CN115011330A - Fluorescent material with reversible pH fluorescence conversion, fluorescent polymer, fluorescent nanoparticles and preparation method and application thereof - Google Patents

Fluorescent material with reversible pH fluorescence conversion, fluorescent polymer, fluorescent nanoparticles and preparation method and application thereof Download PDF

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CN115011330A
CN115011330A CN202210395914.7A CN202210395914A CN115011330A CN 115011330 A CN115011330 A CN 115011330A CN 202210395914 A CN202210395914 A CN 202210395914A CN 115011330 A CN115011330 A CN 115011330A
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黄增芳
周超越
陈伟润
王思懿
付饶
冯泳琦
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University of Electronic Science and Technology of China
University of Electronic Science and Technology of China Zhongshan Institute
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Abstract

The invention discloses a fluorescent material with reversible pH fluorescence conversion, a fluorescent polymer, fluorescent nanoparticles, a preparation method and application thereof, and belongs to the technical field of AIE fluorescent materials. The invention provides a fluorescent material with reversible pH fluorescence conversion, and the molecular structure of the fluorescent material is shown as a formula I. Also provides a preparation method of the fluorescent material, a fluorescent polymer prepared based on the fluorescent material and a preparation method of fluorescent nanoparticles generated by self-assembly of the fluorescent polymer. The invention synthesizes the fluorescent material with pH sensitivity and AIE characteristics from an AIE structural unit and a pH sensitive heterocycle. On the basis of the fluorescent material, the fluorescent material and the hydrophilic monomer are synthesized into the amphiphilic fluorescent polymer through RAFT polymerization reaction, and the amphiphilic fluorescent polymer can be self-assembled into Fluorescent Organic Nanoparticles (FONs) in aqueous solution, so that the problem that the AIE organic fluorescent material is insoluble in water is solved. The pH-sensitive amphiphilic AIE polymer has attractive application prospects in the fields of biological imaging, fluorescence labeling and tumor diagnosis and treatment.

Description

Fluorescent material with reversible pH fluorescence conversion, fluorescent polymer, fluorescent nanoparticles, and preparation method and application thereof
Technical Field
The invention relates to the technical field of AIE fluorescent materials, in particular to a fluorescent material with reversible pH fluorescence conversion, a fluorescent polymer, a fluorescent nanoparticle, a preparation method and application thereof.
Background
With the development of digital imaging and corresponding image analysis techniques, fluorescent materials have therefore become of particular importance. They are indispensable in the fields of bioimaging, drug synthesis, cell tracking, and clinical medicine, etc., because they can make medical and scientific activities more convenient and efficient. Fluorescent nanomaterials can be largely classified into two broad categories, namely fluorescent inorganic materials and fluorescent organic materials. The fluorescent inorganic materials can be further classified into semiconductor quantum dots, carbon quantum dots, noble metal nanoclusters, rare earth fluorescent materials, and the like. The fluorescent organic materials comprise organic small molecule dyes and FONs. Organic light emitting materials have been widely used in optoelectronic devices, chemical/biological sensing, and biological applications. However, increasing their luminous efficiency has been a continuing interest in research in this area. As Forster demonstrated in 1954, conventional fluorescent materials emit bright luminescence in dilute solutions, while in concentrated solutions or solid states, Photoluminescence (PL) is reduced due to quenching (ACQ) effects caused by aggregation. Moreover, the fluorescent materials have the problems of complex synthesis steps, high cost, poor water solubility, low resolution, poor photobleaching resistance, short emission wavelength, poor biocompatibility, high cytotoxicity and the like, and the application of the fluorescent materials is greatly limited. Although researchers have performed methods such as chemical modification and physical processing to reduce the effects of ACQ effects, aggregation is a spontaneous and stabilizing process of matter that progresses slowly.
In 2001, a novel fluorescent material having an AIE phenomenon was discovered, which has attracted much attention due to its unique photophysical properties. The AIE fluorescent material is a general name of a material which can emit strong fluorescence in an aggregation state and generally has the characteristics of distorted structure, free rotation, easy combination with functionalization, larger degree of freedom and the like, and can make up for the defects of the traditional fluorescent material in the application field caused by the ACQ effect. With the efforts of more researchers' attention, more and more structural systems with AIE effects are discovered, such as: hexaphenylsilyl (HPS), Tetraphenylethylene (TPB), pyrrole, 9, 10-Distyrylanthracene (DSA), 1, 3-butadiene. In 2016, the AIE fluorescent material is evaluated as one of four nanometer fluorescent materials in the future, and becomes a research hotspot again. At present, the AIE fluorescent material is widely applied to cell tracking, sensors, drug synthesis, ultrahigh resolution imaging and clinical medicine.
In recent years, active fluorescent materials with AIE characteristics play an important role in the fields of clinical medicine, photoelectricity, environmental science, biological imaging, sensors and the like due to unique photochemical properties. The multiple stimulus response fluorescent material is widely used as an important research field of the AIE fluorescent material because it has a reversible color response to an external stimulus. The detection of the intracellular pH environment and the exploration of related applications have become the hot spot of biomedical research, and fluorescent materials with pH sensitivity have also become a major focus of the research of multiple stimulus response fluorescent materials. The fluorescent material can adjust the charge distribution of ionizable groups (such as carboxyl or amino groups) of molecules, so as to realize protonation/deprotonation and generate pH sensitivity. Due to their specific properties and switching mechanisms, they can be made to perform specific functions in specific tissues by efficient molecular design. The fluorescent material with pH sensitivity can be used in the fields of drug delivery, biological imaging, cell tracking and the like.
At present, the AIE fluorescent materials are in a period of vigorous development and hundreds of flowers are all standing together, and various AIE fluorescent materials are being developed successively, and the proposal of the invention is to meet the market's greater demand for fluorescent materials with pH sensitivity and applications thereof.
Disclosure of Invention
The invention aims to provide a fluorescent material, a fluorescent polymer and a fluorescent nanoparticle with reversible pH fluorescence conversion, and a preparation method and application thereof, so as to solve the problem of meeting the greater demands of the market on the AIE fluorescent material with pH sensitivity and the application thereof.
The technical scheme for solving the technical problems is as follows:
a fluorescent material with reversible pH fluorescence conversion has a molecular structure shown as a formula I:
Figure BDA0003597280640000031
in the formula: r 1 Comprises the following steps: tetraphenylethylene, 9, 10-distyrylanthracene, hexaphenylsilole, phenothiazine or nitrile fumarate; r 2 Comprises the following steps: benzene, biphenyl, naphthalene, pyridine or heteroaromatic rings.
The invention also provides a preparation method of the fluorescent material with reversible pH fluorescence conversion, which comprises the following steps:
preparing an intermediate product I, wherein the molecular structure of the intermediate product I is shown as a formula II:
Figure BDA0003597280640000032
in the formula: r 1 Comprises the following steps: tetraphenylethylene, 9, 10-distyrylanthracene, hexaphenylsilole, phenothiazine or nitrile fumarate;
obtaining an intermediate product II, wherein the molecular structure of the intermediate product II is shown as a formula III:
Figure BDA0003597280640000033
in the formula: r 2 Comprises the following steps: benzene, biphenyl, naphthalene, pyridine or heteroaromatic rings;
synthesizing an intermediate product III from the intermediate product I and the intermediate product II, wherein the molecular structure of the intermediate product III is shown as a formula IV:
Figure BDA0003597280640000034
in the formula: r 1 Comprises the following steps: tetraphenylethylene, 9, 10-distyrylanthracene, hexaphenylsilole, phenothiazine or nitrile fumarate; r 2 Comprises the following steps: benzene, biphenyl, naphthalene, pyridine or heteroaromatic rings;
preparing an intermediate product IV from the intermediate product III, wherein the molecular structure of the intermediate product IV is shown in a formula V:
Figure BDA0003597280640000041
in the formula: r 1 Comprises the following steps: tetraphenylethylene, 9, 10-distyrylanthracene, hexaphenylsilole, phenothiazine or nitrile fumarate; r 2 Comprises the following steps: benzene, biphenyl, naphthalene, pyridine or heteroaromatic rings;
and synthesizing the fluorescent material from the intermediate product IV.
