CN106986876B - A kind of targeting marks fluorescence probe, its preparation and the application of eye lens epithelial cell - Google Patents
A kind of targeting marks fluorescence probe, its preparation and the application of eye lens epithelial cell Download PDFInfo
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- 210000001542 lens epithelial cell Anatomy 0.000 title claims abstract description 32
- 239000000523 sample Substances 0.000 title claims abstract description 30
- 230000008685 targeting Effects 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 239000000843 powder Substances 0.000 claims abstract description 9
- 239000007787 solid Substances 0.000 claims abstract description 9
- 150000003233 pyrroles Chemical class 0.000 claims abstract description 8
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000000926 separation method Methods 0.000 claims abstract description 7
- 238000000605 extraction Methods 0.000 claims abstract description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims abstract description 5
- 238000004440 column chromatography Methods 0.000 claims abstract description 5
- 239000012043 crude product Substances 0.000 claims abstract description 5
- 238000006392 deoxygenation reaction Methods 0.000 claims abstract description 5
- 239000012074 organic phase Substances 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- 238000001816 cooling Methods 0.000 claims abstract description 4
- 230000008556 epithelial cell proliferation Effects 0.000 claims abstract description 4
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- 239000000203 mixture Substances 0.000 claims description 11
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- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 7
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
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- 239000002253 acid Substances 0.000 description 1
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- 238000004458 analytical method Methods 0.000 description 1
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- 229940049954 penicillin Drugs 0.000 description 1
- RQGPLDBZHMVWCH-UHFFFAOYSA-N pyrrolo[3,2-b]pyrrole Chemical compound C1=NC2=CC=NC2=C1 RQGPLDBZHMVWCH-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/006—Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1003—Carbocyclic compounds
- C09K2211/1007—Non-condensed systems
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of fluorescence probe of targeting label eye lens epithelial cell, its preparation and applications, belong to fluorescent sensing material field.The fluorescence probe is DPPHP-2CHO, while having the function of that in situ target marks eye lens epithelial cell and inhibit eye lens epithelial cell proliferation, is suitable for treatment cataract field；First by 1; bis- (the 4- bromophenyls) -2 of 4-; simultaneously [3,2-b] pyrroles, 4- aldehyde radical phenyl boric acid and catalyst are added in reaction vessel 5- diphenyl-Isosorbide-5-Nitrae-pyrrolin; it vacuumizes and fills protection gas more than twice; the solvent Ι of deoxygenation is added, back flow reaction, first cooling adds solvent II and extracted; the organic phase that extraction and separation are obtained is first dry with anhydrous magnesium sulfate, then is spin-dried for obtaining crude product；Purified on column chromatography separating-purifying, dry, obtaining solid powder is the fluorescence probe.
Description
Technical field
The present invention relates to a kind of fluorescence probe of targeting label eye lens epithelial cell, its preparation and applications, and in particular to
One kind containing 2, the 5- diphenyl of 4,4'- dialdehyde-based and the fluorescence probe of azole derivatives, its preparation and application, belongs to fluorescence biography
Feel Material Field.
Background technique
Currently, cataract has become the main reason for global diseases causing blindness, in China, therefore to account for about the whole world white for sick blinding number
The 10% of cataract or glaucoma blinding number, and annual also newly-increased 1,000,000 cataract cases, in particular with aging of population, this number still exists
Sustainable growth.Although cataract extraction and implantable artificial crystalline lens are that current treatment cataract is most mature with ideal method,
Artificial lens cannot replace the function of crystal of human eye there are still certain defect completely, especially for youngsters and children with
The growth at age is frequently accompanied by the pain that some postoperative complications cause patient that must not be not subject to correction of refractive errors or second operation.
