CN101822846A - Magneto-optical dual-mode molecular image probe and preparation method thereof - Google Patents
Magneto-optical dual-mode molecular image probe and preparation method thereof Download PDFInfo
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- CN101822846A CN101822846A CN 201010170947 CN201010170947A CN101822846A CN 101822846 A CN101822846 A CN 101822846A CN 201010170947 CN201010170947 CN 201010170947 CN 201010170947 A CN201010170947 A CN 201010170947A CN 101822846 A CN101822846 A CN 101822846A
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Abstract
The invention relates to the field of multi-mode molecular image probes, in particular to a heteronuclear (Ir-Gd) metal complex containing two functional units, namely an iridium phosphorescent complex and a rare-earth macrocyclic polyamine polyacid complex for magnetic resonance-phosphorescent dual-mode imaging of a living body. The cell fluorescent confocal imaging experiment proves that the Ir-Gd complex in the invention can penetrate a cell membrane to enter the cell, specifically colors the cytoplasm region of the cell, and has high water solubility and lower cell toxicity; and in vitro magnetic resonance imaging data proves that the Ir-Gd complex has higher longitudinal relaxation rate, and further research finds that the complex can be used as a magnetic resonance imaging probe for the living body.
Description
Technical field
The present invention relates to multi-mode molecular image probe field, be specifically related to the double mode imaging of magnetic resonance-phosphorescence that a kind of heteronuclear (Ir-Gd) metal complex that contains iridium phosphorescent complexes and two functional units of rare earth Macrocyclic polyamine polyacid coordination compound is used for live body.
Background technology
Molecular imaging (molecular imaging) is the specific molecular of utilization iconography means display organization level, cell and subcellsular level, molecular level changes under the reflection condition of living organism, its biological behaviour is being carried out qualitative and science quantitative study aspect the image, be Protocols in Molecular Biology and modern medicine iconography to be combined and an emerging frontier branch of science producing.The molecular medicine image technology is the human life information's that shows that naked eyes or other technologies can't or be difficult to be familiar with a medical image method, it is included in bioprocess in cell and the molecular level Noninvasive research body, this just requires to design the synthetic chemistry imaging agents, makes intravital molecule activity process visualization and quantifying.Common molecular image technology has x-ray tomography imaging (CT), ultra sonic imaging (US), optical imagery (OI) nuclear magnetic resonance (MRI), positron emission tomography (PET) and single photon emission computer tomography (SPECT) etc. at present, but the single-mode molecular image technology that has now developed is not perfect, its defective is all arranged, can't provide enough information to clinical diagnosis, relatively poor as the optical imagery penetrance, can only be deep in the in-house several millimeters atmosphere, and be difficult to quantitative analysis; The susceptiveness of nuclear magnetic resonance is lower, though positron emission computerized tomography has very high sensitivity, resolution is too low.Therefore the image technology of several modes is combined, bring into play its advantage separately, exploitation is applicable to that the multi-mode molecular image probe of chemical detection and medical diagnosis has attracted the concern of vast researcher.
Nuclear magnetic resonance (magnetic resonance imageing, MRI) be to invent by Lauterbur in 1973, become at present the strong instrument on the medical clinic applications, because irradiation energy is low, without any side effects to body scans, and in the gatherer process of image, can freely select, the advantage that provides space three-dimensional to differentiate image is provided.It nearly all can scan for any position of human body, even only can accomplish that at certain tissue regions video picture, this advantage is useful for the early discovery and the diagnosis and treatment of cancerous cell.At present, nuclear magnetic resonance replaces the status of CT Scan in clinical diagnosis just gradually.Optical molecular imaging (Optical Imaging) is meant the emerging research field that grows up on the basis of genomics, proteomics and contemporary optics imaging.Its outstanding feature is that Noninvasive ground carries out visual observation to the molecular events that in vivo participates in physiology and pathological process, be generally acknowledge in the world at present carry out one of main flow means of molecules in living organisms event study, have the major application prospect in the life science field.The double mode imaging of magnetic resonance-optics has been applied in biomedical research and the clinical practice in developed country at present owing to had the high and highly sensitive advantage of optical imagery of nuclear magnetic resonance resolution concurrently.Using more magnetic resonance contrast agent at present is kinetics and thermodynamically stable micromolecule Gd coordination compound, and polyamines polyacid part can reduce its toxicity with the gadolinium ion chelating, and it can be applied in the body safely.By carry out on the macro ring chemical modification can binding on the optics active group, and do not influence the sequestering power of macrocyclic ligand and gadolinium ion, can be built into the double mode probe of a class.Have long excitation wavelength (MLCT absorption) based on the luminous complex of iridium of MLCT attitude, characteristics such as higher quantum yield and excellent light stability can realize excited by visible light, thereby reduce the injury to organism; And can realize by the structure that changes cyclic metal complexes emission wavelength from blue light to infrared adjusting.Therefore, utilize TIME RESOLVED TECHNIQUE, complex of iridium can be avoided the interference of cell autofluorescence in bio-imaging, is expected to become the novel Photobiology probe of a class.
