CN114181541A - Squarylium cyanine dye and preparation method and application thereof - Google Patents
Squarylium cyanine dye and preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 title claims abstract description 14
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 23
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 238000000799 fluorescence microscopy Methods 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- 239000000975 dye Substances 0.000 claims description 46
- IHXWECHPYNPJRR-UHFFFAOYSA-N 3-hydroxycyclobut-2-en-1-one Chemical compound OC1=CC(=O)C1 IHXWECHPYNPJRR-UHFFFAOYSA-N 0.000 claims description 33
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- PWEBUXCTKOWPCW-UHFFFAOYSA-N squaric acid Chemical compound OC1=C(O)C(=O)C1=O PWEBUXCTKOWPCW-UHFFFAOYSA-N 0.000 claims description 7
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- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/90—Benzo [c, d] indoles; Hydrogenated benzo [c, d] indoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/226—Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0066—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain being part of a carbocyclic ring,(e.g. benzene, naphtalene, cyclohexene, cyclobutenene-quadratic acid)
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/10—The polymethine chain containing an even number of >CH- groups
- C09B23/105—The polymethine chain containing an even number of >CH- groups two >CH- groups
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
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Abstract
The invention discloses a squarylium cyanine dye and a preparation method and application thereof, and the compound has the advantages of simple preparation method, obvious reaction sites and easy control of reaction process; squarylium cyanine dye with good molar absorptivity and photothermal conversion efficiency, and can be used for preparing optical fiberThe photoacoustic imaging and photothermal therapy for tumor detection have good fluorescence quantum yield, and can be used for fluorescence imaging for tumor detection.
Description
(I) technical field
The invention belongs to the technical field of squaraine dyes, and particularly relates to a squaraine dye, a preparation method thereof and application thereof in tumor photoacoustic and fluorescent imaging and photothermal treatment.
(II) background of the invention
Accurate detection, diagnosis and excision of tumors depend on an accurate imaging system, and compared with traditional biological imaging technologies such as radiation imaging, ultrasonic imaging and magnetic resonance imaging, fluorescence imaging and photoacoustic imaging show huge application potential in diagnosis and guided surgical excision due to the advantages of high sensitivity, high specificity, low cost, non-invasiveness, better biological safety and the like. Many fluorescent materials have also been widely used in fluorescence imaging studies, but most exhibit visible light and near infrared (NIR-I,750-900nm) emissions that are attenuated by absorbing and scattering to varying degrees upon entering biological tissues, thereby reducing imaging depth and contrast. The near infrared region II (NIR-II) is a hotspot direction of biomedical research due to the advantages of longer emission wavelength (1000-1700nm), stronger penetrability of biological tissues, deeper detection depth, higher spatial resolution and the like. At present, some existing inorganic materials such as rare earth down-conversion nanoparticles, carbon nanotubes, quantum dots and the like can realize near-infrared two-region emission, but the emission wavelengths of the inorganic materials are mostly positioned in a near-infrared one region, the biological safety performance of heavy metals is poor, and the application of the inorganic materials is limited due to the defects of slow metabolism after entering a living body and the like. Compared with inorganic materials, the organic squaric acid fluorescent dye has smaller relative molecular weight, is easy to metabolize, has better biocompatibility and stability, is easier to modify, and can realize the emission of a near-infrared second window region.
The photoacoustic imaging technology is an emerging nondestructive and noninvasive imaging mode, and the basic principle of the photoacoustic imaging technology is that local tissues absorb light energy with specific wavelength and convert the light energy into heat energy, thermoelastic expansion is generated, a broadband ultrasonic signal is formed and received by a probe, and therefore functional and structural imaging of the tissues is achieved. The photoacoustic imaging technology is a composite imaging technology, has the characteristics of high sensitivity of optical imaging and high penetrability and resolution of acoustic imaging, and has wide application prospect in biomedical clinical diagnosis, particularly in the aspects of living tissue structure and functional imaging. In order to overcome the scattering effect of light, improve the photoacoustic signal-to-noise ratio and enhance the imaging quality of the photoacoustic imaging technology, an exogenous photoacoustic contrast agent is used as another effective method except that a proper wavelength region is selected as a working region. The exogenous near-infrared contrast agent is used, and the emission wavelength is long, so that the penetration depth of photoacoustic imaging can be improved, the maximum allowable irradiation energy is improved, background signals are reduced, the optical and acoustic properties of local tissues are changed, the contrast and the resolution of imaging are improved, and the imaging effect of photoacoustic imaging is obviously enhanced.
