Symmetrical azaindole-heptamethine cyanine J-aggregate as well as preparation method and application thereof

Abstract

The invention discloses a symmetric azaindole-heptamethine cyanine J-aggregate as well as a preparation method and application thereof, and aims to solve the problems of short absorption wavelength, poor stability and the like in the prior art. The cyanine J-aggregate has the maximum absorption wavelength as long as 1035 nm, is located in an NIR-II region and has excellent photo-thermal performance and stability, and the photo-thermal stability is improved by nearly 68% compared with that of an existing J-aggregate. The preparation method comprises multiple steps of reaction, and finally self-assembly is carried out in a PBS solution to form the J-aggregate. The cyanine J-aggregate shows the capabilities of efficiently killing tumor cells and completely ablating tumors in vivo in tumor photothermal therapy, is good in biocompatibility, expands the application scene of diagnosis and treatment integration, and has a wide prospect in the field of tumor photothermal therapy.

Description

Technical Field

[0001] The present invention relates to a photothermal reagent, and in particular to a symmetrical azaindole-heptamethine cyanine J-aggregate, a preparation method and application thereof. Background Art

[0002] Photothermal therapy (PTT) is a non-invasive treatment strategy that achieves selective killing of tumor cells by utilizing photothermal agents (PTAs) to absorb near-infrared (NIR) light and convert it into thermal energy. In tumor photothermal therapy, in order to reduce phototoxicity and improve deep tissue penetration, PTAs with near-infrared II (NIR-II, 1000-1700nm) absorption characteristics have attracted widespread attention from researchers. Previous studies have shown that a series of NIR-II absorbing photothermal agents, such as gold nanostructures, two-dimensional carbon materials, and conjugated polymers, exhibit excellent photothermal conversion performance. However, the poor biodegradability and low reproducibility of these materials limit their further application in the biomedical field. In contrast, organic small molecule PTAs that absorb NIR-II are highly favored due to their good biocompatibility and high biodegradability. However, existing organic small molecule PTAs still face two major technical bottlenecks: first, the maximum absorption wavelength of traditional heptamethine cyanine dye (Cy7) is usually less than 900nm (for example, the absorption peak of IR-780 reported in the literature is 780nm), which makes it difficult to cover the NIR-II window; second, to achieve a red shift of the absorption wavelength to the NIR-II region, it is necessary to expand the π-conjugated structure or introduce strong electron-pushing and pulling groups, but this will lead to complex molecular synthesis steps, low yield and decreased stability.

[0003] At present, organic small molecules mainly achieve NIR-II absorption by expanding the π-conjugated structure and enhancing the push-pull electron effect. Among them, heptamethine cyanine dye (Cy7) is considered to be an ideal organic PTA due to its excellent photophysical properties, high photothermal conversion efficiency (PCE) and excellent biocompatibility. In addition, the structure of Cy7 dye is easy to modify, which helps to develop multifunctional PTAs with excellent photothermal performance and shows great clinical translation potential. However, the right-side tail absorption wavelength of traditional Cy7 dye is usually less than 900nm (for example, the maximum absorption wavelength of commercial Cy7 dye is only 750-850nm), which is far below the lower limit of the NIR-II window of 1000nm. Therefore, to expand the absorption wavelength to the NIR-II region, it is necessary to increase the conjugated structure on both sides, which undoubtedly increases the complexity of design and synthesis.

[0004] J-aggregates promote intermolecular dipole coupling and enhance excited-state delocalization, leading to a red-shift in the absorption and emission wavelengths of dye molecules. This phenomenon fully utilizes non-covalent interactions such as π-π and van der Waals forces to promote orderly molecular stacking. The J-aggregation strategy provides a new approach for achieving absorption of small organic PTAs in the NIR-II window. However, research on the development of J-aggregates with NIR-II absorption properties based on Cy7 remains very limited. More importantly, the stability of J-aggregates remains unresolved: in existing technologies, J-aggregates are easily affected by pH, ionic strength, or serum proteins, leading to disaggregation. Therefore, it is urgent to explore appropriate design strategies to develop stable and efficient NIR-II absorbing J-aggregates for their application in NIR-II phototherapy. Summary of the Invention

[0005] In order to solve the technical problems existing in the prior art, the present invention provides a preparation and application of a symmetrical azaindole-heptamethylenecyanine J-aggregate to achieve the purpose of NIR-Ⅱ absorption, high stability and excellent photothermal performance.

