A near-infrared II fluorescent conjugated organic small molecule, its preparation method and application

Abstract

This invention proposes a near-infrared II fluorescent conjugated organic small molecule, its preparation method, and its application, belonging to the field of bioimaging and therapy. The conjugated organic small molecule has a D-A-D structure, with the general formula R1 being a C4-C24 branched or straight chain. After being encapsulated into nanoparticles with an amphiphilic polymer, it can guide in vivo tumor type IPDT and PTT combined therapy under the synergistic diagnosis of PA and NIR-II fluorescence dual-modal imaging.

Description

Technical Field

[0001] This invention belongs to the field of bioimaging and therapeutic technology, and particularly relates to a near-infrared II fluorescent conjugated organic small molecule, its preparation method and application. Background Technology

[0002] Cancer remains one of the most deadly diseases threatening human life. Effective treatment of cancer has always been a major challenge worldwide. Phototherapy is a minimally invasive and effective method that provides a convenient way to ablate tumors using light irradiation. In recent years, image-guided phototherapy has attracted widespread attention in tumor treatment because it can provide basic information such as tumor size and location, optimal treatment time window, and real-time assessment of treatment response, showing great potential in guiding light irradiation, monitoring the treatment process, and optimizing treatment effects. Due to the hypoxia caused by abnormal vascularization in tumor tissue and the high oxygen consumption resulting from rapid tumor cell proliferation, the tumor environment has long been considered to inhibit tumor treatment and lead to tumor proliferation and spread. Phototherapy (PDT), as a form of phototherapy, utilizes a type II pathway with energy transfer processes to generate singlet oxygen (PSO). 1 O2 consumption is a significant factor, and tumor hypoxia severely impacts the antitumor efficacy of type II photosensitizers. Fortunately, photosensitizers generate highly cytotoxic free radicals (hydroxyl radicals, superoxide ions, hydrogen peroxide, etc.) via the type I pathway, while exhibiting significantly reduced O2 dependence, making them ideal for tolerating tumor hypoxia. However, research on type I photosensitizers with high fluorescence intensity in the long-wavelength region remains a substantial challenge. Furthermore, PTT (phototherapy-induced tumor ablation), as a light-controlled and effective cancer treatment, uses photosensitizers to generate localized heat for cancer ablation, largely unaffected by tumor hypoxia, making it another option for addressing tumor hypoxia. Numerous studies have shown that combination therapy techniques, compared to single-treatment methods, possess synergistic or additive effects, effectively reducing toxic side effects, addressing the complex mechanisms and changes of tumors, and enhancing treatment efficacy.

[0003] NIR-II fluorescence imaging offers advantages such as good tissue penetration, spatial resolution, and signal-to-noise ratio. Furthermore, PA imaging, as an emerging non-radioactive and non-invasive detection technique in the biomedical field, is rapidly becoming a hot topic in molecular imaging research due to its ability to provide 3D images that accurately depict the size, shape, location, and boundaries of lesions. Dual-modal imaging combining near-infrared II (NIR-II) fluorescence and PA imaging leverages the strengths of each modality while compensating for the inherent limitations of each, thereby improving imaging accuracy and bringing great hope for effective tumor diagnosis.

[0004] For the complexities of cancer, no single imaging technique can provide accurate and comprehensive pathological information, while combined treatment with multiple therapies can more effectively inhibit tumor growth. Therefore, developing a nanomaterial that combines multimodal imaging techniques with multiple treatment methods could enable more precise diagnosis of cancer pathology and more effective treatment.

[0005] With the development of nanotechnology, the nanomaterials currently being developed for multimodal imaging and therapy are mainly inorganic composite nanomaterials. Their drawbacks lie in two aspects: the poor biocompatibility of inorganic nanoparticles and the instability of the multi-element composition of composite nanomaterials. Therefore, developing single-molecule organic nanoparticles for multimodal imaging and therapy is particularly important. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention proposes a near-infrared II (NIR-II, 1000–1700 nm) fluorescent conjugated organic small molecule, its preparation method, and its applications. The near-infrared II fluorescent conjugated organic small molecule provided by this invention, encapsulated in amphiphilic polymers, exhibits multimodal imaging modes, which can compensate for the shortcomings of existing nanomaterials in the combined treatment of hypoxic tumors. These nanoparticles possess high biocompatibility, photostability, and water solubility, while also exhibiting excellent PA imaging and NIR-II fluorescence imaging capabilities. Furthermore, they can produce combined therapeutic effects with Type IPDT and PTT.

