CN104974745B - Amphiphilic illuminant with aggregation induced emission characteristics and applications thereof - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
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Abstract
The invention relates to an amphiphilic illuminant with aggregation induced emission characteristics and applications thereof. The illuminant is prepared by connecting a hydrophilia unit on a classical hydrophobicity unit of the classical aggregation induced emission characteristics (AIE), and can be applied to a fluorescent light chemical sensor and is used for preparing fluorescent light coloring agent which is used for coloring living cells and animal imaging fluorescent light. The amphiphilic coloring agent is specifically suitable for the fluorescent light mark on biopolymer, and can be used as a biocompatibility probe for AIE activation so that the amphiphilic coloring agent can be applied to clinic cancer imaging, diagnose and treatment.
Description
Technical field
The present invention relates to fluorescent material technical field is and in particular to a kind of amphipathic have aggregation-induced emission characteristic
Shiner and its application.
Background technology
In recent years it has been found that a series of helical molecular does not light in the solution, but can be lured after being formed by polymerization
Lead and send high light, the phenomenon of this aggregation-induced emission (aggregation-induced eimission, aie) is glimmering with tradition
The gathering fluorescent quenching effect that light element shows is antipodal.Using this new effect, aie luminescent material can be in many
High-tech area is applied, such as chemical sensor, bioprobe, immune labeled, irritant reaction material and soild state transmitter etc.
[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 that prototype aie is divided
Son, its have be easily-synthesized, the high quantum production rate in the case of solid-state and the advantage such as high chemical stability and light stability, but its
Hydrophobic property significantly limit the application in biological field, in order to reduce its hydrophobicity or improve its hydrophilic, in its structure
In introduce powered functional group.For example, the tpe with two or four ammonium is luminous weaker in aqueous solution, but plus
Enter negatively charged biomolecule and reform into strong luminous body, such as add calf thymuss dna and bovine serum albumin (bsa)
[chem.commun.,2006,3705；chem.–eur.j.,2008,14,6428.].This anion tpe derivant is by sulfonic group
Group brings the hydrophobic intracavity of the main body foldable structure into bsa into, due to restriction (the restriction of of Internal Rotations of Molecules
Intramolecular rotation, rir) make luminescence enhancement.When by introducing surfactant (as lauryl sulphate acid
Sodium sds) when making bsa not folded, then no longer light [j.phys.chem.b, 2007,111,11817].Tang is common with his
Workers report the poly- n- N-isopropylacrylamide (pnipam) including tpe aglucon polymer [chem.commun.,
2009,4974], by fluorescent technique, the conformation that the pnipam chain of tpe labelling can be used for following the tracks of the polymer that temperature causes becomes
Change.On the other hand, seldom there is research and report amphipathic aie molecule.In structure, amphipathic molecule be surfactant with
And generally not only containing hydrophobic structure unit but also the organic compound containing hydrophilic structural unit.Most of amphipathic molecule hydrophobic
Tail is side chain, straight chain or aromatics hydrocarbon chain, hydrophilic head neutral, negative charge and positive charge simultaneously, be sometimes known respectively as 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 etc., wherein hydrophobic tail
Assemble and form core, hydrophilic head is concentrated on surface and contacted with the water environment of surrounding.The shapes and sizes of polymer mainly take
Certainly in the structure of amphipathic molecule and the hydrophilic 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 etc..Amphipathic and aie characteristic combination can produce one and be
Arrange new fluorescence molecule and be used for chemistry and biologic applications aspect.
Content of the invention
It is an object of the invention to provide a kind of amphipathic shiner and its application with aggregation-induced emission characteristic, solution
The shiner with aggregation-induced emission characteristic certainly of the prior art is that hydrophobic shiner leads to apply limited asking
Topic.
The present invention solves technical problem and be the technical scheme is that a kind of amphipathic there is aggregation-induced emission characteristic
Shiner, comprise the hydrophobic unit with aggregation inducing/enhancing characteristics of luminescence, have aggregation inducing/enhancing light spy
Property hydrophobic units on be connected with hydrophilic units, the structural formula of described shiner is selected from 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, described shiner water soluble,
And described shiner formed the concentration >=critical micelle concentration of aqueous solution when can form micelle.
In the amphipathic shiner with aggregation-induced emission characteristic of the present invention, described have aggregation inducing/increasing
The hydrophobic unit of the strong characteristics of luminescence includes at least one first agent structure, and described agent structure is selected from and includes following arbitrary knots
The group of structure:
Wherein, r with r (x) is represented respectively and is connected with the described hydrophobic unit with aggregation inducing/enhancing characteristics of luminescence
Hydrophilic units.
In the amphipathic shiner with aggregation-induced emission characteristic of the present invention, described hydrophilic units are selected respectively
From the group containing at least one of oh, ammonium salt, amino, mercaptan, ethohexadiol, sulfonate, phosphate and carboxylate.
In the amphipathic shiner with aggregation-induced emission characteristic of the present invention, described have aggregation inducing/increasing
The hydrophobic unit of the strong characteristics of luminescence includes structure and isGroup, described hydrophilic units include ethyl
Glycol group；Specifically, described 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 2～3000 natural number respectively,
In the amphipathic shiner with aggregation-induced emission characteristic of the present invention, described shiner is following the trail of cell
In application, the application in preparing cell tracker device, preparation for follow the trail of cell probe in application or thin in monitoring
Application in intracellular drug release process.
