A near-infrared second-region iridium complex with aggregation-induced emission properties, and its preparation method and application

Abstract

The present invention discloses a near-infrared II region iridium complex with aggregation-induced luminescence properties, a preparation method thereof, and an application thereof, wherein the structural formula is as follows: wherein R1 is selected from one of S and Se, R2 and R3 are independently selected from one of H and, and R4 is selected from one of H and F. The present invention designs a D-A-D type N^N ligand and an iridium complex thereof with dipyrido[3,2-a:2',3'-c][1,2,5]thiadiazolo[3,4-i]phenazine as an acceptor (A) and triphenylamine as a donor (D). The large conjugated rigid acceptor and the D-A-D structure can ensure that the molecule has a lower energy gap, so that it has near-infrared II region (NIR-II) emission, and the propeller-type triphenylamine and the ortho-alkyl-substituted thiophene π-bridge can effectively suppress the aggregation of the molecule, so that it has aggregation-induced luminescence properties. At the same time, the electron-withdrawing iridium ion coordination further improves the electron-withdrawing ability of the acceptor, and the absorption and emission of the entire molecule are red-shifted.

Description

Technical Field

[0001] The present invention relates to the technical field of fluorescent molecular probes, and in particular to a near-infrared second-region iridium complex with aggregation-induced luminescence properties, and a preparation method and application thereof. Background Art

[0002] Cancer has become a persistent public health challenge facing the world, imposing a huge burden and economic loss on patients, families, and society. Compared with the traditional model of separate diagnosis and treatment, optical diagnosis and treatment has the advantages of high diagnosis and treatment efficiency, non-invasiveness, low toxicity and side effects, and strong spatiotemporal selectivity. Photothermal-photodynamic synergistic therapy guided by fluorescence-photoacoustic-photothermal imaging is a new multimodal optical diagnosis and treatment that has emerged in recent years. Its advantage is that it can make up for the shortcomings of a single imaging and treatment method by combining the advantages of multiple imaging and treatment methods, thereby maximizing the efficiency of treatment and diagnosis.

[0003] The significantly enhanced luminescence of aggregation-induced emission molecules in their aggregated state makes them a powerful tool for overcoming the aggregation-induced fluorescence quenching problem common among traditional luminescent molecules. Aggregation-induced emission molecules possess a propeller-like structure, numerous rotors, and modifiable groups, allowing them to balance and control the pathway and ratio of energy dissipation from the excited state to the ground state. This makes them ideal templates for constructing molecules with near-infrared II (NIR-II) emission, photothermal properties, and photodynamic properties.

[0004] At present, the construction of NIR-II molecules with aggregation-induced emission characteristics follows the design principle of "skeleton twisting and peripheral rotors". The mainstream molecular configuration is donor-acceptor-donor type, in which the donor is mainly concentrated in triphenylamine and its derivatives, and the acceptor is mainly limited to bisbenzothiadiazole (BBT) and thiadiazolylquinoxaline (PTQ). Moreover, these two acceptors are insufficient to meet the long-term development and wide application of multifunctional aggregation-induced emission photodiagnostic agents due to their stability problems and the defects of insufficient red absorption and emission (the maximum emission wavelength is difficult to exceed 1000nm).

[0005] Therefore, the existing technology still needs to be improved and developed. Summary of the Invention

[0006] In view of the above-mentioned deficiencies in the prior art, the present invention provides a near-infrared region II iridium complex with aggregation-induced emission properties, as well as a preparation method and application thereof, aiming to solve the problem that the maximum emission wavelength of existing near-infrared region II aggregation-induced emission molecules is difficult to exceed 1000nm, and enrich the existing near-infrared region II aggregation-induced emission molecular material construction strategy.

[0007] The technical solutions adopted by the present invention to solve the above technical problems are as follows:

[0008] In a first aspect of the present invention, a near-infrared second-region iridium complex having aggregation-induced emission properties is provided, the structural formula of which is shown below:

[0009]

[0010] Wherein, R1 is selected from one of S and Se, R2 and R3 are independently selected from H and R4 is selected from one of H and F.

[0011] The second aspect of the present invention provides a method for preparing the near-infrared second region iridium complex having aggregation-induced emission properties as described above, the preparation method comprising the following steps:

[0012] Under a protective atmosphere, formula I and formula II are added to a solvent, subjected to a first stirring treatment, and then an ion exchanger is added and subjected to a second stirring treatment to obtain a near-infrared second-region iridium complex having aggregation-induced emission properties having a structural formula as shown in formula III;

[0013] The above reaction scheme is as follows:

[0014]

[0015] Preferably, the molar ratio of Formula I to Formula II is (1.5-2.5):1.