[0007] To achieve the above objectives, the present invention provides the following technical solution:

[0008] One of the technical solutions of the present invention:

[0009] An intermediate for preparing near-infrared II fluorescent conjugated organic small molecules has the following general structural formula:

[0010]

[0011] R1 is either a branch or a straight chain of C4 to C24.

[0012] Furthermore, the structural formula of the intermediate for preparing the near-infrared II fluorescent conjugated organic small molecule is as follows:

[0013]

[0014] The second technical solution of the present invention:

[0015] A near-infrared II fluorescent conjugated organic small molecule prepared from the above intermediate has a donor-acceptor-donor (DAD) type structure, and its general structural formula is as follows:

[0016]

[0017] R1 is either a branch or a straight chain of C4 to C24.

[0018] Furthermore, the structural formula of the near-infrared II fluorescent conjugated organic small molecule is as follows:

[0019]

[0020] The third technical solution of the present invention:

[0021] A method for preparing the near-infrared II fluorescent conjugated organic small molecule includes the following steps:

[0022] A. Pyridine-4-boronic acid, tetra(triphenylphosphine)palladium, tri(4-bromophenyl)amine, 1,4-dioxane and potassium carbonate aqueous solution were mixed, heated to 100°C under nitrogen protection, refluxed and reacted for 20 h. After the reaction was completed, the mixture was cooled to room temperature and the reaction mixture was extracted with dichloromethane. The resulting organic layer was dried by rotary evaporation to obtain an orange-yellow mixture. The orange-yellow mixture was purified by column chromatography to obtain the target yellow solid compound.

[0023] B. Mix the target yellow solid compound obtained in the previous step with hexa-n-butyltin, then add toluene and tetra(triphenylphosphine)palladium, under nitrogen protection, heat to 110°C, react for 20 h, cool the product to room temperature, and purify by column chromatography to obtain the target solid compound;

[0024] C. The target solid compound obtained in the previous step was mixed with the thiadiazoquinoxaline derivative, toluene and tetra(triphenylphosphine)palladium were added, and the mixture was heated to 110°C under nitrogen protection for 48 h. After cooling the product to room temperature, it was purified by column chromatography to obtain the target solid compound BTT. The general structural formula of the target solid compound BTT is as follows:

[0025]

[0026] Where R1 is a branch or straight chain of C4 to C24;

[0027] D. The target solid compound BTT obtained in the previous step, dichloromethane, and methyl trifluoromethanesulfonate were mixed and stirred at room temperature for 24 hours. After the reaction was completed, diethyl ether was added to the solution, and the mixture was filtered to obtain the target solid compound BTT+, with the following general structural formula:

[0028]

[0029] R1 is either a branch or a straight chain of C4 to C24.

[0030] Furthermore, in the preparation method of the near-infrared II fluorescent conjugated organic small molecule:

[0031] The molar ratio of tris(4-bromophenyl)amine, pyridine-4-boronic acid and tetra(triphenylphosphine)palladium is 1:2:0.02;

[0032] The molar ratio of the target yellow solid compound, hexa-n-butyltin, and tetra(triphenylphosphine)palladium obtained in step A is 1:1.5:0.017.

[0033] The molar ratio of the target solid compound, the thiadiazoquinoxaline derivative, and tetra(triphenylphosphine)palladium obtained in step B is 4:1:0.1.

[0034] The molar ratio of the target solid compound BTT to methyl trifluoromethanesulfonate is 1:4000.

