An acid-sensitive magnetic resonance nanocomposite probe, a preparation method and application thereof

Abstract

The application discloses an acid-sensitive magnetic resonance nanocomposite probe with a gastric juice pH detection function and a preparation method and application thereof, wherein the acid-sensitive magnetic resonance nanocomposite probe is a nanocomposite, which is composed of chromium hydroxide and a protein, the protein is coated on the surface of the chromium hydroxide, and the chemical general formula of the chromium hydroxide is Cr(OH)3.The probe is sensitive to pH, specifically, the T1 weighted magnetic resonance signal of the probe in a neutral aqueous solution is extremely low, and the signal intensity can be enhanced with the increase of the acidity of the solution.The probe can be orally taken, the preparation method is simple, and the non-invasive monitoring of the in-vivo gastric juice pH can be realized through magnetic resonance imaging.

Description

Technical Field

[0001] This invention belongs to the field of acid-sensitive magnetic resonance nanocomposite probes, and particularly relates to an acid-sensitive magnetic resonance nanocomposite probe, its preparation method and application. Background Technology

[0002] Gastric acid (mainly hydrochloric acid) is one of the main components of gastric juice. Its main functions include: 1) activating pepsinogen, converting it into pepsin, and providing an acidic catalytic environment for pepsin; 2) breaking down fiber and tissue in food, making it easier to absorb; and 3) inhibiting and killing pathogens in food. Under normal physiological conditions, the pH of gastric juice is maintained between 0.9 and 1.8; a value higher than 3.5 is considered abnormal. Abnormal gastric juice pH can affect the activity of gastric cells and the function of the stomach. Some gastrointestinal diseases, such as gastritis, gastric ulcers, and gastroesophageal reflux disease, are closely related to abnormal gastric juice pH. Therefore, gastric juice pH information has important reference value for the diagnosis of gastrointestinal diseases.

[0003] Clinically, endoscopy is commonly used to examine gastric acid secretion by extracting gastric juice and measuring the pH value of the gastric acid. These methods not only easily cause discomfort to patients but may also cause mechanical damage to the body, induce other diseases, and are not suitable for long-term monitoring.

[0004] Therefore, it is of great significance to develop a simple and efficient non-invasive detection method for gastric juice pH value. Summary of the Invention

[0005] The main objective of this invention is to provide an acid-sensitive magnetic resonance nanocomposite probe, its preparation method, and its application, aiming to solve the problem of in vivo, real-time, and non-invasive monitoring of gastric juice pH.

[0006] To achieve the above and other related objectives, the first aspect of the present invention provides an acid-sensitive magnetic resonance nanocomposite probe comprising chromium hydroxide and a protein, wherein the protein is coated on the surface of the chromium hydroxide.

[0007] Furthermore, the protein is one or more of human serum albumin, bovine serum albumin, and chicken oocyte albumin.

[0008] Furthermore, the pH sensitivity range of this acid-sensitive magnetic resonance nanocomposite probe is 0–7.4, and the T1-weighted magnetic resonance signal intensity of the acid-sensitive magnetic resonance nanocomposite probe increases as the pH decreases.

[0009] The second aspect of the present invention provides a method for preparing the acid-sensitive magnetic resonance nanocomposite probe, the method comprising: using a protein as a template, reacting a chromium source under the action of an alkali and a protein to obtain the acid-sensitive magnetic resonance nanocomposite probe.

[0010] Furthermore, the preparation method specifically includes: 1) dissolving the protein and chromium source in water to obtain a mixture; 2) adjusting the pH of the mixture to 9-11 with alkali to obtain a post-reaction solution; 3) centrifuging and washing the precipitate of the post-reaction solution to obtain the acid-sensitive magnetic resonance nanocomposite probe.

[0011] Further, step 2) specifically includes: after adding alkali to the mixture, stirring magnetically for 20 min to 40 min until the pH value of the mixture reaches 9 to 11, to obtain the reacted solution; step 3) specifically includes: centrifuging the reacted solution at 12000 rpm, washing the precipitate with secondary water and repeating the centrifugation twice to obtain the acid-sensitive magnetic resonance nanocomposite probe.

[0012] Furthermore, the concentration of protein in the mixture is 1-2 g / mL; the mass ratio of the chromium source to the protein is (1-2):1.

