CN115246845B - D-pi-A-pi-D near infrared two-region aggregation-induced emission molecule, nano preparation and application thereof - Google Patents
D-pi-A-pi-D near infrared two-region aggregation-induced emission molecule, nano preparation and application thereof Download PDFInfo
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Abstract
The invention belongs to the fields of nano medical imaging technology and photothermal treatment, and particularly relates to a D-pi-A-pi-D near infrared two-region aggregation-induced emission molecule, a nano preparation and application thereof. The D-pi-A-pi-D near infrared two-region aggregation-induced emission molecule BTQ introduces a plurality of triphenylamine with propeller structures on phenothiazine, promotes molecular absorption and fluorescence emission red shift, and simultaneously effectively inhibits pi-pi accumulation effect among molecules, so that the molecules have aggregation-induced emission (AIE) property. The prepared nano preparation can be used as a near infrared two-region imaging contrast agent and used as a tumor photothermal therapeutic agent.
Description
Technical Field
The invention belongs to the fields of nano medical imaging technology and photothermal treatment, and particularly relates to a D-pi-A-pi-D near infrared two-region aggregation-induced emission molecule, a nano preparation and application thereof.
Background
Fluorescent imaging has attracted wide attention in basic research and practical application in the biomedical field by the inherent advantages of noninvasive detection, high sensitivity, in-situ workability, high time resolution and the like. Among them, fluorescence imaging in the near infrared two-region wavelength range (NIR-II, 1000-1700 nm) has received more attention due to the characteristics of deep tissue penetration, high resolution, low background noise, and the like. Although some NIR-II fluorescent photosensitizers have been reported, the current situation is still less than ideal. Inorganic fluorescent nanomaterials, although having very high fluorescence intensities, often have toxicity problems, severely limiting their biological applications. At present, the organic small molecule photosensitizer is applied to near infrared two-region fluorescence imaging because of the advantages of excellent stability, good biocompatibility and the like. However, most of the small organic molecules in aqueous solution cause serious aggregation fluorescence quenching phenomenon due to strong pi-pi interaction among molecules, so that the fluorescence intensity of the small organic molecules is weaker.
In addition, photothermal therapy (PTT) is an emerging clinical treatment for non-invasive tumors. When irradiated with a laser light of a certain wavelength, photothermal agents (PTAs) absorb light energy, and transition from a ground state to an excited state. Then decays to the ground state by vibratory relaxation and generates high temperatures, thereby killing tumor cells.
Therefore, the photosensitizer for guiding the tumor photothermal treatment by the near infrared two-region fluorescence imaging has very good application prospect.
Disclosure of Invention
The invention aims to overcome the defects and shortcomings of the prior art and provide a D-pi-A-pi-D near infrared two-region aggregation-induced emission molecule, a nano preparation and application thereof.
In a first aspect of the present invention, there is provided a near infrared two-region aggregation-induced emission molecule of the formula:
the D-pi-A-pi-D near infrared two-region aggregation-induced emission molecule BTQ introduces a plurality of triphenylamine with propeller structures on phenothiazine, promotes molecular absorption and fluorescence emission red shift, and simultaneously effectively inhibits pi-pi accumulation effect among molecules, so that the molecules have aggregation-induced emission (AIE) property.