Summary of the invention
The object of the present invention is to provide the molecular probe of a kind of good water solubility, relaxation rate height and good biocompatibility to be used for the nuclear magnetic resonance and the phosphorescence imaging of live body, for live body pathological study and clinical diagnosis provide new means.
A kind of magnetic resonance-phosphorescence dual-mode molecular image probe that the present invention proposes is meant heteronuclear (Ir-Gd) metal complex that contains iridium phosphorescent complexes and two functional units of rare earth Macrocyclic polyamine polyacid coordination compound simultaneously, and the concrete structure formula is:
Magneto-optical dual-mode molecular image probe its preparation method proposed by the invention is:
(1) at first prepares 2-chloro-phenanthroline-5-acetamide 5-nitro phenanthroline.Get the amino phenanthroline of 5-and put into three-necked bottle, ice bath, evacuation, nitrogen protection, toward wherein adding anhydrous THF, volume is 20～100mL and anhydrous triethylamine, volume is 0.5～5mL, after stirring half an hour, chloracetyl chloride is dropwise joined in the flask, wherein amino phenanthroline of 5-and chloracetyl chloride mol ratio are 2～0.2: 1; Rise to room temperature, stirring is spent the night, and gets the brownish red suspension, it is transferred in the separatory funnel, to wherein adding an amount of 5%NaHCO
3Solution, the supernatant is poured out in layering, be spin-dried for the brownish red solid crude product, water and washing with alcohol repeatedly after drying get yellow solid.
(2) secondly prepare 2-phenylpyridine-2-chloro-phenanthroline-5-acetamide complex of iridium.Get iridium 2-phenylpyridine dichloro endo compound, 2-chloro-phenanthroline-5-acetamide 5-nitro phenanthroline places three-neck flask, and the mol ratio of the two is 2～0.2: 1, and nitrogen protection behind the evacuation is toward wherein adding CH
2Cl
2/ CH
3OH=1: 0.5～2 mixed solvent, volume are 20～100mL, and 4～12h postcooling that refluxes is to room temperature, again to wherein adding KPF
6, being spin-dried for solvent behind stirring 1～4h, gained solid column chromatography, eluent are ethanol/methylene=1: 50～1, obtain orange-yellow powder.
(3) prepare phenylpyridine-phenanthroline-1,4 then, 7-three (tert-butyl ester)-1,4,7,10-tetraazacyclododecanand complex of iridium: get 1,4,7-three (tert-butyl ester)-1,4,7, the 10-tetraazacyclododecanand places three-neck flask, blast nitrogen behind the evacuation, triplicate is dissolved in 2-phenylpyridine-2-chloro-phenanthroline-5-acetamide complex of iridium in the dry acetonitrile then, volume is 50～100mL, slowly be added drop-wise in the flask wherein 1,4,7-three (tert-butyl ester)-1,4,7, the 10-tetraazacyclododecanand and and the mol ratio of 2-phenylpyridine-2-chloro-phenanthroline-5-acetamide complex of iridium be 1: 0.5～2; The stopped reaction after 12～48 hours that refluxes is spin-dried for behind the elimination inorganic salt, and gained solid column chromatography, eluent are ethanol/methylene=1: 200～10, pale brown color solid.
