CN114594170A - In-vivo drug analysis method combining magnetic solid phase extraction with rapid in-situ derivatization - Google Patents
In-vivo drug analysis method combining magnetic solid phase extraction with rapid in-situ derivatization Download PDFInfo
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- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
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Abstract
The invention belongs to the technical field of analytical chemistry, and relates to an in vivo drug analysis method combining magnetic solid phase extraction with rapid in-situ derivatization. The method combines the traditional solid phase extraction step and the pre-column derivatization step of the specific drug into one step, shortens the derivatization time of the sample and reduces the consumption of solvent. The method is combined with a mass spectrometry, and can be used for accurately measuring the content of bisphosphonate medicines in a biological sample.
Description
Technical Field
The invention belongs to the technical field of analytical chemistry, and relates to an in-vivo drug analysis method combining magnetic solid-phase extraction with rapid in-situ derivatization, in particular to a pretreatment method for enriching bisphosphonate drugs in a biological sample by using a magnetic solid-phase extraction material and performing rapid in-situ derivatization on the surface of the material.
Background
The prior art discloses that the pretreatment means of biological samples is a key point of in vivo drug analysis and is also a difficult point. How to efficiently and rapidly remove interfering impurities in a sample and enrich a target substance to be detected is a hot spot which is always concerned by a person skilled in the art. In general, sample pretreatment is an indispensable operation step in a complex sample analysis process, which directly affects the sensitivity, selectivity, reliability, analysis speed, etc. of an analysis method, and thus, sample pretreatment of a biological sample has become one of important research fields of in vivo drugs at present.
Research shows that some common medicines do not have ultraviolet and fluorescence absorption per se, the detection means of monomers is poor, and therefore, the introduction of a derivatization means is needed. The traditional pre-column derivatization method can be divided into derivatization before extraction, derivatization after extraction, in-situ derivatization and sample inlet derivatization according to the relative position relationship between the derivatization reaction and the pretreatment step. In the traditional solid phase extraction, an analyte is eluted from an adsorbent, and the analyte is completely separated from the solid phase extraction adsorbent and then subjected to a derivatization reaction; and the in-situ derivatization is performed in the elution process of the solid-phase extraction of the sample. In-situ derivatization combines derivatization pretreatment operation required by the traditional method into the sample elution process, has the advantages of short time consumption of solid phase extraction and low solvent consumption, has the advantages of high sensitivity and selectivity of the derivatization method, and can reduce method errors due to the fact that the transfer process of an analyte between the elution environment and the derivatization environment is omitted. Currently, in situ derivatization methods have been used for in vivo analysis of drugs containing carboxyl, phenolic, amino, carbonyl groups.
Magnetic solid phase extraction is a sample pretreatment technology developed based on the rapid movement of a magnetic material under the action of a magnetic field. The difference between the magnetic solid-phase extraction and the traditional solid-phase extraction is that the filler of the solid-phase extraction adsorbent is dispersed in the solution or suspension of the sample without being filled in a solid-phase extraction column, the target analyte is fully mixed with the dispersed magnetic adsorbent and adsorbed by the groups on the surface of the magnetic adsorbent, and the target analyte is separated from the sample matrix along with the magnetic adsorbent under the action of an external magnetic field. Compared with the traditional solid phase extraction, the magnetic solid phase extraction has the following advantages: (1) the magnetic solid phase extraction method does not need a solid phase extraction cylinder, a vacuum pump and other pressurizing devices, and can realize the separation of the adsorption material and the sample solution only by applying an external magnetic field. (2) The magnetic solid phase extraction saves the complex and time-consuming column packing process, only the magnetic material is required to be dispersed in the sample matrix (3) the adsorbing material exists in the sample solution in a dispersed particle form, and the adsorbent can be fully contacted with the target analyte, thereby being beneficial to improving the mass transfer efficiency, shortening the extraction time and increasing the enrichment multiple of the analyte. (4) When complex samples are processed, the adsorbent is not easy to block. (5) The dosage of the magnetic solid phase extraction material is usually less than that of the filler of the solid phase extraction column, the volume of the required elution solvent is also less, and the magnetic solid phase extraction material is suitable for trace analysis. Based on the advantages, the magnetic solid phase extraction is not only widely applied to the fields of environmental analysis, food safety and the like, but also shows application prospects in-vivo drug analysis.
