CN106631997A - Amphipathic illuminant having aggregation-induced emission characteristic and application - Google Patents
Amphipathic illuminant having aggregation-induced emission characteristic and application Download PDFInfo
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- CN106631997A CN106631997A CN201610671437.7A CN201610671437A CN106631997A CN 106631997 A CN106631997 A CN 106631997A CN 201610671437 A CN201610671437 A CN 201610671437A CN 106631997 A CN106631997 A CN 106631997A
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- 229940073490 sodium glutamate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 description 1
- VSIVTUIKYVGDCX-UHFFFAOYSA-M sodium;4-[2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].COC1=CC([N+]([O-])=O)=CC=C1[N+]1=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=NN1C1=CC=C([N+]([O-])=O)C=C1 VSIVTUIKYVGDCX-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- RSPCKAHMRANGJZ-UHFFFAOYSA-N thiohydroxylamine Chemical compound SN RSPCKAHMRANGJZ-UHFFFAOYSA-N 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K49/00—Preparations for testing in vivo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
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- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
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Abstract
The invention relates to an amphipathic illuminant having an aggregation-induced emission characteristic and application. The illuminant is prepared by connection of a hydrophilic unit on a hydrophobic unit having a typical aggregation-induced emission (AIE) characteristic, the illuminant can be used for differential selection cytomembrane dyeing, used for preparing a differential selection cytomembrane colorant, used for preparing a probe for differential selection cytomembrane dyeing, and used for preparing a photosensitizer, and can be further used for preparing phototherapy drugs and used for preparing phototherapy drugs for treating cancer.
Description
Technical field
The present invention relates to fluorescent material technical field, and in particular to a kind of amphipathic with aggregation-induced emission characteristic
Shiner and its application.
Background technology
In recent years, it has been found that a series of helical moleculars do not light in the solution, but after polymerization is formed can be lured
Lead and send high light, the phenomenon of this aggregation-induced emission (aggregation-induced eimission, AIE) is glimmering with tradition
The aggregation fluorescent quenching effect that light element shows is antipodal.Using this new effect, AIE luminescent materials can be in many
High-tech area is applied, such as chemical sensor, bioprobe, immune labeled, IR material and soild state transmitter
[Chem.Commun.2001,18,1740；J.Mater.Chem.,2001,11,2974；Chem.Soc.Rev.,2011,40,
5361；Adv.Funct.Mater.,2012,22,771；Chem.Commun.,2011,47,7323；Adv.Healthcare
Mater.,2013,2,500；Acc.Chem.Res.,2013,46,2441；Chem.Commun.2013,49,11335；
Biomaterials 2008,29,1345；US 8,029,767；US 2013/0029325；CN103175768].Tetraphenyl ethylene
(tetraphenylethene, TPE) and hexaphenyl Silole (hexaphenylsiole, HPS) are prototypes AIE point
Son, its have be easily-synthesized, the advantage such as the high quantum production rate in the case of solid-state and high chemical stability and photostability, but its
Hydrophobic property significantly limit the application in biological field, in order to reduce its hydrophobicity or improve its hydrophily, in its structure
In introduce powered functional group.For example, the TPE with two or four ammonium is luminous weaker in aqueous solution, but adds
Enter negatively charged biomolecule and reform into strong illuminator, such as add calf thymus DNA and bovine serum albumin(BSA) (BSA)
[Chem.Commun.,2006,3705；Chem.–Eur.J.,2008,14,6428.].Anion TPE derivatives are by sulfonic group
Group is brought into the hydrophobic pocket of the main body foldable structure of BSA, due to restriction (the restriction of of Internal Rotations of Molecules
Intramolecular rotation, RIR) cause luminescence enhancement.When by introducing surfactant (such as dodecyl sulphate
Sodium SDS) cause BSA it is not folded when, then no longer light [J.Phys.Chem.B, 2007,111,11817].Tang is common with his
Workers report the poly-N-isopropyl acrylamide (PNIPAM) for including TPE aglucons polymer [Chem.Commun.,
2009,4974], by fluorescent technique, the PNIPAM chains of TPE marks can be used for tracking the conformation of the polymer that temperature causes and become
Change.On the other hand, seldom there is research and report amphipathic AIE molecules.In structure, amphipathic molecule be surfactant with
And the usual not only organic compound containing hydrophobic structure unit but also containing hydrophilic structural unit.Most of amphipathic molecule it is hydrophobic
Tail is side chain, straight chain or aromatics hydrocarbon chain, while hydrophilic head neutral, negative electrical charge and positive charge, be known respectively as sometimes it is non-from
Sub- surfactant, anion surfactant and cationic surfactant.Therefore, amphipathic molecule is by water-insoluble aglucon
Constitute with water-soluble ligand.In aqueous solution, amphipathic molecule forms polymer, such as colloid and micelle, wherein hydrophobic tail
Aggregation forms core, and hydrophilic head concentrates on surface and contacts with the water environment of surrounding.The shapes and sizes of polymer mainly take
Certainly in the structure of amphipathic molecule and the hydrophily of molecule and hydrophobic equilibrium relation.Amphipathic molecule is widely present in me
Daily life article, including cleaning agent, fabric softener, emulsion, drawing pigment, ink and cosmetics etc., and exist
In biological utilisation aspect, such as protein extraction, cytoplasma membrane, administration.Amphipathic and AIE characteristics combination can produce one and be
The new fluorescence molecule of row is used for chemistry and biologic applications aspect.
The content of the invention
It is an object of the invention to provide a kind of amphipathic shiner with aggregation-induced emission characteristic and its application, solution
Shiner with aggregation-induced emission characteristic certainly of the prior art causes to be asked using limited for hydrophobic shiner
Topic.
The technical proposal for solving the technical problem of the invention is：It is a kind of amphipathic with aggregation-induced emission characteristic
Shiner, comprising the hydrophobic unit with aggregation inducing/enhancing characteristics of luminescence, with the luminous spy of aggregation inducing/enhancing
Property hydrophobic units on be connected with hydrophilic units, the structural formula of the shiner is in following I, II, III, IV, V and VI
Any one；
Wherein,Represent the hydrophobic unit with aggregation inducing/enhancing characteristics of luminescence；
Represent hydrophilic units；
In the amphipathic shiner with aggregation-induced emission characteristic of the present invention, the shiner water soluble,
And can form micella during the concentration >=critical micelle concentration of the aqueous solution of the shiner formation.
It is described with aggregation inducing/increasing in the amphipathic shiner with aggregation-induced emission characteristic of the present invention
The hydrophobic unit of the strong characteristics of luminescence includes at least one first agent structure, and the agent structure is selected from and includes following arbitrary knots
The group of structure：
Wherein, R and R (X) are represented be connected with the hydrophobic unit with aggregation inducing/enhancing characteristics of luminescence respectively
Hydrophilic units.
In the amphipathic shiner with aggregation-induced emission characteristic of the present invention, the hydrophilic units are selected respectively
From the group containing at least one of OH, ammonium salt, amino, mercaptan, ethohexadiol, sulfonate, phosphate and carboxylate.
It is described with aggregation inducing/increasing in the amphipathic shiner with aggregation-induced emission characteristic of the present invention
The hydrophobic unit of the strong characteristics of luminescence includes structure and isGroup, the hydrophilic units include ethyl
Glycol group；Specifically, the shiner includes the base of any structure formula in following structural formula P1/6, P2/6 and P3/6
Group：Wherein n, m, o and p represent respectively 2～3000 natural number,
In the amphipathic shiner with aggregation-induced emission characteristic of the present invention, the shiner is following the trail of cell
In application, the application in cell tracker device is prepared, the application in the probe for following the trail of cell is prepared or thin in monitoring
Application in intracellular drug release process.
