CN113075192A - Multi-drug resistant tumor cell identification method based on Raman spectrum - Google Patents
Multi-drug resistant tumor cell identification method based on Raman spectrum Download PDFInfo
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Abstract
The invention discloses a method for identifying multi-drug resistant tumor cells based on Raman spectrum, which comprises the following steps: 1) preparing a Raman enhanced substrate; 2) drugs which can be specifically combined with multi-drug resistant tumor cells are coupled on the Raman enhancement substrate; 3) constructing a characteristic indication peak database of Raman spectra of various multi-drug resistant tumor cells: 4) and (3) identification of the tumor cells to be detected: and judging whether the tumor cells are multidrug-resistant tumor cells according to the appearance condition of characteristic indication peaks in the Raman spectrum of the tumor cells to be detected. The method is combined with Raman spectrum detection, can realize rapid identification of the multidrug resistant tumor cells under the condition of no damage, has high sensitivity, can realize liquid phase detection, can be used for subsequent multidrug resistant mechanism research or personalized drug screening because the cells do not need to be damaged, and is expected to be applied to development of antitumor drugs.
Description
Technical Field
The invention relates to the technical field of multi-drug resistant tumor cell identification, in particular to a Raman spectrum-based multi-drug resistant tumor cell identification method.
Background
Chemotherapy (chemotherapy) is the main means of tumor therapy at present, but the curative effect is often limited by the phenomenon of multidrug resistance. This phenomenon leads to the failure of chemotherapeutic drugs and the development of drug resistance to various drugs with different structures and different action targets, thus becoming the main cause of tumor recurrence, metastasis and death of more than 90% of chemotherapy patients. The method is used for analyzing the occurrence and generation mechanism of the multidrug resistant tumor of a patient, and further has important significance for screening treatment drugs and determining a scheme for treating the tumor.
However, the appearance of the multidrug resistant tumor is not much different from that of the conventional tumor, and the clinician often needs to perform slicing and cell separation detection after the patient shows the drug resistance phenomenon. Further, drug resistance analysis was performed for each gene, protein, and the like. The current commonly used RNA detection methods comprise Northern blot, Slot blot, RT-PCR, in-situ hybridization and gene chip technology, wherein the RT-PCR has simple, convenient and safe operation and high specificity and sensitivity, so the RNA detection method has wide clinical application. The detection methods on the protein level include immunohistochemistry, Western blot and flow cytometry. With the development of monoclonal antibody technology, flow cytometry is becoming mature in the aspects of monitoring the level of oncogene expression products in tumor cells, researching tumor regulatory factors and the like, such as in the structural aspect, detecting the high expression of Mdr1, in the functional aspect, detecting the intracellular accumulation degree of antitumor drugs, in the aspect of judging the curative effect, detecting the redistribution of drugs in cells, judging whether the drugs are at the drug action sites and intuitively knowing the interference and influence of the drugs on the dynamics of the cancer cells. However, the above methods are often complicated to operate and have long detection period, and the obtained tumor cells cannot be used for the subsequent personalized drug screening because the cells need to be destroyed and then detected.
Disclosure of Invention
The technical problem to be solved by the present invention is to provide a method for identifying multidrug resistant tumor cells based on raman spectroscopy, aiming at the above-mentioned deficiencies in the prior art.
