CN113265042B - Copolymer capable of regulating and controlling fluorescence luminescence mode and preparation method and application thereof - Google Patents

Copolymer capable of regulating and controlling fluorescence luminescence mode and preparation method and application thereof Download PDF

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CN113265042B
CN113265042B CN202110611951.2A CN202110611951A CN113265042B CN 113265042 B CN113265042 B CN 113265042B CN 202110611951 A CN202110611951 A CN 202110611951A CN 113265042 B CN113265042 B CN 113265042B
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aie
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王程
沈悦
周心霈
王彦彬
陈珺
王建浩
崔朋飞
邱琳
周舒文
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Abstract

The invention belongs to the field of chemistry, and particularly discloses a copolymer capable of regulating a fluorescence luminescence mode, and a preparation method and application thereof. The copolymer can regulate and control the conversion of the fluorescence luminescent property of the copolymer between polymerization induced luminescence (AIE) and polymerization induced quenching (ACQ) by regulating the proportion of two groups in the structure of the copolymer. The obtained copolymer with AIE properties is used for preparing stable nanoparticles and loading the drug, and the positioning and accumulation conditions of the drug in cells can be traced in real time.

Description

Copolymer capable of regulating and controlling fluorescence luminescence mode and preparation method and application thereof
Technical Field
The invention belongs to the field of chemistry, and particularly relates to a copolymer capable of regulating a fluorescence lighting mode, a preparation method thereof, and application of the copolymer in positioning and accumulation of a tracer drug in a cell.
Background
Aggregation-induced emission (AIE) and aggregation-induced quenching (ACQ) represent two diametrically opposite behaviors of existing organic fluorescent molecules. However, at high concentrations, the ACQ behavior of fluorophores often severely limits their practical applications due to signal loss. Therefore, how to convert the fluorescent molecule from ACQ to AIE is an important part in promoting the practical application of the fluorescent molecule. Since fluorescent substances need to be encapsulated in a delivery system in a self-assembled/polymerized state together with a drug in image-guided drug delivery and cancer treatment, the use of fluorescent molecules with AIE properties is an effective way to overcome the drawbacks of conventional ACQ probes.
Fluorescence Resonance Energy Transfer (FRET) is a long-range dipole-dipole interaction from the donor to the acceptor. The copolymer can be conveniently fine-tuned by FRET to achieve continuous variation of its properties. Thus, designing a conjugated copolymer with an intramolecular FRET process can easily tailor some of the significant optical properties of the copolymer, such as fluorescence color and emission intensity, to achieve desirable material properties. In previous studies, the transition from ACQ to AIE was largely dependent on additional chemical modifications to modulate the photochemical properties of the fluorophore. The method for controlling the overall luminescence property of the copolymer to change between ACQ and AIE by simply adjusting the ratio of monomers in the copolymer has not been reported.
Disclosure of Invention
In the research of the invention, four monomers of M1, M2, M3 and M4 are subjected to Suzuki coupling reaction according to different proportions to obtain a copolymer, the proportion of the monomers M1 and M2 is adjusted, the fluorescence luminescence characteristic of the obtained copolymer can be conveniently converted between ACQ and AIE, when the molar ratio of M1/M2 is more than or equal to 9, the copolymer presents AIE properties, and when the molar ratio of M1/M2 is less than or equal to 4, the copolymer presents ACQ properties.