[0035] Furthermore, the preparation method of the near-infrared II fluorescent conjugated organic small molecule is as follows:

[0036] A. In a 500 mL two-necked round-bottom flask equipped with a magnetic inlet, pyridine-4-boronic acid (2.5 g, 20.6 mmol), tetra(triphenylphosphine)palladium (239 mg, 0.20 mmol), tri(4-bromophenyl)amine (5.0 g, 10.3 mmol), 1,4-dioxane (100 mL), and 0.5 M potassium carbonate aqueous solution (50 mL) were added and mixed. Under nitrogen protection, the mixture was heated to 100 °C, refluxed, and reacted for 20 h. After the reaction was completed, the mixture was cooled to room temperature, and the reaction mixture was extracted with dichloromethane. The resulting organic layer was dried by rotary evaporation to obtain an orange-yellow mixture. The mixture was purified by column chromatography (silica gel, dichloromethane:ethyl acetate = 1:1, volume ratio) to obtain the target yellow solid compound (1.4 g, 2.9 mmol).

[0037] B. Add 1.4 g (2.9 mmol) of the compound obtained in the previous step and hexa-n-butylditin (2.52 g, 4.35 mmol) to a 200 mL polymerization tube equipped with a magnetic ball, then add 5 mL of toluene and tetra(triphenylphosphine)palladium (55.7 mg, 0.048 mmol), under nitrogen protection, heat to 110 °C, react for 20 h, cool the product to room temperature, and purify by column chromatography (silica gel, ethyl acetate as eluent) to obtain the target solid compound (530 mg, 0.77 mmol);

[0038] C. The compound obtained in the previous step (200 mg, 0.29 mmol) and thiadiazoquinoxaline (62.65 mg, 0.073 mmol) were added to a 200 mL polymerization tube equipped with a magnetic stir bar. Toluene (4 mL) and tetrakis(triphenylphosphine)palladium (8.41 mg, 0.0073 mmol) were added. Under nitrogen protection, the mixture was heated to 110 °C and reacted for 48 h. After cooling to room temperature, the product was purified by column chromatography (silica gel, DCM:MeOH = 100:1, volume ratio) to obtain the target solid compound BTT (30 mg, 0.02 mmol), with the structural formula [insert structural formula here].

[0039]

[0040] D. In a 25 mL round-bottom flask equipped with a magnetic stir bar, add the compound obtained in the previous step (20 mg, 0.013 mmol), 4 mL of dichloromethane solution, and methyl trifluoromethanesulfonate (8.5 g, 0.052 mol). Stir at room temperature for 24 h. After the reaction is complete, add diethyl ether to the solution and filter to obtain the target solid compound BTT+ (15 mg, 0.0096 mmol), with the following structural formula:

[0041]

[0042] The fourth technical solution of the present invention:

[0043] A near-infrared II fluorescent conjugated organic small molecule type I photosensitizer, the raw materials of which include the near-infrared II fluorescent conjugated organic small molecule and an amphiphilic polymer, wherein the near-infrared II fluorescent conjugated organic small molecule is encapsulated with the amphiphilic polymer.

[0044] Furthermore, the amphiphilic polymer includes Pluronic F127, DSPE-PEG (molecular weight: 500, 1000, 2000, 5000 or 10000) or PS-PEG (molecular weight: 500, 1000, 2000, 5000 or 10000), preferably DSPE-PEG5000. Encapsulating these amphiphilic polymers into near-infrared II fluorescent conjugated organic small molecules into nanoparticles can give them high biocompatibility, photostability, and water solubility, while also exhibiting excellent PA imaging and NIR-II fluorescence imaging capabilities, enabling them to produce synergistic therapeutic effects with Type IPDT and PTT.

[0045] The fifth technical solution of the present invention:

[0046] A method for preparing the near-infrared II fluorescent conjugated organic small molecule type I photosensitizer involves dissolving a solid compound BTT+ in acetonitrile to obtain an acetonitrile solution; dissolving an amphiphilic polymer in PBS to obtain a PBS solution; mixing the acetonitrile solution and the PBS solution under ultrasonication; removing the acetonitrile with nitrogen gas; and centrifuging to obtain the near-infrared II fluorescent conjugated organic small molecule type I photosensitizer.