Further, in the preparation method of the fluorescent material with reversible pH fluorescence conversion, the intermediate product I is prepared from a reactant a and a reactant b;
the molecular structure of the reactant a is shown as a formula a:
Figure BDA0003597280640000042
in the formula: r is 3 Comprises the following steps: triphenylethylene, phenothiazine or nitrile fumarate;
the molecular structure of the reactant b is shown as a formula b:
Figure BDA0003597280640000043
in the formula: r 4 Comprises the following steps: benzene, biphenyl, or naphthalene;
the intermediate product I is prepared as shown in a reaction formula 1:
Figure BDA0003597280640000044
preferably, the step of preparing said intermediate product i comprises: under the action of alkali and a catalyst in a solvent under a protective atmosphere, reacting the reactant a with the reactant b to obtain an intermediate product I;
preferably, and/or, the molar ratio of the reactant a to the reactant b is 1: (1-1.5), preferably 1: (1.1-1.3);
and/or, the protective atmosphere comprises one or more of nitrogen, argon and helium;
and/or the solvent is one or more of aromatic solvent, ether solvent and water; the aromatic solvent is preferably toluene; the ethereal solvent is preferably tetrahydrofuran.
And/or the catalyst is tetrakis (triphenylphosphine) palladium and/or palladium (II) acetate;
and/or the molar ratio of the catalyst to the reactant a is (0.01-0.3): 1, preferably (0.05-2.5) 1, more preferably (0.1-2) 1, still more preferably (0.5-1.5) 1;
and/or, the base comprises: one or more of potassium carbonate, sodium carbonate, cesium carbonate and potassium phosphate;
and/or the molar ratio of the base to the reactant a is (2-3): 1, preferably (2.3-2.7) 1;
preferably, the temperature of the reaction is 60-120 ℃.
Further, in the preparation method of the fluorescent material with reversible pH fluorescence conversion, the intermediate product II is prepared by the hydrolysis reaction of a reactant c;
the structure of the reactant c is shown as formula c:
Figure BDA0003597280640000051
in the formula: r is 2 Comprises the following steps: benzene, biphenyl, naphthalene, pyridine or heteroaromatic rings;
the intermediate product II is prepared as shown in a reaction formula 2:
Figure BDA0003597280640000052
preferably, the step of preparing said intermediate product ii comprises: under the action of alkali in a solvent under the protective atmosphere, carrying out hydrolysis reaction on the reactant c to obtain an intermediate product II;
preferably, and/or, the base comprises: potassium hydroxide and/or sodium hydroxide;
and/or the molar ratio of the base to the reactant c is (1-5): 1, preferably (2-4.5): 1;
and/or, the protective atmosphere comprises one or more of nitrogen, argon and helium;
and/or, the solvent comprises: ethylene glycol and/or glycerol;
preferably, the temperature of the hydrolysis reaction is 120-140 ℃.
Further, in the method for preparing the fluorescent material with reversible pH fluorescence conversion, the intermediate product III is prepared from the intermediate product II and the intermediate product I;
the intermediate product III is prepared as shown in the reaction formula 3:
Figure BDA0003597280640000061
preferably, the step of preparing said intermediate product iii comprises: under the protective atmosphere, in an organic solvent, synthesizing the intermediate product II and the intermediate product I by using hantzsch thiazole to obtain an intermediate product III;
preferably, the molar ratio of the intermediate product II to the intermediate product I is (1-2): 1;
and/or, the protective atmosphere comprises one or more of nitrogen, argon and helium;
and/or the temperature of the synthesis reaction is 150-170 ℃.
Further, in the preparation method of the fluorescent material with reversible pH fluorescence conversion, the intermediate product IV is prepared from the intermediate product III;
the intermediate product IV is prepared as shown in a reaction formula 4:
Figure BDA0003597280640000062
preferably, the step of preparing the intermediate product iv comprises: under the protective atmosphere and in a solvent and under the action of a demethylating reagent, carrying out demethylation reaction on the intermediate product III to obtain an intermediate product IV;
preferably, and/or, the demethylating agent comprises: boron tribromide;
and/or the molar ratio of the demethylating agent to the intermediate III is (1.0-2.0): 1;
and/or, the protective atmosphere comprises one or more of nitrogen, argon and helium;
and/or, the solvent comprises: dichloromethane and/or tetrahydrofuran;
preferably, the temperature of the demethylation reaction is 10-60 ℃.
Further, in the preparation method of the fluorescent material with reversible pH fluorescence conversion, the fluorescent material is prepared by the intermediate product IV and the reactant d;
the molecular structure of the reactant d is shown as formula d:
Figure BDA0003597280640000071
preparing a fluorescent material represented by formula I as shown in reaction formula 5:
Figure BDA0003597280640000072
preferably, the step of preparing the fluorescent material comprises: carrying out acylation reaction on the intermediate product IV and the reactant d in a solvent under the action of alkali in a protective atmosphere to obtain the fluorescent material shown in the formula I;
preferably, and/or, the base comprises: one or more of triethylamine, diethylamine and diisopropylethylamine;
and/or the molar ratio of the alkali to the intermediate product IV is (1-4): 1;
and/or, the protective atmosphere comprises one or more of nitrogen, argon and helium;
and/or, the solvent comprises: dichloromethane and/or tetrahydrofuran;
and/or the temperature of the acylation reaction is ice water bath.
The invention also provides a fluorescent polymer, which is synthesized by the fluorescent material with reversible pH fluorescence conversion shown in the formula I, and the molecular structure of the fluorescent polymer is shown in the formula VI:
Figure BDA0003597280640000073
in the formula: r 1 Comprises the following steps: 9, 10-distyrylanthracene, tetraphenylethylene, hexaphenylsilole, phenothiazine or nitrile fumarate; r 2 Comprises the following steps: benzene, biphenyl, naphthalene, pyridine or heteroaromatic rings; r 5 Is a hydrophilic group; m is 7 to 35; n is 28-138.
Preferably, the preparation method of the fluorescent polymer comprises the following steps: synthesizing the fluorescent material with the molecular structure shown as the formula I and a hydrophilic monomer;
the molecular structure of the hydrophilic monomer is shown as formula VII:
Figure BDA0003597280640000081
in the formula: r 5 Is a hydrophilic group;
preferably, the fluorescent polymer is prepared as shown in equation 6:
Figure BDA0003597280640000082
preferably, the step of preparing the fluorescent polymer comprises: under the protective atmosphere and in a solvent, under the action of an initiator and a chain transfer agent, the fluorescent material and the hydrophilic monomer are subjected to RAFT polymerization reaction;
preferably, and/or, the molar ratio of the fluorescent material and the hydrophilic monomer is (0.1-0.5): 1, preferably (0.2-0.4): 1;
and/or, the solvent comprises: one or more of benzene solvents and ether solvents;
and/or, the protective atmosphere comprises one or more of nitrogen, argon and helium;
and/or, the initiator comprises: azobisisobutyronitrile and/or azobisisoheptonitrile;
and/or the molar ratio of the initiator to the fluorescent material is (0.01-0.2): 1, preferably (0.05-0.15): 1;
and/or, the chain transfer agent is a thiocarbonyl sulfide comprising: one or more of dithioesters, thiocarbamates, and xanthates;
and/or the molar ratio of the chain transfer agent to the fluorescent material is (0.05-0.2): 1, preferably (0.05-0.15): 1;
preferably, the temperature of the RAFT polymerisation is from 65 to 75 ℃.