In these complication, most commonly first operation eye lens epithelial cell excision cannot be complete, so that residual fraction continues
Posterior capsule opacification caused by hyperplasia, to influence patient's vision again, 5 years disease incidence are up to 30% after surgery.Although existing
Stage can cut off muddy Lens capsular by operation, but considerably increase body and the financial burden of patient, and can be adjoint
There is new complication to occur.Therefore how disposably to eradicate cataract and prevent the generation of complication as oculist and patient
The problem all extremely paid close attention to.(Barbosa-Sabanero,K.；Hoffmann,A.；Judge,C.；Lightcap,N.；
Tsonis,P.A.；Rio-Tsonis,K.D.Lens and retina regeneration:new perspectives from
model organisms.Biochem.J.,2012,447,321-334.Mamalis,N.；Davis,B.；Nilson,C.D.；
Hickman,M.S.；Leboyer,R.M.J.Complications of foldable intraocular lenses
requiring explantation or secondary intervention.Cataract Refract.Surg.,2004,
30,2209-2218.Lois,N.；Taylor,J.；Mckinnon,A.D.；Forrester,J.V.Posterior capsule
opacification in mice.Arch.Ophthalmol.,2005,123,71-77.Tsonis,P.A.；Rio-Tsonis,
K.D.Lens and retina regeneration:transdifferentiation,stem cells and clinical
applications.Exp.Eye Res.,2004,78,161-172.Arlene Gwon,M.D.Lens regeneration
in mammals:a review.Surv.Ophthalmol.,2006,51,51-62.)。
Summary of the invention
It can not disposably be cut off completely for eye lens epithelial cell in current cataract procedure and cause complicated by postoperative
It is the problem of disease, described glimmering one of the objects of the present invention is to provide a kind of fluorescence probe of targeting label eye lens epithelial cell
Light probe has the function of that in situ target marks eye lens epithelial cell and inhibit eye lens epithelial cell proliferation simultaneously, is controlling
Cataract field is treated to have a good application prospect；The second purpose is to provide a kind of fluorescence of targeting label eye lens epithelial cell
The preparation method of probe, the preparation method is simple, easy to operate.
The purpose of the present invention is realized by the following technical scheme:
It is a kind of targeting label eye lens epithelial cell fluorescence probe, the fluorescence probe be DPPHP-2CHO (4', 4 "-
(2,5- Diphenyl Pyrroles simultaneously [3,2-b] pyrroles-Isosorbide-5-Nitrae-two) bis- ([1,1'- biphenyl] -4- formaldehyde)), structural formula is as follows:
A kind of preparation method of the fluorescence probe of targeting label eye lens epithelial cell of the present invention, the method step
It is rapid as follows:
By bis- (4- the bromophenyl) -2,5- diphenyl -1,4- pyrrolin of 1,4- simultaneously [3,2-b] pyrroles, 4- aldehyde radical phenyl boric acid
And catalyst is added in reaction vessel, is vacuumized and is filled protection gas more than twice, the solvent Ι of deoxygenation is added, flow back 8h~12h
Afterwards, first cooling adds solvent II and is extracted, and the organic phase that extraction and separation are obtained is first dry with anhydrous magnesium sulfate, then is spin-dried for
Obtain crude product；Purified on column chromatography separating-purifying, dry, obtaining solid powder is the fluorescence probe.
The catalyst be four (triphenyl phosphorus) palladiums and potassium carbonate mixture, the amount of the substance of four (triphenyl phosphorus) palladiums with
The ratio between amount of potassium carbonate substance is 1:100.
Bis- (4- the bromophenyl) -2,5- diphenyl -1,4- pyrrolin of 1,4- simultaneously [3,2-b] pyrroles: 4- aldehyde radical phenyl boric acid: four
Triphenyl phosphorus palladium: the preferred 1:3:0.05:5 of the molar ratio of potassium carbonate；
Protect the preferred nitrogen of gas or argon gas.
Solvent Ι is the mixed solvent of toluene and methanol, the volume and the preferred 3:1 of methanol volume ratio of toluene.