The ideal photo-acoustic imaging contrast agent depends on good photo-thermal conversion efficiency, and can convert light energy into heat energy to achieve the purpose of imaging and simultaneously can also use the heat energy for photo-thermal treatment of tumors. Photothermal therapy converts light energy into heat energy to ablate tumors as a non-invasive means for treating tumors, and has the characteristics of high destructive power, high selectivity, low toxicity, few side effects, negligible drug resistance and the like. The near-infrared excitation photothermal therapy system has strong penetrability, can realize deeper tumor ablation, has larger maximum allowable irradiation energy and stronger tumor ablation effect.
Therefore, the invention tries to develop the squaraine dye with absorption in the near infrared region, can realize the combination of fluorescence imaging technology, photoacoustic imaging technology and photothermal therapy, not only can realize the advantage complementation between the imaging technologies, provide richer biological information for the diagnosis of diseases, but also realize the purposes of diagnosis and therapy, avoid the risks and the burden caused by injecting different contrast agents for many times, and have wide application prospect.
Disclosure of the invention
The invention aims to provide a squarylium cyanine dye, a preparation method thereof and application thereof in preparing a tumor preparation, wherein the squarylium cyanine dye can be used for photoacoustic and fluorescent imaging of tumors, can display tumor tissue boundaries under the excitation of near infrared light, provides objective reference for complete resection of the tumors, and can also be used for photothermal treatment of the tumors to effectively ablate the tumor tissues.
The technical scheme adopted by the invention is as follows:
the invention provides a squarylium cyanine dye shown as a formula (I):
the invention also provides a preparation method of the squarylium cyanine dye, which comprises the following steps:
(1) synthesis of a compound of formula B:
dissolving the compound A in anhydrous N, N-Dimethylformamide (DMF), adding N-butyl iodide under the action of a catalyst, stirring at room temperature for 2h, washing the reaction product with saturated sodium chloride water, extracting with ethyl acetate and water in a volume ratio of 1:1, taking an ethyl acetate layer, and performing rotary evaporation to remove the solvent to obtain a crude product; dissolving the crude product with ethyl acetate, loading into a silica gel chromatographic column, eluting with ethyl acetate as an eluent at an elution speed of 1mL/min and an elution amount of 5-7 column volumes, performing thin layer chromatography monitoring with a mixed solvent of ethyl acetate and petroleum ether (volume ratio of 4:1) as a developing agent, collecting components with Rf value of 0.4-0.6, and rotationally evaporating ethyl acetate in vacuum to obtain a compound B; the catalyst is sodium hydride;
(2) synthesis of intermediate C:
dissolving the compound B in anhydrous Tetrahydrofuran (THF), adding a Grignard reagent methyl magnesium Chloride (CH) in an ice-water bath under the protection of nitrogen3MgCl), reacting for 2h at 50-60 ℃, cooling to room temperature, adding perchloric acid, quenching, adding water for precipitation, and performing vacuum freeze drying (preferably-40 ℃) to obtain an intermediate C;
(3) synthesizing a target product shown in a formula (I):
dissolving the intermediate C and squaric acid (3, 4-dihydroxy-3-cyclobutene-1, 2-dione) in n-butanol and toluene, heating to 110-120 ℃ for reflux reaction, performing rotary evaporation on the reaction liquid to remove the solvent, dissolving the concentrate with dichloromethane, loading the concentrate on a silica gel chromatographic column, eluting with dichloromethane as an eluent at the rate of 1mL/min and the amount of 6-8 column volumes, performing thin-layer chromatography monitoring with a mixed solvent of dichloromethane and methanol (the volume ratio is 10:1) as a developing agent, collecting components with the Rf value of 0.2-0.4, and performing rotary evaporation on the dichloromethane to obtain the squaraine dye shown in the formula (I), wherein the squaraine dye is marked as 890 SQ.
Further, the mass ratio of the compound A to the catalyst in the step (1) is 1:0.1-1.0, preferably 1: 0.4; the volume dosage of the anhydrous N, N-dimethylformamide is 10-30mL/g, preferably 19.5mL/g based on the mass of the compound A; the mass ratio of the compound A to n-butyl iodide is 1:1-5, preferably 1: 1.67.