In a second aspect of the present invention, there is provided a method for preparing a near infrared two-region aggregation-induced emission molecule as described above, comprising the steps of: dissolving a compound 6 in DCM, adding absolute ethyl alcohol and a catalyst Pd/C, reacting in a hydrogen atmosphere, filtering and concentrating after the reaction is finished, then dissolving the compound in a solvent together with benzil, and carrying out reflux reaction until the reaction is finished to obtain the D-pi-A-pi-D near infrared two-region aggregation-induced luminescent molecule;
the structural formula of the compound 6 is as follows:
the process for synthesizing the compound 6 comprises the following steps:
dissolving compound 4 and compound 5 in solvent, adding CsCO 3 Water and catalyst Pd (PPh 3 ) 4 Heating to 80-120 ℃ in inert gas atmosphere for reaction, cooling to room temperature after the reaction is finished, and adding water for quenching reaction to obtain a compound 6;
the structural formula of the compound 4 is as follows:
the structural formula of the compound 5 is as follows:
the process for synthesizing the depicted compound 4 comprises the steps of: dissolving compound 3 and bisdiboronate in solvent, adding KOAC and catalyst Pd (dppf 2 )Cl 2 Heating to 80-120 ℃ in inert gas atmosphere for reaction, cooling to room temperature after the reaction is finished, and adding water for quenching reaction to obtain a compound 4;
the structural formula of the compound 3 is as follows:
the process for synthesizing the depicted compound 3 comprises the steps of: dissolving 2, 4-bis (4-methoxyphenyl) aminophenylboronic acid in solvent, adding KOAC and Pd (dppf) 2 )Cl 2 Heating to 80-120 ℃ in inert gas atmosphere for reaction, cooling to room temperature after the reaction is finished, and adding water for quenching reaction to obtain a compound 3;
the structural formula of the compound 2 is as follows:
the process for synthesizing the compound 2 comprises the following steps: dissolving the compound 1 in a solvent, carrying out ice bath, slowly injecting NBS dissolved in the solvent into a reaction solution by using a syringe under the protection of inert gas, naturally heating to room temperature for reaction, and obtaining a compound 2 after the reaction is finished;
the molecular formula of the compound 1 is as follows:
in a third aspect of the present invention, there is provided a nano-preparation prepared from the above-described D-pi-a-pi-D near infrared two-region aggregation-induced emission molecule.
In a fourth aspect of the present invention, there is provided a method of preparing a nano-formulation as described above, comprising the steps of: dissolving the D-pi-A-pi-D near infrared two-region aggregation-induced emission molecules in THF to obtain a solution (1), DSPE-PEG 2000 Dissolving in water to obtain a solution (2), mixing the solution (1) and the solution (2) in water, performing ultrasonic dispersion, stirring overnight to remove THF in the solution, obtaining a D-pi-A-pi-D type near infrared two-region aggregation-induced luminescent molecule nanoparticle aqueous solution, and removing the solvent to obtain the nano preparation.
The preparation method is simple and convenient for production.
In a fifth aspect of the present invention, there is provided the use of a nano-formulation as described above as a near infrared two-region imaging contrast agent, said nano-formulation having a fluorescence emission peak at 1100nm under 808nm laser irradiation. The nanometer preparation can realize stable near infrared two-region fluorescence imaging, and has important significance in the field of biomedicine.
In a sixth aspect of the present invention, there is provided the use of a nano-preparation as described above as a photothermal therapeutic agent for tumors, said nano-preparation generating heat under 808nm laser irradiation, having good photothermal conversion properties, and being useful as a photothermal therapeutic agent for tumors.
The beneficial effects of the invention are as follows:
1. the invention designs and prepares the D-pi-A-pi-D near infrared two-region aggregation-induced emission molecule BTQ, and the introduction of triphenylamine with a propeller structure and phenothiazine with a butterfly-shaped structure can effectively inhibit pi-pi accumulation effect among molecules, so that the molecule has the property of aggregation-induced emission (AIE).
2. The invention relates to a D-pi-A-pi-D near infrared two-region aggregation-induced emission molecular nano preparation which is prepared from BTQ molecules and amphiphilic polymer DSPE-PEG 2000 The self-assembled product is prepared by a very simple preparation method.
3. The D-pi-A-pi-D near infrared two-region aggregation-induced emission molecular nano preparation can realize high-quality near infrared two-region fluorescence imaging of blood vessels and tumor focus areas in living bodies.
4. The D-pi-A-pi-D near infrared two-region aggregation-induced emission molecular nano preparation has good photo-thermal conversion performance.
5. The D-pi-A-pi-D near infrared two-region aggregation-induced emission molecule has the advantages of easily available raw materials and simple reaction. Similar small molecular photosensitizers are not reported to be used for near infrared two-region fluorescence imaging guided tumor photothermal treatment, and have strong commercial value.
