CN113135963A - Near-infrared second window emission rare earth complex fluorescent dye and preparation method and application thereof - Google Patents
Near-infrared second window emission rare earth complex fluorescent dye and preparation method and application thereof Download PDFInfo
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- CN113135963A CN113135963A CN202110283206.XA CN202110283206A CN113135963A CN 113135963 A CN113135963 A CN 113135963A CN 202110283206 A CN202110283206 A CN 202110283206A CN 113135963 A CN113135963 A CN 113135963A
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- rare earth
- fluorescent dye
- earth complex
- complex fluorescent
- ligand
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- 229910052761 rare earth metal Inorganic materials 0.000 title claims abstract description 142
- 150000002910 rare earth metals Chemical class 0.000 title claims abstract description 129
- 239000007850 fluorescent dye Substances 0.000 title claims abstract description 100
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 239000003446 ligand Substances 0.000 claims abstract description 33
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims abstract description 32
- -1 rare earth ion Chemical class 0.000 claims abstract description 24
- 229910052691 Erbium Inorganic materials 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 229910052692 Dysprosium Inorganic materials 0.000 claims abstract description 5
- 229910052693 Europium Inorganic materials 0.000 claims abstract description 5
- 229910052688 Gadolinium Inorganic materials 0.000 claims abstract description 5
- 229910052689 Holmium Inorganic materials 0.000 claims abstract description 5
- 229910052779 Neodymium Inorganic materials 0.000 claims abstract description 5
- 229910052777 Praseodymium Inorganic materials 0.000 claims abstract description 5
- 229910052772 Samarium Inorganic materials 0.000 claims abstract description 5
- 229910052771 Terbium Inorganic materials 0.000 claims abstract description 5
- 229910052775 Thulium Inorganic materials 0.000 claims abstract description 5
- 229910052769 Ytterbium Inorganic materials 0.000 claims abstract description 5
- DSJXIQQMORJERS-AGGZHOMASA-M bacteriochlorophyll a Chemical class C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC([C@H](CC)[C@H]3C)=[N+]4C3=CC3=C(C(C)=O)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 DSJXIQQMORJERS-AGGZHOMASA-M 0.000 claims abstract description 3
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 claims abstract description 3
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- 229920001223 polyethylene glycol Polymers 0.000 claims description 51
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 41
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 36
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 27
- 239000003960 organic solvent Substances 0.000 claims description 27
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- 210000004027 cell Anatomy 0.000 claims description 26
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 24
- 108091003079 Bovine Serum Albumin Proteins 0.000 claims description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 17
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- 238000000108 ultra-filtration Methods 0.000 claims description 16
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 claims description 14
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- 238000003756 stirring Methods 0.000 claims description 10
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 8
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- RELMFMZEBKVZJC-UHFFFAOYSA-N 1,2,3-trichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1Cl RELMFMZEBKVZJC-UHFFFAOYSA-N 0.000 claims description 5
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- 239000008363 phosphate buffer Substances 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims description 4
- 229910052805 deuterium Inorganic materials 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
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- 238000010438 heat treatment Methods 0.000 claims description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
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- 125000000217 alkyl group Chemical group 0.000 claims description 3
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N dihydromaleimide Natural products O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 150000004032 porphyrins Chemical class 0.000 claims description 2
- 229960002317 succinimide Drugs 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 239000011780 sodium chloride Substances 0.000 claims 1
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- 241000699666 Mus <mouse, genus> Species 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
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- BLSAPDZWVFWUTL-UHFFFAOYSA-N 2,5-dioxopyrrolidine-3-sulfonic acid Chemical compound OS(=O)(=O)C1CC(=O)NC1=O BLSAPDZWVFWUTL-UHFFFAOYSA-N 0.000 description 2
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic System
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0036—Porphyrins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0056—Peptides, proteins, polyamino acids
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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- C09B47/00—Porphines; Azaporphines
- C09B47/04—Phthalocyanines abbreviation: Pc
- C09B47/08—Preparation from other phthalocyanine compounds, e.g. cobaltphthalocyanineamine complex
- C09B47/12—Obtaining compounds having alkyl radicals, or alkyl radicals substituted by hetero atoms, bound to the phthalocyanine skeleton
- C09B47/14—Obtaining compounds having alkyl radicals, or alkyl radicals substituted by hetero atoms, bound to the phthalocyanine skeleton having alkyl radicals substituted by halogen atoms
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- C09B47/00—Porphines; Azaporphines
- C09B47/04—Phthalocyanines abbreviation: Pc
- C09B47/08—Preparation from other phthalocyanine compounds, e.g. cobaltphthalocyanineamine complex
- C09B47/18—Obtaining compounds having oxygen atoms directly bound to the phthalocyanine skeleton
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- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
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- Animal Behavior & Ethology (AREA)
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Abstract
The invention discloses a near-infrared second window emission rare earth complex fluorescent dye and a preparation method and application thereof. The rare earth complex consists of a pyrrole macrocyclic ligand A, a rare earth ion Ln and a deuterated or halogenated tripod ligand L; a is a bacteriochlorophyll derivative, phthalocyanine or pyrrole, Ln is selected from Ce, Pm, Eu, Gd, Tb, Pr, Nd, Sm, Dy, Ho, Er, Tm and Yb, and L is a deuterated or halogenated Kl ӓ ui tripod ligand and/or a deuterated or halogenated Tp tripod ligand. The rare earth complex has near-infrared absorption larger than 700nm and near-infrared second window emission larger than 1500nm, large molar extinction coefficient, narrow spectrum peak and adjustable range, Stokes displacement larger than 700nm, good solubility and high quantum efficiency in various solvents, and has application prospect in the fields of biological imaging, optical fiber communication, near-infrared organic light-emitting diodes and the like.
Description
Technical Field
The invention belongs to the technical field of biological materials, and particularly relates to a rare earth complex fluorescent dye emitted by a near-infrared second window, a preparation method thereof, and application of the fluorescent dye in preparation of a contrast agent for lymph imaging and multiple detection.