In the amphipathic shiner with aggregation-induced emission characteristic of the present invention, described hydrophilic units comprise to
Few one second agent structure, described second agent structure is selected from the group including following any structure:
With
Wherein r1、r2、r3、r4And r5It is respectively selected from and include 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 -.
In the amphipathic shiner with aggregation-induced emission characteristic of the present invention, described have aggregation inducing/increasing
The hydrophobic unit of the strong characteristics of luminescence includes structure and isGroup, described hydrophilic units include structure
ForGroup, wherein r1For propyl, x-For br-；Specifically, described shiner includes following knots
The group of structure formula tpe-mem:
In the amphipathic shiner with aggregation-induced emission characteristic of the present invention, described shiner selects in specificity
Select the application in cell membrane dyeing, the application in preparation specific selection cell membrane stain, specific selection is thin preparing
After birth dyeing probe in application, the application in preparing photosensitizer and preparation phototherapy medicine in application or
Prepare for the application in the phototherapy medicine for the treatment of cancer.
In the amphipathic shiner with aggregation-induced emission characteristic of the present invention, described shiner can be with metal
Ion is combined, and described 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, described metal ion is gd3+, institute
State and there is the hydrophobic unit of aggregation inducing/enhancing characteristics of luminescence include structure and beGroup, described hydrophilic
Property unit includes ethohexadiol group；Specifically, described 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
Have in the shiner of aggregation-induced emission characteristic, application in the dyeing of specific selection cytoplasm district for the described shiner, in system
For the application in the stain of specific selection cytoplasm district dyeing, in the application in cell imaging, in tracking tumor cell
Application, preparation follow the trail of tumor cell tumor cell tracker in application or preparation NMR contrast agent in
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 preparing cell tracker device, preparation 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, in preparation specific selection cell membrane
Application in stain, the application in the probe of preparation specific selection cell membrane dyeing, the application in preparing photosensitizer,
Preparation phototherapy medicine in application or preparation for treating cancer phototherapy medicine in application, in specificity
Select cytoplasm district dyeing in application, preparation specific selection cytoplasm district dyeing stain in application, in cell
Application in imaging, the application in following the trail of tumor cell, answering in the tumor cell tracker that tumor cell is followed the trail of in preparation
With or preparation NMR contrast agent in application.
Implement amphipathic shiner and its application with aggregation-induced emission characteristic of the present invention, have following beneficial
Effect: the shiner of the present invention passes through to connect hydrophilic in the hydrophobic unit of typical aggregation-induced emission characteristic (aie)
Unit is prepared from, and this shiner can be used for fluorescence chemical sensor and is used for being prepared as living cells and animal imaging fluorescence dye
The fluorescent dye of color, these amphipathic stains are particularly suitable for the fluorescent labeling of biopolymer, can be used as aie
The biocompatibility probe of activation is so that it all can be applied in terms of clinical cancer imaging, diagnosis and treatment.Specifically, (1)
The present invention is prepared for tetraphenyl ethylene (tpes) shiner that non-ionic water-soluble polyethylene glycol (peg) is modified, by Azide
Alkynes cycloaddition reaction is prepared from, to its aggregation-induced emission, micellization, sensitive characteristic and be used as intracellular one-tenth
The fluorescent visual agent of picture is all studied；(2) present invention is also prepared for the pyridiniujm shiner of the tetraphenyl ethylene base of cation,
It has aie characteristic, and alternative dyes to cell membrane, and this shiner can also produce active oxygen under room light-illuminating
(ros), this makes just to be observed that the effect of necrocytosiss and phototherapy under mild conditions；(3) present invention also successfully closes
Become new double mode NMR (Nuclear Magnetic Resonance)-imaging (mri) contrast agent (tpe-2gd), include hydrophobicity tetraphenyl ethylene unit and parent
The diethylene triamine pentacetic acid (DTPA) of aqueouss-gadolinium complex, has magnetic and can be with fluorescence imaging, experimental result shows that it is a kind of reason
The mri contrast agent thought, has diagnostic long circulation life and the short cycle life short enough removed for body.
