Tumor and cancer cell positioning detection method based on atomic magnetometer

Abstract

The invention discloses a tumor and cancer cell positioning detection method based on an atomic magnetometer. Comprising the following steps: by utilizing targeting and paramagnetism of MNPs, active targeting of tumors and cancer cells is realized by selectively combining a ligand modified on the surface of a magnetic nanoparticle with a specific receptor overexpressed by tumor cells, further marking of MNPs is realized, the MNPs can be instantly polarized in an external polarized magnetic field to complete a detectable macroscopic magnetic field, and the MNPs can be used for detecting the tumor and cancer cells. An atomic magnetometer is used for detecting magnetic field distribution after MNPs excitation, the magnetic field distribution is related to the spatial position of MNPs, and finally tumor and cancer cell positioning is achieved. Compared with the prior art, the atomic magnetometer has the advantages that the atomic magnetometer is high in cost performance, small and flexible, wide in application range, high in measurement efficiency and easy to popularize and apply to clinical detection; the MNPs detection process is free of toxic and side effects, and tumors and cancer cells in deep tissues can be detected.

Description

Technical Field

[0001] The invention relates to the field of atomic magnetometer technology and magnetic nanoparticle detection, and in particular to a tumor and cancer cell positioning detection method based on atomic magnetometer. Background Art

[0002] Traditional cancer diagnosis and localization methods (such as CT, MRI, radiography, etc.) can only be applied to mass tumors, and it is difficult to judge the metastasis of cancer cells through the three pathways of blood, lymph nodes and tissue infiltration. In recent years, the nanobiosensors that have emerged have achieved the purpose of effectively marking, tracing and treating cancer cells by virtue of their unique optical (such as fluorescent quantum dots), magnetic (such as superparamagnetic particles) and thermal (such as metal photothermal materials) functional properties combined with biological targeting antibodies.

[0003] Near-infrared fluorescence imaging has the biggest advantage and feature of in vivo dynamic imaging. Its application in cell tracing technology is currently focused on tumor cells and stem cells. After cells are labeled with quantum dots, organic nanoparticles, etc., they are injected into the body locally or intravenously. The intravenous route usually uses the method of particle-coated cell-specific antibodies for targeted positioning. Near-infrared fluorescence imaging has great application potential, but the fluorescence penetration depth is limited, making it difficult to observe deep subcutaneous tissue.

[0004] Magnetic nanoparticles (MNPs) have good biocompatibility, biodegradability and paramagnetism. During the preparation process, the surface of magnetic nanoparticles can be modified with certain ligands (such as aptamers, antibodies, peptides, small molecules, etc.). These ligands can selectively bind to specific receptors overexpressed by tumor cells, thereby achieving active targeting of tumors and cancer cells, and then achieving the labeling of MNPs, and finally locating tumors and cancer cells through magnetic detection technology. Since the amount of MNPs used in organisms is generally very small, this puts high demands on MNPs magnetic detection technology. Currently, the technologies widely used for quantitative detection of MNPs include superconducting quantum interference magnetometers (SQUID) and atomic magnetometers. SQUID requires liquid helium cooling, and the cost of construction and use and maintenance are extremely high. The atomic magnetometer has a sensitivity close to that of SQUID, is compact and flexible, does not require liquid helium cooling, and has almost no maintenance costs. It is more suitable for the detection of magnetic signals of MNPs in living bodies and tissues. Summary of the invention

[0005] In view of the shortcomings of the prior art, the purpose of the present invention is to provide a method for detecting tumor and cancer cell positioning based on an atomic magnetometer. By utilizing the targeting and paramagnetism of MNPs, the ligands (such as aptamers, antibodies, peptides, small molecules, etc.) modified on the surface of magnetic nanoparticles selectively bind to specific receptors overexpressed by tumor cells, thereby achieving active targeting of tumors and cancer cells, and then achieving the labeling of MNPs. MNPs can be polarized instantly in an external polarized magnetic field to show a detectable macroscopic magnetic field. The magnetic field distribution of MNPs after excitation is detected by an atomic magnetometer, and the magnetic field distribution is related to the spatial position of MNPs, and finally the positioning of tumors and cancer cells is achieved.

