A tumor and cancer cell location detection method based on atomic magnetometer

Abstract

The present invention discloses a method for detecting tumor and cancer cell positioning based on an atomic magnetometer. The method comprises: utilizing the targeting and paramagnetism of MNPs, selectively binding to specific receptors overexpressed by tumor cells through ligands modified on the surface of magnetic nanoparticles, thereby achieving active targeting of tumors and cancer cells, and then labeling the MNPs. The MNPs can be instantly polarized in an external polarized magnetic field to exhibit a detectable macroscopic magnetic field. The magnetic field distribution after excitation of the MNPs is detected using an atomic magnetometer, and the magnetic field distribution is correlated with the spatial position of the MNPs, ultimately achieving tumor and cancer cell positioning. Compared with the existing technology, the present invention has the following advantages: the atomic magnetometer is cost-effective, compact 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.

Description

Technical Field

[0001] The present 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, and radiography) can only be applied to bulk tumors and are difficult to assess the metastasis of cancer cells through the blood, lymph nodes, and tissue infiltration. In recent years, the emergence of nanobiosensors leverages their unique optical (such as fluorescent quantum dots), magnetic (such as superparamagnetic particles), and thermal (such as metal photothermal materials) functional properties, combined with biotargeted antibodies, to effectively label, track, and treat cancer cells.

[0003] Near-infrared fluorescence imaging, with its greatest advantage and unique feature of in vivo dynamic imaging, is currently being used for cell tracking in tumor cells and stem cells. After labeling cells with quantum dots or organic nanoparticles, they are injected topically or intravenously. Intravenous injections typically utilize particles coated with cell-specific antibodies for targeted targeting. While near-infrared fluorescence imaging has enormous potential, its limited penetration depth makes it difficult to observe deep subcutaneous tissue.

[0004] Magnetic nanoparticles (MNPs) possess excellent biocompatibility, biodegradability, and paramagnetic properties. During the preparation process, the surface of magnetic nanoparticles can be modified with specific ligands (such as aptamers, antibodies, peptides, and small molecules). These ligands can selectively bind to specific receptors overexpressed by tumor cells, thereby achieving active targeting of tumors and cancer cells, thereby labeling the MNPs and ultimately locating them through magnetic detection techniques. Since the amount of MNPs used in vivo is generally very small, this places high demands on MNP magnetic detection technology. Currently, the technologies widely used for quantitative detection of MNPs include superconducting quantum interference magnetometers (SQUIDs) and atomic magnetometers. SQUIDs require liquid helium cooling, which is extremely expensive to manufacture, operate, and maintain. Atomic magnetometers offer similar sensitivity to SQUIDs, are compact and flexible, require no liquid helium cooling, and require virtually no maintenance, making them more suitable for detecting the magnetic signals of MNPs in living organisms and tissues. Summary of the Invention

[0005] In response to the shortcomings of the existing technology, the present invention aims to provide a method for detecting tumor and cancer cell localization based on atomic magnetometry. By utilizing the targeting and paramagnetism of MNPs, 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 further labeling of MNPs. MNPs can be instantly polarized in an external polarized magnetic field to exhibit a detectable macroscopic magnetic field. The magnetic field distribution of the MNPs after excitation is detected using an atomic magnetometry. This magnetic field distribution is correlated with the spatial position of the MNPs, ultimately achieving tumor and cancer cell localization.

[0006] To achieve the above-mentioned object, the present invention adopts the following technical solution: a method for detecting tumor and cancer cell location based on an atomic magnetometer, comprising the following steps:

[0007] A magnetic nanoparticle (MNP) detection system is constructed, comprising an atomic magnetometer, an MNP sample, and a non-magnetic displacement tool; the non-magnetic displacement tool is used to achieve relative motion between the sample to be tested and the magnetic sensor in the atomic magnetometer to record magnetic field change data;

[0008] To suppress geomagnetic field interference, 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, which is used 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 measured, and is used to measure the magnetic field during the movement of the sample to be measured;

[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 the MNPs sample under relative motion was measured by atomic magnetometer;

[0012] To locate the MNPs sample, the magnetic field change diagram during the relative displacement process of the MNPs sample and the sensor is compared with the magnetic dipole model to predict the vertical distance between the detector and the MNPs marker, thereby achieving the positioning 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 measured, and its sensitivity is not less than 1pT / Hz. 1 / 2 , able to respond to rapidly changing magnetic fields and record them, with a magnetic field measurement sampling rate of no less than 500Hz.

[0014] Furthermore, 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 action of the external magnetic field, the MNPs sample generates an induced magnetic field in the y direction.

[0015] Furthermore, the generating of the induced magnetic field in the MNPs sample includes: 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.

[0016] Furthermore, the relative movement is achieved by controlling the sample to be tested to move in a flow channel filled with mineral oil through a syringe pump, and 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.

[0017] Furthermore, the MNPs sample positioning includes: the MNPs sample can actively target the tumor and cancer cell sites, thereby achieving MNPs labeling; 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 MNPs magnetic field change diagram.

[0018] The beneficial effects of the present invention are: the atomic magnetometer of the present invention has high cost performance, is compact 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 using 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 the depth positioning prediction result in an embodiment of the present invention. DETAILED DESCRIPTION

[0023] Exemplary embodiments will be described in detail herein, examples of which are illustrated in the accompanying drawings. In the following description, when referring to the drawings, like numbers in different figures represent like or similar elements unless otherwise indicated. The embodiments described in the following exemplary embodiments are not intended to represent all possible embodiments consistent with the present invention. Rather, they are merely examples of apparatus and methods consistent with certain aspects of the present invention, as detailed in the appended claims.

