CN115721739A - Contrast agent for pyelonephritis nuclear magnetic angiography and application thereof - Google Patents
Contrast agent for pyelonephritis nuclear magnetic angiography and application thereof Download PDFInfo
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Abstract
The invention provides a contrast agent for pyelonephritis nuclear magnetic resonance imaging and application thereof, wherein the contrast agent is prepared from 2-4 parts of 4-arm-amino-polyethylene glycol, 2-4 parts of gadopentetate meglumine, 80-120 parts of phospholipid, 2-4 parts of N-acetylneuraminic acid, 5-10 parts of glucan and water for injection. The invention improves the formula of the contrast agent, and improves the enrichment of the contrast agent in renal tissues while reducing the concentration of a molecular complex of paramagnetic metal gadolinium (Gd) in the contrast agent, thereby not only reducing the toxicity of Gd, but also improving the sensitivity of nuclear magnetic resonance imaging, being beneficial to reducing the cost and simultaneously reducing the side effect of the contrast agent.
Description
Technical Field
The invention belongs to the field of diagnostic reagents, and particularly relates to a contrast agent for pyelonephritis nuclear magnetic angiography and application thereof.
Background
Magnetic Resonance Imaging (MRI) produces a fine description of human anatomy and pathology with high spatial resolution. To increase the diagnostic sensitivity and specificity of MRI, for example for imaging cancer, infection, neurological and heart diseases, contrast material is often administered intravenously before and/or during imaging to improve signal.
MRI imaging is carried out by utilizing disordered small magnetic moments formed by hydrogen protons at each part of a human body to generate different vibrations in a radio frequency magnetic field, releasing energy just absorbed by each hydrogen proton after radio frequency pulse evacuation, converting released radio signals into gray pixels of each fault, and completing by gradient magnetic fields GX, GY and GZ for spatial positions of different faults and spatial positions of each hydrogen proton. The MRI signal intensity of water protons in human tissue is dependent on many factors (spin density NH, imaging volume parameter fV, longitudinal relaxation time T1, transverse relaxation time T2, and scan times TE and TR), the two most important of which are relaxation times T1 and T2. Some compounds containing paramagnetic nuclei can be used to significantly alter T1 and T2 of the surrounding hydrogen nuclei, enhancing contrast of imaging, such paramagnetic species being referred to as contrast agents. The action principle is that a local magnetic field generated by a paramagnetic substance has an acceleration effect on the relaxation rate of adjacent detected nuclei such as water protons 1H (the rate of the process of dissipating energy from the detected nuclei excited to a high energy state by radio frequency and then returning to a low energy state), so that the image signal of magnetic resonance imaging depending on the relaxation rate (1/T1 or 1/T2) is enhanced, and the contrast and the definition of the image are improved. According to this principle, when used as contrast agent, the paramagnetic metal chelate actually functions as the paramagnetic metal ion, and the main function of the chelating agent is to form a stable and water-soluble chelate from the paramagnetic metal ion, thereby reducing the toxicity of the metal ion and facilitating the use of the metal ion.
The most common MRI contrast materials are based on molecular complexes containing the paramagnetic metal gadolinium (Gd). In the united states, all nine FDA-approved MRI contrast agents are Gd-based. Gd has strong "paramagnetism" which results in a local increase in MRI signal of T1-weighted images. However, gd-based contrast agents can lead to a rare but severely debilitating condition known as Nephrogenic Systemic Fibrosis (NSF), a syndrome involving extensive fibrosis of the skin, joints, eyes and internal organs. The WHO and FDA have issued restrictions on the use of these agents in patients with renal insufficiency/failure, with the FDA prescribing a "black box" warning on all commercially available media containing gadolinium. As a result, millions of patients in the united states, and more worldwide, are no longer able to accept contrast material for MRI, severely limiting the detection and characterization of several diseases.
