time point.
3, take the mixed mark solution continuous sample introduction three times of intermediate concentration, carry out HPLC-TOF-MS analysis, investigate according to peak height change and built
The precision of cube method.
4, mixed mark solution is diluted the most further, and diluent is carried out HPLC-TOF-MS analysis, by signal to noise ratio
3: 1 and 10: 1, determine the detection limit of each material.
5, creatinine dissolves and is configured to six kinds of solution of 0-20mM/L variable concentrations, draw the standard of creatinine according to above-mentioned same method
Curve.
6, utilize method established above that the urine specimen of 20 collected example healthy volunteers and 20 example tumour patients is carried out respectively
HPLC-TOF-MS and HPLC-TOF-MS/MS analyzes, and wherein first mass spectrometric is used for quantitative analysis, and second order ms is for qualitative
Analyze.Determine the difference of modified nucleoside/creatinine ratio in two groups of samples.Its result is carried out single factor test T inspection and logistic bis-
Item regression analysis, and thus draw Receiver operating curve, draw area under curve (being called for short AUC) value, analyze three kinds
Modified nucleoside material and the dependency of tumor disease.
Beneficial effect
1, needed for the method, proportion of mobile phase is simple and easy to get, low cost, stable in properties, and it is convenient to store, and under set up gradient, institute
Having target substance all to go out peak in 10 minutes, between material, sample peak is independent of each other, i.e. separation efficiency and separating rate is preferable.
2, the present invention is directed to 10 kinds of common nucleosides materials and carried out more systematic research, it is provided that at second order ms 30V voltage
Under the conditions of second order ms fragment ion and first mass spectrometric quantitation curves, for follow-up nucleosides material research provide reference.
3, the method is applied to the qualitative and quantitative analysis of biological specimen, investigates three kinds of nucleoside in tumour patient and healthy volunteer's urine
Class material and the difference of creatinine ratio, through statistical analysis, draw the AUC of ROC curve.
Accompanying drawing explanation
Fig. 1 is that (in figure, peak numbering represents following material respectively: 1. cytidine for the base peak figure of hybrid standard product solution；2.5-methylcytidine；
3. pseudouridine；4.2-thiocytidine；5. uridnine；6. guanosine；7. inosine；8.5-methyluridine；9.1-methyladenosine；10.N-4-
Acetyl group cytidine)；
Fig. 2 is the liquid chromatogram (in figure, the same Fig. 1 of material represented respectively is numbered at peak) of hybrid standard product solution；
Fig. 3 is three kinds of modified nucleosides (M1A, pseudouridine, N-4 acetyl group cytidine) in tumour patient and healthy volunteer's urine
LC-MS total ion current comparison diagram；
Fig. 4 is the MS/MS figure of ten kinds of nucleosides material standard substance；
Fig. 5 is the three kinds of modified nucleosides (M1A, pseudouridine, the N-4 acetyl group cytidine) ROC as diagnosing tumor index
Curve.
Detailed description of the invention
A kind of HPLC-TOF-MS/MS method simultaneously measuring 10 kinds of nucleosides materials and application comprise the following steps.
One, experimental section
1, reagent and instrument:
The mixed mark of nucleosides material (include cytidine, inosine, guanosine, uridnine, M1A, pseudouridine, 5-methylcytidine,
5-methyl-uridin, pseudouridine, N-4-acetyl group cytidine)；Acetonitrile；Ultra-pure water；Formic acid.
Agilent 1250 high performance liquid chromatograph (Agilent company of the U.S.), joins G1315DDAD detector, G1312A
Binary pump, G1322A vacuum degassing machine, G1367B automatic sampler, G1316A column oven；6520Q-TOF mass spectrograph,
ESI ion source；Chromatographic column is Inertsil ODS-3 C18 post, its a size of 250mm × 4.6mm, i.d.5 μm；Electronics sky
Flat；Clothoid type agitator.
2, liquid matter condition:
Flowing phase: A=0.1% formic acid water, B=0.1% formic acid acetonitrile, elution requirement: 0-6min, 5-10%B；6-11min,
10-20%B；11-12min, 20%-100%B；12-18min, 100%B.Chromatographic column is Inertsil ODS-3 C18
Post, its a size of 250mm × 4.6mm, i.d.5 μm, sampling volume 10 μ L, column temperature 25 DEG C, flow velocity 1ml/min；DAD
Detector detection wavelength is 254nm, 220nm.Mass spectrum anions and canons mode condition: nitrogen is used as to be dried gas, nitrogen temperature
325 DEG C, flow velocity 12L/min, atomization air pressure 35psi；Capillary voltage: cation 4000V, anion 3500V；Fragmentation
Voltage: zwitterion pattern is 100V, separator voltage 60V；Quality acquisition range: zwitterion pattern is 0.05
-1KDa。
3, qualitative analysis
Ten kinds of modified nucleoside mixture standard substance (hereinafter referred to as mixed mark) are configured to HB1-HB6 by mother solution successively doubling dilution
The titer of six kinds of concentration, the concentration of all substances see table 1.Choose mother solution and carry out HPLC-TOF-MS/MS analysis, foundation
Molecular weight carries out peak identification and derives second order ms figure, and the material relating to isomers is verified the most by the following method:
1. the HPLC-TOF-MS/MS comparison of single mark is analyzed；2. with reference to mankind metabolism group data base (Human Metabolome Database,
HMDB) compare.
