Aggregation-induced emission mitochondrial targeting near-infrared absorption photosensitizer as well as preparation method and application thereof

Abstract

The invention discloses an aggregation-induced emission mitochondrial targeting near-infrared absorption photosensitizer as well as a preparation method and application thereof. The photosensitizer has a D-pi-A structure, triphenylamine is taken as a donor group, 3, 4-ethylenedioxythiophene is taken as a pi bridge, and quinoline cation salt is taken as an acceptor. The photosensitizer disclosed by the invention can effectively target mitochondria, and can efficiently generate I-type and II-type active oxygen under the excitation of 660nm exciting light, so that tumor cells are efficiently killed, and the potential of developing an efficient photodynamic therapy technology is shown.

Description

Technical Field

[0001] The present invention belongs to the technical field of optical diagnosis and treatment, and specifically relates to an aggregation-induced luminescence mitochondrial targeted near-infrared absorption photosensitizer and a preparation method and application thereof. Background Art

[0002] Traditional cancer treatments include chemotherapy, surgery, immunotherapy, radiotherapy, etc. These methods have their own limitations and cannot solve some of the difficulties currently faced by cancer treatment. Photodynamic therapy (PDT) has the advantages of being non-invasive, low-invasive, and highly spatiotemporal and temporal selectivity, and has received widespread attention from researchers in recent years. Photodynamic therapy has three elements: oxygen, excitation light, and photosensitizer. The treatment method of photodynamic therapy is to irradiate the photosensitizer with excitation light. The photosensitizer can absorb the energy of the excitation light to produce cytotoxic reactive oxygen species (ROS) to kill cancer cells. Photodynamic therapy delivers photosensitizers to the tumor site and activates the photodynamic therapy effect through light irradiation. This process greatly reduces the toxicity to normal tissue parts and has high biosafety.

[0003] ROS, the main weapon of photosensitizers for tumor killing, usually has a short life span and propagation distance, and cannot be released in the key parts of cancer cells, so the photodynamic therapy effect will be greatly reduced. Therefore, photosensitizers with targeted subcellular organelles have relatively better photodynamic therapy effects. Among the subcellular organelles, mitochondria have a highly dynamic structure, which constantly undergoes fusion and fission, providing a place for cell life activities. Designing mitochondria-targeted photosensitizers is conducive to enhancing the photodynamic therapy performance of photosensitizers. Mitochondria in cancer cells are often swollen and fragmented. Mitochondria in the S phase (DNA synthesis phase) appear tubular, and mitochondria in the M phase (mitosis phase) appear uniformly broken. In addition, compared with normal cells (-140mV), the mitochondrial membrane potential (MMP, -220mV) of cancer cells is more polarized. Therefore, the uptake of lipophilic cationic compounds can increase by 100-1000 times compared with extracellular compounds. Therefore, more mitochondrial targeted drugs can be taken up by the mitochondria of cancer cells.

[0004] Traditional photosensitizers usually have large rigid planar structures and hydrophobic structures, which often form aggregates in biological environments, resulting in strong π-π interactions, causing the material's excited state energy to dissipate through rapid non-radiative transitions, resulting in decreased fluorescence and ROS generation efficiency. Aggregation-induced luminescence materials have molecular rotor structures, which are conducive to molecular rotation in a single-molecule state and dissipate excited state energy through non-radiative transitions. However, when the aggregation-induced luminescence material is in an aggregated state, the rotation of its molecular rotor is inhibited, and the excited state energy cannot be dissipated through non-radiative transitions, which facilitates the photosensitizer excited state to reach the triplet state through intersystem crossing, and generate ROS through electron transfer or energy transfer. Therefore, aggregation-induced luminescence photosensitizers have higher photodynamic therapy capabilities. In addition, designing photosensitizers with near-infrared absorption can increase the skin penetration depth, thereby achieving the purpose of treating deep tumors.

[0005] In summary, designing mitochondrial-targeted near-infrared absorbing photosensitizers with aggregation-induced emission is a potential photosensitizer design idea. Summary of the invention

[0006] In view of the problems existing in current photosensitizers, the purpose of the present invention is to provide an aggregation-induced luminescence mitochondrial targeted near-infrared absorption photosensitizer; the photosensitizer material of the present invention has a DA structure, can be excited by 660nm excitation light, and efficiently generates ROS. Under the excitation of 660nm excitation light, the photosensitizer can generate a large amount of Type-I (hydroxyl free radicals, superoxide anions) and Type-II (singlet oxygen) ROS efficiently, and can effectively target cancer cell mitochondria, and maintain targeting on mitochondria within 12 hours, thereby efficiently killing tumor cells.

[0007] Another object of the present invention is to provide a method for preparing the above-mentioned aggregation-induced luminescence mitochondrial-targeted near-infrared absorption photosensitizer.

[0008] Another object of the present invention is to provide the application of the above-mentioned aggregation-induced luminescence mitochondrial targeted near-infrared absorption photosensitizer.

[0009] The purpose of the present invention is achieved through the following technical solutions:

[0010] An aggregation-induced luminescence mitochondrial-targeted near-infrared absorption photosensitizer, the general structural formula of which is as follows:

[0011]

[0012] wherein n is independently an integer of 0 to 16 (0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16); and X is an anion.

[0013] Preferably, X is independently selected from at least one of fluoride ion, chloride ion, bromide ion and iodide ion, and the number is determined according to the positive charge.

[0014] Preferably, the structural formula of the aggregation-induced luminescence mitochondrial targeted near-infrared absorption photosensitizer is as follows:

[0015]

[0016] The aggregation-induced luminescence mitochondrial targeted near-infrared absorption photosensitizer of the invention has a D-π-A structure, uses triphenylamine as a donor group, uses 3,4-ethylenedioxythiophene as a π bridge, uses quinoline cation salt as an acceptor, and is composed of a propyl bonding structure.

[0017] The preparation method of the above-mentioned aggregation-induced luminescence mitochondrial targeted near-infrared absorption photosensitizer comprises the following steps:

[0018] 4-Boric acid triphenylamine reacts with 5-bromo-2-(3,4-vinyldioxythiophene) carboxaldehyde to obtain the intermediate 1, which is reacted with 4-methylquinoline and a halide to obtain N-substituted 4-methylquinoline. The intermediate 1 reacts with N-substituted 4-methylquinoline to obtain an aggregation-induced emission mitochondrial-targeted near-infrared absorption photosensitizer.

