A multi-component metal-organic framework material and its application

Abstract

The present invention discloses a multi-component metal organic framework material and its application. The metal organic framework material is a metal organic framework material synthesized by a solvent thermal method using two organic ligands and AlCl3 metal salt. 129 Xe can be used as 129 Compared with traditional magnetic resonance contrast agents, Xe magnetic resonance contrast agent has the advantages of no background signal interference and high sensitivity, and has good prospects in magnetic resonance imaging.

Description

Technical Field

[0001] The invention belongs to the technical field of magnetic resonance imaging, and in particular relates to a multi-component metal organic framework material and application thereof. Background Art

[0002] Magnetic resonance imaging has developed into an important clinical imaging method due to its advantages of non-destructive, non-ionizing radiation, high tissue penetration and spatial resolution. 1 H MRI signals come from protons in water or fat in the body, with low sensitivity and strong background signals. Therefore, in actual clinical diagnosis, paramagnetic metals (such as Gd 3+ , Mn 2+ ) compounds to improve tissue contrast. Studies have found that Gd 3+ It is harmful to patients with renal insufficiency to a certain extent and may induce nephrogenic systemic fibrosis in patients.

[0003] 129 Xe is non-toxic and harmless, soluble in blood and tissues, and after being hyperpolarized by spin exchange optical pumping technology (SEOP), 129 Xe has extremely high sensitivity and can be used as a contrast agent for structural and functional imaging of the human lung. 129 Xe is not targeted. 129 Xe is difficult to obtain specific imaging of the lesion area when used directly as a contrast agent. In 2001, researchers at the University of California, Berkeley first proposed a solution. They used a cage-like compound, Xe, as the main molecule to encapsulate 129 Xe, through targeted modification of the caveolar molecular cage, imparts hyperpolarization 129 Xe has the ability to specifically detect markers. However, the synthesis of clavatin and its derivatives is complex and expensive, and some clavatin molecules do not respond significantly to markers after modification. Therefore, it is necessary to find new cage molecules to construct targeted hyperpolarized 129 Xe contrast agent.

[0004] Metal-organic framework materials (MOF) are a type of material with a three-dimensional spatial network structure formed by the combination of organic ligands and metal ions in a specific way. This type of material has a large specific surface area, an ordered pore structure, and can be customized to have a suitable pore size and structure according to needs. It has broad application prospects in catalysis, biomedical imaging, drug delivery, gas separation and storage, etc. Our previous research has shown that MOF can be used as a molecular cage to load Xe and construct targeted hyperpolarization. 129The potential of Xe contrast agent (PNAS, 2020, 117, 17558-17563; Chem Sci, 2021, 12, 4300-4308). However, in the previous research work, we constructed MOFs based on single organic ligands. Due to the single structure of organic ligands, there are certain limitations in subsequent functional modification and biological applications. Summary of the invention

[0005] Based on the above prior art, the present invention provides a multi-component metal organic framework material and its application, wherein the metal organic framework material loads hyperpolarized 129 As an MRI contrast agent, Xe has the advantages of no background signal interference, high sensitivity, and multiple functional modification strategies.

[0006] The technical solution adopted to achieve the above-mentioned purpose of the present invention is:

[0007] A multi-component metal organic framework material is prepared by the following method:

[0008] A multi-component metal organic framework material, characterized in that it is prepared by the following method:

[0009] 1. Dissolve 2-aminoterephthalic acid, 2-hydroxyterephthalic acid and aluminum chloride hexahydrate or aluminum chloride in methanol to obtain a precursor solution;

[0010] 2. Subjecting the precursor solution to a solvothermal reaction to obtain the multi-component metal organic framework material.

[0011] Furthermore, the temperature of the solvent thermal reaction is 120-150° C., and the reaction time is 3-20 hours.

[0012] Furthermore, the molar ratio of the two ligands of 2-aminoterephthalic acid and 2-hydroxyterephthalic acid to aluminum chloride hexahydrate or aluminum chloride is 1:3, wherein the molar ratio of 2-aminoterephthalic acid to 2-hydroxyterephthalic acid is 0.43-2.34:1.

[0013] Application of a multi-component metal organic framework material in the preparation of a magnetic resonance imaging agent.

