Near-infrared zone II type I photosensitizer based on aza-BODIPY and its preparation method and application

Abstract

The present invention discloses a near-infrared zone II type I photosensitizer based on aza-BODIPY, and its preparation method and application. The photosensitizer is an alkoxy-substituted triphenylamine derivative group connected to the aza-BODIPY mother as a donor, and the fluorescence wavelength successfully reaches the near-infrared zone II, which can be used for visualization imaging of the tumor site. The photosensitizer of the present invention and the distearoylphosphatidylethanolamine-polyethylene glycol 2000-targeted transmembrane peptide cRGD cyclic peptide containing a tumor targeting peptide are self-assembled by nanoprecipitation to form an optical nano-diagnostic agent, which has good water solubility, excellent near-infrared zone II imaging performance, type I photodynamic and photothermal generation capabilities, can actively target breast cancer tumor sites, and effectively increase the enrichment content of nano-diagnostic agents in tumor sites. Under single-beam 808nm laser irradiation, the diagnostic agent can be used for type I photodynamic / photothermal synergistic therapy guided by near-infrared zone II imaging. Therefore, the present invention provides a new idea for the integration of near-infrared zone II diagnosis and treatment.

Description

Technical Field

[0001] The present invention belongs to the technical field of cancer therapeutic agents, and specifically relates to a near-infrared II zone I type photosensitizer based on aza-borodipyrrole (aza-BODIPY), a preparation method and an application thereof. Background Art

[0002] Cancer has become a major disease that poses a serious threat to human life and social development. Fluorescence imaging in the second near-infrared window (NIR-II, 1000–1700 nm) offers deeper penetration depths and higher resolution than near-infrared imaging (NIR-I) and other imaging modalities. Therefore, NIR-II probes are considered promising tools for preoperative cancer detection. Phototherapy is a treatment method that uses light to selectively ablate tumor cells and minimize their invasiveness. It is broadly categorized as photothermal therapy (PTT) and photodynamic therapy (PDT). The heating effect of PTT enhances the delivery of PDT agents to the intracellular environment and increases oxygen concentration in tumor tissue by improving local blood flow, thereby enhancing PDT efficacy. Furthermore, reactive oxygen species (ROS) generated by PDT block heat shock proteins, thereby disrupting the protective effects of proteins in cancer cells during PTT and making cells more sensitive to heat. Therefore, the synergistic effect of these two methods can achieve a therapeutic effect that is "1+1 greater than 2." However, most optical diagnostic and therapeutic agents tend to produce singlet oxygen through the type II energy transfer process that consumes oxygen, which makes the tumor killing effect in the hypoxic tumor microenvironment still insufficient and the anti-tumor effect is not ideal. Therefore, in order to reduce the dependence on oxygen, type I photosensitizers are a better choice for photodynamic therapy, which can utilize e - / H + transfer to produce cytotoxic free radicals (such as O2 ·- The design of type I photosensitizers is a considerable challenge because the energy transfer process in type II photosensitizers is much faster than the electron transfer process in type I photosensitizers. Therefore, most of the photosensitizers reported so far are type II. There is an urgent need to develop type I optical diagnostic and therapeutic agents with near-infrared second-zone imaging performance to effectively alleviate the problems of shallow penetration depth, oxygen dependence, and low treatment efficiency of current treatment methods, and provide new ideas for integrated cancer diagnosis and treatment research. Summary of the Invention

[0003] The purpose of the present invention is to provide a near-infrared zone II type I photosensitizer based on aza-BODIPY. After the photosensitizer is formed into nanoparticles by a nanoprecipitation method, it can be used for near-infrared zone II imaging-guided type I photodynamic / photothermal combined therapy under single 808nm laser irradiation.

[0004] The structural formula of the near-infrared zone II type I photosensitizer based on aza-BODIPY provided by the present invention is as follows:

[0005]

[0006] Where R is selected from Any one of, m is an integer of 1 to 19, R1 is selected from CH3, OCH3, Cl, Br, I, N3, NH2, Any one of, X is selected from any one of Cl, Br, I.

