Quantitative Detection of Lung Cancer Based on Multi-Nuclide Magnetic Resonance Imaging 23 Method for Na Distribution

Abstract

The present invention proposes a method for quantitatively detecting the distribution of <supgt;23< / supgt;Na in lung cancer based on multi - nuclide magnetic resonance imaging. A quantitative model for the total tissue sodium concentration (TSC) is established, and a quantitative curve of TSC is obtained based on magnetic resonance imaging. A quantitative model for the intracellular sodium concentration (ISC) is established, and a quantitative curve of ISC is obtained based on magnetic resonance imaging. An animal model is established, and the UTE - SQF sequence and the UTE - TQF sequence are respectively used to perform cross - sectional scanning imaging on the animal model to obtain <supgt;23< / supgt;Na - MR images. Then, the T2WI sequence is used to localize tumors in the <supgt;23< / supgt;Na - MR images, delineate the region of interest, and quantitatively analyze the total tissue sodium concentration according to the TSC quantitative curve and the intracellular sodium concentration according to the ISC quantitative curve. The present invention can be unaffected by cardiac and respiratory movements, and can quantitatively detect the sodium ion concentration and its distribution in biological tissues in vivo, non - invasively, providing direct and quantitative biochemical information for judging the viability of tissues, the integrity of cells and their functions.

Description

Technical Field

[0001] The present invention relates to the field of medical nuclear magnetic resonance imaging, and particularly to a method for quantitatively detecting lung cancer based on multinuclear magnetic resonance imaging 23 for the distribution of Na, especially for quantitatively detecting the distribution of Na inside and outside lung cancer cells under ultra-high magnetic field 23 by sodium magnetic resonance. Background Art

[0002] Malignant tumors seriously endanger human health and are major problems in the medical field. Among them, the incidence rate of lung cancer has been rising rapidly, and it has currently become the cancer with the highest incidence and mortality in China. Due to its non-invasive, high-resolution, multi-parameter imaging, and the ability to perform functional and molecular imaging, nuclear magnetic resonance imaging technology has become the preferred imaging detection method for the diagnosis of various diseases. However, due to the influence of respiratory movement and cardiac and arterial pulsation, there are few studies on magnetic resonance imaging of lung cancer and its clinical applications.

[0003] Ion disorders, especially sodium ( 23 Na), are related to the biological behaviors of malignant tumors such as proliferation, invasion, and metastasis. Sodium ion is one of the electrolytes commonly present in living organisms and is widely involved in the physiological and pathological activities of the body. The intracellular-extracellular sodium concentration gradient controlled by the sodium-potassium pump plays an important role in maintaining the integrity of cell structure and function. The sodium concentration in tumor cells is significantly higher than that in normal cells, and the permeability of the tumor cell membrane to sodium ions increases, and the intracellular sodium ion concentration increases by 70% - 350% compared with normal cells. When large areas of necrosis or apoptosis occur in the tumor area, due to the filling of extracellular fluid, the sodium ion concentration in the necrotic area rapidly rises to 140 - 150 mM. Abnormal sodium ions will directly lead to characteristic changes in the tumor microenvironment, further leading to the aggravation of the malignant biological behavior of the tumor. Traditional sodium concentration detection cannot be non-invasive, real-time, and repeated multiple times, so it has limitations in clinical applications.

[0004] Magnetic resonance imaging technology (MRI) is currently an imaging technology with the two major advantages of non-invasive scanning and high-resolution images in the field of medical imaging, and it is an interdisciplinary technology with broad prospects in both basic biomedical research and disease-related applied research. Different from the 1 1H magnetic resonance technology that provides anatomical information, 23 23Na magnetic resonance can provide more functional information, can detect the sodium ion concentration and its distribution in biological tissues in vivo, provide direct and quantitative biochemical information for judging the viability of tissues, the integrity of cells and their functions, and at the same time provide some important information related to tissue metabolism, and can be used for diagnosing diseases and evaluating the prognosis and treatment effects of diseases.

[0005] Although sodium ion is the second most NMR-active element in living organisms (only second to 1H). However, the NMR sensitivity of sodium ions is 9.2% of that of hydrogen, the in vivo density is 2000 times lower than that of hydrogen, and the signal-to-noise ratio is 3000 - 20000 times lower than that of hydrogen. Moreover, there is an electric quadrupole moment property, which shows a double relaxation property, and the transverse relaxation time (T2) is very short. Therefore, it is necessary to apply a very short echo time (TE) value to avoid the loss of T2 signals. Summary of the Invention

[0006] The present invention provides a method for quantitatively detecting lung cancer based on multinuclear magnetic resonance imaging 23 of Na distribution, which can be unaffected by cardiac and respiratory movements, and can detect the sodium ion concentration and its distribution in biological tissues in vivo, non-invasively, and quantitatively, providing direct and quantitative biochemical information for judging the viability of tissues, the integrity of cells and their functions, and at the same time providing some important information related to tissue metabolism, and can be used for diagnosing diseases and evaluating the prognosis and treatment effects of diseases.

