CN115558000A - Ruthenium-gadolinium heteronuclear hetero-metal complex and preparation method and application thereof - Google Patents
Ruthenium-gadolinium heteronuclear hetero-metal complex and preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 229910052688 Gadolinium Inorganic materials 0.000 claims abstract description 25
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 45
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- 238000000034 method Methods 0.000 claims description 17
- 150000000921 Gadolinium Chemical class 0.000 claims description 14
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical class OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 13
- MGAJEYXQYJBLQL-UHFFFAOYSA-L dichlororuthenium;2-pyridin-2-ylpyridine Chemical compound Cl[Ru]Cl.N1=CC=CC=C1C1=CC=CC=N1.N1=CC=CC=C1C1=CC=CC=N1 MGAJEYXQYJBLQL-UHFFFAOYSA-L 0.000 claims description 10
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- MWFSXYMZCVAQCC-UHFFFAOYSA-N gadolinium(iii) nitrate Chemical compound [Gd+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O MWFSXYMZCVAQCC-UHFFFAOYSA-N 0.000 claims description 3
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- 150000002910 rare earth metals Chemical class 0.000 abstract description 2
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- XWFVFZQEDMDSET-UHFFFAOYSA-N gadolinium(3+);trinitrate;hexahydrate Chemical compound O.O.O.O.O.O.[Gd+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XWFVFZQEDMDSET-UHFFFAOYSA-N 0.000 description 1
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- 239000002405 nuclear magnetic resonance imaging agent Substances 0.000 description 1
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- 239000001301 oxygen Substances 0.000 description 1
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
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- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
- C07F15/0053—Ruthenium compounds without a metal-carbon linkage
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- A61K49/0013—Luminescence
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- 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
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Abstract
The invention belongs to the technical field of coordination chemistry, and particularly relates to a ruthenium-gadolinium heteronuclear hetero-metal complex and a preparation method and application thereof. The ruthenium-gadolinium heteronuclear hetero metal complex disclosed by the invention has a structure shown in a formula I, comprises a ruthenium complex phosphorescence functional unit and a rare earth gadolinium chelate magnetic functional unit, has a magnetic-optical dual-function property, can realize magnetic-optical dual-mode imaging, and can generate singlet oxygen under illumination due to the ruthenium-gadolinium heteronuclear hetero metal complex comprising the ruthenium complex phosphorescence functional unit, so that the ruthenium-gadolinium heteronuclear hetero metal complex can be used as a photosensitizer in photodynamic therapy.
Description
Technical Field
The invention belongs to the technical field of coordination chemistry, and particularly relates to a ruthenium-gadolinium heteronuclear hetero-metal complex and a preparation method and application thereof.
Background
At present, the clinically used cancer treatment methods mainly include surgical resection, radiotherapy, chemotherapy and other traditional means. In recent years, with the rapid development of chemical, biological, and medical disciplines, various new cancer diagnosis and treatment methods, such as cancer immunotherapy, photodynamic therapy, and photothermal therapy, are emerging, and these methods have brought new hopes for cancer treatment.
The principle of photodynamic therapy is that photosensitizer is enriched at the position of pathological change tissue through ways of external application or intravenous administration and is selectively absorbed by the pathological change tissue, and the photosensitizer performs photodynamic reaction under the irradiation of light with specific wavelength to generate free radicals which can kill the pathological change tissue and simultaneously enable normal tissue cells not to be damaged; multimodal imaging enables the acquisition of useful information about the location, shape, size, etc. of a tumor. Therefore, the precise treatment under the guidance of the multi-mode imaging can not only effectively avoid the space-time difference generated in the diagnosis and treatment process, but also obviously improve the imaging diagnosis efficiency, increase the treatment effect and reduce the toxic and side effects, thereby being an effective way for realizing the precise diagnosis and the high-efficiency treatment of the tumors.
In the currently applied diagnosis and treatment system, a nano material is mostly used as a drug delivery carrier to load an anti-tumor drug, but the method also faces the problems of low drug loading rate, poor stability, poor repeatability and the like, and is lack of real-time tracing on drug molecules and evaluation and detection on treatment effect. The single-molecule diagnosis and treatment reagent is another effective strategy for realizing precise treatment under the guidance of multi-mode imaging, but because the difficulty in molecular design and synthesis is great, the reports in the aspect are relatively few at present.