Background
The fluorescent multiple coding technology can report the activities of different biomarkers in real time and is an important tool in life activities and medical health research. Compared with the wave band (400nm-900nm) used by the traditional fluorescence imaging, in the near-infrared second window (1000-1700nm), especially the b region (1500nm-1700nm) of the near-infrared second window, the autofluorescence of the biological tissue and the scattering of light are reduced to the minimum, the imaging quality is obviously improved, and the fluorescence imaging is improved in the aspects of detection depth and resolution. Therefore, fluorescence multiple encoding is carried out in the near-infrared second window, and in-situ imaging and detection with higher resolution and signal-to-noise ratio in a living body are expected to be realized. Currently, the commonly used near-infrared second window contrast agents include some organic small molecules and quantum dots. Their stokes shift is small and the overlap of fluorescence spectra is severe, greatly limiting the number of near-infrared second window fluorescence codes. Therefore, the designed light stability is good, the absorption emission half-peak width is narrow, the Stokes displacement is large, and the emission wavelength is long and is the focus of the current near-infrared second window multiple coding fluorophore.
Disclosure of Invention
The invention aims to provide a molecular fluorescent dye emitted in a near-infrared second window b region, which has the advantages of good biocompatibility, high light stability, large Stokes shift, narrow absorption and emission half-peak width and excellent fluorescence performance, and a preparation method and application thereof.
The molecular fluorescent dye emitted by a near-infrared second window b area provided by the invention is a rare earth complex fluorescent dye, consists of a pyrrole macrocyclic ligand (marked as A), rare earth ions (marked as Ln) and a deuterated or halogenated tripod ligand (marked as L), and has a structural general formula shown as the following formula:
wherein, the pyrrole macrocyclic ligand A is bacteriochlorophyll derivative, phthalocyanine or pyrrole, the rare earth ion Ln is selected from one or more of Ce, Pm, Eu, Gd, Tb, Pr, Nd, Sm, Dy, Ho, Er, Tm and Yb, and the deuterated or halogenated tripod ligand L is deuterated or halogenated
A tripod ligand and/or a deuterated or halogenated Tp tripod ligand.
The rare earth complex has near-infrared absorption larger than 700nm and near-infrared second window emission larger than 1500nm, large molar extinction coefficient, narrow spectrum peak (half peak width about 20nm) and adjustable range, Stokes displacement larger than 700nm, good solubility and higher quantum efficiency in various solvents, is not easy to be quenched by the influence of protonic solvent environment, and has huge application prospect in the fields of biological imaging, optical fiber communication, near-infrared organic light-emitting diodes and the like.
In the present invention, the pyrrole macrocyclic ligand a is preferably a porphyrin having the following general formula I, II, III, IV:
wherein R is1、R2、R3、R4Is an aromatic ring, G1、G2、G3、G4、G5、G6、G7、G8Is one of hydrogen, alkyl, alkoxy or hydroxyl, X1、X2、X3、X4Is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, carboxylic ester, benzene ring and alkylOne of (1) and (b).
In the present invention, R1、R2、R3、R4The aromatic ring is preferably any of the following structures:
in the present invention, G1、G2、G3、G4、G5、G6、G7、G8Preferably H, CH3、CH2CH3、OH、OCH3Or OCH2CH3One kind of (1).
In the present invention, X1、X2、X3、X4Preferably H, D, F, Cl, Br, I, CH3、CH2CH3、COOCH2CH3、C6H6One kind of (1).
In the present invention, the pyrrole macrocyclic ligand a is more preferably selected from any one of the following:
in the present invention, the deuterated or halogenated tripod ligand L is preferably represented by one of the following structural formulas:
in the present invention, the structure of the organic complex is selected from any one or more of the following structures:
the preparation method of the rare earth complex fluorescent dye provided by the invention comprises the following specific steps:
(1) under the condition of non-oxidizing inert atmosphere, enabling a pyrrole macrocyclic ligand A and rare earth salt to react in a first organic solvent at the temperature of 60-300 ℃ to obtain an intermediate product;
(2) reacting the intermediate product with a deuterated or halogenated tripod ligand L in a second organic solvent to obtain a rare earth complex intermediate product;
(3) and reducing the intermediate product in a third organic solvent at-78-0 ℃ to obtain the rare earth complex.
Wherein the structural general formula of the rare earth salt is LnB3Wherein, the rare earth ion Ln is any one of Ce, Pm, Eu, Gd, Tb, Pr, Nd, Sm, Dy, Ho, Er, Tm and Yb, and the anion B is Cl-、NO3 -、CH3COO-、CF3COO-、CF3SO3 -、
Any one of them.
The first organic solvent is selected from any one or more of trichlorobenzene, decahydronaphthalene, dimethyl sulfoxide, o-dichlorobenzene, diethylene glycol dimethyl ether, tetrahydrofuran, n-hexanol and toluene, preferably from any one or more of trichlorobenzene, diethylene glycol dimethyl ether, tetrahydrofuran, decahydronaphthalene, dimethyl sulfoxide and toluene;
the non-oxidizing inert atmosphere is nitrogen, argon, helium, hydrogen or a nitrogen-hydrogen mixed gas, preferably nitrogen and argon;
the second organic solvent is selected from any one or more of chloroform, acetone, dimethyl sulfoxide, tetrahydrofuran, o-dichlorobenzene, methanol and toluene, preferably from any one or more of chloroform, acetone, tetrahydrofuran and dimethyl sulfoxide;
the third organic solvent is selected from any one or more of chloroform, acetone, dimethyl sulfoxide, tetrahydrofuran, methanol and toluene, preferably from any one or more of chloroform, acetone, tetrahydrofuran and dimethyl sulfoxide.