[0007] The technical solution of the present invention is realized as follows: A method for quantitatively detecting lung cancer based on multinuclear magnetic resonance imaging 23 of Na distribution includes the following steps:

[0008] (1) Establish a quantitative model of total tissue sodium concentration (TSC). Use the single quantum filtering UTE-SQF sequence in the ultra-short echo pulse sequence to scan and image the TSC quantitative model, and collect the signal intensity in the image to obtain a TSC quantitative curve showing the relationship between the total tissue sodium concentration and the signal intensity in the image;

[0009] (2) Establish a quantitative model of intracellular sodium concentration (ISC). Use the triple quantum filtering UTE-TQF sequence in the ultra-short echo pulse sequence to scan and image the ISC quantitative model, and collect the signal intensity in the image to obtain an ISC quantitative curve showing the relationship between the intracellular sodium concentration and the signal intensity in the image;

[0010] (3) Establish an animal model. Use the UTE-SQF sequence and the UTE-TQF sequence respectively to perform cross-sectional scanning and imaging on the animal model to obtain 23 Na-MR images, and then use the T2WI sequence to 23 locate tumors in the Na-MR images and delineate the regions of interest;

[0011] (4) Collect the signal intensity of the UTE-SQF image in step (3), and quantitatively analyze the total tissue sodium concentration according to the TSC quantitative curve in step (1); collect the signal intensity of the UTE-TQF image in step (3), and quantitatively analyze the intracellular sodium concentration according to the ISC quantitative curve in step (2).

[0012] Further, in step (1), the TSC quantitative model is an aqueous solution of NaCl with different concentrations.

[0013] Furthermore, in step (2), the ISC quantitative model is a NaCl colloidal solution with different concentrations containing 4% agarose.

[0014] Furthermore, in step (3), the animal model is a nude mouse with a subcutaneous tumor of human lung cancer cell line, and the tumor-seeding site is the right buttock.

[0015] Furthermore, in steps (1) and (3), the parameter settings of UTE-SQF are: TR / TE is 150 / 0.219 msec, NEX is 1, Excitation angle is 90°, and Acquisition time is 4 min 23 msec.

[0016] Furthermore, in steps (2) and (3), the parameter settings of UTE-TQF are: TR / TE is 150 / 5 msec, NEX is 12, Excitation angle is 90°, Acquisition time is 52 min 44 msec, and τ = 10 ms.

[0017] Furthermore, in step (3), the parameter settings of the T2WI sequence are: TR / TE is 5000 / 62.4 msec, NEX is 2, Excitation angle is 90°, and Acquisition time is 2 min 40 sec.

[0018] Advantages of the present invention:

[0019] The 23 Na magnetic resonance technology can non-invasively and quantitatively provide the dynamic balance and energy state of sodium ions in vivo, thus making it possible to directly evaluate tissue activity, metabolism, and physiological and pathological related processes, and has been widely developed and applied in disease diagnosis and efficacy evaluation. These advantages cannot be provided by conventional MRI. The present invention combines traditional imaging detection methods with 23 the molecular imaging of Na magnetic resonance, and explains the occurrence and development process of diseases from different levels of "anatomy - function - molecule", so as to better achieve early detection, early diagnosis, and early treatment. By collecting 23 Na, the Na+ concentration and distribution are obtained, the ion channel state is analyzed in vivo, the biological behavior of tumors is simulated and predicted, and ratings are made on the degree of invasion and proliferation, etc., to clarify the dynamic change law between ion disorder and tumor biological behavior. Brief Description of the Drawings

[0020] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the accompanying drawings required for the description of the embodiments or the prior art. Obviously, the accompanying drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other accompanying drawings can be obtained based on these drawings.

[0021] Figure 1 : Method for quantitatively detecting lung cancer based on multi - nuclide magnetic resonance imaging 23 Schematic diagram of the method for Na distribution;

[0022] Figure 2 : Quantitative model sodium magnetic resonance imaging results and quantitative curves, (A) TSC quantitative model, (B) ISC quantitative model;

[0023] Figure 3 : Imaging diagram of the animal model;

[0024] Figure 4 : Quantitative analysis of the animal model imaging, (A) Curve of the change of TSC over time; (B) Curve of the change of ISC over time. Detailed implementation manners

[0025] The following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, rather than all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.

[0026] As Figure 1 shown, a method for quantitatively detecting lung cancer cells based on multi - nuclide magnetic resonance imaging 23 for Na distribution, the process of which is as Figure 1 shown, includes pulse sequence optimization, establishing a quantitative model, establishing an animal model, and data analysis.