(4) prepare target Ir-Gd coordination compound at last: get phenylpyridine-phenanthroline-1,4,7-three (tert-butyl ester)-1,4,7,10-tetraazacyclododecanand complex of iridium places three-neck flask, N
2Add dichloromethane under the atmosphere, volume is that 1～10mL is then to wherein dropwise adding trifluoroacetic acid, wherein phenylpyridine-phenanthroline-1,4,7-three (tert-butyl ester)-1,4,7, the mol ratio of 10-tetraazacyclododecanand complex of iridium and trifluoroacetic acid is 1: 0.1～20; Stirring is spent the night, and the some plate tracks to reaction to be finished, and is spin-dried for solvent and unreacted acid, gets pale brown color grease, gets Gd (NO again
3)
3.6H
2O is soluble in water, and volume is 0.5～5mL, joins in the grease, with 1MNaOH pH is transferred to about 6～8, stirs 12～48 hours, and sucking filtration gets pale brown color solid, gets yellow powder after reversed-phase HPLC is purified.
The present invention carries out uv-vis spectra and phosphorescence spectrum test to prepared target product Ir-Gd coordination compound, the experiment of cell fluorescence co-focusing imaging, cytotoxicity experiment, external and live body nuclear magnetic resonance experiment.
Advantage of the present invention: the magneto-optical dual-mode molecular image probe that the present invention mentions has high relaxation rate, good thermodynamic stability, lower toxic and side effects, characteristics such as higher quantum yield and excellent light stability can effectively be applied to the fluorescence imaging and the nuclear magnetic resonance of living cells and live body.
Description of drawings
Fig. 1 is the uv-vis spectra of Ir-Gd coordination compound, and Fig. 2 is the phosphorescence spectrum of coordination compound.In absorption spectrum, 250nm and 265nm go out to have two significantly strong absorptions, belong to the singlet state transition (π → π of the spin permission that cooperates the species organic ligand
*), the weak absorption at the 350-500nm place belongs to the charge transfer transition (MLCT) for the metal-ligand of singlet state common in the iridium cyclic metal complex and triplet, and wherein abscissa is represented absorbing wavelength, and vertical coordinate is represented absorbance; Excite with 405nm, the yellow phosphorescence that can obtain becoming clear, corresponding at about 560nm place strong emission peak being arranged in the phosphorescent emissions spectrum, wherein abscissa is represented emission wavelength, and vertical coordinate is represented emissive porwer.
Fig. 3 is the confocal fluorescent (a) the KB cell is hatched 30min under the room temperature condition in containing the PBS buffer solution of Ir-Gd coordination compound after, light field (b) and stack (c) image (λ ex=405nm).The stack of burnt luminescent image of copolymerization and light field image shows that intracellular luminous signal mainly is positioned at the endochylema zone rather than on cell membrane, illustrate that coordination compound is not that cell membrane dyes but passes cell membrane and entered in the cell cytosol.
Fig. 4 is the survival rate of KB cell cell after hatching 24h in the culture medium that contains 3.3,8.3,16.7 μ M Ir-Gd coordination compounds, and abscissa is represented coordination compound concentration, and vertical coordinate is represented cell survival rate.Cell is hatched 24 hours in containing Ir-Gd coordination compound culture medium after, obvious variation does not take place in the cell proliferation situation, and cell survival rate all＞90% illustrates that this coordination compound cytotoxicity within the specific limits is very low.
Fig. 5 is the r1 relaxation rate of Ir-Gd coordination compound normal saline solution in the match of 0.5T magnetic field measurement system, and Fig. 6 is the T1 weighted imaging.Longitudinal relaxation rate r1=7.04mM with match gained behind the 3.0T magnetic resonance imager systematic survey
-1.s
-1In the T1 weighted imaging of gained along with Gd
3+The rising of concentration, magnetic resonance weighted imaging picture brightens gradually, and this is the imaging features of typical T1 contrast agent.