In order to solve the technical problems, the invention adopts the technical scheme that: a method for identifying multi-drug resistant tumor cells based on Raman spectrum comprises the following steps:
1) preparing a Raman enhanced substrate;
2) coupling a drug capable of being specifically combined with the multi-drug resistant tumor cells on the Raman enhanced substrate obtained in the step 1);
3) aiming at various types of tumor cells, respectively obtaining the corresponding characteristic indicating peaks of the Raman spectra of the multi-drug resistant tumor cells according to the following method, thereby constructing a characteristic indicating peak database of the Raman spectra of the multi-drug resistant tumor cells:
respectively incubating the multi-drug resistant tumor cells and normal tumor cells of the same kind of tumor cells with the Raman enhancement substrates obtained in the step 2), then performing Raman detection on the two Raman enhancement substrates respectively incubated with the two kinds of tumor cells to obtain a Raman spectrum R1 corresponding to the multi-drug resistant tumor cells and a Raman spectrum R2 corresponding to the normal tumor cells, comparing R1 with R2 to obtain at least one difference peak which exists in R1 but does not exist in R2, and then selecting at least one of all the difference peaks as a characteristic indication peak T for indicating the existence of the multi-drug resistant tumor cells;
4) and (3) identification of the tumor cells to be detected: co-incubating tumor cells to be detected and the Raman enhancement substrate obtained in the step 2), taking out the Raman enhancement substrate, performing Raman detection to obtain a Raman spectrum Rx of the tumor cells to be detected, acquiring all characteristic indication peak data Tn of the multidrug-resistant tumor cells corresponding to the same type of tumor cells from the characteristic indication peak database of the Raman spectrum obtained in the step 2) according to the type of the tumor cells to be detected, and searching the number of the characteristic indication peaks contained in Tn in Rx and marking as X; and if X is more than or equal to A X N, judging that the tumor cells to be detected are multidrug-resistant tumor cells, otherwise, judging that the tumor cells to be detected are normal tumor cells, wherein N represents the number of all characteristic indication peaks in Tn, A is a correction coefficient, and A is more than 0 and less than or equal to 1.
Preferably, the drug is capable of specifically binding to the Mdr1 protein on the multidrug-resistant tumor cell.
Preferably, the drug is one or more of verapamil, cyclosporine, doxorubicin and vincristine.
Preferably, the step 1) specifically includes: etching a plurality of micropores with the depth and the width of 10 mu m on the glass slide by using HF acid with the photoresist as a mask; soaking the glass slide with the micropores in the piranha solution, taking out the glass slide, washing the glass slide with ultrapure water, and drying the glass slide with nitrogen; and completely soaking the glass slide in an ethanol solution containing 3-aminopropyltriethoxysilane, taking out the glass slide, washing the glass slide with pure ethanol, and drying the glass slide with nitrogen to obtain the Raman enhancement substrate.
Preferably, the step 2) specifically includes: preparing a gold nanoparticle solution with the surface modified by mercaptoacetic acid and coupled with a drug, then immersing the Raman enhanced substrate prepared in the step 1) into the gold nanoparticle solution, reacting overnight, taking out the Raman enhanced substrate, cleaning and drying.
Preferably, the step 2) specifically includes: firstly, preparing a gold nanoparticle solution with the surface modified by thioglycollic acid and coupled with a drug; then centrifuging the gold nanoparticle solution, washing and then suspending in ultrapure water to obtain a gold nanoparticle dispersion liquid; and then immersing the Raman enhancement substrate prepared in the step 1) into the gold nanoparticle dispersion liquid, taking out the Raman enhancement substrate after reacting overnight, cleaning with ultrapure water, and drying with nitrogen.
Preferably, the diameter of the gold nanoparticles in the gold nanoparticle solution is <10 nm.
Preferably, in the step 3), the multidrug resistance tumor cells and normal tumor cells of the same tumor cell type are mixed with the gold nanoparticle solution, and the obtained two mixed solutions are incubated with the raman-enhanced substrate obtained in the step 2).
Preferably, in the step 4), the tumor cells to be detected are mixed with the gold nanoparticle solution, and the obtained mixed solution is incubated with the raman-enhanced substrate obtained in the step 2).
Preferably, the parameters for performing raman detection in step 3) and step 4) are as follows: the laser wavelength was 785nm and the maximum excitation power was 14 mW.
The invention has the beneficial effects that:
the method for identifying the multidrug resistant tumor cells based on the Raman spectrum is combined with Raman spectrum detection, can realize rapid identification of the multidrug resistant tumor cells under the condition of no damage, has high sensitivity, can realize liquid phase detection, and can be used for subsequent multidrug resistant mechanism research or personalized drug screening because the cells do not need to be damaged.
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FIG. 1 shows Raman spectra of a multidrug resistant tumor cell and a conventional tumor cell in an example of the present invention;
FIG. 2 shows the results of the Mdr1 protein expression assay of the cells in the examples of the present invention.
Detailed Description
The present invention is further described in detail below with reference to examples so that those skilled in the art can practice the invention with reference to the description.
It will be understood that terms such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other elements or groups thereof.
