Thiazolyl photosensitizer as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of biochemical materials, and particularly relates to a thiazolyl photosensitizer as well as a preparation method and application thereof. The invention provides a thiazolyl photosensitizer. The thiazolyl photosensitizer has a structure as shown in a formula I. The thiazolyl photosensitizer disclosed by the invention has near-infrared two-region fluorescence imaging and photodynamic / photo-thermal synergistic cancer cell killing activity. Once exposed to 660 nm laser, the cell activity can be obviously reduced along with the increase of the concentration of the photosensitizer nanoparticles, the photosensitizer nanoparticles have bright NIR-II emission and successfully extend to 1300 nm, and meanwhile, the photosensitizer nanoparticles have excellent light / heat stability and effective ROS (reactive oxygen species) generation capacity, and are beneficial to in-vivo near-infrared two-region fluorescence bioimaging, light diagnosis and treatment and anticancer application research. Formula I

Description

Technical Field

[0001] This invention belongs to the field of biochemical materials technology, specifically relating to a thiazolium-based photosensitizer, its preparation method, and its application. Background Technology

[0002] Cancer, with its rapid proliferation, spread, and metastasis, poses a serious threat to human health and life. Traditional anti-cancer strategies such as radiotherapy, chemotherapy, and surgery suffer from poor efficacy and significant side effects, prompting the emergence of precision medicine and personalized medicine. The concept of integrating diagnosis and treatment has become an important direction for solving these problems. However, existing diagnostic procedures such as magnetic resonance imaging, X-rays, positron emission tomography (PET), and ultrasound imaging are limited by radioactivity, low sensitivity, and spatiotemporal resolution, making it difficult to meet the needs of real-time guidance for surgery or treatment. Against this backdrop, phototherapy diagnostic strategies based on fluorescence imaging (FLI), photoacoustic imaging (PAI), photodynamic therapy (PDT), and photothermal therapy (PTT) have emerged, enabling precise diagnosis of target areas and selective treatment of lesions. Near-infrared II (NIR-II) organic fluorescent molecules are ideal choices for high-performance fluorescence imaging reagents due to their deep tissue penetration and low autofluorescence interference. High-sensitivity fluorescence imaging has been extensively explored in the field of tumor phototherapy. Currently, many organic phototherapy reagents used in bioimaging and therapy are based on near-infrared I (NIR-I, 650~1000nm) indocyanine green (ICG) dyes. However, these dyes generally suffer from poor photostability, low photothermal conversion efficiency, and low reactive oxygen species (ROS) production efficiency, limiting their further application. Therefore, developing multifunctional organic phototherapy reagents with near-infrared II (NIR-II, 1000~1700nm) fluorescence emission, excellent photostability, high photothermal conversion efficiency, and high ROS yield is an urgent priority. Summary of the Invention

[0003] In view of this, the purpose of this invention is to provide a thiazolium-based photosensitizer, its preparation method, and its applications. The thiazolium-based photosensitizer provided by this invention possesses both near-infrared II fluorescence imaging and photodynamic / photothermal synergistic cancer cell killing activity, and exhibits excellent light / thermal stability and reactive oxygen species generation capacity, making it suitable for in vivo fluorescence imaging and anti-cancer diagnosis and treatment.

[0004] This invention provides a thiazolyl photosensitizer having the structure shown in Formula I: Formula I; In formula I, X is H or a halogen, and R1 is... or .

[0005] Preferably, the thiazole photosensitizer has a structure shown in any one of formulas Ia to Id: Formula Ia; Formula Ib; Formula Ic; FormulaId.