Brief description
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 shiner in the embodiment of the present invention 2；
Fig. 3 is the synthetic route chart of tpe-2gd shiner in the embodiment of the present invention 3；
Fig. 4 a is the thf/h in different moisture content for the p1/6 shiner (0.25mg/ml)2By 365nm wavelength in o mixed liquor
The photo of ultraviolet light；
Fig. 4 b be p1/6 shiner (0.25mg/ml) in the thf/ hexane mixed liquor of different hexane content by 365nm ripple
The photo of long ultraviolet light；
Fig. 4 c is p1/6, p2/6 and p3/6 shiner respectively in the thf/h of different compositions2Relative intensity in o mixed liquor
Thf/h from different compositions2Correlogram between water content in o mixed liquor；Wherein, shiner concentration is 0.25mg/ml,
Excitation wavelength (nm): 320 (p1/6), 335 (p2/6) and 350 (p3/6)；
Fig. 4 d is relative intensity respectively in the thf/ hexane mixed liquor of different compositions for p1/6, p2/6 and p3/6 shiner
From the correlogram between hexane content in the thf/ hexane mixed liquor of different compositions；Wherein, shiner concentration is 0.25mg/
Ml, excitation wavelength (nm): 320 (p1/6), 335 (p2/6) and 350 (p3/6)；
Fig. 5 a is the ultraviolet lighting by 365nm wavelength for the aqueous solution (0.002-2mg/ml) of the p1/6 shiner of variable concentrations
The photo penetrated；
Fig. 5 b is the pl spectrogram of the aqueous solution of p1/6 shiner of variable concentrations；
Fig. 5 c is the i/i of p1/6, p2/6 and p3/6 shiner0Value and the correlation curve between corresponding concentration in water
Figure；
Fig. 6 is the related figure of the cytotoxicity of 24 hours using cck8 experimental analysiss p1/6 shiner to hepg2 cell；
Fig. 7 is the p1/6 shiner of variable concentrations to the hepg2 cell dyeing image of 12 hours lived；
Fig. 8 is p2/6 the and p3/6 shiner of 200 μ g/ml concentration to the hepg2 cell dyeing image of 24 hours lived；
Fig. 9 is the long-term first generation followed the trail of after being dyeed 24 hours by the p1/6 shiner of 150 μ g/ml to the 5th generation
The image of hepg2 cell；
Figure 10 is uv and pl spectrogram in water for the tpe-mem (40 μm), and excitation wavelength is 405nm；
Figure 11 a is tpe-mem in the thf (f containing different contentthf) thf/dmso mixed solvent in pl spectrogram,
Wherein tpe-mem concentration is 25 μm, and excitation wavelength is 405nm；
Figure 11 b is f in the pl intensity of 625nm and thf/dmso mixed solvent for the tpe-memthfBetween correlation curve
Figure, wherein tpe-mem concentration are 25 μm；Internal illustration is tpe-mem respectively in dmso solvent and thf/dmso mixed solvent
(fthf=99%) in by 365nm wavelength ultraviolet light photo；
Figure 12 is correlogram between the pl intensity and concentration of 600nm for the tpe-mem；Internal illustration is different dense
Degree tpe-mem by 365nm wavelength ultraviolet light photo；
Particle diameter photo in aqueous solution for the tpe-mem (100 μm) that Figure 13 a measures for transmission electron microscope (tem)；
The grain size curve figure of the tpe-mem of the variable concentrations that Figure 13 b measures for eletrokinetic potential Particle Size Analyzer；Internal inserts
Figure is grain size distribution in aqueous solution for the tpe-mem (100 μm) being measured by eletrokinetic potential Particle Size Analyzer；
The analysis chart of the impact to hela cell proliferation for the tpe-mem that Figure 14 measures for mtt method；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 dyeing
Laser Scanning Confocal Microscope image；
Figure 15 b is cellmasktmPeony cell membrane stain (c10046,5 μ g/ml, λex=633nm and λem=685
± 55nm) laser scanning co-focusing microscope image to hela cell dyeing；
Figure 15 c is the corresponding bright field image of Figure 15 b；
Figure 15 d is 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 (%) with tpe-mem during the increase of sweep time (solid line circle) fluorescent emission
Change curve；Internal illustration be respectively 325.7s is continuous scan before and continuous scan after by tpe-mem (5 μm)
The fluorescence imaging figure of the hela cell of work of dyeing, λex=405nm and λem=550 ± 50nm；
Figure 17 a is the pl spectrogram that there are the h2dcfda (1 μm) of tpe-mem (10 μm) under room light-illuminating, swashs
Sending out wavelength is 488nm；
Figure 17 b be irradiation time respectively to the solution containing tpe-mem, the solution containing h2dcfda or tpe-mem and
The curve chart of the impact of the pl intensity in 535nm for the solution that both h2dcfda all contain；
A-d photo in Figure 18 is the co-focusing imaging figure of the hela cell in pre-irradiation tpe-mem and pi dyeing；e-h
Photo is the co-focusing imaging figure of the hela cell of tpe-mem and pi dyeing after irradiation；I-l photo is only to use pi after irradiation
The co-focusing imaging figure of the hela cell of dyeing；C, g are respectively the image of the corresponding bright field of a, e, i with k photo；d、h
It is the merging image merging image and i/j/k merging image, e/f/g of a/b/c respectively with l；[tpe-mem]=5 μ
m；[pi]=3 μm；channel i:λex=405nm, λem=550 ± 50nm；channel ii:λex=560nm, λem=620 ±
65nm；
Figure 19 is to measure room light-illuminating tpe-mem by mtt method and do not irradiate tpe-mem respectively to hela cell
The comparison diagram of the impact of propagation；
Figure 20 a is tpe-2gd in different moisture content (fw) thf/h2o mixed solution in by 365nm ultraviolet light
Photo；
Figure 20 b is tpe-2gd in different moisture content (fw) thf/h2o mixed solution in launching light spectrogram, concentration is
100 μm, excitation wavelength is 330nm；
Figure 20 c is the relative pl intensity (i/i of variable concentrations tpe-2gd (1 μm and 100 μm)0) and thf/h2O mixing is molten
The correlogram between water content in liquid；
Figure 21 a is the photo under ultraviolet light for the tpe-2gd aqueous solution of variable concentrations；
Figure 21 b is the launching light spectrogram of the tpe-2gd aqueous solution of variable concentrations, and excitation wavelength is 330nm；
Figure 21 c is the pl intensity of tpe-2gd and the correlogram between the concentration in water, the critical glue of tpe-2gd
Group's concentration (cmc) is 70 μm；
Figure 22 a is transmission electron microscope image in water for the tpe-2gd (100 μm)；
Figure 22 b is granularmetric analyses figure in water for the tpe-2gd (100 μm)；
The fluorescence imaging figure of the hela cell that Figure 23 a dyes for tpe-2gd, [tpe-2gd]=30 μm；
The fluorescence imaging figure of the hela cell for the pi dyeing after tpe-2gd dyeing for Figure 23 b, [tpe-2gd]=30 μm；
Figure 23 c be Figure 23 a and Figure 23 b merge image, [tpe-2gd]=30 μm；
Figure 23 d is the bright field image of hela cell, [tpe-2gd]=30 μm；
Figure 24 is the analysis chart of the cell proliferative conditions to hela cell for the tpe-2gd being measured by mtt method, and cell exposes
In the tpe-2gd 4 hours of variable concentrations, after changing fresh culture medium, continue culture 24 hours；
Figure 25 is different gd3+The tpe-2gd of concentration and commercial reference productT1- weighting nuclear magnetic resonance, NMR figure
Spectrum (mr), sample is diluted by normal saline；
Figure 26 is different gd3+The tpe-2gd of concentration and commercial reference productWater proton longitudinal relaxation speed
Rate (1/t1) curve chart, 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 be 0.1mmol/kg tpe-2gd andCrown t afterwards1- weighting nuclear magnetic resonance, NMR (mr) image；
Figure 28 a is the t of heart1The quantitative analyses figure of-weighted imaging；
Figure 28 b is the t of liver1The quantitative analyses figure of-weighted imaging；
Figure 29 is that the liver angular vein injection to mice contains g d respectively3+Ion concentration be 0.1mmol/kg tpe-2gd andThe t of axial direction afterwards1- weighting nuclear magnetic resonance, NMR (mr) image.