Example 1
The embodiment provides a method for identifying multi-drug resistant tumor cells based on Raman spectrum, which comprises the following steps:
1) preparing a Raman enhanced substrate;
2) coupling a drug capable of being specifically combined with the multi-drug resistant tumor cells on the Raman enhanced substrate obtained in the step 1);
3) aiming at various types of tumor cells, respectively obtaining the corresponding characteristic indicating peaks of the Raman spectra of the multi-drug resistant tumor cells according to the following method, thereby constructing a characteristic indicating peak database of the Raman spectra of the multi-drug resistant tumor cells:
respectively incubating the multi-drug resistant tumor cells and normal tumor cells of the same kind of tumor cells with the Raman enhancement substrates obtained in the step 2), then performing Raman detection on the two Raman enhancement substrates respectively incubated with the two kinds of tumor cells to obtain a Raman spectrum R1 corresponding to the multi-drug resistant tumor cells and a Raman spectrum R2 corresponding to the normal tumor cells, comparing R1 with R2 to obtain at least one difference peak which exists in R1 but does not exist in R2, and then selecting at least one of all the difference peaks as a characteristic indication peak T for indicating the existence of the multi-drug resistant tumor cells;
4) and (3) identification of the tumor cells to be detected: co-incubating tumor cells to be detected and the Raman enhancement substrate obtained in the step 2), taking out the Raman enhancement substrate, performing Raman detection to obtain a Raman spectrum Rx of the tumor cells to be detected, acquiring all characteristic indication peak data Tn of the multidrug-resistant tumor cells corresponding to the same type of tumor cells from the characteristic indication peak database of the Raman spectrum obtained in the step 2) according to the type of the tumor cells to be detected, and searching the number of the characteristic indication peaks contained in Tn in Rx and marking as X; and if X is more than or equal to A X N, judging that the tumor cells to be detected are multidrug-resistant tumor cells, otherwise, judging that the tumor cells to be detected are normal tumor cells, wherein N represents the number of all characteristic indication peaks in Tn, A is a correction coefficient, and A is more than 0 and less than or equal to 1. For example, in one embodiment, when a certain kind of multidrug-resistant tumor cell has 2 characteristic indicating peaks, i.e., N is 2, a is 0.5, and X is greater than or equal to 1, that is, when any one of the 2 characteristic indicating peaks appears in the raman spectrum Rx of the tumor cell to be detected, the multidrug-resistant tumor cell is determined to be the tumor cell to be detected. It will be appreciated that the accuracy of the identification result may be provided by selecting a plurality of characteristic indicator peaks; and the size of A can be adjusted to adapt to different detection objects. For example, for an object whose number of characteristic indicating peaks is large but whose peak type of characteristic indicating peaks is relatively low in distinction, by setting a large a value, the accuracy of identification of the type of tumor cell can be improved.
In a preferred embodiment, the drug is capable of specifically binding to the Mdr1 protein on the multidrug-resistant tumor cell, thereby specifically indicating the expression of the multidrug-resistant protein in the cell. Further, the medicine is one or more of verapamil, cyclosporine, adriamycin and vincristine. These drugs have been demonstrated to be drug molecules with high affinity for Mdr1 protein. In a further preferred embodiment, the occurrence of characteristic indicator peaks at 810nm and 910nm in the Raman spectrum can be considered to determine whether the tumor cell is a multidrug resistant tumor cell. Referring to fig. 1, the raman spectrum peaks at 810nm and 910nm in the present invention are experimentally confirmed to be one of the characteristic peaks of Mdr1 protein (as shown by the oval circles in fig. 1), so that the peaks can be used as the distinguishing peaks between the multidrug-resistant tumor cells and the conventional (normal) tumor cells to indicate the existence of the multidrug-resistant tumor cells.
In a preferred embodiment, the step 1) is specifically: etching a plurality of micropores with the depth and the width of 10 mu m on the glass slide by using HF acid with the photoresist as a mask; slides with microwells were incubated at 80 ℃ in piranha solution (30% H)2O2And H2SO4Mixing the raw materials in a ratio of 1: 3) for 1 hour, then taking out the glass slide, washing the glass slide for 3 times by Milli-Q ultrapure water and drying the glass slide by nitrogen; and (3) completely soaking the glass slide in an ethanol solution containing 10% (mass fraction) of 3-aminopropyltriethoxysilane for 4 hours, then taking out the glass slide, washing the glass slide for 3 times by using pure ethanol, and drying the glass slide by using nitrogen to prepare the Raman enhanced substrate.