[0006] This invention also provides a method for preparing the thiazole-based photosensitizer described in the above technical solution, comprising method one or method two, wherein method one includes the following steps: A thiazole-based photosensitizer is obtained by mixing a first thiazole compound having the structure shown in Formula II, a borate pinacol ester compound having the structure shown in Formula III, an inorganic base, a palladium catalyst, and an organic solvent and carrying out the Suzuki reaction. Formula II, Formula III; In Formula II, X is defined as in Formula I, and in Formula III, R is hydrogen or methoxy. The second method includes the following steps: A second thiazol compound having the structure shown in Formula IV, a borate pinacol ester compound having the structure shown in Formula III, an inorganic base, a palladium catalyst, and an organic solvent were mixed and subjected to the Suzuki reaction to obtain a thiazolyl-triphenylamine derivative having the structure shown in Formula V. The thiazolyl-triphenylamine derivative, malononitrile, inorganic base and organic solvent are mixed and subjected to a condensation reaction to obtain a thiazolyl photosensitizer. Formula IV, Formula V; In equations IV and V, X and R1 are defined as in equation I.

[0007] Preferably, in Method 1, the molar ratio of the first thiazole compound to the borate pinacol ester compound is 1:1 to 1.5.

[0008] Preferably, the palladium catalyst in Method 1 is tetra(triphenylphosphine)palladium, and the molar ratio of the first thiazole compound to the palladium catalyst is 1:0.05~0.1.

[0009] Preferably, the inorganic base in Method 1 is potassium phosphate or potassium carbonate.

[0010] Preferably, in Method 1, the molar ratio of the first thiazole compound, borate pinacol ester compound, palladium catalyst, and inorganic base is 1:1~1.5:0.05~0.1:1~2.

[0011] Preferably, the temperature of the Suzuki reaction is 60~110℃.

[0012] The present invention also provides the application of the thiazolyl photosensitizer described in the above technical solution or the thiazolyl photosensitizer prepared by the preparation method described in the above technical solution in the preparation of products for diagnosing and / or treating tumors.

[0013] Preferably, the dosage form of the diagnostic and / or therapeutic tumor treatment product includes nanoparticles, tablets, capsules, injections, or suspensions.

[0014] Compared with the prior art, the present invention has the following beneficial effects: This invention provides a thiazole-based photosensitizer with the structure shown in Formula I. Thiazole, as an electron-deficient five-membered heterocycle, can be used to construct the electron acceptor core, while the cyano group, as a common electron-withdrawing group, can be used to enhance the electron-withdrawing performance of the acceptor. This invention designs a thiazole-based electron acceptor, enhancing the acceptor's electron-withdrawing ability through the introduction of the cyano group, and modulating the performance of the acceptor unit by altering the parent unit (benzene or difluorobenzene). Simultaneously, triphenylamine or dimethoxytriphenylamine, with excellent electron-donating properties, is selected as the electron donor to form a typical donor-acceptor structure. The distorted configuration of the triphenylamine unit helps prevent fluorescence quenching caused by accumulation of the photosensitizer in the aggregated state, thus improving the photophysical properties of the photosensitizer. After being coated with polyethylene glycol to form nanoparticles, the photosensitizers of this invention all exhibit bright near-infrared II emission, successfully extending to 1300 nm. Photophysical testing results show that the photosensitizer of this invention has good photothermal properties and reactive oxygen species generation capacity. In subsequent biological experiments, it demonstrated excellent tumor enrichment in tumor-bearing mice and near-infrared II fluorescence-guided photodynamic and photothermal synergistic therapeutic effects on cancer. Attached Figure Description

[0015] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0016] Figure 1 The absorption spectrum of PHTPA nanoparticles in water; Figure 2 The fluorescence emission spectrum of PHTPA nanoparticles in water; Figure 3 This is a particle size distribution diagram of PHTPA nanoparticles in water; Figure 4 Photothermal power dependence of PHTPA nanoparticles; Figure 5 This is a graph showing the stability of PHTPA nanoparticles in water. Figure 6The diagram shows the reactive oxygen generation capacity of PHTPA nanoparticles. Figure 7 The absorption and fluorescence spectra of 20 μM 2FTPA in water are shown. Figure 8 The particle size distribution of the 2FTPA nanoparticle aqueous solution is shown. Figure 9 The graph shows the temperature change and photothermal conversion efficiency of the 2FTPA nanoparticle solution under irradiation with a 660nm laser of different powers. Detailed Implementation

[0017] This invention provides a thiazolyl photosensitizer having the structure shown in Formula I: Formula I; In formula I, X is H or a halogen, and R1 is... or .