[0013] Furthermore, the chromium source is one or more of chromium nitrate nonahydrate and chromium chloride hexahydrate; the alkali is one or more of sodium hydroxide and potassium hydroxide.

[0014] A third aspect of the present invention provides the application of the acid-sensitive magnetic resonance nanocomposite probe described above in the field of gastric juice pH detection.

[0015] The fourth aspect of the present invention provides the application of the acid-sensitive magnetic resonance nanocomposite probe as described above in the field of evaluating the effective time of gastric acid-inhibiting drugs.

[0016] The beneficial effects of this invention are reflected in:

[0017] 1) The acid-sensitive magnetic resonance nanocomposite probe provided by the present invention has extremely low T1-weighted magnetic resonance signal intensity in neutral aqueous solution. When the acidity of the solution increases, its T1-weighted magnetic resonance signal intensity increases with the decrease of pH value, and it can sensitively respond to gastric juice with different acidity levels.

[0018] 2) The method for preparing the acid-sensitive magnetic resonance nanocomposite probe provided by this invention is simple, requires no expensive equipment, is safe and easy to operate, has a short preparation cycle, and is green and environmentally friendly.

[0019] 3) The acid-sensitive magnetic resonance nanocomposite probe provided by this invention can be taken orally and has good water solubility and biocompatibility. Attached Figure Description

[0020] One or more embodiments are illustrated by way of example with reference to the accompanying drawings. These illustrations do not constitute a limitation on the embodiments, and unless otherwise stated, the figures in the drawings are not to be limited by scale.

[0021] Figure 1 The diagram shows the hydrated particle size of the acid-sensitive magnetic resonance nanocomposite probe prepared in Example 1.

[0022] Figure 2 The image shown is a transmission electron microscope image of the acid-sensitive magnetic resonance nanocomposite probe prepared in Example 1;

[0023] Figure 3 The image shown is an X-ray energy dispersive spectroscopy (EDS) spectrum of the acid-sensitive magnetic resonance nanocomposite probe prepared in Example 1.

[0024] Figure 4 The image shown is an X-ray photoelectron spectroscopy fitting diagram of the acid-sensitive magnetic resonance nanocomposite probe prepared in Example 1.

[0025] Figure 5 The image shows the longitudinal relaxation curve fitting diagram after the acid-sensitive magnetic resonance nanocomposite probe reacts with hydrochloric acid of various concentrations in Example 4.

[0026] Figure 6 The image shown is an in vitro T1-weighted imaging image of the acid-sensitive magnetic resonance nanocomposite probe after reacting with hydrochloric acid of various concentrations in Example 4.

[0027] Figure 7 The diagram shows the acid response kinetics of the acid-sensitive magnetic resonance nanocomposite probe in Example 4.

[0028] Figure 8 The table shows the gastric pH values ​​of mice 3 hours after oral administration of ranitidine in Example 5.

[0029] Figure 9 The image shown is a T1-weighted image of mice after oral administration of Gd-DTPA and nanocomposite probe in Example 5.

[0030] Figure 10 The following is a statistical analysis of the changes in gastric pH in mice 24 hours after oral administration of ranitidine in Example 6;

[0031] Figure 11 The image shown is a T1-weighted image of mice taken orally with the nanocomposite probe in Example 6 within 24 hours.

[0032] Figure 12 The figures show the routine blood count and blood biochemical parameters of mice 7 and 14 days after oral administration of the nanocomposite probe in Example 7. Detailed Implementation

[0033] Inventors have observed that the technology of monitoring gastric juice pH in vivo through molecular imaging has received increasing attention in recent years. Ma et al. (Chinese Patent CN113461588A, 2021-10-01) proposed a fluorescent small molecule probe for gastric acid monitoring. The fluorescence performance of this molecular probe in aqueous solution changes with pH value, and the pH value of gastric juice is monitored through fluorescence signal. Wang et al. (Chinese Patent CN115806817A, 2023-03-17) invented an inorganic fluorescent material with gastric acid pH detection function. Its luminescence intensity decay value (y) is related to the pH value (z) by the function z = -1.2942y + 2.1238, which can be used to detect the pH value of gastric juice. Lin et al. (Chinese Patent CN110393811B, 2022-02-11) invented an acid-responsive nanoprobe. Its acid-responsive organic molecules can monitor gastric acid secretion in vivo through photoacoustic imaging. However, the intensity of optical imaging signals is limited by the depth of light penetration, making it difficult to detect light signals from internal organs, which hinders its clinical application.