In the amphipathic shiner with aggregation-induced emission characteristic of the present invention, the hydrophilic units are comprising extremely
Few one second agent structure, second agent structure is selected from the group for including following any structures：
Wherein R1、R2、R3、R4And R5It is respectively selected from and includes H, alkyl, unsaturated alkyl, isoalkyl, cycloalkyl, different cycloalkanes
Base, aryl, different aryl and CnH2n+1、C10H7、C12H9、OC6H5、OC10H7、OC12H9、CnH2nCOOH、CnH2nNCS、
CnH2nN3、CnH2nNH2、CnH2nSH、CnH2nCl、CnH2nBr、CnH2nAt least one group in I, n is natural number；
X-For gegenion, X-Selected from I-、Cl-、Br-、PF6 -、ClO4 -、BF4 -、BPh4 -、CH3PhSO3 -。
It is described with aggregation inducing/increasing in the amphipathic shiner with aggregation-induced emission characteristic of the present invention
The hydrophobic unit of the strong characteristics of luminescence includes structure and isGroup, the hydrophilic units include structure
ForGroup, wherein R1For propyl, X-For Br-；Specifically, the shiner includes following knots
The group of structure formula TPE-MEM：
In the amphipathic shiner with aggregation-induced emission characteristic of the present invention, the shiner is in specificity choosing
Select the application in cell membrane dyeing, the application in preparation specific selection cell membrane coloring agent, specific selection is thin preparing
After birth dyeing probe in application, the application in sensitising agent is prepared and prepare lucotherapy medicine in application or
Prepare the application in the lucotherapy medicine for treating cancer.
In the amphipathic shiner with aggregation-induced emission characteristic of the present invention, the shiner can be with metal
Ion is combined, and the metal ion is selected from La3+、Pr3+、Nd3+、Pm3+、Sm3+、Eu3+、Gd3+、Tb3+、Ce3+、Dy3+、Ho3+、Er3+、
Tm3+、Yb3+And Lu3+In at least one.
In the amphipathic shiner with aggregation-induced emission characteristic of the present invention, the metal ion is Gd3+, institute
State the hydrophobic unit with aggregation inducing/enhancing characteristics of luminescence and include structure and beGroup, the parent
Aqueous unit includes ethohexadiol group；Specifically, the shiner includes the group of following structural formula TPE-2Gd：
In the amphipathic shiner with aggregation-induced emission characteristic of the present invention, in the amphipathic tool of the present invention
In having the shiner of aggregation-induced emission characteristic, application of the shiner in the dyeing of specific selection cytoplasm district, in system
For the application in the coloring agent of specific selection cytoplasm district dyeing, the application in cell imaging, in tumour cell is followed the trail of
Application, prepare follow the trail of tumour cell tumour cell tracker in application or in NMR contrast agent is prepared
Application.
The present invention is also described in detail the above-mentioned amphipathic shiner with aggregation-induced emission characteristic and is following the trail of cell
In application, the application in cell tracker device is prepared, prepare for follow the trail of cell probe in application, monitoring cell
Application in interior drug release process, the application in the dyeing of specific selection cell membrane, preparing specific selection cell membrane
Application in coloring agent, the application in the probe for preparing the dyeing of specific selection cell membrane, the application in sensitising agent is prepared,
Prepare lucotherapy medicine in application or prepare for treating cancer lucotherapy medicine in application, in specificity
The application in cytoplasm district dyeing is selected, application in the coloring agent for preparing the dyeing of specific selection cytoplasm district, in cell
Application in imaging, the application in tumour cell is followed the trail of, answering in the tumour cell tracker for following the trail of tumour cell is prepared
With or application in NMR contrast agent is prepared.
Implement the amphipathic shiner with aggregation-induced emission characteristic and its application of the present invention, with following beneficial
Effect：The shiner of the present invention in the hydrophobic unit of typical aggregation-induced emission characteristic (AIE) by connecting hydrophily
Unit is prepared from, and the shiner can be used for the dyeing of specific selection cell membrane, dye for preparing specific selection cell membrane
Agent, for prepare specific selection cell membrane dyeing probe, prepare sensitising agent etc., and then for prepare lucotherapy medicine and
For preparing the lucotherapy medicine for the treatment of cancer.Specifically, the present invention is prepared for the pyridiniujm of the tetraphenyl ethylene base of cation
Shiner, it has AIE characteristics, alternative that cell membrane is dyeed, and the shiner can also be produced under room light-illuminating
Active oxygen (ROS), this is caused under mild conditions just it is observed that meronecrosis and the effect of phototherapy.
Description of the drawings
Fig. 1 is the synthetic route chart of P1/6, P2/6 and P3/6 shiner in the embodiment of the present invention 1；
Fig. 2 is the synthetic route chart of TPE-MEM shiners in the embodiment of the present invention 2；
Fig. 3 is the synthetic route chart of TPE-2Gd shiners in the embodiment of the present invention 3；
Fig. 4 A are THF/H of the P1/6 shiners (0.25mg/mL) in different moisture content2By 365nm wavelength in O mixed liquors
The photo of ultraviolet light；
Fig. 4 B be P1/6 shiners (0.25mg/mL) in the THF/ hexane mixed liquors of different hexane contents by 365nm ripples
The photo of long ultraviolet light；
Fig. 4 C are P1/6, P2/6 and P3/6 shiner respectively in the THF/H of different compositions2Relative intensity in O mixed liquors
From the THF/H of different compositions2Correlogram in O mixed liquors between water content；Wherein, shiner concentration is 0.25mg/
ML, excitation wavelength (nm):320 (P1/6), 335 (P2/6) and 350 (P3/6)；
Fig. 4 D are relative intensity of P1/6, P2/6 and P3/6 shiner respectively in the THF/ hexane mixed liquors of different compositions
From the correlogram in the THF/ hexane mixed liquors of different compositions between hexane content；Wherein, shiner concentration is 0.25mg/
ML, excitation wavelength (nm):320 (P1/6), 335 (P2/6) and 350 (P3/6)；
Fig. 5 A are the ultraviolet lighting of the aqueous solution (0.002-2mg/mL) by 365nm wavelength of the P1/6 shiners of variable concentrations
The photo penetrated；
Fig. 5 B are the PL spectrograms of the aqueous solution of the P1/6 shiners of variable concentrations；
Fig. 5 C are the I/I of P1/6, P2/6 and P3/6 shiner0Value and the correlation curve between the corresponding concentration in water
Figure；
Fig. 6 is the related figure using CCK8 experimental analysis P1/6 shiners to the cytotoxicity of 24 hours of HepG2 cells；
Fig. 7 is the P1/6 shiners of variable concentrations to the HepG2 cell dyeings image of 12 hours living；
Fig. 8 is P2/6 the and P3/6 shiners of 200 μ g/mL concentration to the HepG2 cell dyeings image of 24 hours living；
Fig. 9 is the long-term first generation followed the trail of after being dyeed 24 hours by the P1/6 shiners of 150 μ g/mL to the 5th generation