In order to solve the technical problems, the Chinese granted patent CN108743977B discloses an application of a heavy metal ion-free porphyrin compound as a contrast agent in magnetic resonance imaging, aiming at the problems that the contrast of a normal tissue and a lesion part observed clinically is not obvious and the diagnosis is difficult due to low sensitivity of the magnetic resonance imaging, and the heavy metal ion-containing contrast agent is easy to increase the metabolic burden of the liver and the kidney of a patient and the like.
As another example, chinese granted patent CN107087397B discloses the use of ascorbic acid or a pharmaceutically acceptable salt thereof and co-formulated meglumine, glucose, galactose, fructose, lactose, maltose, sucrose and/or trehalose in the manufacture of a medicament for performing a method of enhancing Magnetic Resonance Imaging (MRI) images of a body or body region of a subject, the method comprising: parenterally administering to the subject a co-formulated ascorbic acid or a pharmaceutically acceptable salt thereof in an MRI image enhancing amount; and then generating an image of the body or body region by MRI of the subject, whereby the co-formulated ascorbic acid or a pharmaceutically acceptable salt thereof enhances the MRI image.
The use of gadolinium (Gd), a metal free from heavy metal ions, as a contrast agent in patients with renal insufficiency/failure is becoming a new direction. However, contrast agents without gadolinium (Gd), which is a heavy metal ion, still have problems such as insufficient contrast. Accordingly, an object of the present invention is to provide a contrast agent containing a molecular complex of paramagnetic metal gadolinium (Gd), which can reduce the toxicity of Gd and improve the sensitivity of nuclear magnetic resonance imaging by reducing the concentration of the molecular complex of paramagnetic metal gadolinium (Gd) and increasing the enrichment of Gd in renal tissue.
Disclosure of Invention
The invention mainly provides a contrast agent for pyelonephritis nuclear magnetic imaging and application thereof. In order to realize the purpose of the invention, the following technical scheme is adopted:
the invention relates to a contrast agent for pyelonephritis nuclear magnetic resonance imaging, which is characterized by being prepared from 2-4 parts of 4-arm-amino-polyethylene glycol, 2-4 parts of gadopentetate glucamine, 80-120 parts of phospholipid, 2-4 parts of N-acetylneuraminic acid, 5-10 parts of glucan and water for injection.
In a preferred embodiment of the invention, the nuclear magnetic resonance contrast agent is prepared from 2-3 parts of 4-arm-amino-polyethylene glycol, 2-3 parts of gadopentetate glucamine, 80-100 parts of phospholipid, 2-3 parts of N-acetylneuraminic acid, 5-7 parts of glucan and water for injection.
In a preferred embodiment of the invention, the phospholipid is egg yolk phospholipid and/or lecithin; preferably egg yolk phospholipids.
In a preferred embodiment of the invention, the nuclear magnetic resonance contrast agent is a liposome preparation.
In another preferred embodiment of the present invention, the liposome preparation has an average particle size of 100 to 150nm.
In another preferred embodiment of the present invention, the mean particle size of the liposome preparation is 120 to 130nm. By controlling the particle size of the liposome within the preferred range of the present invention, the contrast effect can be enhanced.
In a preferred embodiment of the present invention, the nuclear magnetic resonance contrast agent is prepared by the following steps:
(1) Preparing liposome nanoparticles: weighing phospholipid, glucan and 4-arm-amino-polyethylene glycol according to the formula ratio, dissolving the phospholipid, the glucan and the 4-arm-amino-polyethylene glycol in a chloroform solution, stirring uniformly, placing the mixture in a rotary evaporator, carrying out water bath rotation to form a film, drying in vacuum, adding a gadopentetate meglumine solution to prepare a liposome emulsion, and carrying out ultracentrifugation to obtain PEG-amino modified nuclear magnetic resonance contrast agent liposome nanoparticles;
(2) Weighing the PEG amino modified nuclear magnetic resonance contrast agent liposome nano-particles prepared in the step (1) and N-acetylneuraminic acid according to the amount, and incubating in water for injection at the temperature of 20-30 ℃ for 5-15min to obtain the nuclear magnetic resonance contrast agent.
