CN115040650A - Preparation and application methods of quinoline cyanine photo-thermal nanoparticles with aggregation-enhanced photo-thermal characteristics - Google Patents
Preparation and application methods of quinoline cyanine photo-thermal nanoparticles with aggregation-enhanced photo-thermal characteristics Download PDFInfo
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- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical compound C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 claims abstract description 12
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Abstract
The invention provides a preparation method and an application method of quinoline cyanine photo-thermal nanoparticles with aggregation-enhanced photo-thermal characteristics. The invention uses 2-methylquinoline as raw material to synthesize a series of planar near-infrared quinoline cyanine molecules containing different substituent groups, and the photo-thermal nano-particles are prepared by self-assembly. Because the synthesized quinolinylcyanine molecules have good plane rigidity, the molecules are easy to self-assemble to form regularly arranged H aggregates, and the photothermal effect is greatly enhanced; the particle size, aggregation degree and absorption wavelength of the self-assembly formed by the quinolinylcyanine can be controlled by adjusting the substituent groups of the molecules. The quinoline cyanine photo-thermal nanoparticles provided by the invention have the advantages of near-infrared absorption, uniform size, high photo-thermal efficiency and good stability, and the preparation method is simple and efficient, and has good application prospects in the fields of biological photo-acoustic imaging, tumor photo-thermal treatment and the like.
Description
Technical Field
The invention belongs to the technical fields of chemical synthesis, molecular self-assembly and biological diagnosis and treatment, and particularly relates to synthesis of quinoline cyanine molecules with aggregation-enhanced photo-thermal characteristics, a preparation method of photo-thermal nanoparticles of the quinoline cyanine molecules, and application of the quinoline cyanine molecules in photoacoustic imaging and photo-thermal treatment of cancers.
Background
Cancer is a serious threat to human health. At present, the traditional treatment means such as surgical treatment, radiotherapy, chemotherapy and the like are mainly adopted for treating the cancer, but the treatment method has the disadvantages of large wound, strong toxic and side effects, poor targeting property and difficulty in eradicating the tumor. Photothermal therapy is a novel therapeutic method for killing cancer cells by converting light energy into heat energy under irradiation of external light sources such as near-infrared light using a photothermal agent. The organic dye-based photo-thermal material has the advantages of low preparation cost, strong structure designability, good biological safety and biodegradability, and great application potential in photo-thermal treatment. Organic photothermal materials have been developed rapidly in recent years, and their functionality has been expanded. The multifunctional platform constructed based on the organic photothermal material can be combined with chemotherapy, radiotherapy, photodynamic therapy, chemodynamic therapy, gene therapy and immunotherapy to realize combined treatment, and has good effects in treatment of drug-resistant tumors and metastatic tumors and prevention of tumor recurrence. Although the construction of organic photothermal nanomaterials and anti-tumor methods thereof have been extensively studied, further attention is needed to the photothermal properties of organic dyes themselves. Most organic dyes are not generally efficient in photothermal conversion due to their molecular structure, and thus require increased dose or laser irradiation intensity when used, thereby causing potential side effects. The method for improving the photo-thermal conversion efficiency of the organic material is simple and efficient, and has important significance.
H aggregation is a special assembly mode for dye aggregation, and molecules can be arranged in close parallel due to strong pi-pi interaction between the molecules. After the H aggregate is excited by light, more conversion and vibration relaxation can be generated in the process of electron return, so that fluorescence is greatly quenched, and simultaneously, a large amount of energy is released in the form of heat. Therefore, H aggregation of the dye is expected to be an effective means for constructing a high-performance photothermal reagent. At present, the organic dye H aggregate is mainly applied to the photoelectric field, and the research in the field of photothermal therapy is few. Its application is limited for the following reasons: 1) the organic molecule H has low aggregation degree and is easy to depolymerize, so that the photo-thermal efficiency is difficult to improve; 2) h aggregation can cause a large blue shift in dye uptake, further restricting its biological applications.
In order to solve the problems, the invention provides a strategy for constructing a planar and near-infrared quinoline cyanine dye, molecules can be subjected to self-assembly in water to form a stable H aggregate, and the photo-thermal conversion efficiency is greatly improved by the aggregation-enhanced photo-thermal effect.
Disclosure of Invention
The invention provides a preparation method and an application method of a quinolinylcyanine photothermal nanoparticle with aggregation enhanced photothermal characteristics.