The invention also provides fluorescent nanoparticles, and the fluorescent nanoparticles are prepared by self-assembling the fluorescent polymer in an aqueous solution.
The invention also provides application of the fluorescent polymer in biological imaging, fluorescent labeling and tumor diagnosis and treatment.
The invention has the following beneficial effects:
the invention synthesizes the fluorescent material with pH sensitivity and AIE characteristics from an AIE structural unit and a pH sensitive heterocycle. On the basis of the fluorescent material, the fluorescent material and the hydrophilic monomer are subjected to RAFT polymerization reaction to synthesize the amphiphilic fluorescent polymer, and the amphiphilic fluorescent polymer can be self-assembled into Fluorescent Organic Nanoparticles (FONs) in an aqueous solution, so that the problem that the AIE organic fluorescent material is insoluble in water is solved. The pH-sensitive amphiphilic AIE polymer has attractive application prospects in the fields of biological imaging, fluorescence labeling and tumor diagnosis and treatment. The fluorescent material and the hydrophilic monomer are subjected to RAFT polymerization reaction to synthesize the amphiphilic fluorescent polymer, so that the problem that the AIE organic fluorescent material is insoluble in water is solved. Can be completely dissolved in human body fluid, is better dissolved in blood, flows to the whole body along with the blood, and realizes cell imaging.
The prepared fluorescent polymer also has amphipathy, can be self-assembled into FONs with the diameter of about 100-150nm in aqueous solution, and perfectly solves the problem of water solubility of the fluorescent material. And the fluorescence intensity of the compound gradually increases along with the increase of the water content in the THF solution, and the compound also has obvious AIE characteristics. In addition, cell experiments prove that the fluorescent nanoparticles also have the advantages of low cytotoxicity, good biocompatibility, good endocytosis effect and the like.
The fluorescent polymer and the fluorescent nanoparticles have the advantages of obvious AIE characteristics, pH sensitivity, good water solubility, low cytotoxicity, good biocompatibility, good endocytosis effect and the like, and have wide application prospects in the field of biological imaging.
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In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are required to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 shows examples of MTBT, HTBT, TPBMA, PEG-TB1, PEG-TB2 in test example 1 of the present invention 1 H NMR spectrum;
FIG. 2 shows the results of SMA, MTBT, HTBT and TPBMA in test example 1 of the present invention 13 C NMR spectrum;
FIG. 3 is an IR spectrum of MTBT, HTBT, TPBMA, PEG-TB1 in test example 2 of the present invention;
FIG. 4 is a fluorescence emission spectrum of TPBMA in test example 3 of the present invention;
FIG. 5 is a HOMO and LUMO model diagrams of TPB and TPBMA in test example 4 of the present invention;
FIG. 6 shows the fluorescence emission spectrum of PEG-TB1 in test example 5 of the present invention;
FIG. 7 is a TEM image of PEG-TB1 FONs in test example 6 of the present invention;
FIG. 8 is a graph showing the cytotoxicity and cell imaging effects of PEG-TB1 FONs in test example 7 of the present invention.
Detailed Description
The principles and features of the present invention are described below in conjunction with the embodiments and the accompanying drawings, which are set forth by way of illustration only and are not intended to limit the scope of the invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
In organic chemistry, heterocycles always affect the photophysical properties of an organic substance. The polycyclic aromatic hydrocarbon compound containing heteroatoms such as N, O, S, P and the like can be used as an electron donor or acceptor, provides some special bonding modes or plays a role in stabilization, such as hyperconjugation and hydrogen bonding. The lone pair of electrons of the heteroatom can also increase the electron cloud density and increase the dipole-dipole interaction between molecules, thereby reducing the energy band gap and promoting the electron transfer. Therefore, in the scheme design of the invention, the polycyclic aromatic hydrocarbon compound containing heteroatoms such as N, O, S, P and the like is introduced into the structure of the fluorescent material and is used as an electron donor or acceptor.
Specifically, the invention synthesizes a fluorescent material with reversible pH fluorescence conversion, and the molecular structure of the fluorescent material is shown as follows:
Figure BDA0003597280640000111
the fluorescent material is prepared by (1) passing triphenylbromoethylene, and has a molecular formula of
Figure BDA0003597280640000112
And 4-formylphenylboronic acid of the formula
Figure BDA0003597280640000113
Under the action of a catalyst and alkali, in a solvent, an intermediate product TPB (4- (1,2, 2-triphenylvinyl) benzaldehyde) is obtained through a Suzuki coupling reaction, and the synthesis reaction is shown as a reaction formula 7:
Figure BDA0003597280640000114
(2) the benzothiazole derivative is 2-amino-6-methoxybenzothiazole with the molecular formula
Figure BDA0003597280640000115
Hydrolyzing under the action of alkali to obtain an intermediate product SMA (2, 2-mercapto-4-methoxyaniline), wherein the synthesis reaction is shown as a reaction formula 8:
Figure BDA0003597280640000121
(3) intermediate SMA and intermediate TPB, intermediate MTBT was synthesized by hantzsch thiazole, the synthesis reaction of which is shown in equation 9:
Figure BDA0003597280640000122
(4) intermediate MTBT and boron tribromide are subjected to demethylation reaction to obtain intermediate HTBT (6-hydroxy-2- (4- (1,2, 2-triphenylvinyl) benzene) benzothiazole), and the synthesis reaction is shown as a reaction formula 10
Figure BDA0003597280640000123
(5) Intermediate product HTBT and methacryloyl chloride with molecular formula of
Figure BDA0003597280640000124
The fluorescent material TPBMA with reversible pH fluorescence conversion is prepared through acylation reaction, and the synthesis reaction is shown as a reaction formula 11:
Figure BDA0003597280640000125
specifically, the molecular structure of the hydrophilic monomer is shown as formula IX:
Figure BDA0003597280640000131
specifically, a hydrophilic monomer represented by formula IX: poly (ethylene glycol) methacrylate, designated PEGMA.
The fluorescent polymer with the molecular structure shown as the formula X is obtained by RAFT polymerization reaction of a fluorescent material with the molecular formula shown as VIII and a hydrophilic monomer with the molecular formula shown as IX:
Figure BDA0003597280640000132
the synthesis reaction is shown as a reaction formula 12:
Figure BDA0003597280640000133
the molecular structure of the fluorescent polymer as the formula X is self-assembled in water to form FONs, and the fluorescent nanoparticles can penetrate through cell membranes and stably disperse in cytoplasm to realize biological imaging, and the specific process is as follows:
Figure BDA0003597280640000134
the molecular structure of the fluorescent material with reversible pH fluorescence conversion is shown as formula VIII, and the fluorescent material is specifically prepared as follows:
EXAMPLE 1 preparation of intermediate I
1.08g of TPEBr (2.00mmol), 0.36g of 4-formylphenylboronic acid (2.40mmol) and 64.5mg of TBAB (0.20mmol) were weighed into a Schlenk reaction tube, followed by addition of 14mL of toluene and 3.6mL of aqueous potassium carbonate solution (2mol/L) in this order, and the reaction mixture was magnetically stirred at room temperature for 30 minutes to mix well. 2.7mg of tetrakis (triphenylphosphine) palladium (0) (2.34X 10) are subsequently weighed out -3 mmol) was added to the reaction tube and the reaction mixture was deoxygenated by stirring again for 30 minutes while passing nitrogen. The reaction tube was then placed in an oil bath at 90 ℃ for 48 hours. After completion of the reaction, an appropriate amount of deionized water was added to the reaction solution, and extracted three times with dichloromethane, and the organic phase was retained and dried over anhydrous magnesium sulfate. The reaction solution was then filtered under reduced pressure to remove magnesium sulfate, and the organic solvent was removed by a rotary evaporator to obtain a crude product. The crude product was finally isolated on a silica gel column using dichloromethane/n-hexane (v/v ═ 2: 1) as eluent and completely dried under vacuum to give the product TPB in a yield of 0.928g with a yield of about 82%. See reaction 7 for details.