Typically, the rare earth complex fluorescent dye has a structural general formula (1) and a structural general formula (2); wherein:
the chemical synthesis route of the rare earth complex fluorescent dye general structural formula (1) is as follows:
the method comprises the following specific steps:
(1) synthesis of intermediate 1
Anhydrous and anaerobic operation, dissolving a pyrrole macrocyclic ligand (compound 1) and a rare earth salt (compound 2) in a first organic solvent, and carrying out reflux reaction at the temperature of 60-300 ℃ for 12-24 hours; centrifuging for 1000-5000 rpm twice after cooling; filtering to remove solid insoluble substances, concentrating the organic phase, and separating by column chromatography under reduced pressure to obtain intermediate 1; wherein the feeding molar ratio of the compound 1, the compound 2 and the first organic solvent is 1 (3-10) to (10-15); the first organic solvent is preferably trichlorobenzene, diethylene glycol dimethyl ether, tetrahydrofuran, decahydronaphthalene, dimethyl sulfoxide and toluene.
(2) Synthesis of rare earth complexes
Dissolving the intermediate 1 and the tripod ligand L (compound 3) in a second organic solvent, and reacting for 4-12 hours at 25-80 ℃; cooling to room temperature, filtering, concentrating the organic phase, and separating by column chromatography to obtain the rare earth complex (general formula I); wherein the feeding molar ratio of the intermediate 1, the compound 3 and the second organic solvent is 1 (1-5) to 10-15; the second organic solvent is preferably chloroform, acetone, tetrahydrofuran, dimethyl sulfoxide.
The chemical synthesis route of the rare earth complex fluorescent dye general structural formula (2) is as follows:
the method comprises the following specific steps:
(1) synthesis of intermediate 1
Anhydrous and anaerobic operation, dissolving a pyrrole macrocyclic ligand (compound 1) and a rare earth salt (compound 2) in a first organic solvent, and carrying out reflux reaction at the temperature of 60-300 ℃ for 12-24 hours; centrifuging for 1000-5000 rpm twice after cooling; filtering to remove solid insoluble substances, concentrating the organic phase, and separating by column chromatography under reduced pressure to obtain intermediate 1; wherein the feeding molar ratio of the compound 1, the compound 2 and the first organic solvent is 1 (3-10) to (10-15); the first organic solvent is preferably trichlorobenzene, diethylene glycol dimethyl ether, tetrahydrofuran, decahydronaphthalene, dimethyl sulfoxide and toluene.
(2) Synthesis of intermediate 2
Dissolving the intermediate 1 and the tripod ligand L (compound 3) in a second organic solvent, and reacting for 4-12 hours at 25-80 ℃; cooling to room temperature, filtering, concentrating the organic phase, and separating by column chromatography to obtain intermediate 2; wherein the feeding molar ratio of the intermediate 1, the compound 3 and the second organic solvent is 1 (3-10) to 10-15; the second organic solvent is preferably chloroform, acetone, tetrahydrofuran, dimethyl sulfoxide.
(3) Synthesis of rare earth complexes
Dissolving the intermediate 2 and a reducing agent (compound 4) in a third organic solvent, and reacting at-78-0 ℃ for 0.5-4 hours; cooling to room temperature, filtering, concentrating the organic phase, and separating by column chromatography to obtain the rare earth complex (general formula II); wherein the feeding molar ratio of the intermediate 1, the compound 4 and the third organic solvent is 1 (1-4) to 10-15; the third organic solvent is preferably chloroform, acetone, tetrahydrofuran, or dimethyl sulfoxide.
The invention also provides the application of the near-infrared second window emission rare earth complex, including the application in preparing a contrast agent for lymph imaging/blood vessel imaging and multiple detection, and the application in preparing a cell-labeled contrast agent.
The application of the rare earth complex emitted by the near-infrared second window in preparing a lymph imaging/blood vessel imaging and multiple detection contrast agent comprises the following specific steps:
dissolving a rare earth complex fluorescent dye (for example, 1a, prepared in example 1) and phospholipid polyethylene glycol (2000) in chloroform, stirring for 0.5-1 hour, performing rotary evaporation to remove a solvent, performing vacuum drying, heating to 40-80 ℃, adding into Phosphate Buffered Saline (PBS) at 40-80 ℃ for dissolution, performing ultrasonic treatment, cooling to room temperature, and performing ultrafiltration concentration through an ultrafiltration tube of 30KD to obtain a final contrast agent; wherein the mass percentage of the rare earth complex fluorescent dye and the phospholipid polyethylene glycol (2000) is (1 (500-50)), and the final concentration of the contrast agent is 0.01-1 mM.
The micelle can be used as a contrast agent for imaging blood vessels of the whole body of a mouse, imaging lymphatic drainage of legs, multiple markers of blood circulation and lymphatic system of the mouse, and multiple marker detection imaging of digestive system, blood circulation system and the like.
The application of the rare earth complex emitted by the near-infrared second window in the preparation of the cell-labeled contrast agent comprises the following specific steps:
adding 4- (N-maleimide methyl) cyclohexane-1-carboxylic acid sulfonic group succinimide ester sodium salt into a dimethyl sulfoxide solution of cell penetrating peptide (RKKRRQRRRC), and stirring at room temperature for 0.5-4 hours; then adding the mixture into Phosphate Buffered Saline (PBS) of Bovine Serum Albumin (BSA), and stirring the mixture for 1 to 8 hours at room temperature; then adding rare earth complex fluorescent dye (such as 1a, prepared in example 1), performing ultrasonic treatment, and performing ultrafiltration concentration by a 30KD ultrafiltration tube to obtain the final contrast agent. Wherein the molar ratio of the rare earth complex fluorescent dye to Bovine Serum Albumin (BSA) is (1-5)), and the final concentration of the contrast agent is 10-25 μ M.
The complex can mark and light the cell, and the cell can be tracked. The metastatic pathway of cancer cells in mice was observed.