[0016] Preferably, the solvent is a mixed solvent including dichloromethane and methanol.

[0017] Preferably, the molar ratio of the ion exchanger to formula I is (1-2):1.

[0018] Preferably, the ion exchanger is potassium hexafluorophosphate or potassium tetrafluoroborate.

[0019] Preferably, the first stirring treatment is specifically: stirring at 40-60° C. for 12-18 hours in dark conditions; and the second stirring treatment is specifically: stirring at room temperature for 4-6 hours.

[0020] Preferably, after the second stirring process, the method further comprises the following steps:

[0021] After the mixed solvent is evaporated, purification treatment is performed to obtain the near-infrared second-zone iridium complex with aggregation-induced emission properties.

[0022] The third aspect of the present application provides the use of the above-mentioned near-infrared second-region iridium complex with aggregation-induced emission properties in the preparation of multimodal integrated diagnosis and treatment reagents.

[0023] Preferably, the multimodal integrated diagnosis and treatment reagent is used to treat cancer.

[0024] Beneficial effects:

[0025] The present invention discloses a near-infrared II region iridium complex with aggregation-induced emission properties, as well as a preparation method and application thereof. The present invention designs a DAD-type N^N ligand with dipyrido[3,2-a:2',3'-c][1,2,5]thiadiazolo[3,4-i]phenazine as an acceptor (A) and triphenylamine as a donor (D), as well as an iridium complex thereof. The large conjugated rigid acceptor and the DAD structure can ensure that the molecule has a low energy gap, so that it has near-infrared II region (NIR-II) emission. The propeller-shaped triphenylamine and the ortho-alkyl-substituted thiophene π-bridge can effectively inhibit the aggregation of the molecule, so that it has aggregation-induced emission properties.

[0026] At the same time, the electron-withdrawing iridium ion coordination further enhances the electron-withdrawing capacity of the receptor, red-shifting the absorption and emission of the molecule as a whole. The aggregation-induced luminescence (AILE) near-infrared region II iridium complex provided by this invention exhibits excellent fluorescence, reactive oxygen species (ROS) generation, and photothermal conversion capabilities, making it a multimodal phototherapeutic agent that combines imaging and treatment, and can be used for integrated multimodal cancer diagnosis and treatment research. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is a synthetic route for preparing a near-infrared region II iridium complex having aggregation-induced emission properties according to an embodiment of the present invention;

[0028] Figure 2 This is a hydrogen nuclear magnetic resonance spectrum of the near-infrared second-region iridium complex ppy-oiC8-N^N with aggregation-induced emission properties prepared in Example 1 of the present invention in deuterated chloroform;

[0029] Figure 3 This is the carbon nuclear magnetic resonance spectrum of the near-infrared second-region iridium complex ppy-oiC8-N^N with aggregation-induced emission properties prepared in Example 1 of the present invention in deuterated chloroform;

[0030] Figure 4 This is a hydrogen nuclear magnetic resonance spectrum of the near-infrared second-region iridium complex 2Fppy-oiC8-N^N with aggregation-induced emission properties prepared in Example 2 of the present invention in deuterated chloroform;

[0031] Figure 5 This is the NMR fluorine spectrum of the near-infrared second-region iridium complex 2Fppy-oiC8-N^N with aggregation-induced emission properties prepared in Example 2 of the present invention in deuterated chloroform;

[0032] Figure 6 This is the carbon nuclear magnetic resonance spectrum of the near-infrared second-region iridium complex 2Fppy-oiC8-N^N with aggregation-induced emission properties prepared in Example 2 of the present invention in deuterated chloroform;

[0033] Figure 7 This is a hydrogen nuclear magnetic resonance spectrum of the near-infrared second-region iridium complex ppy-miC8-N^N with aggregation-induced emission properties prepared in Example 3 of the present invention in deuterated chloroform;

[0034] Figure 8 This is the carbon NMR spectrum of the near-infrared second-region iridium complex ppy-miC8-N^N with aggregation-induced emission properties prepared in Example 3 of the present invention in deuterated chloroform;

[0035] Figure 9 This is a hydrogen nuclear magnetic resonance spectrum of the near-infrared second-region iridium complex 2Fppy-miC8-N^N with aggregation-induced emission properties prepared in Example 4 of the present invention in deuterated chloroform;