In a preferred embodiment, the step 2) specifically includes: firstly, preparing a gold nanoparticle solution with the surface modified by thioglycollic acid and coupled with a drug; then centrifuging the gold nanoparticle solution at 5000rpm for 10 minutes, washing twice, and then suspending in Milli-Q ultrapure water to obtain a gold nanoparticle dispersion liquid; and then immersing the Raman enhancement substrate prepared in the step 1) into the gold nanoparticle dispersion liquid, taking out the Raman enhancement substrate after reacting overnight, washing with Milli-Q ultrapure water for 3 times, and drying with nitrogen.
Furthermore, in the gold nanoparticle solution, the diameter of the gold nanoparticles is less than 10 nm. The gold nanoparticles are coupled with drugs and can be specifically combined with Mdr1 in tumor cells.
The etching aperture can ensure that single cells enter, and the entered single cells can be fully contacted with the gold nanoparticles on the Raman enhancement substrate, thereby ensuring the acquisition of the Raman spectrum of the cells.
In a preferred embodiment, in step 3), the multidrug-resistant tumor cells and normal tumor cells of the same tumor cell type are mixed with the gold nanoparticle solution, and the obtained two mixed solutions are incubated with the raman-enhanced substrate obtained in step 2). Wherein, after the multidrug resistant tumor cells and normal tumor cells are cultured to 80-90% of fusion, the cells are digested by pancreatin and suspended in phosphate buffer solution for standby, and the pH value of the phosphate buffer solution is preferably 7.4.
In a preferred embodiment, in step 4), the tumor cells to be detected are mixed with the gold nanoparticle solution, and the obtained mixed solution is incubated with the raman-enhanced substrate obtained in step 2). Wherein, after the tumor cells to be detected are cultured to 80% -90% of fusion, the tumor cells are trypsinized and suspended in phosphate buffer solution for standby, and the pH value of the phosphate buffer solution is preferably 7.4.
In a preferred embodiment, the parameters for performing raman detection in step 3) and step 4) are: the laser wavelength was 785nm, the maximum excitation power was 14mW, and the integration time was 10 s. The selected wavelength is the wavelength with lower noise in detection, and the power can ensure that the Raman detection result can be obtained under the condition of not damaging cells.
Example 2
Raman detection is carried out on the commercially available A549 multi-drug resistant cells (A549-Mdr 1) and A549 cells, MCF-7 multi-drug resistant cells (MCF-7-Pgp) and MCF-7 cells by adopting the method of example 1, and the detection result shows that characteristic indication peaks appear on the Raman spectra of the A549 multi-drug resistant cells and the MCF-7 multi-drug resistant cells at 810nm and 910nm, but the Raman spectra of the A549 cells and the MCF-7 cells do not appear. Then, Mdr1 protein expression detection is carried out on the A549 multidrug resistance cells, the A549 cells, the MCF-7 multidrug resistance cells and the MCF-7 cells, the detection result is shown in figure 2, and the result can prove that the identification result of the method in example 1 is accurate.
While embodiments of the invention have been disclosed above, it is not limited to the applications listed in the description and the embodiments, which are fully applicable in all kinds of fields of application of the invention, and further modifications may readily be effected by those skilled in the art, so that the invention is not limited to the specific details without departing from the general concept defined by the claims and the scope of equivalents.
