CN114617981B - Vanadium doped iron-based magnetic resonance contrast agent and preparation method thereof - Google Patents
Vanadium doped iron-based magnetic resonance contrast agent and preparation method thereof Download PDFInfo
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 title claims abstract description 218
- 229910052742 iron Inorganic materials 0.000 title claims abstract description 93
- 239000002405 nuclear magnetic resonance imaging agent Substances 0.000 title claims abstract description 89
- 229910052720 vanadium Inorganic materials 0.000 title claims abstract description 68
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 title claims abstract description 65
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- 239000002243 precursor Substances 0.000 claims abstract description 44
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- 238000003756 stirring Methods 0.000 claims abstract description 24
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- 239000004094 surface-active agent Substances 0.000 claims abstract description 16
- 239000000126 substance Substances 0.000 claims abstract description 14
- 229920001477 hydrophilic polymer Polymers 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims abstract description 12
- 239000012046 mixed solvent Substances 0.000 claims abstract description 12
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 8
- 239000000376 reactant Substances 0.000 claims abstract description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 41
- 229910001456 vanadium ion Inorganic materials 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 17
- 239000002245 particle Substances 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 229920002873 Polyethylenimine Polymers 0.000 claims description 8
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 8
- FSJSYDFBTIVUFD-SUKNRPLKSA-N (z)-4-hydroxypent-3-en-2-one;oxovanadium Chemical compound [V]=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FSJSYDFBTIVUFD-SUKNRPLKSA-N 0.000 claims description 7
- 230000036571 hydration Effects 0.000 claims description 7
- 238000006703 hydration reaction Methods 0.000 claims description 7
- CDVAIHNNWWJFJW-UHFFFAOYSA-N 3,5-diethoxycarbonyl-1,4-dihydrocollidine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C CDVAIHNNWWJFJW-UHFFFAOYSA-N 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 3
- -1 cyclopentadienyl vanadium tetracarbonyl vanadium Chemical compound 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 3
- OGUCKKLSDGRKSH-UHFFFAOYSA-N oxalic acid oxovanadium Chemical compound [V].[O].C(C(=O)O)(=O)O OGUCKKLSDGRKSH-UHFFFAOYSA-N 0.000 claims description 3
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 claims description 3
- 239000000956 alloy Substances 0.000 claims 1
- 229910045601 alloy Inorganic materials 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 239000003791 organic solvent mixture Substances 0.000 claims 1
- 239000002105 nanoparticle Substances 0.000 abstract description 56
- 206010028980 Neoplasm Diseases 0.000 description 36
- 239000000243 solution Substances 0.000 description 32
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 24
- 239000002872 contrast media Substances 0.000 description 23
- 238000003745 diagnosis Methods 0.000 description 15
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- LZKLAOYSENRNKR-LNTINUHCSA-N iron;(z)-4-oxoniumylidenepent-2-en-2-olate Chemical compound [Fe].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O LZKLAOYSENRNKR-LNTINUHCSA-N 0.000 description 9
- 241000699660 Mus musculus Species 0.000 description 8
- 238000011580 nude mouse model Methods 0.000 description 8
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- 238000011056 performance test Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- FSJSYDFBTIVUFD-XHTSQIMGSA-N (e)-4-hydroxypent-3-en-2-one;oxovanadium Chemical compound [V]=O.C\C(O)=C/C(C)=O.C\C(O)=C/C(C)=O FSJSYDFBTIVUFD-XHTSQIMGSA-N 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
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- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- DWWOZCUXMGDXEX-UHFFFAOYSA-N [Fe+2].[O-2].[V+5] Chemical compound [Fe+2].[O-2].[V+5] DWWOZCUXMGDXEX-UHFFFAOYSA-N 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
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- 210000003462 vein Anatomy 0.000 description 2
- MFWFDRBPQDXFRC-LNTINUHCSA-N (z)-4-hydroxypent-3-en-2-one;vanadium Chemical compound [V].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O MFWFDRBPQDXFRC-LNTINUHCSA-N 0.000 description 1
- 238000012307 MRI technique Methods 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- RWGZYRVMWDOZDJ-UHFFFAOYSA-N [O].[Fe].[V] Chemical compound [O].[Fe].[V] RWGZYRVMWDOZDJ-UHFFFAOYSA-N 0.000 description 1
- 238000012984 biological imaging Methods 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
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- SZVJSHCCFOBDDC-UHFFFAOYSA-N ferrosoferric oxide Chemical compound O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
- C01G49/00—Compounds of iron
- C01G49/02—Oxides; Hydroxides
- C01G49/08—Ferroso-ferric oxide (Fe3O4)
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/01—Particle morphology depicted by an image
- C01P2004/04—Particle morphology depicted by an image obtained by TEM, STEM, STM or AFM
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/60—Particles characterised by their size
- C01P2004/62—Submicrometer sized, i.e. from 0.1-1 micrometer
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/80—Particles consisting of a mixture of two or more inorganic phases
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2006/00—Physical properties of inorganic compounds
- C01P2006/42—Magnetic properties
Abstract
The application discloses a vanadium doped iron-based magnetic resonance contrast agent and a preparation method thereof, comprising the following steps: step 1, fe is contained 3+ Organic complex precursors and V-containing 4+ Adding the organic complex precursor into an organic mixed solvent, heating, stirring and dissolving to obtain a reaction solution; step 2, adding a hydrophilic polymer surfactant into the reaction solution, and continuously heating and stirring; step 3, after the heating and stirring in the step 2 are finished, adding an alkaline substance into the reaction solution to adjust the pH value of the reaction solution, so as to promote the metal ions in the reactant to form hydroxide; and 4, carrying out a hydrothermal reaction on the reaction solution containing the hydroxide obtained in the step 3, and obtaining the vanadium doped iron-based magnetic resonance contrast agent after the completion of the hydrothermal reaction. The preparation method is simple, convenient, efficient, mature and exquisite, and the prepared vanadium doped iron-based magnetic resonance contrast agent nano particles have uniform morphology, good dispersibility and excellent magnetic properties and show excellent magnetic resonance contrast capability.