[0019] Preferably, the preparation method of the aggregation-induced luminescence mitochondrial targeted near-infrared absorption photosensitizer comprises the following steps:

[0020] (1) 4-boric acid triphenylamine, 5-bromo-2-(3,4-vinyldioxythiophene) carboxaldehyde, tetrakis(triphenylphosphine)palladium and cesium carbonate were added to a mixed solvent of THF and water under a protective atmosphere, refluxed and purified to obtain an intermediate 1;

[0021] (2) Preparation of DTEVQ

[0022] (2.1) 4-Methylquinoline and 1,3-diiodopropane were added to ethanol, refluxed, and purified to obtain intermediate 2;

[0023] (2.2) Ethanol and piperidine are added to intermediate product 1 and intermediate product 2, refluxed, and purified to obtain DTEVQ;

[0024] (3) Preparation of TEVQ-1

[0025] (3.1) 4-Methylquinoline and iodomethane were added to ethanol, refluxed, and purified to obtain intermediate 3;

[0026] (3.2) Add ethanol and piperidine to intermediate product 1 and intermediate product 3, reflux reaction, and purify to obtain TEVQ-1;

[0027] (4) Preparation of TEVQ-2

[0028] (4.1) 4-Methylquinoline and 1-iodopropane were added to ethanol, refluxed, and purified to obtain intermediate 4;

[0029] (4.2) Add ethanol and piperidine to intermediate product 1 and intermediate product 4, reflux reaction, and purify to obtain TEVQ-2;

[0030] (5) Preparation of TEVQ-3

[0031] (5.1) 4-Methylquinoline and (3-bromopropyl)trimethylammonium bromide were added to ethanol, refluxed and purified to obtain intermediate 5;

[0032] (5.2) Ethanol and piperidine were added to intermediate product 1 and intermediate product 5, refluxed and purified to obtain TEVQ-3.

[0033] Further preferably, in step (1), the molar ratio of 4-boric acid triphenylamine, 5-bromo-2-(3,4-vinyldioxythiophene) carboxaldehyde, tetrakis(triphenylphosphine)palladium and cesium carbonate is 11-15:10:0.02-0.05:20-30;

[0034] Further preferably, in step (1), the volume ratio of THF to water is 20-27:3-10;

[0035] Further preferably, in step (1), the molar volume ratio of 5-bromo-2-(3,4-vinyldioxythiophene)carboxaldehyde to the mixed solvent is 10 mmol:30-50 mL;

[0036] Further preferably, in step (1), the reflux reaction temperature is 70 to 80° C. and the time is 24 to 36 hours;

[0037] Further preferably, in step (1), the protective atmosphere is nitrogen.

[0038] Further preferably, in step (2.1), the molar ratio of 4-methylquinoline to 1,3-diiodopropane is 10 to 15:4;

[0039] Further preferably, in step (2.1), the molar volume ratio of 1,3-diiodopropane to ethanol is 4 mmol:5-20 mL;

[0040] Further preferably, in step (2.1), the reflux reaction temperature is 80 to 90° C. and the time is 12 to 36 h;

[0041] Further preferably, in step (2.2), the molar ratio of intermediate product 1 to intermediate product 2 is 1-1.5:0.4;

[0042] Further preferably, in step (2.2), the usage ratio of the intermediate product 2, ethanol and piperidine is 0.4 mmol: 15-30 mL: 15-30 μL;

[0043] Further preferably, in step (2.2), the reflux reaction temperature is 80 to 90° C. and the time is 12 to 36 hours.

[0044] Further preferably, in step (3.1), the molar ratio of 4-methylquinoline to methyl iodide is 5 to 10:4;

[0045] Further preferably, in step (3.1), the molar volume ratio of methyl iodide to ethanol is 4 mmol:5-20 mL;

[0046] Further preferably, in step (3.1), the reflux reaction temperature is 80 to 90° C. and the time is 12 to 36 h;

[0047] Further preferably, in step (3.2), the molar ratio of intermediate product 1 to intermediate product 3 is 1 to 1.5:1;

[0048] Further preferably, in step (3.2), the ratio of the intermediate product 3, ethanol and piperidine is 1 mmol: 15-30 mL: 15-30 μL;

[0049] Further preferably, in step (3.2), the reflux reaction temperature is 80 to 90° C. and the time is 12 to 36 hours.

[0050] Further preferably, in step (4.1), the molar ratio of 4-methylquinoline to 1-iodopropane is 5 to 10:4;

[0051] Further preferably, in step (4.1), the molar volume ratio of 1-iodopropane to ethanol is 4 mmol:5-20 mL;

[0052] Further preferably, in step (4.1), the reflux reaction temperature is 80 to 90° C. and the time is 12 to 36 hours.

[0053] Further preferably, in step (4.2), the molar ratio of intermediate product 1 to intermediate product 4 is 1 to 1.5:1;

[0054] Further preferably, in step (4.2), the ratio of the intermediate product 4, ethanol and piperidine is 1 mmol: 15-30 mL: 15-30 μL;

[0055] Further preferably, in step (4.2), the reflux reaction temperature is 80 to 90° C. and the time is 12 to 36 hours.

[0056] Further preferably, in step (5.1), the molar ratio of 4-methylquinoline to (3-bromopropyl)trimethylammonium bromide is 5 to 10:4;

[0057] Further preferably, in step (5.1), the molar volume ratio of (3-bromopropyl)trimethylammonium bromide to ethanol is 4 mmol:5-20 mL;

[0058] More preferably, in step (5.1), the reflux reaction temperature is 80-90° C. and the time is 12-36 h.

[0059] Further preferably, in step (5.2), the molar ratio of intermediate product 1 to intermediate product 5 is 1 to 1.5:1;

[0060] Further preferably, in step (5.2), the ratio of the intermediate product 5, ethanol and piperidine is 1 mmol: 15-30 mL: 15-30 μL;

[0061] Further preferably, in step (5.2), the reflux reaction temperature is 80 to 90° C. and the time is 12 to 36 hours.

[0062] The application of the above-mentioned aggregation-induced luminescence mitochondrial targeted near-infrared absorption photosensitizer in the preparation of cancer cell photodynamic therapy agents. The photosensitizer of the present invention has near-infrared absorption ability, efficient reactive oxygen generation ability and mitochondrial targeting ability, effectively generates type I and type II ROS under 660nm laser irradiation and is used in cancer cell photodynamic therapy.

[0063] Compared with the prior art, the present invention has the following beneficial effects:

[0064] (1) The photosensitizer of the present invention has near-infrared absorption capability and can be excited by 660nm excitation light; and has the ability to efficiently generate type I ROS and type II ROS.