Solvent II is the mixture of water and methylene chloride.
The mixture of the preferred methylene chloride of eluant, eluent, ethyl acetate and petroleum ether, dichloro in pillar layer separation purification process
Methane: ethyl acetate: the preferred 1:1:6 of the volume ratio of petroleum ether.
A kind of application of the fluorescence probe of targeting label eye lens epithelial cell of the present invention, the fluorescence probe are suitable
For treating cataract field, there is targeting mark function in situ to eye lens epithelial cell, and have and inhibit on eye lens
The function of epithelial cell proliferation.
The utility model has the advantages that
(1) fluorescence probe of the present invention can carry out eye lens epithelial cell to target fluorescent marker in situ, and for
The ICR mouse embryonic fibroblasts of normal cell model be can be used as without obvious fluorescent marker effect, can effectively screen eye lens
Epithelial cell and normal cell help to remove eye lens epithelial cell in cataract procedure as much as possible, to realize
One-time cure cataract；
(2) fluorescence probe of the present invention is proliferated without obvious inhibiting effect (administration 96 ICR mouse embryonic fibroblasts
Cell survival rate is still 90% or more after hour), and occur after administration 24 hours to the proliferation of eye lens epithelial cell obvious
Inhibit, illustrate this fluorescence probe to the other cells of eye and organize without overt toxicity, and can effectively inhibit to remain eye lens epithelium
The proliferation of cell effectively avoids the appearance of postoperative complications.
Detailed description of the invention
Fig. 1 is the synthetic route of DPPHP-2CHO in embodiment 1.
Fig. 2 is fluorescence spectrum of the DPPHP-2CHO in dimethyl sulfoxide/phosphate buffer solution system in embodiment 1
Figure, excitation wavelength 340nm.
Fig. 3 is fluorescence spectrum of the DPPHP-2CHO in dimethyl sulfoxide/phosphate buffer solution system in embodiment 1
Figure, excitation wavelength 450nm.
Fig. 4 be embodiment 1 in DPPHP-2CHO in dimethyl sulfoxide/phosphate buffer solution system fluorescence intensity with phosphorus
The increased change curve of hydrochlorate buffer solution content, excitation wavelength 340nm.
Fig. 5 be embodiment 1 in DPPHP-2CHO in dimethyl sulfoxide/phosphate buffer solution system fluorescence intensity with phosphorus
The increased change curve of hydrochlorate buffer solution content, excitation wavelength 450nm.
Fig. 6 is fluorescence spectrum of the DPPHP-2CHO in dimethyl sulfoxide/DMEM in high glucose culture medium system in embodiment 2
Figure, excitation wavelength 340nm.
Fig. 7 is fluorescence spectrum of the DPPHP-2CHO in dimethyl sulfoxide/DMEM in high glucose culture medium system in embodiment 2
Figure, excitation wavelength 450nm.
Fig. 8 be embodiment 2 in DPPHP-2CHO in dimethyl sulfoxide/DMEM in high glucose culture medium system fluorescence intensity with training
Support the increased change curve of base content, excitation wavelength 340nm.
Fig. 9 be embodiment 2 in DPPHP-2CHO in dimethyl sulfoxide/DMEM in high glucose culture medium system fluorescence intensity with training
Support the increased change curve of base content, excitation wavelength 450nm.
Figure 10 is that DPPHP-2CHO concentration is 1 × 10 in embodiment 4-4Respectively to eye lens epithelial cell and ICR when mol/L
The survival rate of mouse embryonic fibroblasts changes with time comparison diagram.
Specific embodiment
The present invention is described in detail in the following with reference to the drawings and specific embodiments.
The main agents information mentioned in following embodiment is shown in Table 1, and key instrument and facility information are shown in Table 2.