Further, in the step (2), the volume dosage of the anhydrous Tetrahydrofuran (THF) is 5-20mL/g, preferably 10mL/g based on the mass of the compound B; methyl magnesium Chloride (CH)3MgCl) volume dosage is 1-10mL/g, preferably 5mL/g based on the mass of the compound B; the volume usage of perchloric acid is 1-10mL/g, preferably 2mL/g, based on the mass of compound B.
Further, in the step (3), the mass ratio of the intermediate C to the squaric acid is 1:0.1-1.0, preferably 1: 0.26; the volume usage of the n-butanol is 100-200mL/g, preferably 148mL/g based on the mass of the intermediate C; the volume ratio of the n-butanol to the toluene is 1:1.
the invention also provides application of the squaraine dye shown in the formula (I) in preparing a tumor imaging reagent, and the squaraine dye is used for photoacoustic imaging or fluorescence imaging for tumor detection.
The invention also provides application of the squaraine dye shown in the formula (I) in preparation of tumor cell activity inhibitors, wherein the tumor cells comprise solid tumor cells such as breast cancer cells, oral cancer cells, liver cancer cells, lung cancer cells, stomach cancer cells, pancreatic cancer cells, colorectal cancer cells, bladder cancer cells, prostate cancer cells and the like. More specifically breast cancer cell 4T1, human tongue squamous carcinoma cell CAL27, and human tongue squamous carcinoma cell UM 1.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a symmetrical squarylium cyanine dye, which forms a rigid resonance plane structure of stable zwitterion by introducing electron donating groups to enlarge the pi conjugation degree of a system and having a donor-acceptor-donor structure, effectively regulates the absorption and emission wavelengths of the cyanine dye, and red-shifts the cyanine dye to a near-infrared region with longer wavelength. The compound has simple preparation method, obvious reaction sites and easy control of reaction process.
The squaraine dye provided by the invention has good absorption performance in a near infrared region, and can be used for photoacoustic imaging of tumor detection.
The squarylium cyanine dye provided by the invention has good fluorescence quantum yield, and can be used for fluorescence imaging of tumor detection.
The squarylium cyanine dye provided by the invention has good photo-thermal conversion efficiency, and can be used for photo-thermal treatment of tumor treatment.
(IV) description of the drawings
FIG. 1 shows the nuclear magnetic hydrogen spectrum of squaraine dye (SQ890) obtained in example 2.
FIG. 2 shows the nuclear magnetic carbon spectrum of squaraine dye (SQ890) obtained in example 2.
FIG. 3 is a UV-VIS absorption spectrum of the squaraine dye of example 3.
FIG. 4 is a fluorescence emission spectrum of the squaraine dye of example 3.
Fig. 5 is a photoacoustic signal spectrum of the squaraine dye in example 3.
FIG. 6 is a graph showing the effect of photothermal temperature increase of squaraine dye in example 4.
FIG. 7 is a graph of cancer cell survival for squaraine dye of example 5.
(V) detailed description of the preferred embodiments
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:
the room temperature of the invention is 25-30 ℃.
Example 1 Synthesis of intermediate C
(1) Putting compound A (2.56g) into a round-bottom flask containing 50mL of DMF, adding sodium hydride (1.09g) under the condition of ice-water bath after completely dissolving, stirring for 5 minutes at room temperature, adding n-butyl iodide (4.27g), stirring for 2 hours at room temperature, washing the reaction product with saturated sodium chloride water (2X 50mL), extracting with ethyl acetate and water (volume ratio is 1:1), taking an ethyl acetate layer, and removing the solvent by rotary evaporation to obtain a crude product; the crude product was dissolved in 1mL of ethyl acetate and the whole was used as a silica gel column chromatography sample. Filling 50g of 100-200-mesh column chromatography silica gel and 50mL of ethyl acetate into a chromatography column (3cm multiplied by 30cm), slowly loading the column along the tube wall after releasing the ethyl acetate, eluting by using the ethyl acetate as an eluent at the elution speed of 1mL/min for 6 column volumes, carrying out thin-layer chromatography monitoring by using a mixed solvent (volume ratio of 4:1) of the ethyl acetate and petroleum ether as a developing agent, collecting the components with the Rf value of 0.4-0.6, and rotationally evaporating the ethyl acetate in vacuum to obtain the compound B1.41g.