[0006] The technical solution provided by the present invention is: a symmetrical azaindole-heptamethine cyanine J-aggregate, the structure of which is shown in Formula I:

[0007]

[0008] The maximum absorption wavelength (1035 nm) of the cyanine J-aggregate reaches the NIR-II region (1000-1700 nm);

[0009] in:

[0010] R1 is selected from one of hydrogen, alkyl having 1-18 carbon atoms, carboxyalkyl having 1-18 carbon atoms, halogen, and alkyl ester group, more preferably one of alkyl having 1-8 carbon atoms, carboxyalkyl having 1-8 carbon atoms, halogen, and alkyl ester group, and most preferably methyl ester group;

[0011] R2 is selected from one of an alkyl group having 1-18 carbon atoms, a carboxyalkyl group having 1-18 carbon atoms, an alkyl sulfonate group having 1-18 carbon atoms, and an alkyl sulfonate salt having 1-18 carbon atoms, more preferably an alkyl group having 1-8 carbon atoms, a carboxyalkyl group having 1-8 carbon atoms, an alkyl sulfonate group having 1-8 carbon atoms, and an alkyl sulfonate salt having 1-8 carbon atoms, and most preferably a methyl group;

[0012] X is selected from one of hydrogen, an alkyl group having 1 to 18 carbon atoms, an alkylhydroxyl group having 1 to 18 carbon atoms, a halogen, an alkyl halide having 1 to 18 carbon atoms, and NR12, more preferably one of an alkyl group having 1 to 18 carbon atoms, an alkylhydroxyl group having 1 to 18 carbon atoms, a halogen, and an alkyl halide having 1 to 18 carbon atoms, and most preferably a chlorine atom;

[0013] Y - Selected from halogen ions, CIO4 - 、BF4 - 、CH3COO - CF3COO - or OTs - One of the following, the most preferred being iodide ion;

[0014] n is selected from 1 or 2, and is most preferably 1.

[0015] Another aspect of the present invention is a method for preparing the symmetrical azaindole-heptamethine cyanine J-aggregate, comprising the following steps:

[0016]

[0017] Step 1: Compound S1 and 3-methyl-2-butanone are added to an organic solvent I at 60-120°C, wherein the molar ratio of S1 to 3-methyl-2-butanone is 1:1-5; after stirring for 3-12 hours, the solvent is evaporated, and the residue is added to an acid solution, stirred at 80-150°C for 0.5-4 hours, and the pH is adjusted to alkaline with a base. Extraction, concentration, and purification are performed to obtain the intermediate product S2;

[0018] Step 2: adding an R1-substituted indole intermediate compound S2 and an R2-substituted halogenated alkane to an organic solvent II at 60-120° C. to carry out a quaternization reaction for 3-24 hours, and then recrystallizing to obtain an azaindole quaternary ammonium salt S3 containing an N-R2-substituted side chain; wherein the molar ratio of the R1-substituted indole intermediate compound to the R2-substituted halogenated alkane is 1:1-10;

[0019] Step 3: Add a condensing agent S4 and an azaindole quaternary ammonium salt S3 containing an N-R2 substituted side chain to an organic solvent III at 50-160°C, wherein the molar ratio of S3 to S4 is 1:2.5-10. The reaction is carried out under the catalysis of anhydrous sodium sulfate for 3-12 hours. The symmetrical azaindole-heptamethine cyanine is obtained by recrystallization and silica gel column purification. The cyanine can self-assemble into cyanine J-aggregates in a PBS solution.

