Magnetic resonance enhancer based on Prussian blue compound as well as preparation method and application of magnetic resonance enhancer
By preparing polymetallic Prussian blue compounds and modifying palladium sulfide source, the problems of low relaxation efficiency, structural instability and insufficient targeting in MRI imaging were solved, and efficient enhancement of tumor MRI imaging and biocompatibility were achieved, reducing the risk of clinical application.
Patent Information
- Application Number
- CN202510421141.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-03
- Publication Date
- 2025-07-04
AI Technical Summary
Prussian blue compounds have problems such as low relaxation efficiency, unstable structural structure, lack of active targeting, high cost and unclear biocompatibility in MRI imaging, which limits their clinical application.
By preparing a polymetallic Prussian blue compound, it is further vulcanized and modified with a palladium source to form a magnetic resonance enhancer based on the Prussian blue compound, and its MR signal performance is enhanced.
Significantly enhance MR signal, improve tumor MRI imaging effect, reduce clinical application risks, improve biocompatibility and targeting, and be more competitive in cost-effectiveness.
Smart Images
Figure CN120242082A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of magnetic resonance contrast agents, and particularly relates to a magnetic resonance contrast agent based on Prussian blue compounds, a preparation method thereof, and an application thereof. Background Art
[0002] Although the application of Prussian blue compounds as magnetic contrast agents in MRI imaging shows potential, there are still many deficiencies. First, their relaxation efficiency (r1 or r2 value) is relatively low. Especially in T1-weighted imaging, it is inferior to the clinically commonly used gadolinium-based contrast agents, which may lead to insufficient enhancement of the imaging signal and require dose compensation by increasing the dose, while high doses may pose biosafety risks. Second, Prussian blue compounds are easily affected by the physiological environment (such as pH, ion concentration) in the body, resulting in unstable structures, which may decompose and release iron ions and cyanide ligands, and long-term retention has potential neurotoxicity or organ deposition risks. In addition, the lack of active targeting makes the enrichment efficiency in the lesion area relatively low, and non-specific distribution will interfere with the background signal and reduce the diagnostic specificity. Although the targeting can be improved by nanoengineering modification, the complex synthesis process increases the difficulty of clinical translation, and compared with the mature gadolinium-based or superparamagnetic iron oxide contrast agents, its cost-benefit ratio and feasibility of large-scale production have not been fully verified. Finally, the metabolic pathway and long-term biocompatibility of Prussian blue compounds still require more in vivo studies. Especially, the pharmacokinetic behavior in patients with renal insufficiency has not been clarified, which limits the scope of its clinical application. These deficiencies jointly restrict the rapid progress of this type of material from the laboratory to the clinic. Summary of the Invention
[0003] The main purpose of the present invention is to provide a magnetic resonance contrast agent based on Prussian blue compounds, a preparation method thereof, and an application thereof to overcome the deficiencies of the prior art.
[0004] To achieve the foregoing invention purpose, the technical solutions adopted by the present invention include:
[0005] An embodiment of the present invention provides a preparation method of a magnetic resonance contrast agent based on Prussian blue compounds, which includes:
[0006] React at least a cobalt source, a nickel source, a manganese source, trisodium citrate, and potassium ferrocyanide to obtain a multi-metal Prussian blue compound;
[0007] Mix and react the multi-metal Prussian blue compound with a sulfur source to obtain a sulfided multi-metal Prussian blue compound;
[0008] And mix and react the sulfided multi-metal Prussian blue compound with a palladium source to obtain a magnetic resonance contrast agent based on Prussian blue compounds.
[0009] An embodiment of the present invention also provides a magnetic resonance contrast agent based on Prussian blue analogs prepared by the aforementioned preparation method.
[0010] An embodiment of the present invention also provides the use of the aforementioned magnetic resonance contrast agent based on Prussian blue analogs in tumor MRI imaging or for preparing an enhanced MR agent.