Table 1
Table 2
In embodiment bis- (4- bromophenyl) -2,5- diphenyl -1,4- pyrrolin of 1,4- used simultaneously [3,2-b] pyrroles be by
According to document (Peng, Z.；Ji Y.C.；Wang,Z.；Tong,B.；Shi,J.B.；Dong,Y.P.Properties of
polymorphism and acid response of pyrrolopyrrole-based derivative with
Aggregation-induced emission behavior.Acta.Chim.Sinica., 2016,74,942-948.) in note
The method preparation of load.
0.05% trypsase: made of being diluted 0.25% trypsase of purchase with PBS.
The lagophthalmos Lens Epithelial Cells (BLE cell) and ICR mice embryonic of confluent cultures ware bottom 80~90% are at fibre
Dimension cell (MEF cell): respectively by BLE cell for being derived from 9 weeks male rabbit eye lens, be derived from the 12.5 days females of being pregnant
In the DMEM in high glucose culture medium that it is 20%FBS containing volume fraction that the MEF cell of ICR mice embryonic, which is put into, then it is placed in 37 DEG C, CO2
It cultivates and obtains in the incubator that volume fraction is 5%.
Embodiment 1
(1) bis- (4- the bromophenyl) -2,5- diphenyl -1,4- pyrrolin of the 1,4- of 56.8mg (0.1mmol) simultaneously [3,2- is taken
B] pyrroles, 45mg (0.3mmol) 4- aldehyde radical phenyl boric acid, 6mg (0.005mmol) four (triphenyl phosphorus) palladium, 67.5mg (0.5mmol)
Potassium carbonate is added to two mouthfuls of round-bottomed flasks of 100mL, and three times, the mixing of the toluene and methanol of 12mL deoxygenation is added in vacuum nitrogen gas
Solvent (toluene and methanol volume ratio be 3:1), it is after the 8h that flows back at 110 DEG C, the reaction solution in two mouthfuls of round-bottomed flasks is cooling
To room temperature, the mixture (V of water and methylene chloride that volume is twice of reaction solution volume is addedWater:VMethylene chloride=1:1) extraction
Reaction solution, the organic phase isolated is first dry with anhydrous magnesium sulfate, then be spin-dried at 40 DEG C using Rotary Evaporators,
Obtain crude product；Purified on column chromatography separating-purifying is dried under being placed in 25 DEG C of vacuum oven, obtains yellow
Solid powder is the fluorescence probe for targeting label eye lens epithelial cell, and the synthetic route of the fluorescence probe is detailed in Fig. 1, is produced
Rate 24%；
Wherein, eluant, eluent used by pillar layer separation purifies is the mixture of methylene chloride, ethyl acetate and petroleum ether,
Methylene chloride: ethyl acetate: the volume ratio of petroleum ether is 1:1:6.
As nuclear magnetic resonance chemical analyser and MALDI _ TOFMS instrument to obtained by the present embodiment
To yellow solid powder characterized, nucleus magnetic hydrogen spectrum and mass spectrometric data are as follows:
1H-NMR (400MHz, CDCl3) δ (ppm): 10.07 (s, 2H), 7.98-7.96 (d, 4H), 7.80-7.78 (d,
2H), 7.67-7.65 (d, 2H), 7.42-7.40 (d, 2H), 7.29-7.21 (m, 29H), 6.51 (s, 2H)；
MS(MALDI-TOF):calcd.for C44H30N2O2, 618.3；Found, 618.6；
According to nucleus magnetic hydrogen spectrum and mass spectrographic data it is found that the obtained yellow solid powder of the present embodiment is DPPHP-
2CHO。
(2) DPPHP-2CHO prepared in 1.9mg step (1) is dissolved in 3mL dimethyl sulfoxide (DMSO) be made into it is dense
Degree is 1 × 10-3The solution a of mol/L, then taking 0.3mL solution a and being diluted to concentration with DMSO is 1 × 10-4The solution b of mol/L,