The invention also relates to the application of the nuclear magnetic resonance contrast agent in preparing a contrast agent for diagnosing kidney tissue diseases.
In a preferred embodiment of the present invention, the renal tissue disease is pyelonephritis.
The invention has the advantages of
The invention improves the formula of the contrast agent, and improves the enrichment of the contrast agent in renal tissues while reducing the concentration of a molecular complex of paramagnetic metal gadolinium (Gd) in the contrast agent, thereby not only reducing the toxicity of Gd, but also improving the sensitivity of nuclear magnetic resonance imaging, being beneficial to reducing the cost and simultaneously reducing the side effect of the contrast agent.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments.
Example 1: preparation of nuclear magnetic resonance contrast agent
2 parts of 4-arm-amino-polyethylene glycol, 2 parts of gadopentetate meglumine, 80 parts of egg yolk phospholipid, 2 parts of N-acetylneuraminic acid, 5 parts of glucan and a proper amount of injection water, and the preparation method comprises the following steps:
(1) Preparing liposome nanoparticles: weighing yolk phospholipid, glucan and 4-arm-amino-polyethylene glycol according to the formula ratio, dissolving the yolk phospholipid, the glucan and the 4-arm-amino-polyethylene glycol in a chloroform solution, uniformly stirring, placing in a rotary evaporator, carrying out rotary film formation in a water bath at 55 ℃, drying in vacuum, adding a gadopentetate dimeglumine solution to prepare a liposome emulsion, and carrying out ultracentrifugation to obtain PEG amino modified nuclear magnetic resonance contrast agent liposome nanoparticles;
(2) Weighing the PEG amino modified nuclear magnetic resonance contrast agent liposome nano-particles prepared in the step (1) and N-acetylneuraminic acid according to the amount, incubating the PEG amino modified nuclear magnetic resonance contrast agent liposome nano-particles and the N-acetylneuraminic acid together in water for injection at 25 ℃ for 10min to obtain the contrast agent for renal pelvis nuclear magnetic resonance contrast, and analyzing the contrast agent by using a Malvern particle size analyzer, wherein the average particle size of the contrast agent is 126nm.
Example 2: preparation of nuclear magnetic resonance contrast agent
The same as in example 1, except that lecithin was used in place of egg yolk phospholipid, and the average particle size of the contrast medium was 132nm as analyzed by a Malvern particle size analyzer.
Example 3: preparation of nuclear magnetic resonance contrast agent
The same as in example 1, except that the amount of N-acetylneuraminic acid used is 3 parts, and the average particle size of the contrast agent analyzed by a Malvern particle size Analyzer is 124nm.
Comparative example 1:
the same as in example 1, except that the same weight of cholesterol was used in place of dextran, and the average particle size of the contrast agent was 156nm as analyzed by a Malvern particle size analyzer.
Comparative example 2:
the same as in example 1, except that salicylic acid was used in the same amount by weight in place of N-acetylneuraminic acid, and the average particle size of the contrast medium was 183nm as analyzed by a Malvern particle size analyzer.
Effect experimental example 1: enrichment Effect of contrast Agents in Kidney tissue
1.1 test substance:
the ultrasonic contrast agent and the gadopentetate meglumine injection described in examples 1-3 and comparative examples 1-2.