The rare earth complex fluorescent dye provided by the invention has the advantages of large molar extinction coefficient, long absorption and emission wavelength, narrow half-peak width and adjustable wavelength. The fluorescent dye is not easy to cause color change due to solvation in a polar solvent, and has more excellent light stability and brighter fluorescence intensity in water compared with the existing common near-infrared fluorescent dye in the second window b area, so that high-resolution imaging of lymphatic vessels and blood vessels of a mouse, multiple labeling of blood circulation and lymphatic system of the mouse, multiple labeling detection imaging of digestive system and blood circulation system and the like can be realized. The rare earth complex fluorescent dye is emitted in a near infrared second window b area, so that in-vivo cell tracking microscopic imaging with high resolution and high signal-to-noise ratio and deeper tissue penetration depth can be realized.
The rare earth complex fluorescent dye (1a, shown below) has a maximum absorption peak at 766nm and a maximum emission peak at 1532nm in a dichloromethane solution.
The rare earth complex fluorescent dye (1a, shown below) of the present invention has a molar extinction coefficient of 113000M in a dichloromethane solution-1cm-1。
The rare earth complex fluorescent dye (1a, as shown below) of the present invention has an absolute fluorescence quantum yield of 0.0138% in a dichloromethane solution.
The micelle formed by the rare earth complex fluorescent dye (1a, shown as the following) and phospholipid polyethylene glycol 2000 has the maximum absorption peak at 768nm and the maximum emission peak at 1532nm in a phosphate buffer solution.
The micelle formed by the rare earth complex fluorescent dye (1a, shown as the following) and phospholipid polyethylene glycol 2000 has a molar extinction coefficient of 108000M in phosphate buffer solution-1cm-1。
The absolute fluorescence quantum yield of the micelle formed by the rare earth complex fluorescent dye (1a, shown as the following) and the phospholipid polyethylene glycol 2000 in the phosphate buffer solution is 0.0104%.
The micelle formed by the rare earth complex fluorescent dye (1a, shown as the following) and phospholipid polyethylene glycol 2000 and the rare earth nano-particles doped with erbium ions respectively emit 1450-1650nm fluorescence under the excitation of 760nm and 980nm in aqueous solution.
The micelle formed by the rare earth complex fluorescent dye (1a, shown as the following) and phospholipid polyethylene glycol 2000 and the micelle formed by the Cy7.5 dye and the phospholipid polyethylene glycol 2000 emit fluorescence in the range of 1450-1650nm and 1000-1400nm under the excitation of 760nm in aqueous solution.
The rare earth complex fluorescent dye (1a, shown below) and a cell penetrating peptide-bovine serum albumin complex emit fluorescence in the 1450-1650nm range under the excitation of 760nm in an aqueous solution.
The rare earth complex fluorescent dye (2a, shown below) of the invention has a maximum absorption peak at 742nm and a maximum emission peak at 1532nm in a dichloromethane solution.
The rare earth complex fluorescent dye (2a, shown below) of the present invention has a molar extinction coefficient of 69000M in a dichloromethane solution-1cm-1。
The rare earth complex fluorescent dye (2a, as shown below) of the present invention has an absolute fluorescence quantum yield of 0.0112% in a dichloromethane solution.
The micelle formed by the rare earth complex fluorescent dye (2a, shown as the following) and phospholipid polyethylene glycol 2000 has a maximum absorption peak at 750nm and a maximum emission peak at 1532nm in a phosphate buffer solution.
The micelle formed by the rare earth complex fluorescent dye (2a, shown as the following) and phospholipid polyethylene glycol 2000 has a molar extinction coefficient of 36000M in a phosphate buffer solution-1cm-1。
The absolute fluorescence quantum yield of the micelle formed by the rare earth complex fluorescent dye (2a, shown as the following) and the phospholipid polyethylene glycol 2000 in the phosphate buffer solution is 0.0082%.
The micelle formed by the rare earth complex fluorescent dye (2a, shown below) and phospholipid polyethylene glycol 2000 and the rare earth nanoparticles doped with erbium ions respectively emit 1450-1650nm fluorescence under the excitation of 730nm and 980nm in aqueous solution.
The micelle formed by the rare earth complex fluorescent dye (2a, shown below) and phospholipid polyethylene glycol 2000 and the micelle formed by the Cy7.5 dye and the phospholipid polyethylene glycol 2000 emit fluorescence in the range of 1450-1650nm and 1000-1400nm under the excitation of 730nm in aqueous solution.
The rare earth complex fluorescent dye (2a, shown below) and the cell penetrating peptide-bovine serum albumin complex emit fluorescence in the 1450-1650nm range under the excitation of 730nm in aqueous solution. .
Drawings
Fig. 1 is an absorption spectrum of a rare earth complex type fluorescent dye (1a, shown below) in dichloromethane.
FIG. 2 shows fluorescence emission spectra of rare earth complex fluorescent dye (1a, shown below) in dichloromethane and phosphate buffered saline solution.
FIG. 3 is an image of mouse leg lymphatic drainage by micelles formed by a rare earth complex fluorescent dye (1a, as shown below) and phospholipid polyethylene glycol 2000.
FIG. 4 shows the imaging of the micelles formed by the rare earth complex fluorescent dye (1a, as shown below) and phospholipid polyethylene glycol 2000 on the brain and leg vessels of mice.
Fig. 5 is an image of a micelle formed by the rare earth complex fluorescent dye (1a, shown below) and the phospholipid polyethylene glycol 2000 and a micelle formed by the rare earth nanoparticle doped with erbium ions and the phospholipid polyethylene glycol 2000, which respectively emit fluorescence spectra of 1450-1650nm under the excitation of 760nm and 980nm in an aqueous solution, and an image of a micelle formed by the rare earth complex fluorescent dye (1a, shown below) and the phospholipid polyethylene glycol 2000 and a micelle formed by the rare earth nanoparticle doped with erbium ions and the phospholipid polyethylene glycol 2000, which respectively illuminate lymphatic vessels and blood vessels of a mouse under the excitation light sources.