[0018] In this invention, the halogen is preferably F or Cl.

[0019] In this invention, the thiazolyl photosensitizer preferably has a structure shown in any one of formulas Ia to Id: Formula Ia; Formula Ib; Formula Ic; FormulaId.

[0020] This invention also provides a method for preparing the thiazole-based photosensitizer described in the above technical solution, comprising method one or method two, wherein method one includes the following steps: A thiazole-based photosensitizer is obtained by mixing a first thiazole compound having the structure shown in Formula II, a borate pinacol ester compound having the structure shown in Formula III, an inorganic base, a palladium catalyst, and an organic solvent and carrying out the Suzuki reaction. Formula II; Formula III; In Formula II, X is defined as in Formula I, and in Formula III, R is hydrogen or methoxy. The second method includes the following steps: A second thiazol compound having the structure shown in Formula IV, a borate pinacol ester compound having the structure shown in Formula III, an inorganic base, a palladium catalyst, and an organic solvent were mixed and subjected to the Suzuki reaction to obtain a thiazolyl-triphenylamine derivative having the structure shown in Formula V. The thiazolyl-triphenylamine derivative, malononitrile, inorganic base and organic solvent are mixed and subjected to a condensation reaction to obtain a thiazolyl photosensitizer. Formula IV, Formula V; In equations IV and V, X and R1 are defined as in equation I.

[0021] Unless otherwise specified, all materials and equipment used in this invention are commercially available products in the field.

[0022] The following explains Method 1: The present invention does not specifically limit the source of the first thiazole compound having the structure shown in Formula II and the borate pinacol ester compound having the structure shown in Formula III. They can be prepared by methods known to those skilled in the art. Specifically, the thiazole compound having the structure shown in Formula II can be prepared with reference to "Bull. Chem. Soc. Jpn. 2021, 94, 183–190", and the borate pinacol ester compound having the structure shown in Formula III can be prepared with reference to the invention patent (WO2016 / 136425 A1).

[0023] In this invention, the borate pinacol ester compound having the structure shown in Formula III is specifically triphenylamine-4-boronate pinacol ester or 4-boronate pinacolyl-4',4''-dimethoxytriphenylamine.

[0024] In this invention, the molar ratio of the first thiazole compound to the borate pinacol ester compound is preferably 1:1 to 1.5, specifically 1:1.2 or 1:1.5.

[0025] In this invention, the palladium catalyst is preferably tetrakis(triphenylphosphine)palladium. The molar ratio of the first thiazole compound to the palladium catalyst is preferably 1:0.05~0.1, specifically 1:0.05.

[0026] In this invention, the inorganic base is preferably potassium phosphate or potassium carbonate.

[0027] This invention does not impose any particular limitation on the type of organic solvent used; any organic solvent well-known to those skilled in the art and suitable for carrying out the Suzuki reaction may be used, such as toluene or tetrahydrofuran. This invention also does not impose any particular limitation on the amount of organic solvent used, as long as it is sufficient to allow the reaction to proceed smoothly.

[0028] In this invention, the molar ratio of the first thiazole compound, borate pinacol ester compound, palladium catalyst and inorganic base is preferably 1:1~1.5:0.05~0.1:1~2, specifically 1:1.2:0.05:2.

[0029] In this invention, the Suzuki reaction is preferably carried out under a protective atmosphere. This invention does not specifically limit the protective atmosphere; it can be carried out under a conventional protective atmosphere, such as a nitrogen atmosphere or an inert gas atmosphere, where the inert gas can be argon.

[0030] The present invention does not have any special requirements on the mixing method of the first thiazole compound having the structure shown in Formula II, the borate pinacol ester compound having the structure shown in Formula III, the inorganic base, the palladium catalyst and the organic solvent, and any mixing method known to those skilled in the art can be used.