[0006] In order to achieve the above object, the present invention adopts the following technical solution: a tumor and cancer cell location detection method based on atomic magnetometer, comprising the following steps:

[0007] Constructing a magnetic nanoparticle MNPs detection system, the magnetic nanoparticle detection system comprising an atomic magnetometer, an MNPs sample, and a non-magnetic displacement tool; the non-magnetic displacement tool is used to achieve relative movement between the sample to be tested and the magnetic sensor in the atomic magnetometer to record magnetic field change data;

[0008] To suppress the interference of the geomagnetic field, the atomic magnetometer is placed in a shielding tube to shield the geomagnetic field and magnetic field noise; the shielding tube can shield the geomagnetic field to the order of 10nT for weak magnetic signal detection;

[0009] Fixing the position of a magnetic sensor in an atomic magnetometer, wherein a core atomic gas chamber in the magnetic sensor is located above a sample to be tested, and is used to measure the magnetic field during the movement of the sample to be tested;

[0010] The external polarization coil is energized, and the external polarization coil is used to polarize the MNPs sample so that the MNPs sample generates an induced magnetic field;

[0011] The magnetic field change data of MNPs samples under relative motion were measured by atomic magnetometer;

[0012] To locate the MNPs sample, the magnetic field change diagram of the relative displacement process of the MNPs sample and the sensor is compared with the magnetic dipole model, and the vertical distance between the detector and the MNPs marker is predicted, thereby realizing the location of tumors and cancer cells.

[0013] Furthermore, the atomic magnetometer is an integrated atomic magnetometer, the internal space of the magnetic sensor core atomic gas chamber of the integrated atomic magnetometer is less than 3×3×3mm, located 1-2cm above the sample to be tested, and its sensitivity is not less than 1pT / Hz 1 / 2 , able to respond to and record rapidly changing magnetic fields, with a magnetic field measurement sampling rate of no less than 500Hz.

[0014] Furthermore, the external polarization coil can generate a stable millitesla-level polarization magnetic field in the z direction after being energized, which is used to polarize the MNPs sample. The paramagnetic MNPs sample is non-magnetic in the magnetic shielding tube. Under the polarization action of the external magnetic field, the MNPs sample generates an induced magnetic field in the y direction.

[0015] Furthermore, the method of causing the MNPs sample to generate an induced magnetic field includes: the distribution of the induced magnetic field in the z direction conforms to a magnetic dipole model, and By has two extreme points on the Z axis.

[0016] Furthermore, the relative movement is controlled by a syringe pump to move the sample to be tested in a flow channel filled with mineral oil, and the flow channel passes through an external polarization coil, so as to achieve relative displacement of the sample to be tested and the sensor in the z-axis direction.

[0017] Furthermore, the MNPs sample positioning includes: the MNPs sample can actively target the tumor and cancer cell site, thereby achieving the labeling of the MNPs; the interval between the two extreme points in the MNPs magnetic field distribution curve is equal to the vertical distance δy from the center of the detector core atomic gas chamber to the MNPs sample in the y direction, thereby predicting the position based on the magnetic field change diagram of the MNPs.

[0018] The beneficial effects of the present invention are: the atomic magnetometer of the present invention has high cost performance, is small and flexible, has a wide range of applications, has high measurement efficiency, and is easy to promote for clinical testing; the MNPs detection process has no toxic side effects and can detect tumors and cancer cells in deep tissues. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 A schematic diagram of the system and principle in an embodiment of the present invention;

[0020] Figure 2 The principle of depth prediction of the magnetic dipole model in the embodiment of the present invention;

[0021] Figure 3 This is a test diagram of MNPs samples in an embodiment of the present invention;

[0022] Figure 4 This is a diagram of depth positioning prediction results in an embodiment of the present invention. DETAILED DESCRIPTION

[0023] Exemplary embodiments will be described in detail herein, examples of which are shown in the accompanying drawings. When the following description refers to the drawings, the same numbers in different drawings represent the same or similar elements unless otherwise indicated. The embodiments described in the following exemplary embodiments do not represent all embodiments consistent with the present invention. Instead, they are merely examples of devices and methods consistent with some aspects of the present invention as detailed in the appended claims.

[0024] The terms used in the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The singular forms "a", "the" and "the" used in the present invention and the appended claims are also intended to include plural forms unless the context clearly indicates other meanings. It should also be understood that the term "and / or" used herein refers to and includes any or all possible combinations of one or more associated listed items.

[0025] It should be understood that although the terms first, second, third, etc. may be used in the present invention to describe various information, these information should not be limited to these terms. These terms are only used to distinguish the same type of information from each other. For example, without departing from the scope of the present invention, the first information may also be referred to as the second information, and similarly, the second information may also be referred to as the first information. Depending on the context, the word "if" as used herein may be interpreted as "at the time of" or "when" or "in response to determining".