FIG. 6 is an image of the micelle of rare earth complex fluorescent dye (1a, shown below) and phospholipid polyethylene glycol 2000 and the micelle of Cy7.5 dye and phospholipid polyethylene glycol 2000 emitting fluorescence in the range of 1450-1650nm and 1000-1400nm under 760nm excitation in aqueous solution, and the image of the micelle of rare earth complex fluorescent dye (1a, shown below) and phospholipid polyethylene glycol 2000 and the micelle of Cy7.5 dye and phospholipid polyethylene glycol 2000 respectively illuminating the liver and the intestinal tract under 760nm excitation.
FIG. 7 is an image of the complex of the rare earth complex fluorescent dye (1a, as shown below) and bovine serum albumin and the micelle of Cy7.5 dye and phospholipid polyethylene glycol 2000, which respectively illuminate cells and cerebral vessels under 760nm excitation.
Fig. 8 is a graph showing absorption and emission spectra of the rare earth complex-based fluorescent dye (2a, shown below) in dichloromethane.
Fig. 9 is an image of mouse leg lymphatic drainage by micelles formed by rare earth complex fluorescent dye (2a, as shown below) and phospholipid polyethylene glycol 2000.
Fig. 10 shows the imaging of mouse leg and brain blood vessels by micelles formed by the rare earth complex fluorescent dye (2a, as shown below) and phospholipid polyethylene glycol 2000.
Fig. 11 is an image of a micelle formed by the rare earth complex fluorescent dye (2a, shown below) and the phospholipid polyethylene glycol 2000 and a micelle formed by the erbium ion-doped rare earth nanoparticle and the phospholipid polyethylene glycol 2000, which respectively emit fluorescence spectra of 1450 nm and 1650nm under the excitation of 730nm and 980nm in an aqueous solution, and an image of a micelle formed by the rare earth complex fluorescent dye (2a, shown below) and the phospholipid polyethylene glycol 2000 and a micelle formed by the erbium ion-doped rare earth nanoparticle and the phospholipid polyethylene glycol 2000, which respectively illuminate lymphatic vessels and blood vessels of a mouse under the excitation of the respective excitation light sources.
FIG. 12 is an image of the micelles formed by the rare earth complex fluorescent dye (2a, shown below) and phospholipid polyethylene glycol 2000 and micelles formed by the Cy7.5 dye and phospholipid polyethylene glycol 2000, which emit fluorescence in the 1450-1650nm range and fluorescence in the 1000-1400nm range under the excitation of 730nm in aqueous solution, and the micelles formed by the rare earth complex fluorescent dye (2a, shown below) and phospholipid polyethylene glycol 2000 and micelles formed by the Cy7.5 dye and phospholipid polyethylene glycol 2000 respectively illuminate the liver and the intestinal tract under the excitation of 730 nm.
FIG. 13 is an image of the complex of a rare earth complex fluorescent dye (2a, as shown below) and bovine serum albumin and the micelle of Cy7.5 dye and phospholipid polyethylene glycol 2000, which respectively illuminate cells and cerebral vessels under 730nm excitation.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described with the following embodiments, but the present invention is by no means limited to these examples. The following description is only a preferred embodiment of the present invention, and is only for the purpose of explaining the present invention, and should not be construed as limiting the scope of the present invention. It should be understood that any modification, substitution or improvement made within the spirit and principle of the present invention shall fall within the protection scope of the present invention.
Example 1:
the preparation of the rare earth complex fluorescent dye 1a has the following structural formula:
the specific synthetic route is as follows:
the method comprises the following specific steps:
(1) synthesis of intermediate 1
Dissolving bis-reduced pentafluotetraphenylporphyrin (compound 1) and tris [ N, N-bis (trimethylsilane) amine ] erbium (III) (compound 2) in toluene, and carrying out reflux reaction at 110 ℃ for 24 hours; centrifuging for 5000 r/min twice after cooling; filtering to remove solid insoluble substances, concentrating the organic phase, and separating by column chromatography under reduced pressure to obtain intermediate 1; wherein the feeding molar ratio of the compound 1 to the compound 2 to the toluene is 1:5: 15;
(2) synthesis of rare earth complexes
The intermediate 1,
Dissolving tripod ligand sodium salt (compound 3) in tetrahydrofuran solvent, and reacting at 80 ℃ for 8 hours; cooling to room temperature, filtering, concentrating the organic phase, and separating by column chromatography to obtain the rare earth complex 1 a; wherein the feeding molar ratio of the intermediate 1, the compound 3 and the tetrahydrofuran is 1:3: 15.
Example 2:
the preparation of the rare earth complex fluorescent dye 2a has the following structural formula:
the specific synthetic route is as follows:
the method comprises the following specific steps:
(1) synthesis of intermediate 1
Dissolving dilactone pentafluotetraphenylporphyrin (compound 1) and tris [ N, N-bis (trimethylsilane) amine ] erbium (III) (compound 2) in toluene, and carrying out reflux reaction at 110 ℃ for 24 hours; centrifuging for 5000 r/min twice after cooling; filtering to remove solid insoluble substances, concentrating the organic phase, and separating by column chromatography under reduced pressure to obtain intermediate 1; wherein the feeding molar ratio of the compound 1 to the compound 2 to the toluene is 1:5: 15;
(2) synthesis of intermediate 2
The intermediate 1,
Dissolving tripod ligand sodium salt (compound 3) in tetrahydrofuran solvent, and reacting at 80 ℃ for 8 hours; cooling to room temperature, filtering, concentrating the organic phase and separating by column chromatographyFinally obtaining an intermediate 2; wherein the feeding molar ratio of the intermediate 1, the compound 3 and the tetrahydrofuran is 1:3: 15.