[0031] In this invention, the temperature of the Suzuki reaction is preferably 60-110°C, specifically 65°C or 80°C. The Suzuki reaction is preferably carried out under stirring conditions. This invention does not have a specific limitation on the stirring rate, as long as it is sufficient to achieve uniform stirring. This invention does not have a specific limitation on the time of the Suzuki reaction; it is preferred to monitor the reaction using a TLC plate (thin-layer chromatography plate) until the first thiazole compound completely disappears.

[0032] In this invention, the reaction after the Suzuki reaction preferably further includes: post-treatment of the obtained reaction solution, the post-treatment preferably including the following steps: extracting the obtained reaction solution, concentrating the obtained organic phase to obtain a concentrate; performing column chromatography on the concentrate to remove the solvent and obtain a thiazolyl photosensitizer; The extraction preferably includes: adding a saturated ammonium chloride aqueous solution and dichloromethane to the reaction solution for extraction, separating the organic phase, and then adding a saturated ammonium chloride aqueous solution and dichloromethane to extract the remaining aqueous phase twice, combining the organic phases; the volume ratio of dichloromethane to saturated ammonium chloride aqueous solution used in each extraction is preferably 1:1; the eluent used for column chromatography is preferably a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate in the mixture is preferably 5:1. This invention does not specifically limit the method of solvent removal; conventional solvent removal methods, such as rotary evaporation, are acceptable.

[0033] The second method will be explained below: A second thiazol compound having the structure shown in Formula IV, a borate pinacol ester compound having the structure shown in Formula III, an inorganic base, a palladium catalyst, and an organic solvent were mixed and subjected to the Suzuki reaction to obtain a thiazolyl-triphenylamine derivative having the structure shown in Formula V. The thiazolyl-triphenylamine derivative, malononitrile, inorganic base and organic solvent are mixed and subjected to a condensation reaction to obtain a thiazolyl photosensitizer. Formula IV, Formula V; In equations IV and V, X and R1 are defined as in equation I.

[0034] In this invention, the molar ratio of the second thiazole compound to the borate pinacol ester compound is preferably 1:1 to 1.5, specifically 1:1.2 or 1:1.5.

[0035] In this invention, the palladium catalyst is preferably tetrakis(triphenylphosphine)palladium. The molar ratio of the second thiazole compound to the palladium catalyst is preferably 1:0.05 to 0.2, specifically 1:0.05 or 1:0.2.

[0036] In this invention, the inorganic base is preferably potassium phosphate or potassium carbonate.

[0037] The present invention does not specifically limit the type of organic solvent, such as tetrahydrofuran.

[0038] In this invention, the molar ratio of the second thiazole compound, borate pinacol ester compound, palladium catalyst and inorganic base is preferably 1:1~1.5:0.05~0.2:1~2, specifically 1:1.5:0.2:2.

[0039] In this invention, the Suzuki reaction is preferably carried out under a protective atmosphere. This invention does not specifically limit the protective atmosphere; it can be carried out under a conventional protective atmosphere, such as a nitrogen atmosphere or an inert gas atmosphere, where the inert gas can be argon.

[0040] In this invention, the temperature of the Suzuki reaction is preferably 60~110°C, specifically 65°C or 80°C.

[0041] In this invention, the molar ratio of the thiazolyl-triphenylamine derivative, malononitrile, and inorganic base is preferably 1:5:2; the inorganic base is preferably ammonium acetate.

[0042] In this invention, the condensation reaction is preferably carried out under nitrogen protection and stirring at room temperature, and the condensation reaction time is preferably 12 hours.

[0043] The present invention also provides the application of the thiazolyl photosensitizer described in the above technical solution or the thiazolyl photosensitizer prepared by the preparation method described in the above technical solution in the preparation of products for diagnosing and / or treating tumors.

[0044] In this invention, the dosage form of the product for diagnosing and / or treating tumors preferably includes nanoparticles, tablets, capsules, injections, or suspensions.