[0026] The present invention is described in detail below in conjunction with the accompanying drawings. In the absence of conflict, the features of the following embodiments and implementations can be combined with each other.

[0027] like Figure 1 As shown, the embodiment of the present invention provides a method for locating and detecting tumors and cancer cells based on an atomic magnetometer, comprising the following steps:

[0028] Step 1: Construct a magnetic nanoparticle MNPs detection system, which includes an atomic magnetometer, an MNPs sample, and a non-magnetic displacement tool; the atomic magnetometer is an integrated atomic magnetometer, the internal space of the magnetic sensor core atomic gas chamber of the integrated atomic magnetometer is less than 3×3×3mm, and is located 1-2cm above the sample to be tested, and its sensitivity is not less than 1pT / Hz 1 / 2 , can respond to and record rapidly changing magnetic fields, and the magnetic field measurement sampling rate is not less than 500 Hz. The non-magnetic displacement tool is used to achieve relative movement between the sample to be measured and the magnetic sensor in the atomic magnetometer to record magnetic field change data.

[0029] Step 2: Suppress the interference of the geomagnetic field and place the atomic magnetometer in a shielding tube to shield the geomagnetic field and magnetic field noise; the shielding tube can shield the geomagnetic field to the order of 10nT for weak magnetic signal detection.

[0030] Step 3: Fix the position of the magnetic sensor in the atomic magnetometer, wherein the core atomic gas chamber in the magnetic sensor is located above the sample to be tested, and is used to measure the magnetic field during the movement of the sample to be tested.

[0031] Step 4: The external polarization coil is energized, and the external polarization coil is used to polarize the MNPs sample, so that the MNPs sample generates an induced magnetic field; the external polarization coil can generate a stable millitera-level polarization magnetic field in the z direction after being energized, which is used to polarize the MNPs sample. The paramagnetic MNPs sample is non-magnetic in the magnetic shielding tube, and under the polarization of the external magnetic field, the MNPs sample generates an induced magnetic field in the y direction. The distribution of the induced magnetic field in the z direction conforms to the magnetic dipole model, and By has two extreme points on the Z axis.

[0032] Step 5: Measure the magnetic field change data of the MNPs sample under relative motion by an atomic magnetometer. The sample to be tested is controlled by a syringe pump to move in a flow channel filled with mineral oil, and the flow channel passes through an external polarization coil to achieve relative displacement of the sample to be tested and the sensor in the z-axis direction.

[0033] Step 6: Position the MNPs sample, compare the magnetic field change diagram of the relative displacement process between the MNPs sample and the sensor with the magnetic dipole model, and predict the vertical distance between the detector and the MNPs mark, so as to achieve the positioning of tumors and cancer cells. The MNPs sample can actively target the tumor and cancer cell sites, thereby achieving the marking of MNPs; the interval between the two extreme points in the MNPs magnetic field distribution curve is equal to the vertical distance δy from the center of the detector core atomic gas chamber to the MNPs sample in the y direction, so as to predict the position according to the magnetic field change diagram of the MNPs, such as Figure 2 shown.

[0034] The specific implementation case scheme of the present invention is shown in Figure 3 , 2 μl of the MNPs sample to be tested is controlled by a syringe pump to move in a flow channel filled with mineral oil. The flow channel passes through the external polarization coil, and the atomic magnetometer is placed directly above the center of the external polarization coil.

[0035] The solenoid is wound using an outer polarization coil frame with an inner diameter of 2 mm. After winding, AB resin is used to solidify the coil and placed horizontally in the pre-designed coil slot. The MNPs flow channel has an inner diameter of 1.2 mm and an outer diameter of 1.6 mm, which can smoothly pass through the outer polarization coil.

[0036] The atomic magnetometer is placed about 10 mm above the center of the polarization coil, and the atomic gas chamber is about 16 mm away from the center axis of the coil. The atomic magnetometer can detect magnetic fields parallel to the coil axis and in the vertical direction.

[0037] MNPs are paramagnetic nanoparticles, and their particle size is much smaller than the measurement distance. Therefore, the magnetic field in the external polarization coil conforms to the magnetic dipole model. According to the magnetic dipole model, B y Maximum point and B y The minimum point spacing is equal to the distance δy between the magnetic sensor core component of the detector (the atomic gas chamber in the present invention) and the sample to be tested. Therefore, B can be selectedy The depth of the sample to be tested is estimated by analyzing the time domain signal value.

