Application of a magnetic resonance contrast agent in targeting adrenal cortex and imaging method

Abstract

The invention discloses an application of a magnetic resonance contrast agent in targeting the adrenal cortex. The magnetic resonance contrast agent is prepared by the following method: 18.5 mg of gadolinium trifluoromethanesulfonate, gadolinium chloride or gadolinium nitrate is weighed and dissolved in 2 ml of water, and then 2 ml of Na2CO3 / NaHCO3 buffer solution with a pH of 9-12 is added to precipitate it, and the precipitate is resuspended with water after centrifugation to form a suspension, and then human serum albumin or bovine serum albumin is dissolved in water, and is added dropwise to the suspension during shaking, and after adding a magnetic particle, the supernatant is centrifuged after stirring and reacting at 25-45°C, and finally the supernatant is ultrafiltered, concentrated and filtered with a 100K ultrafiltration tube to obtain a magnetic resonance contrast agent; the magnetic resonance contrast agent is used to target the adrenal cortex and can be taken up by macrophages in the adrenal cortex. The contrast agent has a mechanism for targeting the adrenal cortex, and the contrast agent is taken up by macrophages in the adrenal cortex. The magnetic resonance contrast agent can have a targeting enhancement effect on the adrenal cortex for at least 7 days.

Description

Technical Field

[0001] The present invention relates to the field of magnetic resonance imaging, and in particular to an application of a magnetic resonance contrast agent in targeting adrenal cortex and an imaging method. Background Art

[0002] The adrenal gland is an endocrine organ located at the upper pole of the kidney, consisting of the cortex and medulla. The adrenal cortex originates from the mesoderm, and is divided into the zona glomerulosa, zona fasciculata, and zona reticularis from the outside to the inside, which secrete mineralocorticoids, glucocorticoids, and sex hormones respectively. The adrenal medulla originates from the neuroectoderm and secretes catecholamines, etc. These hormones are essential for maintaining the normal physiological function of the body. Magnetic resonance imaging has high resolution for soft tissue imaging and is not limited by tissue depth.

[0003] Adrenal adenomas and other space-occupying lesions are common. Since the adrenal cortex and medulla have completely different histological and embryological origins and physiological functions, the treatment method depends on the localization and characterization of the lesions by imaging examinations.

[0004] Currently, commonly used adrenal imaging methods in clinical practice include ultrasound, CT, MRI, and radionuclide imaging. Ultrasound relies on the fat around the adrenal glands to outline the adrenal gland contours; CT and MRI rely on soft tissue density and signal intensity to distinguish the adrenal glands from surrounding tissues, respectively. Since the density and water content of the adrenal cortex and medulla are similar, the above examinations can only determine the overall morphology, position, size, uniformity, etc. of the adrenal glands. More importantly, commercial CT and MRI contrast agents lack targeting and therefore cannot specifically distinguish between the cortex and medulla; radionuclide imaging can be used to diagnose adrenal cortical lesions by means of the differential uptake of radionuclide-labeled cholesterol derivatives such as iodinated cholesterol by cortical and medullary cells. However, radionuclide imaging is expensive, has low resolution, and is radioactive, and is not commonly used in clinical practice.

[0005] However, there is a lack of effective specific adrenal imaging methods in clinical practice, especially imaging methods that can distinguish between the cortex and medulla. MRI has the advantages of high soft tissue resolution, no limitation on tissue depth, and no ionizing radiation. Therefore, the development of cortical-targeted magnetic resonance contrast agents has important clinical significance and application prospects. Summary of the invention

[0006] The purpose of the present invention is to provide an application of a magnetic resonance contrast agent in targeting the adrenal cortex and an imaging method to solve the technical problem of the lack of effective specific adrenal imaging methods in the prior art, especially imaging means that can distinguish the cortex and medulla.

[0007] In order to solve the above technical problems, the present invention specifically provides the following technical solutions:

[0008] Use of a magnetic resonance contrast agent for targeting the adrenal cortex,

[0009] The magnetic resonance contrast agent is prepared by the following method:

[0010] 18.5 mg of gadolinium trifluoromethanesulfonate or gadolinium chloride or gadolinium nitrate is weighed and dissolved in 2 ml of water, and then 2 ml of Na2CO3 / NaHCO3 buffer solution with a pH of 9-12 is added to precipitate it, and the precipitate is resuspended with water after centrifugation to form a suspension, and then human serum albumin or bovine serum albumin is dissolved in water, and then added dropwise to the suspension during shaking, and a magnetic particle is added, and the mixture is stirred under heating at 25-45° C., and then the supernatant is centrifuged to obtain a magnetic resonance contrast agent;

[0011] The magnetic resonance contrast agent is used for targeting the adrenal cortex and can be taken up by macrophages in the adrenal cortex.