[0020] For the technical solution described above, further preferably, the organic solvent I is selected from one of toluene, ethanol, methanol, isopropanol, acetonitrile and tetrahydrofuran.

[0021] For the technical solution described above, it is further preferred that the organic solvent II is selected from one of benzene, toluene, o-dichlorobenzene, DMF, n-butanol, n-pentanol, and ethanol.

[0022] For the technical solution described above, it is further preferred that the organic solvent III is selected from one of DMF, ethanol, isopropanol, and acetic anhydride.

[0023] For the technical solution described above, it is further preferred that in step 1, the base is selected from one of sodium hydroxide, potassium hydroxide, ammonia water, and sodium bicarbonate.

[0024] For the technical solution described above, it is further preferred that in step 1, the acid is selected from any one of acetic acid, hydrochloric acid, sulfuric acid, and polyphosphoric acid.

[0025] For the technical solution described above, it is further preferred that in steps 2 and 3, the recrystallization solvent is selected from any one of methanol, ethanol, acetonitrile, ethyl acetate, diethyl ether, acetone, and propanol, or a mixed solvent of several combinations thereof.

[0026] Another aspect of the present invention is to protect the use of the cyanine J-aggregate described above in the preparation of a photothermal therapeutic agent or a tumor photothermal therapeutic agent. More preferably, the photothermal therapeutic agent described above comprises the symmetrical azaindole-heptamethine cyanine J-aggregate and a pharmaceutically acceptable carrier.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] The symmetrical azaindole-heptamethine cyanine J-aggregates provided by the present invention have a red-shifted absorption spectrum that can reach the NIR-II region, which is more than 135 nm red-shifted compared to traditional Cy7 dyes (<900 nm), and have high photostability, which is nearly 68% higher than the reported NIR-II J-aggregates (such as PCE = 38% in J.Am.Chem.Soc.2020,142,1); they show good stability in both acidic and physiological environments, and the absorption spectrum does not attenuate in the pH range of 3-11 ( Figure 5 ), the structural stability retention rate is >95% within 24 hours in a physiological environment containing serum ( Figure 6 ), overcoming the technical difficulty of the existing J-aggregates being easily deaggregated, with excellent photothermal stability and a photothermal conversion efficiency PCE of 63.7%, which is nearly 68% higher than that of the reported NIR-II J-aggregates (such as PCE = 38% in J.Am.Chem.Soc.2020,142,1); and good biocompatibility. Under 1064nm laser irradiation, a concentration of 50μM can achieve an in vitro tumor cell killing rate of >90% ( Figure 11 ), and in vivo experiments showed complete tumor ablation ( Figure 13 ), with both high efficacy and low toxic side effects (no significant weight loss in mice); this cyanine J-aggregate has broad application prospects in the field of tumor photothermal therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is the CyN-OMe H NMR spectrum;

[0030] Figure 2 It is CyN-OMe high-resolution mass spectrometry;

[0031] Figure 3 is the absorption spectrum of CyN-OMe in different solutions;

[0032] Figure 4 is the fluorescence spectra of CyN-OMe in different solutions;

[0033] Figure 5 The absorption spectrum changes of cyanine J-aggregate (CyN-OMe) in different pH solutions;

[0034] Figure 6 The absorption spectrum changes of cyanine J-aggregates (CyN-OMe) in cell culture medium DMEM (containing 10% FBS);

[0035] Figure 7 is the PCE of cyanine J-aggregate (CyN-OMe);

[0036] Figure 8 is the temperature rise curve of cyanine J-aggregate in PBS solution with different laser powers;

[0037] Figure 9 is the temperature rise curve of cyanine J-aggregate in PBS solution with different concentrations;

[0038] Figure 10 Photothermal cycling experiments of CyN-OMe in aqueous solution and PBS solution;

[0039] Figure 11 For in vitro experiments of CyN-OMe J-aggregate nanoparticles;

[0040] Figure 12 Photothermal imaging of CyN-OMe J-aggregate nanoparticles at the tumor site;