[0065] (2) The photosensitizer of the present invention can efficiently target cancer cell mitochondria and efficiently kill cancer cells under 660nm excitation light, and has low toxicity (negligible toxicity) to cells under non-illumination conditions.

[0066] (3) The photosensitizer of the present invention has a simple structure and is easy to synthesize. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] Figure 1 It is the molecular structure formula of photosensitizer DTEVQ.

[0068] Figure 2 is the synthesis formula of photosensitizer DTEVQ.

[0069] Figure 3 It is the molecular structure formula of photosensitizer TEVQ-1.

[0070] Figure 4 is the synthesis formula of photosensitizer TEVQ-1.

[0071] Figure 5 It is the molecular structure formula of photosensitizer TEVQ-2.

[0072] Figure 6 is the synthesis formula of photosensitizer TEVQ-2.

[0073] Figure 7 It is the molecular structure formula of photosensitizer TEVQ-3.

[0074] Figure 8 is the synthesis formula of photosensitizer TEVQ-3.

[0075] Fig. 9 It is the molecular structure and synthesis formula of photosensitizer TTVP.

[0076] Fig.10 It is the molecular structure and synthesis formula of photosensitizer TEVP.

[0077] Fig.11 It is the molecular structure and synthesis formula of photosensitizer TTVQ.

[0078] Fig.12 These are the UV-visible absorption spectra of photosensitizers DTEVQ, TEVQ-3, TTVQ, TEVP, and TTVP.

[0079] Fig.13 These are the UV-visible absorption spectra and fluorescence emission spectra of photosensitizers DTEVQ, TEVQ-1, TEVQ-2, and TEVQ-3.

[0080] Fig.14 Fluorescence emission spectra of photosensitizers DTEVQ, TEVQ-2 and TEVQ-3 in DMSO / toluene mixtures with different toluene fractions.

[0081] Fig.15 The fluorescence response of photosensitizers DTEVQ, TEVQ-1, TEVQ-2, TEVQ-3 and Ce6 to DCFH after 660nm laser irradiation at different times and the comparison of fluorescence intensity at 60s.

[0082] Fig.16 This is the fluorescence response of photosensitizers DTEVQ, TEVQ-1, TEVQ-2, TEVQ-3 and Ce6 to DHR123 after 660nm laser irradiation at different times and the comparison of fluorescence intensity at 60s.

[0083] Fig.17The fluorescence responses of photosensitizers DTEVQ, TEVQ-1, TEVQ-2, and TEVQ-3 to HPF after 660nm laser irradiation at different times and the comparison of fluorescence intensity at 300s.

[0084] Fig.18 This is a comparison of the absorption response of photosensitizers DTEVQ, TEVQ-1, TEVQ-2, and TEVQ-3 to ABDA after 660nm laser irradiation at different times and the fluorescence intensity at 40s.

[0085] Fig.19 These are the co-localization images of photosensitizers DTEVQ, TEVQ-2, and TEVQ-3 on mitochondria in 4TI cells.

[0086] Fig. 20 The graph shows the cell activity results after 4T1 cells were acted upon by photosensitizers DTEVQ, TEVQ-2, and TEVQ-3 with or without 660nm laser irradiation.

[0087] Fig.21 This is the fluorescence response of photosensitizers DTEVQ, TEVQ-1, TEVQ-2, TEVQ-3 and commercial photosensitizer Ce6 to DCFH after white light illumination for different times and a comparison of fluorescence intensities at 110s.

[0088] Fig. 22 This is the fluorescence response of photosensitizers DTEVQ, TEVQ-1, TEVQ-2, and TEVQ-3 to DHR123 after white light illumination for different periods of time and a comparison of fluorescence intensities at 90 seconds.

[0089] Fig.23 The fluorescence responses of photosensitizers DTEVQ, TEVQ-1, TEVQ-2, and TEVQ-3 to HPF after white light illumination for different periods of time and the comparison of fluorescence intensity at 360s.

[0090] Fig.24 This is a graph showing the degradation rate changes of ABDA by photosensitizers DTEVQ, TEVQ-1, TEVQ-2, and TEVQ-3 after white light illumination for different periods of time, and a comparison of fluorescence intensities at 180s.

[0091] Fig.25 This is the fluorescence response of photosensitizers DTEVQ, TEVQ-3, TEVP, and TTVP to DCFH after white light illumination for different periods of time and a comparison of fluorescence intensities at 60 seconds.

[0092] Fig.26 Schematic diagram of the structure of the photosensitizer DTEVQ and its process of generating ROS after 660nm laser irradiation to affect the mitochondria of cancer cells and effectively kill cancer cells. DETAILED DESCRIPTION

[0093] In order to better understand the technical solution of the present invention, the implementation mode of the present invention is described in detail below with reference to the accompanying drawings and embodiments.

[0094] The experimental methods in the following examples are conventional methods unless otherwise specified, and the experimental materials used in the following examples can be purchased through conventional commercial channels unless otherwise specified.

[0095] Example 1

[0096] Synthesis of the bridging intramolecular dimer aggregation-induced luminescence mitochondrial-targeted near-infrared absorbing photosensitizer DTEVQ.

[0097] (1) Add 4-boronic acid triphenylamine (11mmol, 3.18g), 5-bromo-2-(3,4-vinyldioxythiophene) carboxaldehyde (10mmol, 2.49g), 2% equivalent of tetrakis(triphenylphosphine)palladium (0.2mmol, 231.1mg) and cesium carbonate (20mmol, 6.52g) into a 250mL double-necked reaction bottle, fill with nitrogen three times, and add 27mL of THF and 3mL of ultrapure water under nitrogen protection. Heat to reflux at 70℃ for 24h, and monitor the progress of the reaction by thin layer chromatography. After the reaction is completed, the reaction solution is cooled to room temperature, THF is removed by a rotary evaporator, extracted with dichloromethane and saturated brine, the organic phase is collected, and purified by silica gel chromatography, using dichloromethane / petroleum ether as eluent (1:1), and vacuum dried to obtain a yellow solid powder, which is the intermediate 1;

[0098] (2) 4-Methylquinoline (10 mmol, 1.43 g) and 1,3-diiodopropane (4 mmol, 1.18 g) were added to a 100 mL double-necked reaction bottle, and 5 mL of ethanol was added. The mixture was heated to reflux at 80°C and reacted overnight. After the reaction was completed, the reaction solution was cooled to room temperature, and ether was added dropwise to the reaction solution. The solid was precipitated, quickly filtered, and vacuum dried to obtain a light yellow solid powder, which was the intermediate 2;

[0099] (3) Add intermediate product 1 (1 mmol, 413.5 mg) and intermediate product 2 (0.4 mmol, 233 mg) to a 50 mL double-necked reaction bottle, add 15 mL of ethanol and 1-2 drops of piperidine, heat to reflux at 80 ° C, and react overnight. After the reaction is completed, the reaction solution is cooled to room temperature, the solvent is removed by a rotary evaporator, and purified by silica gel chromatography using dichloromethane / methanol as an eluent (20:1), and vacuum dried to obtain a blue-purple solid powder, which is DTEVQ. Its molecular structure is as follows Figure 1 As shown, the synthesis equation is as Figure 2 shown.