Description
Technical Field
The application relates to the technical field of medical contrast agents, in particular to a vanadium doped iron-based magnetic resonance contrast agent and a preparation method thereof.
Background
Magnetic Resonance Imaging (MRI) is widely used as a revolutionary biological imaging technique for clinical diagnosis of tumor patients, but the application of MRI technique is limited due to the defects of low spatial resolution, poor specificity, low sensitivity, etc. In recent years, magnetic iron oxide nanoparticles, which are used as magnetic resonance contrast agents for magnetic resonance imaging diagnosis of tumor patients, are widely used because of their good compatibility, which can shorten the transverse relaxation time of hydrogen protons. However, since iron oxide contrast agents are susceptible to bleeding, metal deposition or calcification during magnetic resonance imaging, artifacts are created, significantly affecting the diagnostic accuracy of tumor patients. Therefore, in order to improve the accuracy of tumor diagnosis, there is an urgent need to develop a preparation method capable of synthesizing an iron-based magnetic resonance contrast agent with high performance.
Disclosure of Invention
In order to solve the problem that the existing contrast agent is low in accuracy in tumor diagnosis, one of the purposes of the application is to provide a preparation method of the vanadium-doped iron-based magnetic resonance contrast agent.
The technical scheme for solving the technical problems is as follows: a preparation method of a vanadium doped iron-based magnetic resonance contrast agent comprises the following steps:
step 1, fe is contained 3+ Organic complex precursors and V-containing 4+ Adding the organic complex precursor into an organic mixed solvent, heating, stirring and dissolving to obtain a reaction solution;
step 2, adding a hydrophilic polymer surfactant into the reaction solution, and continuously heating and stirring;
step 3, after the heating and stirring in the step 2 are finished, adding an alkaline substance into the reaction solution to adjust the pH value of the reaction solution, so as to promote the metal ions in the reactant to form hydroxide;
and 4, carrying out a hydrothermal reaction on the reaction solution containing the hydroxide obtained in the step 3, and obtaining the mass doping ratio of vanadium ions after finishing: 0.04-0.13 of vanadium doped iron-based magnetic resonance contrast agent.
The beneficial effects of the application are as follows: the preparation method of the vanadium doped iron-based magnetic resonance contrast agent is simple, convenient, efficient, mature and exquisite, and meanwhile, the vanadium doped iron-based magnetic resonance contrast agent prepared by the method also has uniform morphology, good dispersibility and excellent magnetic properties, and shows excellent magnetic resonance contrast capability, so that the method is beneficial to improving the accuracy of diagnosis of tumor patients.
Based on the technical scheme, the application can also be improved as follows:
further, in step 1, fe is contained 3+ Organic complex precursorsContaining V 4+ The mass ratio of the organic complex precursors is 2-10:1.
Further, fe is contained in 3+ The organic complex precursor comprises any one of ferric acetylacetonate, ferrocene and ferric acrylate; containing V 4+ The organic complex precursor comprises any one of vanadyl acetylacetonate, cyclopentadienyl vanadium tetracarbonyl vanadium and vanadyl oxalate.
Further, the mass of the hydrophilic polymer surfactant in the step 2 and the content of Fe 3+ Organic complex precursors and V-containing 4+ The mass sum ratio of the organic complex precursors is 1:1-3; the hydrophilic polymer surfactant comprises any one of polyethylenimine, polyvinylpyrrolidone and sodium polyacrylate.
The beneficial effects of the above further technical scheme are: the dispersibility of the vanadium doped iron-based magnetic resonance contrast agent is further improved by utilizing the hydrophilic polymer surface activity, and the application of the contrast agent in a patient is facilitated.
Further, in the step 3, an alkaline substance is added to adjust the pH value of the reaction solution to 9-10.
Further, the alkaline substance in the step 3 comprises any one of triethanolamine, triethylamine and diethylamine.
Further, the hydrothermal reaction conditions in step 4 are: reacting for 8-14 h at 80-200 ℃.