Specific embodiment
With reference to the accompanying drawings and examples, the amphipathic shiner with aggregation-induced emission characteristic to the present invention and
Its application is described further:
It is found that aggregation-induced emission (aggregation-induced eimission, aie) is existing in calendar year 2001 by tang
As current aie phenomenon is because it is in the life of Organic Light Emitting Diode (oleds), chemical sensor, biosensor and inside and outside
The potential application of the aspects such as thing preparation has become as one of the hottest research field in the world, but most of aie molecule be all by
Aromatic ring is constituted, and therefore aie molecule is in hydrophobicity, insoluble in aqueous medium.On the other hand, seldom have been reported that with regard to water solublity aie
Molecule or amphipathic aie molecule.From this viewpoint, present invention design has synthesized some water solublity and amphipathic aie molecule, opens
Send out their potential source biomolecule application.
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) synthesize (n, m, o and p represent 2～3000 natural number respectively)
As shown in figure 1, the supply ratio synthesizing the reagent used by shiner p1/6 is as follows, the 6th compound 6, the first chemical combination
Concentration ratio [6]/[1]/[cubr]/[pmdeta] between thing 1, cubr and pmdeta be 1/4/4/4, synthesis shiner p2/6 and
The ratio of 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 compound 2 and the 3rd compound 3 is [6]/[2]/[3]=1/1/0.5.Under room temperature, equipped with 30mldmf, cubr
In the schlenk bottle of the 50ml of (172mg, 1.2mmol) and 5.3ml pmdeta (1.2mmol), the 6th compound 6 (1.05mg,
0.3mmol) He the first compound 1 (430mg, 1.2mmol) carries out Ligature, after being stirred 36 hours, with water (300ml)
Reactant mixture is diluted, with dichloromethane to this extraction with aqueous solution four times, all organic faciess is mixed, further by
Strong brine rinses six times, and passes through 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 benzotriazole), 3.85 (4h, t, j=
4.8hz,ch2ch2- triazole benzotriazole), 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 benzotriazole), 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 benzotriazole), 3.79 (8h, s, och2ch2-
Triazole benzotriazole), 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) applied research:
By the non-ionic water solublity with different chains number Polyethylene Glycol (peg) for the cycloaddition synthesis of nitrine-alkynes
Tetraphenyl ethylene (tpe)-functionalization Polyethylene Glycol (peg) shiner (p1/6, p2/6 and p3/6), by hydrophobic tpe become
Become hydrophilic molecules.These shiners show preferable heat stability, referring to table 1, the wherein t of p1/6, p2/6 and p3/6dRespectively
For 351.6 DEG C, 342.2 DEG C and 352.1 DEG C.As shown in figures 4a-4d, the polymer after these synthesis is water solublity and amphipathic
, all show aie characteristic in thf/ aqueous solvent system and thf/ hexane solvent system.In a large amount of aqueous solutions, these gather
Compound exceedes formation micellar copolymerization thing during critical micelle concentration (cmc).As shown in Fig. 5 a, 5b and 5c, by using these polymerizations
During thing coherent condition autofluorescence light property 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, the micelle of these polymer is by the nonpolar tpe head in inner side
With the hydrophilic peg chain composition pointing to aqueous medium.These polymer in below cmc, are then individually dissolved in medium and do not send out
Light, when increasing concentration to more than cmc, these polymer initially form micelle, and tpe moiety aggregation, in hydrophobic interior, shows
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 the impact to living cells for the p1/6, cytotoxicity analysis are carried out using cck8.wst-8([2-(2-
methoxy-4-nitropheny)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2h-tetrazoliun,
Monosodium salt], [2- (2- methoxyl group -4- nitrobenzophenone) -3- (4- nitrobenzophenone) -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.As Fig. 6 institute
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%, reaches 150 μ g/ in concentration
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
The compatibility.