[0045] The thiazole-based photosensitizer described in this invention can be used to prepare near-infrared II guided photothermal / photodynamic anticancer drugs. The tumors described in this invention include, but are not limited to, breast cancer, gastric cancer, esophageal cancer, liver cancer, uterine cancer, or lung cancer.

[0046] This invention designs and synthesizes novel thiazolyl electron acceptors with different structures. The electron-withdrawing ability of the acceptor is enhanced by introducing a cyano group, and the performance of the acceptor unit is modulated by altering the parent unit (benzene or difluorobenzene). Simultaneously, triphenylamine or dimethoxytriphenylamine, with excellent electron-donating properties, is selected as the electron donor to form a typical donor-acceptor structure. The distorted configuration of the triphenylamine unit also helps prevent fluorescence quenching caused by accumulation of the photosensitizer in the aggregated state, thus improving the photophysical properties of the photosensitizer. After being coated with polyethylene glycol into nanoparticles, the photosensitizers of this invention all exhibit bright near-infrared II emission, successfully extending to 1300 nm. Photophysical testing results show that the photosensitizers of this invention have good photothermal properties and reactive oxygen species generation capacity. In subsequent biological experiments, they demonstrated excellent tumor enrichment in tumor-bearing mice and synergistic photodynamic and photothermal therapeutic effects guided by near-infrared II fluorescence in cancer treatment.

[0047] To further illustrate the present invention, the thiazole-based photosensitizer, its preparation method, and its application provided by the present invention will be described in detail below with reference to the accompanying drawings and embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0048] Example 1 Thiazole-based photosensitizers were prepared according to the following reaction formula: Compound 1 (6 mmol), compound 2 (7.2 mmol), tetra(triphenylphosphine)palladium (0.3 mmol), potassium carbonate (12 mmol), and tetrahydrofuran were mixed and refluxed at 65 °C under nitrogen protection. The reaction process was monitored by TLC until compound 1 was completely eliminated. The resulting reaction solution was extracted with saturated ammonium chloride aqueous solution and dichloromethane to separate the organic phase. The remaining aqueous phase was then extracted twice with dichloromethane. The resulting organic phases were combined and purified by silica gel column chromatography using petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate was 5:1). The solvent in the obtained column chromatography product was then evaporated to dryness to obtain 1.5 g of dark green solid, with a calculated yield of 53%. The resulting dark green solid was characterized, and the specific data are as follows: 1H NMR (600 MHz, Chloroform-d) δ 8.15 (d, J=7.6 Hz, 1H), 7.89 (d, J=8.8 Hz, 2H), 7.59 (d, J=7.3 Hz, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.40-7.34 (m,4H), 7.31-7.28 (m, 2H), 7.20 (dd, J=7.6, 5.4 Hz, 6H), 7.06 (d, J=8.9 Hz, 2H). Characterization data show that the obtained dark green solid has the structure shown in PHTPA.

[0049] The obtained compound was encapsulated in polyethylene glycol using a nanoprecipitation method to form nanoparticles. The obtained compound (1 mg) and DSPE-mPEG2000 (3 mg) were dissolved separately in 1 mL of tetrahydrofuran (THF) and mixed thoroughly. Under sonication, the mixture was injected into 9 mL of double-distilled water and sonicated for 5 min. After sonication, the solution was transferred to a dialysis bag (molecular weight cutoff of 3600) and dialyzed continuously with deionized water for 24 h, changing the water every 4 h. After all the THF had been dialyzed out, the solution was filtered through a 0.45 μm filter membrane. The prepared nanoparticles were concentrated and their concentration was determined before use.

[0050] Performance testing: (1) Photoluminescence ability test of photosensitizer: 20 μL of PHTPA aqueous solution (2 mM) was added to 2 mL of dimethyl sulfoxide to obtain a 20 μM PHTPA solution. The absorption and fluorescence spectra of the resulting mixed solution were measured.