[0007] The preparation method of the aza-BODIPY-based near-infrared zone II type I photosensitizer comprises the following steps:

[0008] Step 1: Add the iodinated aromatic hydrocarbon represented by Formula I, p-aminoacetophenone, cuprous iodide, 1,10-phenanthroline, and potassium hydroxide to dry toluene, reflux and stir at 100-120° C. for 24-36 hours, and separate and purify to obtain compound 1.

[0009]

[0010] Step 2: Add phosphorus oxychloride dropwise to the DMF solution of the triphenylamine derivative represented by formula II, reflux and stir at 90-100°C for 3-6 hours, and separate and purify to obtain compound 2.

[0011]

[0012] Step 3: Compound 1 and compound 2 are added to ethanol, and sodium hydroxide is added, and the mixture is stirred at room temperature for 8 to 12 hours, and separated and purified to obtain compound 3.

[0013]

[0014] Step 4: Add compound 3, nitromethane, diethylamine and sodium hydroxide to ethanol, reflux and react with stirring at 90-100° C. for 12-18 hours, and separate and purify to obtain compound 4.

[0015]

[0016] Step 5: Add compound 4 and ammonium acetate to n-butanol, reflux and stir at 105-115°C for 12-18 hours, and separate and purify to obtain compound 5.

[0017]

[0018] Step 6: Add compound 5, anhydrous N,N-diisopropylethylamine and boron trifluoride etherate to ultra-dry dichloromethane, stir at room temperature under nitrogen atmosphere for 8-12 hours, and separate and purify to obtain the target product.

[0019]

[0020] In the above step 1, the molar ratio of the iodinated aromatic hydrocarbon to p-aminoacetophenone, cuprous iodide, 1,10-phenanthroline, and potassium hydroxide is preferably 2-3:1:0.15-0.3:0.2-0.3:7-8.

[0021] In the above step 2, the molar ratio of the triphenylamine derivative to phosphorus oxychloride is preferably 1:1.3-2.0.

[0022] In the above step 3, the molar ratio of compound 1 to compound 2 and sodium hydroxide is preferably 1:1-1.3:12-14.

[0023] In the above step 4, the molar ratio of the compound 3 to nitromethane, diethylamine, and sodium hydroxide is preferably 1:8-12:9-12:0.2-0.5.

[0024] In the above step 5, the molar ratio of the compound 4 to ammonium acetate is preferably 1:25-30.

[0025] In the above step 6, the molar ratio of the compound 5 to boron trifluoride etherate and anhydrous N,N-diisopropylethylamine is preferably 1:18-22:18-25.

[0026] The present invention also provides the use of aza-BODIPY-based near-infrared II Type I photosensitizer in the preparation of optical nano-diagnostic and therapeutic agents. A specific application method comprises dissolving the photosensitizer in tetrahydrofuran, adding distearoylphosphatidylethanolamine-polyethylene glycol 2000-targeted cell-penetrating peptide cRGD cyclic peptide, and mixing thoroughly. The resulting mixture is then added dropwise to deionized water under ultrasonic conditions, followed by ultrafiltration and centrifugation to obtain the optical nano-diagnostic and therapeutic agent. The mass ratio of the photosensitizer to the distearoylphosphatidylethanolamine-polyethylene glycol 2000-targeted cell-penetrating peptide cRGD cyclic peptide is 1:10-15.

[0027] The beneficial effects of the present invention are as follows:

[0028] 1. The present invention connects a triphenylamine derivative group as a donor to the aza-BODIPY matrix. On the one hand, the triphenylamine derivative group can act as both an electron donor and a molecular rotor, creating a twisted structure similar to a propeller. This structure prevents fluorescence quenching in the aggregated state by limiting intermolecular π-π stacking, and at the same time acts as an extender of the molecular conjugation length, thereby extending the fluorescence emission. On the other hand, the alkoxy group can promote triplet sensitization and accelerate the excited state ISC process. The free rotation of the benzene ring can also promote photothermal conversion, thereby achieving a balance between photodynamic and photothermal effects. Compared with existing near-infrared region II small molecule technologies, the near-infrared region II type I photosensitizer constructed by the present invention has cheap raw materials, simple synthesis, and high yield. By utilizing the structural characteristics of DAD, the strong electron-donating group triphenylamine derivative group is modified on the aza-BODIPY matrix, and the absorption and emission wavelengths are significantly red-shifted, and the fluorescence wavelength successfully reaches the near-infrared region II, which can be used for visual imaging of tumor sites.