[0047] The sixth technical solution of the present invention:

[0048] The application of the near-infrared II fluorescent conjugated organic small molecule or the near-infrared II fluorescent conjugated organic small molecule type I photosensitizer in the preparation of photodynamic drugs for treating hypoxic tumor cells.

[0049] The seventh technical solution of the present invention:

[0050] The application of the near-infrared II fluorescent conjugated organic small molecule or the near-infrared II fluorescent conjugated organic small molecule type I photosensitizer in combination with Type IPDT and PTT in the preparation of photodynamic drugs for treating hypoxic tumor cells.

[0051] Furthermore, the excitation source for the Type IPDT and PTT is 808 nm, and the laser power is 0.5–1 W cm⁻¹. -2 .

[0052] Compared with the prior art, the present invention has the following advantages and technical effects:

[0053] This invention designs and synthesizes a donor-acceptor-donor (DAD) structure organic fluorophore (BTT+ and unmethylated BTT+, the unmethylated BTT+ being named BTT) using a triphenylamine unit as an electron donor and a thiadiazoquinoxaline derivative as an electron acceptor. Due to its strong intramolecular charge transfer, BTT+ exhibits near-infrared absorption, NIR-II fluorescence emission, and excellent photostability. BTT+ is synthesized in four steps, and its structure is further confirmed by electrospray ionization mass spectrometry (ESI-MS). To impart water solubility to the photosensitizer, the synthesized BTT+ is non-covalently encapsulated with an amphiphilic polymer to obtain multifunctional nanoparticles BTT+NPs (i.e., photosensitizers). These multifunctional nanoparticles exhibit good photostability, significant type I photodynamic (IPDT) and photothermal (PTT) effects, and excellent photoacoustic (PA) and NIR-II fluorescence signals. In summary, this invention successfully provides a near-infrared II fluorescent conjugated organic small molecule whose nanoparticles encapsulated by an amphiphilic polymer can serve as photosensitizers, possessing multimodal imaging modes. It can guide combined in vivo tumor type IPDT and PTT treatment under the synergistic diagnosis of PA and NIR-II fluorescence dual-modal imaging. Attached Figure Description

[0054] The accompanying drawings, which form part of this application, are used to provide a further understanding of this application. The illustrative embodiments and descriptions of this application are used to explain this application and do not constitute an undue limitation of this application. In the drawings:

[0055] Figure 1 Synthetic route for the near-infrared II fluorescent conjugated organic small molecule BTT+;

[0056] Figure 2 The ESI mass spectrum of the near-infrared II fluorescent conjugated organic small molecule BTT+ is shown.

[0057] Figure 3 The UV-vis-NIR absorption spectrum and NIR-II fluorescence emission spectrum of the multifunctional nanoparticles BTT+NPs are shown.

[0058] Figure 4 To enhance the photostability of multifunctional nanoparticles BTT+NPs;

[0059] Figure 5 The in vitro PDT effect diagram of multifunctional nanoparticles BTT+NPs;

[0060] Figure 6 Image showing the in vitro Type IPDT effect of multifunctional nanoparticles BTT+NPs;

[0061] Figure 7 The in vitro PTT effect diagram of multifunctional nanoparticles BTT+NPs;

[0062] Figure 8 This is an in vitro NIR-II fluorescence imaging image of multifunctional nanoparticles BTT+NPs;

[0063] Figure 9 PA imaging of live mice injected with BTT+NPs multifunctional nanoparticles via tail vein.

[0064] Figure 10 NIR-II fluorescence imaging of live mice injected with BTT+NPs via tail vein;

[0065] Figure 11 Photothermal imaging and photothermal therapy images of live mice injected with BTT+NPs nanoparticles via tail vein.

[0066] Figure 12 Changes in tumor size after different treatments in four groups of 4T1 tumor-bearing mice;

[0067] Figure 13 This is a schematic diagram of dual-mode imaging-guided combined Type IPDT and PTT therapy using multifunctional nanoparticles BTT+NPs. Detailed Implementation

[0068] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0069] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0070] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0071] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0072] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0073] Unless otherwise specified, the room temperature in the embodiments of the present invention is 25±2℃.