Nuclear magnetic data for compound B:1H NMR(400MHz,DMSO)δ8.10(d,J＝8.0Hz,1H),8.00(d,J＝8.0Hz,1H),7.74(t,J＝8Hz,1H),7.56(d,J＝8Hz,1H),7.48(t,J＝8Hz,1H),7.08(t,J＝8.0Hz,1H),3.82(t,J＝8Hz,2H),1.66-1.58(m,2H),1.32-1.23(m,2H),0.84(t,J＝8Hz,3H).13C NMR(101MHz,DMSO)δ167.25,139.33,131.27,129.22,129.05,126.33,124.63,124.25,120.28,105.87,40.16,39.95,39.74,39.62,30.68,19.93,13.91.
(2) putting the compound B (300mg) into a round-bottomed flask containing 3ml of anhydrous THF, adding methyl magnesium chloride (1.5ml) under the conditions of ice-water bath and nitrogen protection, reacting for 30 minutes at room temperature, transferring to the water bath at 60 ℃ for reaction for 2 hours, cooling the ice-water bath to 0 ℃, adding perchloric acid (0.6ml) for quenching, adding water (50ml) for precipitation, washing with water (7X 50ml), freezing at 40 ℃ and drying in vacuum to obtain the intermediate C280 mg.
Nuclear magnetic data for compound C:
1H NMR(400MHz,DMSO)8.95(d,J＝8Hz,1H),8.77(d,J＝8Hz,1H),8.51(d,J＝4Hz,1H),8.43(d,J＝8Hz,1H),8.15(t,J＝8Hz,1H),7.99(d,J＝8Hz,1H),4.66(t,J＝8Hz,2H),3.24(s,3H),1.92(d,J＝8Hz,2H),1.46(t,J＝8Hz,2H),0.95(t,J＝8Hz,3H).
example 2 synthesis of squaraine dye SQ 890.
Intermediate C (27mg) prepared in example 1 and squaric acid (7mg) were put in a round-bottomed flask containing n-butanol (4mL) and toluene (4mL), and the mixture was heated under reflux at 110 ℃ for 1 hour, and the solvent was removed by rotary evaporation of the reaction mixture, and the concentrate was dissolved in 1mL of dichloromethane and used as a sample for silica gel column chromatography. Filling a chromatographic column (3cm multiplied by 30cm) with 50g of 100-200 mesh column chromatography silica gel and 50mL of dichloromethane, slowly loading along the tube wall after dichloromethane is released, eluting with dichloromethane as an eluent at the elution speed of 1mL/min and the elution amount of 7 column volumes, monitoring by thin layer chromatography with a mixed solvent (volume ratio of 10:1) of dichloromethane and methanol as a developing agent, collecting components with the Rf value of 0.2-0.4, and rotationally evaporating dichloromethane to obtain 5.9mg of the squaraine dye (marked as SQ890) shown in the formula (I). The nuclear magnetic hydrogen spectrum is shown in figure 1, and the nuclear magnetic carbon spectrum is shown in figure 2.
Nuclear magnetic data of SQ 890:
1H NMR(400MHz,DMSO)δ9.05(d,J＝4Hz,2H),8.13(d,J＝4Hz,2H),7.88(t,J＝8Hz,2H),7.69(d,J＝8Hz,2H),7.62(t,J＝8Hz,2H),7.48(d,J＝8Hz,2H),6.29(s,2H),4.34(t,J＝4Hz,4H),1.80(t,J＝4Hz,4H),1.47-1.41(m,4H),0.95(t,J＝8Hz,6H).
13C NMR(101MHz,DMSO)δ182.10,176.72,149.96,141.58,130.23,130.15,129.84,129.67,129.49,124.88,121.98,108.97,92.23,43.54,30.88,20.11,14.13.
example 3 detection of absorption and emission spectra of squaraine dyes
And (3) testing an ultraviolet visible absorption spectrum: the squaraine dye SQ890 prepared in example 2 was subjected to ultraviolet-visible absorption spectroscopy using an ultraviolet-visible spectrophotometer (UV-5500PC, shanghai nyuan analyzer ltd): 300 microliter of SQ890DMF solution with the concentration of 0.15mg/ml is placed in a quartz cuvette, DMF zero setting is taken as a base line, the wavelength range of 650nm to 1100nm is selected for spectrum scanning, and the result is shown in figure 3, and SQ890 has strong absorption between 750nm and 950 nm.