Compared with some reported organic small molecule near infrared two-region photosensitizers, the invention has the following advantages and technical effects: the introduction of triphenylamine with a propeller structure and phenothiazine with a butterfly structure can promote the absorption and fluorescence emission red shift of molecules and simultaneously effectively inhibit pi-pi stacking effect among the molecules, so that the molecules have aggregation-induced emission (AIE) property and the fluorescence emission intensity of the molecules is enhanced. In addition, the molecule has good photo-thermal conversion efficiency, and can be used for photo-thermal treatment of tumors.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions of the prior art, the drawings which are required in the description of the embodiments or the prior art will be briefly described, it being obvious that the drawings in the description below are only some embodiments of the invention, and that it is within the scope of the invention to one skilled in the art to obtain other drawings from these drawings without inventive faculty.
FIG. 1 is a chemical formula of BTQ synthesized in example 1;
FIG. 2 is a synthetic route diagram of the synthetic BTQ of example 1;
FIG. 3 is a hydrogen spectrum of BTQ synthesized in example 1;
FIG. 4 is a mass spectrum of BTQ synthesized in example 1;
FIG. 5 (a) shows the BTQ synthesized in example 1 at different THF/H 2 FIG. 5 (b) shows the fluorescence emission pattern of BTQ at different THF/H 2 A graph of relative fluorescence intensity change at O volume ratio;
FIG. 6 (a) is a dynamic light scattering particle size distribution diagram of BTQ nanoparticles prepared in example 2; FIG. 6 (b) is a transmission electron micrograph of BTQ nanoparticles prepared in example 2;
FIG. 7 is a photo-thermal property of the BTQ nanofabricated preparation prepared in example 2;
FIG. 8 is a near infrared two-region fluorescence living body blood vessel imaging application diagram of the BTQ nanometer preparation prepared in example 2 on a nude mouse;
FIG. 9 is a near infrared two-region fluorescence imaging application diagram of the BTQ nano-preparation prepared in example 2 on tumor-bearing mice;
fig. 10 is a photo-thermal therapeutic application diagram of the BTQ nanoformulation synthesized in example 2 on tumor-bearing mice.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings, for the purpose of making the objects, technical solutions and advantages of the present invention more apparent.
Example 1
The chemical structural formula of the D-pi-A-pi-D near infrared two-region aggregation-induced emission molecule BTQ is shown in figure 1, the synthetic route is shown in figure 2, and the nuclear magnetic hydrogen spectrum and the high-resolution mass spectrum of the prepared BTQ molecule are shown in figures 3 and 4.
The specific synthesis process is as follows:
(1) Synthesis of Compound 2
200mg (0.4 mmol) of Compound 2 was dissolved in 5ml of DCM under argon gas and ice-bath conditions, then 150mg (0.84 mmol) of NBS dissolved in 1ml of DMF was slowly injected into the reaction solution by syringe, naturally warmed to room temperature and reacted overnight, 30ml of deionized water was added to the reaction solution after the reaction was completed, extracted with DCM, the combined organic phases were washed with water multiple times, dried over anhydrous magnesium sulfate, concentrated by rotary evaporation under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography with petroleum ether: dichloromethane (4:1) was the mobile phase to give (0.265 g) compound 2 as a white solid in 66% yield. 1 H NMR(400MHz,CDCl 3 )δ7.16(d,J＝8.4Hz,4H),7.07–7.02(m,6H),6.94(dd,J＝8.8,2.1Hz,2H),6.89(d,J＝8.6Hz,4H),6.12(d,J＝8.8Hz,2H),3.82(s,6H)。
(2) Synthesis of Compound 3
2.4g (3.6 mmol) of Compound 2,1.5g (4.32 mmol) of 4-bis (4-methoxyphenyl) aminophenylboronic acid, 3.5g (10.8 mmol) of CsCO are placed in a 100ml two-necked round-bottomed flask under the protection of argon 3 To 25ml of 1, 4-dioxane and 5ml of deionized water, followed by 208mg of Pd (PPh) 3 ) 4 A catalyst. The reaction mixture was warmed to 100 ℃ and reacted overnight. After cooling to room temperature, 30ml of deionized water was added to the reaction solution, and the mixture was extracted with methylene chloride several times. The organic phase obtained by extraction and combination is dried by anhydrous magnesium sulfate, then the organic solvent is removed by rotary evaporation, and the crude product is separated and purified by silica gel column chromatography, and petroleum ether is used for preparing: dichloromethane: ethyl acetate (10:1:1) was the mobile phase to give (1.02 g) compound 3 as a yellow solid in 32% yield. 1 H NMR(400MHz,DMSO-d 6 )δ7.37(d,J＝8.5Hz,2H),7.21(m,2H),7.18–7.13(m,7H),7.10–7.04(m,1H),7.01–6.94(m,8H),6.90–6.87(m,6H),6.77–6.75(m,2H),6.21(d,J＝8.5Hz,1H),6.11(d,J＝8.9Hz,1H),3.74–3.72(m,12H).