[0027] Table 1 Pulse sequence parameters of the quantitative model and the animal model imaging

[0028]

[0029] Pulse sequence optimization includes changing the pulse repetition time (TR), echo time (TE), number of repeated excitations (NEX), etc., to obtain a higher signal-to-noise ratio, resolution, and shorter imaging time. The preferred imaging sequence parameters in this experiment are shown in Table 1. To minimize the loss of T2 signal, on the basis of ensuring image quality, the TE time used in this experiment is 0.219 ms. On the premise of ensuring the shortest acquisition time and optimizing image quality, the TR value used is 150 ms, the NEX of UTE-SQF is 1, the NEX of UTE-TQF is 12, the τ of UTE-TQF = 10 ms, τ is the preparation time, and Acquisition time is the image acquisition time.

[0030] The quantitative models include the TSC quantitative model and the ISC quantitative model.

[0031] Quantitative detection of lung cancer cells based on multinuclear magnetic resonance imaging 23 Method for Na distribution, the specific steps are as follows:

[0032] (1) The TSC quantitative model is an aqueous NaCl solution with concentrations of 30 mM, 50 mM, 100 mM, and 150 mM, which is filled into a 1.5 ml EP tube and then the whole is placed into a large EP tube filled with deionized water. The UTE-SQF sequence is used to scan and image the TSC quantitative model, and the signal intensity in the image is collected. The results are as Figure 2 (A) shown. The relationship between the sodium concentration of the TSC quantitative curve and the signal intensity in the image is y = 6.2245x - 72.864, R 2 = 0.9964. mM in the text is the unit abbreviation for millimole.

[0033] (2) The ISC quantitative model is a NaCl colloidal solution with concentrations of 30 mM, 50 mM, 100 mM, and 150 mM added with 4% agarose, which is filled into a 1.5 ml EP tube and then the whole is placed into a large EP tube filled with deionized water. The UTE-TQF sequence is used to image the ISC quantitative model, and the signal intensity in the image is collected. The results are as Figure 2 (B) shown. The relationship between the sodium concentration of the ISC quantitative curve and the signal intensity in the image is y = 17.601x + 42.86, R 2 = 0.9866.

[0034] (3) The animal model used was a subcutaneous xenograft nude mouse model with the human non-small cell lung cancer H1975 cell line. To avoid the influence of respiration and cardiac movement, the tumor implantation site was the right hip of the nude mouse. The nude mice were standardizedly raised in a specific pathogen-free (SPF) level breeding room. The temperature of the breeding room was controlled at 25 °C, and the humidity was controlled at 45%. The incandescent lamp was manually switched on and off to ensure the day-night rhythm of the nude mice. The tumor volume change of the tumor-bearing mice was regularly monitored, and after the volume was appropriate, routine 1 H magnetic resonance and 23 Na magnetic resonance scans were performed. Isoflurane was used for general anesthesia throughout the scanning process, and the water temperature was kept constant, and respiration was monitored.

[0035] During the animal modeling process, magnetic resonance imaging was performed at different time points. The T2WI sequence in Table 1 was used for scanning and imaging to localize the tumor, and the region of interest was obtained. The UTE-SQF and UTE-TQF sequences in Table 1 were respectively used to scan and image the region of interest. As Figure 3 shown, from left to right are the T2WI, UTE-SQF, and UTE-TQF images, and the circled part is the tumor.

[0036] (4) Collect the signal intensity of the UTE-SQF image in step (3), and quantitatively analyze the total tissue sodium concentration according to the TSC quantitative curve in step (1); collect the signal intensity of the UTE-TQF image in step (3), and quantitatively analyze the intracellular sodium concentration according to the ISC quantitative curve in step (2).

[0037] In steps (1), (2), and (4), image acquisition and data analysis both included image optimization and noise reduction, quantitative curves, and quantitative analysis. The analysis software was MATLAB.

[0038] The above image optimization and noise reduction were achieved through MATLAB code.

[0039] The quantitative curves involved in steps (1) and (2) were applied with the corresponding quantitative models for 23 Na magnetic resonance imaging, and a linear regression curve between the signal intensity and concentration was obtained after image optimization and noise reduction.