[0011] Compared with the prior art, the beneficial effects of the present invention are as follows: When the magnetic resonance contrast agent based on Prussian blue analogs prepared by the present invention is used as an enhanced MR agent, it can significantly enhance the MR signal and has good application prospects in tumor MRI imaging. BRIEF DESCRIPTION OF THE DRAWINGS
[0012] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are only some embodiments recorded in the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.
[0013] Figures 1a - 1c It is the electron micrograph of CNMF, S-CNMF, and Pd-S-CNMF in Example 1 of the present invention;
[0014] Figure 2 It is the XRD pattern of CNMF, S-CNMF, and Pd-S-CNMF in Example 1 of the present invention;
[0015] Figure 3 It is the simulated tumor microenvironment performance diagram of CNMF, S-CNMF, and Pd-S-CNMF in Example 1 of the present invention;
[0016] Figure 4 It is the MR signal observed at the tumor site when Pd-S-CNMF is injected into tumor-bearing mice as an enhanced MR agent in Example 1 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS
[0017] In view of the deficiencies of the prior art, the inventors of this case have proposed the technical solution of the present invention through long-term research and a large number of practices. The following will clearly and completely describe the technical solution of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of them. All other embodiments obtained by those of ordinary skill in the art without creative efforts based on the embodiments of the present invention belong to the scope of protection of the present invention.
[0018] Specifically, as an aspect of the technical solution of the present invention, a preparation method of a magnetic resonance contrast agent based on Prussian blue analogs includes:
[0019] React at least a cobalt source, a nickel source, a manganese source, trisodium citrate, and potassium ferrocyanide to obtain a polymetallic Prussian blue compound;
[0020] Mix and react the polymetallic Prussian blue compound with a sulfur source to obtain a sulfurized polymetallic Prussian blue compound;
[0021] And, mix and react the sulfurized polymetallic Prussian blue compound with a palladium source to obtain a magnetic resonance enhancer based on a Prussian blue compound.
[0022] In some preferred embodiments, the preparation method specifically includes:
[0023] Dissolve a cobalt source, a nickel source, a manganese source, and trisodium citrate in water to obtain a first solution;
[0024] Dissolve potassium ferrocyanide in water to obtain a second solution;
[0025] And, add the second solution to the first solution and stir for 8 - 15 min, then let it stand at room temperature for 20 - 30 h, and then perform centrifugation and washing treatments to obtain a polymetallic Prussian blue compound.
[0026] Further, the cobalt source includes cobalt chloride, and is not limited thereto.
[0027] Further, the nickel source includes nickel nitrate, and is not limited thereto.
[0028] Further, the manganese source includes anhydrous manganese chloride, and is not limited thereto.
[0029] Further, the molar ratio of the cobalt source, the nickel source, the manganese source, trisodium citrate, and potassium ferrocyanide is 1 - 5:1 - 3:1 - 3:2 - 5:1 - 4.
[0030] Further, the dosage ratio of the cobalt source, the nickel source, the manganese source, trisodium citrate, and water in the first solution is 1 - 5 mmol:1 - 3 mmol:1 - 3 mmol:2 - 5 mmol:50 mL.
[0031] Further, the dosage ratio of potassium ferrocyanide and water in the second solution is 1 - 4 mmol:50 mL.
[0032] In some preferred embodiments, the preparation method specifically includes: Mix the polymetallic Prussian blue compound with ethanol and perform ultrasonic treatment for 8 - 15 min, add the sulfur source Na2S·9H2O dissolved in water and stir and mix for 2 - 8 min, then place the obtained mixed solution in an autoclave and react at 90 - 100 °C for 5 - 7 h, and then perform centrifugation and washing treatments to obtain a sulfurized polymetallic Prussian blue compound.
[0033] Further, the sulfur source includes Na2S·9H2O, and is not limited thereto.