The image of HepG2 cells；
Figure 10 is UV and PL spectrograms of the TPE-MEM (40 μM) in water, and excitation wavelength is 405nm；
Figure 11 A are TPE-MEM in the THF (f containing different contentTHF) THF/DMSO mixed solvents in PL spectrograms,
Wherein TPE-MEM concentration is 25 μM, and excitation wavelength is 405nm；
Figure 11 B are fs of the TPE-MEM in the PL intensity and THF/DMSO mixed solvents of 625nmTHFBetween correlation curve
Figure, wherein TPE-MEM concentration are 25 μM；Internal illustration is TPE-MEM respectively in DMSO solvents and THF/DMSO mixed solvents
(fTHF=99%) in by 365nm wavelength ultraviolet light photo；
Figure 12 A are correlograms of the TPE-MEM between the PL intensity and concentration of 600nm；Internal illustration is difference
The TPE-MEM of concentration by 365nm wavelength ultraviolet light photo；
Figure 13 A are particle diameter photos of the TPE-MEM (100 μM) of transmission electron microscope (TEM) measure in aqueous solution；
Figure 13 B are the grain size curve figure of the TPE-MEM of the variable concentrations that eletrokinetic potential Particle Size Analyzer is determined；Internal inserts
Figure is grain size distributions of the TPE-MEM (100 μM) determined by eletrokinetic potential Particle Size Analyzer in aqueous solution；
Figure 14 is the analysis chart of the impact that the TPE-MEM that mtt assay is determined breeds to HeLa cells；Cell is exposed to different dense
The TPE-MEM of degree 6 hours；
Figure 15 A be TPE-MEM (5 μM, λex=405nm and λem=550 ± 70nm) laser scanning to HeLa cell dyeings
Laser Scanning Confocal Microscope image；
Figure 15 B are CellMaskTMPeony cell membrane coloring agent (C10046,5 μ g/mL, λex=633nm and λem=685
± 55nm) laser scanning co-focusing microscope image to HeLa cell dyeings；
Figure 15 C are the corresponding bright-field images of Figure 15 B；
Figure 15 D are the merging image of Figure 15 A-15C, and the overlap coefficient of Figure 15 A and Figure 15 B is calculated as 72%；
Figure 16 is the loss of signal (%) of TPE-MEM (solid line circle) fluorescent emission during increase with sweep time
Change curve；Internal illustration be respectively before 325.7s is continuously scanned and after continuous scanning by TPE-MEM (5 μM)
The fluorescence imaging figure of the HeLa cells of the work of dyeing, λex=405nm and λem=550 ± 50nm；
Figure 17 A swash to there are PL spectrograms of the H2DCFDA (1 μM) of TPE-MEM (10 μM) under room light-illuminating
It is 488nm to send out wavelength；
Figure 17 B be irradiation time respectively to the solution containing TPE-MEM, the solution containing H2DCFDA or TPE-MEM and
Curve map of the solution that both H2DCFDA contain in the impact of the PL intensity of 535nm；
A-D photos in Figure 18 are the co-focusing imaging figure of the HeLa cells in pre-irradiation TPE-MEM and PI dyeing；E-H
Photo is the co-focusing imaging figure of the HeLa cells of TPE-MEM and PI dyeing after irradiation；I-L photos are only to use PI after irradiation
The co-focusing imaging figure of the HeLa cells of dyeing；C, G are respectively the image of the corresponding bright-field of A, E, I with K photos；D、H
With the merging image for merging image and I/J/K for merging image, E/F/G that L is respectively A/B/C；The μ of [TPE-MEM]=5
M；[PI]=3 μM；Channel I:λex=405nm, λem=550 ± 50nm；Channel II:λex=560nm, λem=620 ±
65nm；
Figure 19 is to determine room light-illuminating TPE-MEM by mtt assay and do not irradiate TPE-MEM respectively to HeLa cells
The comparison diagram of the impact of propagation；
Figure 20 A are TPE-2Gd in different moisture content (fw) THF/H2O mixed solutions in by 365nm ultraviolet light
Photo；
Figure 20 B are TPE-2Gd in different moisture content (fw) THF/H2O mixed solutions in launching light spectrogram, concentration is
100 μM, excitation wavelength is 330nm；
Figure 20 C are the relative PL intensity (I/I of variable concentrations TPE-2Gd (1 μM of 100 μM of and)0) and THF/H2O mixing is molten
The correlogram between water content in liquid；
Figure 21 A are photo of the TPE-2Gd aqueous solution of variable concentrations under ultraviolet light；
Figure 21 B are the launching light spectrogram of the TPE-2Gd aqueous solution of variable concentrations, and excitation wavelength is 330nm；
Figure 21 C are the correlogram between the PL intensity and the concentration in water of TPE-2Gd, the critical glue of TPE-2Gd
Group's concentration (CMC) is 70 μM；
Figure 22 A are transmission electron microscope images of the TPE-2Gd (100 μM) in water；
Figure 22 B are granularmetric analysis figures of the TPE-2Gd (100 μM) in water；
The fluorescence imaging figure of the HeLa cells that Figure 23 A are dyeed for TPE-2Gd, [TPE-2Gd]=30 μM；
The fluorescence imaging figure of the HeLa cells that Figure 23 B are dyeed for the PI after TPE-2Gd dyeing, [TPE-2Gd]=30 μM；
Figure 23 C are that Figure 23 A and Figure 23 B merge image, [TPE-2Gd]=30 μM；
Figure 23 D for HeLa cells bright-field image, [TPE-2Gd]=30 μM；
Figure 24 is the analysis chart by the TPE-2Gd of mtt assay measure to the cell proliferative conditions of HeLa cells, and cell exposes
In the TPE-2Gd 4 hours of variable concentrations, to change continue after fresh culture medium and cultivate 24 hours；
Figure 25 is difference Gd3+The TPE-2Gd and commercial reference product of concentrationT1- weighting nuclear magnetic resonance figure
Spectrum (MR), sample is diluted by physiological saline；
Figure 26 is difference Gd3+The TPE-2Gd and commercial reference product of concentrationWater proton longitudinal relaxation speed
(1/T1) curve map, according to equation：1/T1=1/T1,0+R1×[CGd], rate transition R1,TPE-2Gd=3.36 ± 0.10mM-1·s-1；R1, magnevist=3.70 ± 0.02mM-1·s-1；
Figure 27 is to contain G d to mouse mainline respectively3+Ion concentration for 0.1mmol/kg TPE-2Gd andCoronal T afterwards1- weighting nuclear magnetic resonance (MR) image；
Figure 28 A are the T of heart1The quantitative analysis figure of-weighted imaging；
Figure 28 B are the T of liver1The quantitative analysis figure of-weighted imaging；
Figure 29 is that the liver internal jugular vein injection respectively to mouse contains G d3+Ion concentration for 0.1mmol/kg TPE-2Gd andAxial T afterwards1- weighting nuclear magnetic resonance (MR) image.
Specific embodiment
With reference to the accompanying drawings and examples, to the present invention the amphipathic shiner with aggregation-induced emission characteristic and
Its application is described further：
It is found that aggregation-induced emission (aggregation-induced eimission, AIE) is existing by Tang in calendar year 2001
As current AIE phenomenons are because it is in the life of Organic Light Emitting Diode (OLEDs), chemical sensor, biology sensor and inside and outside
The potential application of the aspects such as thing preparation has become one of most hot research field in the world, but major part AIE molecules be all by
Aromatic ring is constituted, therefore AIE molecules are in hydrophobicity, insoluble in aqueous medium.On the other hand, seldom have been reported that with regard to water-soluble AIE
Molecule or amphipathic AIE molecules.From this viewpoint, present invention design has synthesized some water-soluble and amphipathic AIE molecules, opens
Their potential source biomolecule application is sent out.