The fluorescence intensity that solution b is surveyed using sepectrophotofluorometer, is denoted as I0；
(3) the solution a in 0.3mL step (2) is taken respectively, is separately added into the phosphate buffer solution (PBS) of different volumes
By solution a with architectonical be DMSO/PBS, concentration is 1 × 10-4The solution c of mol/L, and the fluorescence intensity of solution c is measured, it is denoted as
Ik；
Wherein, the pH of PBS solution is 7.4, and the volume ratio of DMSO and PBS is respectively 9:1,8:2,7 in system DMSO/PBS:
3,6:4,5:5,4:6,3:7,2:8,1:9；IkIndicate DMSO/PBS in proportion k mixing after corresponding DPPHP-2CHO fluorescence it is strong
Degree, k 9:1,8:2,7:3,6:4,5:5,4:6,3:7,2:8,1:9；
(4) according to the test result of step (3) draw DPPHP-2CHO in DMSO/PBS mixed system fluorescence intensity with
The variation of PBS content and the tendency chart that changes, as shown in Fig. 2, when excitation wavelength is 340nm, the DPPHP- at 429nm
2CHO fluorescent absorption peak intensity is gradually reduced with the increase of PBS content；And DPPHP-2CHO is only at wavelength 560nm
Fluorescence is weaker in the presence of DMSO, as the increase fluorescence intensity of PBS content gradually increases, when DMSO in system and PBS volume ratio
Fluorescence intensity reaches maximum when for 5:5, the increment rate (I compared with initial fluorescent intensityk-I0)/I0About 1.82 (Fig. 4), with
PBS content continues growing, and fluorescence intensity is on a declining curve, and when DMSO is 1:9 with PBS volume ratio, increment rate is about 0.93,
It is still higher than I0, show that there is DPPHP-2CHO aggregation to enhance (AEE) characteristic that shines.When PBS content is more than 50%, by excitation wave
Length is changed to 450nm, and DPPHP-2CHO maximum absorption band from 560nm red shift to 618nm (Fig. 3), fluorescence intensity is with PBS content
Increase and increase, when DMSO and PBS volume ratio are 2:8 in system, fluorescence intensity reaches maximum (Fig. 5).
Embodiment 2
(1) take bis- (4- the bromophenyl) -2,5- diphenyl -1,4- pyrrolin of the 1,4- of 113.6mg (0.2mmol) simultaneously [3,
2-b] pyrroles, 90mg (0.6mmol) 4- aldehyde radical phenyl boric acid, 12mg (0.01mmol) four (triphenyl phosphorus) palladium, 135mg (1mmol)
Potassium carbonate is added to two mouthfuls of round-bottomed flasks of 100mL, and three times, the mixing of the toluene and methanol of 12mL deoxygenation is added in vacuum nitrogen gas
Solvent (toluene and methanol volume ratio be 3:1), after the 8h that flows back at 110 DEG C, but extremely by the reaction solution in two mouthfuls of round-bottomed flasks
Room temperature adds the mixture (V of water and methylene chloride that volume is twice of reaction solution volumeWater:VMethylene chloride=1:1) extraction is instead
Solution is answered, the organic phase isolated is first dry with anhydrous magnesium sulfate, then be spin-dried at 40 DEG C using Rotary Evaporators, it obtains
To crude product；Purified on column chromatography separating-purifying is dried under being placed in 25 DEG C of vacuum oven, and it is solid to obtain yellow
Body powder is the fluorescence probe for targeting label eye lens epithelial cell, yield 24%；
Wherein, eluant, eluent used by pillar layer separation purifies is the mixture of methylene chloride, ethyl acetate and petroleum ether,
Methylene chloride: ethyl acetate: the volume ratio of petroleum ether is 1:1:6.