(3) Synthesis of Compound 4
700mg (0.8 mmol) of Compound 3, 241mg (0.96 mmol) of Di-diboronate, 157mg (1.6 mmol) of KOAC are added to 15ml of 1, 4-dioxane and then a further 50mg of Pd (dppf) are added under argon in a 100ml two-necked round-bottomed flask 2 )Cl 2 A catalyst. The reaction mixture was warmed to 100 ℃ and reacted overnight. After cooling to room temperature, 30ml of deionized water was added to the reaction solution, and the mixture was extracted with methylene chloride several times. The organic phase obtained by extraction and combination is dried by anhydrous magnesium sulfate, then the organic solvent is removed by rotary evaporation, and the crude product is separated and purified by silica gel column chromatography, and petroleum ether is used for preparing: dichloromethane (1:1) was the mobile phase to give (0.56 g) compound 4 as a yellow solid in 75% yield. 1 H NMR(400MHz,DMSO-d 6 )δ7.38(d,J＝8.6Hz,2H),7.22–7.11(m,10H),7.02–6.95(m,8H),6.90–6.88(m,6H),6.76(d,J＝8.7Hz,2H),6.21–6.17(m,2H),3.74–3.72(m,12H),1.24(s,12H).
(4) Synthesis of Compound 6
290mg (0.31 mmol) of Compound 4, 80mg (0.146 mmol) of Compound 5, 143mg (0.438 mmol) of CsCO are placed in a 50ml two-necked round bottom flask under the protection of argon 3 To 10ml of 1, 4-dioxane and 2ml of deionized water, and then 40mg of Pd (PPh) 3 ) 4 A catalyst. The reaction mixture was warmed to 100 ℃ and reacted overnight. After cooling to room temperature, 30ml of deionized water was added to the reaction solution, and the mixture was extracted with methylene chloride several times. Extracting the combined organic phases, drying with anhydrous magnesium sulfate, removing organic solvent by rotary evaporation, separating and purifying the crude product by silica gel column chromatography, and purifying with petroleum ether: dichloromethane (1:4) was the mobile phase to give (0.198 g) of compound 6 as a greenish black solid in 31% yield. 1 H NMR(400MHz,DMSO-d 6 )δ7.57–7.54(m,2H),7.47–7.44(m,2H),7.42–7.39(m,6H),7.32–7.24(m,4H),7.21–7.16(m,13H),7.03(d,J＝8.8Hz,8H),6.99(d,J＝8.7Hz,8H),6.95–6.91(m,13H),6.79(d,J＝8.3Hz,4H),6.27–6.22(m,4H),3.77–3.75(m,24H).