[0074] In this embodiment of the invention, PBS refers to phosphate buffer with pH = 7.4.

[0075] The technical solution of the present invention will be further illustrated by the following embodiments.

[0076] Example 1

[0077] The synthetic route for the near-infrared II fluorescent conjugated organic small molecule BTT+ is shown below. Figure 1 ,in:

[0078] The preparation steps of compound 3 are as follows:

[0079] In a 500 mL two-necked round-bottom flask equipped with a magnetic stir bar, pyridine-4-boronic acid (2.5 g, 20.6 mmol), tetra(triphenylphosphine)palladium (239 mg, 0.20 mmol), tri(4-bromophenyl)amine (5.0 g, 10.3 mmol), 1,4-dioxane (100 mL), and 0.5 M potassium carbonate aqueous solution (50 mL) were added and mixed thoroughly. Under nitrogen protection, the mixture was heated to 100 °C, refluxed, and reacted for 20 h. After the reaction was completed, the mixture was cooled to room temperature, and the reaction mixture was extracted with dichloromethane. The resulting organic layer was dried by rotary evaporation to obtain an orange-yellow mixture. The mixture was purified by column chromatography (silica gel, dichloromethane:ethyl acetate = 1:1, volume ratio) to obtain the target yellow solid compound 3 (1.4 g, 2.9 mmol).

[0080] The preparation steps of compound 5 are as follows:

[0081] 1.4 g (2.9 mmol) of the target yellow solid compound 3 obtained in the previous step and 2.52 g (4.35 mmol) of hexa-n-butylditin were added to a 200 mL polymerization tube equipped with a magnetic ball. Then, 5 mL of toluene and tetra(triphenylphosphine)palladium (55.7 mg, 0.048 mmol) were added. Under nitrogen protection, the mixture was heated to 110 °C and reacted for 20 h. After cooling the product to room temperature, it was purified by column chromatography (silica gel and ethyl acetate as eluent) to obtain the target yellow compound 5 (530 mg, 0.77 mmol).

[0082] The preparation steps of compound 7 are as follows:

[0083] The target yellow compound 5 (200 mg, 0.29 mmol) and the thiadiazoquinoxaline derivative (62.65 mg, 0.073 mmol) obtained in the previous step were added to a 200 mL polymerization tube equipped with a magnetic ball. Toluene (4 mL) and tetrakis(triphenylphosphine)palladium (8.41 mg, 0.0073 mmol) were added. Under nitrogen protection, the mixture was heated to 110 °C and reacted for 48 h. After the product was cooled to room temperature, it was purified by column chromatography (silica gel, DCM:MeOH = 100:1, volume ratio) to obtain the target green solid compound 7 (BTT, 30 mg, 0.02 mmol).

[0084] The preparation steps of compound 8 are as follows:

[0085] In a 25 mL round-bottom flask equipped with a magnetic stir bar, the target green solid compound 7 (20 mg, 0.013 mmol) obtained in the previous step, along with 4 mL of dichloromethane and methyl trifluoromethanesulfonate (8.5 g, 0.052 mol), was added. The mixture was stirred at room temperature for 24 h. After the reaction was completed, diethyl ether was added to the solution, and the mixture was filtered to obtain the target brownish solid compound 8 (BTT+, 15 mg, 0.0096 mmol).

[0086] The mass spectrometry characterization results of the obtained product BTT+ are as follows: Figure 2 As shown.

[0087] Preparation of multifunctional nanoparticles BTT+NPs:

[0088] 1 mg of compound 8 (BTT+) was dissolved in 1 mL of acetonitrile to obtain an acetonitrile solution; 10 mg of DSPE-PEG 5000 was dissolved in 10 mL of PBS to obtain a PBS solution; the above acetonitrile solution and PBS solution were mixed under ultrasonication at 260 W for 5 min, and after removing the acetonitrile with nitrogen, the mixture was centrifuged (3000 rpm) for 20 min using a 50 kDa centrifugal filter to finally obtain multifunctional nanoparticles BTT+NPs (these multifunctional nanoparticles BTT+NPs are near-infrared II fluorescent conjugated organic small molecule type I photosensitizers).