The hydrogen nuclear magnetic data are: 1 H NMR(400MHz,CDCl 3 ,δ):7.03-7.07(m,6H；Ar H),7.03-7.07(m,11H；Ar H),7.49(s,1H；CH),7.68-7.79(m,8H；Ar H),7.97-7.99(d,J＝8.0Hz,2H；Ar H),10.07(s,1H；-CHO).
EXAMPLE 2 preparation of intermediate II
2-amino-6-methoxybenzothiazole (22.0g, 0.12mol), H 2 O (13.0mL), KOH (20.0g, 0.36mol) and ethylene glycol (3.30g, 0.05mol) were added to a Schlenk reaction tube, which was then sealed, N 2 Purge for 30 minutes to create a nitrogen atmosphere. The reaction mixture was reacted in a constant temperature magnetic stirring oil bath at 130 ℃ for 20 hours. After the reaction was complete, 35mL of H was added to the crude product 2 O was diluted, and was allowed to cool to room temperature, and then filtered. The pH value of the filtrate is adjusted to 1-2 by concentrated hydrochloric acid, and then 50mL of toluene is used for extraction for 3 times. Then, anhydrous MgSO was added 4 Excess water was removed from the extract and the remaining solvent was removed using a rotary evaporator. Finally, the intermediate product II is obtained by purifying the mixture by a gel chromatographic column with petroleum ether/ethyl acetate (2: 1) as a mobile phase. The yield of intermediate II was 15.3g, 81.0%. See reaction formula 8 for details.
The hydrogen nuclear magnetic spectrum of the intermediate product SMA is shown in figure 1, and the hydrogen nuclear magnetic data are as follows: 1 H NMR(400MHz,CDCl 3 ,δ):3.63(s,3H；-CH 3 ),3.83(s,1H；-SH),4.08(s,2H；-NH 2 ),6.72-6.73(d,J＝4.0Hz,2H；Ar H),6.81-6.84(m,J＝4.0Hz,1H；Ar H). 13 C NMR(400MHz,CDCl 3 ,δ):55.86,116.57,118.99,119.90,142.71,151.81.Anal.Calcd for C 7 H 9 NOS:C,54.17；H,5.84；N,9.02％.Found:C,54.91；H,5.47；N,8.71％.
specifically, this intermediate was named SMA.
EXAMPLE 3 preparation of intermediate III
Mixing TPB: tetraphenylethylene (1.80mg, 5.00mmol) and SMA (0.82g, 5.30mmol) and DMSO 20ml were added to a Schlenk reaction tube. Sealing the reaction tube, tying the bottle mouth with iron wire, freezing in liquid nitrogen, and vacuum-filling nitrogen for 5 times or more. After the nitrogen is filled, the reaction tube is waited to return to the room temperature, and redundant nitrogen is discharged in time in the process, so that the reaction tube is prevented from bursting due to gas heating expansion. Then, the reaction tube was placed in a thermostat water bath at 170 ℃ and reacted for 12 hours with magnetic stirring. After the reaction is finished, the crude product is returned to room temperature, poured into 20mL of ice water and added with CH 2 Cl 2 Extracting for 3 times, and collecting organic phase. The extract was extracted with anhydrous MgSO 4 Dried and then the solvent removed on a rotary evaporator. Finally, by n-hexane/CH 2 Cl 2 (3: 1) purification by gel chromatography on a mobile phase to obtain the intermediate product III. The yield of intermediate III was 1.86g, 75.0%. See reaction formula 9 for details.
The intermediate MTBT product has hydrogen nuclear magnetic spectrum as shown in FIG. 1, and its hydrogen nuclear magnetic dataComprises the following steps: 1 H NMR(400MHz,CDCl 3 ,δ):3.91(s,3H；-CH 3 ),7.07-7.14(m,18H；Ar H),7.35-7.36(d,J＝4.0Hz,1H；Ar H),7.79-7.80(d,J＝4.0Hz,2H；Ar H),7.91-7.93(d,J＝8.0Hz,1H；Ar H). 13 C NMR(400MHz,CDCl 3 ,δ):55.55,104.06,115.68,123.52,126.65,127.81,131.33,131.82,136.28,139.87,141.91,143.28,146.41,148.82,157.57,165.20.Anal.Calcd for C 34 H 25 NOS:C,82.39；H,5.08；N,2.83％.Found:C,82.04；H,5.10；N,2.60％.MS(m/z):[MTBT] + ＝496.29.
specifically, this intermediate was named MTBT.
EXAMPLE 4 preparation of intermediate IV
MTBE (1.20g, 2.42mmol) was placed in a Schlenk reaction tube. Sealing the reaction tube, fastening the mouth of the bottle with an iron wire, freezing in liquid nitrogen, and performing vacuum-nitrogen filling circulation for more than 5 times. Then use CH 2 Cl 2 Mixing BBr with the solution 3 (4.80mmol) was injected into a Schlenk reaction tube. The reaction was then allowed to react at room temperature with magnetic stirring for 12 h. After the reaction is finished, the crude product is firstly saturated NaHCO 3 The solution is neutralized, followed by CH 2 Cl 2 The extraction was performed 3 times (10mL each). The extract was washed with distilled water and anhydrous MgSO 4 Dried and then filtered off anhydrous MgSO 4 Solid, solvent was removed using a rotary evaporator. Finally, by CH 2 Cl 2 And purifying the gel chromatographic column serving as a mobile phase to obtain an intermediate product IV. The yield of this intermediate IV was 0.91g, 78.0%. See reaction formula 10 for details.
The hydrogen nuclear magnetic spectrum of the intermediate product HTBT is shown in a figure 1, and the hydrogen nuclear magnetic data thereof are as follows: 1 H NMR(400MHz,CDCl 3 ,δ):5.63(s,1H；-OH),6.90-6.91(d,J＝4.0Hz,1H；Ar H),6.95-7.00(m,6H；Ar H),7.03-7.06(m,11H；Ar H),7.21-7.22(d,J＝4.0Hz,1H；Ar H),7.68-7.70(d,J＝8.0Hz,2H；Ar H),7.77-7.79(d,J＝8.0Hz,1H；Ar H). 13 C NMR(400MHz,CDCl 3 ,δ):105.90,114.71,122.63,125.66,126.66,130.16,130.92,135.39,139.06,141.08,142.07,145.31,147.51,152.77.Anal.Calcd for C 33 H 23 NOS:C,82.30；H,4.81；N,2.91％.Found:C,82.25；H,4.90；N,2.81％.MS(m/z):[HTBT] + ＝482.30.
specifically, this intermediate product was named HTBT.