[0029] 2. The photosensitizer of the present invention and the tumor-targeting peptide-containing distearoylphosphatidylethanolamine-polyethylene glycol 2000-targeted transmembrane peptide cRGD cyclic peptide are self-assembled by nanoprecipitation to form an optical nano-diagnostic agent, which can actively target breast cancer tumor sites. Compared with traditional EPR passive targeting, active targeting effectively increases the enrichment content of nano-diagnostic agents at the tumor site, thereby improving the therapeutic effect in vivo. Under the irradiation of a single 808nm laser, on the one hand, the cytotoxic substance superoxide anion is generated through the type I photodynamic pathway. Compared with the type II photodynamic pathway, the type I photodynamic pathway is independent of oxygen, which significantly improves the cell killing effect in the hypoxic tumor microenvironment; on the other hand, heat is generated through the photothermal process, and the two work synergistically to achieve an anti-tumor effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 This is the H NMR spectrum of the photosensitizer OTAB in Example 1.

[0031] Figure 2 is the mass spectrum of the photosensitizer OTAB in Example 1.

[0032] Figure 3 1 is the absorption and emission spectrum of the photosensitizer OTAB in Example 1.

[0033] Figure 4 This is the H NMR spectrum of the photosensitizer MTAB in Example 2.

[0034] Figure 5 It is the mass spectrum of the photosensitizer MTAB in Example 2.

[0035] Figure 6 It is the absorption and emission spectrum of the photosensitizer MTAB in Example 2.

[0036] Figure 7 This is the fluorescence spectrum of the superoxide anion probe DHR123 (containing the optical nano-diagnostic agent cRGD@OTAB NPs) under 808nm laser irradiation in Example 3 (a) and the absorption spectrum of the singlet oxygen probe ABDA (containing the optical nano-diagnostic agent cRGD@OTABNPs) under 808nm laser irradiation (b).

[0037] Figure 8 This is the fluorescence spectrum of the superoxide anion probe DHR123 (containing the optical nano-diagnostic agent cRGD@MTAB NPs) under 808nm laser irradiation in Example 3 (a) and the absorption spectrum of the singlet oxygen probe ABDA (containing the optical nano-diagnostic agent cRGD@MTABNPs) under 808nm laser irradiation (b).

[0038] Figure 9 This is a temperature curve of the optical nano-diagnostic agent cRGD@OTAB NPs under 808nm laser irradiation in Example 3.

[0039] Figure 10 This is a diagram showing the cytotoxicity experiment of the optical nano-diagnostic agent cRGD@OTAB NPs on 4T1 cells in Example 3.

[0040] Figure 11 These are fluorescence imaging images of the optical nano-diagnostic agent cRGD@OTAB NPs in Example 3 at different time points in 4T1 tumor-bearing mice.

[0041] Figure 12 This is a quantitative graph showing the tumor growth inhibitory effect of the optical nano-diagnostic agent cRGD@OTAB NPs on 4T1 tumor-bearing mice in Example 3. DETAILED DESCRIPTION

[0042] The present invention is described in detail below with reference to the accompanying drawings and embodiments, but the protection scope of the present invention is not limited to these embodiments.