[0038] This example tests the MNPs produced by Aladdin, with a diameter of 15-30nm. The test results are shown in Figure 4 The solid points are the predicted positions of MNPs particles, the dotted lines are the positions of the atomic gas chambers, and the horizontal axis is the experiment under different flow rates. The measurement results show that the predicted depth is highly consistent with the actual depth, with an error of about 1 mm. That is, the present invention can achieve millimeter-level depth positioning of MNPs, and thus achieve the positioning of tumors and cancer cells.

[0039] Those skilled in the art will readily appreciate other embodiments of the present application after considering the description and practicing the contents disclosed herein. The present application is intended to cover any variations, uses or adaptations of the present application, which follow the general principles of the present application and include common knowledge or customary technical means in the art that are not disclosed in the present application. The description and examples are intended to be exemplary only.

[0040] It should be understood that the present application is not limited to the exact construction that has been described above and shown in the drawings, and that various modifications and changes may be made without departing from the scope thereof.

Claims

1. A method for detecting tumor and cancer cell location based on atomic magnetometer, characterized in that: include: Constructing a magnetic nanoparticle MNPs detection system, the magnetic nanoparticle detection system comprising an atomic magnetometer, an MNPs sample, and a non-magnetic displacement tool; the non-magnetic displacement tool is used to achieve relative movement between the sample to be tested and the magnetic sensor in the atomic magnetometer to record magnetic field change data; To suppress the interference of the geomagnetic field, the atomic magnetometer is placed in a shielding tube to shield the geomagnetic field and magnetic field noise; the shielding tube can shield the geomagnetic field to the order of 10nT for weak magnetic signal detection; Fixing the position of a magnetic sensor in an atomic magnetometer, wherein a core atomic gas chamber in the magnetic sensor is located above a sample to be tested, and is used to measure the magnetic field during the movement of the sample to be tested; The external polarization coil is energized, and the external polarization coil is used to polarize the MNPs sample so that the MNPs sample generates an induced magnetic field; The magnetic field change data of MNPs samples under relative motion were measured by atomic magnetometer; To locate the MNPs sample, the magnetic field change diagram of the relative displacement process of the MNPs sample and the sensor is compared with the magnetic dipole model, and the vertical distance between the detector and the MNPs marker is predicted, thereby realizing the location of tumors and cancer cells.

2. The method for detecting tumor and cancer cell location based on atomic magnetometer according to claim 1, characterized in that: The atomic magnetometer is an integrated atomic magnetometer. The internal space of the magnetic sensor core atomic gas chamber of the integrated atomic magnetometer is less than 3×3×3mm and is located 1-2cm above the sample to be tested. Its sensitivity is not less than 1pT / Hz 1 / 2 , able to respond to and record rapidly changing magnetic fields, with a magnetic field measurement sampling rate of no less than 500Hz.

3. The method for detecting tumor and cancer cell location based on atomic magnetometer according to claim 1, characterized in that: The external polarization coil can generate a stable millitesla polarization magnetic field in the z direction after being energized, which is used to polarize the MNPs sample. The paramagnetic MNPs sample is non-magnetic in the magnetic shielding tube. Under the polarization effect of the external magnetic field, the MNPs sample generates an induced magnetic field in the y direction.

4. The method for detecting tumor and cancer cell location based on atomic magnetometer according to claim 1, characterized in that: The method of causing the MNPs sample to generate an induced magnetic field comprises: the distribution of the induced magnetic field in the z direction conforms to a magnetic dipole model, and By has two extreme value points on the Z axis.

5. The method for detecting tumor and cancer cell location based on atomic magnetometer according to claim 1, characterized in that: The relative movement is achieved by controlling the sample to be tested to move in a flow channel filled with mineral oil through an injection pump. The flow channel passes through an external polarization coil, thereby achieving relative displacement of the sample to be tested and the sensor in the z-axis direction.

6. The method for detecting tumor and cancer cell location based on atomic magnetometer according to claim 1, characterized in that: The MNPs sample positioning includes: the MNPs sample can actively target the tumor and cancer cell site, thereby achieving the labeling of the MNPs; the interval between the two extreme points in the MNPs magnetic field distribution curve is equal to the vertical distance δy from the center of the detector core atomic gas chamber to the MNPs sample in the y direction, thereby predicting the position based on the magnetic field change diagram of the MNPs.

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