Fluorescence emission spectroscopy test: fluorescence emission spectroscopy was performed on squaraine dye SQ890 prepared in example 2 using a fluorescence spectrophotometer (PerkinElmer Lambda 750): 3ml of SQ890DMF solution with the concentration of 10 mu M is taken, the wavelength range of 800nm to 1550nm is selected for spectral scanning, and the result is shown in figure 4, and the SQ890 has wide emission between 800nm and 1400 nm.
And (3) testing the photoacoustic signal: photoacoustic signal detection was performed on the squaraine dye SQ890 prepared in example 2 using a photoacoustic imager (Vevo LAZR, FUJIFILM visual sonics): photoacoustic spectra of SQ890DMF solutions of different concentrations (1000. mu.M, 500. mu.M, 250. mu.M, 120. mu.M, 60. mu.M) were detected with 680nm to 970nm excitation light, and as a result, SQ890 has a strong photoacoustic signal at 750nm to 950nm as shown in FIG. 5.
The result shows that the absorption spectrum and the emission spectrum of SQ890 are both in the near infrared region, the emission spectrum extends to the near infrared region two, and the strong photoacoustic signal is obtained.
Example 4 photo-thermal warming Effect of squaraine dye SQ890
The squaraine dye SQ890 prepared in example 2 was dissolved in dimethyl sulfoxide, and prepared into solutions of different concentrations (5. mu.M, 10. mu.M, 20. mu.M, and 40. mu.M), followed by continuous irradiation with a laser beam of 808nm for 480 seconds, and recording the temperature change of the SQ890 solution of each concentration with an infrared camera. As shown in FIG. 6, the SQ890 temperature raising effect increases with increasing concentration, and the temperature rises to 60 ℃ after 480s of 808nm laser irradiation at a concentration of 40 μ M, exhibiting good photothermal conversion efficiency.
Example 5 anti-4T 1 tumor cell proliferation Activity of squaraine dye SQ890
This example demonstrates the photothermal therapeutic effect of squaraine dyes on tumor cells.
1. The squaraine dye SQ890 prepared in the example 2 is prepared into a nano preparation by a film dispersion method to improve bioavailability and biosafety, and the method comprises the following specific operations: 2mg of SQ890 and 10mg of DSPE-mPEG5000 (distearoylphosphatidylacetamide-methoxypolyethylene glycol 5000) were dissolved together in dichloromethane (2ml), and the dichloromethane was evaporated to dryness to spread the sample uniformly on the surface of the glass bottle. Subsequently, distilled water (1mL) was added and sonicated at 40KHz for 2 minutes to give nanoparticles 10mg, 140nm in size, denoted SQ890 NPs.
2. The MTT (3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazolium bromide) method is used for evaluating the metabolic activity of SQ890 NPs on breast cancer cells 4T1, and the specific steps are as follows:
breast cancer cell 4T1 (purchased from Nanfenghui Biotech Co., Ltd.) was inoculated into RPMI 1640 complete medium and placed in an incubator (37 ℃ C., 5% CO)2) Incubating, culturing for 3 generations, inoculating the cells in logarithmic growth phase in 96-well plate at density of 5 × 103Cells/well, incubate overnight to allow cells to adhere well. Old medium was discarded and divided into experimental (SQ890 NPs + L) and blank control (SQ890 NPs) groups, each set with 3 replicates (error in calculation). The experimental group (SQ890 NPs + L) was supplemented with 100. mu.L of RPMI 1640 complete medium containing different concentrations (2.5. mu.M, 5. mu.M, 10. mu.M, 20. mu.M, 40. mu.M) of SQ890 NPs, and the blank control group (SQ890 NPs) was supplemented with 100. mu.L of RPMI 1640 complete medium. After further culturing for 4 hours, the experimental groups were each administered with 1W/cm2The 808nm laser irradiation time is 5min, and the blank control group is not subjected to the light irradiation treatment. After further incubation for 24h after irradiation, a microplate reader (Thermo Scientific) was usedTM MultiskanTMFC) detecting the absorbance value of each group at 490nm, and calculating the influence of the drug on the survival rate of the tumor cells according to the ratio of the absorbance of the experimental group to the absorbance of the blank control group. The results are shown in FIG. 7. As can be seen from the results, squaraine dyes showed dose-dependent photo-cytotoxicity, and cell survival rate decreased with increasing concentration of the dye under illumination conditions, indicating that they have high cell killing efficiency under these conditions. At the same time, these dyes were found to have high cell viability in the dark, indicating that they are non-toxic in the absence of light. These results show the application prospects of the squaraine dye in photothermal therapy.