Further, the organic mixed solvent includes ethylene glycol.
The beneficial effects of the above further technical scheme are: the glycol in the organic mixed solvent can promote Fe 3+ Fe in organic Complex precursor 3+ Generating Fe by valence state change 2+ The reaction solution contains Fe at the same time 3+ And Fe (Fe) 2+ Thereby ensuring that the vanadium doped iron-based magnetic resonance contrast agent is prepared.
The second purpose of the application is to provide a vanadium doped iron-based magnetic resonance contrast agent, wherein the mass doping ratio of vanadium ions in the vanadium doped iron-based magnetic resonance contrast agent is as follows: 0.04-0.13, and the hydration particle size of the vanadium doped iron-based magnetic resonance contrast agent is 120-240 nm.
The beneficial effects of the application are as follows: the vanadium ion mass doping ratio in the range forms the vanadium doped iron-based magnetic resonance contrast agent with the hydration particle size of 120-240nm, and the vanadium doped iron-based magnetic resonance contrast agent with the particle size in the range has better dispersibility and excellent contrast performance, is not only beneficial to in vivo use, but also can improve the accuracy of tumor diagnosis in application.
Further, the mass doping ratio of vanadium ions in the vanadium doped iron-based magnetic resonance contrast agent is as follows: 0.09.
the application has the following beneficial effects:
according to the application, ferric acetylacetonate and vanadium acetylacetonate are used as precursors, the iron vanadium oxide nano particles (namely the vanadium doped iron-based magnetic resonance contrast agent) are prepared by a hydrothermal method, and the dispersion capacity of the iron-based magnetic resonance contrast agent is improved by doping vanadium ions with a certain mass into the iron-based magnetic resonance contrast agent, so that the in vivo contrast performance of the iron-based magnetic resonance contrast agent is enhanced, and the accuracy of the vanadium doped iron-based magnetic resonance contrast agent on tumor diagnosis is improved. In addition, the application prepares a series of high-performance iron-based magnetic resonance contrast agents by regulating and controlling the doping amount of vanadium ions, which is beneficial to realizing accurate magnetic resonance imaging diagnosis of tumors; in addition, it was found by study that: when the mass doping ratio of vanadium ions is 0.09, the obtained vanadium-doped iron-based nano particles have higher transverse relaxation rate, excellent magnetic resonance contrast performance is shown in vivo, and the contrast performance is obviously superior to that of undoped iron-based contrast agent.
Drawings
FIG. 1 is a structural characterization diagram and a performance test result diagram of VIO-2 with a mass doping ratio of 0.13 of vanadium ions, wherein a is a TEM diagram of the VIO-2, and b is a transverse relaxation rate diagram of the VIO-2;
FIG. 2 is a structural characterization diagram and a performance test result diagram of VIO-3 with a mass doping ratio of 0.04 of vanadium ions, wherein a is a TEM diagram of the VIO-3, and b is a transverse relaxation rate diagram of the VIO-3;
FIG. 3 is a structural characterization diagram and performance test result diagram of VIO-4 with a mass doping ratio of 0.09, wherein a is a TEM diagram of VIO-4, b is a transverse relaxation rate diagram of VIO-4, c is a signal-to-noise ratio spectrum of magnetic resonance imaging of tumor regionD is the magnetic resonance T of nude mice bearing tumor 2 -a weighted spectrogram;
FIG. 4 is a graph of structural characterization and performance test results of ION (undoped iron-based magnetic resonance contrast agent), wherein a is a TEM (Transmission electron microscope) graph of ION, and b is a transverse relaxation rate graph of ION; c is the signal-to-noise ratio of the magnetic resonance imaging of the tumor region, d is the magnetic resonance T of the nude tumor-bearing mouse 2 -a weighted graph;
FIG. 5 is a structural representation of VIO-1 with a mass doping ratio of 0.30 for vanadium ions and a structure diagram for performance test, wherein a is a TEM diagram of VIO-1, and b is a transverse relaxation rate diagram of VIO-1;
fig. 6 is a graph of the relationship between the doping amount of vanadium ions in the vanadium doped iron-based magnetic resonance contrast agent and the transverse relaxation rate of VIO nanoparticles.
Detailed Description
The vanadium doped iron-based magnetic resonance contrast agent and the preparation method thereof in the present application will be described below with reference to examples. This application may, however, be embodied in many different forms and should not be construed as limited to the specific embodiments set forth herein, but rather should be construed in order that the application will be thorough and complete, and will fully convey the scope of the application to those skilled in the art.
The inventor finds that in the research process of the iron-based magnetic resonance contrast agent, the hydrothermal method can prepare the magnetic iron-based nano particles with uniform size, good dispersibility and high specific surface area, and tries to achieve the aim of improving the magnetic resonance contrast performance of the iron-based nano particles by optimizing the size, the components, the shape and other ways of the iron-based nano particles. However, the effect of improving the contrast performance of the iron-based nanoparticle is limited only by optimizing the size, the composition and the shape of the nanoparticle, and the requirement of the clinical diagnosis of tumor patients on the accuracy of the contrast agent still cannot be met.