Table 1
4, study on the stability
Taking mixed 4 DEG C of mother solution of mark to transfer and set to 0,4,12,24h, sample introduction carries out HPLC-TOF-MS analysis respectively, at masshunter
In software, according to characterization of molecules, total ion flow graph being derived compound list, it is stable to change investigation according to the peak height of same substance
Property.
5, precision is investigated
Taking the mixed mark solution continuous sample introduction three times of intermediate concentration, carry out HPLC-TOF-MS analysis, same method derives chemical combination
Thing list, investigates the precision of institute's method for building up according to peak height change.
6, detection limit is investigated
Mixed mark solution is diluted the most further, and diluent is carried out HPLC-TOF-MS analysis, according to noise
The detection limit of each material is determined than 3: 1 and 10: 1.
7, quantitative analysis
The titer of six kinds of variable concentrations is carried out HPLC-TOF-MS analysis respectively, derives compound list according to result, paint
Make peak height and the concentration standard curve of every kind of material；Creatinine dissolves and is configured to six kinds of solution of 0-20mMol/L variable concentrations,
Sample introduction successively, same method draws the standard curve of creatinine.
8, detection of biological samples application
Gathering healthy volunteer and the random urine of tumour patient, take urine sample 500ul, 14000rpm is centrifuged 20min, takes 400u1
Supernatant is directly used in HPLC-TOF-MS and HPLC-TOF-MS/MS loading analysis, analyzes method ibid, HPLC-TOF-MS
For quantitative analysis, HPLC-TOF-MS/MS is used for qualitative analysis.According to mark song obtained as above, draw in urine three kinds with swollen
There is the ratio of closely-related modified nucleoside and creatinine content in tumor.
Two, experimental result
1, separating resulting
It is fast that this law analyzes speed, and it is complete that all substances all go out peak in 10min, and the ten kinds of material sample peaks analyzed are not subject to
Impact.
2, testing result
1) precision of ten kinds of materials, stability result (representing with RSD value) are summarized as follows:
Table 2
2) standard curve and the lowest detectable limit result of ten kinds of materials are as follows:
Table 3
3, biology sample detection application
Between tumour patient and healthy volunteer, tri-kinds of modified nucleosides of Pseu, 1-mA, N-4-acyl-C and the ratio of creatinine in urine
Value (in units of nmol/umol Cre), tumour patient: 30.912 ± 14.507,4.460 ± 2.027,0.499 ± 0.252；
Healthy volunteer: 20.815 ± 9.461,2.974 ± 1.327,0.312 ± 0.142.By data above through single factor test T inspection point
Analysis, the significance level obtaining group difference is sig. (PU/Cre)=0.004, sig. (1-mA/Cre)=0.039 respectively,
Sig. (N-4-acyl-C/Cre)=0.003, respectively less than α=0.05, it is known that the average of these three material and creatinine ratio is at tumour patient
And it is respectively provided with significant difference between healthy volunteer's group；
Drawing ROC curve according to three's logistic binomial regression analysis gained Predicted probability data, it analyzes knot
Fruit is such as following table:
Table 4
Wherein AUC=0.783, the P value of significance test is less than 0.05, refuses null hypothesis (area under curve is 0.5), illustrates three
The comprehensive of kind of modified nucleoside and creatinine ratio is effective as tumorigenic test rating.95% confidence district of area under curve
Between be [0.635,0.930].
Claims (7)
1. detect a HPLC-TOF-MS and HPLC-TOF-MS/MS assay method for 10 kinds of nucleosides materials, including such as simultaneously
Lower step:
A 10 kinds of nucleosides materials are hybridly prepared into the solution of variable concentrations by ():
B the HPLC-TOF-MS/MS of () 10 kinds of nucleosides materials analyzes；
C the HPLC-TOF-MS of () variable concentrations nucleosides material mixed solution analyzes and the stability of institute's method for building up, precision,
Detection limit is analyzed；
The drafting of (d) 10 kinds of nucleosides material standard curves.