[0034] Magnetic resonance imaging (MRI), as a truly depth-free non-ionizing imaging method, plays an irreplaceable role in clinical diagnosis. However, there are few reports on techniques for monitoring gastric acid using MRI. Existing gadolinium-based contrast agents for the stomach cannot reflect gastric acid levels and are prone to gadolinium ion leakage, leading to safety concerns. Therefore, there is an urgent need to develop magnetic resonance probes and imaging techniques for real-time, non-invasive monitoring of gastric pH.

[0035] In view of this, the present invention provides an acid-sensitive magnetic resonance nanocomposite probe comprising chromium hydroxide and a protein, wherein the protein is coated on the surface of the chromium hydroxide. The general chemical formula of the chromium hydroxide is Cr(OH)3.

[0036] The preparation method includes: using protein as a template, reacting a chromium source under the action of alkali and protein to obtain the acid-sensitive magnetic resonance nanocomposite probe.

[0037] The preparation method specifically includes: 1) dissolving the protein and chromium source in water to obtain a mixture; 2) adjusting the pH of the mixture to 9-11 with alkali to obtain a post-reaction solution; 3) centrifuging and washing the precipitate of the post-reaction solution to obtain the acid-sensitive magnetic resonance nanocomposite probe.

[0038] The technical solution of the present invention will be described below with reference to specific embodiments. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification.

[0039] Before further describing specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terminology used in the embodiments of the present invention is for describing specific embodiments and not for limiting the scope of protection of the present invention. Test methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the respective manufacturers.

[0040] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the present invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. In addition to the specific methods, apparatus, and particles used in the embodiments, based on the knowledge of the prior art possessed by one of ordinary skill in the art and the description of this invention, any prior art methods, apparatus, and particles similar to or equivalent to those described, apparatus, and particles in the embodiments of this invention may be used to implement the present invention.

[0041] In the following embodiments of this application, chromium nitrate nonahydrate as the chromium source and sodium hydroxide as the alkali are used for illustration. It should be noted that chromium hydroxide can be obtained by using chromium nitrate nonahydrate or chromium chloride hexahydrate as the chromium source.

[0042] In this embodiment of the application, human serum albumin (HSA), bovine serum albumin (BSA), and ovalbumin (OVA) were purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0043] Example 1

[0044] In Example 1, the preparation of the acid-sensitive magnetic resonance nanocomposite probe includes the following steps:

[0045] 1) Add 20 mg HSA and 30 mg chromium nitrate nonahydrate to 10 mL of deionized water and stir magnetically to dissolve and obtain a mixture.

[0046] 2) Add 400 μL of 1M sodium hydroxide solution and stir magnetically at 25°C for 30 minutes.

[0047] 3) Centrifuge the solution after the reaction at 12,000 rpm, wash the precipitate with secondary water and repeat the centrifugation twice to obtain the chromium hydroxide-protein nanocomposite probe, labeled as Cr(OH)3-HSA.

[0048] Take an appropriate amount of Cr(OH)3@HSA aqueous solution and perform particle size distribution testing and morphological observation by transmission electron microscopy.

[0049] Figure 1 The image shows the dynamic light scattering (DLS) particle size distribution of the nanocomposite. The DLS image shows that the average hydrated particle size of the nanocomposite probe is approximately 40 nm.

[0050] Figure 2 The image shows a transmission electron microscope (TEM) image of the nanocomposite. The TEM image shows that the nanocomposite probe has a rod-shaped structure, good dispersibility, and the particle size is consistent with the DLS results.

[0051] Figure 3 The image shows the energy dispersive spectroscopy (EDS) spectrum of the nanocomposite. The EDS spectrum reveals that the main elements in the nanocomposite are chromium, oxygen, and sulfur. The sulfur is derived from the protein. The concentration of chromium in the Cr(OH)3-HSA aqueous solution was measured to be 7 mM using inductively coupled plasma mass spectrometry (ICP-MS).