[0012] On the other hand, a method for imaging a magnetic resonance contrast agent on a targeted adrenal cortex is provided, characterized in that:

[0013] After administration of magnetic resonance contrast agent, the adrenal cortex is observed within 5 minutes to 1500 minutes using contrast-enhanced magnetic resonance imaging technology.

[0014] As a preferred solution of the present invention, the adrenal cortex development is observed within 1440 minutes, and the difference between the cortex and medulla signals is the greatest.

[0015] Compared with the prior art, this application has the following beneficial effects:

[0016] The contrast agent has a targeting mechanism to the adrenal cortex, where it is taken up by macrophages within the adrenal cortex.

[0017] The magnetic resonance contrast agent's targeted enhancement effect on the adrenal cortex can last for at least 7 days.

[0018] Contrast agents have the characteristics of high relaxation rate and long circulation time. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the implementation methods of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for the implementation methods or the description of the prior art. Obviously, the drawings in the following description are only exemplary, and for ordinary technicians in this field, other implementation drawings can be derived from the provided drawings without creative work.

[0020] Figure 1 The fluorescence imaging diagram for verifying the targeting of the contrast agent to the adrenal cortex of the present invention;

[0021] Figure 2An imaging diagram for verifying the localization of the contrast agent in macrophages in the adrenal cortex of the present invention;

[0022] Figure 3 This is an image diagram of the scanning result of adrenal frozen section of the present invention;

[0023] Figure 4 The whole body T1WI magnetic resonance imaging images of rats before and after administration to verify the enhancement effect of the contrast agent on the adrenal cortex; DETAILED DESCRIPTION

[0024] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0025] The present invention focuses on the discovery of new uses of a magnetic resonance contrast agent prepared by the following method. The magnetic resonance contrast agent is prepared by the following method:

[0026] Weigh 18.5 mg of gadolinium trifluoromethanesulfonate, gadolinium chloride or gadolinium nitrate and dissolve it in 2 ml of water. Add Na2CO3 / NaHCO3 buffer with a pH of 9-12 to precipitate it. Centrifuge at 9000g for 3 minutes and discard the supernatant. At the same time, take 4 ml of water to resuspend the precipitate and blow it thoroughly to form a suspension and transfer it to a glass bottle.

[0027] Dissolve human serum albumin or bovine serum albumin in water, add it dropwise to the suspension while shaking, add a magnetic particle, heat at 25-45°C, stir and react, centrifuge to obtain the supernatant, and use a 100K ultrafiltration tube to concentrate and filter the supernatant. The albumin is human serum albumin or bovine serum albumin, with a mass of 300 mg, and BSA is dissolved in 6 ml of water.

[0028] The stirring reaction time is 2 hours, S2 is centrifuged at 9000g for 3 minutes to remove the precipitate, S3 is ultrafiltered for 12 minutes with a centrifugal force of 7200g, the supernatant in S3 is ultrafiltered to a constant volume of 3 ml, and filtered through a 0.22um filter membrane to obtain a magnetic resonance contrast agent.

[0029] The magnetic resonance contrast agent has the characteristics of high relaxation rate, long circulation time, etc., which are disclosed in the existing comparative document CN115317628A.

[0030] The present invention focuses on discovering that the magnetic resonance contrast agent is used to target the adrenal cortex and can be taken up by macrophages in the adrenal cortex, which has never been found in the prior art.

[0031] The imaging method is: after the administration of magnetic resonance contrast agent, the adrenal cortex is observed within 5 minutes to 1500 minutes through contrast-enhanced magnetic resonance imaging technology (ceMRA).

[0032] Clinical ceMRA usually performs imaging immediately after administration (commercial contrast agents are metabolized quickly), but our imaging method requires imaging 5-10 minutes after administration to observe the adrenal cortex. The best imaging effect is at 24 hours (1440 minutes) after administration, and the difference between cortical and medullary signals is the greatest.

[0033] 1) The following experiments were performed to verify the targeting of the contrast agent to the adrenal cortex:

[0034] The MRI contrast agent was labeled with the fluorescent dye indocyanine green (ICG). The mouse adrenal glands were removed and frozen 10 minutes after intravenous injection of the contrast agent. The adrenal glands were then scanned under a confocal microscope. The results are shown in the attached figure. Figure 1 .