Wherein, the structural formula of M1 is as follows: the structural formula of M2 is:
Figure BDA0003095988340000021
the structural formula of M3 is: the structural formula of M4 is:
Figure BDA0003095988340000022
the synthetic route of the copolymer is as follows:
Figure BDA0003095988340000023
the copolymer prepared by the invention has the structural general formula as follows:
Figure BDA0003095988340000031
the Mw molecular weight is between 15000 and 20000, and the Mn molecular weight is between 10000 and 15000.
The copolymer can be prepared into stable nanoparticles by using a precipitation method, loads a drug, and can trace the positioning and accumulation conditions of the drug in cells in real time.
Advantageous effects
The copolymer of the present invention provides a convenient way to switch between ACQ and AIE by adjusting the ratio between the monomers. The luminescent property of the obtained polymer can be conveniently adjusted, and the possibility of adapting to more application approaches is provided.
Drawings
FIG. 1 shows the hydrogen nuclear magnetic resonance spectrum of the copolymer obtained when the molar ratio M1/M2 is 9.
FIG. 2 shows a gel permeation chromatogram of the copolymer obtained when the molar ratio M1/M2 is 9.
FIG. 3 shows fluorescence spectra of the resulting copolymer in different ratios of water to tetrahydrofuran at a molar ratio M1/M2 of 9 (the bars in the figure from top to bottom represent the decreasing ratio of water to tetrahydrofuran).
FIG. 4 shows the intracellular fluorescence of the copolymer obtained by nano-precipitation method after incubation with HT29 cells for different time after the copolymer is prepared into nanoparticles with a molar ratio of M1/M2 of 9.
FIG. 5 shows the NMR spectrum of the copolymer obtained at a molar ratio of M1/M2 of 4.
FIG. 6 shows a gel permeation chromatogram of the copolymer obtained when the molar ratio M1/M2 is 4.
FIG. 7 shows fluorescence emission spectra of the resulting copolymer in different ratios of water to tetrahydrofuran at a molar ratio of M1/M2 of 4 (the bars in the figure from top to bottom represent increasing water/tetrahydrofuran ratio).
FIG. 8 shows the intracellular fluorescence of the copolymer obtained after the copolymer is prepared into nanoparticles by a nanoprecipitation method and incubated with HT29 cells for different times when the molar ratio of M1/M2 is 4.
Detailed Description
The invention is further illustrated by the examples.
M1-M4 were synthesized by reference to the following references:
M1：Z.Wang,Y.Feng,N.Wang,Y.Cheng,Y.Quan and H.Ju,The journal of physical chemistry letters,2018,9,5296-5302.
M2：Z.Wang,Y.Feng,N.Wang,Y.Cheng,Y.Quan and H.Ju,The journal of physical chemistry letters,2018,9,5296-5302.
M3：Z.Wang,C.Wang,Y.Fang,H.Yuan,Y.Quan and Y.Cheng,Polymer Chemistry,2018,9,3205-3214.
M4：C.Wang,Z.Wang,X.Zhao,F.Yu,Y.Quan,Y.Cheng and H.Yuan,Acta biomaterialia,2019,85,218-228.
example 1
M1 (0.150g, 0.315mmol), M2 (0.016g, 0.035mmol), M3 (0.224g, 0.350mmol) and Pd (PPh) 3 ) 4 (0.040 g) was dissolved in the reaction mixture (containing 10mL of toluene, 5mL of ethanol, 5mL of water and 1.00g of Na 2 CO 3 ). The reaction system is placed under the protection of argon gas and stirred and refluxed for reaction for 12 hours. Separating the organic phase with Na 2 SO 4 Drying to remove water, and spin-drying to remove solvent. The resulting solid was mixed with M4 (0.57 g), pd (PPh) 3 ) 4 (0.040 g) and NaHCO 3 (0.80 g) were mixed and dissolved in a mixed solvent (containing 30mL of tetrahydrofuran and 15mL of water), and the reaction mixture was refluxed for 36 hours under an argon atmosphere. After the reaction was completed, the organic phase was collected, diluted with 50mL of dichloromethane, and washed 3 times with 50mL of water. The organic phase obtained is Na 2 SO 4 Drying to remove water, and spin-drying to remove solvent. A dark red solid (0.373 g) was obtained. The NMR spectrum of the deuterated chloroform solution at 400MHz is shown in FIG. 1, and the characteristic peaks are shown as delta 7.69-7.69 (m, 5H), 7.58-7.41 (m, 8H), 7.17-7.12 (m, 9H), 3.65 (s, 271H), 2.66 (s, 7H), 2.00 (s, 3H), 1.06 (s, 16H) and 0.77-0.66 (m, 8H).