[0014] Furthermore, the magnetic resonance imaging agent is the multi-component metal organic framework material loaded with hyperpolarized 129 Magnetic resonance imaging contrast agent composed of Xe.

[0015] Compared with the prior art, the advantages and beneficial effects of the present invention are:

[0016] 1. The metal organic framework material is a metal organic framework material synthesized by a solvothermal method using two organic ligands and AlCl3 metal salt. 129 Xe can be used as 129 Compared with traditional magnetic resonance contrast agents, Xe magnetic resonance contrast agent has the advantages of no background signal interference and high sensitivity, and has good prospects in magnetic resonance imaging.

[0017] 2. Compared with metal-organic framework materials based on a single organic ligand, this metal-organic framework material has the advantages of being customizable, easy to modify, and having multiple functional modification strategies, and has very broad prospects in biomedical applications.

[0018] 3. The preparation method of the metal organic framework material is simple and can be prepared by only one step of solvent thermal method. It is easy to operate, has low preparation cost, and can be mass-produced in factories. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 These are the SEM and TEM images of the multi-component metal-organic framework material prepared in Example 1, wherein A is the SEM image and B is the TEM image.

[0020] Figure 2 This is the PXRD pattern of the multi-component metal organic framework material prepared in Example 1.

[0021] Figure 3 The multi-component metal organic framework material prepared in Example 1 1 H NMR spectrum.

[0022] Figure 4 This is the Hyper-CEST test spectrum of the multi-component metal-organic framework material prepared in Example 1.

[0023] Figure 5 This is the Hyper-CEST imaging image of the multi-component metal-organic framework material prepared in Example 1. DETAILED DESCRIPTION

[0024] The present invention is described in detail below with reference to specific embodiments.

[0025] The main reagents and instruments used in the following examples are as follows:

[0026] 2-Aminoterephthalic acid and 2-hydroxyterephthalic acid were purchased from Aladdin Reagent Co., Ltd., and methanol and aluminum chloride hexahydrate were purchased from Sinopharm Chemical Reagent Co., Ltd.

[0027] The hyperpolarization instrument is an independently developed instrument (developed by the Institute of Precision Measurement Science and Technology Innovation, Chinese Academy of Sciences, no model);

[0028] Nuclear magnetic resonance instrument (400MHz Bruker AV400 wide bore spectrometer).

[0029] Example 1

[0030] 1. Synthesis of MTV-CAU-1

[0031] 1) 2-aminoterephthalic acid (50 mg, 0.276 mmol) and 2-hydroxyterephthalic acid (50 mg, 0.276 mmol) were ultrasonically dissolved in 3 mL of methanol to obtain a biligand methanol solution after complete dissolution;

[0032] 2) Aluminum chloride hexahydrate (397.4 mg, 1.656 mmol) was ultrasonically dissolved in 2.5 mL of methanol to obtain an aluminum salt solution after complete dissolution;

[0033] 3) mixing the biligand methanol solution and the aluminum salt solution uniformly to obtain a precursor solution;

[0034] 4) The precursor solution was transferred to a 10 mL Teflon-lined stainless steel high-pressure reactor, and the reactor was then placed in a preheated 125° C. oven for solvothermal reaction. The reaction was completed after 5 hours of reaction, and the reactor was naturally cooled to room temperature. The resulting mixed product was then centrifuged at 10,000 r / min for 10 minutes. The resulting precipitate was washed with deionized water and methanol in turn, and the washing was repeated 3 times. The resulting solid was vacuum dried for 24 hours to obtain the multi-component metal organic framework material, which was labeled as MTV-CAU-1.

[0035] 2. Morphological Characterization of MTV-CAU-1

[0036] 1) Grinding the multi-component metal organic framework material prepared above to obtain a powder sample, taking 1 mg of the powder sample and adding it into 1 mL of ethanol, and ultrasonicating it at room temperature for 30 min to disperse it evenly to obtain a sample dispersion;

[0037] 2) Take a drop of sample dispersion and add it to a clean silicon wafer, let it dry naturally at room temperature, and place the silicon wafer loaded with the dried sample under a scanning electron microscope (SEM) for scanning;

[0038] 3) Take a drop of sample dispersion and add it to a clean silicon wafer, let it dry naturally at room temperature, and place the silicon wafer loaded with the dried sample under a transmission electron microscope (TEM) for scanning;

[0039] 4) The obtained SEM images are as follows Figure 1 The obtained TEM image is shown in A. Figure 1 As shown in B, Figure 1 A and Figure 1 B It can be seen that the multi-component metal organic framework material prepared in this embodiment is in granular form with regular morphology and a particle size within 400 nm.