[0041] Figure 13 This is the curve of changes in mouse tumor volume and mouse body weight;

[0042] Figure 14 is the absorption spectrum of Cy-OMe in different solutions;

[0043] Figure 15 is the fluorescence spectra of Cy-OMe in different solutions;

[0044] Figure 16 is the PCE of Cy-OMe in PBS solution;

[0045] Figure 17 This is the photothermal cycling test of Cy-OMe in PBS solution;

[0046] Figure 18 is the absorption spectrum of IR786 in different solutions;

[0047] Figure 19 is the fluorescence spectrum of IR786 in different solutions;

[0048] Figure 20 is the PCE of IR78e in PBS solution;

[0049] Figure 21 This is the photothermal cycling test of IR786 in PBS solution;

[0050] Figure 22 Photothermal cycle contrast images of CyN-OMe monomer (in aqueous solution), Cy-OMe J-aggregate (in PBS solution), Cy-OMe (in PBS solution), and IR786 (in PBS solution);

[0051] Figure 23 Comparative images of PCE of CyN-OMe monomer (in aqueous solution), Cy-OMe J-aggregate (in PBS solution), Cy-OMe (in PBS solution), and IR786 (in PBS solution);

[0052] Figure 24 Comparative images of the photostability of CyN-OMe monomer (in aqueous solution), Cy-OMe J-aggregate (in PBS solution), Cy-OMe (in PBS solution), and IR786 (in PBS solution). DETAILED DESCRIPTION

[0053] Unless otherwise specified, the terms used herein have the following meanings.

[0054] As used herein, the term "halogen" includes fluorine, chlorine, bromine and iodine.

[0055] The term "alkyl group" used in the present invention includes straight-chain alkyl groups and branched-chain alkyl groups.

[0056] Y- is used herein to represent a negative ion, which can be any suitable negative ion, including inorganic negative ions and organic negative ions.

[0057] Ions, such as but not limited to halogen ions, ClO4- PF6 - 、BF4 - 、CH3COO - CF3COO - or OTs - .

[0058] The instruments and equipment used in the examples are:

[0059] In the process of detecting compounds, the mass spectrometer used was a Synapt G2-Si HDMS high-resolution mass spectrometer from Waters Corporation of the United States, which employed a dual-needle electrospray ion source to detect the compounds in positive and negative modes.

[0060] The absorption and emission spectra of the dyes were measured using an Agilent Cary 60 UV-visible spectrophotometer and a Cary Eclipse fluorescence spectrophotometer.

[0061] The cytotoxicity test was measured using Varioskan LUX Multimode Microplate Reader from Thermofisher, USA.

[0062] The present invention is further described in detail below with reference to the examples and accompanying drawings. However, it should be noted that the examples described in this specification are merely exemplary embodiments, which are used to fully disclose the technical solutions of the present invention and are not intended to limit the scope of protection of the claims. Based on the core inventive concept of the present invention, those skilled in the art may reasonably adjust the raw material ratios, reaction conditions or formulation forms without departing from the essence of the present invention. The experimental methods, test parameters and instrument models (such as the Bruker AVANCE III 400 MHz nuclear magnetic resonance spectrometer) involved in the examples have been fully disclosed to ensure that those skilled in the art can repeat the implementation.

[0063] Example 1

[0064] The symmetrical azaindole-heptamethine cyanine J-aggregate provided in this embodiment has the following structural formula:

[0065]

[0066] The symmetrical azaindole-heptamethine cyanine J-aggregate of this embodiment was prepared by the following method:

[0067]

[0068] Methyl 6-hydrazinepyridine-3-carboxylate (2.00 g, 12 mmol) and 3-methyl-2-butanone (1.03 g, 12 mmol) were added to a mixed solution of 22 mL of acetic acid and concentrated sulfuric acid (v / v = 10:1). The reaction mixture was heated at 100°C for 72 hours under stirring. After the reaction was completed, the mixture was filtered, diluted, extracted, and the pH was adjusted to neutral with alkali, dried, and concentrated to obtain intermediate 1.