[0100] Example 2

[0101] Synthesis of aggregation-induced emission mitochondria-targeted near-infrared absorbing photosensitizer TEVQ-1.

[0102] (1) Referring to step (1) of Example 1, intermediate product 1 was prepared;

[0103] (2) 4-Methylquinoline (5 mmol, 716 mg) and iodomethane (4 mmol, 568 mg) were added to a 100 mL double-necked reaction bottle, and 5 mL of ethanol was added. The mixture was heated to reflux at 80°C and reacted overnight. After the reaction was completed, the reaction solution was cooled to room temperature, and ether was added dropwise to the reaction solution. The solid was precipitated, quickly filtered, and vacuum dried to obtain a light yellow solid powder, which was the intermediate product 3;

[0104] (3) Add intermediate product 1 (1.1mmol, 454.9mg) and intermediate product 3 (1mmol, 285mg) to a 50mL double-necked reaction bottle, add 15mL ethanol and 1-2 drops of piperidine, heat to reflux at 80°C, and react overnight. After the reaction is completed, the reaction solution is cooled to room temperature, the solvent is removed by a rotary evaporator, and purified by silica gel chromatography using dichloromethane / methanol as the eluent (20:1), and vacuum dried to obtain a blue-purple solid powder, which is TEVQ-1. Its molecular structure is as follows Figure 3 As shown, the synthesis equation is as Figure 4 shown.

[0105] Example 3

[0106] Synthesis of aggregation-induced emission mitochondria-targeted near-infrared absorbing photosensitizer TEVQ-2.

[0107] (1) Referring to step (1) of Example 1, intermediate product 1 was prepared;

[0108] (2) 4-Methylquinoline (5 mmol, 716 mg) and 1-iodopropane (4 mmol, 680 mg) were added to a 100 mL double-necked reaction bottle, and 5 mL of ethanol was added. The mixture was heated to reflux at 80°C and reacted overnight. After the reaction was completed, the reaction solution was cooled to room temperature, and ether was added dropwise to the reaction solution. The solid was precipitated, quickly filtered, and vacuum dried to obtain a light yellow solid powder, which was the intermediate product 4;

[0109] (3) Add intermediate product 1 (1.1mmol, 454.9mg) and intermediate product 4 (1mmol, 313.2mg) to a 50mL double-necked reaction bottle, add 15mL ethanol and 1-2 drops of piperidine, heat to reflux at 80°C, and react overnight. After the reaction, cool the reaction solution to room temperature, remove the solvent using a rotary evaporator, and purify it using silica gel chromatography, using dichloromethane / methanol as the eluent (20:1), and vacuum dry to obtain a blue-purple solid powder, which is TEVQ-2. Its molecular structure is as follows Figure 5 As shown, the synthesis equation is as Figure 6 shown.

[0110] Example 4

[0111] Synthesis of aggregation-induced emission mitochondria-targeted near-infrared absorbing photosensitizer TEVQ-3.

[0112] (1) Referring to step (1) of Example 1, intermediate product 1 was prepared;

[0113] (2) 4-Methylquinoline (5 mmol, 716 mg) and (3-bromopropyl)trimethylammonium bromide (4 mmol, 1044 mg) were added to a 100 mL double-necked reaction bottle, and 5 mL of ethanol was added. The mixture was heated to reflux at 80°C and reacted overnight. After the reaction was completed, the reaction solution was cooled to room temperature, and ether was added dropwise to the reaction solution. The solid was precipitated, quickly filtered, and vacuum dried to obtain a light yellow solid powder, which was the intermediate product 5;

[0114] (3) Add intermediate product 1 (1.1mmol, 454.9mg) and intermediate product 5 (1mmol, 404.2mg) to a 50mL double-necked reaction bottle, add 15mL ethanol and 1-2 drops of piperidine, heat to reflux at 80°C, and react overnight. After the reaction, cool the reaction solution to room temperature, remove the solvent using a rotary evaporator, and purify it using silica gel chromatography, using dichloromethane / methanol as the eluent (20:1), and vacuum dry to obtain a blue-purple solid powder, which is TEVQ-3. Its molecular structure is as follows Figure 7 As shown, the synthesis equation is as Figure 8 shown.

[0115] Comparative Example 1

[0116] Synthesis of aggregation-induced emission mitochondria-targeted near-infrared absorbing photosensitizer TTVP.

[0117] (1) Referring to step (1) of Example 1, 5-bromothiophene-2-carboxaldehyde was used to prepare intermediate 6;

[0118] (2) Referring to step (2) of Example 4, 4-methylpyridine was used to prepare intermediate 7;

[0119] (3) Referring to step (3) of Example 4, intermediate products 6 and 7 were used to obtain a red solid powder, which is TTVP. Its molecular structure and synthesis equation are as follows: Fig. 9 shown.

[0120] Comparative Example 2

[0121] Synthesis of aggregation-induced emission mitochondria-targeted near-infrared absorbing photosensitizer TEVP.

[0122] (1) Referring to step (1) of Example 1, intermediate product 1 was prepared;

[0123] (2) Referring to step (2) of Example 4, 4-methylpyridine was used to prepare intermediate 7;

[0124] (3) Referring to step (3) of Example 4, intermediate product 1 and intermediate product 7 were used to obtain a red solid powder, which is TEVP. Its molecular structure and synthesis equation are as follows: Fig.10 shown.

[0125] Comparative Example 3

[0126] Synthesis of aggregation-induced emission mitochondria-targeted near-infrared absorbing photosensitizer TTVQ.

[0127] (1) Referring to step (1) of Comparative Example 1, 5-bromothiophene-2-carboxaldehyde was used to prepare intermediate 6;

[0128] (2) Referring to step (2) of Example 4, intermediate product 5 was prepared;

[0129] (3) Referring to step (3) of Example 4, intermediate product 6 and intermediate product 5 were used to obtain a red solid powder, which is TTVQ. Its molecular structure and synthesis equation are as follows: Fig.11 shown.