[0051] Figure 1 The absorption spectrum of 20 μM PHTPA in water; Figure 2 The fluorescence spectrum of 20 μM PHTPA in water is given by... Figure 1 and Figure 2 It can be seen that under 660 nm excitation light, PHTPA emits fluorescence at 1000 nm and has a Stokes shift of 400 nm, indicating that PHTPA has good luminescence ability.

[0052] (2) Particle size test of photosensitizer aggregates: 40 μL of an aqueous solution of PHTPA nanoparticles (1 mM) was added to 2 mL of PBS solution (5 mM, pH 7.4) to obtain a 20 μM PHTPA nanoparticle solution. The particle size distribution of the nanoparticle solution was then determined.

[0053] Figure 3 The particle size distribution of the PHTPA nanoparticle aqueous solution is shown. Figure 3 It can be seen that the particle size distribution of PHTPA aggregate nanoparticles in aqueous solution is concentrated at around 100 nm, indicating that PHTPA nanoparticles can passively target tumor cells by retaining the enhancement effect (EPR effect).

[0054] (3) Photothermal performance test of photosensitizer: 40 μL of PHTPA nanoparticle aqueous solution (1 mM) was added to 2 mL of PBS solution (5 mM, pH 7.4) to obtain a 20 μM PHTPA nanoparticle solution. The change in solution temperature under irradiation with different powers of 660 nm laser was measured.

[0055] Figure 4 The graph shows the temperature variation and photothermal conversion efficiency of the PHTPA nanoparticle solution under irradiation with different powers of 660nm laser. Figure 4 It can be seen that PHTPA nanoparticles have good photothermal properties in aqueous solution, with a photothermal conversion efficiency of 35%.

[0056] (4) Stability test of photosensitizer: 40 μL of PHTPA nanoparticle aqueous solution (1 mM) was added to 2 mL of PBS solution (5 mM, pH 7.4) to obtain a 20 μM PHTPA nanoparticle solution. The temperature change of the solution was measured after irradiation with a 0.5 W 660 nm laser for 6 min followed by cooling for 6 min, and after 5 cycles.

[0057] Figure 5 This is a graph showing the temperature changes of the PHTPA nanoparticle solution. Figure 5 It can be seen that the PHTPA nanoparticles remained stable after 5 cycles in aqueous solution, indicating that the PHTPA nanoparticles have good stability.

[0058] (5) Test of reactive oxygen species generation capacity of photosensitizer: 40 μL of aqueous solution of PHTPA nanoparticles (1 mM) was added to 2 mL of PBS solution (5 mM, pH 7.4) to obtain a 20 μM PHTPA nanoparticle solution. The reactive oxygen species scavenger 2',7'-dichlorodihydrofluorescein (DCFH) was added to the above solution. Using 489 nm as the excitation light source, the fluorescence spectrum of the mixed solution at 500~600 nm was measured. Then, the mixed solution was irradiated with a solar simulator equipped with a 400 nm filter, and the fluorescence spectrum of the mixed solution at 500~600 nm was measured as a function of irradiation time.

[0059] Figure 6 This shows the change in fluorescence intensity at 530 nm with illumination time. Figure 6 It can be seen that as the illumination time increases, the fluorescence intensity of the reactive oxygen species scavenger DCFH gradually increases and eventually reaches a plateau and remains stable, indicating that PHTPA has the ability to generate reactive oxygen species and is a potential photodynamic photosensitizer.

[0060] Examples 2-3 Compound A3 (1 mmol), pinacol triphenylamine borate (1.5 mmol), potassium carbonate (2 mmol), and tetraphenylphosphine palladium (0.2 mmol) were added to 20 mL of THF / H2O (5 / 1 v / v) under nitrogen protection. The mixture was stirred at 80 °C for 12 h under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, poured into water, and extracted with dichloromethane. The resulting organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether / dichloromethane v / v = 5 / 1).