[0035] Green is ICG fluorescence, and the arrow points to the adrenal medulla. Figure 1 As shown, the ICG-containing magnetic resonance contrast agent is only distributed in the adrenal cortex area, which is consistent with the results of magnetic resonance imaging, indicating that it has good targeting.

[0036] 2) The following experiments verified that the contrast agent is localized in macrophages in the adrenal cortex:

[0037] Mice were intraperitoneally injected with chloroquine phosphate (Chlo) at 50 mg / kg daily for one week to inhibit the phagocytic function of macrophages in mice. Mice injected with PBS were used as controls (Control). ICG-labeled contrast agents were injected intravenously into the above mice. The adrenal glands were removed 10 minutes later, and the left adrenal acid was dissolved and the Gd content was determined by ICP-MS. The right adrenal gland was used for frozen section scanning.

[0038] like Figure 2 As shown, A and B are the scan results of adrenal frozen sections taken out 10 minutes after intravenous injection of contrast agent in mice injected with PBS and Chlo, respectively.

[0039] Figure 3 In the figure, A is the quantitative results of fluorescence intensity after scanning of adrenal frozen sections of two groups of mice, among which the fluorescence intensity of the control group injected with PBS was significantly stronger than that of the Chlo group, and B is the Gd content in the adrenal glands of the two groups of mice, among which the Gd content of the control group injected with PBS was significantly higher than that of the Chlo group.

[0040] The above results indicate that after macrophage function is inhibited, the content of magnetic resonance contrast agent in the adrenal gland is significantly reduced. Therefore, the targeting mechanism of magnetic resonance contrast agent to the adrenal cortex is the uptake of magnetic resonance contrast agent by macrophages in the cortex.

[0041] 3) The following experiments verify the strengthening effect of the adrenal cortex:

[0042] 0.1 mmol / kg of the magnetic resonance contrast agent of the present invention was injected into the rat's tail vein.

[0043] T1WI magnetic resonance imaging was performed before and at different time points after drug administration.

[0044] like Figure 4 Shown are whole-body T1WI magnetic resonance imaging images of rats before and after drug administration.

[0045] Pre is before drug administration. The round organ pointed by the arrow is the adrenal gland. The adrenal cortex is enhanced 5 minutes after drug administration. After 30 days, the signal returns to the level before drug administration. The low signal area in the middle of the adrenal gland is the medulla.

[0046] By the attached Figure 4 It can be seen that the targeted enhancement effect of this magnetic resonance contrast agent on the adrenal cortex can last for at least 7 days.

[0047] The above embodiments are only exemplary embodiments of the present invention and are not intended to limit the present invention. The protection scope of the present invention is defined by the claims. Those skilled in the art may make various modifications or equivalent substitutions to the present invention within the essence and protection scope of the present invention, and such modifications or equivalent substitutions shall also be deemed to fall within the protection scope of the present invention.

Claims

1. Use of a magnetic resonance contrast agent in the preparation of an adrenal cortex-targeted contrast agent, characterized in that: The magnetic resonance contrast agent is prepared by the following method: 18.5 mg of gadolinium trifluoromethanesulfonate or gadolinium chloride or gadolinium nitrate is weighed and dissolved in 2 ml of water, and then 2 ml of Na2CO3 / NaHCO3 buffer solution with a pH of 9-12 is added to precipitate it, and the precipitate is resuspended with water after centrifugation to form a suspension, and then human serum albumin or bovine serum albumin is dissolved in water, and then added dropwise to the suspension during shaking, and a magnetic particle is added, and the mixture is stirred under heating at 25-45° C., and then the supernatant is centrifuged to obtain a magnetic resonance contrast agent; The magnetic resonance contrast agent is used for targeting the adrenal cortex and can be taken up by macrophages in the adrenal cortex.

2. The use of a magnetic resonance contrast agent according to claim 1 in the preparation of an adrenal cortex-targeted contrast agent, characterized in that: After administration, the adrenal cortex was observed within 5 minutes to 1500 minutes using contrast-enhanced magnetic resonance imaging.

3. The use of a magnetic resonance contrast agent according to claim 2 in the preparation of an adrenal cortex-targeted contrast agent, characterized in that: The adrenal cortex was observed within 1440 min, and the signal difference between the cortex and medulla was the greatest.

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