Disclosure of Invention
In view of this, the invention provides a ruthenium-gadolinium heteronuclear hetero metal complex, which can realize magnetic-optical dual-mode imaging and can be used as a photosensitizer in photodynamic therapy.
In order to achieve the above object, the present invention provides a ruthenium-gadolinium heteronuclear hetero metal complex having a structure represented by formula I:
said M comprises Cl - 。
Preferably, said M is replaced by Br - 、I - 、NO 3 - 、BF 4 - 、SbF 6 - 、CF 3 SO 3 - Or PF 6 - 。
The invention also provides a preparation method of the ruthenium-gadolinium heteronuclear hetero metal complex, which comprises the following steps:
dissolving inorganic gadolinium salt and a diethylenetriaminepentaacetic acid derivative, and performing a first coordination reaction to obtain a gadolinium complex;
dissolving the gadolinium complex and bis (2, 2' -bipyridine) ruthenium dichloride, and performing a second coordination reaction to obtain the ruthenium-gadolinium heteronuclear hetero-metal complex;
the diethylene triamine pentaacetic acid derivative has a structure shown in a formula I-1;
the gadolinium complex has a structure shown as a formula I-2;
preferably, the inorganic gadolinium salt comprises one or more of gadolinium nitrate, gadolinium chloride and gadolinium perchlorate.
Preferably, the ratio of the number of moles of the inorganic gadolinium salt to the sum of the number of moles of the inorganic gadolinium salt and the diethylenetriaminepentaacetic acid derivative is 0.2 to 0.8:1.
preferably, the ratio of the number of moles of said gadolinium complex to the sum of the number of moles of gadolinium complex and bis (2, 2' -bipyridine) ruthenium dichloride is from 0.3 to 0.7:1.
preferably, the temperature of the first coordination reaction is 40-60 ℃ and the time is 20-25 h.
Preferably, the temperature of the second coordination reaction is 40-60 ℃ and the time is 22-26 h.
Preferably, when M is replaced by Br - 、I - 、NO 3 - 、BF 4 - 、SbF 6 - 、CF 3 SO 3 - Or PF 6 - The replacing method comprises the following steps: carrying out ion replacement reaction on a product obtained by the second coordination reaction; the reagent for the ion exchange reaction comprises NH 4 Br、NaI、NH 4 NO 3 、AgBF 4 、NaSbF 6 、AgCF 3 SO 3 、NH 4 BPh 4 Or NH 4 PF 6 。
The invention also provides the application of the ruthenium-gadolinium heteronuclear hetero metal complex or the ruthenium-gadolinium heteronuclear hetero metal complex prepared by the preparation method in preparing a magneto-optical dual-mode imaging agent or a photosensitizer.
The ruthenium-gadolinium heteronuclear hetero metal complex disclosed by the invention has a structure shown in a formula I, comprises a ruthenium complex phosphorescence functional unit and a rare earth gadolinium chelate magnetic functional unit, has a magneto-optical dual-function property, and can be used for preparing an imaging agent in magneto-optical dual-mode imaging.
Drawings
FIG. 1 is a reaction diagram of a ruthenium-gadolinium heteronuclear metal complex prepared in example 1 of the present invention;
FIG. 2 is an electrospray mass spectrum of the ruthenium-gadolinium heteronuclear metal complex prepared in example 1 of the present invention;
FIG. 3 is an image of living cell confocal laser microscope of the Ru-Gd heteronuclear metal complex prepared in example 1 of the present invention;
FIG. 4 is a MRI image of the Ru-Gd heteronuclear metal complex prepared in example 1 of the present invention;
FIG. 5 is a graph showing the in vitro photodynamic effect of the ruthenium-gadolinium heteronuclear complex prepared in example 1 of the present invention.
Detailed Description
The invention provides a ruthenium-gadolinium heteronuclear hetero metal complex which has a structure shown in a formula I:
said M comprises Cl - 。
Preferably, said M is replaced by Br - 、I - 、NO 3 - 、BF 4 - 、SbF 6 - 、CF 3 SO 3 - Or PF 6 - 。
The invention also provides a preparation method of the ruthenium-gadolinium heteronuclear hetero metal complex, which comprises the following steps:
dissolving inorganic gadolinium salt and a diethylene triamine pentaacetic acid derivative, and carrying out a first coordination reaction to obtain a gadolinium complex;
dissolving the gadolinium complex and bis (2, 2' -bipyridine) ruthenium dichloride, and performing a second coordination reaction to obtain the ruthenium-gadolinium heteronuclear hetero-metal complex;
the diethylene triamine pentaacetic acid derivative has a structure shown in a formula I-1;
the gadolinium complex has a structure shown as a formula I-2;
in the invention, inorganic gadolinium salt and diethylene triamine pentaacetic acid derivative are dissolved and subjected to a first coordination reaction to obtain a gadolinium complex.