[0061] Thiazolyl-triphenylamine derivative (1 mmol), malononitrile (5 mmol), and ammonium acetate (2 mmol) were added to a 100 mL reaction flask. 10 mL of chloroform was added to dissolve the compounds completely. The reaction system was stirred under nitrogen protection at room temperature for 12 h to induce Knoevenagel condensation. After the reaction, the reaction solution was poured into water and extracted with dichloromethane. The resulting organic phase was concentrated under reduced pressure and purified by silica gel chromatography (petroleum ether / dichloromethane volume ratio = 5 / 1) to obtain the target product.

[0062] The resulting dark green solid was characterized, and the specific data are as follows: 2FTPA: Dark green solid, yield 48%. 1H NMR (600 MHz, Chloroform-d) δ 8.03 (dd,J = 9.7, 6.7 Hz, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.45–7.39 (m, 1H), 7.41 –7.35 (m, 4H), 7.21 (d, J = 7.7 Hz, 6H), 7.05 (d, J = 8.8 Hz, 2H). 13C NMR (151 MHz, Chloroform-d) δ 181.88, 168.92, 154.19, 152.09, 146.11, 128.56,126.14, 125.13, 124.59, 120.27, 117.00, 116.85, 113.35, 112.39, 111.17,111.03. HRMS (MALDI-TOF): m / z: [M+H]+ calcd for C 31 H 16 F2N4S: 515.1064; found:515.1138. 2FTPO: Dark green solid, yield 38%. 1H NMR (600 MHz, Chloroform-d) δ 8.03 (dd,J = 9.7, 6.8 Hz, 2H), 7.83 (d, J = 8.7 Hz, 4H), 7.42 (t, J = 7.8 Hz, 2H),7.28 (s, 1H), 7.16 (d, J = 8.5 Hz, 8H), 6.93 (d, J = 8.5 Hz, 8H), 6.89 (d, J= 8.5 Hz, 4H), 3.85 (s, 12H). 13C NMR (151 MHz, Chloroform-d) δ 181.88,168.92, 154.19, 152.09, 146.11, 128.56, 126.14, 125.13, 124.59, 120.27,117.00, 116.85, 113.35, 112.39, 111.17, 111.03. HRMS (MALDI-TOF): m / z: [M+H]+calcd for C 33 H 20 F2N4O2S: 575.1275; found: 575.1349. The obtained compound was encapsulated in polyethylene glycol using a nanoprecipitation method to form nanoparticles. The compound (1 mg) and DSPE-mPEG2000 (3 mg) were dissolved separately in 1 mL of tetrahydrofuran (THF) and mixed thoroughly. Under sonication, the mixture was injected into 9 mL of double-distilled water and sonicated for 5 min. After sonication, the solution was transferred to a dialysis bag (molecular weight cutoff of 3600) and dialyzed continuously with deionized water for 24 h, changing the water every 4 h. After all the THF had been dialyzed out, the solution was filtered through a 0.45 μm filter membrane. The prepared nanoparticles were concentrated and their concentration was determined before use.

[0063] Performance testing: (1) Photoluminescence ability test of photosensitizer: 20 μL of 2FTPA aqueous solution (2mM) was added to 2 mL of dimethyl sulfoxide to obtain 20 μM 2FTPA solution, and the absorption spectrum and fluorescence spectrum of the obtained mixed solution were measured.

[0064] Figure 7 The left image shows the absorption spectrum of 20 μM 2FTPA in water, and the right image shows the fluorescence spectrum of 20 μM 2FTPA in water. Figure 7 It can be seen that under 660 nm excitation light, 2FTPA emits fluorescence at 1000 nm and has a Stokes shift of 400 nm, indicating that 2FTPA has good luminescence ability.

[0065] (2) Photosensitizer aggregate particle size test: 40 μL of 2FTPA nanoparticle aqueous solution (1 mM) was added to 2 mL PBS solution (5 mM, pH 7.4) to obtain 20 μM 2FTPA nanoparticle solution, and the particle size distribution of the nanoparticle solution was determined.

[0066] Figure 8 The particle size distribution of the 2FTPA nanoparticle aqueous solution is shown. Figure 8 It can be seen that the particle size distribution of 2FTPA aggregate nanoparticles in aqueous solution is concentrated at around 100 nm, indicating that 2FTPA nanoparticles can passively target tumor cells by retaining the enhancement effect (EPR effect).