The molecular weight of table 1:p1/6, p2/6 and p3/6 and thermal property
It is used for clinical practice aspect as pharmaceutical carrier, peg is bio-compatible and is applied to transmission organic coloring agent
Extremely intracellular.Pure stain tpe cannot penetrate into intracellular space (non-video data) because of its high hydrophobicity.Due to having
The preferably optical characteristics of aie property, are used 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 endocytosiss
Born of the same parents absorb.As shown in fig. 7, when hepg2 cell is by p1/6 dyeing 12h, can light from cytoplasmic region.Increasing with p1/6 concentration
Plus, fluorescence becomes higher, shows that the efficiency of endocytosiss depends on p1/6 dosage in the medium.Although as shown in figure 8, thin
Born of the same parents carry out cultivating the longer time with p2/6 and p3/6 of high concentration, but light 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 done the best improve dyeing after load time.For example, business is thin
Born of the same parents' tracker, celltrackertmBlue cmac (7-amino-4-chloromethylcoumarin, 7- amino -4- chloromethyl
Coumarin) and blue cmhc (4-chloromethyl-7-hydroxycoumarin, 4- chloromethyl-umbelliferone) by chlorine
Methyl functional group's functionalization.When the probe of tracker enters intracellular, probe can be entered with the mercaptan on proteins and peptides
Row reaction, but cell only can be illuminated after dyeing about 24 hours according to agreement stain.As shown in figure 9, as first
In generation, the hepg2 cell lived is exposed to p1/6 polymer 24 hours, sends high light.Because biomacromolecule peg can lock in the cell
Live fluorogen, intracellular p1/6 is passed to careful intracellular.Although the increase in hypertrophy generation makes fluorescence 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, is 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 experimentation of application aspect to it
(1) synthesize
As shown in Fig. 2 in a nitrogen environment, 1- (3- trimethyl amido propyl) -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 dehydrated alcohol, adds three piperidines to be catalyzed, cooling
To room temperature, evaporation under reduced pressure solvent, purification is carried out to residue by silica gel column chromatography, using dichloromethane and
The mixed solvent of methanol (2:1v/v), as eluant, obtains yellow product tpe-mem (0.72g, 59%).1h nmr
(400mhz, methanol-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: value of calculation, 791.3571 [m-br-]+；
Measured value, 791.3570 [m-br-]+.
(2) applied research
Cell membrane is the protective barrier of cell, most important for the integrity of cell, growth and death.In the urgent need to
Shiner to cell membrane imaging in living cells and dying cell.There is provided in the present embodiment a kind of new amphipathic with four benzene second
Pyridiniujm (tetraphenylethene-based pyridinium salt, tpe-mem) based on alkene, has significantly
Aggregation-induced emission (aie) characteristic, and for the dyeing of selecting cell film.Fluorescent probe (the tpe- of the shiner of this high yield
Mem) pass through following being synthesized, including asymmetric mcmurry reaction, suzuki coupled reaction and the doubly charged pyridiniujm of band
Condensation reaction and hexyloxy tetraphenyl ethylene benzaldehyde (hexyloxytetraphenylethene benzaldehyde) between.
Due to double charge characteristic, tpe-mem has poor dissolubility in non-polar solven, such as in thf and dcm non-polar solven
In, but solvable in polar solvent, such as solvable in water, dmf, dmso and methanol.
Figure 10 shows ultraviolet (uv) in aqueous solution (40 μm) for the tpe-mem and luminescence generated by light (pl) spectrum.tpe-
The absorption maximum wavelength of mem falls in 395nm.Biologic applications for convenience, are used 405nm to carry out pl mensure as excitation wavelength.
The light of aqueous solution excites induction in 590nm Yellow light-emitting low temperature, represents a large amount of displacements that there occurs 185nm, this is to be made by extended conjugation
With and from electron donor tpe aglucon to the Intramolecular electron transfer (intramolecular of electron acceptor pyridine unit
Charge transfer, ict) cause.
As shown in figures 11a and 11b, tpe-mem shows substantially contrary aie property, and this is due to its highly polar property
Matter leads to.The dmso solution of tpe-mem (25 μm) is luminous weaker, and in the thf of content 99%, lights in 625nm and become strong.
Molecular structure in view of tpe-mem is thus it is speculated that amphipathic tpe-mem molecule can form micelle in the case of high concentration.Deq
In the property of aie, the critical micelle concentration (cmc) of tpe-mem can be measured using the fluorescence intensity of its own.As Figure 12
Shown, the concentration of tpe-mem is molecular melting in below cmc, does not therefore produce fluorescence；In more than 0.01mm, pl intensity is anxious
Increase severely strong；Correlation curve between pl intensity and stain concentration produces two lines, and the cross point of two lines determines that cmc is
0.02mm.As shown in figures 13a andb, be 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, effectively straight with being dehydrated
Footpath tapers to 40nm.When tpe-mem when cmc the following is molecular melting it is impossible to microgranule is detected；When in cmc
(0.02mm) it can be observed that microgranule when more than.The inflection point being measured by pl is identical with cmc value.Additionally, the grain of nanometer polymer
Footpath had both been suitable for cell in vitro picked-up and body-internal-circulation, was suitable for bio distribution again.