Claims (10)
1. A method for identifying multidrug resistant tumor cells based on Raman spectrum is characterized by comprising the following steps:
1) preparing a Raman enhanced substrate;
2) coupling a drug capable of being specifically combined with the multi-drug resistant tumor cells on the Raman enhanced substrate obtained in the step 1);
3) aiming at various types of tumor cells, respectively obtaining the corresponding characteristic indicating peaks of the Raman spectra of the multi-drug resistant tumor cells according to the following method, thereby constructing a characteristic indicating peak database of the Raman spectra of the multi-drug resistant tumor cells:
respectively incubating the multi-drug resistant tumor cells and normal tumor cells of the same kind of tumor cells with the Raman enhancement substrates obtained in the step 2), then performing Raman detection on the two Raman enhancement substrates respectively incubated with the two kinds of tumor cells to obtain a Raman spectrum R1 corresponding to the multi-drug resistant tumor cells and a Raman spectrum R2 corresponding to the normal tumor cells, comparing R1 with R2 to obtain at least one difference peak which exists in R1 but does not exist in R2, and then selecting at least one of all the difference peaks as a characteristic indication peak T for indicating the existence of the multi-drug resistant tumor cells;
4) and (3) identification of the tumor cells to be detected: co-incubating tumor cells to be detected and the Raman enhancement substrate obtained in the step 2), taking out the Raman enhancement substrate, performing Raman detection to obtain a Raman spectrum Rx of the tumor cells to be detected, acquiring all characteristic indication peak data Tn of the multidrug-resistant tumor cells corresponding to the same type of tumor cells from the characteristic indication peak database of the Raman spectrum obtained in the step 2) according to the type of the tumor cells to be detected, and searching the number of the characteristic indication peaks contained in Tn in Rx and marking as X; and if X is more than or equal to A X N, judging that the tumor cells to be detected are multidrug-resistant tumor cells, otherwise, judging that the tumor cells to be detected are normal tumor cells, wherein N represents the number of all characteristic indication peaks in Tn, A is a correction coefficient, and A is more than 0 and less than or equal to 1.
2. The method for identifying multidrug resistant tumor cells based on Raman spectroscopy of claim 1, wherein the drug is capable of specifically binding with Mdr1 protein on the multidrug resistant tumor cells.
3. The method for identifying multidrug resistant tumor cells based on Raman spectroscopy of claim 2, wherein the drug is one or more of verapamil, cyclosporine, doxorubicin, and vincristine.
4. The method for identifying multidrug resistant tumor cells based on raman spectroscopy according to claim 1, wherein the step 1) specifically comprises: etching a plurality of micropores with the depth and the width of 10 mu m on the glass slide by using HF acid with the photoresist as a mask; soaking the glass slide with the micropores in the piranha solution, taking out the glass slide, washing the glass slide with ultrapure water, and drying the glass slide with nitrogen; and completely soaking the glass slide in an ethanol solution containing 3-aminopropyltriethoxysilane, taking out the glass slide, washing the glass slide with pure ethanol, and drying the glass slide with nitrogen to obtain the Raman enhancement substrate.
5. The method for identifying multidrug resistant tumor cells based on raman spectroscopy according to claim 1, wherein the step 2) specifically comprises: preparing a gold nanoparticle solution with the surface modified by mercaptoacetic acid and coupled with a drug, then immersing the Raman enhanced substrate prepared in the step 1) into the gold nanoparticle solution, reacting overnight, taking out the Raman enhanced substrate, cleaning and drying.
6. The method for identifying multidrug resistant tumor cells based on Raman spectroscopy according to claim 5, wherein the step 2) specifically comprises: firstly, preparing a gold nanoparticle solution with the surface modified by thioglycollic acid and coupled with a drug; then centrifuging the gold nanoparticle solution, washing and then suspending in ultrapure water to obtain a gold nanoparticle dispersion liquid; and then immersing the Raman enhancement substrate prepared in the step 1) into the gold nanoparticle dispersion liquid, taking out the Raman enhancement substrate after reacting overnight, cleaning with ultrapure water, and drying with nitrogen.
7. The method for identifying multidrug resistant tumor cells based on Raman spectroscopy according to claim 5 or 6, wherein the diameter of gold nanoparticles in the gold nanoparticle solution is less than 10 nm.
8. The method for identifying the multidrug resistant tumor cells based on Raman spectroscopy of claim 1, wherein in the step 3), the multidrug resistant tumor cells and normal tumor cells of the same tumor cell type are mixed with the gold nanoparticle solution, and the obtained two mixed solutions are incubated with the Raman-enhanced substrate obtained in the step 2).
9. The method for identifying the multidrug resistant tumor cells based on the raman spectrum of claim 1, wherein in the step 4), the tumor cells to be detected are mixed with the gold nanoparticle solution, and the obtained mixed solution is incubated with the raman-enhanced substrate obtained in the step 2).
10. The method for identifying multidrug resistant tumor cells based on Raman spectroscopy according to claim 1, wherein the parameters for Raman detection in step 3) and step 4) are: the laser wavelength was 785nm and the maximum excitation power was 14 mW.
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