[0036] Figure 10 This is the NMR fluorine spectrum of the near-infrared second-region iridium complex 2Fppy-miC8-N^N with aggregation-induced emission properties prepared in Example 4 of the present invention in deuterated chloroform;

[0037] Figure 11 This is the carbon NMR spectrum of the near-infrared second-region iridium complex 2Fppy-miC8-N^N with aggregation-induced emission properties prepared in Example 4 of the present invention in deuterated chloroform;

[0038] Figure 12 is the ultraviolet absorption spectrum of the near-infrared second-region iridium complexes with aggregation-induced emission properties prepared in Examples 1, 2, 3 and 4 of the present invention in tetrahydrofuran;

[0039] Figure 13 1 is a fluorescence emission spectrum of the near-infrared second region iridium complexes having aggregation-induced emission properties in tetrahydrofuran according to Examples 1, 2, 3 and 4 of the present invention;

[0040] Figure 14 This is an aggregation-induced emission curve of the near-infrared second-region iridium complex with aggregation-induced emission properties prepared in Example 1 of the present invention in tetrahydrofuran / water;

[0041] Figure 15 This is an aggregation-induced emission curve of the near-infrared second-region iridium complex with aggregation-induced emission properties prepared in Example 2 of the present invention in tetrahydrofuran / water;

[0042] Figure 16 This is a graph showing the photothermal conversion efficiency of nanoparticles ppy-oiC8-N^N NPs prepared from the near-infrared second-region iridium complex with aggregation-induced emission properties in Example 1 of the present invention under 808nm laser irradiation;

[0043] Figure 17is a graph showing the ROS generation capacity of the nanoparticles ppy-oiC8-N^N NPs prepared in Example 5 of the present invention;

[0044] Figure 18 This is an experimental diagram showing the dark toxicity and photothermal-photodynamic synergistic killing effect of the nanoparticles ppy-oiC8-N^N NPs prepared in Example 5 of the present invention on 4T1 cells;

[0045] Figure 19 This is a diagram showing the fluorescence / photoacoustic / photothermal synergistic imaging effect of the nanoparticles ppy-oiC8-N^N NPs prepared in Example 5 of the present invention on breast cancer;

[0046] Figure 20 This is a diagram showing the photothermal-photodynamic synergistic treatment effect of breast cancer using nanoparticles ppy-oiC8-N^N NPs prepared from the near-infrared second-region iridium complex with aggregation-induced emission properties in Example 1 of the present invention. DETAILED DESCRIPTION

[0047] The present invention provides a near-infrared region II iridium complex with aggregation-induced emission properties, as well as a preparation method and application thereof. To clarify and clarify the objectives, technical solutions, and effects of the present invention, the present invention is described in further detail below. It should be understood that the specific embodiments described herein are intended only to illustrate the present invention and are not intended to limit the present invention.

[0048] The present invention provides a near-infrared second-region iridium complex with aggregation-induced emission properties, the structural formula of which is shown below:

[0049]

[0050] Wherein, R1 is selected from one of S and Se, R2 and R3 are independently selected from H and R4 is selected from one of H and F.

[0051] In this embodiment, the molecular structure of the near-infrared II region iridium complex with aggregation-induced emission properties is a DAD-type N^N ligand with dipyrido[3,2-a:2',3'-c][1,2,5]thiadiazolo[3,4-i]phenazine as the acceptor (A) and triphenylamine as the donor (D), as well as its iridium complex. The large conjugated rigid acceptor and DAD structure can ensure that the molecule has a low energy gap, giving it near-infrared II (NIR-II) emission. The propeller-shaped triphenylamine and the ortho-alkyl-substituted thiophene π-bridge can effectively inhibit the aggregation of the molecule, giving it aggregation-induced emission properties. At the same time, the electron-withdrawing iridium ion coordination further enhances the electron-withdrawing ability of the acceptor, red-shifting the absorption and emission of the entire molecule.

[0052] An embodiment of the present invention provides a method for preparing a near-infrared second-region iridium complex having aggregation-induced emission properties, characterized in that the preparation method comprises the following steps:

[0053] Under a protective atmosphere, formula I and formula II are added to a solvent, subjected to a first stirring treatment, and then an ion exchanger is added and subjected to a second stirring treatment to obtain a near-infrared second-region iridium complex having aggregation-induced emission properties having a structural formula as shown in formula III;

[0054] The above reaction scheme is as follows:

[0055]

[0056] In some embodiments, the molar ratio of Formula I to Formula II is 1.5-2.5:1.