[0024] The terms used in this invention are for the purpose of describing specific embodiments only and are not intended to limit the invention. The singular forms "a," "the," and "the" used in this invention and the appended claims are also intended to include plural forms unless the context clearly indicates otherwise. It should also be understood that the term "and / or" as used herein refers to and includes any or all possible combinations of one or more of the 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, such information should not be limited to these terms. These terms are merely used to distinguish information of the same type from one another. For example, first information may also be referred to as second information, and similarly, second information may also be referred to as first information, without departing from the scope of the present invention. Depending on the context, the term "if" as used herein may be interpreted as "when," "when," or "in response to determining."

[0026] The present invention will be described in detail below with reference to the accompanying drawings. Unless there is any conflict, the features of the following embodiments and implementations may be combined with each other.

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

[0028] Step 1: Construct a magnetic nanoparticle (MNP) detection system, which includes an atomic magnetometer, an MNP 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. Its sensitivity is not less than 1pT / Hz. 1 / 2 , capable of responding to and recording rapidly changing magnetic fields, with a magnetic field measurement sampling rate of no 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, where the core atomic gas chamber in the magnetic sensor is located above the sample to be measured, and is used to measure the magnetic field during the movement of the sample to be measured.

[0031] Step 4: The external polarization coil is energized to polarize the MNP sample, generating an induced magnetic field. When energized, the coil generates a stable millitesla-level polarized magnetic field in the z-direction, which is used to polarize the MNP sample. The paramagnetic MNP sample is nonmagnetic within the magnetic shielding tube. Under the polarization effect of the external magnetic field, the MNP 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, with two extreme points on the z-axis.

[0032] Step 5: An atomic magnetometer measures the magnetic field variation of the MNP sample under relative motion. A syringe pump controls the movement of the sample through a mineral oil-filled flow channel that passes through an external polarization coil, achieving relative displacement between the sample and the sensor along the z-axis.

[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, thereby achieving the positioning of tumors and cancer cells. The MNPs sample can actively target the tumor and cancer cell sites, thereby achieving the labeling 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 the position is predicted based on the magnetic field change diagram of the MNPs, as shown in the figure. Figure 2 shown.

[0034] The specific implementation case 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] A solenoid was wound using a 2mm inner diameter, externally polarized coil skeleton. After winding, it was cured and shaped using AB resin and placed horizontally in a pre-designed coil slot. The MNPs flow channel had an inner diameter of 1.2mm and an outer diameter of 1.6mm, allowing it to pass smoothly through the externally polarized 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 inside 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 core magnetic sensor component of the detector (the atomic gas chamber in this invention) and the sample to be measured. 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 15-30 nm. The test results are shown in Figure 4 The solid dots represent the predicted positions of the MNPs, the dotted lines represent the atomic chamber positions, and the horizontal axis represents experiments conducted at different flow rates. The measurement results show that the predicted depths are highly consistent with the actual depths, with an error of approximately 1 mm. This indicates that the present invention can achieve millimeter-level depth positioning of MNPs, and thus 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 specification and practicing the contents disclosed herein. This application is intended to cover any variations, uses, or adaptations of the present application that follow the general principles of this application and include common knowledge or customary techniques in the art not disclosed herein. The description and examples are to be considered as exemplary only.

[0040] It will 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 positioning based on atomic magnetometer, characterized in that: include: A magnetic nanoparticle (MNP) detection system was constructed, in which ligands modified on the surface of the magnetic nanoparticles selectively bind to specific receptors overexpressed by tumors and cancer cells. The magnetic nanoparticle detection system includes an atomic magnetometer, an MNP sample, and a non-magnetic displacement tool. The non-magnetic displacement tool is used to achieve relative motion between the sample to be tested and the magnetic sensor in the atomic magnetometer to record magnetic field change data. To suppress geomagnetic field interference, 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, which is used 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 measured, and is used to measure the magnetic field during the movement of the sample to be measured; 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 the MNPs sample under relative motion was measured by atomic magnetometer; To locate the MNPs sample, the magnetic field change diagram during the relative displacement process of the MNPs sample and the sensor is compared with the magnetic dipole model to predict the vertical distance between the detector and the MNPs marker, thereby achieving the positioning of tumors and cancer cells.

2. The method for detecting tumor and cancer cell positioning 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 measured. Its sensitivity is not less than 1pT / Hz. 1 / 2 , able to respond to rapidly changing magnetic fields and record them, with a magnetic field measurement sampling rate of no less than 500Hz.

3. The method for detecting tumor and cancer cell positioning 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 action 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 positioning based on atomic magnetometer according to claim 1, characterized in that: 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.

5. The method for detecting tumor and cancer cell positioning based on atomic magnetometer according to claim 1, characterized in that: The relative motion is achieved by controlling the sample to be tested to move in a flow channel filled with mineral oil through a syringe 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 positioning based on atomic magnetometer according to claim 1, characterized in that: The MNPs sample positioning includes: the MNPs sample can actively target tumors and cancer cells, thereby achieving MNPs labeling; 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 MNPs magnetic field change diagram.

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