[0052] Figure 4 The image shows the X-ray photoelectron spectroscopy (XPS) fitting diagram of the nanocomposite. The peak fitting results show that the chromium in the nanocomposite is in the form of chromium hydroxide Cr(OH)3.

[0053] Example 2

[0054] In Example 2, the preparation of the acid-sensitive magnetic resonance nanocomposite probe includes the following steps:

[0055] 1) Add 20 mg BSA and 40 mg chromium nitrate nonahydrate to 10 mL of deionized water and stir magnetically to dissolve and obtain a mixture.

[0056] 2) Add 500 μL of 1M sodium hydroxide solution and stir magnetically at 25°C for 30 minutes.

[0057] 3) Centrifuge the solution after the reaction at 12,000 rpm, wash the precipitate with secondary water and repeat the centrifugation twice to obtain the chromium hydroxide-protein nanocomposite probe, labeled as Cr(OH)3-BSA.

[0058] In this embodiment, the mass ratio of chromium nitrate nonahydrate to BSA is 2:1; the average hydrated particle size of the nanocomposite probe is 50 nm.

[0059] Example 3

[0060] In Example 3, the preparation of the acid-sensitive magnetic resonance nanocomposite probe includes the following steps:

[0061] 1) Add 20 mg OVA and 30 mg chromium nitrate nonahydrate to 10 mL of deionized water and stir magnetically to dissolve and obtain a mixed solution.

[0062] 2) Add 400 μL of 1M sodium hydroxide solution and stir magnetically at 25°C for 30 minutes.

[0063] 3) Centrifuge the solution after the reaction at 12,000 rpm, wash the precipitate with secondary water and repeat the centrifugation twice to obtain the chromium hydroxide-protein nanocomposite probe, labeled as Cr(OH)3-OVA.

[0064] In this embodiment, the mass ratio of chromium nitrate nonahydrate to OVA is 1.5:1; the average hydrated particle size of the nanocomposite probe is 60 nm.

[0065] Example 4

[0066] In this Example 4, the acid-sensitive magnetic resonance nanocomposite probe (Cr(OH)3-HSA) prepared in Example 1 was used to test its acid response performance.

[0067] T1-weighted relaxation time test of Cr(OH)3-HSA before and after acid response: Take 100 μL of six Cr(OH)3-HSA solutions and add an equal volume of hydrochloric acid (HCl) to make the final HCl concentrations 0 mM, 0.5 mM, 1.25 mM, 2.5 mM, 5 mM and 10 mM respectively. After 10 minutes, the T1-weighted relaxation time of each sample is measured by time-domain nuclear magnetic resonance analyzer. The T1-weighted relaxation rate of Cr(OH)3-HSA before and after acid response is obtained by statistical analysis.

[0068] T1-weighted imaging test of Cr(OH)3-HSA before and after acid response: Take 500 μL of six Cr(OH)3-HSA solutions and add an equal volume of hydrochloric acid (HCl) to make the final HCl concentrations 0 mM, 0.5 mM, 1.25 mM, 2.5 mM, 5 mM and 10 mM respectively. Transfer the samples to the sample tube of the nuclear magnetic resonance imaging instrument (1.0T) and collect the T1-weighted relaxation signal of each sample.

[0069] T1-weighted relaxation kinetics of Cr(OH)3-HSA before and after acid response: Take 100 μL of six Cr(OH)3-HSA solutions and add an equal volume of hydrochloric acid (HCl) to make the final HCl concentrations 0 mM, 0.5 mM, 1.25 mM, 2.5 mM, 5 mM and 10 mM respectively. Immediately transfer them to a time-domain nuclear magnetic resonance analyzer and test the T1-weighted relaxation time of each sample. Monitor every 10 minutes until 40 minutes.

[0070] Figure 5 The figure shows the relaxation curves of Cr(OH)3-HSA after the addition of hydrochloric acid at various concentrations. As can be seen from the figure, the r1 relaxation rates of Cr(OH)3-HSA at hydrochloric acid concentrations of 0 mM, 0.5 mM, 1.25 mM, 2.5 mM, 5 mM, and 10 mM (pH values ​​of 6.5, 6, 5.5, 5.0, 4.0, and 3.0) are 0.1727, 0.3773, 1.145, 2.143, 3.164, and 3.276, respectively. This indicates that the r1 relaxation rate of the probe Cr(OH)3-HSA increases with increasing acidity; at pH 3.0, its r1 relaxation rate is 18.97 times that at pH 6.5.