[0069] At 100° C., azaindole compound 1 (20 mmol) and iodomethane (7.1 g, 50 mmol) were mixed in 5 mL of acetonitrile and stirred for 12 hours. Intermediate product 2 was obtained through recrystallization.

[0070] Compound 3 (172 mg, 1 mmol, 1 eq), methyl-substituted quaternary ammonium salt 2 (2.5 mmol, 2.5 eq), and anhydrous sodium acetate (82 mg, 1 mol, 1 eq) were mixed in 10 mL of acetic anhydride at 80°C and stirred for 6 hours. Cyanocyanine CyN-OMe was obtained through recrystallization and silica gel column purification. CyN-OMe self-assembled into cyanine J-aggregates in PBS solution.

[0071] The obtained CyN-OMe structure was verified. Figure 1 is the hydrogen nuclear magnetic resonance spectrum of CyN-OMe, Figure 2 This is the high-resolution mass spectrum of CyN-OMe.

[0072] The absorption spectra of CyN-OMe in different solvents are as follows Figure 3 The maximum absorption wavelength of CyN-OMe is 875nm, which red-shifts to 1035nm in PBS, reaching the NIR-Ⅱ (900-1700nm) region. The experimental results show that CyN-OMe self-assembles into J-aggregates in PBS.

[0073] Fluorescence spectra of CyN-OMe in different solvents Figure 4 shown.

[0074] The absorption spectrum of CyN-OMe J-aggregates in pH aqueous solution changes as shown in Figure 5 The experimental results show that the absorption spectrum of CyN-OMe J-aggregates remains basically unchanged under different pH environments, showing good acid-base stability.

[0075] The absorption spectrum of CyN-OMe J-aggregates in cell culture medium DMEM (containing 10% FBS) changes as shown in Figure 6 The experimental results show that the absorption spectrum of CyN-OMe J-aggregates remains essentially unchanged within the range of 0-24 hours, indicating that they have good physiological stability.

[0076] Using 1064nm laser (0.5W / cm 2 ) as the light source, the in vitro photothermal curves of CyN-OMe J-aggregates are shown in Figure 2. Figure 7 As shown in Figure 2, it can be seen that the temperature of CyN-OMe J-aggregates can rise from 26°C to 71°C after 10 minutes of 1064 nm laser irradiation. Photothermal conversion efficiency (PCE 1064 nm, 0.5 W / cm 2 ) can reach 63.7%.

[0077] Using 1064 nm laser as the light source, the temperature rise curve of 50 μL CyN-OMe J-aggregate in PBS solution with different laser powers is shown in Figure 2. Figure 8 As shown. The powers are 0.1, 0.3, and 0.5 W / cm 2 The irradiation time is 5 min. As can be seen from the figure, with the increase of laser power, the final temperature of CyN-OMe J-aggregate PBS solution continues to rise, indicating its excellent photothermal performance.

[0078] Using 1064nm laser (0.5W / cm 2 ) as the light source, the temperature rise curves of CyN-OMe J-aggregates with different concentrations in PBS solution are shown in Figure 2. Figure 9 As shown in the figure, the concentrations are 0, 10, 30, and 50 μL, and the irradiation time is 5 min. As can be seen from the figure, the photothermal temperature of the CyN-OMe J-aggregate increases with increasing concentration.

[0079] Photothermal cycling tests of CyN-OMe in aqueous solution and PBS solution Figure 10 The experimental results show that after four cycles of illumination-cooling, the temperature of the CyN-OMe monomer changes greatly and its photothermal stability is poor, while the temperature rise of the CyN-OMe J-aggregate is almost unchanged, indicating that J-aggregation can significantly improve its photothermal stability.

[0080] In vitro experiments of CyN-OMe J-aggregate nanoparticles were performed as follows Figure 11 As shown. In 4T1 and MCF-7 cells. Under non-irradiation conditions, cell viability exceeded 80% in the concentration range of 0 to 10 μM. Under 1064 nm laser irradiation (0.5 W / cm 2 ) significantly decreased the cell survival rate.