Before cell imaging, using mtt colorimetry in the intracellular cytoactive that can measure tpe-mem of hela and thin
Cellular toxicity.Under the conditions of 37 DEG C, dark co2 incubator inner cell 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 proliferation in the fresh culture medium of incubator.As figure
Shown in 14, even if result shows that the concentration of tpe-mem in the dark reaches 20 μm of also typically no cytotoxicities.Then as pre-
Phase, tpe-mem is used for selective cell membrane dyeing and is estimated.As shown in Figure 15 a-15d, using cellmasktm
The combined staining experiment that deep red cell membrane stain (c10046) is carried out shows that the fluorescence observed from tpe-mem is to be derived from
In the cell membrane of the hela cell lived, wherein this cell membrane stain is a kind of commercially available cell membrane imaging agent.Logical
Cross and use Laser Scanning Confocal Microscope (clsm lsm7；Carl zeiss, germany) software, measure 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 stains
Suppression.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 cell microvilluss are seen on ground.Except complex staining experiment, also enter
The Z-shaped clsm that gone scans (z-stack clsm scanning).
Cell membrane is the organelle showing larger nagative potential on the interface of film, phospholipid bilayer master on this organelle
To be made up of thin amphipathic phospholipid bilayer.Therefore, cell membrane target organism stain typically requires that to meet be amphipathic
And cation., to meet the amphipathic of cell membrane, this is new for designing for the hydrophobicity of coordinated balance molecule and hydrophilic
Cell membrane biological stain is most important.Tpe-mem has the amphipathic and characteristic with positive lotus, therefore can be used as splendid using it
Biological dye, for the cell membrane of specific stain living cells.Amphipathic tpe-mem is spontaneous to be arranged in phospholipid bilayer,
So that make hydrophobic tail region with around polar liquid be isolated bilayer in and hydrophilic head region be to electrostatically attracted to
The phosphate of negative charge.As electrostatic force and Van der Waals interaction force (van der waals interactions)
Dye etc. leading to specific targets.
For cell imaging stain, light resistance is one of most important standard.Some for specific cell dyeing
Aie stain is all high-light-fastness.Helical molecular structures and its polymerization forming process can stop oxygen from diffusing into aie
In microgranule, oxygen enters meeting oxyluciferin in aie microgranule and rolls into a ball and so that its pl is lighted and bleaches.As shown in figure 16, in living cells
Obtain similar light resistance result.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 and imaging are bright
Degree slightly decreases, and this is diffusion due to stain and the movement of cell.
As shown in figure 16, bubble can be seen in series of scans in clsm time course.It is apparent that cell fine hair shrinks
And disappear, it is then based on laser scanning, cell expansion is simultaneously revealed it is seen that cytoplasma membrane becomes discontinuous and is seepage.This
Phenomenon shows the reason cell death is led to by laser scanning, and this just excites people's follow-up study strongly.Pi-conjugated
Phenothiazine (phenothiazinium) the base molecule in system with positive charge is widely used in active oxygen (ros) generation and light
Therapy.Compared with phenothiazine, tpe-mem also has positive charge in Pi-conjugated systems, and this is possible to so that photoinduction ros is given birth to
Become, lead to cell death.
In order to confirm above-mentioned it is assumed that carrying out ros detection using commercial ros fluorescent probe h2dcfda.When by already present
During ros oxidation h2dcfda, can detect in 535nm (λex=488nm) transmitting hyperfluorescence.Surprisingly, normally white
Room light (LED lamp steeps, 3w) is irradiated to during tpe-mem solution and produces ros enough.Pbs solution containing h2dcfda, contain
The pl spectrum of the pbs solution of tpe-mem and simultaneously the pbs solution containing h2dcfda and tpe-mem is all in identical room
Light-illuminating obtains.Pl spectrum (Figure 17 a, the λ of record sample difference irradiation timeex=488nm) and the peak value of 535nm strong
Correlation curve (Figure 17 b) between degree and irradiation time.In Figure 17 a, when there is h2dcfda and tpe-mem in solution simultaneously
When, oxidized h2dcfda occurs and with light irradiation enhancing in the characteristic peak of 535nm.Even if measurement result shows compartment lamp
The light irradiation time, pl intensity still persistently strengthened, and so that fluorescence is bleached within ultraviolet light only a few minutes more than 120 minutes
(non-video 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 producing when tpe-mem, lead to cell damage and death.
However, the pathology of cell death still cannot be explained.The integrity of cell membrane be most important morphological feature it
One, for distinguishing apoptosis and necrocytosiss.During necrocytosiss, cell expansion, cell membrane become leaky simultaneously
Division, final cell exchanges material with surrounding.Propidium iodide (propidium iodide, pi) is impermeable by thin
After birth, generally exclusion is outside living cells.When cell membrane is leaky, pi is usually used in the karyon dyeing to dead cell.Cause
This, pi is open to be used for identifying dead cell in a large amount of cells and as counterstain in multicolor fluorescence technology.In this example
In, as shown in figure 18, tpe-mem adds and is marked to the culture medium have living cells, then is introduced to observe base by pi
Interior.As shown in the a-d in Figure 18, the tpe-mem (channel coming from cell membrane only can be detected before light irradiation
I) gold-tinted.When irradiating cell about 5 minutes (30scans), then irradiate another and be used for absorbing pi for 5 minutes, such as Figure 18
In e-h shown in, in the cell it is observed that the change of cellular morphology and come from pi in the Cytoplasm in portion and nucleus
The HONGGUANG that (channel ii) is sent out.Coming from the HONGGUANG that pi sent out in nucleus is because pi Intercalation leads to dna
Pi glows, and intracytoplasmic danger signal is likely to be cell karyorhexises enters to and cause in Cytoplasm.Do not having
In the Control release of tpe-mem, after pre-irradiation (non-video data) and irradiation, (i-l in Figure 18) is all not detected by redness
Signal (channel ii).All observed result display cell membrane become leaky, show in the case of there are tpe-mem
Carry out light irradiation and can cause necrocytosiss.