The invention uses 2-methylquinoline as raw material to synthesize a series of planar near-infrared quinoline cyanine dyes containing different substituent groups, and prepares photo-thermal nano-particles by self-assembly. Because the synthesized quinoline cyanine dye has good plane rigidity, molecules are easy to self-assemble to form regularly arranged H aggregates, and the photo-thermal effect is enhanced therewith; the particle size, aggregation degree and absorption wavelength of the self-assembly formed by the quinolinylcyanine can be controlled by adjusting the substituent groups of the molecules. In addition, the quinolinylcyanine still has near-infrared absorption after forming the H aggregate, and ensures the application of the quinolinylcyanine in the fields of biological imaging and tumor treatment. The structural formula of the quinoline cyanine dye for forming the photo-thermal nano-particles is as follows:
wherein R is 1 Is methyl, ethyl, propyl sulfonic group; r 2 Is chlorine, thiophenyl, phenylseleno.
Further, the preparation method of the chinoline cyanine photo-thermal nanoparticles with the aggregation enhanced photo-thermal characteristic comprises the following steps: 1) synthesizing quinoline cyanine molecules, and 2) forming quinoline molecules into photo-thermal nanoparticles by a self-assembly method.
Further, the method for synthesizing the quinolinylcyanine molecule in the step 1) comprises the following steps:
s1, dissolving 2-methylquinoline and a quaternizing agent in a proper amount of acetonitrile, and carrying out reflux reaction for 12 hours under the protection of nitrogen, wherein the molar ratio of the 2-methylquinoline to the quaternizing agent is 1: 2-5. And cooling the mixture to room temperature, precipitating with methyl tert-butyl ether, washing for multiple times, and drying to obtain the quaternized quinoline derivative.
S2, dissolving the quaternary amination quinoline derivative and equimolar 2-chloro-3- (hydroxy methylene) -1-cyclohexene-1-formaldehyde into a mixed solvent of toluene and n-butyl alcohol, wherein the volume ratio of the toluene to the n-butyl alcohol is 2:1-1.5, and carrying out reflux reaction for 8 hours under the protection of nitrogen. Subsequently, the quaternized quinoline derivative and a small amount of pyridine were added again to the reaction solution, and the reaction was continued under reflux for 8 hours. After the reaction is finished, the reaction liquid is cooled and filtered, and the obtained crude product solid is washed by methyl tertiary butyl ether. The crude product is further separated by column chromatography to obtain the quinoline cyanine compound QCy 1.
S3, dissolving QCy1 and a meso-position substitution reagent in N, N-dimethylformamide according to the molar ratio of 1:2-6, adding a catalytic amount of triethylamine, and reacting for 3-5 hours at 85 ℃ under the protection of nitrogen. Subsequently, an appropriate amount of dichloromethane was added to the reaction solution and extracted with water, and the resulting crude product was separated by column chromatography after drying the organic phase to obtain quinolinylcyanine compound QCy 2.
Further, the quaternizing agent described in step S1 includes methyl iodide, ethyl iodide, propyl iodide, caprolactone sulfonate, and the like.
Further, the quaternized quinoline derivative described in step S2 is added to the reaction solution in two times, and the molar amounts added in the two times are the same.
Further, the meso-position substitution reagent described in step S3 is thiophenol, phenylselenol, or the like.
Further, the self-assembly method in step 2) is as follows: dissolving quinolinylcyanine compound in DMSO (1-5X 10) -3 M), a certain volume of the dye solution was dropped into water, rapidly stirred for 5 to 10 minutes, and then DMSO was removed by dialysis. Wherein the volume ratio of the DMSO solution to water is 1: 20-200.
After the quinolinylcyanine forms the nano particles, the photo-thermal conversion efficiency of the quinolinylcyanine is improved by 2-3 times compared with that of a single molecular state.
The quinoline cyanine photo-thermal nanoparticles with the aggregation enhanced photo-thermal characteristic are applied to photo-acoustic imaging of cancers.
The quinoline cyanine photo-thermal nanoparticles with the aggregation enhanced photo-thermal characteristic are applied to photo-thermal treatment of cancers.
The invention has the following beneficial effects:
1. the designed and synthesized planar near-infrared quinoline cyanine molecules have an aggregation-enhanced photo-thermal effect, namely, after the quinoline cyanine molecules are self-assembled by the method, H aggregates can be formed, and the photo-thermal efficiency is remarkably improved;
2. the quinoline cyanine photo-thermal nanoparticles prepared by the invention still have near-infrared absorption characteristics after H aggregates are formed, and the absorption wavelength of the quinoline cyanine photo-thermal nanoparticles is larger than 650 nm, so that the quinoline cyanine photo-thermal nanoparticles are beneficial to biological application;
3. the quinoline cyanine photo-thermal nanoparticles prepared by the method are stable in morphology and uniform in particle size;
4. the quinoline cyanine photo-thermal nanoparticles prepared by the method have good photo-stability, and the photo-thermal performance is not obviously attenuated after multiple laser irradiation;
5. the quinoline cyanine photo-thermal nanoparticles prepared by the invention can be used for photo-thermal treatment of cancers guided by photo-acoustic imaging, and have high tumor inhibition rate;
6. the photo-thermal nano particle provided by the invention has the advantages of mature and simple preparation process and high biological safety.