[0130] Example 5

[0131] UV-visible absorption spectra of aggregation-induced emission mitochondria-targeted near-infrared absorbing photosensitizer DTEVQ and TEVQ-3, TTVQ, TEVP, and TTVP.

[0132] The absorption of DTEVQ, TEVQ-3, TTVQ, TEVP, and TTVP solutions was tested at room temperature using a UV-2600 UV spectrophotometer produced by Shimadzu, Japan. The solvents were all dimethyl sulfoxide, and the molecular concentrations of DTEVQ were 5 μM, TEVQ-3, TTVQ, TEVP, and TTVP were 10 μM. The data collection range was 300 to 800 nm.

[0133] Fig.12 The UV-visible absorption spectra of photosensitizers DTEVQ, TEVQ-3, TTVQ, TEVP, and TTVP are shown in Figure 1. TTVP, TEVP, TTVQ, DTEVQ, and TEVQ-3 have a gradual red shift, which confirms that with the improvement of the π bridge and the acceptor part, the photosensitizer has a red shift trend.

[0134] Example 6

[0135] Photophysical properties testing of the intramolecular dimer aggregation-induced luminescence mitochondrial targeted near-infrared absorption photosensitizer DTEVQ and the aggregation-induced luminescence mitochondrial targeted near-infrared absorption photosensitizers TEVQ-1, TEVQ-2, and TEVQ-3.

[0136] The solution absorption of DTEVQ, TEVQ-1, TEVQ-2, and TEVQ-3 was tested at room temperature using a UV-2600 UV spectrophotometer produced by Shimadzu, Japan. The solvents were all dimethyl sulfoxide, and the molecular concentrations of DTEVQ were 5 μM, TEVQ-1, TEVQ-2, and TEVQ-3 were 10 μM. The data collection range was 300 to 800 nm.

[0137] The fluorescence emission of DTEVQ, TEVQ-1, TEVQ-2, and TEVQ-3 in the aggregated state was tested at room temperature using a highly sensitive integrated fluorescence spectrometer, model Horiba FluoroMax-4, produced by HORIBA Scientific in the United States. The solvent was a dimethyl sulfoxide / toluene mixed solvent (99:1), and the molecular concentrations of DTEVQ were 5μM, TEVQ-1, TEVQ-2, and TEVQ-3 were 10μM. The excitation slit width used in the test was 4nm, the emission slit width was 4nm, the excitation wavelength was 560nm, and the data collection range was 600 to 900nm. The fluorescence emission values ​​were homogenized.

[0138] The fluorescence emission of DTEVQ, TEVQ-2, and TEVQ-3 in a dimethyl sulfoxide / toluene mixed solvent was tested at room temperature using a highly sensitive integrated fluorescence spectrometer, model Horiba FluoroMax-4, produced by HORIBA Scientific in the United States. The proportion of toluene in the mixed solvent ranged from 0% to 99%. The molecular concentrations of DTEVQ were 5μM, TEVQ-2, and TEVQ-3 were 10μM. The excitation slit width used in the test was 4nm, the emission slit width was 4nm, the excitation wavelength was 560nm, and the data collection range was 600 to 900nm.

[0139] Fig.13 The UV-visible absorption spectra and fluorescence emission spectra of photosensitizers DTEVQ, TEVQ-1, TEVQ-2, and TEVQ-3 are shown in Figure 1. All materials have strong absorption in the near-infrared region.

[0140] Fig.14The fluorescence emission spectra of photosensitizers DTEVQ, TEVQ-2 and TEVQ-3 in dimethyl sulfoxide / toluene mixtures with different toluene fractions are shown in Figure 2. It can be observed that with the increase of toluene content, the photosensitizer gradually aggregates in the solvent and the fluorescence emission gradually increases, proving that the material has an obvious aggregation-induced emission effect.

[0141] Example 7

[0142] The production of ROS in the bridging molecule intradimer aggregation-induced luminescence mitochondrial targeted near-infrared absorption photosensitizer DTEVQ and aggregation-induced luminescence mitochondrial targeted near-infrared absorption photosensitizer TEVQ-1, TEVQ-2, and TEVQ-3 under 660nm laser irradiation.

[0143] (1) Total ROS generation test:

[0144] First, 2′,7′-dichlorodihydrofluorescein (DCFH) was used as an indicator to detect the total ROS generation capacity. 1mM DCFH-DA stock solution was prepared with anhydrous ethanol, 0.1mL of the stock solution was taken, 0.9mL of anhydrous ethanol and 4mL of 0.01M NaOH solution were added, and after standing at room temperature and away from light for 30 minutes, 15mL of PBS (pH=7.4) was added to prepare a DCFH solution with a final concentration of 50μM. Photosensitizer stock solution (1mM photosensitizer stock solution) was added to the DCFH solution, and the final concentration of the photosensitizer solution was prepared to be 0.25μM for DTEVQ, and 0.5μM for TEVQ-1, TEVQ-2, and TEVQ-3. 660nm laser illumination was used with a power of 0.5W / cm 2 The total illumination time was 60 seconds, and the fluorescence intensity was measured every 5 seconds. The change of fluorescence intensity was monitored by Horiba Fluoromax-4 fluorescence spectrometer. Excitation was performed at 480nm, and the luminescence intensity at 525nm was recorded. The same test process was also applied to the control photosensitizer Ce6.

[0145] (2) Superoxide cation generation test

[0146] Dihydrorhodamine 123 (DHR123) was used as an indicator to detect superoxide anion (O 2 ·- ) generation capacity. Prepare 10mM DHR123 mother solution with DMF, and use ultrapure water to prepare a DHR123 solution with a final concentration of 20μM. Add photosensitizer mother solution (1mM photosensitizer mother solution) to the DHR123 solution, and prepare the photosensitizer solution with a final concentration of 2.5μM for DTEVQ, and 5μM for TEVQ-1, TEVQ-2, and TEVQ-3. Use 660nm laser illumination with a power of 0.5W / cm 2The total illumination time was 60s, the interval time was 5s, and the fluorescence intensity was measured once every interval. The change of fluorescence intensity was monitored by Horiba Fluoromax-4 fluorescence spectrometer. Excitation was at 480nm, and the luminescence intensity at 525nm was recorded.