Following examples are only the illustrative examples of the present invention, rather than restricted.
Embodiment 1：Shiner P1/6, P2/6 and P3/6 of synthesis non-ion amphiphilic simultaneously carry out the reality of application aspect to it
Test research
(1) (n, m, o and p represent respectively 2～3000 natural number) is synthesized
As shown in figure 1, the supply ratio of the reagent used by synthesis shiner P1/6 is as follows, the 6th compound 6, the first chemical combination
Thing 1, concentration ratio [6]/[1]/[CuBr]/[PMDETA] between CuBr and PMDETA are 1/4/4/4, synthesis shiner P2/6 and
The ratio of the supply ratio concentration of the reagent of P3/6 and shiner P1/6 are a difference in that the 6th compound 6 respectively with second
The concentration ratio of the compound 3 of compound 2 and the 3rd is [6]/[2]/[3]=1/1/0.5.Under room temperature, equipped with 30mLDMF, CuBr
In the Schlenk bottles of the 50mL of (172mg, 1.2mmol) and 5.3mL PMDETA (1.2mmol), the 6th compound 6 (1.05mg,
0.3mmol) Ligature is carried out with the first compound 1 (430mg, 1.2mmol), after being stirred 36 hours, with water (300mL)
Reactant mixture is diluted, with dichloromethane to the extraction with aqueous solution four times, all organic phases is mixed, further by
Strong brine is rinsed six times, and by Na2SO4It is dried.After solvent evaporation, residue is concentrated into～20mL, in ether (300mL)
Precipitation 3 times, filtering precipitate simultaneously obtains corresponding product with excessive washed with ether.
Shiner P1/6, yield 82%, Mw3200；Mw/Mn1.03；IR(KBr),ν(cm-1):3435,2885,1641,
1466,1346,1281,1244,1111,953,841,756,700,623,581,523；1H NMR(400MHz,DMSO-d6),δ
(ppm):8.46 (2H, s, benzotriazole triazole-H), 7.62 (4H, d, J=8.0Hz, benzotriazole triazole-Ar-H),
7.17-6.99 (34H, m, Ar-H), 4.56 (4H, t, J=4.8Hz, CH2- triazole benzotriazoles), 3.85 (4H, t, J=
4.8Hz,CH2CH2- triazole benzotriazoles), 3.53-3.46 (300H, m, OCH2)；13C NMR(100MHz,DMSO-d6),δ
(ppm):145.86,143.15,143.02,142.63,140.77,140.19,131.20,130.70,130.65,128.97,
127.86,127.82,126.62,124.50,121.72,72.36,69.90,69.73,69.64,68.67,60.23,49.58。
Shiner P2/6, yield 81%, Mw34700；Mw/Mn1.39；IR(KBr),ν(cm-1):3416,2880,1639,
1466,1352,1281,1250,1113,951,845,770,704,675,527；1H NMR(400MHz,DMSO-d6),δ
(ppm):8.41 (2H, s, triazole-H), 7.57 (4H, t, J=8.0Hz, benzotriazole triazole-Ar-H), 7.14-6.99
(14H,m,Ar-H),4.50(4H,m,CH2- triazole benzotriazoles), 3.80 (4H, t, J=4.8Hz, OCH2CH2-triazole
Benzotriazole), 3.60-3.39 (300H, m, OCH2)；13C NMR(100MHz,DMSO-d6),δ(ppm):145.87,145.86,
143.06,142.65,140.42,131.26,130.77,129.03,127.93,126.77,124.52,121.76,72.37,
69.92,69.74,69.53,68.69.60.25,49.60。
Shiner P3/6, yield 88%, Mw27,600；Mw/Mn1.39；IR(KBr),ν(cm-1):3439,3136,
2873,1639,1463,1350,1286,1249,1109,954,840,663,530；1H NMR(400MHz,DMSO-d6),δ
(ppm):8.41 (4H, s, benzotriazole triazole-H), 7.61 (8H, d, J=8.0Hz, benzotriazole triazole-Ar-H),
7.07 (8H, d, J=8.0Hz, Ar-H), 4.49 (8H, s, CH2- triazole benzotriazoles), 3.79 (8H, s, OCH2CH2-
Triazole benzotriazoles), 3.64-3.40 (600H, m, OCH2)；13C NMR(100MHz,DMSO-d6),δ(ppm):145.85,
142.53,140.21,131.42,129.24,124.66,121.79,72.36,69.68,68.68,60.23,49.59。
(2) application study：
By the non-ionic water solubility of the cycloaddition synthesis with different chains number polyethylene glycol (PEG) of nitrine-alkynes
Tetraphenyl ethylene (TPE)-functionalization polyethylene glycol (PEG) shiner (P1/6, P2/6 and P3/6), by hydrophobic TPE become
Into hydrophilic molecules.These shiners show preferable heat endurance, referring to table 1, the wherein T of P1/6, P2/6 and P3/6dPoint
Wei 351.6 DEG C, 342.2 DEG C and 352.1 DEG C.As shown in figs. 4 a-4d, the polymer after these synthesis is water-soluble and amphipathic
, show AIE characteristics in THF/ aqueous solvent systems and THF/ hexane solvent systems.In a large amount of aqueous solution, these gather
Compound forms micellar copolymerization thing when exceeding critical micelle concentration (CMC).As shown in Fig. 5 A, 5B and 5C, by using these polymerizations
During thing coherent condition the luminous property of autofluorescence obtain P1/6, P2/6 and P3/6 CMC be respectively 0.09mM, 0.12mM and
0.20mM, particle diameter respectively may be about 100nm.All results show that the micella of these polymer is by the nonpolar TPE heads in inner side
With the hydrophilic PEG chains composition for pointing to aqueous medium.These polymer are then individually dissolved in medium and do not send out in below CMC
Light, when concentration is increased to more than CMC, these polymer initially form micella, and TPE moiety aggregations show in hydrophobic interior
Stronger fluorescence radiation.Therefore, because restriction (the restriction of intramolecular of Internal Rotations of Molecules
Rotation, RIR) impact to micellization, these polymer become to light.
In order to study impacts of the P1/6 to living cells, using CCK8 cytotoxicity analysis are carried out.WST-8([2-(2-
methoxy-4-nitropheny)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazoliun,
Monosodium salt], [2- (2- methoxyl group -4- nitrobenzophenones) -3- (4- nitrobenzophenones) -5- (2,4- double sulfophenyls) -2H-
Tetrazole, sodium glutamate] first a ceremonial jade-ladle, used in libation is changed into by intracellular dehydrogenase, it is directly proportional to the quantity of living cells.Such as Fig. 6 institutes
Show, the cytotoxicity of P1/6 is in dose dependent after P1/6 is exposed to HepG2 cell 24h.Concentration is 50,75,100,125 μ
Cell survival rate corresponding to g/mL is respectively 99.93%, 98.1%, 95.82% and 92.94%, and in concentration 150 μ g/ are reached
During mL, cell survival rate still remains above 86%.There is data to suggest that P1/6 has the preferable biology for living cells imaging
Compatibility.