In recent years, with the improvement of research and development capability, some researchers try to dope metal ions into the iron-based nanoparticles, and the aim of greatly enhancing the performance of the iron-based magnetic resonance contrast agent is fulfilled by changing the crystal structure, magnetic parameters and the like of the iron-based nanoparticles. However, no suitable metal ion doped with iron-based nano particles has been found to improve the accuracy of the iron-based magnetic resonance contrast agent in diagnosis.
The inventors herein have prepared a vanadium doped iron-based magnetic resonance contrast agent based on a hydrothermal method, which has a uniform morphology, good dispersibility, excellent magnetic resonance contrast capability, and high accuracy in tumor diagnosis.
An embodiment of a first aspect of the present application provides a method for preparing a vanadium doped iron-based magnetic resonance contrast agent, including the steps of:
step 1, fe is contained 3+ Organic complex precursors and V-containing 4+ Adding the organic complex precursor into an organic mixed solvent, heating, stirring and dissolving to obtain a reaction solution;
step 2, adding a hydrophilic polymer surfactant into the reaction solution, and continuously heating and stirring;
step 3, after the heating and stirring in the step 2 are finished, adding an alkaline substance into the reaction solution to adjust the pH value of the reaction solution, so as to promote the metal ions in the reactant to form hydroxide;
and 4, carrying out a hydrothermal reaction on the reaction solution containing the hydroxide obtained in the step 3, and obtaining the mass doping ratio of vanadium ions after finishing: 0.04-0.13 of vanadium doped iron-based magnetic resonance contrast agent (VIO).
The mass doping ratio of the vanadium ions in the embodiment refers to the mass content of the vanadium ions in the vanadium doped iron-based magnetic resonance contrast agent.
The contrast agent (VIO) prepared in the embodiment has better contrast capability compared with an undoped iron-based magnetic resonance contrast agent (ION), and also has uniform morphology, good dispersibility and excellent magnetic properties, so that the contrast agent (VIO) has higher accuracy in tumor diagnosis during application.
In addition, the mass doping ratio of vanadium ions in the vanadium doped iron-based magnetic resonance contrast agent in the embodiment may be further 0.09.
To ensure that vanadium doped iron-based magnetic resonance contrast agents (i.e. iron-vanadium-oxide nanoparticles, which are vanadium)Ion doping into the lattice of the ferroferric oxide), in some embodiments, the organic mixed solvent comprises ethylene glycol; in this embodiment, the ethylene glycol has weak reducibility and can promote Fe content 3+ Part of Fe in organic complex precursor 3+ Generating Fe by valence state change 2+ The reaction solution contains Fe at the same time 3+ And Fe (Fe) 2+ Thereby facilitating the formation of vanadium doped iron-based magnetic resonance contrast agents. In addition, the mass of ethylene glycol and Fe in the present example 3+ Organic complex precursors and V-containing 4+ The ratio of the mass sum of the two organic complex precursors may be 40:1; in practice, 20ml of ethylene glycol may be used to promote a mass of 0.375-0.45g of iron acetylacetonate (Fe (acac) 3 ) Part of Fe in (3) 3+ A change in valence state occurs. In addition, diethylene glycol is also included in the organic mixed solvent in this embodiment, and the mass ratio between ethylene glycol and diethylene glycol may be 2:3.
Due to the Fe content in this example 3+ Organic complex precursors and V-containing 4+ The organic complex precursors are all organic matters, and organic mixed solvents comprising ethylene glycol and diethylene glycol are selected to be favorable for containing Fe 3+ Organic complex precursors and V-containing 4+ The dispersion of the organic complex precursor in the organic mixed solvent is beneficial to the formation of the vanadium doped iron-based magnetic resonance contrast agent.
In addition, in some embodiments, step 1 contains Fe 3+ Organic complex precursors and V-containing 4+ The mass ratio of the organic complex precursors can be 2-10:1; preferably, the present embodiment contains Fe 3+ Organic complex precursors and V-containing 4+ The mass ratio of the organic complex precursor may also be 3-9:1, and further preferably, the Fe-containing precursor in this embodiment 3+ Organic complex precursors and V-containing 4+ The mass ratio of the organic complex precursor may be one of 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, and 9:1. Containing Fe 3+ The organic complex precursor comprises any one of ferric acetylacetonate, ferrocene and ferric acrylate, and contains V 4+ The organic complex precursor comprises any one of vanadyl acetylacetonate, cyclopentadienyl vanadium tetracarbonyl vanadium and vanadyl oxalate. The organic complex precursor in the embodiment can be fully dissolved in the organic mixed solvent, and is beneficial to the preparation of the vanadium doped iron-based magnetic resonance contrast agent.