1.2 Experimental methods:
SD rats 90 male, weighing 180-220 g, were injected at a concentration of 10% according to the method of (J.Chinese Experimental zoology, 1998,8 (1): 31-34.) 8 Escherichia coli ATCC 25922/ml was used to prepare the acute pyelonephritis model. Collecting urine after 3d, performing bacteria culture, observing the growth condition of bacteria, successfully preparing by taking the positive as a model, and rejecting unqualified people. From the successfully prepared rats, 35 rats were selected and randomized after 2d acclimation: model group, control group, examples 1-3 group and comparative examples 1-2 group, each group comprising 5 animals. Injecting corresponding nuclear magnetic resonance contrast agent into tail vein of each group of rats, wherein the injection dosage is 0.04mmol/kg body weight calculated by gadopentetate meglumine, and the injection amount of the contrast group is equal to that of the contrast groupThe gadopentetate meglumine injection and the model group are injected with physiological saline with the same volume. After administration for 4h, the rats are killed after neck breakage, kidney tissues are taken, washed by physiological saline and then drained by filter paper, 3mL of concentrated nitric acid is added, nitrification is carried out for 12h under the condition of 60 ℃ water bath, the gadolinium concentration contained in the kidney tissues of the rats in each group is measured by using inductively coupled plasma-emission spectrometry, and the increase and decrease proportion of the content of the gadolinium pentaacetic acid meglumine in the kidney tissues of the rats in each group relative to the content of the gadolinium pentaacetic acid meglumine in the kidney tissues of the rats in the control group is calculated by taking the content of the gadolinium pentaacetic acid meglumine in the kidney tissues of the rats in the control group as a reference.
1.3 results of the experiment
The specific experimental results are shown in table 1.
Table 1: enrichment of nuclear magnetic resonance contrast agents in renal tissue
| Group of | Gadolinium concentration (based on control) |
| Model set | 0 |
| Control group | 100％ |
| Example 1 | 628±25％ |
| Example 2 | 552±28％ |
| Example 3 | 568±21％ |
| Comparative example 1 | 180±26％ |
| Comparative example 2 | 254±32％ |
The experimental results show that the renal tissue site targeting of the gadopentetate meglumine liposome nanoparticle can be remarkably increased in the embodiments 1 to 3 of the invention. Wherein the increase of example 1 is higher than that of examples 2 and 3.
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are only exemplary embodiments of the present invention and are not intended to limit the present invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The contrast agent for pyelonephritis nuclear magnetic resonance imaging is characterized by being prepared from 2-4 parts of 4-arm-amino-polyethylene glycol, 2-4 parts of gadopentetate meglumine, 80-120 parts of phospholipid, 2-4 parts of N-acetylneuraminic acid, 5-10 parts of glucan and water for injection.
2. The contrast agent according to claim 1, wherein the nuclear magnetic resonance contrast agent is prepared from 2-3 parts of 4-arm-amino-polyethylene glycol, 2-3 parts of gadopentetate glucamine, 80-100 parts of phospholipid, 2-3 parts of N-acetylneuraminic acid, 5-7 parts of glucan and water for injection.
3. The contrast agent according to claim 1, wherein the phospholipid is egg yolk phospholipid and/or lecithin.
4. The contrast agent according to claim 1, wherein the phospholipid is egg yolk phospholipid.
5. The contrast agent according to any of claims 1 to 4, which is a liposome preparation.
6. The contrast agent according to claim 5, wherein the liposome preparation has an average particle size of 100-150nm.
7. The contrast agent according to claim 5, wherein the liposome preparation has an average particle size of 120-130nm.
8. The contrast agent according to claim 1, which is prepared by the following steps:
(1) Preparing liposome nanoparticles: weighing phospholipid, glucan and 4-arm-amino-polyethylene glycol according to the formula ratio, dissolving the phospholipid, the glucan and the 4-arm-amino-polyethylene glycol in a chloroform solution, stirring uniformly, placing the mixture in a rotary evaporator, carrying out water bath rotation to form a film, drying in vacuum, adding a gadopentetate meglumine solution to prepare a liposome emulsion, and carrying out ultracentrifugation to obtain PEG-amino modified nuclear magnetic resonance contrast agent liposome nanoparticles;
(2) Weighing the PEG amino modified nuclear magnetic resonance contrast agent liposome nano-particles prepared in the step (1) and N-acetylneuraminic acid according to the amount, and incubating in water for injection at the temperature of 20-30 ℃ for 5-15min to obtain the nuclear magnetic resonance contrast agent.
9. Use of a nuclear magnetic resonance contrast agent according to any one of claims 1 to 8 in the preparation of a contrast agent for the diagnosis of renal tissue disorders.
10. The use of claim 9, wherein the renal tissue disease is pyelonephritis.
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