[0034] Further, the mass-volume ratio of the polymetallic prussian blue compound to ethanol is 10-20 mg: 14 mL.
[0035] Further, the mass ratio of the polymetallic prussian blue compound to the sulfur source is 10-20: 20-40.
[0036] In some preferred embodiments, the preparation method specifically includes: dissolving the sulfurized polymetallic prussian blue compound in ethanol, adding a palladium source, and stirring and reacting at a rotation speed of 300-500 r and a temperature of 20-50 °C for 25-35 min, and then performing centrifugation and washing treatments to obtain a magnetic resonance enhancer based on the prussian blue compound.
[0037] Further, the mass-volume ratio of the sulfurized polymetallic prussian blue compound to ethanol is 1-10 mg: 10 mL.
[0038] Further, the mass ratio of the sulfurized polymetallic prussian blue compound to the palladium source is 1-10 mg: 1-3 mg.
[0039] Further, the palladium source includes palladium chloride, and is not limited thereto.
[0040] In some more specific embodiments, the preparation method of the magnetic resonance enhancer based on the prussian blue compound (denoted as: Pd-S-CNMF) includes:
[0041] Dissolve 1-5 mmol of cobalt chloride, 1-3 mmol of nickel nitrate, 1-3 mmol of anhydrous manganese chloride, and 2-5 mmol of trisodium citrate in 50 mL of water, and stir until clear to obtain solution A. Dissolve 1-4 mmol of potassium ferrocyanide in 50 mL of water, and stir to obtain solution B. Pour solution B into solution A and stir for 10 min, let stand at room temperature for 24 h, and then perform centrifugation and washing to obtain a hollow CoNiMnFe polymetallic prussian blue compound, denoted as: CNMF;
[0042] Sulfuration: Take 10 - 20 mg of CNMF and add it to 14 mL of absolute ethanol. After ultrasonic treatment for 10 min, add 20 - 40 mg of Na2S·9H2O dissolved in water. Stir for 2 - 8 min and then place it in an autoclave. React at 100 °C for 6 h, centrifuge and wash with absolute ethanol to obtain sulfurized polymetallic Prussian blue-like compound, denoted as: S-CNMF. Pd deposition: Dissolve 1 - 10 mg of S-CNMF in 10 mL of absolute ethanol, add 1 - 3 mg of palladium chloride, stir at 400 r for 30 min, centrifuge and wash with absolute ethanol to prepare S, Pd-modified hollow CoNiMnFe polymetallic Prussian blue-like compound, namely: magnetic resonance enhancer based on Prussian blue-like compound (Pd-S-CNMF).
[0043] Another aspect of the embodiments of the present invention also provides a magnetic resonance enhancer based on Prussian blue-like compound prepared by the foregoing preparation method.
[0044] Another aspect of the embodiments of the present invention also provides the use of the foregoing magnetic resonance enhancer based on Prussian blue-like compound in tumor MRI imaging or in the preparation of an enhanced MR agent.
[0045] The technical solutions of the present invention will be further described in detail below in conjunction with several preferred embodiments and the accompanying drawings. These embodiments are implemented on the premise of the technical solutions of the present invention, and detailed implementation manners and specific operation processes are given. However, the protection scope of the present invention is not limited to the following embodiments.
[0046] In the following embodiments, the experimental materials used can be purchased from conventional biochemical reagent companies without special instructions.
[0047] Example 1
[0048] Dissolve 3 mmol of cobalt chloride, 2 mmol of nickel nitrate, 2 mmol of anhydrous manganese chloride and 3 mmol of trisodium citrate in 50 mL of water, stir until clear to obtain solution A. Dissolve 2 mmol of potassium ferricyanide in 50 mL of water, stir to obtain solution B. Pour solution B into solution A and stir for 10 min, leave it at room temperature for 24 h, then centrifuge and wash to obtain CNMF;
[0049] Sulfuration: Take 15 mg of CNMF and add it to 14 mL of absolute ethanol. After ultrasonic treatment for 10 min, add 30 mg of Na2S·9H2O dissolved in water. Stir for 5 min and then place it in an autoclave. React at 100 °C for 6 h, centrifuge and wash with absolute ethanol to obtain S-CNMF.