In order to further improve the dispersibility of the prepared vanadium doped iron-based magnetic resonance contrast agent (VIO), a hydrophilic polymer surfactant is added to the reaction solution in step 2 in the embodiment, and the surfactant is attached to the hydroxide generated in the reaction solution, and is formed on the surface of the vanadium doped iron-based magnetic resonance contrast agent or is partially positioned in the vanadium doped iron-based magnetic resonance contrast agent along with the hydrothermal reaction (i.e. the hydroxide crystallization process) in step 4, so that the prepared vanadium doped iron-based magnetic resonance contrast agent is further ensured to have good dispersibility. In addition, in some embodiments, the mass of the hydrophilic polymeric surfactant in step 2 is equal to the mass of the Fe-containing surfactant 3+ Organic complex precursors and V-containing 4+ The mass sum ratio of the organic complex precursor is 1:1-3, preferably the mass of the hydrophilic macromolecule surfactant and the Fe content in the embodiment 3+ Organic complex precursors and V-containing 4+ The ratio of the mass sum of the organic complex precursors may be 1:2; in addition, the hydrophilic polymer surfactant in the present embodiment includes any one of polyethylenimine, polyvinylpyrrolidone, and sodium polyacrylate; of course, in the actual process, the hydrophilic polymer surfactant in the present embodiment may be other substances with the same performance.
To ensure that metal ions (e.g. Fe 3+ 、Fe 2+ And V 4+ ) Forming hydroxide, and crystallizing under the condition of hydrothermal reaction to form iron-vanadium-oxygen nano particles; in some embodiments, the pH of the reaction solution is adjusted to 9-10 in step 3 using an alkaline substance. The basic substance for adjusting the pH value of the reaction solution in this embodiment includes any one of triethanolamine, triethylamine, and diethylamine; the alkaline substances in the embodiment can be better dispersed in the reaction solution, so that the metal ions in the reaction solution can be promoted to form hydroxide as completely as possible, the yield of the vanadium doped iron-based magnetic resonance contrast agent is improved to a certain extent, and the yield can be reducedThe content of impurities in the contrast agent can further improve the magnetic resonance contrast capability of the contrast agent to a certain extent, and finally improve the accuracy of tumor magnetic resonance imaging diagnosis. The alkaline substance in this embodiment may be another organic alkaline substance into which no impurity is introduced, and this will not be described in detail in this embodiment.
In addition, in some embodiments, the hydrothermal reaction conditions in step 4 are: reacting for 8-14 h at 180-200 ℃. Under the temperature range, the appearance of the crystallized vanadium doped iron-based magnetic resonance contrast agent is ensured to have uniformity, the spherical vanadium doped iron-based magnetic resonance contrast agent with the hydration particle size of 120-240nm is formed, and the dispersibility of the vanadium doped iron-based magnetic resonance contrast agent is enhanced. In addition, in order to ensure stable heating and avoid the influence of the rapid heating on the morphology and the performance of the generated vanadium-doped iron-based magnetic resonance contrast agent, in the example, the heating rate of 3 ℃/min is selected to heat to 180-200 ℃ during the hydrothermal reaction.
In addition, in order to let Fe 3+ Organic complex precursors and V-containing 4+ The organic complex precursor is better dispersed in the organic mixed solvent, so that the hydrophilic macromolecule surfactant is better dispersed in the reaction solution, and the heating and stirring temperature in the step 1 and the step 2 in the embodiment can be 70-90 ℃, preferably the heating and stirring temperature in the step 1 and the step 2 can be 80 ℃.
An embodiment of the second aspect of the present application provides a vanadium doped iron-based magnetic resonance contrast agent prepared by adopting the embodiment of the first aspect, wherein the mass doping ratio of vanadium ions in the vanadium doped iron-based magnetic resonance contrast agent is as follows: 0.04-0.13, and the hydration particle size of the vanadium doped iron-based magnetic resonance contrast agent is 120-240 nm.
The vanadium ion mass doping ratio in the range of the embodiment forms the vanadium doped iron-based magnetic resonance contrast agent with the hydration particle size of 120-240nm, so that the vanadium doped iron-based magnetic resonance contrast agent has better dispersibility and excellent contrast performance, is beneficial to the use of the contrast agent in vivo, has higher accuracy for tumor diagnosis, is beneficial to further improving the accuracy of clinical magnetic resonance imaging diagnosis of tumor patients, and brings good news to the majority of patients.
In addition, in some embodiments, the mass doping ratio of vanadium ions in the vanadium doped iron-based magnetic resonance contrast agent is: 0.09.
examples
Example 1
The preparation of the vanadium doped iron-based magnetic resonance contrast agent comprises the following steps:
step 1, 0.375g of iron acetylacetonate (Fe (acac) 3 ) And 0.125g vanadyl acetylacetonate (VO (acac) 2 ) To a mixed solution of ethylene glycol (20 mL) and diethylene glycol (30 mL), the mixture was stirred at 80℃for 40min.
Step 2, adding polyethyleneimine (1.0 g) into the reaction solution, heating and stirring for 30min.
Step 3, dropwise adding triethanolamine (5 mL) into the mixed solution, heating and stirring for 30min.