[0057] In the embodiment of the present invention, the molar ratio of Formula I to Formula II is controlled at 1.5 to 2.5:1. A higher molar ratio will cause a waste of raw materials, while a lower molar ratio will result in an incomplete reaction, thereby improving the utilization rate of raw materials.

[0058] In some preferred embodiments, the molar ratio of Formula I to Formula II is 2:1.

[0059] In some embodiments, the solvent is a mixed solvent comprising dichloromethane and methanol, wherein the volume ratio of dichloromethane to methanol is 3:1.

[0060] In some embodiments, the molar ratio of the ion exchanger to Formula I is 1 to 2:1.

[0061] In the embodiment of the present invention, the molar ratio of the ion exchanger to formula I is 1 to 2:1. More will cause a waste of raw materials, and less will cause incomplete reaction, thereby improving the utilization rate of raw materials.

[0062] In some preferred embodiments, the molar ratio of the ion exchanger to the compound of formula I is 1.5:1.

[0063] In some embodiments, the ion exchanger is potassium hexafluorophosphate or potassium tetrafluoroborate.

[0064] In some embodiments, the first stirring treatment is specifically: stirring at 40-60° C. in the dark for 12-18 hours; the second stirring treatment is specifically: stirring at room temperature for 4-6 hours.

[0065] In some preferred embodiments, the first stirring treatment is specifically: stirring at 40° C. for 12 hours in the dark; and the second stirring treatment is specifically: stirring at room temperature for 4 hours.

[0066] In some embodiments, after the second stirring process, the method further comprises the following steps:

[0067] After the mixed solvent is evaporated, purification treatment is performed to obtain the near-infrared second-zone iridium complex with aggregation-induced emission properties.

[0068] In some embodiments, the preparation of formula I comprises the following steps:

[0069] Equimolar amounts of Formula IV and 1,10-phenanthroline-5,6-dione were added to a mixture of chloroform and acetic acid (volume ratio 1:1) and stirred at 80°C for 24 hours. After completion of the reaction, the mixture was cooled to room temperature and extracted three times with dichloromethane. The organic layer was then dried over anhydrous Na2SO4 and concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography using petroleum ether and dichloromethane as eluents to obtain Formula I. The reaction scheme is as follows:

[0070]

[0071] Wherein, R1 is independently selected from one of S and Se, R2 and R3 are independently selected from H and One of them.

[0072] In some embodiments, the preparation of the compound of formula IV comprises the following steps:

[0073] Under a nitrogen atmosphere, Formula VI and Fe (molar ratio of 1:12) were added to an acetic acid solvent and stirred at 80°C for 12 hours. After the reaction was completed, the solution was cooled to room temperature and water was added. A large amount of yellow solid precipitated from the solution. The yellow solid was filtered, washed with water, then redissolved and extracted with dichloromethane and dried by spin drying. Finally, the product was precipitated with methanol, filtered, and vacuum dried to obtain a yellow powder product IV. The reaction route is as follows:

[0074]

[0075] Wherein, R1 is independently selected from one of S and Se, R2 and R3 are independently selected from H and One of them.

[0076] In some embodiments, the preparation of the compound of formula VI comprises the following steps:

[0077] Under a nitrogen atmosphere, Formula VII, Formula VIII, and bistriphenylphosphine palladium dichloride (molar ratio of 5:10:2) were added to a toluene solvent and stirred at 110°C for 12 hours. After completion, the reaction was separated using a silica gel column using dichloromethane and petroleum ether as eluents. The separated blue-purple solution was collected, dried, and then washed with methanol to obtain a dark brown solid of Formula VI. The reaction scheme is as follows:

[0078]

[0079] Wherein, R1 is independently selected from one of S and Se, R2 and R3 are independently selected from H and One of them.

[0080] In some embodiments, the preparation of the compound of formula VIII comprises the following steps:

[0081] Under a nitrogen atmosphere, Formula IX, n-butyl lithium, and tributyltin chloride (molar ratio of 1:1:1) were added to tetrahydrofuran solvent and stirred at -78°C for 12 hours, resulting in a tan-brown color. Water was added to quench the reaction, and the mixture was then spin-dried. The mixture was then extracted with dichloromethane, washed with water, spin-dried, and dried. A tan-brown, viscous solution of Formula VIII was obtained. The reaction scheme is as follows:

[0082]

[0083] Wherein, R2 and R3 are independently selected from H and One of them.