Fig. 7 is for adding the magnetic resonance weighted imaging picture of Ir-Gd coordination compound front and back mice intracorporeal organ: arrow indication position is liver (a), kidney portion (b); Before be followed successively by adding, add 0,22,44, the T1 weighted imaging of being gathered behind the 100min (Siemens 3T Trio nuclear magnetic resonance instrument system) from a left side.After adding contrast agent 22min, mice liver obviously brightens, and kidney portion also slightly brightens, and along with the increase of time, contrast agent is constantly metabolism in vivo, and during to 100min, the obvious brightness of mice liver weakens slightly, and then there is the trend that obviously brightens at the kidney position.
The specific embodiment
Embodiment 1
The preparation of Ir-Gd coordination compound: get chemical compound phenylpyridine-phenanthroline-1,4,7-three (tert-butyl ester)-1,4,7,10-tetraazacyclododecanand complex of iridium 74.7mg (0.05mmol) places three-neck flask, N
2Add the 2mL dichloromethane under the atmosphere, to wherein dropwise adding the 1mL trifluoroacetic acid, stirring is spent the night then, and the some plate tracks to reaction to be finished, and is spin-dried for solvent and unreacted acid, gets pale brown color grease, gets 22.55mg (0.05mmol) Gd (NO again
3)
3.6H
2O is dissolved in the 1.5mL water, joins in the grease, with 1M NaOH pH is transferred to about 7, stirs 24 hours, and sucking filtration gets pale brown color solid, gets yellow powder after reversed-phase HPLC is purified.MS(ESI
+)m/z：1237.3([M+H]
+).
Embodiment 2
The uv-vis spectra of Ir-Gd coordination compound and phosphorescence spectrum test: the test of UV, visible light and phosphorescence spectrum is all carried out in aqueous solution, and wherein phosphorescence spectrum is to use the 405nm ultraviolet excitation, and test result is seen Fig. 1 and Fig. 2.
Embodiment 3
The cell fluorescence co-focusing imaging experiment of Ir-Gd coordination compound: the KB cell is provided by Chinese biological chemistry and RESEARCH ON CELL-BIOLOGY.Cell is to contain breed in the culture fluid (MEM) of 10% fetal bovine serum (FBs) under 37 ℃, and breeding environment is at 5%CO
2In carry out.Cell climbing sheet 24 hours, cell concentration are 5 * 10
8/ L.Cell imaging experiment co-focusing imaging is to finish under OLYMPUS FV1000 laser scanning microscope and 60 times of object lens.Excite the phosphorescent emissions of Ir-Gd coordination compound with the 405nm semiconductor laser, collecting wavelength then is the emission of 520nm to scope between the 620nm.Before experimentizing, cell will clean with PBS buffer solution, uses the PBS buffer solution of Ir-Gd coordination compound (16.7 μ M) to hatch under 37 ℃ then 30 minutes; Carry out the cell imaging experiment after cleaning with PBS buffer solution afterwards, experimental result is seen Fig. 3.
Embodiment 4
The cytotoxicity experiment of Ir-Gd coordination compound: the cytotoxicity of Ir-Gd coordination compound is estimated with the MTS method.The KB cell inoculation of logarithmic (log) phase is on 96 porocyte culture plates (1 * 10
4Individual cells/well), at 37 ℃, 5%CO
2With cultivate 24h under 95% air atmosphere.The solution of Ir-Gd coordination compound is added (100uL/ hole) in the cell respectively, and final concentration is 3.3,8.3,16.7 μ M, as experimental group.The RPMI1640 culture medium that will contain 0.2%DMSO adds in the cell (100uL/ hole), in contrast group.Above-mentioned cell is at 37 ℃, 5%CO
2With hatch 24h under 95% air atmosphere respectively and after 48 hours, every hole adds MTS/PMS solution, continues to hatch 2h.With the OD value (absorbance) at microplate reader mensuration 560nm wavelength place, make reference with 630nm.Calculate the survival rate of cell as follows: cell survival rate (%)=(experimental group absorbance/matched group absorbance) * 100%, last experimental result is averaged by five groups of parallel laboratory test data and standard deviation obtains, and experimental result is seen Fig. 4.