[0081] Photothermal imaging of CyN-OMe J-aggregate nanoparticles at the tumor site Figure 12 As shown in the figure, as the illumination time increases, the temperature of the tumor site gradually increases.

[0082] During the 14-day treatment period, the changes in tumor volume and body weight of mice in the experimental and control groups were as follows: Figure 13 As shown, the "CyN-OMe J-aggregate nanoparticles + 1064nm laser" group showed obvious anti-tumor effect.

[0083] Comparative Example 1

[0084] Symmetrical indole-heptamethine cyanine, the structural formula is as follows

[0085]

[0086] The absorption spectra of Cy-OMe in different solvents are as follows: Figure 14 The maximum absorption wavelength of Cy-OMe is 800 nm, and no obvious red shift is observed in PBS. The experimental results show that Cy-OMe cannot self-assemble into J-aggregates in PBS.

[0087] The fluorescence spectra of Cy-OMe in different solvents are as follows Figure 15 shown.

[0088] Using 760nm laser (0.5W / cm 2 ) as the light source, the in vitro photothermal curve of Cy-OMe is as follows Figure 16 As shown in FIG. 3 , it can be seen that the temperature of Cy-OMe-1 increased from 28° C. to 49° C. after 10 minutes of 760 nm laser irradiation. The photothermal conversion efficiency (PCE) of Cy-OMe-1 in PBS solution is only 30%.

[0089] Photothermal cycling experiments of Cy-Ome in PBS solution Figure 17 The experimental results show that after four cycles of illumination-cooling, the temperature of Cy-Ome changes greatly and the photothermal stability is poor.

[0090] Comparative Example 2

[0091] IR786, the structural formula is as follows

[0092]

[0093] The absorption spectra of IR786 in different solvents are as follows: Figure 18 As shown. The maximum absorption wavelength of IR786 is 756nm

[0094] The fluorescence spectra of IR786 in different solvents are as follows Figure 19 shown.

[0095] Using 760nm laser (0.5W / cm 2 ) as the light source, the in vitro photothermal curve of IR786 is as follows Figure 20As shown in the figure, it can be seen that the temperature of IR786- only increased from 27° C. to 39° C. after 10 minutes of 760 nm laser irradiation. The photothermal conversion efficiency (PCE) of IR786 in PBS solution was only 11.5%.

[0096] Photothermal cycling experiments of IR786 in PBS solution Figure 21 The experimental results show that after four cycles of illumination-cooling, the temperature of IR786 changes greatly and the light-heat stability is poor.

[0097] Comprehensive comparison of CyN-OMe monomers, Cy-OMeJ aggregates, C-OMe, and IR786;

[0098] Photothermal cycle images of CyN-OMe monomer (in aqueous solution), Cy-OMe J-aggregate (in PBS solution), Cy-OMe (in PBS solution), and IR786 (in PBS solution) Figure 22 As shown, it can be seen that after four illumination-cooling cycles, the heating effect and photothermal stability of Cy-OMe J-aggregates are much better than the other three.

[0099] Comparison of photothermal conversion efficiency PCE of CyN-OMe monomer (in aqueous solution), Cy-OMe J-aggregate (in PBS solution), Cy-OMe (in PBS solution), and IR786 (in PBS solution) Figure 23 As shown in the Figure 3, it can be seen that the PCE of Cy-OMe J-aggregate is much higher than that of the other three.

[0100] Comparison of the photostability of CyN-OMe monomer (in aqueous solution), Cy-OMe J-aggregate (in PBS solution), Cy-OMe (in PBS solution), and IR786 (in PBS solution) Figure 24 As shown in the figure, it can be seen that the photostability of Cy-OMe J-aggregate is much higher than that of the other three.