[0089] The UV-vis-NIR absorption spectrum and NIR-II fluorescence emission spectrum of the multifunctional nanoparticles BTT+NPs are shown below. Figure 3 As shown. The multifunctional nanoparticles BTT+NPs were compared with indocyanine green (ICG) under an 808 nm laser (0.5 W cm⁻¹). -2 Under irradiation, from Figure 4 It can be seen that BTT+NPs have excellent photostability.

[0090] Application Example 1

[0091] In vitro PDT and PTT effects and NIR-II fluorescence imaging effects of multifunctional nanoparticles BTT+NPs:

[0092] PDT effect: such as Figure 5 and Figure 6 As shown, Figure 5 DCFH was used as an indicator for detecting reactive oxygen species (ROS) generation, using an 808nm laser (0.5W cm⁻¹). -2 ROS generation of BTT+NPs under irradiation. Figure 6 As an indicator of hydroxyl radical generation, APF was used in an 808 nm laser (0.5 W cm⁻¹). -2The generation of hydroxyl radicals in BTT+NPs under irradiation. This indicates that BTT+NPs have a significant Type IPDT effect.

[0093] PTT effect: such as Figure 7 As shown, in an 808nm laser (0.5W cm⁻¹), -2 The nanoparticles exhibited a good PTT effect, and the resulting temperature increase was sufficient to kill cancer cells, laying a good foundation for subsequent in vivo PTT therapy.

[0094] NIR-II fluorescence imaging: Images were acquired using an NIR-II fluorescence imaging system of aqueous solutions containing BTT+NPs nanoparticles at different concentrations (0 μM, 6.25 μM, 12.5 μM, 25 μM, and 50 μM). Figure 8 The results showed that the nanoparticles possess excellent NIR-II fluorescence imaging capabilities and exhibit a significant positive correlation with concentration.

[0095] Application Example 2

[0096] In vivo PA imaging and NIR-II fluorescence imaging of multifunctional nanoparticles BTT+NPs:

[0097] PA imaging: BTT+NPs were injected via the tail vein, and PA imaging images of the tumor site in mice were collected before injection and at 1h, 8h, 12h, 24h, and 48h after injection. Figure 9 Due to the enhanced penetration and retention (EPR) effect of tumors, the PA signal intensity at the tumor site in mice gradually increased, reaching its maximum value at 24 hours. This further demonstrates that the multifunctional nanoparticles BTT+NPs of this invention have excellent PA imaging performance in live mice.

[0098] NIR-II fluorescence imaging: From Figure 10 It can also be seen that the nanoparticles have excellent NIR-II fluorescence imaging effect, and consistent with the PA imaging experiment in live mice, the tumor site in mice reached the maximum NIR-II fluorescence imaging signal intensity at 24h.

[0099] Application Example 3

[0100] Type IPDT and PTT combined treatment: 4T1 tumor-bearing mice were randomly divided into three groups and treated as follows: (1) PBS (150 μL), (2) PBS (150 μL) & laser irradiation (808 nm, 0.5 W cm⁻¹). -2 (3) BTT+NPs (100μM, 150μL), (4) BTT+NPs (100μM, 150μL) & laser irradiation (808nm, 0.5W cm⁻¹) -2), where (2) and (4) were injected 24 hours later, and then subjected to laser irradiation. Figure 11 It was observed that the temperature of the tumor sites in mice injected with PBS showed little change, while the temperature of the tumor sites in mice injected with polymer nanoparticles increased sharply, reaching a maximum temperature of 55.4℃ after 10 minutes of laser irradiation. Further monitoring of mouse tumors was conducted later. Figure 12 It was found that mice injected with the multifunctional nanoparticles of this invention showed significant tumor inhibition after photothermal therapy, while the tumors in the other three groups of mice did not show significant inhibition. A schematic diagram of dual-mode imaging guided Type IPDT and PTT combined therapy using multifunctional nanoparticles BTT+NPs is shown below. Figure 13 .