In the present invention, the inorganic gadolinium salt includes one or more of gadolinium nitrate, gadolinium chloride and gadolinium perchlorate, and more preferably, gadolinium nitrate hexahydrate. The ratio of the number of moles of the inorganic gadolinium salt to the sum of the number of moles of the inorganic gadolinium salt and the diethylene triamine pentaacetic acid derivative is preferably 0.2 to 0.8:1, more preferably 0.5:1.
in the present invention, the agent for dissolving the inorganic gadolinium salt and the diethylenetriaminepentaacetic acid derivative preferably includes methanol.
In the present invention, the temperature of the first coordination reaction is preferably 40 to 60 ℃, more preferably 50 ℃; the time is preferably 20 to 25 hours; more preferably 24h. In the present invention, the first coordination reaction is preferably performed in a protective atmosphere, which preferably includes helium or nitrogen, more preferably nitrogen.
After the gadolinium complex is obtained, the gadolinium complex and bis (2, 2' -bipyridine) ruthenium dichloride are dissolved and subjected to a second coordination reaction to obtain the ruthenium-gadolinium heteronuclear hetero-metal complex.
In the present invention, the ratio of the number of moles of the gadolinium complex to the sum of the number of moles of the gadolinium complex and bis (2, 2' -bipyridine) ruthenium dichloride is preferably 0.3 to 0.7:1, more preferably 0.33:1.
in the present invention, the agent in which the gadolinium complex and bis (2, 2' -bipyridine) ruthenium dichloride are dissolved is preferably a mixed solvent of dichloromethane and methanol; the volume ratio of dichloromethane to methanol in the mixed solvent is preferably 1. In the present invention, the temperature of the second coordination reaction is preferably 40 to 60 ℃, more preferably 50 to 55 ℃; the time is preferably 22 to 26 hours; more preferably 24 to 25 hours. In the present invention, the second coordination reaction is preferably carried out in a protective atmosphere, which preferably comprises helium or nitrogen, more preferably nitrogen.
In the present invention, when M is replaced by Br - 、I - 、NO 3 - 、BF 4 - 、SbF 6 - 、CF 3 SO 3 - Or PF 6 - The replacing method comprises the following steps: carrying out ion displacement reaction on a product obtained by the second coordination reaction; the reagent for the ion exchange reaction comprises NH 4 Br、NaI、NH 4 NO 3 、AgBF 4 、NaSbF 6 、AgCF 3 SO 3 、NH 4 BPh 4 Or NH 4 PF 6 。
In the present invention, before the ion exchange reaction, it is preferable to further include concentrating the product obtained by the second coordination reaction to dryness, and redissolving the concentrated product with methylene chloride.
In the invention, the reagent for the ion replacement reaction comprises NaBr, naI and NaNO 3 Or ammonium hexafluorophosphate, preferably ammonium hexafluorophosphate. In the present invention, the molar ratio of the product obtained by the second coordination reaction to the reagent for the ion exchange reaction is preferably 1:1 to 1.5, more preferably 1:1.2 to 1.3. In the present invention, the temperature of the ion exchange reaction is preferably 20 to 30 ℃, more preferably 25 ℃, and the time is preferably 0.5 to 2 hours, more preferably 1 hour.
The invention preferably further comprises the step of sequentially carrying out column chromatography separation and concentration on the crude probe obtained by the ion exchange reaction, wherein an eluent of the column chromatography separation is a mixed solvent of dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol in the mixed solvent is 1:1. the concentration is not particularly limited in the present invention, and the solvent in the eluate may be removed by a procedure well known to those skilled in the art.