Example 5 preparation of fluorescent Material with reversible pH fluorescence transition
HTBT (0.60g, 1.25mmol) is added into a Schlenk reaction tube, the reaction tube is sealed, the mouth of the reaction tube is tightened by an iron wire, the reaction tube is placed in liquid nitrogen for freezing, and the circulation of vacuumizing and nitrogen filling is carried out for more than 5 times. In an ice-water bath, Et-containing solution 3 N (0.24g, 2.38mmol) CH 2 Cl 2 (5mL) solution and methacryloyl chloride (0.20g, 1.92mmol) in CH 2 Cl 2 The solutions (5mL) were sequentially injected into the reaction tube and reacted for 1.5 h. The reaction mixture was then allowed to continue to react for 24h at room temperature with magnetic stirring. Upon completion of the reaction, the solvent was removed by rotary evaporator. Finally, by CH 2 Cl 2 The yield of the fluorescent material for purification by a mobile phase gel chromatography column was 0.55g, and the yield was 80.0%. See reaction formula 11 for details.
The hydrogen nuclear magnetic spectrum of the fluorescent material is shown in figure 1, and the hydrogen nuclear magnetic data is as follows: 1 H NMR(400MHz,CDCl 3 ,δ):2.09(s,3H；-CH 3 ),5.80(s,1H；CH),6.39(s,1H；CH),7.04-7.08(m,7H；Ar H),7.10-7.14(m,10H；Ar H),7.21-7.23(d,J＝8.0Hz,1H；Ar H),7.66-7.67(d,J＝4.0Hz,1H；Ar H),7.79-7.81(d,J＝8.0Hz,2H；Ar H),7.99-8.01(d,J＝8.0Hz,1H；Ar H). 13 C NMR(400MHz,CDCl 3 ,δ):114.45,120.65,123.48,126.77,127.65,131.20,131.97,135.70,139.95,142.18,143.22,146.95,148.34,151.96.Anal.Calcd for C 37 H 27 NO 2 S:C,80.85；H,4.95；N,2.55％.Found:C,78.87；H,5.17；N,2.39％.MS(m/z):[TPBMA] + ＝550.59.
specifically, this product was named TPBMA.
EXAMPLE 6 preparation of fluorescent Polymer
To a Schlenk reaction tube was added AIBN: azobisisobutyronitrile (1.1mg, 6.70. mu. mol), Chain Transfer Agent (CTA) (3.6mg, 1.40X 10. mu.l) -2 mmol) and TPBMA (69.3mg, 0.13mmol), sealing the reaction tube, fastening the bottle mouth with iron wire, freezing in liquid nitrogen, vacuumizing, and fillingThe nitrogen is circulated for more than 5 times. In N 2 Toluene (1.7mL) containing PEGMA (248.6mg, 0.52mmol) was injected into a Schlenk tube under protection. The reaction mixture was reacted in a constant temperature oil bath at 70 ℃ for 24 hours with magnetic stirring. After the reaction was complete, the crude product was dialyzed against acetone and the solvent was evaporated by rotary evaporation. THF was added dropwise to the flask containing the solid product to dissolve the product completely, and then petroleum ether was added to precipitate it, and the above operation was repeated 3 times. Finally, the product was dried in vacuo to give a fluorescent polymer having a yield of 0.25 g. Specifically, this fluorescent polymer was designated PEG-TB 1. See reaction scheme 12 for details.
Referring to the procedure of example 5, a fluorescent polymer was synthesized with a yield of 0.24g by adjusting the charge ratio of TPBMA to 25%. Specifically, this fluorescent polymer was designated PEG-TB 2.
Example 7 self-Assembly of PEG-TB
The fluorescent material PEG-TB1 prepared in example 5 was self-assembled in water to form FONs named PEG-TB1 FONs.
The hydrophobic TPBMA and the hydrophilic PEGMA endow the PEG-TB polymer with amphipathy, and the PEG-TB polymer can self-assemble to form FONs in aqueous solution.
Test example 1: NMR hydrogen and carbon spectroscopy
Hydrogen nuclear magnetic resonance spectroscopy (MTBT, HTBT, TPBMA, PEG-TB1 and PEG-TB 2) 1 H NMR) was performed to verify the chemical structure with Tetramethylsilane (TMS) with zero chemical shift as internal standard, deuterated chloroform (CDCl) 3 ) As a solvent, the results are shown in FIG. 1.
Carbon spectra (C) of SMA, MTBT, HTBT and TPBMA 13 C NMR) was performed to verify the chemical structure with Tetramethylsilane (TMS) with zero chemical shift as internal standard, deuterated chloroform (CDCl) 3 ) The results are shown in FIG. 2.
FIG. 1 shows the preparation of MTBT, HTBT, TPBMA monomers and copolymers PEG-TB1 and PEG-TB2 1 H NMR spectrum.
FIG. 2 shows SMA, MTBT, HTBT, TPBMA 13 C NMR spectrum.
In FIG. 1, in MTBT 1 H NMR spectrumIn the figure, -CH 3 The proton peak of TPB aromatic ring hydrogen appears at 3.84ppm, and the proton peak of TPB aromatic ring hydrogen appears at 7.10-7.90ppm, which indicates that the coupling reaction of TPB and SMA is successfully carried out. With MTBT 1 H NMR spectra were compared with HTBT having a hydroxyl peak at 5.35ppm and MTBT at 3.84ppm of-CH 3 The peak disappeared completely.
And shown in FIG. 2 13 In the C NMR spectrum, the original existence of-CH at 55.55ppm in HTBT 3 The peak had also disappeared completely. The above results indicate that-CH of MTBE 3 Successfully converted into-OH through a demethylation reaction. Two characteristic peaks of methacryloyl chloride at 5.85 and 6.52ppm appeared for TPBMA 1 In the H NMR spectrum, the acylation of the hydroxyl group with methacryloyl chloride was successful.
For the PEG-TB1 and PEG-TB2 spectra, the characteristic peaks at 5.85 and 6.52ppm in TPBMA disappeared completely, but new proton peaks at 7.10-7.9ppm appeared, and the proton peak corresponding to PEGMA also appeared at 4.08 ppm. In addition, the proton peak intensities at 7.10-7.9ppm and 4.08ppm increased with increasing TPBMA and PEGMA charge ratio, confirming that TPBMA and PEGMA successfully synthesized PEG-TB by RAFT polymerization. The ratio of TPBMA in the copolymer PEG-TB was obtained by calculating the peak areas at 4.08 and 7.10-7.90 ppm. When the feeding ratio of the TBMTA is increased from 20.0 percent to 25.0 percent, the ratio of the TBMTA in the PEG-TB is also increased from 17.4 percent to 22.6 percent.
Test example 2: infrared spectroscopic analysis
To further confirm that the synthesized MTBT, HTBT, TPBMA and PEG-TB1 structures were consistent with the theoretical design, their FT-IR spectra are shown in FIG. 3.
In FIG. 3, in the MTBT spectrum, -OCH 3 The peak of the stretching vibration of the diaphragm appears at 2960cm -1 And 3019cm -1 This is sufficient to demonstrate the successful progress of the coupling reaction between TPB and SMA. Compared with the spectrum of MTBT, HTBT was at 3538cm -1 A characteristic peak of-OH appears, indicating-OCH of MTBT 3 Successfully converted into-OH through a demethylation reaction. 3538cm in the TPBMA spectrum -1 The absorption peak at 1730cm disappears completely -1 And 2930cm -1 With C ═ O and-C (CH) present 3 )＝CH 2 CorrelationIndicating that HTBT successfully introduced methacryloyl groups via acylation. Copolymer PEG-TB1 Spectrum in-CH 2 The absorption peaks of C ═ C and C-O stretching vibration are respectively 2870, 1730 and 1120cm -1 . In summary, the FT-IR spectrum further confirmed the successful synthesis of PEG-TB1 copolymer and its intermediates.