(3) Synthesis of rare earth complexes
Dissolving the intermediate 2 and DIBAL-H (compound 4) in tetrahydrofuran solution, and reacting at-78 ℃ for 1 hour; cooling to room temperature, filtering, concentrating the organic phase, and separating by column chromatography to obtain the rare earth complex (2 a); wherein the feeding molar ratio of the intermediate 1, the compound 4 and the tetrahydrofuran is 1:2: 15.
Example 3:
the preparation of the rare earth complex fluorescent dye 3a has the following structural formula:
the specific synthetic route is as follows:
the method comprises the following specific steps:
(1) synthesis of intermediate 1
Dissolving bis-reduced pentafluotetraphenylporphyrin (compound 1) and tris [ N, N-bis (trimethylsilane) amine ] erbium (III) (compound 2) in toluene, and carrying out reflux reaction at 110 ℃ for 24 hours; centrifuging for 5000 r/min twice after cooling; filtering to remove solid insoluble substances, concentrating the organic phase, and separating by column chromatography under reduced pressure to obtain intermediate 1; wherein the feeding molar ratio of the compound 1 to the compound 2 to the toluene is 1:5: 15;
(2) synthesis of rare earth complexes
Dissolving the intermediate 1 and Tp tripod ligand sodium salt (compound 3) in a tetrahydrofuran solvent, and reacting for 8 hours at 80 ℃; cooling to room temperature, filtering, concentrating the organic phase, and separating by column chromatography to obtain the rare earth complex (3 a); wherein the feeding molar ratio of the intermediate 1, the compound 3 and the tetrahydrofuran is 1:3: 15.
Example 4:
the preparation method of the micelle formed by the rare earth complex fluorescent dye and phospholipid polyethylene glycol takes the rare earth complex fluorescent dye 1a and DOPE-PEG2000 as examples. The method comprises the following specific steps:
dissolving 1.6mg of rare earth complex fluorescent dye 1a and 160mg of DOPE-PEG2000 in 20mL of trichloromethane, stirring for 1 hour, performing rotary evaporation to remove the solvent, performing vacuum drying, heating to 80 ℃, adding 20mL of Phosphate Buffered Saline (PBS) at 80 ℃ for dissolution, performing ultrasonic treatment, cooling to room temperature, and performing ultrafiltration concentration through an ultrafiltration tube with 30KD to obtain the final contrast agent; wherein, the mass percentage of the rare earth complex fluorescent dye and the DOPE-PEG2000 is (1:100), and the concentration of the final contrast agent is 1 mM.
Application example:
the rare earth complex fluorescent dye 1a and phospholipid polyethylene glycol form micelles to image the leg lymph of the mouse. The method comprises the following specific steps:
injecting 25 μ L of micelle solution with dye concentration of 1mM into anesthetized web of mouse, and irradiating right leg of mouse with 760nm external laser with power density of 55mW/cm2(see FIG. 3).
The micelle formed by the rare earth complex fluorescent dye 1a and phospholipid polyethylene glycol images the brain and leg blood vessels of the mouse. The method comprises the following specific steps:
anesthetized mice were injected via the tail vein with 200. mu.L of a 1mM dye micelle solution, and the mice were irradiated at their brains and legs with an external 760nm laser at a power density of 55mW/cm2(see fig. 4).
The micelle formed by the rare earth complex fluorescent dye 1a and phospholipid polyethylene glycol, the micelle formed by the phospholipid polyethylene glycol 2000 and the rare earth nano-particles doped with erbium ions mark the blood and lymphatic system of a mouse respectively. The method comprises the following specific steps:
injecting 25 mul of micellar solution with the dye concentration of the rare earth complex being 1mM at the fin of an anesthetized mouse, then injecting 200 mul of micellar solution with the concentration of rare earth nano particles being 20mg/mL into the anesthetized mouse through the tail vein, and then respectively irradiating the leg of the mouse by 760nm laser and 980nm laser with the power of 55mW/cm respectively2And 100mW/cm2(see FIG. 5).
Micelles formed by the rare earth complex fluorescent dye 1a and phospholipid polyethylene glycol 2000 and micelles formed by the Cy7.5 dye and the phospholipid polyethylene glycol 2000 respectively mark the blood circulation and digestive system of a mouse. The method comprises the following specific steps:
anesthetized mice were injected via tail vein with 200 μ lcy7.5 dye concentration of 125 μ M in micellar solution; one hour later, the anesthetized mice were orally perfused with 100. mu.L of a micellar solution of a rare earth complex dye concentration of 1mM, and the abdomen of the mice was irradiated with a 760nm external laser having a power density of 55mW/cm2The fluorescence of 1000-1400nm and 1400-1700nm was collected by using combinations of 850nm long pass, 1000nm long pass, 1400nm short pass, 850nm long pass, 1000nm long pass, and 1400nm long pass filters (see FIG. 6).
Example 5:
a preparation method of a compound formed by rare earth complex fluorescent dye and cell penetrating peptide-bovine serum albumin takes rare earth complex fluorescent dye 1a and cell penetrating peptide (RKKRRQRRRC) -bovine serum albumin as an example, and comprises the following specific steps:
the sodium salt of sulfosuccinimide 4- (N-maleimidomethyl) cyclohexane-1-carboxylate was added to a solution of cell-penetrating peptide (RKKRRQRRRC) in dimethyl sulfoxide, and the mixture was stirred at room temperature for 1 hour. Then adding Phosphate Buffered Saline (PBS) of Bovine Serum Albumin (BSA), stirring for 4 hours at room temperature, then adding the rare earth complex fluorescent dye 1a, performing ultrasonic treatment, and then performing ultrafiltration concentration through an ultrafiltration tube with the voltage of 30KD to obtain the final contrast agent. Wherein, the molar ratio of the rare earth complex fluorescent dye to Bovine Serum Albumin (BSA) is (1:1), and the final concentration of the contrast agent is 25 μ M.