And 4, placing the reaction solution into a stainless steel reaction kettle, placing the stainless steel reaction kettle into an oven at room temperature for heating, and heating to 200 ℃ at 3 ℃/min for hydrothermal reaction for 12 hours. Finally, washing and collecting the obtained product, and naming the collected nano particles as VIO-2; wherein the mass doping ratio of vanadium ions in the VIO-2 nano particles is 0.13.
Example 2
The preparation of the vanadium doped iron-based magnetic resonance contrast agent comprises the following steps:
step 1, 0.45g of iron acetylacetonate (Fe (acac) 3) and 0.05g of vanadyl acetylacetonate (VO (acac) 2) were added to a mixed solution of ethylene glycol (20 mL) and diethylene glycol (30 mL), and stirred at 80℃for 40min.
Step 2, adding polyethyleneimine (1.0 g) into the reaction solution, heating and stirring for 30min.
Step 3, dropwise adding triethanolamine (5 mL) into the mixed solution, heating and stirring for 30min.
And 4, placing the reaction solution in a stainless steel reaction kettle, placing the stainless steel reaction kettle into an oven at room temperature for heating, and heating to 200 ℃ at 3 ℃/min for hydrothermal reaction for 12 hours. Finally, washing and collecting the obtained product, and naming the collected nano particles as VIO-3; wherein the mass doping ratio of vanadium ions in the VIO-3 nano particles is 0.04.
Example 3
The preparation of the vanadium doped iron-based magnetic resonance contrast agent comprises the following steps:
step 1, 0.43g of iron acetylacetonate (Fe (acac)) 3 ) And 0.07g vanadyl acetylacetonate (VO (acac) 2 ) To a mixed solution of ethylene glycol (20 mL) and diethylene glycol (30 mL), the mixture was stirred at 80℃for 40min.
Step 2, adding polyethyleneimine (1.0 g) into the reaction solution, heating and stirring for 30min.
Step 3, dropwise adding triethanolamine (5 mL) into the mixed solution, heating and stirring for 30min.
And 4, placing the reaction solution in a stainless steel reaction kettle, placing the stainless steel reaction kettle into an oven at room temperature for heating, and heating to 200 ℃ at 3 ℃/min for hydrothermal reaction for 12 hours. Finally, washing and collecting the obtained product, and naming the collected nano particles as VIO-4; wherein the mass doping ratio of vanadium ions in the VIO-4 nano particles is 0.09.
Comparative example 1
A method for preparing an iron-based magnetic resonance contrast agent, comprising the steps of:
step 1, 0.5g of iron acetylacetonate (Fe (acac)) 3 ) To a mixed solution of ethylene glycol (20 mL) and diethylene glycol (30 mL), the mixture was stirred at 80℃for 40min.
Step 2, adding polyethyleneimine (1.0 g) into the reaction solution, heating and stirring for 30min.
Step 3, dropwise adding triethanolamine (5 mL) into the mixed solution, heating and stirring for 30min.
And 4, placing the reaction solution into a stainless steel reaction kettle, placing the stainless steel reaction kettle into an oven at room temperature for heating, and heating to 200 ℃ at 3 ℃/min for hydrothermal reaction for 12 hours. Finally, the obtained product was collected by washing, and the collected nanoparticles were named ION.
Comparative example 2
The preparation of the vanadium doped iron-based magnetic resonance contrast agent comprises the following steps:
step 1, 0.25g of iron acetylacetonate (Fe (acac)) 3 ) And 0.25g vanadyl acetylacetonate (VO (acac) 2 ) To a mixed solution of ethylene glycol (20 mL) and diethylene glycol (30 mL), the mixture was stirred at 80℃for 40min.
Step 2, adding polyethyleneimine (1.0 g) into the reaction solution, heating and stirring for 30min.
Step 3, dropwise adding triethanolamine (5 mL) into the mixed solution, heating and stirring for 30min.
And 4, placing the reaction solution in a stainless steel reaction kettle, placing the stainless steel reaction kettle into an oven at room temperature for heating, and heating to 200 ℃ at 3 ℃/min for hydrothermal reaction for 12 hours. Finally, the obtained product was collected by washing, and the collected nanoparticle was named as VIO-1, wherein the mass doping ratio of vanadium ions in the VIO-1 nanoparticle was 0.30.
Test analysis:
1. TEM test analysis:
the contrast agents prepared in the above examples and comparative examples were dispersed in water, and the dispersion of the contrast agents in water was recorded by TEM (transmission electron microscope), and the test results thereof are shown in fig. 1a, 2a, 3a, 4a and 5a, respectively.
As can be seen from fig. 5a, the vanadium-doped iron-based magnetic resonance contrast agent (VIO-1) prepared in comparative example 2, in which the mass doping ratio of the vanadium ions is 0.3, is agglomerated in a large scale in an aqueous solution, and the morphology of the formed VIO-1 nanoparticles is not uniform, so that the VIO-1 contrast agent prepared in comparative example 2 is not advantageous for use as a magnetic resonance contrast agent in vivo.
As can be seen from fig. 1a to 3a, the VIO-2, VIO-3 and VIO-4 nanoparticles all showed a more uniform sphere shape with decreasing doping amount of vanadium ions in examples 1 to 3, and showed better dispersibility in solution (i.e., aqueous solution) than the VIO-1 particles.