[0084] In some embodiments, the preparation of Formula IX comprises the following steps:

[0085] Under a nitrogen atmosphere, 4-bromotriphenylamine, Formula X, and tributyltin chloride (in a 1:1:1 molar ratio) were added to a toluene solvent and stirred at 110°C for 12 hours. After completion of the reaction, the mixture was separated using a silica gel column using dichloromethane and petroleum ether as eluents. A colorless, viscous substance was collected and dried to yield Formula IX. The reaction scheme is as follows:

[0086]

[0087] Wherein, R2 and R3 are independently selected from H and One of them.

[0088] In one embodiment, the preparation of formula II comprises the following steps:

[0089] Under an N2 atmosphere, Formula V and iridium chloride hydrate (molar ratio of 1:2) were added to a mixed solvent of 2-methoxyethanol and water (volume ratio of 3:1) and stirred at 115°C for 18 hours. After the reaction was completed, the solution was cooled to room temperature and water was added, resulting in the precipitation of a large amount of yellow-green solid. The yellow-green solid was filtered, washed sequentially with water, petroleum ether, and n-hexane, and then vacuum dried to obtain a yellow-green powder product of Formula II. The reaction scheme is as follows:

[0090]

[0091] wherein R4 is independently selected from one of H and F.

[0092] The present invention also provides a nanoparticle, wherein the preparation of the nanoparticle comprises the following steps:

[0093] A tetrahydrofuran solution of a near-infrared region II iridium complex exhibiting aggregation-induced emission properties was mixed with distearoylphosphatidylethanolamine-polyethylene glycol 2000. The mixture was then ultrasonically agitated for 2 minutes using an ultrasonicator. The resulting mixture was placed in a dialysis bag and dialyzed against ultrapure water for 24 hours. Finally, the resulting nanoparticles were concentrated by ultrafiltration.

[0094] In some embodiments, there is provided a use of the aforementioned near-infrared region II iridium complex having aggregation-induced emission properties or the aforementioned nanoparticles in the preparation of a multimodal integrated diagnosis and treatment reagent.

[0095] In some embodiments, the multimodal diagnostic and therapeutic integrated reagent is used to treat cancer.

[0096] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them, and are intended only to illustrate the present invention and in no way limit the present invention. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort shall fall within the scope of protection of the present invention.

[0097] Example 1

[0098] A preparation method of a near-infrared second-region iridium complex with aggregation-induced emission properties comprises the following steps:

[0099] Under N2 atmosphere, 200 mg of formula I (wherein R1 is S, R2 is R3 is H) and 97 mg of Formula II (wherein R4 is H) were added to 24 mL of a mixed solvent of dichloromethane and methanol (dichloromethane and methanol volume ratio of 3:1), and the reaction was stirred at 40°C under dark conditions for 12 hours. After the reaction was completed, 200 mg of potassium hexafluorophosphate was added, and the resulting mixture was stirred for another 4 hours at room temperature. After the mixed solvent was completely evaporated, it was purified by column chromatography using dichloromethane and methanol (dichloromethane and methanol volume ratio of 80:1) as eluents to obtain 240 mg of a black solid of Formula III (denoted as ppy-oiC8-N^N) with a yield of 83%.

[0100] Example 2

[0101] A preparation method of a near-infrared second-region iridium complex with aggregation-induced emission properties comprises the following steps:

[0102] Under N2 atmosphere, 200 mg of formula I (wherein R1 is S, R2 is R3 is H) and 110.03 mg of Formula II (wherein R4 is F) were added to 24 mL of a mixed solvent of dichloromethane and methanol (the volume ratio of dichloromethane to methanol was 3:1), and the reaction was stirred at 40°C for 12 hours under dark conditions. After the reaction was completed, 200 mg of potassium hexafluorophosphate was added, and the resulting mixture was stirred for another 4 hours at room temperature. After the mixed solvent was completely evaporated, it was purified by column chromatography using dichloromethane and methanol (the volume ratio of dichloromethane to methanol was 100:1) as eluents to obtain 290 mg of a black solid of Formula III (denoted as 2Fppy-oiC8-N^N) with a yield of 83%.

[0103] Example 3

[0104] A preparation method of a near-infrared second-region iridium complex having aggregation-induced emission properties comprises the following steps:

[0105] Under N2 atmosphere, 100 mg of formula I (wherein R1 is S, R2 is H, and R3 is ) and 48.51 mg of Formula II (wherein R4 is H) were added to 12 mL of a mixed solvent of dichloromethane and methanol (the volume ratio of dichloromethane to methanol was 3:1), and the reaction was stirred at 40°C for 12 hours under dark conditions. After the reaction was completed, 300 mg of potassium hexafluorophosphate was added, and the resulting mixture was stirred for another 4 hours at room temperature. After the mixed solvent was completely evaporated, it was purified by column chromatography using dichloromethane and methanol (the volume ratio of dichloromethane to methanol was 50:1) as eluents to obtain 126 mg of a black solid Formula III (denoted as ppy-miC8-N^N) with a yield of 80%.