Application example:
the movement of the osteosarcoma cells (143b cells) marked by the complex formed by the rare earth complex fluorescent dye and the cell penetrating peptide-bovine serum albumin in the cerebral vessels of the mice is tracked.
The method comprises the following specific steps:
incubating the complex formed by the rare earth complex fluorescent dye 1a and bovine serum albumin with 143b cells for 12 hours, discarding the culture medium, washing the culture dish twice by using phosphate buffer solution, and removing the rare earth complex fluorescent dye 1a without marked cells. The cells were then re-digested and finally dispersed in a phosphate buffer (100. mu.L approximately containing 1X 1)06143b cells). The left ventricle of the anesthetized mice was injected with 100. mu.L of the above solution, while the vessels were illuminated by tail vein injection of 200. mu.L of Cy7.5 dye in 125. mu.M micellar solution. Irradiating mouse brain with 760nm external laser with power density of 55mW/cm2The fluorescence of 1000-1400nm and 1400-1700nm was collected by using combinations of 850nm long pass, 1000nm long pass, 1400nm short pass, 850nm long pass, 1000nm long pass, and 1400nm long pass filters (see FIG. 7).
Example 6:
dissolving 1.6mg of rare earth complex fluorescent dye 2a and 160mg of DOPE-PEG2000 in 20mL of trichloromethane, stirring for 1 hour, performing rotary evaporation to remove the solvent, performing vacuum drying, heating to 80 ℃, adding 20mL of Phosphate Buffered Saline (PBS) at 80 ℃ for dissolution, performing ultrasonic treatment, cooling to room temperature, and performing ultrafiltration concentration through an ultrafiltration tube with 30KD to obtain the final contrast agent; wherein, the mass percentage of the rare earth complex fluorescent dye and the DOPE-PEG2000 is (1:100), and the concentration of the final contrast agent is 1 mM.
Application example:
the rare earth complex fluorescent dye 2a and phospholipid polyethylene glycol form micelles to image the leg lymph of the mouse. The method comprises the following specific steps:
injecting 25 μ L of micelle solution with dye concentration of 1mM into anesthetized web of mouse, irradiating right leg of mouse with 730nm external laser with power density of 80mW/cm2(see fig. 9).
The micelle formed by the rare earth complex fluorescent dye 2a and phospholipid polyethylene glycol images the blood vessels of the legs and the brains of the mice. The method comprises the following specific steps:
anesthetized mice were injected via the tail vein with 200. mu.L of a 1mM dye micelle solution, and the brain and legs of the mice were irradiated with a 730nm external laser at a laser power density of 80mW/cm2(see FIG. 10).
The micelle formed by the rare earth complex fluorescent dye 2a and phospholipid polyethylene glycol, the micelle formed by the phospholipid polyethylene glycol 2000 and the rare earth nano-particles doped with erbium ions mark the blood and lymphatic system of a mouse respectively. The method comprises the following specific steps:
mouse flipper under anesthesiaInjecting 25 mul of micellar solution with the dye concentration of the rare earth complex being 1mM, then injecting 200 mul of micellar solution with the concentration of rare earth nano particles doped with erbium ions being 20mg/mL into the anesthetized mouse through the tail vein, and then respectively irradiating the leg of the mouse with 730nm laser and 980nm laser with the power of 80mW/cm respectively2And 100mW/cm2(see FIG. 11).
Micelles formed by the rare earth complex fluorescent dye 2a and the phospholipid polyethylene glycol 2000 and micelles formed by the Cy7.5 dye and the phospholipid polyethylene glycol 2000 respectively mark the blood circulation and the digestive system of a mouse. The method comprises the following specific steps:
anesthetized mice were injected via tail vein with 200 μ lcy7.5 dye concentration of 125 μ M in micellar solution; one hour later, the anesthetized mice were orally perfused with 100. mu.L of a micellar solution of a rare earth complex dye concentration of 1mM, and the abdomen of the mice was irradiated with a 730nm external laser having a power density of 80mW/cm2The fluorescence of 1000-1400nm and 1400-1700nm was collected respectively using 850nm long pass, 1000nm long pass, 1400nm short pass and 850nm long pass, 1000nm long pass, 1400nm long pass filter combinations (see FIG. 12).
Example 7:
the sodium salt of sulfosuccinimide 4- (N-maleimidomethyl) cyclohexane-1-carboxylate was added to a solution of cell-penetrating peptide (RKKRRQRRRC) in dimethyl sulfoxide, and the mixture was stirred at room temperature for 1 hour. Then adding Phosphate Buffered Saline (PBS) of Bovine Serum Albumin (BSA), stirring for 4 hours at room temperature, then adding rare earth complex fluorescent dye 2a, performing ultrasonic treatment, and then performing ultrafiltration concentration through an ultrafiltration tube with the voltage of 30KD to obtain the final contrast agent. Wherein, the molar ratio of the rare earth complex fluorescent dye to Bovine Serum Albumin (BSA) is (1:1), and the final concentration of the contrast agent is 25 μ M.
Application example:
the movement of the osteosarcoma cells (143b cells) marked by the complex formed by the rare earth complex fluorescent dye and the cell penetrating peptide-bovine serum albumin in the cerebral vessels of the mice is tracked.
The method comprises the following specific steps:
formed by rare earth complex fluorescent dye 2a and bovine serum albuminAfter the complex and 143b cells are incubated for 12 hours, the culture medium is discarded, and the culture dish is washed twice with phosphate buffer solution to remove the rare earth complex fluorescent dye 2a which is not marked with the cells. The cells were then re-digested and finally dispersed in a phosphate buffer (100. mu.L approximately containing 1X 106143b cells). The left ventricle of the anesthetized mice was injected with 100. mu.L of the above solution, while the vessels were illuminated by tail vein injection of 200. mu.L of Cy7.5 dye in 125. mu.M micellar solution. The mouse brain was irradiated with a 730nm external laser. The power density of the laser is 80mW/cm2The fluorescence of 1000-1400nm and 1400-1700nm was collected by using combinations of 850nm long pass, 1000nm long pass, 1400nm short pass, 850nm long pass, 1000nm long pass, and 1400nm long pass filters (see FIG. 13).