[0050] Pd deposition: Dissolve 5 mg of S-CNMF in 10 mL of absolute ethanol, add 2 mg of palladium chloride, and stir at 25 °C and 400 r for 30 min, centrifuge and wash with absolute ethanol to prepare Pd-S-CNMF.
[0051] As shown Figure 1a in Example 1, typical CoNiMnFe(CNMF) nanocubes with sizes between 60 - 100 nm were prepared. After introducing S 2- , it can be found Figure 1b that the inner layer of CNMF becomes hollow and the outer layer becomes blurred due to the chemical etching effect of S 2- . After adding pd 2+ to S - CNMF, it can be seen Figure 1c that nanoparticles with a size of 2 - 6 nm are formed on the surface of S - CNMF in
[0052] , indicating the formation of Pd - S - CNMF. Figure 2 XRD characterization: As shown
[0053] in Figure 3 , after introducing S and Pd, it can be found that S has no substantial effect on the structure of CNMF because the positions of all peaks are similar. However, a new peak can be observed at 68.1° for Pd - S - CNMF, which can correspond to the standard Pd (JCPDS 46 - 1043) peak. Figure 4 Since there are metal ions in Pd - S - CNMF, it is expected to be used for tumor MRI imaging. In
[0054] Example 2
[0055] 1 mmol of cobalt chloride, 1 mmol of nickel nitrate, 1 mmol of anhydrous manganese chloride, and 2 mmol of trisodium citrate were dissolved in 50 mL of water and stirred until clear to obtain Solution A. 2 mmol of potassium ferricyanide was dissolved in 50 mL of water and stirred to obtain Solution B. Solution B was poured into Solution A and stirred for 8 min, then left at room temperature for 20 h and centrifuged and washed to obtain CNMF;
[0056] Sulfidation: 10 mg of CNMF was added to 14 mL of absolute ethanol, ultrasonicated for 8 min, then 20 mg of Na2S·9H2O dissolved in water was added, stirred for 2 min, and then placed in an autoclave and reacted at 90 °C for 7 h, centrifuged and washed with absolute ethanol to obtain S - CNMF.
[0057] Pd deposition: Dissolve 1 mg of S-CNMF in 10 mL of absolute ethanol, add 1 mg of palladium chloride, stir at 50 °C and 300 r for 35 min, centrifuge and wash with absolute ethanol to obtain Pd-S-CNMF.
[0058] Example 3
[0059] Dissolve 5 mmol of cobalt chloride, 3 mmol of nickel nitrate, 3 mmol of anhydrous manganese chloride and 5 mmol of trisodium citrate in 50 mL of water, stir until clear to obtain Solution A. Dissolve 4 mmol of potassium ferricyanide in 50 mL of water, stir to obtain Solution B. Pour Solution B into Solution A and stir for 15 min, leave at room temperature for 30 h, then centrifuge and wash to obtain CNMF;
[0060] Sulfuration: Take 20 mg of CNMF and add it to 14 mL of absolute ethanol. After ultrasonic treatment for 15 min, add 40 mg of Na2S·9H2O dissolved in water. After stirring for 8 min, put it into an autoclave and react at 95 °C for 5 h, centrifuge and wash with absolute ethanol to obtain S-CNMF.
[0061] Pd deposition: Dissolve 5 mg of S-CNMF in 10 mL of absolute ethanol, add 3 mg of palladium chloride, stir at 20 °C and 500 r for 25 min, centrifuge and wash with absolute ethanol to obtain Pd-S-CNMF.
[0062] In addition, the inventor of this case also referred to the foregoing embodiments and conducted tests with other raw materials, process operations, and process conditions described in this specification, and all obtained relatively ideal results.