[0043] Example 1

[0044] This example takes the preparation of aza-BODIPY-based near-infrared zone II type I photosensitizer OTAB as an example, and the specific synthesis route and method are as follows:

[0045]

[0046] Step 1: 4-iodoanisole (1.20 g, 5.13 mmol), p-aminoacetophenone (270 mg, 2.05 mmol), cuprous iodide (76 mg, 0.41 mmol), 1,10-phenanthroline (83 mg, 0.51 mmol), and potassium hydroxide (840 mg, 15.00 mmol) were added to dry toluene (30 mL), and the mixture was stirred under reflux at 100 ° C for 24 h. After the reaction was completed, it was cooled to room temperature, extracted with water and dichloromethane, dried, filtered, distilled under reduced pressure, and separated by silica gel column chromatography (PE / EA, v:v=5:1) to obtain compound 1-1.

[0047] Step 2: Phosphorus oxychloride (900 μL, 9.66 mmol) was added dropwise to DMF (20 mL) containing 4,4′-dimethoxytriphenylamine (2.00 g, 6.55 mmol), and the mixture was refluxed and stirred at 90°C for 3 h. After the reaction was completed, it was cooled to room temperature, extracted with water and dichloromethane, dried, filtered, distilled under reduced pressure, and separated by silica gel column chromatography (DCM / PE, v:v = 2:1) to obtain compound 2-1.

[0048] Step 3: Compound 1-1 (1.88 g, 5.25 mmol) and compound 2-1 (1.75 g, 5.25 mmol) and sodium hydroxide (2.5 g, 63.00 mmol) were added to ethanol (15 mL), stirred at room temperature for 8 h, and after completion of the reaction, cooled to room temperature, extracted with water and dichloromethane, dried, filtered, distilled under reduced pressure, and separated by silica gel column chromatography (PE / EA, v:v = 20:1) to obtain compound 3-1.

[0049] Step 4: Compound 3-1 (1.04 g, 1.58 mmol), nitromethane (840 μL, 15.80 mmol), diethylamine (1.62 mL, 15.80 mmol), and sodium hydroxide (15.8 mg, 0.40 mmol) were added to ethanol (20 mL), and the mixture was stirred under reflux at 90°C for 12 h. After the reaction was completed, the mixture was cooled to room temperature, extracted with water and ethyl acetate, dried, filtered, distilled under reduced pressure, and separated by silica gel column chromatography (PE / EA, v:v = 20:1) to obtain compound 4-1.

[0050] Step 5: Compound 4-1 (235 mg, 0.33 mmol) and ammonium acetate (752 mg, 9.75 mmol) were added to n-butanol (20 mL), stirred under reflux at 115°C for 12 h, filtered, and washed three times with cold ethanol to obtain compound 5-1.

[0051] Step 6: Compound 5-1 (110 mg, 0.08 mmol), anhydrous N,N-diisopropylethylamine (282 μL, 1.62 mmol), and boron trifluoride etherate (200 μL, 1.62 mmol) were added to ultra-dry dichloromethane (10 mL), and the mixture was stirred at room temperature under a nitrogen atmosphere for 8 h. The mixture was extracted with water and dichloromethane, dried, filtered, distilled under reduced pressure, and separated by silica gel column chromatography (DCM / PE, v:v = 5:1) to obtain the photosensitizer OTAB.

[0052] The photosensitizer OTAB was tested by nuclear magnetic hydrogen spectrum and mass spectrometry, and the test results are as follows:

[0053] like Figure 1 As shown, the H NMR spectrum data of the photosensitizer OTAB is: 1 H NMR(400MHz,Chloroform-d)δ7.94(d,J=8.9Hz,4H),7.88(d,J=8.9Hz,4H),7.13(d,J=8.9Hz,8H ), 7.08 (d, J = 8.9Hz, 8H), 6.88 (t, J = 8.9Hz, 18H), 6.82 (d, J = 9.0Hz, 8H), 3.80 (d, J = 9.6Hz, 24H).

[0054] like Figure 2 As shown, the mass spectrum data of photosensitizer OTAB is: MALDI-MS:C 88 H 74 BF2N7O8[M] + Theoretical value is 1406.4, measured value is 1405.3.