As can be seen from fig. 4a, the ION nanoparticles have a uniform spherical morphology, but are clustered or linearly dispersed in an aqueous solution, which indicates that the ION nanoparticles have poor dispersibility in the solution, and are unfavorable for the application of the ION nanoparticles as a magnetic resonance contrast agent in vivo.
From the analysis of the above results (i.e. from examples 1-3 and comparative example 1), doping an iron-based magnetic resonance contrast agent with a certain amount of vanadium ions can improve the dispersibility of the iron-based magnetic resonance contrast agent, which is advantageous for the use of the vanadium doped iron-based magnetic resonance contrast agent in vivo.
2. Particle size distribution test
The hydrated particle diameters of the nanoparticles prepared in the above examples and comparative examples were tested in the present application using a dynamic light scattering instrument, and the test results are shown in table 1:
table 1, hydrated particle size of contrast agent nanoparticles prepared in examples and comparative examples
| Group of | Particle size of hydration (nm) |
| Example 1 | 240 |
| Example 2 | 200 |
| Example 3 | 120 |
| Comparative example 1 | 180 |
| Comparative example 2 | 600 |
It can be seen from examples 1-3 in table 1 that the particle size of the vanadium doped iron-based magnetic resonance contrast agent nanoparticle gradually decreases with the decrease of the doping amount of the vanadium ions, and it is further known from fig. 1a-3a that the particle size of the vanadium doped iron-based magnetic resonance contrast agent nanoparticle decreases with the decrease of the particle size, but the dispersibility thereof gradually increases, because the decrease of the particle size is beneficial to increasing the specific surface area of the contrast agent nanoparticle, thereby increasing the contact area between the contrast agent nanoparticle and water molecules, further accelerating the interaction between the water molecules and the vanadium doped iron-based magnetic resonance contrast agent nanoparticle, improving the dispersibility of the contrast agent nanoparticle, and realizing the enhancement of the magnetic resonance contrast performance of the contrast agent nanoparticle.
3. Magnetic testing
The contrast agent nanoparticles prepared in the above examples and comparative examples were subjected to magnetic testing, and the test results thereof are shown in fig. 1b, 2b, 3b, 4b and 5b, respectively.
According to FIG. 1b, the transverse relaxation rate (r 2 ) 612.4mM -1 s -1 The method comprises the steps of carrying out a first treatment on the surface of the According to FIG. 2b, the transverse relaxation rate (r 2 ) 654.7mM -1 s -1 The method comprises the steps of carrying out a first treatment on the surface of the As shown in FIG. 3b, the transverse relaxation rate (r 2 ) 832.6mM -1 s -1 According to FIG. 5b, the transverse relaxation rate (r 2 ) 298.8mM -1 s -1 The method comprises the steps of carrying out a first treatment on the surface of the As shown in fig. 6, by analyzing the relationship between the doping amount of vanadium ions in the contrast agent nanoparticles and the relaxation rate thereof, it can be found that the relaxation rate of the vanadium-doped iron-based magnetic resonance contrast agent nanoparticles gradually increases as the doping amount of vanadium ions decreases in the early stage of the doping of vanadium ions, and that the VIO nanoparticles exhibit the highest relaxation rate when the doping amount of vanadium ions is 0.09, and then the relaxation rate of the VIO nanoparticles also exhibits a gradually decreasing trend as the doping amount of vanadium ions decreases.
As shown in FIG. 4b, the transverse relaxation rate of ION is 540.5mM -1 s -1 Comparing FIGS. 1b-3b with FIG. 4b, it was found that the good VIO-4 nanoparticles of VIO-2 and VIO-3 have excellent magnetic resonance contrast properties compared with the ION nanoparticles. Therefore, the contrast capability of the iron-based magnetic resonance contrast agent can be improved by doping vanadium, and the application of the vanadium-doped iron-based magnetic resonance contrast agent can improve the accuracy of tumor diagnosis.
4. Magnetic resonance imaging test
To further verify the in vivo imaging effect of the vanadium doped iron-based magnetic resonance contrast agent, the VIO-4 nanoparticle prepared in example 3 and the ION nanoparticle prepared in comparative example 1 were injected into tumor-bearing nude mice via tail vein at a dose of 2mg (contrast agent nanoparticle)/kg (nude mice weight) and imaged by a magnetic resonance imaging scanner, and the test results are shown in fig. 3c-3d and 4c-4d, respectively.