Drawings
FIG. 1 is a reaction scheme for the synthesis of quinolinylcyanine molecules.
FIG. 2 nuclear magnetic hydrogen spectrum of the product of example 1.
FIG. 3 Mass Spectrometry of the product of example 1.
FIG. 4 scanning and transmission (inset) electron microscope images of photo-thermal nanoparticles of example 4.
FIG. 5 is a comparison of the absorption spectra of the quinolincyanine molecules (DMSO as solvent) in example 1 and the photo-thermal nanoparticles (water as solvent) in example 4.
FIG. 6 photo-thermal temperature rise curves (660nm, 1W/cm) of photo-thermal nanoparticles in example 4 2 )。
Fig. 7 photo-stability of photo-thermal nanoparticles as tested in example 4, control molecule is indocyanine green (ICG).
FIG. 8 "concentrated enhanced photothermal" effect: as the degree of aggregation increases, the photothermal conversion efficiency of QCy increases.
FIG. 9 photo-acoustic imaging photographs and photo-acoustic signal intensities of tumor-bearing mice at different time points in example 5.
FIG. 10 is a graph of tumor volume as a function of treatment time for tumor-bearing mice from different treatment groups in example 6.
Detailed Description
The invention will be further illustrated with reference to specific examples. The present invention is not limited to these specific embodiments.
Example 1: synthesis of quinoline cyanine molecule QCy1 substituted by meso-position chlorine
(1) 0.5g (3.5mmol) of 2-methylquinoline and acetonitrile were added to 1.5g (7mmol) of iodomethane reagent and dissolved in 10mL of acetonitrile, and the reaction was refluxed for 8 hours under a nitrogen atmosphere. And cooling the mixture to room temperature, precipitating with methyl tert-butyl ether, washing for multiple times, and drying to obtain the quaternized quinoline derivative.
(2) 250mg (0.92mmol) of the quaternized quinoline derivative and 144mg (0.92mmol) of 2-chloro-3- (hydroxymethylene) -1-cyclohexene-1-carbaldehyde were dissolved in 10mL of a mixed solvent of toluene and n-butanol (containing 7mL of toluene and 3mL of n-butanol), and the reaction was refluxed for 8 hours under a nitrogen atmosphere. Subsequently, 250mg (0.92mmol) of the quaternized quinoline derivative and 2mL of pyridine were added to the reaction solution, and the reaction was continued under reflux for 8 hours. After the reaction was completed, the reaction solution was cooled and filtered, and the obtained crude product solid was washed 3 times with methyl t-butyl ether. The crude product is further separated by column chromatography to obtain the quinolinylcyanine compound QCy 1.
Example 2: synthesis of quinoline cyanine molecule substituted by meso-position thiophenyl
50mg (0.087mmol) of QCy1 and 54mg (0.346mmol) of thiophenol were dissolved in 5mL of N, N-dimethylformamide and reacted at 85 ℃ for 3 hours under nitrogen with the addition of a catalytic amount of triethylamine. Adding a proper amount of dichloromethane into the reaction liquid, extracting for 3 times by using water, and further separating the crude product by using column chromatography to obtain quinoline cyanine molecules substituted by meso-position thiophenyl.
Example 3: synthesis of quinoline cyanine molecule substituted by meso-position phenylseleno group
50mg (0.087mmol) of QCy1 and 52mg (0.346mmol) of phenylselenophenol are dissolved in 5mL of N, N-dimethylformamide, and a catalytic amount of triethylamine is added to react at 85 ℃ for 5 hours under nitrogen protection. Adding a proper amount of dichloromethane into the reaction solution, extracting for 3 times by using water, and further separating the crude product by using column chromatography to obtain the quinoline cyanine molecule substituted by the meso-position phenylseleno group.
Example 4: QCy NPs for preparing photo-thermal nanoparticles based on QCy1
Quinoline cyanine dye QCy1 molecule is dissolved in DMSO (4X 10) -3 M), dropping 0.1mL of dye solution into 2-10mL of water, rapidly stirring for 5-10 minutes, and then removing DMSO by a dialysis method to obtain an aqueous solution of the photo-thermal nano-particle QCy NPs.
Example 5: application of QCy NPs in photoacoustic imaging of cancer
Female BALB/c mice (3-5 weeks old) are selected to establish a 4T1 (mouse breast cancer cell) subcutaneous tumor model. The tumor volume is about 100mm 3 At this time, mice were injected with QCy NPs aqueous solution (40 μ M,100 μ L) through the tail vein, followed by photoacoustic imaging using a multispectral tomography system. The time points for acquiring the images were 0, 2, 4, 6, 8, 12 hours. Wherein, after the QCy NPs are injected for 6 hours, the intensity of the photoacoustic signal at the tumor part reaches the maximum value, which shows that the enrichment amount of the QCy NPs at the tumor part is maximum at the moment.