(5) Synthesis of near infrared two-region aggregation-induced emission molecule BTQ
100mg (0.05 mmol) of Compound 6 are dissolved in 10ml of DCM, 2ml of absolute ethanol are added, and 20mg of Pd/C catalyst are added. Stirring the reaction solution at room temperature under the action of hydrogen for reaction for 3 hours until the color of the reaction solution turns orange, filtering out redundant Pd/C by using diatomite after the reaction is finished, concentrating the filtrate by reduced pressure rotary evaporation, and directly carrying out the next reaction without further purification; 100mg of the reduced product and 21mg (0.1 mmol) of benzil were dissolved in 5ml of CHCl 3 And 5ml CH 3 In COOH mixed solvent, the reaction liquid is refluxed overnight at 70 ℃, the reaction is finished and cooled to room temperature, the reaction liquid is filtered by a buchner funnel, washed by PE, the solid is taken as a crude product, and is separated and purified by column chromatography, and petroleum ether is used for preparing the catalyst: dichloromethane (1:5) was the mobile phase to give (0.033 g) the green solid compound BTQ in 31% yield. 1 H NMR(400MHz,THF-d 8 )δ7.70–7.69(m,4H),7.51–7.29(m,12H),7.13(d,J＝8.8Hz,12H),7.08–7.02(m,18H),6.94–6.92(d,J＝8.2Hz,8H),6.88–6.83(m,20H),3.75–3.74(m,24H).
AIE performance test was performed on the prepared near infrared two-region aggregation-induced emission molecule BTQ, as shown in FIG. 5. In THF/H 2 The AIE properties of BTQ were tested in O-mixed solvents. It can be seen from fig. 5a and 5b that as the water fraction increases to 60%, the fluorescence intensity of the solution gradually decreases, which is a typical intramolecular twisted charge transfer effect (tic). As the water fraction continues to increase, the fluorescence intensity increases instead, indicating that BTQ molecules have typical aggregation-inducing propertiesLight-guiding (AIE) performance.
Example 2
A near infrared two-region aggregation-induced emission molecule BTQ nano preparation is prepared by the following steps: 1mg of BTQ was dissolved in 1ml of THF, and 4mg of DSPE-PEG was used 2000 Dissolving in 1ml double distilled water, adding the two solutions into 8ml double distilled water, performing ultrasonic treatment for 10min by using a cell ultrasonic breaker, stirring overnight to remove THF in the solution, thus obtaining BTQ nanoparticle aqueous solution, filtering the BTQ nanoparticle aqueous solution by using a 0.22 mu m filter head, concentrating by adopting an ultrafiltration concentration mode, and finally performing freeze drying to obtain the final BTQ nanoparticle preparation.
The prepared BTQ nano preparation is subjected to transmission electron microscopy and dynamic light scattering characterization, as shown in fig. 6. The shape of the nanoparticle is spherical, and the diameter is about 110nm.
And (5) carrying out photo-thermal property research on the prepared BTQ nano preparation. As shown in FIG. 7a, at a power of 500mW/cm 2 With 808nm laser irradiation, the temperature increased more as the BTQ nanofabrication concentration increased. BTQ nanofabrics at a concentration of 100 μm can be warmed to 60.4 ℃ after 5min of irradiation. As shown in fig. 7b, in the case of maintaining the concentration of BTQ nanofabricated at 50 μm, the temperature of the nanofabricated solution increases higher as the 808nm laser power increases. The result shows that the near infrared two-region aggregation-induced emission molecule BTQ has good photo-thermal performance and has the potential of anti-tumor photo-thermal treatment.
Example 3:
the BTQ nano preparation prepared in the example 2 is used for near infrared two-region fluorescence imaging of blood vessels in organisms. The nude mice were injected with BTQ nanoformulation via tail vein and imaged with a near infrared two-zone small animal fluorescence imager, as shown in fig. 8, which clearly imaged the blood vessels of the mice (blood vessels of brain, abdomen and thigh).
Example 4:
the BTQ nano preparation prepared in the example 2 is used for near infrared two-region fluorescence imaging of tumors in organisms. The 4T1 tumor-bearing nude mice are injected with the BTQ nano preparation through tail vein, and the mice are imaged by a near infrared two-region small animal fluorescence imager. As shown in fig. 9, after 6 hours of tail vein injection of the BTQ nano-preparation, the nano-preparation is obviously enriched in tumor sites, and proved to be capable of well imaging tumor tissues, and hopefully used for fluorescence imaging guided tumor photothermal treatment.
Example 5:
the BTQ nano preparation prepared in the example 2 is used for tumor photothermal treatment. Under 808nm laser irradiation, the mice are photographed by an infrared thermal imager, as shown in fig. 10, the temperature of the tumor part can reach 55 ℃, and the temperature is enough to kill tumor cells, so that the nano preparation can realize photo-thermal treatment on tumors.