As nuclear magnetic resonance chemical analyser and MALDI _ TOFMS instrument to obtained by the present embodiment
To yellow solid powder characterized, nucleus magnetic hydrogen spectrum and mass spectrometric data are as follows:
1H-NMR (400MHz, CDCl3) δ (ppm): 10.07 (s, 2H), 7.98-7.96 (d, 4H), 7.80-7.78 (d,
2H), 7.67-7.65 (d, 2H), 7.42-7.40 (d, 2H), 7.29-7.21 (m, 29H), 6.51 (s, 2H)；
MS(MALDI-TOF):calcd.for C44H30N2O2, 618.3；Found, 618.6；
According to nucleus magnetic hydrogen spectrum and mass spectrographic data it is found that the obtained yellow solid powder of the present embodiment is DPPHP-
2CHO。
(2) DPPHP-2CHO prepared in 3.8mg step (1) is dissolved in 6mL dimethyl sulfoxide (DMSO) be made into it is dense
Degree is 1 × 10-3The solution d of mol/L, then taking 0.3mL solution d and being diluted to concentration with DMSO is 1 × 10-4The solution e of mol/L,
The fluorescence intensity that solution e is surveyed using sepectrophotofluorometer, is denoted as I01；
(3) the solution d in 0.3mL step (2) is taken respectively, is separately added into the DMEM in high glucose culture medium (DMEM) of different volumes
By solution d with architectonical be DMSO/DMEM, concentration is 1 × 10-4The solution f of mol/L, and the fluorescence intensity of solution f is measured, remember
For Ii；
Wherein, in system DMSO/DMEM the volume ratio of DMSO and DMEM be respectively 9:1,8:2,7:3,6:4,5:5,4:6,
3:7,2:8,1:9；
DMEM in high glucose culture medium contains 15~20% fetal calf serums, 5% penicillin and streptomycin mixture；
IiIndicate DMSO/DMEM in proportion i mixing after corresponding DPPHP-2CHO fluorescence intensity, i 9:1,8:2,7:3,
6:4,5:5,4:6,3:7,2:8,1:9；
(4) according to the test result of step (3) draw DPPHP-2CHO in DMSO/DMEM mixed system fluorescence intensity with
The variation of DMEM content and the tendency chart that changes.As can be known from Fig. 6, when excitation wavelength is 340nm, at wavelength 535nm
DPPHP-2CHO change in fluorescence trend is similar with variation tendency of the DPPHP-2CHO in DMSO/PBS system in embodiment 1,
Show AIEE characteristic, fluorescence intensity reaches maximum when DMSO and DMEM volume ratio are 5:5 in system, with initial fluorescent intensity
Compared to increment rate (Ii-I0)/I0About 1.09 (Fig. 8), with continuing growing for DMEM content, fluorescence intensity is on a declining curve, when
When DMSO and PBS volume ratio are 1:9, increment rate is about 0.13, is still higher than I0.When DMEM content is more than 50%, by excitation wavelength
It is changed to 450nm, DPPHP-2CHO maximum absorption band from 535nm red shift to 600nm (Fig. 7), fluorescence intensity is with DMEM content
Increase and increase, when DMSO and DMEM volume ratio are 2:8 in system, fluorescence intensity reaches maximum (Fig. 9).