[0101] The above are merely preferred embodiments of this application, but the scope of protection of this application is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in this application should be included within the scope of protection of this application. Therefore, the scope of protection of this application should be determined by the scope of the claims.

Claims

1. A near-infrared II fluorescent conjugated organic small molecule, characterized in that, It is a donor-recipient-donor type structure, with the structural formula as follows: .

2. A method for preparing the near-infrared II fluorescent conjugated organic small molecule as described in claim 1, characterized in that, Includes the following steps: A. Pyridine-4-boronic acid, tetra(triphenylphosphine)palladium, tri(4-bromophenyl)amine, 1,4-dioxane, and potassium carbonate aqueous solution were mixed, heated to 100°C under nitrogen protection, and refluxed for 20 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with dichloromethane. The resulting organic layer was dried by rotary evaporation to obtain an orange-yellow mixture. The orange-yellow mixture was purified by column chromatography to obtain the target yellow solid compound, whose structural formula is [insert structural formula here]. ; B. The target yellow solid compound obtained in the previous step was mixed with hexa-n-butylditin, and then toluene and tetra(triphenylphosphine)palladium were added. Under nitrogen protection, the mixture was heated to 110°C and reacted for 20 hours. After cooling the product to room temperature, the target solid compound was purified by column chromatography. Its structural formula is as follows: ; C. The target solid compound obtained in the previous step was mixed with the thiadiazoquinoxaline derivative, toluene and tetra(triphenylphosphine)palladium were added, and the mixture was heated to 110°C under nitrogen protection for 48 h. After cooling the product to room temperature, it was purified by column chromatography to obtain the target solid compound BTT. The structural formula of the target solid compound BTT is as follows: ； D. The target solid compound BTT obtained in the previous step, dichloromethane, and methyl trifluoromethanesulfonate were mixed and stirred at room temperature for 24 hours. After the reaction was completed, diethyl ether was added to the solution, and the mixture was filtered to obtain the target solid compound BTT+, with the following structural formula: 。 3. The method for preparing near-infrared II fluorescent conjugated organic small molecules according to claim 2, characterized in that, The molar ratio of tris(4-bromophenyl)amine, pyridine-4-boronic acid and tetra(triphenylphosphine)palladium is 1:2:0.02; The molar ratio of the target yellow solid compound, hexa-n-butyltin, and tetra(triphenylphosphine)palladium obtained in step A is 1:1.5:0.

017. The molar ratio of the target solid compound, the thiadiazoquinoxaline derivative, and tetra(triphenylphosphine)palladium obtained in step B is 4:1:0.

1. The molar ratio of the target solid compound BTT to methyl trifluoromethanesulfonate is 1:4000.

4. A near-infrared II fluorescent conjugated organic small molecule type I photosensitizer, characterized in that, The raw materials include the near-infrared II fluorescent conjugated organic small molecule and the amphiphilic polymer as described in claim 1, wherein the near-infrared II fluorescent conjugated organic small molecule is encapsulated with the amphiphilic polymer. The amphiphilic polymer is DSPE-PEG.

5. A method for preparing the near-infrared II fluorescent conjugated organic small molecule type I photosensitizer according to claim 4, characterized in that, Solid compound BTT+ was dissolved in acetonitrile to obtain an acetonitrile solution; an amphiphilic polymer was dissolved in PBS to obtain a PBS solution; the acetonitrile solution and the PBS solution were mixed under ultrasonication, the acetonitrile was removed with nitrogen, and then centrifuged to obtain a near-infrared II fluorescent conjugated organic small molecule type I photosensitizer. The structural formula of BTT+ is as follows: 。 6. The use of the near-infrared II fluorescent conjugated organic small molecule of claim 1 or the near-infrared II fluorescent conjugated organic small molecule type I photosensitizer of claim 4 in the preparation of photodynamic drugs for treating hypoxic tumor cells.

7. The use of the near-infrared II fluorescent conjugated organic small molecule of claim 1 or the near-infrared II fluorescent conjugated organic small molecule type I photosensitizer of claim 4 in combination with Type I PDT and PTT in the preparation of photodynamic drugs for treating hypoxic tumor cells.

Images