The foregoing disclosure is illustrative of the present invention and is not to be construed as limiting the scope of the invention, which is defined by the appended claims.
Claims (10)
1. A D-pi-A-pi-D near infrared two-region aggregation-induced emission molecule is characterized by having the structural formula:
2. a method for preparing the D-pi-a-pi-D near infrared two-region aggregation-induced emission molecule according to claim 1, comprising the steps of: dissolving a compound 6 in DCM, adding absolute ethyl alcohol and a catalyst Pd/C, reacting in a hydrogen atmosphere, filtering, concentrating after the reaction is finished, dissolving the compound in a solvent together with benzil, and carrying out reflux reaction until the reaction is finished to obtain the D-pi-A-pi-D near infrared two-region aggregation-induced emission molecule according to claim 1;
the structural formula of the compound 6 is as follows:
3. the preparation method according to claim 2, characterized in that: the process for synthesizing the compound 6 comprises the following steps:
dissolving compound 4 and compound 5 in solvent, adding CsCO 3 Water and catalyst Pd (PPh 3 ) 4 Heating to 80-120 ℃ in inert gas atmosphere for reaction, cooling to room temperature after the reaction is finished, and adding water for quenching reaction to obtain a compound 6;
the structural formula of the compound 4 is as follows:
the structural formula of the compound 5 is as follows:
4. a method of preparation according to claim 3, characterized in that: the process for synthesizing the depicted compound 4 comprises the steps of: dissolving compound 3 and bisdiboronate in solvent, adding KOAC and catalyst Pd (dppf 2 )Cl 2 Heating to 80-120 ℃ in inert gas atmosphere for reaction, cooling to room temperature after the reaction is finished, and adding water for quenching reaction to obtain a compound 4;
the structural formula of the compound 3 is as follows:
5. the method of manufacturing according to claim 4, wherein: the process for synthesizing the depicted compound 3 comprises the steps of: dissolving 2, 4-bis (4-methoxyphenyl) aminophenylboronic acid in solvent, adding KOAC and Pd (dpp)f 2 )Cl 2 Heating to 80-120 ℃ in inert gas atmosphere for reaction, cooling to room temperature after the reaction is finished, and adding water for quenching reaction to obtain a compound 3;
the structural formula of the compound 2 is as follows:
6. the method of manufacturing according to claim 5, wherein: the process for synthesizing the compound 2 comprises the following steps: dissolving the compound 1 in a solvent, carrying out ice bath, slowly injecting NBS dissolved in the solvent into a reaction solution by using a syringe under the protection of inert gas, naturally heating to room temperature for reaction, and obtaining a compound 2 after the reaction is finished;
the molecular formula of the compound 1 is as follows:
7. a nano-preparation prepared by the D-pi-a-pi-D near infrared two-region aggregation-induced emission molecule according to claim 1.
8. The method of preparing a nano-formulation according to claim 7, comprising the steps of: dissolving the D-pi-A-pi-D near infrared two-region aggregation-induced emission molecule according to claim 1 in THF to obtain solution (1), DSPE-PEG 2000 Dissolving in water to obtain a solution (2), mixing the solution (1) and the solution (2) in water, performing ultrasonic dispersion, stirring overnight to remove THF in the solution, obtaining a D-pi-A-pi-D type near infrared two-region aggregation-induced luminescent molecule nanoparticle aqueous solution, and removing the solvent to obtain the nano preparation.
9. Use of a nano-formulation according to claim 7, having a fluorescence emission peak at 1100nm under 808nm laser irradiation, as a preparation of a near infrared two-region imaging contrast agent.
10. Use of a nano-formulation according to claim 7, which generates heat under 808nm laser irradiation, as a preparation of a photothermal therapeutic agent for tumors.
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| CN113444089A (en) * | 2021-06-09 | 2021-09-28 | 上海交通大学 | Near-infrared two-region aggregation-induced emission molecule based on perylene diimide derivative, and preparation method and application thereof |
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