Claims (11)
1. The rare earth complex fluorescent dye emitting in a near infrared second window is characterized by consisting of pyrrole macrocyclic ligand (marked as A), rare earth ions (marked as Ln) and deuterated or halogenated tripod ligand (marked as L), and the structural general formula of the rare earth complex fluorescent dye is shown as the following formula:
wherein the pyrrole macrocyclic ligand A is bacteriochlorophyll derivative, phthalocyanine or pyrrole, the rare earth ion Ln is selected from one or more of Ce, Pm, Eu, Gd, Tb, Pr, Nd, Sm, Dy, Ho, Er, Tm and Yb, and the deuterated or halogenated tripod ligand L is deuterated or halogenated
A tripod ligand and/or a deuterated or halogenated Tp tripod ligand.
2. The rare earth complex fluorescent dye according to claim 1, wherein the pyrrole macrocyclic ligand a is a porphyrin represented by the following structural formula I, II, III or IV:
wherein R is1、R2、R3、R4Is an aromatic ring, G1、G2、G3、G4、G5、G6、G7、G8Is one of hydrogen, alkyl, alkoxy or hydroxyl, X1、X2、X3、X4Is one of hydrogen, deuterium, fluorine, chlorine, bromine, iodine, carboxylate, benzene ring and alkyl.
3. The rare earth complex fluorescent dye according to claim 2, wherein R is1、R2、R3、R4The structure of the aromatic ring is selected from any one of the following structures:
4. the rare earth complex fluorescent dye according to claim 3, wherein G is1、G2、G3、G4、G5、G6、G7、G8Is H, CH3、CH2CH3、OH、OCH3、OCH2CH3。
5. The rare earth complex fluorescent dye according to claim 3, wherein X is1、X2、X3、X4Is H, D, F, Cl, Br, I, CH3、CH2CH3、COOCH2CH3、C6H6One kind of (1).
6. The rare earth complex fluorescent dye according to claim 3, wherein the pyrrole macrocyclic ligand A is selected from any one of the following:
7. the rare earth complex fluorescent dye according to any of claims 1 to 6, wherein said deuterated or halogenated tripod ligand L is preferably of one of the following formulae:
8. the rare earth complex fluorescent dye according to claim 1, wherein the structure of the organic complex is selected from any one or more of the following structures:
9. a method for preparing the rare earth complex fluorescent dye according to any one of claims 1 to 8, which is characterized by comprising the following specific steps:
(1) under the condition of non-oxidizing inert atmosphere, reacting a pyrrole macrocyclic ligand A and rare earth salt in a first organic solvent at the temperature of 60-300 ℃ to obtain an intermediate product;
(2) reacting the intermediate product with a deuterated or halogenated tripod ligand L in a second organic solvent to obtain a rare earth complex intermediate product;
(3) reducing the intermediate product in a third organic solvent at-78-0 ℃ to obtain the rare earth complex;
the structural general formula of the rare earth salt is LnB3Wherein, the rare earth ion Ln is any one of Ce, Pm, Eu, Gd, Tb, Pr, Nd, Sm, Dy, Ho, Er, Tm and Yb, and the anion B is Cl-、NO3 -、CH3COO-、CF3COO-、CF3SO3 -、
Any one of the above;
the first organic solvent is selected from any one or more of trichlorobenzene, decahydronaphthalene, dimethyl sulfoxide, o-dichlorobenzene, diethylene glycol dimethyl ether, tetrahydrofuran, n-hexanol and toluene;
the non-oxidizing inert atmosphere is nitrogen, argon, helium, hydrogen or a nitrogen-hydrogen mixed gas;
the second organic solvent is selected from any one or more of chloroform, acetone, dimethyl sulfoxide, tetrahydrofuran, o-dichlorobenzene, methanol and toluene;
the third organic solvent is selected from any one or more of chloroform, acetone, dimethyl sulfoxide, tetrahydrofuran, methanol and toluene.
10. The application of the rare earth complex fluorescent dye in preparing a contrast agent for lymph imaging and multiple detection according to claim 1 comprises the following steps:
dissolving a rare earth complex fluorescent dye and phospholipid polyethylene glycol (2000) in chloroform, stirring for 0.5-1 hour, removing the solvent by rotary evaporation, drying in vacuum, heating to 40-80 ℃, adding Phosphate Buffer Saline (PBS) at 40-80 ℃ for dissolving, performing ultrasonic treatment, cooling to room temperature, and performing ultrafiltration concentration by using an ultrafiltration tube with the pressure of 30KD to obtain a final contrast agent; wherein the mass percentage of the rare earth complex fluorescent dye and the phospholipid polyethylene glycol (2000) is (1 (500-50)), and the final concentration of the contrast agent is 0.01-1 mM.
11. The application of the rare earth complex fluorescent dye in preparing a cell-labeled contrast agent according to claim 1 comprises the following specific steps:
adding 4- (N-maleimide methyl) cyclohexane-1-carboxylic acid sulfonic group succinimide ester sodium salt into a dimethyl sulfoxide solution of cell penetrating peptide (RKKRRQRRRC), and stirring at room temperature for 0.5-4 hours; then adding the mixture into Phosphate Buffered Saline (PBS) of Bovine Serum Albumin (BSA), and stirring the mixture for 1 to 8 hours at room temperature; then adding rare earth complex fluorescent dye, carrying out ultrasonic treatment, and then carrying out ultrafiltration concentration through an ultrafiltration tube with the voltage of 30KD to obtain the final contrast agent; wherein the molar ratio of the rare earth complex fluorescent dye to Bovine Serum Albumin (BSA) is (1-5)), and the final concentration of the contrast agent is 10-25 μ M.
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