Test example 3: TPBMA material fluorescence emission test
And (3) carrying out a fluorescence emission test under natural light and a fluorescence emission spectrum test under an ultraviolet lamp on the solid TPBMA material. The results are shown in FIG. 4.
FIG. 4 (A) shows the reversible fluorescence emission of TPBMA dye, the left is the TPBMA sample in the sun using HCl and NH 3 Color change after repeated fumigation, left is TPBMA sample under UV lamp using HCl and NH 3 Colour change after repeated fumigation. Fig. 4 (B) shows a fluorescence emission spectrum of TPBMA: (S) 1 ) TPBMA raw sample; (F) a1 ) After HCl fumigation; (F) b1 )NH 3 After fumigation; (F) a2 ) Fumigate again with HCl.
FIG. 4 shows reversibility of two-photon fluorescence wavelength of TPBMA when the solid-state fluorescence characteristic of TPBMA is investigated, we find that the maximum emission wavelength changes with the change of pH. In a neutral environment, the emission wavelength appeared to have a maximum at 506nm (blue-green) and in an acidic environment increased to 579nm (yellow), indicating a significant red shift in the maximum emission wavelength of TPBMA with decreasing pH. Subsequently, the sample is passed over NH 3 After fumigation, the emission wavelength returned from 579nm to 500nm, and the sample was again fumigated with HCl, with the emission wavelength continuing to red-shift. The above operations were repeated to obtain the same experimental results, which indicate that TPBMA has obvious pH sensitivity and fluorescence reversibility. This pH sensitivity phenomenon may be caused by the change of the electron cloud distribution of the heterocycle in the compound TPBMA under the acidic, basic or neutral environment. Namely, the benzothiazole heterocycle in the TPBMA structure can receive hydrogen ions in an acid environment, so that electron transfer is promoted, the electron cloud distribution is changed, the energy level difference between HOMO and LUMO is changed, and the TPBMA dye is endowed with pH sensitivity. TPBMA dye has moderate intensity fluorescence with fluorescence quantum yield (. PHI.F.)) About 0.239.
Test example 4: HOMO and LUMO models
HOMO and LUMO models of TPB (right), TPBMA (medium, original) and TPBMA (right, acidified) obtained by quantum computation, the results are shown in fig. 5.
FIG. 5 is a HOMO and LUMO model of TPB and TPBMA obtained by quantum chemical calculations. For the HOMO of TPB, ground-state electrons are mainly concentrated on tetraphenylethylene, and in the excited state, the electrons are transferred to — CHO. For the HOMO of TPBMA, their electrons are also mainly concentrated on tetraphenylethylene, except that benzothiazole, which is an electron acceptor, can accept electrons from tetraphenylethylene, and thus electrons are transferred to benzothiazole in an excited state, resulting in a more dispersed electron distribution. The more dispersed electron distribution effectively reduces the energy level difference between the HOMO and LUMO, causing a red shift in the emission wavelength. It can also be found from fig. 5 that the energy level differences Δ E of HOMO and LUMO of TPB, virgin TPBMA and acidified TPBMA are 3.63, 3.54 and 2.14eV, respectively, confirming the theoretical assumption that the electron acceptor-donor structure can significantly reduce the energy difference Δ E between HOMO and LUMO and increase the emission wavelength. In addition, the lower Δ E values of acidic TPBMA compared to virgin TPBMA may be responsible for its significant red shift in fluorescence emission wavelength in acidic medium.
Test example 5: PEG-TB1 fluorescence emission Spectroscopy
To understand the optical properties of the PEG-TB1 copolymer, the PEG-TB1 was tested at different THF/H ratios 2 The fluorescence emission spectrum was measured in O solution. The preparation process of the test sample solution comprises the following steps: 10mg of PEG-TB1 were weighed out and THF/H was added in different ratios 2 O mixed solution (total volume 4mL) and dissolved thoroughly by ultrasonic vibration. The results are shown in FIG. 6.
FIG. 6 shows PEG-TB1 at different ratios H 2 Fluorescence emission spectra in O/THF mixed solution, insert in the upper right corner of the graph showing PEG-TB1 in the corresponding H 2 Fluorescence intensity of O/THF ratio solution. As can be seen, PEG-TB1 has a maximum emission wavelength of 526nm and little fluorescence emission in pure THF. When the water content is less than 75%, there is almost no fluorescence emission in the solution; when the water content exceeds 75%, the fluorescence intensity is rapidly enhanced and reaches the value in pure waterTo the maximum, PEG-TB1 was shown to have significant AIE properties. When PEG-TB1 is sufficiently dissolved in an organic solvent to be excited by ultraviolet light, electrons in the HOMO will transfer to the LUMO, i.e., electrons transfer from the ground state (S0) to the excited state (S1), and due to intramolecular motion confinement, non-radiative decay provides a channel for excited state energy dissipation, suppressing fluorescence emission. When the water content reaches a critical value, the PEG-TB1 copolymer can self-assemble in water to form FONs, the TPBMA fluorophore in the shell cannot freely move in the micelle due to the increase of steric hindrance, a non-radiative decay channel is closed, and excited state energy is released from a radiative channel to cause fluorescence emission. The AIE properties of TPBMA motivate us to further study its solid state fluorescence properties. The maximum emission wavelength of TPB is 470nm and a significant red shift of the maximum emission wavelength of TPBMA can be found. Under the excitation of ultraviolet light, electrons of an electron donor (TPB) are transferred to an electron acceptor benzothiazole through a conjugated system to form an electron A-D (acceptor-donor) structure, so that the energy level difference between HOMO (highest emission index) and LUMO (lowest emission index) of fluorescent molecules is reduced, and fluorescence emission and red shift are promoted. The increase of the emission wavelength can obviously increase the penetration depth of fluorescence and reduce the damage of the fluorescence to cells, so that the TPBMA has more advantages in the field of biological imaging.
Test example 6: transmission electron microscopy analysis of PEG-TB1 FONs
Transmission electron microscopy tests were performed on PEG-TB1 FONs. The preparation process of the test sample comprises the following steps: a small amount of a mixed solution of PEG-TB1 polymer (10mg) and deionized water (4mL) was dropped onto a copper mesh with a carbon membrane, and the resulting TEM sample was dried naturally. The results are shown in FIG. 7.
FIG. 7 is a TEM image of PEG-TB1 FONs dispersed in aqueous solution with a scale of 1000 nm.
Due to the existence of two structures, namely hydrophilic PEGMA and hydrophobic TPBMA, the two structures have different affinities for water molecules, so that the copolymer has local phase separation in an aqueous solution. TPBMA is nucleated due to hydrophobic aggregation, and PEGMA is coated on the outer layer of the TPBMA in a spontaneous stretching way in an aqueous solution due to the hydrophilic property of the TPBMA to form a shell structure. Therefore, the PEG-TB polymer can be self-assembled in aqueous solution to form stable FONs with a core-shell structure through intermolecular non-covalent interactions. To confirm the above theoretical assumptions, a TEM image of PEG-TB1 FONs dispersed in aqueous solution is shown in FIG. 7. As can be seen from the figure, PEG-TB1 FONs are uniformly distributed in the aqueous solution in a spherical shape with a diameter of about 100-150nm, indicating that the theoretical assumption about self-assembly is completely correct.