[0071] Figure 6 The image shows T1-weighted imaging of Cr(OH)3-HSA before and after acid response. As can be seen from the image, the T1-weighted signal intensity of Cr(OH)3-HSA gradually increases with increasing acidity, and... Figure 5 The increase in the mid-r1 relaxation rate is consistent with this.

[0072] Figure 7 The figure shows the acid response kinetics of Cr(OH)3-HSA. It can be seen from the figure that even at an HCl concentration of 0.5 mM, its T1 relaxation time shows a significant response within 5 minutes; when the HCl concentration is 10 mM, its T1 relaxation time decreases to its lowest value within 5 minutes. This data indicates that Cr(OH)3-HSA has high acid response sensitivity.

[0073] Example 5

[0074] In this embodiment, the clinically widely used, acid-free gadolinium-based contrast agent Gd-DTPA was used as a control to evaluate the gastric acid responsiveness of Cr(OH)3-HSA prepared in Example 1 at the animal level.

[0075] Seven-week-old BALB / c mice weighing 18-20g were randomly divided into four groups of three mice each. Mice were fasted for 8 hours before the experiment. Subsequently, groups A and C were administered 200μL of ultrapure water via gavage, while groups B and D were administered 200μL of ranitidine (40mg / kg) via gavage. Three hours later, groups A and B were administered 200μL of Gd-DTPA (7mM) via gavage, and groups C and D were administered 200μL of Cr(OH)3-HSA (7mM) via gavage. After anesthetizing the mice, they were transferred to a 1.0T magnetic resonance imaging (MRI) scanner, and T1-weighted imaging signals were collected every 15 minutes for 1 hour.

[0076] Figure 8 The average gastric pH value was measured by dissecting the stomach of mice 3 hours after administration of ranitidine.

[0077] Figure 9 T1-weighted imaging images of four groups of mice one hour after gavage administration of Cr(OH)3-HSA. Comparison of imaging results between groups A and B shows that the clinically used contrast agent Gd-DTPA rapidly illuminates the stomach after gavage. The signal intensity of group B mice, which received pre-administered acid-suppressing drugs, showed no significant difference from group A mice, indicating that Gd-DTPA cannot respond to changes in gastric pH to produce magnetic resonance signal changes. Group C mice also rapidly illuminated their stomachs after administration of Cr(OH)3-HSA, but group D mice, which received pre-administered acid-suppressing drugs, did not illuminate their stomachs after administration of Cr(OH)3-HSA. Figure 8 This indicates that Cr(OH)3-HSA can respond to and illuminate the stomach of normal mice at the animal level, but does not produce signal enhancement in the stomach when the pH of the gastric juice is neutral.

[0078] Example 6

[0079] In this embodiment, Cr(OH)3-HSA prepared in Example 1 was used to evaluate the effective duration of ranitidine, a gastric acid inhibitor.

[0080] Seven-week-old BALB / c mice weighing 18-20g were fasted for 8 hours before the experiment. Then, 200μL of ranitidine (40mg / kg), a gastric acid suppressant, was administered via gavage. Three hours later, the mice were administered 200μL of Cr(OH)3-HSA (7mM) via gavage. After anesthetizing the mice, they were transferred to a 1.0T magnetic resonance imaging (MRI) scanner, and T1-weighted imaging signals were collected every 15 minutes for 0.5 hours. Two and a half hours later, the mice were again administered 200μL of Cr(OH)3-HSA (7mM) via gavage, followed by imaging. This process was repeated for 24 hours.

[0081] Figure 10 The average pH value of gastric juice was measured by dissecting the stomach of mice at various time points after administration of ranitidine.

[0082] Figure 11 T1-weighted imaging images of mice after administration of Cr(OH)3-HSA at various time points. The images show a significant increase in T1 signal in the mouse stomach 9 hours after ranitidine administration, followed by similar enhancements after re-administration of Cr(OH)3-HSA at 12 and 24 hours. Figure 10 This indicates that mice lose the effect of inhibiting gastric acid secretion after about 9 hours at the current ranitidine dosage.