[0063] It should be understood that the technical solution of the present invention is not limited to the limitations of the above specific embodiments. Any technical deformation made according to the technical solution of the present invention without departing from the spirit of the present invention and the scope protected by the claims falls within the protection scope of the present invention.
Claims
1. A preparation method of a magnetic resonance contrast agent based on Prussian blue analogues, characterized in that, Comprising: Reacting at least a cobalt source, a nickel source, a manganese source, trisodium citrate, and potassium ferrocyanide to obtain a polymetallic Prussian blue compound; Mixing and reacting the polymetallic Prussian blue compound with a sulfur source to obtain a sulfided polymetallic Prussian blue compound; And mixing and reacting the sulfided polymetallic Prussian blue compound with a palladium source to obtain a magnetic resonance enhancer based on a Prussian blue compound.
2. The preparation method according to claim 1, wherein Specifically comprising: Dissolving a cobalt source, a nickel source, a manganese source, and trisodium citrate in water to obtain a first solution; Dissolving potassium ferrocyanide in water to obtain a second solution; And adding the second solution to the first solution and stirring for 8 - 15 min, then standing at room temperature for 20 - 30 h, and then performing centrifugation and washing to obtain a polymetallic Prussian blue compound.
3. The preparation method according to claim 2, characterized in that: The cobalt source includes cobalt chloride; And / or, the nickel source includes nickel nitrate; And / or, the manganese source includes anhydrous manganese chloride.
4. The preparation method according to claim 2, characterized in that: The molar ratio of the cobalt source, nickel source, manganese source, trisodium citrate to potassium ferrocyanide is 1 - 5:1 - 3:1 - 3:2 - 5:1 - 4; And / or, the dosage ratio of the cobalt source, nickel source, manganese source, trisodium citrate to water in the first solution is 1 - 5 mmol:1 - 3 mmol:1 - 3 mmol:2 - 5 mmol:50 mL; And / or, the dosage ratio of potassium ferrocyanide to water in the second solution is 1 - 4 mmol:50 mL.
5. The preparation method according to claim 1, characterized in that, Specifically comprising: Mixing the polymetallic Prussian blue compound with ethanol and performing ultrasonic treatment for 8 - 15 min, adding a sulfur source dissolved in water and stirring and mixing for 2 - 8 min, then placing the obtained mixed solution in an autoclave and reacting at 90 - 100 °C for 5 - 7 h, and then performing centrifugation and washing to obtain a sulfided polymetallic Prussian blue compound.
6. The preparation method according to claim 5, characterized in that: The sulfur source includes Na2S·9H2O; And / or, the mass - to - volume ratio of the polymetallic Prussian blue compound to ethanol is 10 - 20 mg:14 mL; And / or, the mass ratio of the polymetallic Prussian blue compound to the sulfur source is 10 - 20:20 - 40.
7. The preparation method according to claim 1, wherein Specifically comprising: Dissolving the sulfided polymetallic Prussian blue compound in ethanol, adding a palladium source and stirring and reacting at a rotation speed of 300 - 500 r and a temperature of 20 - 50 °C for 25 - 35 min, and then performing centrifugation and washing to obtain a magnetic resonance enhancer based on a Prussian blue compound.
8. The preparation method according to claim 7, characterized in that: The mass - to - volume ratio of the sulfided polymetallic Prussian blue compound to ethanol is 1 - 10 mg:10 mL; And / or, the mass ratio of the sulfided polymetallic Prussian blue compound to the palladium source is 1 - 10:1 - 3; And / or, the palladium source includes palladium chloride.
9. A magnetic resonance enhancer based on a Prussian blue compound prepared by the preparation method according to any one of claims 1 - 8.
10. Use of the magnetic resonance enhancer based on a Prussian blue compound according to claim 9 in tumor MRI imaging or in the preparation of an enhanced MR agent.