[0040] The quantitative analysis in step (4) optimized and reduced the noise of the original image, located the region of interest according to the 1 H magnetic resonance image and SPM software, outlined the tumor area, the contralateral normal muscle area, and the background area, measured the signal intensity, and brought it into the quantitative curves involved in steps (1) and (2) for quantitative analysis of different regions and 23 Na distribution. As Figure 3 shown, from left to right are the T2WI, UTE-SQF, and UTE-TQF, and the circled part is the tumor. As the tumor implantation time increased, the tumor volume increased. Unimplanted nude mice were used ( Figure 4The Muscle in [reference] was used as the control group, as Figure 4 shown. The TSC and ISC within the tumor increased as the tumor volume increased, as Figure 3 shown. The thick arrow in A indicates normal muscle tissue, the thin arrow in B indicates the tumor parenchymal area, and the dashed arrow in C indicates the necrotic area. The higher the sodium ion concentration, the darker the color. It can be seen from Figure 3 that for TSC and ISC, the tumor necrotic area > the tumor parenchymal area > the contralateral normal muscle tissue.

[0041] 23 The Na magnetic resonance technology can non-invasively and quantitatively provide the dynamic balance and energy state of sodium ions in vivo, thus making it possible to directly evaluate tissue activity, metabolism, and physiological and pathological related processes, and has been widely developed and applied in disease diagnosis and treatment evaluation. These advantages cannot be provided by conventional MRI. The present invention combines the traditional imaging detection method with 23 the molecular imaging of Na magnetic resonance to explain the occurrence and development process of diseases from different levels of "anatomy - function - molecule", so as to better achieve early detection, early diagnosis, and early treatment. By collecting 23 Na, the Na + concentration and distribution are obtained, the ion channel state is analyzed in vivo, the biological behavior of the tumor is simulated and predicted, and ratings are made on the degree of invasion and proliferation, etc., to clarify the dynamic change law between ion disorder and tumor biological behavior.

[0042] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. Method for quantitatively detecting lung cancer based on multi-nuclide magnetic resonance imaging 23 The method for the distribution of Na, characterized in that Including the following steps: (1) Establish a quantitative model for total tissue sodium concentration (TSC). Use the single quantum filtered UTE-SQF sequence in the ultra-short echo pulse sequence to scan and image the TSC quantitative model, and collect the signal intensity in the image to obtain the TSC quantitative curve showing the relationship between the total tissue sodium concentration and the signal intensity in the image; (2) Establish a quantitative model for intracellular sodium concentration (ISC). Use the triple quantum filtered UTE-TQF sequence in the ultra-short echo pulse sequence to scan and image the ISC quantitative model, and collect the signal intensity in the image to obtain the ISC quantitative curve showing the relationship between the intracellular sodium concentration and the signal intensity in the image; (3) Establish an animal model, and use the UTE-SQF sequence and the UTE-TQF sequence to perform cross-sectional scanning imaging on the animal model respectively to obtain 23 Na-MR images, and then use the T2WI sequence to 23 locate tumors in the Na-MR images and delineate the regions of interest; (4) Collect the signal intensity of the region of interest in the UTE-SQF image in step (3), and quantify the total tissue sodium concentration according to the TSC quantitative curve in step (1); collect the signal intensity of the region of interest in the UTE-TQF image in step (3), and quantify the intracellular sodium concentration according to the ISC quantitative curve in step (2); In step (1), the TSC quantitative model is an aqueous NaCl solution with different concentrations; In step (2), the ISC quantitative model is a colloidal NaCl solution with different concentrations added with 4% agarose; In step (3), the scanning imaging includes 1 H magnetic resonance and 23 Na magnetic resonance scanning imaging; In step (4), based on 1 H magnetic resonance images and SPM software, the region of interest is located, the tumor region, the contralateral normal muscle region and the background region are outlined, and the signal intensity is measured.

2. Method for quantitatively detecting lung cancer based on multi - nuclide magnetic resonance imaging according to claim 1 23 characterized in that the In step (3), the animal model is a nude mouse with a subcutaneous tumor of a human lung cancer cell line, and the tumor implantation site is the right buttock.

3. Method for quantitatively detecting lung cancer based on multi - nuclide magnetic resonance imaging according to claim 1 23 for Na distribution, characterized in that, In steps (1) and (3), the parameter settings of UTE-SQF are: TR / TE is 150 / 0.219 msec, NEX is 1, Excitation angle is 90°, and Acquisition time is 4 min 23 msec.

4. Method for quantitatively detecting lung cancer based on multi - nuclide magnetic resonance imaging as claimed in claim 1 23 for Na distribution, characterized in that, In steps (2) and (3), the parameter settings of UTE-TQF are: TR / TE is 150 / 5 msec, NEX is 12, Excitation angle is 90°, Acquisition time is 52 min 44 msec, and τ = 10 ms.

5. A method for quantitatively detecting lung cancer based on multi - nuclide magnetic resonance imaging according to claim 1 23 for Na distribution, characterized in that In step (3), the parameter settings of the T2WI sequence are: TR / TE is 5000 / 62.4 msec, NEX is 2, Excitation angle is 90°, and Acquisition time is 2 min 40 sec.

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