[0106] Example 4

[0107] A preparation method of a near-infrared second-region iridium complex having aggregation-induced emission properties comprises the following steps:

[0108] Under N2 atmosphere, 200 mg of formula I (wherein R1 is S, R2 is H, R3 is ) and 110.03 mg of Formula II (wherein R4 is F) were added to 24 mL of a mixed solvent of dichloromethane and methanol (the volume ratio of dichloromethane to methanol was 3:1), and the reaction was stirred at 40°C for 12 hours under dark conditions. After the reaction was completed, 300 mg of potassium hexafluorophosphate was added, and the resulting mixture was stirred for another 4 hours at room temperature. After the mixed solvent was completely evaporated, it was purified by column chromatography using dichloromethane and methanol (the volume ratio of dichloromethane to methanol was 100:1) as eluents to obtain 270 mg of a black solid Formula III (denoted as 2Fppy-miC8-N^N) with a yield of 83%.

[0109] The synthetic route for preparing the near-infrared second-region iridium complexes (ppy-oiC8-N^N, 2Fppy-oiC8-N^N, ppy-miC8-N^N, 2Fppy-miC8-N^N) with aggregation-induced emission properties in the above Examples 1-4 is as follows: Figure 1 shown.

[0110] The H NMR spectrum and C NMR spectrum of ppy-oiC8-N^N in deuterated chloroform are as follows Figure 2 and Figure 3 shown.

[0111] The H NMR spectrum, F NMR spectrum and C NMR spectrum of 2Fppy-oiC8-N^N in deuterated chloroform are as follows: Figure 4 、 Figure 5 and Figure 6 shown.

[0112] The H NMR spectrum and C NMR spectrum of ppy-miC8-N^N in deuterated chloroform are shown in Figure 2. Figure 7 and Figure 8 shown.

[0113] The H NMR spectrum, F NMR spectrum and C NMR spectrum of 2Fppy-miC8-N^N in deuterated chloroform are as follows: Figure 9 、 Figure 10 and Figure 11 shown.

[0114] Performance testing

[0115] The ultraviolet absorption spectra of ppy-oiC8-N^N in Example 1, 2Fppy-oiC8-N^N in Example 2, ppy-miC8-N^N in Example 3 and 2Fppy-miC8-N^N in Example 4 in tetrahydrofuran are shown in FIG. Figure 12 shown.

[0116] The fluorescence emission spectra of ppy-oiC8-N^N in Example 1, 2Fppy-oiC8-N^N in Example 2, ppy-miC8-N^N in Example 3 and 2Fppy-miC8-N^N in Example 4 in tetrahydrofuran are shown in FIG. Figure 13 As shown, the emission wavelengths of the molecules in the four embodiments are all located in the second near-infrared region (greater than 1000 nm).

[0117] The fluorescence emission spectra of ppy-oiC8-N^N in Example 1 and 2Fppy-oiC8-N^N in Example 2 in a mixed solvent of tetrahydrofuran and water (the volume content of water in the mixed solvent is 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% and 90% respectively) are shown in FIG. Figure 14 and Figure 15 As shown, I represents the luminescence intensity in a solution with a certain water content, and I0 represents the luminescence intensity in pure tetrahydrofuran. It can be seen that ppy-oiC8-N^N and 2Fppy-oiC8-N^N have the property of aggregation-induced emission and are aggregation-induced emission materials.

[0118] Example 5

[0119] A method for preparing nanoparticles comprises the following steps:

[0120] A tetrahydrofuran solution of ppy-oiC8-N^N prepared in Example 1 (1 mg of ppy-oiC8-N^N and 1 mL of tetrahydrofuran) was mixed with distearoylphosphatidylethanolamine-polyethylene glycol 2000 (10 mg of distearoylphosphatidylethanolamine and 9 mL of polyethylene glycol 2000). Subsequently, ultrasonic stirring was performed for 2 minutes using an ultrasonicator. After ultrasonic stirring, the resulting mixture was placed in a dialysis bag and dialyzed in ultrapure water for 24 hours. Finally, nanoparticles (denoted as ppy-oiC8-N^N NPs) were obtained by ultrafiltration and concentration.