Example 6: application of QCy NPs in photothermal treatment of cancer
Female BALB/c mice (3-5 weeks old) are selected to establish a 4T1 (mouse breast cancer cell) subcutaneous tumor model. Tumor volume is about 100mm 3 At the time, mice were injected with different reagents via tail vein, grouped as follows: (1) PBS control group, (2) PBS + illumination group, (3) QCy NPs group, (4) QCy NPs + illumination group, wherein QCy NPs dose is (40 μ M,100 μ L), illumination is 10min (660nm, 1.0W/cm) 2 ). Every two days, the tumor size was measured using a vernier caliper and the volume was calculated to obtain the change of tumor volume with time. The tumor growth of the mice in the QCy NPs + light group was significantly inhibited compared to the other control groups, indicating that the QCy NPs can be used for photothermal treatment of tumors.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. A quinoline cyanine photo-thermal nano particle with aggregation enhanced photo-thermal characteristics is characterized in that a quinoline cyanine dye forming the photo-thermal nano particle has a structural formula as follows:
wherein R is 1 Is methyl, ethyl, propyl sulfonic group; r 2 Is chlorine, thiophenyl, phenylseleno.
2. A preparation method of quinoline cyanine photo-thermal nanoparticles with aggregation-enhanced photo-thermal characteristics is characterized by comprising the following steps: 1) synthesizing quinoline cyanine molecules, and 2) forming quinoline molecules into photo-thermal nanoparticles by a self-assembly method.
3. The method for preparing quinolinylcyanine photothermal nanoparticles with "aggregation enhanced photothermal" characteristics as claimed in claim 2, wherein the quinolinylcyanine molecules in step 1) can be synthesized by the method in steps S1-S2 or S1-S3:
s1, mixing the components in a molar ratio of 1: 2-5, dissolving 2-methylquinoline and a quaternizing reagent in a proper amount of acetonitrile, carrying out reflux reaction for 12 hours under the protection of nitrogen, precipitating with methyl tert-butyl ether, washing for multiple times and drying to obtain a quaternizing quinoline derivative;
s2, dissolving a quaternized quinoline derivative and equimolar 2-chloro-3- (hydroxymethylene) -1-cyclohexene-1-formaldehyde into a mixed solvent of toluene and n-butyl alcohol in a volume ratio of 2:1-1.5, carrying out reflux reaction for 8 hours under the protection of nitrogen, then adding the quaternized quinoline derivative and a small amount of pyridine into the reaction solution again, continuing reflux reaction for 8 hours, cooling and filtering the reaction solution, washing the obtained solid with methyl tert-butyl ether, and separating by column chromatography to obtain a quinolincyanine compound QCy 1;
s3, dissolving QCy1 and a meso-position substitution reagent in N, N-dimethylformamide according to the molar ratio of 1:2-6, adding a catalytic amount of triethylamine, reacting for 3-5 hours at 85 ℃ under the protection of nitrogen, adding a proper amount of dichloromethane into a reaction solution, extracting with water, and separating the obtained crude product by column chromatography after the organic phase is dried to obtain the quinolinylcyanine compound QCy 2.
4. The method of claim 3, wherein the quaternizing agent of step S1 comprises methyl iodide, ethyl iodide, propyl iodide, caprolactone sulfonate, etc.
5. The method for synthesizing quinolincyanine molecule of claim 3, wherein the quaternized quinoline derivative of step S2 is added to the reaction solution in two portions, and the molar weight of the added portions is the same.
6. The method for synthesizing quinolincyanine molecule as in claim 3, wherein the meso-position substitution reagent in step S3 is thiophenol, phenylselenol, etc.
7. The method for preparing chinoline cyanine photo-thermal nanoparticles with aggregation-enhanced photo-thermal characteristics as claimed in claim 2, wherein the self-assembly method in step 2) is as follows: the quinoline cyanine compound is prepared into 1-5 multiplied by 10 -3 M in DMSO solution, dropping a certain volume of dye solution into water with the volume 20-200 times of that of the dye solution,stirring was carried out rapidly for 5-10 minutes, followed by removal of DMSO by dialysis.
8. The quinolinylcyanine photothermal nanoparticles with "aggregation-enhanced photothermal" properties as claimed in claim 1, wherein the quinolinylcyanine formed nanoparticles have photothermal conversion efficiency 2-3 times higher than that of single molecular state.
9. The use of the quinolincyanine photothermal nanoparticles with "aggregation-enhanced photothermal" properties of claim 1 in photoacoustic imaging of cancer.
10. The use of quinolincyanine photothermal nanoparticles with "aggregation-enhanced photothermal" properties as claimed in claim 1 in the photothermal treatment of cancer.
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