The molecular weight of the product was determined by gel permeation chromatography. The apparatus used was Waters244, the sample size was 20. Mu.L, the column temperature was 30 ℃, the liquid phase column type was PLgel MIXED-C (pore size: 5 μm; size: 7.5 mm. Times.300 mm), tetrahydrofuran was used as the solvent, the flow rate was 0.6mL/min, polystyrene was used as the standard, and the resulting liquid chromatography was shown in FIG. 2. Calculated, mw =17451, mn =11588, pdi =1.51.
And detecting the fluorescence luminescence condition of the polymer in tetrahydrofuran-water mixed solvents with different volume ratios by adopting a fluorescence spectrophotometer. Referring to fig. 3, it can be found that the copolymer synthesized under this condition has AIE properties.
The copolymer nanoparticles are prepared by a precipitation method. 1mg of the copolymer was dissolved in 5mL of tetrahydrofuran. Then, the tetrahydrofuran solution of the copolymer was rapidly injected into 50mL of water under sonication. Sonication was performed for 5min, then the solution was rotary evaporated to a residual volume of 5mL.
HT29 cells were seeded in glass culture dishes (1X 10) of 35mm diameter 4 Each cell per dish), incubated with an incubator for 24h, the primary medium was discarded, and fresh medium containing 200 μ Ι _ of 50ppm copolymer nanoparticle solution was added. After incubation with cells at different time points (4,8, 12 h), the culture medium was discarded, washed 3 times with PBS (pH = 7.4), and then fixed with 4.0% formaldehyde for 15min. Intracellular fluorescence signals were recorded using a confocal laser microscope. The results are shown in fig. 4, and the obtained polymer nanoparticles have stronger luminescence performance, which is consistent with the results predicted by fig. 3.
Example 2
Mixing M1 (0.133g, 0.280mmol), M2 (0.032g, 0.070mmol), M3 (0.224g, 0.350mmol) and Pd (PPh) 3 ) 4 (0.040 g) was dissolved in the reaction mixture (containing 10mL of toluene, 5mL of ethanol, 5mL of water and 1.00g of Na) 2 CO 3 ). The reaction system is placed under the protection of argon and stirred and refluxed for 12 hours. Separating the organic phase with Na 2 SO 4 Drying to remove water, and spin-drying to remove solvent. The resulting solid was mixed with M4 (0.57 g), pd (PPh) 3 ) 4 (0.040 g) and NaHCO 3 (0.80 g) were mixed and dissolved in a mixed solvent (containing 30mL of tetrahydrofuran and 15mL of water), and the reaction mixture was refluxed for 36 hours under an argon atmosphere. After the reaction was completed, the organic phase was collected, diluted with 50mL of dichloromethane, and washed 3 times with 50mL of water. The obtained organic phase is Na 2 SO 4 Is dried toRemoving water from the solution, and spin-drying to remove the solvent. A dark red solid (0.373 g) was obtained. The NMR spectrum of the deuterated chloroform solution at 400MHz is shown in FIG. 5, and characteristic peaks are represented by delta 7.71-7.66 (m, 4H), 7.59-7.40 (m, 8H), 7.17-7.12 (m, 9H), 3.65 (s, 354H), 2.71 (s, 7H), 1.99 (s, 3H), 1.07 (s, 17H), 0.78 (s, 5H) and 0.66 (s, 2H).
The molecular weight of the product obtained was determined by gel permeation chromatography. The apparatus used was Waters244, the sample size was 20. Mu.L, the column temperature was 30 ℃, the liquid phase column type was PLgel MIXED-C (pore size: 5 μm; size: 7.5 mm. Times.300 mm), tetrahydrofuran was used as the solvent, the flow rate was 0.6mL/min, polystyrene was used as the standard, and the resulting liquid chromatography was shown in FIG. 6. Calculated, mw =15030, mn =11830, pdi =1.27.