[0121] Performance testing:

[0122] (1) The photothermal conversion efficiency of ppy-oiC8-N^N NPs (100 μM) prepared in Example 5 under 808 nm laser irradiation was tested. The results are as follows: Figure 16 As shown in FIG, its photothermal conversion efficiency is 60.5%, indicating that it has excellent photothermal conversion capability, wherein θ represents the ratio of the temperature change (ΔT) to the maximum temperature change (ΔTmax).

[0123] (2) Testing the ROS generation ability of the ppy-oiC8-N^N NPs prepared in Example 5 under 808 nm laser irradiation, the specific steps are as follows:

[0124] 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) was used as a ROS indicator to detect the ROS production of ppy-oiC8-N^N NPs in solution under irradiation of 808 nm laser (0.8 W cm-2).

[0125] First, an ethanol solution of DCFH-DA (1 mM DCFH-DA, 0.5 mL ethanol) was added to 2 mL of NaOH solution (0.01 M) and stirred at room temperature for 30 minutes to hydrolyze DCFH-DA to DCFH. The hydrolyzate was then neutralized with 10 mL of 1× PBS (pH 7.4) to obtain an activated ROS indicator (40 μM, 12.5 mL) and stored at 4°C in the dark until ready to use. The activated ROS indicator (40 μM) was then mixed with ppy-oiC8-N^N NPs in PBS to a final concentration of 1 μM for both the ROS indicator and ppy-oiC8-N^N NPs. After irradiation with an 808 laser for various times, the fluorescence intensity of DCFH, triggered by ROS production from the ppy-oiC8-N^N NPs, was measured using a fluorescence spectrometer to reflect ROS production. The excitation wavelength was 488 nm, and the fluorescence signals were collected in the range of 490–600 nm.

[0126] The results are as follows Figure 17 As shown in the figure, the fluorescence intensity of DCFH increased by nearly 250 times after 808 nm laser irradiation for 10 minutes, indicating that it has good ROS generation ability, where I represents the fluorescence intensity of DCFH triggered by ROS generation by ppy-oiC8-N^N NPs, and I0 represents the fluorescence intensity of DCFH without light irradiation.

[0127] (3) The dark toxicity and photothermal killing effects of the ppy-oiC8-N^N NPs prepared in Example 5 (at concentrations of 0 μM, 10 μM, 20 μM, 40 μM, 60 μM, 80 μM, and 100 μM, respectively) on 4T1 cells were tested. The specific steps are as follows:

[0128] 4T1 cells were seeded in 96-well plates with an initial density of 5×103 cells / well and incubated for 24 hours. 4T1 cells were then treated with different concentrations of ppy-oiC8-N^N NPs. After incubation for 12 hours, 4T1 cells were directly exposed to 808nm laser (0.8W·cm-2) and irradiated for 5 minutes. At the same time, 4T1 cells without laser irradiation were used for dark toxicity assay. Subsequently, the cells were further cultured for 12 hours before the addition of CCK-8. Finally, cell viability was recorded using a microplate reader with a detection wavelength of 450nm.

[0129] The results are as follows Figure 18 The results are shown as the survival percentage of 4T1 cells after various treatments relative to the control 4T1 cells without any treatment. ppy-oiC8-N^N NPs still have low dark cytotoxicity in the range of 100μM and have excellent photothermal killing ability of 4T1 cells.

[0130] (4) Synergistic imaging (fluorescence / photoacoustic / photothermal, NIR-II FLI / PAI / PTI) experiment of breast cancer using ppy-oiC8-N^N NPs prepared in Example 5, specifically comprising the following steps:

[0131] After 4T1 tumor-bearing mice were injected with ppy-oiC8-N^N NPs (200 μL, 1.5 mM), fluorescence / photoacoustic imaging was performed on the mice at 0 h, 1 h, 3 h, 24 h, 36 h, and 48 h, respectively, to detect the fluorescence / photoacoustic signals of the mouse tumors. The results are shown in Figure 2. Figure 19 As shown in the figure, ppy-oiC8-N^N NPs tended to be enriched in the tumor site of mice and reached a peak at 36h.

[0132] After fluorescence / photoacoustic imaging of 4T1 tumor-bearing mice, thermal imaging of the tumor site was performed 36 h after injection of ppy-oiC8-N^N NPs (200 μL, 1.5 mM). Figure 19 As shown in the figure, under 808nm laser irradiation, the temperature of the mouse tumor site gradually increased.

[0133] Therefore, ppy-oiC8-N^N NPs have excellent specific imaging and therapeutic capabilities for tumors.