Embodiment 5
The external nuclear magnetic resonance experiment of Ir-Gd coordination compound: the Ir-Gd coordination compound is dissolved in ultra-pure water, be made into variable concentrations, step NMI20-Analyst 0.5T magnetic nuclear resonance analyzer system with knob then, adopt inversion recovery (IR) pulse train, measure relaxation time and corresponding magnetic resonance weighted imaging, concrete parameter is: TR/TE=1000/60ms, and selecting layer thickness is 0.6mm, spectrum width SW=50KHz, receiver gain RG=3.Simulate relaxation rate according to concentration then, (1/T1)
Obsd=(1/T1)
d+ r1 * [CA], wherein (1/T1)
ObsdBe the longitudinal relaxation speed of the solvent proton of paramagnet, (1/T1)
dBe the longitudinal relaxation speed of neat solvent proton, r1 is the relaxation efficient of coordination compound, and [CA] is the concentration of coordination compound, and experimental result is seen Fig. 5 and Fig. 6.
Embodiment 6
The live body nuclear magnetic resonance experiment of Ir-Gd coordination compound: select for use the clean level public Mus in adult Kunming (about 100g) as live body nuclear magnetic resonance animal for research model, test the previous day, stop the mice normal diet; During experiment, mice is fixed on the self-control fixing head earlier, adopts Siemens 3T superconduction highfield (Siemens 3T Trio nuclear magnetic resonance instrument system), knee coil, saturation recovery (SR) pulse train, T1WI transverse section and coronal scan.Finish unenhanced after, inject prepared contrast agent Ir-Gd coordination compound with the dosage of 0.1mM/Kg through caudal vein, inject successfully after, fixing mice, the selection different time points scans.The MRI sweep parameter: the SR sequence, T1WI, TR=500ms, TE=13ms, bed thickness: 2mm, the number of plies: 14, FOV=120mm, matrix: 320 * 320; Experimental result is seen Fig. 7.
Claims (3)
1. a magneto-optical dual-mode molecular image probe is a kind of heteronuclear (Ir-Gd) metal complex that contains iridium phosphorescent complexes and two functional units of rare earth Macrocyclic polyamine polyacid coordination compound specifically, it is characterized in that structural formula is as follows:
2. the preparation method of a magneto-optical dual-mode molecular image probe as claimed in claim 1 is characterized in that preparation process is as follows:
(1) at first prepares 2-chloro-phenanthroline-5-acetamide 5-nitro phenanthroline.Get the amino phenanthroline of 5-and put into three-necked bottle, ice bath, evacuation; nitrogen protection, toward wherein adding anhydrous THF, volume is 20～100mL and anhydrous triethylamine; volume is 0.5～5mL, stir half an hour after, dropwise join chloracetyl chloride in the flask; wherein amino phenanthroline of 5-and chloracetyl chloride mol ratio are 2～0.2: 1; rise to room temperature, stirring is spent the night, and gets the brownish red suspension; it is transferred in the separatory funnel, to wherein adding an amount of 5%NaHCO
3Solution, the supernatant is poured out in layering, be spin-dried for the brownish red solid crude product, water and washing with alcohol repeatedly after drying get yellow solid.
(2) secondly prepare 2-phenylpyridine-2-chloro-phenanthroline-5-acetamide complex of iridium.Get iridium 2-phenylpyridine dichloro endo compound, 2-chloro-phenanthroline-5-acetamide 5-nitro phenanthroline places three-neck flask, and the mol ratio of the two is 2～0.2: 1, and nitrogen protection behind the evacuation is toward wherein adding CH
2Cl
2/ CH
3OH=1: 0.5～2 mixed solvent, volume are 20～100mL, and 4～12h postcooling that refluxes is to room temperature, again to wherein adding KPF
6, being spin-dried for solvent behind stirring 1～4h, gained solid column chromatography, eluent are ethanol/methylene=1: 50～1, obtain orange-yellow powder.