As shown in FIGS. 3c-3d, the magnetic resonance T of nude mice bearing tumor 2 The weighted spectrum shows that the brightness of the tumor area of the VIO-4 nano particles gradually darkens after the VIO-4 nano particles are injected into the nude mice through tail vein, which indicates that the VIO-4 shows T in vivo 2 Magnetic resonance contrast agent function. In addition, after 60min of injection, the tumor region of tumor-bearing nude mice exhibited the lowest brightness, indicating that a large amount of VIO-4 nanoparticles accumulated in the tumor region, and that it exhibited the best contrast effect. Over time, the tumor area became progressively brighter, indicating that the contrast effect of the VIO-4 nanoparticles on the tumor area was progressively weaker and it was progressively expelled from the tumor tissue. Meanwhile, the magnetic resonance signal-to-noise ratio spectrogram of the tumor area shows that the magnetic resonance signal-to-noise ratio of the tumor area of the tumor-bearing nude mice gradually rises with the increase of time in the early stage, and reaches the highest value of 29.5% in 60 min. After 60min of injection, the signal-to-noise ratio of the magnetic resonance imaging of the VIO-4 group is reduced with the increase of time, and the change trend is similar to the T 2 The observed phenomenon of the weighted graph is consistent, indicating VIO-4 nanoparticles as T 2 Magnetic resonance contrast agents exhibit a more excellent contrast effect in vivo.
As shown in FIGS. 4c-4d, T in tumor-bearing nude mice injected with ION nanoparticles, the tumor region thereof 2 The weighted graph shows that the best contrast effect is exhibited 60min after injection and the corresponding MR signal to noise ratio value (20.55%) is poor in contrast capability relative to VIO-4.
In summary, the magnetic resonance imaging signal-to-noise ratio of the VIO-4 nanoparticles is higher than that of the ION group, which indicates that the magnetic resonance contrast performance of the VIO-4 nanoparticles is better than that of the ION nanoparticles. Further explaining that the doping of vanadium can improve the contrast capability of the iron-based magnetic resonance contrast agent.
According to the application, the vanadium ion with certain mass is doped into the iron-based magnetic resonance contrast agent, so that the contrast capability of the iron-based magnetic resonance contrast agent is improved, and the accuracy of a tumor patient in magnetic resonance imaging is further improved. In addition, the application further adjusts the doping amount of vanadium ions to finally obtain the vanadium doped iron-based magnetic resonance contrast agent with good dispersivity, high transverse relaxation rate and strong contrast capability, thereby solving the problem that the contrast agent in the prior art affects the diagnosis accuracy of tumor patients.
The foregoing description of the preferred embodiments of the application is not intended to limit the application to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the application are intended to be included within the scope of the application.
Claims (10)
1. The preparation method of the vanadium doped iron-based magnetic resonance contrast agent is characterized by comprising the following steps of:
step 1, fe is contained 3+ Organic complex precursors and V-containing 4+ Adding the organic complex precursor into an organic mixed solvent, heating, stirring and dissolving to obtain a reaction solution;
step 2, adding a hydrophilic polymer surfactant into the reaction solution, and continuously heating and stirring;
step 3, after the heating and stirring in the step 2 are finished, adding an alkaline substance into the reaction solution to adjust the pH value of the reaction solution, so as to promote the metal ions in the reactant to form hydroxide;
and 4, carrying out a hydrothermal reaction on the reaction solution containing the hydroxide obtained in the step 3, and obtaining the mass doping ratio of vanadium ions after finishing: 0.04-0.09 of vanadium doped iron-based magnetic resonance contrast agent.
2. The method according to claim 1, wherein the Fe-containing material in the step 1 3+ Organic complex precursors and V-containing 4+ The mass ratio of the organic complex precursors is 2-10:1.
3. The system according to claim 2The preparation method is characterized in that the Fe-containing alloy comprises 3+ The organic complex precursor comprises any one of ferric acetylacetonate, ferrocene and ferric acrylate; the V-containing 4+ The organic complex precursor comprises any one of vanadyl acetylacetonate, cyclopentadienyl vanadium tetracarbonyl vanadium and vanadyl oxalate.
4. The method according to claim 1, wherein the hydrophilic polymer surfactant in the step 2 has a mass and a content of Fe 3+ Organic complex precursors and V-containing 4+ The mass sum ratio of the organic complex precursors is 1:1-3; the hydrophilic polymer surfactant comprises any one of polyethylenimine, polyvinylpyrrolidone and sodium polyacrylate.
5. The preparation method according to claim 1, wherein the alkaline substance is added in the step 3 to adjust the pH of the reaction solution to 9-10.
6. The method according to claim 1 or 5, wherein the basic substance in the step 3 comprises any one of triethanolamine, triethylamine and diethylamine.
7. The method according to claim 1, wherein the hydrothermal reaction conditions in step 4 are: reacting for 8-14 h at 80-200 ℃.
8. The method of claim 1, wherein the organic solvent mixture comprises ethylene glycol.
9. The vanadium doped iron-based magnetic resonance contrast agent prepared by the method of any one of claims 1 to 8, wherein the mass doping ratio of vanadium ions in the vanadium doped iron-based magnetic resonance contrast agent is as follows: 0.04-0.09, wherein the hydration particle size of the vanadium doped iron-based magnetic resonance contrast agent is 120-240 nm.
10. The vanadium doped iron-based magnetic resonance contrast agent according to claim 9, wherein the mass doping ratio of vanadium ions in the vanadium doped iron-based magnetic resonance contrast agent is: 0.09.
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