[0067] (3) Photothermal performance test of photosensitizer: 40 μL of aqueous solution of 2FTPA nanoparticles (1 mM) was added to 2 mL PBS solution (5 mM, pH 7.4) to obtain 20 μM 2FTPA nanoparticle solution, and the change of solution temperature under different power 660nm laser irradiation was measured.

[0068] Figure 9The graph shows the temperature variation and photothermal conversion efficiency of the 2FTPA nanoparticle solution under irradiation with different powers of 660nm laser. Figure 9 It can be seen that 2FTPA nanoparticles have good photothermal properties in aqueous solution, with a photothermal conversion efficiency of 30%.

[0069] The thiazolyl photosensitizer provided by this invention has both near-infrared II fluorescence imaging and photodynamic / photothermal synergistic cancer cell killing activity. It can kill tumor cells efficiently at low concentrations under 660 nm laser, and has excellent light / thermal stability and reactive oxygen species generation ability, making it suitable for in vivo fluorescence imaging and anti-cancer diagnosis and treatment.

[0070] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, not all embodiments. People can obtain other embodiments based on the present invention without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A thiazolyl photosensitizer, characterized in that, It has the structure shown in Equation I: Formula I; In formula I, X is H or a halogen, and R1 is... or .

2. The thiazolyl photosensitizer according to claim 1, characterized in that, The thiazole photosensitizer has a structure shown in any of formulas Ia to Id: Formula Ia; Formula Ib; Formula Ic; FormulaId.

3. The method for preparing the thiazolyl photosensitizer according to claim 1 or 2, characterized in that, This includes either method one or method two, wherein method one includes the following steps: A thiazole-based photosensitizer is obtained by mixing a first thiazole compound having the structure shown in Formula II, a borate pinacol ester compound having the structure shown in Formula III, an inorganic base, a palladium catalyst, and an organic solvent and carrying out the Suzuki reaction. Formula II, Formula III; In Formula II, X is defined as in Formula I, and in Formula III, R is hydrogen or methoxy. The second method includes the following steps: A second thiazol compound having the structure shown in Formula IV, a borate pinacol ester compound having the structure shown in Formula III, an inorganic base, a palladium catalyst, and an organic solvent were mixed and subjected to the Suzuki reaction to obtain a thiazolyl-triphenylamine derivative having the structure shown in Formula V. The thiazolyl-triphenylamine derivative, malononitrile, inorganic base and organic solvent are mixed and subjected to a condensation reaction to obtain a thiazolyl photosensitizer. Formula IV, Formula V; In equations IV and V, X and R1 are defined as in equation I.

4. The preparation method according to claim 3, characterized in that, In Method 1, the molar ratio of the first thiazole compound to the borate pinacol ester compound is 1:1 to 1.

5.

5. The preparation method according to claim 3 or 4, characterized in that, The palladium catalyst described in Method 1 is tetra(triphenylphosphine)palladium, and the molar ratio of the first thiazole compound to the palladium catalyst is 1:0.05~0.

1.

6. The preparation method according to claim 3, characterized in that, The inorganic base mentioned in Method 1 is potassium phosphate or potassium carbonate.

7. The preparation method according to claim 3 or 6, characterized in that, In Method 1, the molar ratio of the first thiazole compound, borate pinacol ester compound, palladium catalyst, and inorganic base is 1:1~1.5:0.05~0.1:1~2.

8. The preparation method according to claim 3, characterized in that, The temperature of the Suzuki reaction is 60~110℃.

9. The use of the thiazolyl photosensitizer according to claim 1 or 2 or the thiazolyl photosensitizer prepared by the preparation method according to any one of claims 3 to 8 in the preparation of products for diagnosing and / or treating tumors.

10. The application according to claim 9, characterized in that, The dosage forms of the diagnostic and / or therapeutic tumor products include nanoparticles, tablets, capsules, injections, or suspensions.

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