Research reports that transition metal ions represented by titanium ions have extremely high selectivity and affinity to phosphate groups, and the titanium ion-modified ferroferric oxide magnetic spheres are successfully applied to selective enrichment of phosphorylated peptides and isopentene pyrophosphate in a biological matrix; the titanium ion modified material has been fully demonstrated for its ability to enrich for compounds containing phosphate groups.
Based on the foundation and the current situation of the prior art, the inventor of the application intends to provide a new, simpler and faster method for enriching and derivatizing bisphosphonate in a sample in vivo, the method combines a magnetic solid-phase extraction technology and an in-situ derivatization technology, and combines the elution operation of analyte derivatization and magnetic solid-phase extraction into one step from the aspect of operation, so that the manual operation required by the solid-phase extraction and derivatization processes can be obviously reduced, the pretreatment time of bisphosphonate in vivo analysis is effectively shortened, and the sensitivity of analysis is improved.
Disclosure of Invention
The invention aims to provide a new, simple and rapid method for enriching and derivatizing bisphosphonate in an in-vivo sample based on the basis and the current situation of the prior art, and particularly relates to an in-vivo drug analysis method combining magnetic solid-phase extraction with rapid in-situ derivatization.
In the method, the existing two sample pretreatment technologies, namely the magnetic solid phase extraction technology and the analyte in-situ derivatization technology are combined, the respective advantages of the two technologies are inherited, and the method for enriching and rapidly derivatizing the bisphosphonate in the in-vivo sample is more convenient and rapid. Tests prove that the method is simple, convenient and quick, has high extraction efficiency, good reproducibility, less consumption of solvent and reagent, is safe and environment-friendly, and can accurately determine the content of the bisphosphonate medicines in the in-vivo sample.
The ferroferric oxide magnetic microsphere coated by titanium dioxide has the special properties of large specific surface area, strong adsorption capacity, strong stability and the like, is applied to the pretreatment of a sample in a complex body, is mainly based on the principle of a solid phase extraction technology, simplifies the extraction method into two steps of sample loading and elution (and in-situ derivatization), and is simpler, more convenient and faster than the traditional technology of firstly carrying out solid phase extraction and then derivatizing.
More specifically, the purpose of the invention is realized by the following technical scheme:
the method comprises the steps of taking ferroferric oxide magnetic microspheres coated by titanium dioxide as a magnetic solid-phase extraction adsorbent, loading plasma and urine samples containing bisphosphonate, carrying out in-situ derivatization and elution by using a mixed solvent containing a derivatization reagent, completing the enrichment and derivatization processes of bisphosphonate in a biological sample, carrying out nitrogen-blown concentration, redissolving by using a certain solvent, and then analyzing by using high performance liquid chromatography-tandem mass spectrometry to determine the content of bisphosphonate in the in-vivo sample.
In the invention, factors such as material dosage, sample loading solution acid concentration, extraction time, derivatization temperature and the like are selected and determined aiming at the influence factors of the extraction efficiency of the titanium dioxide coated ferroferric oxide magnetic microsphere adsorbent;
in the present invention, in the above-mentioned magnetic solid phase extraction in-situ derivatization method, the amount of the magnetic material is 100-800 μ g.
In the method for magnetic solid-phase extraction in-situ derivatization, the concentration of trifluoroacetic acid in the loading solution is 0.5-8%.
In the method for magnetic solid phase extraction in-situ derivatization, the extraction time is 0.5 min-12 min.
In the method for magnetic solid phase extraction in-situ derivatization, an elution solvent and a derivatization reagent are mixed according to a certain volume ratio, the volume of the mixed solvent is 100-.
In the method for the magnetic solid-phase extraction in-situ derivatization, the derivatization time is 1-16 min, and the derivatization temperature is 25-60 ℃.
The test shows that the magnetic solid phase extraction in-situ derivatization method of the invention adopts the experimental materials integrating extraction, concentration and in-situ derivatization into a whole: the ferroferric oxide magnetic microspheres coated by titanium dioxide enable the sample pretreatment of bisphosphonate in vivo samples to be simple, accurate, reliable, rapid, good in reproducibility, safe and environment-friendly; has the advantages of good selectivity, strong specificity, rapidness and convenience, and can be used for accurately measuring the concentration of bisphosphonate medicines in vivo samples.