The invention also provides the application of the ruthenium-gadolinium heteronuclear hetero metal complex or the ruthenium-gadolinium heteronuclear hetero metal complex prepared by the preparation method in preparing a magneto-optical dual-mode imaging agent or a photosensitizer.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
122mg of Gd (NO) 3 ) 3 ·6H 2 Adding O, 200mg of diethylenetriaminepentaacetic acid derivative and 20mL of methanol into a reaction container, carrying out a first coordination reaction for 24 hours at 50 ℃ under the protection of nitrogen, filtering a product obtained by the first coordination reaction, and collecting precipitate to obtain a gadolinium complex; 200mg of the obtained gadolinium complex and 215mg of bis (2, 2' -bipyridine) ruthenium dichloride are added into a mixed solvent of dichloromethane and methanol (the volume ratio of dichloromethane to methanol is 1). After the reaction is finished, the product obtained by the second coordination reaction is rotated to be evaporated to dryness, a small amount of dichloromethane is added for dissolution, the product and 80mg ammonium hexafluorophosphate are mixed for ion exchange reaction for 1h at room temperature, the product obtained by ion conversion is subjected to column chromatography separation, eluent is a mixed solvent of dichloromethane and methanol with the volume ratio of 1.
FIG. 1 is a reaction equation for preparing a ruthenium-gadolinium heteronuclear hetero metal complex in example 1, and it can be seen from FIG. 1 that: gd (NO) 3 ) 3 ·6H 2 Dissolving O and a diethylene triamine pentaacetic acid derivative, and performing a first coordination reaction to obtain a gadolinium complex; and then dissolving the obtained gadolinium complex and bis (2, 2' -bipyridine) ruthenium dichloride into a mixed solvent of dichloromethane and methanol to perform a second coordination reaction, mixing a product obtained by the second coordination reaction with ammonium hexafluorophosphate, and performing an ion exchange reaction to obtain the ruthenium-gadolinium heteronuclear hetero metal complex.
The invention performs electrospray chromatography characterization on the ruthenium-gadolinium heteronuclear mixed metal prepared in example 1, and the experimental steps are as follows: the ruthenium-gadolinium heteronuclear metal complex obtained in example 1 was dissolved in acetonitrile and then characterized by electrospray mass spectrometry, and the results are shown in fig. 2, and it can be seen from fig. 2 that: the high-resolution mass spectrum is determined by experiments to be consistent with the mass spectrum which is theoretically simulated, no matter the molecular weight or the isotope peak type. Molecular formula of C 78 H 66 GdN 17 O 8 Ru 2 Average molecular weight 1730.26 due to bandingThe molecular weight is measured by experiment, the molecular weight is 432.3165, and the complex structure is correct because the molecular weight is 432.3155 under the theoretical simulation condition.
FIG. 3 is a living cell optical image of the ruthenium-gadolinium heterogeneous polynuclear metal complex prepared in example 1. The experimental steps are as follows: a549 cells in logarithmic growth phase are divided into confocal 35mm confocal culture dishes, the cells are subjected to adherent growth for 24 hours in 1640 culture solution containing 10% fetal bovine serum at 37 ℃, then 30 mu M of ruthenium-gadolinium heterogeneous multi-core metal complex is added, the cells are incubated for 2 hours, the cells are washed by PBS, and then confocal microscopic imaging is immediately carried out, the experimental result is shown in figure 3, and as can be seen from figure 3: when 50 mu M of ruthenium-gadolinium heterogeneous polynuclear metal complex is added and incubated for 1h, then laser confocal microscopy imaging is carried out, bright red spots appear in cells, and the ruthenium-gadolinium heterogeneous polynuclear metal complex can enter the cells.
The relaxation rate of the ruthenium-gadolinium heterogeneous polynuclear metal complex prepared in example 1 was determined. The test process is as follows: the ruthenium-gadolinium heterogeneous polynuclear metal complex prepared in example 1 was dissolved in water to prepare a solution having a total volume of 1.5mL and concentrations of 0.4, 0.2, 0.1, 0.05, 0.025, and 0mM, and T1-weighted imaging was performed on the sample using a MesoMR NMR analysis and imaging System (manufactured by Nimehmei electronics, inc., shanghai) at a resonance frequency of 23.314MHz and a magnet strength of 0.5T, a coil diameter of 60mM, and a magnet temperature of 32.0 ℃. The experimental results are shown in fig. 4, and it can be seen from fig. 4 that: the concentration of the ruthenium-gadolinium heterogeneous multi-core metal complex is in direct proportion to the strength of a magnetic resonance imaging signal, the higher the concentration of the complex is, the stronger the signal is, and the linear relation is better, so that the relaxation rate of the ruthenium-gadolinium heterogeneous multi-core metal complex can be calculated to be 8.2mM -1 s -1 Much higher than commercial magnetic resonance imaging contrast agents.