[0134] (5) The experiment of photothermal / photodynamic synergistic treatment of breast cancer by ppy-oiC8-N^N NPs prepared in Example 5 specifically includes the following steps:

[0135] 4T1 tumor-bearing mice were randomly divided into 4 groups (n=5 in each group) for different treatments, namely "PBS" group, "PBS+L" group, "ppy-oiC8-N^N NPs" group and "ppy-oiC8-N^N NPs+L" group.

[0136] For the “PBS+L” group, mice were injected with PBS (200 μL) via the tail vein on day 0 and exposed to 808 nm laser (0.8 W cm-2) for 10 min 36 h after injection;

[0137] For the “PBS” group, mice were injected with PBS (200 μL) via the tail vein on day 0 without light exposure, serving as the control group for the “PBS + L” group;

[0138] For the “ppy-oiC8-N^N NPs+L” group, mice were injected with ppy-oiC8-N^N NPs (200 μL, 1.5 mM) via the tail vein on day 0 and exposed to 808 nm laser (0.8 W cm-2) for 10 min continuously 36 h after injection;

[0139] For the “ppy-oiC8-N^N NPs” group, mice were injected with ppy-oiC8-N^N NPs (200 μL, 1.5 mM) via the tail vein on day 0 without light exposure, serving as the control group for the “ppy-oiC8-N^N NPs+L” group;

[0140] The tumor volume of mice was recorded every 3 days during treatment and calculated as V = a × b2 / 2 (a: tumor length; b: tumor width). The relative tumor volume (RTV) was calculated as RTV = V / V0, where V0 is the initial tumor volume.

[0141] The results are as follows Figure 19 and Figure 20 As shown, it can be seen that ppy-oiC8-N^N NPs can effectively perform photothermal / photodynamic therapy on breast cancer tumors. After the third day, the tumors in the treatment group "ppy-oiC8-N^N NPs+L" group completely disappeared.

[0142] It should be understood that the application of the present invention is not limited to the above examples. For those skilled in the art, improvements or changes can be made based on the above description. All these improvements and changes should fall within the scope of protection of the claims attached to the present invention.

Claims

1. A near-infrared second-region iridium complex with aggregation-induced emission properties, characterized in that: Its structural formula is shown below: ； wherein R1 is selected from one of S and Se, R4 is selected from one of H and F, When R2 is selected from H, R3 is selected from ; When R2 is selected from When R3 is selected from H.

2. A method for preparing the near-infrared second region iridium complex with aggregation-induced emission properties as claimed in claim 1, characterized in that: The preparation method comprises the following steps: Under a protective atmosphere, formula I and formula II are added to a solvent, subjected to a first stirring treatment, and then an ion exchanger is added and subjected to a second stirring treatment to obtain a near-infrared second-region iridium complex having aggregation-induced emission properties having a structural formula as shown in formula III; The above reaction scheme is as follows: 。 3. The method for preparing the near-infrared second region iridium complex with aggregation-induced emission properties according to claim 2, characterized in that: The molar ratio of Formula I to Formula II is (1.5-2.5):

1.

4. The method for preparing the near-infrared second region iridium complex with aggregation-induced emission properties according to claim 2, characterized in that: The solvent is a mixed solvent including dichloromethane and methanol.

5. The method for preparing the near-infrared second region iridium complex with aggregation-induced emission properties according to claim 2, characterized in that: The molar ratio of the ion exchanger to formula I is (1-2):

1.

6. The method for preparing the near-infrared second region iridium complex with aggregation-induced emission properties according to claim 2, characterized in that: The ion exchanger is potassium hexafluorophosphate or potassium tetrafluoroborate.

7. The method for preparing the near-infrared second region iridium complex with aggregation-induced emission properties according to claim 2, characterized in that: The first stirring treatment specifically comprises: stirring at 40-60°C for 12-18 hours in the dark; The second stirring treatment specifically includes stirring at room temperature for 4 to 6 hours.

8. The method for preparing the near-infrared second region iridium complex with aggregation-induced emission properties according to claim 2, characterized in that: After the second stirring process, the method further comprises the following steps: After the mixed solvent is evaporated, purification treatment is performed to obtain the near-infrared second-zone iridium complex with aggregation-induced emission properties.

9. Use of the near-infrared second-region iridium complex with aggregation-induced emission properties as described in claim 1 in the preparation of multimodal integrated diagnosis and treatment reagents.

10. Use according to claim 9, characterized in that The multimodal integrated diagnosis and treatment reagent is used to treat cancer.

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