The invention provides a simpler, more convenient and faster method for enriching and derivatizing bisphosphonate in an in-vivo sample, wherein the magnetic solid-phase extraction in-situ derivatization technology can provide technical support for in-vivo analysis and research of a medicament needing a pre-column derivatization technology, and meanwhile, the invention provides a new method for developing a complex sample pretreatment technology.
Drawings
FIG. 1 is a schematic diagram of the structure and synthesis of a magnetic ferroferric oxide microsphere coated with titanium dioxide.
FIG. 2 is a transmission electron microscope photograph of the ferroferric oxide magnetic microspheres coated with titanium dioxide.
FIG. 3 is a schematic diagram of the operation steps of the magnetic solid phase extraction in-situ derivatization technique.
Detailed Description
The following examples are further illustrative of the present invention and are not intended to limit the scope of the present invention.
Example 1 magnetic solid phase extraction in situ derivatization method for detection of alendronate sodium in plasma samples
1) Synthesizing titanium dioxide coated magnetic ferroferric oxide microspheres:
(1) and (3) synthesis of nano ferroferric oxide: fe3O4Magnetic sphere synthesized by solvothermal method[9]The specific operation of the synthesis is as follows: FeCl is added3·6H2Fully grinding O into fine powder, taking 1.35g of ethylene glycol dispersed in 75mL, stirring for a period of time until the solution is clear, slowly adding 3.6g of sodium acetate into the solution, continuously stirring until the solution is uniform, transferring the obtained suspension into a 200mL reaction kettle, and heating and reacting for 16 hours at 200 ℃; then cooling the reaction kettle to room temperature, alternately washing the obtained product with water and ethanol for three times, and performing vacuum drying;
(2) synthesizing ferroferric oxide-dopamine magnetic microspheres: 40mg of dried Fe3O4Dispersing the powder in 40mL Tris aqueous solution (10mM, pH 8.5), adding 80mL ethanol, mixing, weighing 160mg dopamine hydrochloride, dissolving in 60mL deionized water, adding the dopamine hydrochloride solution into the reaction system, stirring at room temperature for 12h, and finally adding the product (Fe)3O4@ PD) was washed with water and ethanol alternately 3 times and dried under vacuum;
(3) synthesizing the ferroferric oxide-titanium dioxide magnetic microspheres: 40mg of dried Fe3O4@ PD microspheres were added to 200ml of 50mM titanium sulfate solution, stirred at room temperature for 4 hours, washed with water three times, vacuum dried, and the dried material was calcined at 400 ℃ for 2 hours. Completely cooling to obtain the required material;
2) detection of alendronate sodium in rat plasma by magnetic solid phase extraction in-situ derivatization method
(1) The instrument comprises the following steps: agilent 1200 high performance liquid chromatograph; AB SCIEX 4000 triple quadrupole mass spectrometer; a nitrogen blowing device; an Eppendorf ThermoMixer C oscillator; eppendorf 5418R bench centrifuge; a magnetic separation rack;
(2) materials: standard alendronate sodium; alendronate sodium-d 6 standard; trimethylsilyl diazomethane solution; methanol; deionized water; ammonium acetate; acetonitrile; trifluoroacetic acid; titanium dioxide modified ferroferric oxide magnetic microspheres; rat plasma samples;
(3) sample pretreatment: adding 200 mul of blood plasma and 200 mul of trifluoroacetic acid solution into a 2ml centrifuge tube containing titanium dioxide modified ferroferric oxide magnetic microspheres, oscillating for 4min, separating materials by a magnetic field, and discarding supernatant; adding 400 μ l of cleaning solvent, oscillating for 30s, separating material with magnetic field, and discarding supernatant; adding 200 μ l methanol and 100 μ l trimethyl silyl diazomethane solution, oscillating for 2min at 50 deg.C, separating material by magnetic field, transferring supernatant into another clean centrifuge tube, blow-drying the solution in the centrifuge tube at 40 deg.C with nitrogen, redissolving with 100 μ l mobile phase, and analyzing by LC-MS/MS sample injection;
(4) LC-MS/MS conditions
A chromatographic column: agilent ZORBAX Eclipse Plus-C18 (150X 2.1mm, 5 μm) + (12.5X 2.1mm, 5 μm) guard column;
mobile phase: mobile phase A: 10mM ammonium acetate solution, pH 4, mobile phase B: acetonitrile;