[0040] 3. X-ray diffraction characterization of MTV-CAU-1

[0041] 1) taking the powder sample obtained in step 2 and placing it in the sample cell of an X-ray diffractometer;

[0042] 2) PXRD data were collected on an X-ray diffractometer. The diffractometer used a Cu target as the X-ray light source, Kα , using parallel light mode, the scanning step size was 0.01°, and the scanning range was 2θ = 2 to 50°.

[0043] 3) The obtained PXRD pattern is as follows Figure 2 As shown, the powder X-ray diffraction peak of MTV-CAU-1 is at the same position as the diffraction peak of the metal organic framework material CAU-1, indicating that MTV-CAU-1 and CAU-1 have the same topological structure and crystal form. At the same time, the diffraction peak of MTV-CAU-1 has no impurity peaks, indicating that the structure of the multi-component metal organic framework material prepared above is complete and free of impurity phases.

[0044] 4. Characterization of the components of MTV-CAU-1

[0045] 1) Take 10 mg of the powder sample obtained in step 2 and add it to 2 mL of NaOH solution. Shake and disperse the powder sample to completely dissolve it to obtain a sample solution.

[0046] 2) Slowly add dilute hydrochloric acid to the sample solution to adjust the pH to about 7. During the addition process, solid precipitation will be found. Be careful not to add excessive hydrochloric acid, otherwise part of the precipitate will dissolve in the solution again;

[0047] 3) After the precipitation is complete, filter and vacuum dry the obtained filter cake;

[0048] 4) Take 4 mg of the dried solid and dissolve it in 0.6 mL of deuterated dimethyl sulfoxide (DMSO-d6), and then collect the 1 H NMR spectrum, the obtained 1 H NMR spectrum Figure 3 As shown, from Figure 3 It can be seen that the product after the cracking of MTV-CAU-1 contains 2-aminoterephthalic acid and 2-hydroxyterephthalic acid, and from the integration of the signal peak, it can be seen that the ratio of the two is close to 1:1, which is basically consistent with the ratio when the feed is added. The above results show that the MTV-CAU-1 material prepared in the embodiment is indeed a multi-ligand metal-organic framework material.

[0049] Experiment 1: Magnetic resonance performance test of the multi-component metal organic framework material of the present invention

[0050] Test method:

[0051] 1) 4 mg of the multi-component metal organic framework material prepared in Example 1 was added to 2 mL of ultrapure water and ultrasonicated at room temperature (25° C.) for 30 min to disperse it uniformly to obtain a concentrated dispersion of MTV-CAU-1;

[0052] 2) Take 200 μL of MTV-CAU-1 concentrated dispersion and dilute it to 2 mL with ultrapure water to obtain MTV-CAU-1 detection solution;

[0053] 3) Take 2 mL of MTV-CAU-1 test solution and put it into a 10 mm NMR sample tube for testing. The sequence used in the test is the CEST sequence. 129 Xe was directly introduced into the sample tube, and after 20 seconds of ventilation, the ventilation was stopped for 3 seconds. After the bubbles disappeared, a continuous wave selective pulse (pulse intensity of 6.5 μT, pulse length of 10 seconds) was used to saturate the pores of MTV-CAU-1. 129 Xe signal, then excited with 90° pulse 129 During the experiment, the saturation irradiation range was 120ppm-230ppm, and a point was taken every 2ppm. After obtaining a series of spectra, the dissolved state 129 The Xe signal was normalized and then normalized to the dissolved state 129 The Hyper-CEST spectrum can be obtained by plotting the Xe signal as the ordinate and the saturated irradiation site as the abscissa.