[0101] The above description of the disclosed embodiments is intended to enable one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be readily apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention is not limited to the embodiments shown herein but is intended to conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A symmetrical azaindole-heptamethinecyanine J-aggregate, characterized in that: Its general structural formula is shown in Formula I: The maximum absorption wavelength of the cyanine J-aggregate is 1000-1700 nm; wherein: R1 is selected from one of hydrogen, an alkyl group having 1 to 18 carbon atoms, a carboxyalkyl group having 1 to 18 carbon atoms, a halogen, and an alkyl ester group; R2 is selected from one of an alkyl group having 1 to 18 carbon atoms, a carboxyalkyl group having 1 to 18 carbon atoms, an alkylsulfonate group having 1 to 18 carbon atoms, and an alkylsulfonate salt having 1 to 18 carbon atoms; n is selected from 1 or 2; X is selected from one of hydrogen, an alkyl group having 1 to 18 carbon atoms, an alkylhydroxyl group having 1 to 18 carbon atoms, a halogen, a haloalkyl group having 1 to 18 carbon atoms, and NR12; Y - Selected from halogen ions, CIO4 - 、BF4 - 、CH3COO - CF3COO - or OTs - One of them.

2. The method for preparing the symmetrical azaindole-heptamethinecyanine J-aggregate according to claim 1, wherein: The steps include: Step 1: Compound S1 and 3-methyl-2-butanone are added to an organic solvent I at 60-120°C, wherein the molar ratio of S1 to 3-methyl-2-butanone is 1:1-5; after stirring for 3-12 hours, the solvent is evaporated, and the residue is added to an acid solution, stirred at 80-150°C for 0.5-4 hours, and the pH is adjusted to alkaline with a base. Extraction, concentration, and purification are performed to obtain the intermediate product S2; Step 2: adding an R1-substituted indole intermediate compound S2 and an R2-substituted halogenated alkane to an organic solvent II at 60-120° C. to carry out a quaternization reaction for 3-24 hours, and then recrystallizing to obtain an azaindole quaternary ammonium salt S3 containing an N-R2-substituted side chain; wherein the molar ratio of the R1-substituted indole intermediate compound to the R2-substituted halogenated alkane is 1:1-10; Step 3: Add a condensing agent S4 and an azaindole quaternary ammonium salt S3 containing an N-R2 substituted side chain to an organic solvent III at 50-160° C., wherein the molar ratio of S3 to S4 is 1:2.5-10; react for 3-12 hours under the catalysis of anhydrous sodium sulfate, and obtain a symmetrical azaindole-heptamethine cyanine through recrystallization and silica gel column purification; the cyanine can self-assemble in a PBS solution to form a cyanine J-aggregate.

3. The method according to claim 2, wherein: The organic solvent I is selected from one of toluene, ethanol, methanol, isopropanol, acetonitrile and tetrahydrofuran.

4. The method according to claim 2, wherein: The organic solvent II is selected from one of benzene, toluene, o-dichlorobenzene, DMF, n-butanol, n-pentanol and ethanol.

5. The method according to claim 2, wherein: The organic solvent III is selected from one of DMF, ethanol, isopropanol and acetic anhydride.

6. The method according to claim 2, wherein: In step 1, the base is selected from one of sodium hydroxide, potassium hydroxide, ammonia water, and sodium bicarbonate.

7. The method according to claim 2, characterized in that: The acid is selected from any one of acetic acid, hydrochloric acid, sulfuric acid and polyphosphoric acid.

8. The method according to claim 2, wherein: In steps 2 and 3, the recrystallization solvent is selected from any one of methanol, ethanol, acetonitrile, ethyl acetate, ether, acetone, and propanol, or a mixed solvent of several combinations thereof.

9. Use of the cyanine J-aggregate according to claim 1 in the preparation of a photothermal therapeutic agent or a drug reagent for tumor photothermal therapy.

10. The use according to claim 10, characterized in that: The photothermal therapeutic agent comprises the symmetrical azaindole-heptamethine cyanine J-aggregate and a pharmaceutically acceptable carrier.

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