sample introduction amount: 10 mu L of the solution; column temperature: 30 ℃; flow rate: 0.5 mL/min; elution time: 6.5 min;
gradient elution program settings: keeping the ratio of A to B to 90 to 10 in 0-0.5min, and adjusting the ratio of A to B to 70 in 0.5-1 min: keeping A, B and B equal to 70: 30, 2-3min, adjusting A: B-90: 10, 3-6.5min, keeping A: B-90: 10;
mass spectrum conditions:
an ionization mode: ESI (+) ion source: turbo iospray, air curtain pressure (currin gas, CUR): 30psi, ion source temperature (source temperature): 550 ℃, carrier gas pressure (nebulizer gas, GS 1): 45psi, heater gas (GS 2): 50psi, ion spray voltage: 4500V, inlet voltage (EP: 10V, collision cell exit voltage (CXP: 10V;
(5) accuracy, precision and matrix effect:
processing the quantitative lower limit, low, medium and high standard-added plasma with different concentrations according to the same magnetic solid phase extraction in-situ derivatization method, performing LC-MS/MS analysis, and calculating the accuracy and precision according to a fitted quantitative curve, wherein the batch accuracy and precision are respectively as follows: 100.5-102.7%, 0.2-4.0% (n ═ 5); the batch accuracy and precision were respectively: 100.7-105.3%, 1.1-5.3% (n 15);
matrix effect:
firstly, derivatizing the reference substances with low and high concentrations by using trimethylsilane and diazomethane to prepare a derivatized reference substance solution; processing a blank plasma sample by using a magnetic solid phase extraction in-situ derivatization method, mixing the processed solution with a derivatized reference substance solution, respectively feeding a sample into the mixed matrix effect sample and the derivatized reference substance solution, and evaluating the interference of endogenous components in the plasma on analyte detection by comparing the variation coefficient of the ratio of the peak area response values of the matrix effect sample and the derivatized reference substance solution with the same concentration; the results show that the matrix effect of rat plasma at both concentrations is 7.3% and 0.7%, respectively (n ═ 6).
Claims (8)
1. An in vivo drug analysis method combining magnetic solid phase extraction with rapid in situ derivatization, which is characterized by comprising the following steps: 1) synthesizing titanium dioxide coated ferroferric oxide magnetic microspheres; 2) the magnetic microsphere is used as an adsorbent for dispersive magnetic solid phase extraction to quickly enrich bisphosphonate medicines in a biological sample, and 3) elution of the magnetic solid phase extraction and sample derivatization are combined into a whole, and heating is introduced into the whole to improve the reaction rate and realize quick elution and derivatization of an analyte.
2. The method according to claim 1, wherein the magnetic solid phase extraction material used in the method is titanium dioxide coated magnetic microspheres with core-shell structures, and the titanium dioxide coated magnetic microspheres can be rapidly aggregated under the action of a magnetic field.
3. The method as claimed in claim 1, wherein the amount of the magnetic solid phase extraction material used in each sample is 100 μ g.
4. The method according to claim 1, wherein the biological sample is a plasma sample or a urine sample, and the sample loading amount is 200-400 μ l.
5. The method according to claim 1, wherein the incubation time is 2-10min with shaking during loading.
6. The method of claim 1, wherein the derivatization reaction time is 2-10 min.
7. The method of claim 1, wherein: in the method, the elution solvent and the derivatization reagent are mixed according to the volume ratio of 3:1 to 1:1, and the volume of the mixed solvent is 100-.
8. The method of claim 1, wherein: in the method, heating is carried out in the derivatization process, and the temperature control range of the derivatization process is 25-60 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115420886A (en) * | 2022-09-13 | 2022-12-02 | 中国人民解放军军事科学院军事医学研究院 | Method for extracting liposome in plasma and determining contents of free drug, encapsulated drug and total drug based on titanium dioxide microspheres |
| CN116482242A (en) * | 2022-12-30 | 2023-07-25 | 杭州百杏生物技术有限公司 | LC-MS/MS method for determining alendronate concentration in biological sample |
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