[0054] Experimental results:

[0055] The resulting Hyper-CEST spectrum is as follows: Figure 4 As shown, from Figure 4 It can be seen that the signal at 193ppm comes from the dissolved 129 Xe, the signal around 157ppm comes from the MTV-CAU-1 channel 129 Xe, the signal intensity value of Hyper-CEST is about 0.6, which shows that MTV-CAU-1 nanoparticles have a good Hyper-CEST effect.

[0056] Experiment 2: Magnetic resonance imaging experiment of the multi-component metal organic framework material of the present invention

[0057] Test method:

[0058] 1) 4 mg of the multi-component metal organic framework material prepared in Example 1 was added to 2 mL of ultrapure water, and ultrasonicated at room temperature (25° C.) for 30 min to disperse it uniformly to obtain a concentrated dispersion of MTV-CAU-1;

[0059] 2) Take 200 μL of the concentrated dispersion of MTV-CAU-1 and dilute it to 2 mL with ultrapure water to obtain the MTV-CAU-1 detection solution;

[0060] 3) Take 2 mL of MTV-CAU-1 test solution and transfer it to a 10 mm NMR sample tube for Hyper-CEST imaging. 129 Xe was directly introduced into the NMR sample tube, and after 20 seconds of ventilation, the ventilation was stopped for 3 seconds. After the bubbles disappeared, a 13 μT saturation pulse was used to saturate the MTV-CAU-1 channel. 129 Xe signal for 5s, then RARE sequence (sampling times 4 times, layer thickness 30mm, sampling matrix 32×32, FOV 30×30mm) 2 , echo time 4.97ms, repetition time 82.3ms, acceleration factor 8, K space encoded by center encoding) to obtain a saturated image, and then use the same pulse to saturate the channel 129 The symmetric position of Xe signal (in dissolved state 129 Xe is the symmetry center), the unsaturated image is obtained by RARE sequence, and Matlab program is used for data processing and image reconstruction. The difference between the unsaturated image and the saturated image is divided by the unsaturated image, and the Hyper-CEST image is reconstructed.

[0061] Experimental results:

[0062] The resulting MRI images are as follows Figure 5 As shown, from Figure 5 It can be seen that MTV-CAU-1 has a good imaging effect in aqueous solution, and the Hyper-CEST signal intensity value is about 0.45.

[0063] Example 2

[0064] The operation steps are basically the same as those in Example 1, except that the ratio of 2-aminoterephthalic acid to 2-hydroxyterephthalic acid is different. In this example, the masses of 2-aminoterephthalic acid and 2-hydroxyterephthalic acid added are 30 mg and 70 mg, respectively.

[0065] Example 3

[0066] The operation steps are basically the same as those in Example 1, except that the ratio of 2-aminoterephthalic acid to 2-hydroxyterephthalic acid is different. In this example, the mass of 2-aminoterephthalic acid and 2-hydroxyterephthalic acid added is 70 mg and 30 mg, respectively.

[0067] The multi-component metal organic framework material prepared in Example 2-3 was tested and found to be able to load hyperpolarization. 129 Xe, with a distinct signal.

Claims

1. A multi-component metal organic framework material, characterized in that Prepared by the following method: 1.

1. Dissolve 2-aminoterephthalic acid, 2-hydroxyterephthalic acid and aluminum chlorohexahydrate or aluminum chloride in methanol, wherein the molar ratio of the two ligands of 2-aminoterephthalic acid and 2-hydroxyterephthalic acid to aluminum chlorohexahydrate or aluminum chloride is 1:3, wherein the molar ratio of 2-aminoterephthalic acid to 2-hydroxyterephthalic acid is 0.43-2.34:1, to obtain a precursor solution; 1.

2. The precursor solution is subjected to a solvothermal reaction at a temperature range of 120-150° C. and a reaction time of 3-20 h to obtain the multi-component metal organic framework material.

2. Use of the multi-component metal organic framework material according to claim 1 in the preparation of a magnetic resonance imaging agent.

3. The use of the multi-component metal organic framework material according to claim 2, characterized in that: The magnetic resonance imaging agent is the multi-component metal organic framework material loaded with hyperpolarized 129 Magnetic resonance imaging contrast agent composed of Xe.

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