Table 1：The molecular weight and thermal property of P1/6, P2/6 and P3/6
As pharmaceutical carrier be used for clinical practice aspect, PEG be bio-compatible and suitable for transmit organic coloring agent
It is extremely intracellular.Pure coloring agent TPE cannot be penetrated into intracellular space (non-display data) because of its high hydrophobicity.Due to having
The preferably optical characteristics of AIE properties, using the PEG polymer of TPE- functionalization to adherent type HepG2 cell dyeing as life
Physical prospecting pin.Amphipathic nature polyalcohol tends to form nanometer polymer in aqueous solution, and it can be promoted thin by endocytosis
Born of the same parents absorb.As shown in fig. 7, when HepG2 cells dye 12h by P1/6, can light from cytoplasmic region.With the increasing of P1/6 concentration
Plus, fluorescence becomes higher, and the efficiency for showing endocytosis depends on P1/6 dosage in the medium.Although as shown in figure 8, thin
The P2/6 and P3/6 of born of the same parents and high concentration carries out cultivating the longer time, but lights compared with P1/6 and want much weaker.This species diversity is returned
Because of the ratio between TPE and PEG.
In order to monitor cellular morphology for a long time, manufacturer has done the best the load time improved after dyeing.For example, business is thin
Born of the same parents' tracker, CellTrackerTMBlue CMAC (7-Amino-4-Chloromethylcoumarin, 7- amino -4- chloromethyls
Cumarin) and blueness CMHC (4-chloromethyl-7-hydroxycoumarin, 4- chloromethyl-umbelliferone) by chlorine
Methyl functional group's functionalization.When the probe of tracker enters intracellular, probe can enter with the mercaptan on proteins and peptides
Row reaction, but cell can only be illuminated after dyeing about 24 hours according to agreement coloring agent.As shown in figure 9, as first
Generation, HepG2 cells living are exposed to P1/6 polymer 24 hours, send high light.Because in the cell large biological molecule PEG can lock
Firmly fluorogen, intracellular P1/6 is passed to careful intracellular.Although the increase in hyperplasia generation causes fluorescence to die down, probe is also
It is can to follow the trail of to the 5th generation.Therefore, P1/6 can be used as long-term living cells tracker, be potential alternative.Therefore, this is glimmering
Photopolymer can be applicable to monitor Intracellular drug release.
Embodiment 2：The amphipathic shiner TPE-MEM of synthesizing cationic simultaneously carries out the experimental study of application aspect to it
(1) synthesize
As shown in Fig. 2 in a nitrogen environment, 1- (3- trimethyl amido propyls) -4- picoline dibromide (1-
(3-trimethylammoniopropyl) -4-methylpyridinium dibromide) (0.5g, 1.4mmol) and the 3rd
The solution of compound 3 (1.5016g, 2.8mmol) back flow reaction in absolute ethyl alcohol, adds three to drip piperidines and is catalyzed, and cools down
To room temperature, evaporation under reduced pressure solvent is purified by silica gel column chromatography to residue, using dichloromethane and
Methyl alcohol (2：Mixed solvent 1v/v) as eluant, eluent, obtain yellow product TPE-MEM (0.72g, 59%).1H NMR
(400MHz, methyl alcohol-d4,δ):8.948 (d, 2H, J=6.8Hz), 8.213-8.190 (m, 2H), 7.946 (6,1H, J=
16Hz), 7.737-7.717 (m, 2H), 7.576 (d, 2H, J=8Hz), 7.430-7.331 (m, 3H), 7.061-6.843 (m,
14H), 6.605-6.570 (m, 2H), 4.698 (t, 2H, J=15.2Hz), 3.797 (t, 2H, J=14.8Hz), 3.644 (t,
2H, J=16.4Hz), 3.240 (s, 9H), 2.663-2.581 (m, 2H), 1.693-1.619 (m, 2H), 1.421-1.262 (m,
6H), 0.871 (t, 3H, J=14.4Hz)；13C NMR(100MHz,CDCl3,δ):157.362,157.260,153.875,
143.411,143.306,143.250,143.227,143.198,141.993,140.990,140.597,138.760,
136.680,135.055,133.295,131.619,131.584,131.140,130.482,128.135,126.902,
126.855,126.798,126.683,126.281,125.676,125.507,125.457,125.216,125.115,
123.440,121.585,112.874,112.700,66.856,61.787,55.965,52.066,30.728,30.716,
28.311,24.791,24.216,21.625,12.399；HRMS(MALDI-TOF)m/z:Calculated value, 791.3571 [M-Br-]+；
Measured value, 791.3570 [M-Br-]+。
(2) application study
Cell membrane is the protective barrier of cell, and the integrality, growth and death for cell is most important.In the urgent need to
Shiner in living cells and dying cell to cell membrane imaging.There is provided a kind of new amphipathic with four benzene second in the present embodiment
Pyridiniujm (tetraphenylethene-based pyridinium salt, TPE-MEM) based on alkene, with significant
Aggregation-induced emission (AIE) characteristic, and for the dyeing of selecting cell film.Fluorescence probe (the TPE- of the shiner of the high yield
MEM) it is synthesized by following, including asymmetric McMurry reactions, Suzuki coupled reactions and with doubly charged pyridiniujm
And the condensation reaction between hexyloxy tetraphenyl ethylene benzaldehyde (hexyloxytetraphenylethene benzaldehyde).
Due to double charge characteristic, TPE-MEM has poor dissolubility in non-polar solven, such as in THF and DCM non-polar solvens
In, but it is solvable in polar solvent, it is such as solvable in water, DMF, DMSO and methyl alcohol.
Figure 10 shows ultraviolet (UVs) and luminescence generated by light (PL) spectrum of the TPE-MEM in aqueous solution (40 μM).TPE-
The absorption maximum wavelength of MEM falls in 395nm.For convenience biologic applications, using 405nm as excitation wavelength PL measure is carried out.
The light of aqueous solution excites induction in 590nm Yellow light-emitting low temperatures, and expression there occurs a large amount of displacements of 185nm, and this is made by extended conjugation
With and from the Intramolecular electron transfer (intramolecular of electron donor TPE aglucons to electron acceptor pyridine unit
Charge transfer, ICT) cause.
As shown in Figure 11 A and 11B, TPE-MEM shows substantially contrary AIE properties, and this is due to its highly polar property
Caused by matter.The DMSO solution of TPE-MEM (25 μM) is luminous weaker, and in the THF of content 99%, it is strong in the luminous changes of 625nm.
In view of the molecular structure of TPE-MEM, thus it is speculated that amphipathic TPE-MEM molecules can form micelle in the case of high concentration.Benefit
In the property of AIE, the critical micelle concentration (CMC) of TPE-MEM can be measured using the fluorescence intensity of its own.Such as Figure 12
Shown, the concentration of TPE-MEM is molecular melting in below CMC, therefore does not produce fluorescence；In more than 0.01mM, PL intensity urgency
Increase severely strong；Correlation curve between PL intensity and stain concentration produces two lines, and the crosspoint of two lines determines that CMC is
0.02mM.As illustrated in figures 13 a and 13b, also demonstrate that in high dye by transmission electron microscope and eletrokinetic potential Particle Size Analyzer
The formation of nanometer polymer and CMC value in toner concentration.The effective diameter of aqueous micellar is 77.4nm, with dehydration effectively directly
Footpath tapers to 40nm.When TPE-MEM the following is molecular melting in CMC, it is impossible to detect particulate；When in CMC
(0.02mM) when more than, it can be observed that particulate.The inflection point determined by PL is identical with CMC value.Additionally, the grain of nanometer polymer
Footpath had both been suitable for cell in vitro intake and body-internal-circulation, and bio distribution is suitable for again.