[0147] (3) Hydroxyl radical generation test

[0148] Hydroxyphenyl fluorescein (HPF) was used as an indicator to detect the ability to generate hydroxyl radicals (·OH). A 5mM HPF stock solution was prepared with DMF, and a final concentration of 10μM HPF solution was prepared with ultrapure water. A photosensitizer stock solution (1mM photosensitizer stock solution) was added to the HPF solution, and the final concentration of the photosensitizer solution was prepared to be 2.5μM for DTEVQ, and 5μM for TEVQ-1, TEVQ-2, and TEVQ-3. A 660nm laser was used for illumination, with a power of 0.5W / cm 2 The total illumination time was 300s, and the intervals were 5s, 10s, 30s, and 60s, respectively. The fluorescence intensity was measured once at each interval. The change of fluorescence intensity was monitored using a Horiba Fluoromax-4 fluorescence spectrometer. Excitation was performed at 480nm, and the luminescence intensity at 514nm was recorded.

[0149] (4) Singlet oxygen generation test:

[0150] 9,10-Anthracenediylbis(methylene)-dimalonic acid (ABDA) was used as an indicator to detect singlet oxygen ( 1 O 2 ) generation capacity. Prepare 10mM ABDA stock solution with DMF, and use ultrapure water to prepare a final concentration of 50μM ABDA solution. Add photosensitizer stock solution (1mM photosensitizer stock solution) to the ABDA solution, and prepare the photosensitizer solution with a final concentration of 2.5μM for DTEVQ, and 5μM for TEVQ-1, TEVQ-2, and TEVQ-3. Use 660nm laser illumination with a power of 0.5W / cm 2 The total illumination time is 40s, the interval time is 5s, and the absorption intensity is measured once every interval. The UV-2600 ultraviolet spectrophotometer of Shimadzu of Japan monitors the absorbance change of ABDA at 400nm. The absorption background of the photosensitizer itself should be deducted in advance during the test.

[0151] Fig.15 The fluorescence response of photosensitizers DTEVQ, TEVQ-1, TEVQ-2, TEVQ-3 and commercial photosensitizer Ce6 to DCFH after illumination for different time periods and the fluorescence intensity comparison at 60s. Fig.15 As shown, the total ROS production capacity of the four photosensitizers was greater than that of the commercial photosensitizer Ce6.

[0152] Fig.16 The fluorescence response of photosensitizers DTEVQ, TEVQ-1, TEVQ-2, and TEVQ-3 to DHR123 after illumination for different time periods and the fluorescence intensity comparison at 60 seconds. Fig.16 As shown, DTEVQ, TEVQ-1 and TEVQ-2 have good superoxide anion production capabilities.

[0153] Fig.17 The fluorescence response of photosensitizers DTEVQ, TEVQ-1, TEVQ-2, and TEVQ-3 to HPF after illumination for different time periods and the fluorescence intensity comparison at 300s. Fig.17 As shown, the four photosensitizers all have good ability to generate hydroxyl radicals.

[0154] Fig.18 The following is a graph showing the degradation rate of ABDA by photosensitizers DTEVQ, TEVQ-1, TEVQ-2, and TEVQ-3 after illumination for different time periods and a comparison of fluorescence intensities at 40 seconds. Fig.18 As shown, the order of singlet oxygen generation ability of the four photosensitizers is: DTEVQ>TEVQ-1>TEVQ-2>TEVQ-3.

[0155] Example 8

[0156] DTEVQ, TEVQ-2 and TEVQ-3 were selected for subsequent biological experiments.

[0157] (1) Mitochondrial colocalization

[0158] In mitochondrial co-localization imaging, 4T1 cells were used as a cancer cell model. 4T1 cells were co-incubated with DTEVQ, TEVQ-2 and TEVQ-3 for 12 hours, with a DTEVQ concentration of 3 μM and TEVQ-2 and TEVQ-3 concentrations of 6 μM. They were then co-incubated with Mito-Tracker Green for 30 minutes, with a Mito-Tracker Green concentration of 1 μM. The fluorescence of DTEVQ, TEVQ-2 and TEVQ-3 in cells and their overlap with Mito-Tracker Green fluorescence were observed using a Zeiss LSM710 confocal laser scanning biological microscope in Germany.

[0159] (2) Effect of photodynamic therapy

[0160] In the cytotoxicity experiment, 4T1 cells were used as a cancer cell model. 4T1 cells were co-incubated with DTEVQ, TEVQ-2 and TEVQ-3. Culture media containing 0, 0.5, 1, 1.5, 2, 2.5, 3 μM DTEVQ and 0, 1, 2, 3, 4, 5, 6 μM TEVQ-2 and TEVQ-3 were added to a 96-well plate containing 4T1 cells. After 12 hours of culture, the cells were irradiated with a 660 nm laser (0.1 W cm-2) for 10 minutes and then cultured for another 12 hours. The old culture medium was then discarded, the 4T1 cells were washed with PBS, the culture medium was replaced with a culture medium containing 0.5 mg / mL MTT, the culture medium was continued for 3 hours in the dark, and the culture medium was replaced with DMSO. Finally, the 96-well plate was shaken for 5 minutes using a multifunctional microplate reader, and the absorbance value of each well at 570 nm was tested.

[0161] Fig.19 This is a laser confocal cell imaging image of 4T1 cells after incubation with photosensitizers DTEVQ, TEVQ-2 and TEVQ-3 and the commercial mitochondrial dye Mito-TrackerGreen. It can be seen that the three photosensitizers DTEVQ, TEVQ-2 and TEVQ-3 all have good mitochondrial targeting capabilities.

[0162] Fig. 20 The dark toxicity of different concentrations of photosensitizers DTEVQ, TEVQ-2 and TEVQ-3 and the statistical graph of in vitro photodynamic therapy. Photosensitizers DTEVQ, TEVQ-2 and TEVQ-3 can effectively kill 4T1 cells under light, among which DTEVQ has the best therapeutic effect. And in the absence of laser irradiation, DTEVQ, TEVQ-2 and TEVQ-3 show negligible toxicity to 4T1 cells.

[0163] Example 9

[0164] The production of ROS under white light by the intramolecular dimer aggregation-induced luminescence mitochondria-targeted near-infrared absorption photosensitizer DTEVQ and the aggregation-induced luminescence mitochondria-targeted near-infrared absorption photosensitizer TEVQ-1, TEVQ-2, and TEVQ-3.