Test example 7: PEG-TB FONs cytotoxicity and bioimaging studies
The biocompatibility of the polymer PEG-TB directly determines whether the polymer PEG-TB can be applied in the field of cell imaging, so that the exploration of the toxicity of the polymer PEG-TB to cells is very important. To study the effect of PEG-TB on fibroblast activity in L929 mice, the medium used to culture L929 cells was removed, washed with PBS buffer, trypsinized, centrifuged, pipetted to remove the digest, medium containing 10% fetal bovine serum was added, and the total cell density was maintained at 5X 10 4 100uL of medium per well was inoculated into 96-well plates and cultured in a cell incubator for 24 hours (37 ℃ C., 5% CO) 2 ). Then, the concentrations of PEG-TB1 were 0, 10, 20, 40, 80, and 120 ug/mL, respectively -1 The culture medium replaces the original culture medium, and the culture is continued for 8 hours and 24 hours. After incubation, the medium was removed and washed 3 times with buffer. Preparing culture medium containing 10% CCK-8, adding into 96-well plate, and culturing in 37 deg.C cell culture box for 2 hr (37 deg.C, 5% CO) 2 ). Finally, the absorbance (OD) at 450nm of each well was measured by a microplate reader. The more cells, the lower the toxicity and the darker the color; the less cells, the more toxic and the lighter the color, so this property can be used directly for cytotoxicity analysis. The method for calculating the cell viability is shown in the formula (1-1).
Figure BDA0003597280640000221
Wherein the cell survival rate is cell proliferation activity or cell toxicity activity; the A dosing is the OD value of the well with cells, CCK-8 solution and drug solution; a is not dosed as the OD value of wells with cells, CCK-8 solution, but no drug solution; the a blank is the OD value of wells without cells.
Observation of the images by confocal scanning Electron microscope (CLSM)The cellular imaging effect of FONs was investigated by the uptake behavior of the polymer PEG-TB1 by L929 cells. HeLa cells were seeded at 1X 10 5 The cells were cultured in a 35mm dish in a cell culture incubator for 24 hours (37 ℃ C., 5% CO) in a medium containing 10% fetal bovine serum 2 ). The concentration of the replaced FONs is 20 ug/mL -1 The new medium was cultured for a further 3 h. Washed three times with PBS buffer, fixed with 4% paraformaldehyde for 10 minutes, and images taken by CLSM.
Evaluation of biocompatibility and cellular imaging effect as described in fig. 8 was obtained: (A) effect of PEG-TB1 FONs on L929 cell activity; (B-D) L929 cells at a PEG-TB1 FONs concentration of 20. mu.g/mL -1 CLSM images incubated in medium, (B) brightfield, (C)405nm uv excitation, (D) images B, C were combined and synthesized with a scale of 100 μm.
The biomaterial should have good biocompatibility and low toxicity, as should the copolymer PEG-TB. In FIG. 8(A), L929 cells were cultured in FBS medium containing different concentrations of PEG-TB1 FONs for 8h and 24h, respectively, and the toxicity of the FONs to the cells was evaluated by the CCK-8 method. As can be seen from the figure, the activity of L929 cells was more than 90% after incubation in the culture medium containing different FONs concentration for 8 hours or 24 hours. Even if the concentration of FONs is as high as 120 mu g/mL -1 Cell viability was also hardly affected. Therefore, PEG-TB1 FONs are judged to have almost no cytotoxicity and excellent biocompatibility. FIG. 8(B-D) shows that L929 cells had a concentration of 20. mu.g.mL for PEG-TB1 FONs -1 After incubation in medium for 3h, CLSM images under bright field and 405nm laser excitation, respectively. As can be seen from FIGS. 8(C) and (D), the fluorescence is mainly concentrated at the inner edge of the cell, and the central region has almost no fluorescence. Considering the size of the cells, nuclei and PEG-TB1 FONs, it was determined that the area with no fluorescence in the center was where the nuclei were located, indicating that the FONs could easily cross the cell membrane, but could not enter the nuclei. From the above results, it can be seen that PEG-TB1 FONs exhibit good bio-imaging effect due to their AIE characteristics, good water dispersibility, and excellent biocompatibility.
The invention synthesizes the pH-sensitive compound based on TPB and benzothiazole through a series of reactionsAnd novel fluorescent monomers TPBMA of sexual and AIE characteristics. The maximum emission wavelength of the fluorescent material is 506nm and 579nm in neutral medium and acidic medium respectively, and the fluorescent material has excellent pH sensitivity. TPBMA in HCl/NH 3 The maximum emission wavelength under repeated fumigation can be repeatedly changed between 500nm and 579nm, which shows that the composite has excellent reversible fluorescence conversion characteristics. The maximum emission wavelength of the TPBMA fluorescence emission spectrum is significantly red-shifted compared to the TPB dye, consistent with the change in Δ E between HOMO and LUMO by quantum chemical calculations. Subsequently, TPBMA and PEGMA successfully produced a copolymer PEG-TB having an average molecular weight (Mw) and a polydispersity index (PDI) of about 2.12X 10, respectively, by RAFT polymerization 4 And 1.30. 1 H NMR analysis revealed that when the feed ratio of TBMTA was changed from 20.0% to 25.0%, the proportion of TPBMA in the PEG-TB copolymer increased from 17.4% to 22.6%. PEG-TB can self-assemble into FONs with the diameter of about 100-150nm in aqueous solution, and the fluorescence intensity of the FONs gradually increases along with the increase of the water content in the THF solution, and also has obvious AIE characteristics. In addition, cell experiments prove that the PEG-TB FONs also have the advantages of low cytotoxicity, good biocompatibility, good endocytosis effect and the like. In conclusion, the PEG-TB copolymer has the advantages of obvious AIE characteristics, pH sensitivity, good water solubility, low cytotoxicity, good biocompatibility, good endocytosis effect and the like, and has wide application prospect in the field of biological imaging.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims (10)

1. A fluorescent material with reversible pH fluorescence conversion is characterized in that the molecular structure is shown as formula I:
Figure FDA0003597280630000011
in the formula: r 1 Comprises the following steps: tetraphenylethylene, 9, 10-distyrylanthraceneHexa-phenyl silole, phenothiazine or nitrile fumarate; r 2 Comprises the following steps: benzene, biphenyl, naphthalene, pyridine or heteroaromatic rings.
2. A method of preparing a fluorescent material with reversible pH fluorescence transition as claimed in claim 1, comprising the steps of:
preparing an intermediate product I, wherein the molecular structure of the intermediate product I is shown as a formula II:
R l -CHO
formula II
In the formula: r 1 Comprises the following steps: tetraphenylethylene, 9, 10-distyrylanthracene, hexaphenylsilole, phenothiazine or nitrile fumarate;
obtaining an intermediate product II, wherein the molecular structure of the intermediate product II is shown as a formula III:
Figure FDA0003597280630000012
in the formula: r 2 Comprises the following steps: benzene, biphenyl, naphthalene, pyridine or heteroaromatic rings;
synthesizing an intermediate product III from the intermediate product I and the intermediate product II, wherein the molecular structure of the intermediate product III is shown as a formula IV:
Figure FDA0003597280630000013
in the formula: r 1 Comprises the following steps: tetraphenylethylene, 9, 10-distyrylanthracene, hexaphenylsilole, phenothiazine or nitrile fumarate; r 2 Comprises the following steps: benzene, biphenyl, naphthalene, pyridine or heteroaromatic rings;
preparing an intermediate product IV from the intermediate product III, wherein the molecular structure of the intermediate product IV is shown as a formula V:
Figure FDA0003597280630000021
in the formula: r 1 Comprises the following steps: tetraphenylethylene, 9, 10-distyrylanthracene, hexaphenylsilole, phenothiazine or nitrile fumarate; r 2 Comprises the following steps: benzene, biphenyl, naphthalene, pyridine or heteroaromatic rings;
and synthesizing the fluorescent material from the intermediate product IV.