Embodiment 3
(1) the 0.95mg DPPHP-2CHO prepared in embodiment 1 is dissolved in 1.5mL DMSO be made into concentration be 1 ×
10-3The solution g of mol/L, then taking 0.1mL solution g and being diluted to concentration with DMEM is 1 × 10-4The solution h of mol/L, uses aperture
0.22 μm of filtering with microporous membrane solution h obtains solution I；
(2) by the lagophthalmos Lens Epithelial Cells (BLE cell) and ICR Development of Mouse Embryos of confluent cultures ware bottom 80~90%
Tire fibroblast (MEF cell) is passaged to the small culture dish (Φ=20mm) of bottom belt slide, and every group contains parallel laboratory test three
Dish, in 37 DEG C, CO212h is cultivated in the incubator that volume fraction is 5%；
(3) culture medium is sucked out in culture dish containing cell, the solution I that volume is 0.5mL is added and is placed in laser co-focusing
Under microscope (excitation wavelength 543nm, 555~700nm of wave-length coverage) observe solution I in BLE cell and MEF cell at
As situation.From the experimental results, there is more visible red fluorescence in BLE cell cytoplasm in DPPHP-2CHO, and in MEF
Occur in cell without obvious fluorescence, illustrate DPPHP-2CHO in BLE cell while fluorescence imaging and can by BLE cell and
Other normal cells distinguish, and facilitate in cataract procedure clearly to identify the position BLE cell and remove；
(4) will continue to be placed in laser containing the BLE cell Tissue Culture Dish by DPPHP-2CHO dyeing in step (3)
Under Laser Scanning Confocal Microscope, the prolonged exposure 10min under the exciting light of excitation wavelength 543nm observes DPPHP-2CHO in cell
It is anti-light Bleachability, DPPHP-2CHO is in the fluorescence intensity in BLE cell cytoplasm and before not irradiating after prolonged exposure 10min
Comparison illustrates that DPPHP-2CHO photostability is preferable substantially without significant change.
Embodiment 4
(1) the 1.9mg DPPHP-2CHO prepared in embodiment 1 being dissolved in 3mL DMSO and being made into concentration is 1 × 10- 3The solution m of mol/L, then taking 1mL solution m and being diluted to concentration with DMEM is 1 × 10-4The solution n of mol/L, with 0.22 μm of aperture
Filtering with microporous membrane solution n obtain solution p；
(2) by the lagophthalmos Lens Epithelial Cells (BLE cell) and ICR Development of Mouse Embryos of confluent cultures ware bottom 80~90%
Tire fibroblast (MEF cell) is passaged to 25mL culture bottle respectively, and BLE cell is divided into four bottles, MEF cell be divided into two groups,
Every group four bottles, wherein every group 4 bottles of every kind of cell are respectively one bottle of blank group, three bottles of parallel laboratory test groups, in 37 DEG C, CO2Volume point
12h is cultivated in the incubator that number is 5%；
(3) culture medium in the culture bottle after culture 12h in step (2) is all sucked out, in two kinds of cell experiment groups
2mL solution p is added, isometric DMEM in high glucose culture medium is added in blank group.After cultivating 5min, the whole being sucked out in experimental group is molten
Three times with 9g/L normal saline flushing cell 10mL DMEM in high glucose culture medium, supplemented medium in blank group is added in liquid in every bottle
To 10mL, all culture bottles are put into 37 DEG C, CO2Continue to cultivate in the incubator that volume fraction is 5%；
(4) culture medium will be sucked out completely after BLE cell culture for 24 hours in step (3), is rinsed twice with PBS, is added 2mL's
0.05% trypsase covers all cell, observes that most cells have disengaged from bottle wall under the microscope after standing 5min,
5mL culture medium is added, liquid in bottle is sucked out after mixing, and in 15mL centrifuge tube, 3000rpm is centrifuged 5min, and upper layer is sucked out
The PBS of 6mL is added into centrifuge tube for clear liquid, and 3000rpm is centrifuged 5min after mixing, then supernatant liquor is sucked out, then into centrifuge tube
The PBS of 6mL is added, 3000rpm is centrifuged 5min after mixing, and phosphate buffer is sucked out；With the bis- dye streams of Annexin V-FITC/PI
Formula cell detection kit carries out cell dyeing；By the cell suspension of dyeing flow cytomery Apoptosis situation；
(5) two groups of MEF cell in step (3) are taken out after cultivating 48h, 96h and culture medium is sucked out, rinse two with PBS
Secondary, 0.05% trypsase that 2mL is added covers all cell, observes most cells under the microscope after standing 5min
Bottle wall is had disengaged from, 5mL culture medium is added, liquid in bottle is sucked out after mixing, and in 15mL centrifuge tube, 3000rpm is centrifuged
Supernatant liquor is sucked out in 5min, and the PBS of 6mL is added into centrifuge tube, and 3000rpm is centrifuged 5min after mixing, then that upper layer is sucked out is clear
Liquid, then into centrifuge tube be added 6mL PBS, after mixing 3000rpm be centrifuged 5min, be sucked out phosphate buffer；Use Annexin
The bis- dye FCM analysis kits of V-FITC/PI carry out cell dyeing；By the cell suspension flow cytomery of dyeing
Apoptosis situation.