[0165] (1) Total ROS generation test:

[0166] First, 2′,7′-dichlorodihydrofluorescein (DCFH) was used as an indicator to detect the total ROS generation capacity. 1mM DCFH-DA stock solution was prepared with anhydrous ethanol. 0.1mL of the stock solution was taken, and 0.9mL of anhydrous ethanol and 4mL of 0.01M NaOH solution were added. After standing at room temperature and away from light for 30 minutes, 15mL of PBS (pH=7.4) was added to prepare a DCFH solution with a final concentration of 50μM. Photosensitizer stock solution (1mM photosensitizer stock solution) was added to the DCFH solution, and the final concentration of the photosensitizer solution was prepared to be 0.5μM for DTEVQ, and 1μM for TEVQ-1, TEVQ-2, and TEVQ-3. White light was used for illumination, and the power was 20mW / cm 2 The total illumination time was 110s, and the fluorescence intensity was measured every 10s. The change of fluorescence intensity was monitored by Horiba Fluoromax-4 fluorescence spectrometer. Excitation was performed at 480nm, and the luminescence intensity at 525nm was recorded. The same test process was also applied to the control photosensitizer Ce6.

[0167] (2) Superoxide cation generation test

[0168] Dihydrorhodamine 123 (DHR123) was used as an indicator to detect superoxide anion (O 2 ·- ) generation capacity. Prepare 10mM DHR123 mother solution with DMF, and use ultrapure water to prepare a DHR123 solution with a final concentration of 20μM. Add photosensitizer mother solution (1mM photosensitizer mother solution) to the DHR123 solution, and prepare the photosensitizer solution with a final concentration of 5μM DTEVQ, and 10μM TEVQ-1, TEVQ-2, and TEVQ-3. Use white light illumination with a power of 20mW / cm 2 The total illumination time was 90 s, and the intervals were 10 s and 30 s respectively. The fluorescence intensity was measured once at each interval. The change of fluorescence intensity was monitored by Horiba Fluoromax-4 fluorescence spectrometer. The fluorescence intensity was recorded at 525 nm after excitation at 480 nm.

[0169] (3) Hydroxyl radical generation test

[0170] Hydroxyphenyl fluorescein (HPF) was used as an indicator to detect the ability to generate hydroxyl radicals (·OH). A 5mM HPF stock solution was prepared with DMF, and a final concentration of 10μM HPF solution was prepared with ultrapure water. A photosensitizer stock solution (1mM photosensitizer stock solution) was added to the HPF solution, and the final concentration of the photosensitizer solution was prepared to be 2.5μM for DTEVQ, and 5μM for TEVQ-1, TEVQ-2, and TEVQ-3. White light was used for illumination, with a power of 20mW / cm 2The total illumination time was 360s, and the intervals were 5s, 10s, 30s, and 60s, respectively. The fluorescence intensity was measured once at each interval. The change of fluorescence intensity was monitored using a Horiba Fluoromax-4 fluorescence spectrometer. Excitation was performed at 480nm, and the luminescence intensity at 514nm was recorded.

[0171] (4) Singlet oxygen generation test:

[0172] 9,10-Anthracenediylbis(methylene)-dimalonic acid (ABDA) was used as an indicator to detect singlet oxygen ( 1 O 2 ) generation capacity. Prepare 10mM ABDA stock solution with DMF, and use ultrapure water to prepare a final concentration of 50μM ABDA solution. Add photosensitizer stock solution (1mM photosensitizer stock solution) to the ABDA solution, and prepare the photosensitizer solution with a final concentration of 2.5μM for DTEVQ, and 5μM for TEVQ-1, TEVQ-2, and TEVQ-3. Use white light illumination with a power of 20mW / cm 2 The total illumination time is 180s, the interval time is 10s and 30s, and the absorption intensity is measured once every interval. The UV-2600 ultraviolet spectrophotometer of Shimadzu of Japan monitors the absorbance change of ABDA at 400nm. The absorption background of the photosensitizer itself should be deducted in advance during the test.

[0173] Fig.21 The fluorescence response of photosensitizers DTEVQ, TEVQ-1, TEVQ-2, TEVQ-3 and commercial photosensitizer Ce6 to DCFH after white light illumination for different time periods and the fluorescence intensity comparison at 110s. The total ROS production capacity of the four photosensitizers is greater than that of the commercial photosensitizer Ce6.

[0174] Fig. 22 The fluorescence response of photosensitizers DTEVQ, TEVQ-1, TEVQ-2, and TEVQ-3 to DHR123 after white light illumination for different time periods and the fluorescence intensity comparison at 90 seconds. DTEVQ, TEVQ-1, and TEVQ-2 have good superoxide anion production capabilities.

[0175] Fig.23 The fluorescence response of photosensitizers DTEVQ, TEVQ-1, TEVQ-2, and TEVQ-3 to HPF after white light illumination at different times and the fluorescence intensity comparison at 360s. All four photosensitizers have good hydroxyl radical generation capabilities.

[0176] Fig.24The degradation rate of ABDA by photosensitizers DTEVQ, TEVQ-1, TEVQ-2, and TEVQ-3 after white light irradiation for different time periods and the fluorescence intensity comparison at 180s are shown. All four photosensitizers have good singlet oxygen generation capabilities.

[0177] Example 10

[0178] The total ROS production of the dimer aggregation-induced luminescent mitochondrial-targeted near-infrared absorption photosensitizer DTEVQ and TEVQ-3, TEVP, and TTVP under white light.

[0179] 2′,7′-dichlorodihydrofluorescein (DCFH) was used as an indicator to detect the total ROS generation capacity. 1mM DCFH-DA stock solution was prepared with anhydrous ethanol. 0.1mL of the stock solution was taken, and 0.9mL of anhydrous ethanol and 4mL of 0.01M NaOH solution were added. After standing at room temperature and away from light for 30 minutes, 15mL of PBS (pH=7.4) was added to prepare a DCFH solution with a final concentration of 50μM. Photosensitizer stock solution (1mM photosensitizer stock solution) was added to the DCFH solution, and the final concentration of the photosensitizer solution was prepared to be 1.25μM for DTEVQ, 2.5μM for TEVQ-3, TEVP, and TTVP. White light was used for illumination at a power of 20mW / cm 2 The total illumination time was 60 seconds, and the fluorescence intensity was measured every 10 seconds. The change of fluorescence intensity was monitored by Horiba Fluoromax-4 fluorescence spectrometer. The fluorescence intensity was recorded at 525 nm after excitation at 480 nm.

[0180] Fig.25 The fluorescence response of photosensitizers DTEVQ, TEVQ-3, TEVP, and TTVP to DCFH after white light illumination at different times and the fluorescence intensity comparison at 60s. The order of total ROS generation capacity of the four photosensitizers is: DTEVQ>TEVQ-3>TEVP>TTVP, which confirms that with the improvement of the π bridge and the receptor part, the total ROS generation capacity of the photosensitizer is enhanced.