HPLC-TOF-MS and HPLC-TOF-MS/MS condition determination the most according to claim 1, its feature is as follows:
(a) flowing phase: A=0.1% formic acid water, B=0.1% formic acid acetonitrile, elution requirement: 0-6min, 5-10%B；6-11min,
10-20%B；11-12min, 20%-100%B；12-18min, 100%B；
B () chromatographic column is Inertsil ODS-3C18 post, its a size of 250mm × 4.6mm, i.d.5 μm, sampling volume 10 μ
L, column temperature 25 DEG C, flow velocity 1mL/min；
C () DAD detector detection wavelength is 254nm, 220nm；
(d) mass spectrum anions and canons mode condition: nitrogen is used as to be dried gas, nitrogen temperature 325 DEG C, flow velocity 12L/min, atomization gas
Pressure 35psi；Capillary voltage: cation 4000V, anion 3500V；Fragmentation voltage: zwitterion pattern is 100V
Separator voltage 60V；Quality acquisition range: zwitterion pattern is 0.05-1KD；HPLC-TOF-MS/MS's is additional
Voltage is 10V, 20V or 30V.
10 kinds of nucleosides materials the most according to claim 1 are: cytidine, guanosine, inosine, uridnine, pseudouridine, 1-methyl gland
Glycosides, 5-methylcytidine, 5-methyl-uridin, 2-sulfydryl-cytidine, N-4 acetyl group cytidine.All substances all went out peak in 10 minutes
Completely.
4. analyzing a detection system for multiple nucleosides material, its detectable biological specimen is blood or urine simultaneously.
The qualitative and quantitative analysis system of nucleosides material in biological sample the most according to claim 4, it is characterised in that biological sample
This preprocess method is as follows:
A () urine sample 10000-15000r/min is centrifuged 10-20min, take supernatant and obtain HPLC-TOF-MS and HPLC-TOF-MS/MS
Sample:
B () blood sample methanol or acetonitrile precipitation Deproteinization, 10000-15000r/min is centrifuged 10-20min, takes supernatant and obtains
HPLC-TOF-MS and HPLC-TOF-MS/MS sample.
The fast qualitative of nucleosides material, detection by quantitative system in biological sample the most according to claim 4, it is characterised in that inspection
Cls analysis step is as follows:
A HPLC-TOF-MS and the HPLC-TOF-MS/MS sample introduction of () biological specimen is analyzed；
B () carries out qualitative point according to the HPLC-TOF-MS/MS data of every kind of nucleosides material to the nucleosides material in biological specimen
Analysis；Nucleosides material in biological specimen is carried out by HPLC-TOF-MS data and standard curve according to every kind of nucleosides material
Quantitative analysis；
C biological sample analysis result is carried out statistical analysis by (), including single factor test T inspection, logistic binomial regression analysis, be subject to
Examination person's performance curve is analyzed, and finds out the relation between analyzed material and tumor generation.
The qualitative and quantitative analysis system of nucleosides material in biological sample the most according to claim 4, it is characterised in that three kinds
Modified nucleoside (pseudouridine, M1A, N-4 acetyl group cytidine) and creatinine ratio comprehensive is in tumour patient group with health will
Hope person's group is analyzed, and its result is: under ROC curve, area (being called for short AUC) value is 0.783, shows three kinds of modifications
The comprehensive of nucleoside and creatinine ratio is effective as tumorigenic test rating.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108318594A (en) * | 2018-01-12 | 2018-07-24 | 上海中医药大学 | A kind of method that liquid chromatography tandem mass spectrometry measures activity of adenosine deaminase and screens its inhibitor |
| CN108398495A (en) * | 2018-02-08 | 2018-08-14 | 兰州大学 | A kind of metal affinity adsorbent is for removing the albumen in serum and detecting the nucleosides in serum |
| CN112834644A (en) * | 2020-12-31 | 2021-05-25 | 郑州大学第一附属医院 | Bladder cancer related combined marker and detection kit |
| CN112858499A (en) * | 2020-12-31 | 2021-05-28 | 郑州大学第一附属医院 | Method for simultaneously determining modified nucleoside and creatinine in urine |
-
2016
- 2016-01-27 CN CN201610064098.6A patent/CN106018572A/en active Pending
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| WEI-YI HSU等: "Analysis of urinary nucleosides as potential tumor markers in human colorectal cancer by high performance liquid chromatography/electrospray ionization tandem mass spectrometry", 《CLINICA CHIMICA ACTA》 * |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108318594A (en) * | 2018-01-12 | 2018-07-24 | 上海中医药大学 | A kind of method that liquid chromatography tandem mass spectrometry measures activity of adenosine deaminase and screens its inhibitor |
| CN108398495A (en) * | 2018-02-08 | 2018-08-14 | 兰州大学 | A kind of metal affinity adsorbent is for removing the albumen in serum and detecting the nucleosides in serum |
| CN108398495B (en) * | 2018-02-08 | 2020-07-03 | 兰州大学 | A metal affinity adsorbent for removing protein and detecting nucleoside in serum |
| CN112834644A (en) * | 2020-12-31 | 2021-05-25 | 郑州大学第一附属医院 | Bladder cancer related combined marker and detection kit |
| CN112858499A (en) * | 2020-12-31 | 2021-05-28 | 郑州大学第一附属医院 | Method for simultaneously determining modified nucleoside and creatinine in urine |
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