And (3) detecting the fluorescence luminescence condition of the polymer in the tetrahydrofuran-water mixed solvent with different volume ratios by using a fluorescence spectrophotometer. Referring to fig. 7, it can be seen that the copolymer synthesized under this condition has ACQ properties.
The copolymer nanoparticles are prepared by a precipitation method. 1mg of the copolymer was mixed and dissolved in 5mL of tetrahydrofuran. Then, the tetrahydrofuran solution of the copolymer was rapidly injected into 50mL of water under sonication. Sonication was performed for 5min, then the solution was rotary evaporated to a residual volume of 5mL.
HT29 cells were seeded in glass culture dishes 35mm in diameter (1X 10) 4 Each cell per dish), incubated with an incubator for 24h, the primary medium was discarded, and fresh medium containing 200 μ Ι _ of 50ppm copolymer nanoparticle solution was added. After incubation with cells at different time points (4,8, 12 h), the culture broth was discarded, washed 3 times with PBS (pH = 7.4), and then fixed with 4.0% formaldehyde for 15min. Intracellular fluorescence signals were recorded using a confocal laser microscope. Compared with fig. 4, the nanoparticles prepared from the copolymer synthesized under this condition have a weaker fluorescence signal (see fig. 8 for the result).
Example 3
The copolymer nanoparticles loaded with adriamycin are prepared by a precipitation method. 0.3mg of doxorubicin and 1mg of the copolymer from example 1 were mixed and dissolved in 5mL of tetrahydrofuran. Then, the tetrahydrofuran solution containing doxorubicin and the copolymer was rapidly injected into 50mL of water under sonication. Sonication for 5min, followed by rotary evaporation of the solution to a residual volume of 5mL.
HT29 cells were seeded in glass culture dishes (1X 10) of 35mm diameter 4 Each cell per dish), incubated in a constant temperature incubator for 24h, the primary medium was discarded, and fresh medium containing 200 μ Ι _, 50ppm of the doxorubicin copolymer nanoparticle-loaded solution was added. After incubation with cells at different time points (4,8, 12 h), the culture medium was discarded, washed 3 times with PBS (pH = 7.4), and then fixed with 4.0% formaldehyde for 15min. The fluorescence signals of the doxorubicin and the polymer in the cells were recorded by confocal laser microscopy, and the content of the doxorubicin in the cells was determined by high performance liquid chromatography. The result shows that the fluorescent signals of the adriamycin and the polymer in the cells have better co-localization condition, and the coincidence rate is 89.2% at 4 h. After different time points, the content of the adriamycin in the cells is in positive correlation with the fluorescent signal of the polymer in the cells, and the correlation coefficient is 0.92.

Claims (1)

1. Copolymer nanoparticles loaded with adriamycin are characterized in that the copolymer nanoparticles are prepared by a precipitation method and used for tracing the positioning and accumulation conditions of a drug in a cell in real time;
the structural general formula of the adriamycin-loaded copolymer is as follows:
Figure FDA0004109467640000011
the copolymer has Mw of between 15000 and 20000 and Mn of between 10000 and 15000;
the preparation method of the copolymer comprises the following steps: m1, M2, M3 and M4 are obtained by Suzuki coupling reaction according to the proportion,
wherein, the structural formula of M1 is as follows:
Figure FDA0004109467640000012
the structural formula of M2 is:
Figure FDA0004109467640000013
the structural formula of M3 is:
Figure FDA0004109467640000014
the structural formula of M4 is:
Figure FDA0004109467640000015
when the molar ratio of M1/M2 is more than or equal to 9, the prepared copolymer presents AIE properties, and when the molar ratio of M1/M2 is less than or equal to 4, the prepared copolymer presents ACQ properties. />
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