All results show that tpe-mem promotes to produce ros under room light-illuminating.Tpe-mem is except having cell membrane
Selectivity and fabulous light resistance, tpe-mem can the potential phototherapy medicine as treating cancer.In order to assess using normal
The impact to hela cancer cell multiplication for the phototherapy of room light-illuminating tpe-mem, as shown in figure 19, by mtt method, for
Room light-illuminating 2 hours and do not irradiate 2 hours two kinds of situations and measure the cell survival of the tpe-mem containing variable concentrations respectively
Rate.Relation preparation standard between the mtt value being recorded by the mtt value measuring and the sample not containing tpe-mem and non-illumination
Curve and then calculating 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 not containing tpe-mem does not show toxicity after room light-illuminating.However, the tpe- through room light-illuminating
Mem produces ros, is down to 47% in the cell survival rate of the tpe-mem containing 10 μm.In the case of containing tpe-mem, through room
Between obtain than larger cell survival rate difference between the sample of light-illuminating and the sample without room light-illuminating.White room
Between light-illuminating be gentle, be readily available and cheaply, in conjunction with the high yield producing ros so that phototherapy non-hazardous, resistance to
Light, dark toxicity are low.It is a kind of preferable photosensitizer (being referred to as photosensitizer) that all of advantage makes tpe-mem.
Even if being difficult to the mechanism that identification ros material and explanation ros produce, but it is observed that the generation of ros.ros
Have shown that the propagation that can strengthen cancerous cell, but the ros level of excess can lead to cancer cell-apoptosis and necrosis.In this example
In, cell membrane biological stain (tpe-mem) passes through room light-illuminating and produces excessive ros, can visualize former in real time
The process of position cancer cellular necrosis.
In a word, the asymmetrical amphipathic tetraphenyl ethylene yl pyridines salt with strong aie characteristic of synthesis
(tetraphenylethene-based pyridinium salt, tpe-mem) can be used for cell membrane dyeing.Due to cation
With amphipathic, tpe-mem has high specific and has splendid light resistance in living cells to cell membrane.Unexpected
It is only to pass through tpe-mem under normal room light-illuminating and just can effectively induce generation ros, lead to necrocytosiss.These are unique
Feature allows to the process of Real Time Observation necrocytosiss in the original location and the process of phototherapy.Therefore, produce ros and can light
The result of gamma therapy makes the shiner of the present embodiment can be used for preparing the new aie phototherapy medicine for the treatment of cancer.
Embodiment 3: the amphipathic shiner tpe-2gd of synthetic anionic simultaneously carries out the experimentation of application aspect to it
(1) synthesize tpe-2+
As shown in figure 3, in a nitrogen environment, 1- (3- trimethyl amido propyl) -4- picoline dibromide (1-
(3-trimethylammoniopropyl) -4-methylpyridinium dibromide) (0.5g, 1.4mmol) and 4- (1,
2,2- triphenyl vinyl) benzaldehyde (4- (1,2,2-triphenylvinyl) benzaldehyde) (1.01g, 2.8mmol)
Solution in absolute methanol back flow reaction, add three piperidines be catalyzed, after being cooled to room temperature, evaporation under reduced pressure
Solvent, carries out purification by silica gel column chromatography to residue, and the mixed solvent using dichloromethane and methanol (2:1v/v) is made
For eluant, obtain yellow product tpe-2+ (0.56g, 57%).1H nmr (400mhz, methanol-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, methanol-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: value of calculation, 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), dcc (136.2mg, 0.66mmol) and dmap (80.6mg, 0.66mmol) is dissolved completely in the dmf of 30ml, plus
After entering the triethylamine of 3ml, under room temperature condition, in a nitrogen environment said mixture is stirred 48 hours, the mixture after stirring
The trifluoroacetic acid of middle addition 10ml is acidified 30 minutes, then filters, and precipitates 3 times in hexane, the 5th being needed accordingly
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 amide), 7.60 (m, 4h；H-ar-triazole benzotriazole), 7.12-7.01 (m, 14h；h-ar),
4.53(s,4h；ch2- triazole benzotriazole), 3.83 (m, 4h；ch2C-triazole benzotriazole), 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: value of calculation, 1670.5896
[m-4h+3na+k]；Measured value, 1669.1871 [m-5h+3na+k]+；Value of calculation, 1698.5795 [m-6h+6na]；Measured value,
1697.1949[m-7h+6na]+；Value of calculation, 1724.8194；[m-5h+2na+3k]；Measured value, 1724.2223 [m-6h+2na
+3k]+.
As shown in figure 3, then by the 5th compound 5 (235.0mg, 0.15mmol), gdac3(107.0mg,0.32mmol)
It is dissolved in the dmf of 20ml with naac (131.2mg, 1.6mmol), after being stirred overnight under the conditions of 70 DEG C, to the mixing obtaining
Thing filters, and precipitates 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: value of calculation, 1984.5525 [m+6h2o]；Measured value, 1984.4323 [m+6h2o].
(3) applied research
In order to reach dual-use function, synthesize in the present embodiment and contained gd- diethylenetriamine pentaacetic acid (gd-
Diethylenetriamine pentaacetic acid, dtpa) chelate tpe derivant (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 of element-tpe is similar (non-video data).As shown in Figure 20 a-20c, when 330nm excites, when thf/ 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, become high intensity in pure water solution to light, show obvious aie effect.The photo of Figure 20 a clearly demonstrates, with
FwThf/ aqueous solution is gradually increased, the fluorescence of tpe-2gd is strengthened.