[0181] Fig.26 Schematic diagram of the structure of the photosensitizer DTEVQ and its process of generating ROS after 660nm laser irradiation to affect the mitochondria of cancer cells and effectively kill cancer cells.

[0182] The embodiments described above are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

Claims

1. An aggregation-induced luminescence mitochondrial targeted near-infrared absorption photosensitizer, characterized in that: The general structure is as follows: wherein n is independently an integer of 0 to 16; and X is an anion.

2. The aggregation-induced luminescence mitochondrial targeted near-infrared absorption photosensitizer according to claim 1, characterized in that: The structural formula is as follows:

3. The method for preparing the aggregation-induced luminescence mitochondrial targeted near-infrared absorption photosensitizer according to any one of claims 1 to 2, characterized in that: The following steps are involved: 4-Boric acid triphenylamine reacts with 5-bromo-2-(3,4-vinyldioxythiophene) carboxaldehyde to obtain the intermediate 1, which is reacted with 4-methylquinoline and a halide to obtain N-substituted 4-methylquinoline. The intermediate 1 reacts with N-substituted 4-methylquinoline to obtain an aggregation-induced emission mitochondrial-targeted near-infrared absorption photosensitizer.

4. The preparation method according to claim 3, characterized in that: The following steps are involved: (1) 4-boric acid triphenylamine, 5-bromo-2-(3,4-vinyldioxythiophene) carboxaldehyde, tetrakis(triphenylphosphine)palladium and cesium carbonate were added to a mixed solvent of THF and water under a protective atmosphere, refluxed and purified to obtain an intermediate 1; (2) Preparation of DTEVQ (2.1) 4-Methylquinoline and 1,3-diiodopropane were added to ethanol, refluxed, and purified to obtain intermediate 2; (2.2) Ethanol and piperidine are added to intermediate product 1 and intermediate product 2, refluxed, and purified to obtain DTEVQ; (3) Preparation of TEVQ-1 (3.1) 4-Methylquinoline and iodomethane were added to ethanol, refluxed, and purified to obtain intermediate 3; (3.2) Add ethanol and piperidine to intermediate product 1 and intermediate product 3, reflux reaction, and purify to obtain TEVQ-1; (4) Preparation of TEVQ-2 (4.1) 4-Methylquinoline and 1-iodopropane were added to ethanol, refluxed, and purified to obtain intermediate 4; (4.2) Ethanol and piperidine are added to intermediate product 1 and intermediate product 4, refluxed and purified to obtain TEVQ-2; (5) Preparation of TEVQ-3 (5.1) 4-Methylquinoline and (3-bromopropyl)trimethylammonium bromide were added to ethanol, refluxed and purified to obtain intermediate 5; (5.2) Ethanol and piperidine were added to intermediate product 1 and intermediate product 5, refluxed and purified to obtain TEVQ-3.

5. The preparation method according to claim 4, characterized in that: In step (1), the molar ratio of 4-boric acid triphenylamine, 5-bromo-2-(3,4-vinyldioxythiophene) formaldehyde, tetrakis(triphenylphosphine)palladium and cesium carbonate is 11-15:10:0.02-0.05:20-30; In step (1), the volume ratio of THF to water is 20-27:3-10; In step (1), the molar volume ratio of 5-bromo-2-(3,4-vinyldioxythiophene)carboxaldehyde to the mixed solvent is 10 mmol:30-50 mL; In step (1), the reflux reaction temperature is 70 to 80° C. and the time is 24 to 36 hours; In step (1), the protective atmosphere is nitrogen.

6. The preparation method according to claim 4, characterized in that: In step (2.1), the molar ratio of 4-methylquinoline to 1,3-diiodopropane is 10-15:4; In step (2.1), the molar volume ratio of 1,3-diiodopropane to ethanol is 4 mmol:5-20 mL; In step (2.1), the reflux reaction temperature is 80 to 90° C. and the time is 12 to 36 hours; In step (2.2), the molar ratio of intermediate product 1 to intermediate product 2 is 1-1.5:0.4; In step (2.2), the ratio of the intermediate product 2, ethanol and piperidine is 0.4 mmol: 15-30 mL: 15-30 μL; In step (2.2), the reflux reaction temperature is 80 to 90° C. and the time is 12 to 36 hours.

7. The preparation method according to claim 4, characterized in that: In step (3.1), the molar ratio of 4-methylquinoline to methyl iodide is 5 to 10:4; In step (3.1), the molar volume ratio of methyl iodide to ethanol is 4 mmol:5-20 mL; In step (3.1), the reflux reaction temperature is 80 to 90° C. and the time is 12 to 36 hours; In step (3.2), the molar ratio of intermediate product 1 to intermediate product 3 is 1 to 1.5:1; In step (3.2), the ratio of the intermediate product 3, ethanol and piperidine is 1 mmol: 15-30 mL: 15-30 μL; In step (3.2), the reflux reaction temperature is 80 to 90° C. and the time is 12 to 36 hours.

8. The preparation method according to claim 4, characterized in that: In step (4.1), the molar ratio of 4-methylquinoline to 1-iodopropane is 5 to 10:4; In step (4.1), the molar volume ratio of 1-iodopropane to ethanol is 4 mmol:5-20 mL; In step (4.1), the reflux reaction temperature is 80 to 90° C. and the time is 12 to 36 hours; In step (4.2), the molar ratio of intermediate product 1 to intermediate product 4 is 1 to 1.5:1; In step (4.2), the ratio of the intermediate product 4, ethanol and piperidine is 1 mmol: 15-30 mL: 15-30 μL; In step (4.2), the reflux reaction temperature is 80 to 90° C. and the time is 12 to 36 hours.

9. The preparation method according to claim 4, characterized in that: In step (5.1), the molar ratio of 4-methylquinoline to (3-bromopropyl)trimethylammonium bromide is 5 to 10:4; In step (5.1), the molar volume ratio of (3-bromopropyl)trimethylammonium bromide to ethanol is 4 mmol:5-20 mL; In step (5.1), the reflux reaction temperature is 80 to 90° C. and the time is 12 to 36 hours; In step (5.2), the molar ratio of intermediate product 1 to intermediate product 5 is 1 to 1.5:1; In step (5.2), the ratio of the intermediate product 5, ethanol and piperidine is 1 mmol: 15-30 mL: 15-30 μL; In step (5.2), the reflux reaction temperature is 80 to 90° C. and the time is 12 to 36 hours.

10. Use of the aggregation-induced luminescence mitochondrial targeted near-infrared absorption photosensitizer according to any one of claims 1 to 2 in the preparation of a cancer cell photodynamic therapy agent.

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