(3) prepare phenylpyridine-phenanthroline-1,4 then, 7-three (tert-butyl ester)-1,4,7,10-tetraazacyclododecanand complex of iridium: get 1,4,7-three (tert-butyl ester)-1,4,7, the 10-tetraazacyclododecanand places three-neck flask, blast nitrogen behind the evacuation, triplicate is dissolved in 2-phenylpyridine-2-chloro-phenanthroline-5-acetamide complex of iridium in the dry acetonitrile then, volume is 50～100mL, slowly be added drop-wise in the flask wherein 1,4,7-three (tert-butyl ester)-1,4,7, the 10-tetraazacyclododecanand and and the mol ratio of 2-phenylpyridine-2-chloro-phenanthroline-5-acetamide complex of iridium be 1: 0.5～2; The stopped reaction after 12～48 hours that refluxes is spin-dried for behind the elimination inorganic salt, and gained solid column chromatography, eluent are ethanol/methylene=1: 200～10, pale brown color solid.
(4) prepare target Ir-Gd coordination compound at last: get phenylpyridine-phenanthroline-1,4,7-three (tert-butyl ester)-1,4,7,10-tetraazacyclododecanand complex of iridium places three-neck flask, N
2Add dichloromethane under the atmosphere, volume is that 1～10mL is then to wherein dropwise adding trifluoroacetic acid, wherein phenylpyridine-phenanthroline-1,4,7-three (tert-butyl ester)-1,4,7, the mol ratio of 10-tetraazacyclododecanand complex of iridium and trifluoroacetic acid is 1: 0.1～20; Stirring is spent the night, and the some plate tracks to reaction to be finished, and is spin-dried for solvent and unreacted acid, gets pale brown color grease, gets Gd (NO3) again
3.6H
2O is soluble in water, and volume is 0.5～5mL, joins in the grease, with 1MNaOH pH is transferred to about 6～8, stirs 12～48 hours, and sucking filtration gets pale brown color solid, gets yellow powder after reversed-phase HPLC is purified.
3. the application of magneto-optical dual-mode molecular image probe as claimed in claim 1 in nuclear magnetic resonance and phosphorescence imaging is characterized in that the magneto-optical dual-mode imaging and can be used for living imaging.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103380509A (en) * | 2011-02-16 | 2013-10-30 | 株式会社半导体能源研究所 | Light-emitting element |
| CN104764706A (en) * | 2015-04-03 | 2015-07-08 | 上海师范大学 | Melamine dual-mode sensor based on Au-Fe3O4 composite nanoparticles and preparation method thereof |
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| CN101475597A (en) * | 2008-12-25 | 2009-07-08 | 北京师范大学 | Preparation and use of ruthenium and iridium metal complex singlet oxygen fluorescent probe |
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| CN101475597A (en) * | 2008-12-25 | 2009-07-08 | 北京师范大学 | Preparation and use of ruthenium and iridium metal complex singlet oxygen fluorescent probe |
Non-Patent Citations (2)
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| 《Magnetic Resonance Imaging》 20071231 Pál Surányi et al. Equilibrium signal intensity mapping, an MRI method for fast mapping of longitudinal relaxation rates and for image enhancement 641-651 1-3 第25卷, 2 * |
| 《中国药物与临床》 20030630 曾骏 现代生物技术和分子影像探针的设计与研发 165-171 1-3 第3卷, 第3期 2 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103380509A (en) * | 2011-02-16 | 2013-10-30 | 株式会社半导体能源研究所 | Light-emitting element |
| US9538607B2 (en) | 2011-02-16 | 2017-01-03 | Semiconductor Energy Laboratory Co., Ltd. | Light-emitting element |
| US10403839B2 (en) | 2011-02-16 | 2019-09-03 | Semiconductor Energy Laboratory Co., Ltd. | Light-emitting element |
| US11038135B2 (en) | 2011-02-16 | 2021-06-15 | Semiconductor Energy Laboratory Co., Ltd. | Light-emitting element |
| US11812626B2 (en) | 2011-02-16 | 2023-11-07 | Semiconductor Energy Laboratory Co., Ltd. | Light-emitting element |
| CN104764706A (en) * | 2015-04-03 | 2015-07-08 | 上海师范大学 | Melamine dual-mode sensor based on Au-Fe3O4 composite nanoparticles and preparation method thereof |
| CN104764706B (en) * | 2015-04-03 | 2017-08-15 | 上海师范大学 | Based on Au Fe3O4The double mode sensor of melamine of composite nanoparticle and preparation |
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