Before cell imaging, using MTT colorimetric methods in the intracellular cytoactives that can determine TPE-MEM of HeLa and
Cytotoxicity.Under the conditions of 37 DEG C, dark CO2 incubator inner cells be exposed to variable concentrations (0,2.5 μM, 5 μM, 10 μM,
20 μM) TPE-MEM 6 hours, be then further cultured for 18 hours carrying out cell propagation in the fresh culture medium of incubator.Such as
Shown in Figure 14, even if the concentration for as a result showing TPE-MEM in the dark reaches 20 μM of also typically no cytotoxicities.Then as
It is contemplated that be used for the dyeing of selective cell membrane to TPE-MEM being estimated.As shown in figures 15 a-d, using CellMaskTM
The experiment of combined staining that Deep Red cell membrane coloring agents (C10046) is carried out show the fluorescence observed from TPE-MEM be from
In the cell membrane of HeLa cells living, the wherein cell membrane coloring agent is a kind of commercially available cell membrane imaging agent.It is logical
Cross and use Laser Scanning Confocal Microscope (CLSM LSM7；Carl Zeiss, Germany) software, determine Figure 15 A and Figure 15 B between
Overlap coefficient is 72%.Overlap coefficient is at a relatively high, and this is due to the competition between thin-layer cell membrane structure and two kinds of coloring agents
Suppress.Compared with C10046, TPE-MEM shows less internalization effect, and the imaging to cell membrane shows preferably
Imaging resolution.More very, by TPE-MEM it will be appreciated also that see cell microvillus.Except complex staining experiment, also enter
The Z-type CLSM that gone scans (Z-stack CLSM scanning).
Cell membrane is the organelle that larger negative potential is shown on the interface of film, the phospholipid bilayer master on the organelle
To be made up of thin amphipathic phospholipid bilayer.Therefore, it is amphipathic that cell membrane target organism coloring agent generally needs to meet
And cation.The hydrophobicity and hydrophily of coordinated balance molecule is to meet the amphipathic of cell membrane, and this is new for designing
Cell membrane biological coloring agent is most important.TPE-MEM has a characteristic amphipathic and with positive lotus, therefore can be used as splendid using it
Biological stain, for the cell membrane of specific stain living cells.Amphipathic TPE-MEM is spontaneous to be arranged in phospholipid bilayer,
To make hydrophobic tail region be to electrostatically attracted in the double-deck interior and hydrophilic head region that the polar liquid with around is isolated
The phosphate of negative electrical charge.Such as electrostatic force and Van der Waals interaction force (van der Waals interactions)
Dye etc. specific targets are caused.
For cell imaging coloring agent, light resistance is one of most important standard.Some for specific cell dyeing
AIE coloring agents are all high-light-fastness.Helical molecular structures and its polymerization forming process can prevent oxygen from diffusing into AIE
In particulate, oxygen meeting oxyluciferin into AIE particulates is rolled into a ball and makes its PL light and bleaches.As shown in figure 16, in living cells
Similar light resistance result is obtained.According to initial fluorescent intensity standardized fluorescent intensity.As shown in figure 16, total irradiation time 5
Minute (30 scanning), the loss of signal of TPE-MEM is less than 40%.Time from 0s to 325.7s, the loss of signal is bright with imaging
Degree is slightly decreased, and this is the diffusion due to coloring agent and the movement of cell.
As shown in figure 16, bubble can be seen in series of scans in CLSM time courses.It is apparent that cell fine hair shrinks
And disappear, laser scanning is then based on, cell expansion is simultaneously revealed, it is seen that cytoplasma membrane becomes discontinuous and is seepage.It is this
Phenomenon shows that cell death is by the reason for caused by laser scanning, this just excites people's follow-up study strongly.Pi-conjugated
Phenthazine (phenothiazinium) the base molecule with positive charge is widely used in active oxygen (ROS) and generates and light in system
Therapy.Compared with phenthazine, TPE-MEM also has positive charge in Pi-conjugated systems, and this is possible to that photoinduction ROS can be caused to give birth to
Into causing cell death.
In order to confirm above-mentioned it is assumed that carrying out ROS detections using commercial ROS fluorescence probes H2DCFDA.When by already present
During ROS oxidation H2DCFDA, can detect in 535nm (λex=488nm) transmitting hyperfluorescence.Surprisingly, it is normally white
Room light (LED bulb, 3W) produces enough ROS when being irradiated to TPE-MEM solution.PBS solution containing H2DCFDA, contain
The PL spectrum of the PBS solution of TPE-MEM and the PBS solution simultaneously containing H2DCFDA and TPE-MEM are all in identical room
What light-illuminating was obtained.PL spectrum (Figure 17 A, the λ of record sample difference irradiation timeex=488nm) and the peak value of 535nm it is strong
Correlation curve (Figure 17 B) between degree and irradiation time.In Figure 17 A, when there is H2DCFDA and TPE-MEM simultaneously in solution
When, oxidized H2DCFDA occurs and as light irradiation strengthens in the characteristic peak of 535nm.Even if measurement result shows compartment lamp
The light irradiation time, PL intensity still persistently strengthened, and just makes fluorescence bleach within ultraviolet light only a few minutes more than 120 minutes
(non-display data).Individually H2DCFDA solution and single TPE-MEM solution are by the PL Strength Changes after room light-illuminating
Slightly.Observation indicate that actually light is radiated at the ROS produced when TPE-MEM, causes cell damage and death.
However, the pathology of cell death are still without method interpretation.The integrality of cell membrane be most important morphological feature it
One, for distinguishing Apoptosis and meronecrosis.During meronecrosis, cell expansion, cell membrane become it is leaky simultaneously
Division, final cell exchanges material with surrounding environment.Propidium iodide (propidium iodide, PI) is impermeable by thin
After birth, generally exclude outside living cells.When cell membrane is leaky, PI is usually used in the karyon to dead cell and dyes.Cause
This, PI is opened for dead cell being recognized in a large amount of cells and in multicolor fluorescence technology as counterstain.In this example
In, as shown in figure 18, TPE-MEM is added and is marked to the culture medium with living cells, is then introduced to PI to observe base
It is interior.As shown in the A-D in Figure 18, the TPE-MEM (channel come from cell membrane can be only detected before light irradiation
I gold-tinted).When irradiating cell about 5 minutes (30scans), then another 5 minutes are irradiated for absorbing PI, such as Figure 18
In E-H shown in, it is observed that the change of cellular morphology and coming from PI in the cytoplasm and nucleus in portion in the cell
The ruddiness that (channel II) sends out.It is because PI Intercalations cause to DNA to come from the ruddiness that PI sends out in nucleus
PI glows, and intracytoplasmic danger signal is likely to be cell karyorhexis and enters to what is caused in cytoplasm.Do not having
In the Control release of TPE-MEM, (I-L in Figure 18) is all not detected by redness after pre-irradiation (non-display data) and irradiation
Signal (channel II).All observation results show that cell membrane becomes leaky, show in the case where there are TPE-MEM
Carrying out light irradiation can cause meronecrosis.
All results show that TPE-MEM promotes to produce ROS under room light-illuminating.TPE-MEM is except with cell membrane
Selective and fabulous light resistance, TPE-MEM can the potential lucotherapy medicine as treating cancer.In order to assess using normal
Impact of the lucotherapy of room light-illuminating TPE-MEM to HeLa cancer cell multiplications, as shown in figure 19, by mtt assay, for
Room light-illuminating 2 hours and do not irradiate 2 hours two kinds of situations and determine the cell survival of the TPE-MEM containing variable concentrations respectively
Rate.By the MTT values for determining and the relation preparation standard between the MTT values that the sample of TPE-MEM and non-illumination is measured is not contained
Curve further calculates cell survival rate.