Claims (10)
1. A squarylium cyanine dye of formula (I):
2. a process for the preparation of squaraine dyes according to claim 1, comprising the steps of:
(1) synthesis of a compound of formula B:
dissolving a compound A in anhydrous N, N-dimethylformamide, adding N-butyl iodide under the action of a catalyst, stirring at room temperature for 2 hours, washing a reactant with saturated sodium chloride water, extracting with ethyl acetate and water in a volume ratio of 1:1, taking an ethyl acetate layer, and performing rotary evaporation to remove the solvent to obtain a crude product; dissolving the crude product with ethyl acetate, loading the crude product into a silica gel chromatographic column, eluting with ethyl acetate as an eluent at the eluting speed of 1mL/min and the eluting amount of 5-7 column volumes, carrying out thin-layer chromatography monitoring by using a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 4:1 as a developing agent, collecting components with the Rf value of 0.4-0.6, and carrying out vacuum rotary evaporation of ethyl acetate to obtain a compound B; the catalyst is sodium hydride;
(2) synthesis of intermediate C:
dissolving the compound B in anhydrous tetrahydrofuran, adding a Grignard reagent methyl magnesium chloride in an ice water bath under the protection of nitrogen, reacting for 2 hours at 50-60 ℃, adding perchloric acid after cooling to room temperature, quenching, adding water for precipitation, and performing vacuum freeze drying to obtain an intermediate C;
(3) synthesizing a target product shown in a formula (I):
dissolving the intermediate C and squaric acid in n-butyl alcohol and toluene, heating to 110-120 ℃ for reflux reaction, performing rotary evaporation on reaction liquid to remove the solvent, dissolving the concentrate with dichloromethane, loading the concentrate on a silica gel chromatographic column, eluting with dichloromethane as an eluent at the speed of 1mL/min and the elution amount of 6-8 column volumes, performing thin-layer chromatography monitoring with a mixed solvent of dichloromethane and methanol in a volume ratio of 10:1 as a developing agent, collecting components with the Rf value of 0.2-0.4, and performing rotary evaporation on dichloromethane to obtain the squaraine dye shown in the formula (I).
3. The method according to claim 2, wherein the mass ratio of the compound A to the catalyst in the step (1) is 1: 0.1-1.0; the volume dosage of the anhydrous N, N-dimethylformamide is 10-30mL/g based on the mass of the compound A; the mass ratio of the compound A to the n-butyl iodide is 1: 1-5.
4. The method according to claim 2, wherein in the step (2), the volume of the anhydrous tetrahydrofuran is 5-20mL/g based on the mass of the compound B; the volume dosage of the methyl magnesium chloride is 1-10mL/g calculated by the mass of the compound B; the volume dosage of perchloric acid is 1-10mL/g based on the mass of the compound B.
5. The method according to claim 2, wherein in the step (3), the mass ratio of the intermediate C to the squaric acid is 1: 0.1-1.0; the volume usage of the n-butanol is 100-200mL/g based on the mass of the intermediate C; the volume ratio of the n-butanol to the toluene is 1:1.
6. use of the squaraine dye of claim 1 in the preparation of a tumor imaging agent.
7. Use according to claim 6, wherein the imaging agent is a photoacoustic imaging agent or a fluorescence imaging agent.
8. Use of the squaraine dye of claim 1 for the preparation of an inhibitor of tumor cell activity.
9. Use according to claim 8, wherein said tumor cells comprise breast cancer cells, oral cancer cells, liver cancer cells, lung cancer cells, stomach cancer cells, pancreatic cancer cells, colorectal cancer cells, bladder cancer cells or prostate cancer cells.
10. The use according to claim 8, wherein said tumor cells comprise breast cancer cell 4T1, human tongue squamous carcinoma cell CAL27, and human tongue squamous carcinoma cell UM 1.
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