[0083] Example 7

[0084] In this embodiment, Cr(OH)3-HSA prepared in Example 1 was used for routine blood tests and blood biochemistry tests to evaluate its biosafety.

[0085] Seven-week-old BALB / c mice weighing 18-20g were selected and divided into three groups of three mice each. One group served as the control group, which was administered 200μL of ultrapure water via gavage. The other two groups were administered 200μL of Cr(OH)3-HSA (7mM) aqueous solution. On days 7 and 14, 0.5 ml of blood was collected for complete blood count and blood biochemistry tests, and the samples were labeled as the 7-day group and the 14-day group, respectively.

[0086] Figure 12 The figures show the complete blood count and blood biochemistry data of mice in each group. As can be seen from the figure, there were no significant differences in the complete blood count and blood biochemistry parameters of mice 7 and 14 days after administration of Cr(OH)3-HSA compared with the control group, indicating that Cr(OH)3-HSA has no obvious toxic side effects at this dose.

[0087] Understandably, the choice of protein has little impact on the performance of the product acid-sensitive magnetic resonance nanocomposite probe, so the effectiveness verification of Cr(OH)3-BSA and Cr(OH)3-OVA will not be elaborated here.

[0088] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.

Claims

1. An acid-sensitive magnetic resonance nanocomposite probe, characterized in that, The acid-sensitive magnetic resonance nanocomposite probe comprises chromium hydroxide and a protein, wherein the protein is coated on the surface of the chromium hydroxide; The protein is one or more of human serum albumin, bovine serum albumin, and chicken oval albumin; The pH sensitivity range of this acid-sensitive magnetic resonance nanocomposite probe is 0~7.4, and the T1-weighted magnetic resonance signal intensity of this acid-sensitive magnetic resonance nanocomposite probe increases as the pH decreases. The preparation method of the acid-sensitive magnetic resonance nanocomposite probe specifically includes: 1) Dissolve the protein and chromium source in water to obtain a mixture; 2) Adjust the pH of the mixture to 9-11 using alkali to obtain the reacted solution; 3) Centrifuge and wash the precipitate after the reaction to obtain the acid-sensitive magnetic resonance nanocomposite probe; Step 2) specifically includes: after adding alkali to the mixture, magnetically stirring the mixture for 20 min to 40 min until the pH value of the mixture reaches 9 to 11, to obtain the reacted solution; Step 3) specifically includes: centrifuging the solution after the reaction at 12000 rpm, washing the precipitate with deionized water and centrifuging twice to obtain the acid-sensitive magnetic resonance nanocomposite probe. The concentration of protein in the mixture is 1~2 g / mL; the mass ratio of chromium source to protein is (1~2):

1.

2. The method for preparing the acid-sensitive magnetic resonance nanocomposite probe according to claim 1, characterized in that, The preparation method specifically includes: 1) Dissolve the protein and chromium source in water to obtain a mixture; 2) Adjust the pH of the mixture to 9-11 using alkali to obtain the reacted solution; 3) Centrifuge and wash the precipitate after the reaction to obtain the acid-sensitive magnetic resonance nanocomposite probe; Step 2) specifically includes: after adding alkali to the mixture, magnetically stirring the mixture for 20 min to 40 min until the pH value of the mixture reaches 9 to 11, to obtain the reacted solution; Step 3) specifically includes: centrifuging the solution after the reaction at 12000 rpm, washing the precipitate with deionized water and centrifuging twice to obtain the acid-sensitive magnetic resonance nanocomposite probe. The concentration of protein in the mixture is 1~2 g / mL; the mass ratio of chromium source to protein is (1~2):

1.

3. The method for preparing the acid-sensitive magnetic resonance nanocomposite probe according to claim 2, characterized in that, The chromium source is one or more of chromium nitrate nonahydrate and chromium chloride hexahydrate; the alkali is one or more of sodium hydroxide and potassium hydroxide.

4. The application of the acid-sensitive magnetic resonance nanocomposite probe as described in claim 1 in the field of gastric juice pH detection.

5. The application of the acid-sensitive magnetic resonance nanocomposite probe as described in claim 1 in the field of evaluating the effective time of gastric acid-suppressing drugs.

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