The ruthenium-gadolinium heterogeneous polynuclear metal complex prepared in example 1 is subjected to detection of active oxygen generated by illumination. The detection steps are as follows: placing the aqueous solution containing the ruthenium-gadolinium heterogeneous polynuclear metal complex (10 mu M) and the singlet oxygen probe DPBF (10 mu M)) in a quartz cuvette, placing the cuvette in a light source of 450nm, and detecting the absorbance of the solution before and after illumination by an ultraviolet-visible spectrophotometer every 1s of radiation. The results are shown in FIG. 5, and it can be seen from FIG. 5 that: the method comprises the steps of taking 1, 3-diphenyl isobenzofuran (DPBF) as a singlet oxygen probe, mixing a ruthenium-gadolinium heteronuclear mixed metal complex with the DPBF, illuminating the mixture at different time nodes, and then testing the change of an ultraviolet-visible absorption spectrum by an ultraviolet-visible spectrophotometer, wherein the gradual decrease of the absorption at the 410nm position along with the increase of illumination time is found, which indicates that singlet oxygen is generated and the obvious photodynamic effect is achieved.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, it is possible to make various improvements and modifications without departing from the principle of the present invention, and those improvements and modifications should be considered as the protection scope of the present invention.
Claims (10)
1. A ruthenium-gadolinium heteronuclear heterometal complex is characterized by having a structure shown in formula I:
said M comprises Cl - 。
2. The ruthenium-gadolinium heteronuclear heterometal complex according to claim 1, wherein the substitution of M to Br - 、I - 、NO 3 - 、BF 4 - 、SbF 6 - 、CF 3 SO 3 - Or PF 6 - 。
3. The method of preparing a ruthenium-gadolinium heteronuclear metal complex as claimed in claim 1, comprising the steps of:
dissolving inorganic gadolinium salt and a diethylene triamine pentaacetic acid derivative, and carrying out a first coordination reaction to obtain a gadolinium complex;
dissolving the gadolinium complex and bis (2, 2' -bipyridine) ruthenium dichloride, and performing a second coordination reaction to obtain the ruthenium-gadolinium heteronuclear hetero-metal complex;
the diethylene triamine pentaacetic acid derivative has a structure shown in a formula I-1;
the gadolinium complex has a structure shown in a formula I-2;
4. the method of claim 3, wherein the inorganic gadolinium salt comprises one or more of gadolinium nitrate, gadolinium chloride, and gadolinium perchlorate.
5. The method according to claim 3, wherein the ratio of the number of moles of the inorganic gadolinium salt to the sum of the number of moles of the inorganic gadolinium salt and the diethylene triamine pentaacetic acid derivative is 0.2 to 0.8:1.
6. a production method according to claim 3, wherein the ratio of the number of moles of the gadolinium complex to the sum of the number of moles of the gadolinium complex and bis (2, 2' -bipyridine) ruthenium dichloride is 0.3 to 0.7:1.
7. the method according to claim 3 or 5, wherein the temperature of the first coordination reaction is 40 to 60 ℃ and the time is 20 to 25 hours.
8. The method according to claim 3 or 6, wherein the temperature of the second coordination reaction is 40 to 60 ℃ and the time is 22 to 26 hours.
9. The method according to claim 3, wherein when M is replaced by Br - 、I - 、NO 3 - 、BF 4 - 、SbF 6 - 、CF 3 SO 3 - Or PF 6 - The replacing method comprises the following steps: carrying out ion replacement reaction on a product obtained by the second coordination reaction; the reagent for the ion exchange reaction comprises NH 4 Br、NaI、NH 4 NO 3 、AgBF 4 、NaSbF 6 、AgCF 3 SO 3 、NH 4 BPh 4 Or NH 4 PF 6 。
10. Use of the ruthenium-gadolinium heteronuclear metal complex according to claim 1 or the ruthenium-gadolinium heteronuclear metal complex prepared by the preparation method according to any one of claims 2 to 9 in the preparation of a magneto-optical dual-mode imaging agent or a photosensitizer.
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| Title |
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| GEERT DEHAEN ET AL.: "A Heterobimetallic Ruthenium-Gadolinium Complex as a Potential Agent for Bimodal Imaging", 《INORG. CHEM.》, vol. 50, 13 September 2011 (2011-09-13), pages 2 * |
| WENBO SHI ET AL.: "A novel heterobimetallic Ru(II)–Gd(III) complex-based magnetoluminescent agent for MR and luminescence imaging", 《RSC ADV.》, vol. 5, 4 November 2015 (2015-11-04), pages 1 * |
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