The result of Figure 19 shows that undosed cell is that have survival rate and the cell survival rate from 0 μM -10 μM is about
90%, the sample for not containing TPE-MEM does not show toxicity Jing after room light-illuminating.However, the TPE- of Jing rooms light-illuminating
MEM produces ROS, and in the cell survival rate of the TPE-MEM containing 10 μM 47% is down to.In the case of containing TPE-MEM, Jing rooms
Between light-illuminating sample and the sample without room light-illuminating between obtain than larger cell survival rate difference.White room
Between light-illuminating be gentle, be readily available and cheaply, with reference to the high yield for producing ROS so that lucotherapy non-hazardous, resistance to
Light, dark toxicity are low.It is a kind of preferable sensitising agent (being referred to as emulsion) that all of advantage causes TPE-MEM.
Even if it is difficult to identify the mechanism that ROS materials and explanation ROS are produced, but being observed that the generation of ROS.ROS
Having shown that can strengthen the propagation of cancer cell, but the ROS levels of excess can cause cancer cell-apoptosis and necrosis.In this example
In, cell membrane biological coloring agent (TPE-MEM) produces excessive ROS by room light-illuminating, can in real time visualize original
The process of position cancer cellular necrosis.
In a word, the asymmetrical amphipathic tetraphenyl ethylene yl pyridines salt with strong AIE characteristics of synthesis
(tetraphenylethene-based pyridinium salt, TPE-MEM) can be used for cell membrane dyeing.Due to cation
With it is amphipathic, TPE-MEM cell membrane is had high specific and in living cells have splendid light resistance.Unexpected
It is only generation ROS just can effectively to be induced by TPE-MEM under normal room light-illuminating, causes meronecrosis.These are unique
Feature allows to the process of Real Time Observation meronecrosis in the original location and the process of lucotherapy.Therefore, ROS and can light is produced
The result of gamma therapy causes the shiner of the present embodiment to can be used to prepare the new AIE lucotherapy medicines for the treatment of cancer.
Embodiment 3：The amphipathic shiner TPE-2Gd of synthetic anionic simultaneously carries out the experimental study of application aspect to it
(1) TPE-2+ is synthesized
As shown in figure 3, in a nitrogen environment, 1- (3- trimethyl amido propyls) -4- picoline dibromide (1-
(3-trimethylammoniopropyl) -4-methylpyridinium dibromide) (0.5g, 1.4mmol) and 4- (1,
2,2- triphenyl vinyls) benzaldehyde (4- (1,2,2-triphenylvinyl) benzaldehyde) (1.01g, 2.8mmol)
Solution in absolute methanol back flow reaction, add three drip piperidines be catalyzed, after being cooled to room temperature, evaporation under reduced pressure
Solvent, is purified by silica gel column chromatography to residue, using dichloromethane and methyl alcohol (2：Mixed solvent 1v/v) is made
For eluant, eluent, obtain yellow product TPE-2+ (0.56g, 57%).1H NMR (400MHz, methyl alcohol-d4,δ):8.913(d,2H,J
=6.8Hz), 8.177 (d, 2H, J=6.8Hz), 7.875 (d, 1H, J=16.0Hz), 7.501 (d, 2H, J=8.4Hz),
7.352 (d, 1H, J=16.4Hz), 7.120-6.985 (m, 17H), 4.678 (t, 2H, J=12.4Hz), 3.611 (t, 2H, J=
16.8Hz),3.224(s,9H),2.600(m,2H)；13C NMR (100MHz, methyl alcohol-d4,δ):153.985,146.064,
143.359,142.763,142.666,142.535,141.710,141.079,139.581,132.603,131.121,
130.342,130.261,126.910,126.741,125.901,125.794,123.366,121.556,61.776,
55.939,52.015,24.136；HRMS(MALDI-TOF)m/z:Calculated value, 535.3102 [M-HBr-Br-]+；Measured value,
537.3263[M-HBr-Br-]+。
(2) synthesize the 5th compound 5, and TPE-2Gd is synthesized by the 5th compound 5
As shown in figure 3, by the 3rd compound 3 (163.3mg, 0.2mmol), the 4th compound 4 (214.4mg,
0.6mmol), during DCC (136.2mg, 0.66mmol) and DMAP (80.6mg, 0.66mmol) are dissolved completely in the DMF of 30mL, plus
After entering the triethylamine of 3mL, under room temperature condition, said mixture is stirred 48 hours in a nitrogen environment, the mixture after stirring
The trifluoroacetic acid of middle addition 10mL is acidified 30 minutes, then filters, and precipitates 3 times in hexane, obtains the 5th of corresponding needs the
Compound 5, yield 92%.1H NMR(400MHz,DMSO-d6,δ):8.45 (m, 2H, H of triazole benzotriazoles), 8.05
(m, 2H, H of amide acid amides), 7.60 (m, 4H；H-Ar-triazole benzotriazoles), 7.12-7.01 (m, 14H；H-Ar),
4.53(s,4H；CH2- triazole benzotriazoles), 3.83 (m, 4H；CH2C-triazole benzotriazoles), 3.57-3.13 (m, 20H；
OCH2),3.02(s,20H；CH2), C=O 2.90 (s, 20H；NCH2)；13C NMR(100MHz,DMSO-d6,δ):172.6,
169.2,145.9,143.0,142.6,140.4,131.3,130.7,129.0,127.9,126.7,124.6,121.8,69.6,
68.6,64.9,55.1,51.7,49.6；IR(KBr):ν=3437.2,2954.9,1726.3,1635.6,1460.1,
1396.4,1226.7,1089.8,974.1,908.5,700.2cm-1；HRMS(MALDI-TOF)m/z:Calculated value, 1670.5896
[M-4H+3Na+K]；Measured value, 1669.1871 [M-5H+3Na+K]+；Calculated value, 1698.5795 [M-6H+6Na]；Measured value,
1697.1949[M-7H+6Na]+；Calculated value, 1724.8194；[M-5H+2Na+3K]；Measured value, 1724.2223 [M-6H+2Na
+3K]+。
As shown in figure 3, and then by the 5th compound 5 (235.0mg, 0.15mmol), GdAc3(107.0mg,0.32mmol)
In the DMF of 20mL being dissolved in NaAc (131.2mg, 1.6mmol), after being stirred overnight under the conditions of 70 DEG C, the mixing to obtaining
Thing is filtered, and is precipitated three times in hexane, obtains corresponding required compound TPE-2Gd, yield 95%.IR(KBr):ν=
3439.1,1595.1,1409.9,1330.9,1273.0,1220.6,1095.6,933.5,707.9,653.9cm-1；HRMS
(MALDI-TOF)m/z:Calculated value, 1984.5525 [M+6H2O]；Measured value, 1984.4323 [M+6H2O]。
(3) application study
In order to reach dual-use function, synthesize in the present embodiment containing GD- diethylenetriamine pentaacetic acid (Gd-
Diethylenetriamine pentaacetic acid, DTPA) chelate TPE derivatives (TPE-2Gd), then to it
Carry out the detection of photophysical property.Uv-vis spectra shows the maximum absorption wavelength of TPE-2Gd in 330nm, with parental generation fluorescence
The maximum absorption wavelength similar (non-display data) of element-TPE.As shown in figures 20 a-20 c, when 330nm is excited, when THF/ it is water-soluble
Water content (f in liquidw) less than 50% when, the fluorescence radiation of TPE-2Gd is weaker.With fwIncrease, the fluorescence of solution gradually becomes
By force, high intensity is become in pure water solution to light, obvious AIE effects are shown.The photo of Figure 20 A is clearly demonstrated, with
FwGradually increase in the THF/ aqueous solution, the fluorescence of TPE-2Gd is strengthened.