From Figure 20 c it is noted that when stain concentration is when increasing to 100 μm for 1 μm, tpe-2gd is glimmering in pure water
Light intensity increased one times.Micelle can be formed when speculating amphipathic tpe-2gd molecule high concentration.Due to aie property, tpe-
The critical micelle concentration (cmc) of 2gd can be estimated using fluorescence intensity.When concentration is less than cmc, dyeing agent molecule is permissible
Preferably it is dissolved in solution, therefore not luminescence.When stain concentration is higher than 10 μm, solution lights.As Figure 21 a-21c institute
Show, the correlation curve between fluorescence intensity and stain concentration forms two, the cross point of two lines provides cmc and is 70 μm, should
Value is more much lower than the value (cmc=8.2mm) of sodium lauryl sulphate, and the strong-hydrophobicity mainly due to tpe aglucon leads to.
Even so low cmc also ensures that formation nanometer polymer in vivo under blood flow dilution.As shown in Figure 22 a and 22b,
Formation nanometer polymer under high stain concentration is confirmed by transmission electron microscope and eletrokinetic potential Particle Size Analyzer.Contain
The effective diameter of glue bundle is 164.9nm, is reduced to 70nm after dehydration.The particle diameter of nanometer polymer is suitable for cell in vitro picked-up
With body-internal-circulation and bio distribution.
A kind of commercial gd- base mr (gd-based mr) contrast agent ratified by fdaIt is a kind of typical case
Extracellular fluid reagent, can Rapid Circulation in cell outskirt or interstice.On the other hand, tpe-2gd can be with nanometer polymerization
The form of thing enters in tumor cell, is imaged into line justification by living cells.Hela cell cultivates 4 by 30 μm of tpe-2gd
Hour, tpe-2gd enters to that this is intracellular, illuminates cytoplasm district by blue-fluorescence.In order to be further characterized by the dye of tpe-2gd
Zone, is used pi as counterstain.Pi is the nuclear nuclei dyeing toner that can dye fixing cell.As Figure 23 a-23d
Shown, clearly illustrate that tpe-2gd selectivity only dyes to cytoplasm district in perinuclear blue-fluorescence.Tpe-2gd's
Nanometer polymer is internalized into living cells by the approach of endocytosiss so that tpe-2gd can chase after on a cellular level
Track tumor, compensate forThe defect of tumor is followed the trail of on tissue level.
Determine tpe-2gd using mtt method in the intracellular toxicity of hela.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 impact of polymer cell proliferation.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 stain, about 98.8% cell is all alive.Even if concentration increases to 60 μm, compare cell imaging
The working concentration of experiment exceeds 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 carry out further In vivo study.
On the other hand, in order to detect whether tpe-2gd is effective mri contrast agent, using 3.0t NMR (Nuclear Magnetic Resonance)-imaging
(mri) instrument is at room temperature according to gd3+The longitudinal relaxation time of tpe-2gd or spin lattice (t in concentration mensuration aqueous solution1).
As shown in figure 25, with the increase of tpe-2gd concentration in buffer solution, the signal intensity (brightness) of mixture becomes strong, and identical
gd3+ConcentrationSimilar.As shown in figure 26, the relaxivity measuring tpe-2gd is 3.36 ± 0.10mm-1·s-1,Relaxivity be 3.70 ± 0.02mm-1·s-1, relaxivity refers in the contrast agent of per unit concentration
The paramagnetism composition of spin lattice.WithCompare, tpe-2gd has high relaxation speed, show that tpe-2gd is permissible
Strengthen the relaxation rate of its neighbouring water proton, and then lead to signal intensity to strengthen.As Figure 27, Figure 28 a, Figure 28 b and Figure 29 institute
Show, as nanoparticle, the half-life in blood is longer for tpe-2gd, can be used for extend liver and heart mri imaging when
Between window.
It should be appreciated that for those of ordinary skills, can be improved according to the above description or be converted,
All these improvement or conversion all should belong within the protection domain of claims of the present invention.
Claims (3)
1. a kind of amphipathic shiner with aggregation-induced emission characteristic, comprises with aggregation inducing/enhancing characteristics of luminescence
Hydrophobic unit it is characterised in that being connected with hydrophilic list on the hydrophobic units with aggregation inducing/enhancing characteristics of luminescence
Unit, the structural formula of described shiner is selected from any one in following i, ii, iii, iv, v and vi；
Wherein,Represent the hydrophobic unit with aggregation inducing/enhancing characteristics of luminescence；
Represent hydrophilic units；
The described hydrophobic unit with aggregation inducing/enhancing characteristics of luminescence includes structure and is
Group, described hydrophilic units include ethohexadiol group；Specifically, the knot of described shiner
Structure formula is any structure formula in following structural formula p1/6, p2/6 and p3/6；Wherein n, m, o and p represent 2～3000 nature respectively
Number,
2. the amphipathic shiner with aggregation-induced emission characteristic according to claim 1 is it is characterised in that described
Shiner water soluble, and micelle can be formed during the concentration >=critical micelle concentration of aqueous solution of described shiner formation.
3. the amphipathic shiner with aggregation-induced emission characteristic described in any claim in a kind of claim 1-2
Application in following the trail of cell, the application in preparing cell tracker device, the application in preparing the probe being used for following the trail of cell
Or the application during monitoring Intracellular drug release.
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