3. The method of claim 2, wherein the intermediate product is prepared from a reactant a and a reactant b;
the molecular structure of the reactant a is shown as the formula a:
R 3 -Br
formula a
In the formula: r is 3 Comprises the following steps: triphenylethylene, phenothiazine, or nitrile fumarate;
the molecular structure of the reactant b is shown as the formula b:
(HO) 2 B-R 4 -CHO
formula b
In the formula: r 4 Comprises the following steps: benzene, biphenyl, or naphthalene;
the intermediate product I is prepared as shown in a reaction formula 1:
Figure FDA0003597280630000022
preferably, the step of preparing said intermediate product i comprises: under the action of alkali and a catalyst in a solvent under a protective atmosphere, reacting the reactant a with the reactant b to obtain an intermediate product I;
preferably, and/or, the molar ratio of the reactant a to the reactant b is 1: (1-1.5);
and/or, the protective atmosphere comprises one or more of nitrogen, argon and helium;
and/or the solvent is one or more of aromatic solvent, ether solvent and water;
and/or the catalyst is tetrakis (triphenylphosphine) palladium and/or palladium (II) acetate;
and/or the molar ratio of the catalyst to the reactant a is (0.01-0.3): 1;
and/or, the base comprises: one or more of potassium carbonate, sodium carbonate, cesium carbonate and potassium phosphate;
and/or the molar ratio of the base to the reactant a is (2-3): 1;
preferably, the temperature of the reaction is 60-120 ℃.
4. The method for preparing a fluorescent material with reversible pH fluorescence transition as claimed in claim 2, wherein the intermediate product II is prepared by hydrolysis reaction of reactant c;
the molecular structure of the reactant c is shown as formula c:
Figure FDA0003597280630000031
in the formula: r 2 Comprises the following steps: benzene, biphenyl, naphthalene, pyridine or heteroaromatic rings;
the intermediate product II is prepared as shown in a reaction formula 2:
Figure FDA0003597280630000032
preferably, the step of preparing said intermediate product ii comprises: under the action of alkali in a solvent under the protective atmosphere, carrying out hydrolysis reaction on the reactant c to obtain an intermediate product II;
preferably, and/or, the base comprises: potassium hydroxide and/or sodium hydroxide;
and/or the molar ratio of the base to the reactant c is (1-5): 1;
and/or, the protective atmosphere comprises one or more of nitrogen, argon and helium;
and/or, the solvent comprises: ethylene glycol and/or glycerol;
preferably, the temperature of the hydrolysis reaction is 120-140 ℃.
5. The method of claim 2, wherein said intermediate iii is prepared from said intermediate ii and said intermediate i;
the intermediate product III is prepared as shown in the reaction formula 3:
Figure FDA0003597280630000041
preferably, the step of preparing said intermediate product iii comprises: under a protective atmosphere, in an organic solvent, synthesizing the intermediate product II and the intermediate product I by using hantzsch thiazole to obtain an intermediate product III;
preferably, the molar ratio of the intermediate product II to the intermediate product I is (1-2): 1;
and/or, the protective atmosphere comprises one or more of nitrogen, argon and helium;
and/or the temperature of the synthesis reaction is 150-170 ℃.
6. The method of claim 2, wherein said intermediate product iv is prepared from said intermediate product iii;
the intermediate product IV is prepared as shown in a reaction formula 4:
Figure FDA0003597280630000042
preferably, the step of preparing the intermediate product iv comprises: under the protective atmosphere and in a solvent and under the action of a demethylating reagent, carrying out demethylation reaction on the intermediate product III to obtain an intermediate product IV;
preferably, and/or, the demethylating agent comprises: boron tribromide;
and/or the molar ratio of the demethylating agent to the intermediate III is (1.0-2.0): 1;
and/or, the protective atmosphere comprises one or more of nitrogen, argon and helium;
and/or, the solvent comprises: dichloromethane and/or tetrahydrofuran;
preferably, the temperature of the demethylation reaction is 10-60 ℃.
7. The method of claim 2, wherein the fluorescent material is prepared from the intermediate product iv and a reactant d;
the molecular structure of the reactant d is shown as formula d:
Figure FDA0003597280630000051
preparing a fluorescent material represented by formula I as shown in reaction formula 5:
Figure FDA0003597280630000052
preferably, the step of preparing the fluorescent material comprises: carrying out acylation reaction on the intermediate product IV and the reactant d in a solvent under the action of alkali in a protective atmosphere to obtain the fluorescent material shown in the formula I;
preferably, and/or, the base comprises: one or more of triethylamine, diethylamine and diisopropylethylamine;
and/or the molar ratio of the alkali to the intermediate product IV is (1-4): 1;
and/or, the protective atmosphere comprises one or more of nitrogen, argon and helium;
and/or, the solvent comprises: dichloromethane and/or tetrahydrofuran;
and/or the temperature of the acylation reaction is ice water bath.
8. A fluorescent polymer synthesized from the fluorescent material with reversible pH fluorescence transition of claim 1, wherein the molecular structure of the fluorescent polymer is represented by formula vi:
Figure FDA0003597280630000053
in the formula: r 1 Comprises the following steps: tetraphenylethylene, 9, 10-distyrylanthracene, hexaphenylsilole, phenothiazine or nitrile fumarate; r 2 Comprises the following steps: benzene, biphenyl, naphthalene, pyridine or heteroaromatic rings; r is 5 Is a hydrophilic group; m is 7 to 35; n is 28 to 138;
preferably, the preparation method of the fluorescent polymer comprises the following steps: synthesizing the fluorescent material with the molecular structure shown as the formula I and a hydrophilic monomer;
the molecular structure of the hydrophilic monomer is shown as formula VII:
Figure FDA0003597280630000061
in the formula: r is 5 Is a hydrophilic group;
preferably, the fluorescent polymer is prepared as shown in equation 6:
Figure FDA0003597280630000062
preferably, the step of preparing the fluorescent polymer comprises: under the protective atmosphere, in a solvent and under the action of an initiator and a chain transfer agent, carrying out RAFT polymerization reaction on the fluorescent material and the hydrophilic monomer;
preferably, and/or, the molar ratio of the fluorescent material and the hydrophilic monomer is (0.1-0.5): 1;
and/or, the solvent comprises: one or more of benzene solvents and ether solvents;
and/or, the protective atmosphere comprises one or more of nitrogen, argon and helium;
and/or, the initiator comprises: azobisisobutyronitrile and/or azobisisoheptonitrile;
and/or the molar ratio of the initiator to the fluorescent material is (0.01-0.2): 1;
and/or, the chain transfer agent is a thiocarbonyl sulfide comprising: one or more of dithioesters, thiocarbamates, and xanthates;
and/or the molar ratio of the chain transfer agent to the fluorescent material is (0.05-0.2): 1;
preferably, the temperature of the RAFT polymerisation is from 65 to 75 ℃.
9. A fluorescent nanoparticle made by self-assembly of the fluorescent polymer of claim 8 in an aqueous solution.
10. The fluorescent polymer of claim 8 for use in biological imaging, fluorescence labeling, and tumor diagnosis and treatment.
CN202210395914.7A 2022-04-14 2022-04-14 Fluorescent material with reversible pH fluorescence conversion, fluorescent polymer, fluorescent nanoparticles and preparation method and application thereof Pending CN115011330A (en)

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