From Figure 20 C it is noted that when stain concentration from increase to 100 μM for 1 μM when, TPE-2Gd is glimmering in pure water
Luminous intensity increased one times.Micella can be formed when speculating amphipathic TPE-2Gd molecules high concentration.Due to AIE properties, TPE-
The critical micelle concentration (CMC) of 2Gd can be estimated using fluorescence intensity.When concentration is less than CMC, dyeing agent molecule can
To be preferably dissolved in solution, therefore not luminescence.When stain concentration is higher than 10 μM, solution lights.Such as Figure 21 A-21C institutes
Show, the correlation curve between fluorescence intensity and stain concentration forms two, and the crosspoint of two lines provides CMC for 70 μM, should
Value is more much lower than the value (CMC=8.2mM) of lauryl sodium sulfate, caused by the strong-hydrophobicity mainly due to TPE aglucons.
Even so low CMC is also ensured that under blood flow dilution formed in vivo nanometer polymer.As shown in Figure 22 A and 22B,
Confirmed by transmission electron microscope and eletrokinetic potential Particle Size Analyzer and form nanometer polymer under high stain concentration.Contain
The effective diameter of glue beam is 164.9nm, and 70nm is reduced to after dehydration.The particle diameter of nanometer polymer is suitable for cell in vitro intake
With body-internal-circulation and bio distribution.
A kind of commercial Gd- base MR (Gd-based MR) contrast preparation ratified by FDAIt is a kind of allusion quotation
The extracellular fluid reagent of type, can Rapid Circulation in cell outskirt or tissue space.On the other hand, TPE-2Gd can be poly- with nanometer
The form of compound is entered in tumour cell, is imaged into line justification by living cells.HeLa cells are cultivated by 30 μM of TPE-2Gd
4 hours, TPE-2Gd entered to that this is intracellular, and by blue-fluorescence cytoplasm district is illuminated.In order to be further characterized by TPE-2Gd's
Dyeing area, using PI as counterstain.PI is the nuclear nuclei dyeing toner that can dye fixed cell.Such as Figure 23 A-
Shown in 23D, clearly illustrate that TPE-2Gd is selective in perinuclear blue-fluorescence and only cytoplasm district is dyeed.TPE-2Gd
Nanometer polymer living cells is internalized into by the approach of endocytosis so that TPE-2Gd can be on a cellular level
Tumour is followed the trail of, be compensate forThe defect of tumour is followed the trail of in tissue level.
Using mtt assay TPE-2Gd is determined in HeLa intracellular toxicity.Expose cells to the TPE- of variable concentrations
2Gd (0,15 μM, 30 μM, 45 μM and 60 μM) 4 hours, then cultivates 24 hours, for assessing nanometer in fresh culture medium
The internalization of polymer cell proliferation affects.As shown in figure 24, when the concentration of TPE-2Gd is less than 30 μM, typically do not have
Toxicity, after being processed with coloring agent, about 98.8% cell is all living.Even if concentration increases to 60 μM, compare cell imaging
The working concentration of experiment is higher by 2 times, and cell survival rate still there are about 87.8%.This result shows that TPE-2Gd is that biology can phase
Hold for cell imaging, and be expected to further carry out In vivo study.
On the other hand, in order to detect whether TPE-2Gd is effective MRI contrast agent, using 3.0T Magnetic resonance imagings
(MRI) instrument is at room temperature according to Gd3+The longitudinal relaxation time of TPE-2Gd or spin lattice (T in the concentration mensuration aqueous solution1)。
As shown in figure 25, with the increase of TPE-2Gd concentration in cushioning liquid, the signal strength signal intensity (brightness) of mixture becomes strong, and identical
Gd3+ConcentrationIt is similar.As shown in figure 26, the relaxivity for determining TPE-2Gd is 3.36 ± 0.10mM-1·s-1,Relaxivity be 3.70 ± 0.02mM-1·s-1, relaxivity referred in the contrast preparation of per unit concentration
The paramagnetism composition of spin lattice.WithCompare, TPE-2Gd has high relaxation speed, show that TPE-2Gd can be with
Strengthen the relaxation rate of its neighbouring water proton, and then cause signal strength signal intensity to strengthen.Such as Figure 27, Figure 28 A, Figure 28 B and Figure 29 institutes
Show, TPE-2GD is used as nano-particle, and the half-life in blood is longer, can be used for extending liver and cardiac MRI imaging when
Between window.
It should be appreciated that for those of ordinary skills, can according to the above description be improved or be converted,
All these improvement or conversion all should belong within the protection domain of claims of the present invention.
Claims (6)
1. a kind of amphipathic shiner with aggregation-induced emission characteristic, comprising with aggregation inducing/enhancing characteristics of luminescence
Hydrophobic unit, it is characterised in that be connected with hydrophily list on the hydrophobic units with aggregation inducing/enhancing characteristics of luminescence
Unit, any one of the structural formula of the shiner in following I, II, III, IV, V and VI；
Wherein,Represent the hydrophobic unit with aggregation inducing/enhancing characteristics of luminescence；
Represent hydrophilic units；
2. the amphipathic shiner with aggregation-induced emission characteristic according to claim 1, it is characterised in that described
Shiner water soluble, and can form micella during the concentration >=critical micelle concentration of the aqueous solution of shiner formation.
3. the amphipathic shiner with aggregation-induced emission characteristic according to claim 1, it is characterised in that described
Hydrophobic unit with aggregation inducing/enhancing characteristics of luminescence includes at least one first agent structure, first agent structure
Selected from the group for including following any structures：
Wherein, R and R (X) represent respectively the parent being connected with the hydrophobic unit with aggregation inducing/enhancing characteristics of luminescence
Aqueous unit.
4. the amphipathic shiner with aggregation-induced emission characteristic according to claim 3, it is characterised in that described
Hydrophilic units include at least one second agent structure, and second agent structure is selected from the base for including following any structures
Group：
Wherein R1、R2、R3、R4And R5Be respectively selected from include H, alkyl, unsaturated alkyl, isoalkyl, cycloalkyl, different cycloalkyl,
Aryl, different aryl and CnH2n+1、C10H7、C12H9、OC6H5、OC10H7、OC12H9、CnH2nCOOH、CnH2nNCS、CnH2nN3、
CnH2nNH2、CnH2nSH、CnH2nCl、CnH2nBr、CnH2nAt least one group in I, n is natural number；
X-For gegenion, X-Selected from I-、Cl-、Br-、PF6 -、ClO4 -、BF4 -、BPh4 -、CH3PhSO3 -。
5. the amphipathic shiner with aggregation-induced emission characteristic according to claim 4, it is characterised in that described
Hydrophobic unit with aggregation inducing/enhancing characteristics of luminescence includes structure and isGroup, the hydrophily
Unit includes structureGroup, wherein R1For propyl, X-For Br-；Specifically, it is described luminous
Thing includes the group of following structural formula TPE-MEM：
6. the amphipathic shiner with aggregation-induced emission characteristic described in a kind of claim 1-5 any claim exists
Application, the application in specific selection cell membrane coloring agent is prepared in the dyeing of specific selection cell membrane, prepare it is special
Sexual behavior mode cell membrane dyeing probe in application, the application in sensitising agent is prepared and prepare lucotherapy medicine in
Using or prepare for treating cancer lucotherapy medicine in application.
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