As shown in Figure 10, it is compared with blank group, BLE cell is 1 × 10-4Cell survival after the solution p dyeing for 24 hours of mol/L
Rate falls to 74.6%, and the survival rate that MEF cell dyes 96h under the same conditions is still 96.6%, illustrates DPPHP-2CHO
In high concentration (1 × 10-4Mol/L under) when cell imaging to normal cell without overt toxicity, the other tissues of eye will not be damaged, and
The proliferation that BLE cell can effectively be inhibited has huge application value to the BLE cell for removing hand postoperative residue.
The present invention includes but is not limited to above embodiments, it is all carried out under the principle of spirit of that invention it is any equivalent
Replacement or local improvement, all will be regarded as within protection scope of the present invention.
Claims (6)
1. it is a kind of targeting label eye lens epithelial cell fluorescence probe, it is characterised in that: the fluorescence probe be 4', 4 "-(2,
5- Diphenyl Pyrrole simultaneously [3,2-b] pyrroles-Isosorbide-5-Nitrae-two) bis- ([1,1'- biphenyl] -4- formaldehyde), structural formula is as follows:
2. a kind of preparation method of the fluorescence probe of targeting label eye lens epithelial cell as described in claim 1, feature
It is: the method comprises the following steps:
Bis- (4- the bromophenyl) -2,5- diphenyl -1,4- pyrrolin of 1,4- simultaneously [3,2-b] pyrroles, 4- aldehyde radical phenyl boric acid and are urged
Agent is added in reaction vessel, is vacuumized and is filled protection gas more than twice, the solvent Ι of deoxygenation is added, after the 8h~12h that flows back, first
Cooling adds solvent II and is extracted, and the organic phase that extraction and separation are obtained is first dry with anhydrous magnesium sulfate, then is spin-dried for obtaining
Crude product；Purified on column chromatography separating-purifying, dry, obtaining solid powder is the fluorescence probe；
The catalyst is the mixture of four (triphenyl phosphorus) palladiums and potassium carbonate；
Protecting gas is nitrogen or argon gas；
Solvent Ι is the mixed solvent of toluene and methanol；
Solvent II is the mixture of water and methylene chloride.
3. a kind of preparation method of the fluorescence probe of targeting label eye lens epithelial cell according to claim 2, special
Sign is: bis- (4- the bromophenyl) -2,5- diphenyl -1,4- pyrrolin of 1,4- simultaneously [3,2-b] pyrroles: 4- aldehyde radical phenyl boric acid: four
(triphenyl phosphorus) palladium: the molar ratio of potassium carbonate is 1:3:0.05:5.
4. a kind of preparation method of the fluorescence probe of targeting label eye lens epithelial cell according to claim 2, special
Sign is: the volume of toluene and methanol volume ratio are 3:1 in solvent Ι.
5. a kind of preparation method of the fluorescence probe of targeting label eye lens epithelial cell according to claim 2, special
Sign is: eluant, eluent is the mixture of methylene chloride, ethyl acetate and petroleum ether, dichloromethane in pillar layer separation purification process
Alkane: ethyl acetate: the volume ratio of petroleum ether is 1:1:6.
6. a kind of fluorescence probe of targeting label eye lens epithelial cell as described in claim 1 is in preparation for inhibiting eye brilliant
Application in the drug of body epithelial cell proliferation.
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