[0055] The absorption and emission spectra of photosensitizer OTAB are as follows: Figure 3 As shown, the maximum absorption peak of the photosensitizer OTAB is located at 858 nm, and the maximum emission peak is located at 1090 nm.

[0056] Example 2

[0057] This example takes the preparation of aza-BODIPY-based near-infrared II type I photosensitizer MTAB as an example, and the specific synthesis route and method are as follows:

[0058]

[0059] Step 1: 1-iodo-4-(2-methoxyethoxy)benzene (1.00 g, 3.60 mmol), p-aminoacetophenone (194 mg, 1.44 mmol), cuprous iodide (52 mg, 0.28 mmol), 1,10-phenanthroline (59 mg, 0.36 mmol), and potassium hydroxide (589 mg, 10.52 mmol) were added to dry toluene (30 mL), refluxed and stirred at 100 ° C for 24 h. After the reaction was completed, it was cooled to room temperature, extracted with water and dichloromethane, dried, filtered, distilled under reduced pressure, and separated by silica gel column chromatography (PE / EA, v:v = 2:1) to obtain compound 1-2.

[0060] Step 2: Phosphorus oxychloride (690 μL, 7.49 mmol) was added dropwise to DMF (20 mL) containing 4,4′-bis(2-methoxyethoxy)triphenylamine (2.00 g, 5.08 mmol), and the mixture was refluxed and stirred at 90°C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, extracted with water and dichloromethane, dried, filtered, distilled under reduced pressure, and separated by silica gel column chromatography (DCM / PE, v:v=1:1) to obtain compound 2-2.

[0061] Step 3: Compound 1-2 (1.50 g, 4.18 mmol) and compound 2-2 (1.76 g, 4.18 mmol) and sodium hydroxide (2 g, 50.16 mmol) were added to ethanol (15 mL), stirred at room temperature for 8 hours, and after completion of the reaction, cooled to room temperature, extracted with water and dichloromethane, dried, filtered, distilled under reduced pressure, and separated by silica gel column chromatography (PE / EA, v:v = 2:1) to obtain compound 3-2.

[0062] Step 3: Compound 3-2 (1.00 g, 1.19 mmol), nitromethane (633 μL, 11.90 mmol), diethylamine (1.22 mL, 11.90 mmol), and sodium hydroxide (11 mg, 0.30 mmol) were added to ethanol (20 mL), and the mixture was stirred at reflux at 90°C for 12 h. After the reaction was completed, the mixture was cooled to room temperature, extracted with water and ethyl acetate, dried, filtered, distilled under reduced pressure, and separated by silica gel column chromatography (PE / EA, v:v=2:1) ​​to obtain compound 4-2.

[0063] Step 5: Compound 4-2 (300 mg, 0.33 mmol) and ammonium acetate (752 mg, 9.75 mmol) were added to n-butanol (20 mL), stirred under reflux at 115°C for 12 h, filtered, and washed three times with cold ethanol to obtain compound 5-2.

[0064] Step 6: Compound 5-2 (100 mg, 0.06 mmol), anhydrous N,N-diisopropylethylamine (212 μL, 1.22 mmol), and boron trifluoride etherate (150 μL, 1.50 mmol) were added to ultra-dry dichloromethane (10 mL), and the reaction was stirred at room temperature under a nitrogen atmosphere for 8 h. The mixture was extracted with water and dichloromethane, dried, filtered, distilled under reduced pressure, and separated by silica gel column chromatography (DCM / MeOH, v:v = 20:1) to obtain the photosensitizer MTAB.

[0065] The photosensitizer MTAB was tested by nuclear magnetic hydrogen spectrum and mass spectrometry, and the test results are as follows:

[0066] like Figure 4 As shown, the H NMR spectrum data of the photosensitizer MTAB is: 1 H NMR(600MHz,Chloroform-d)δ7.97-7.83(m,6H),7.12(dd,J=16.3,7.1Hz,8H),7.05(d,J=8.5Hz,8H),6.92(s,4H),6.91-6. 87(m,12H),6.84(d,J=8.6Hz,12H),4.10(dt,J=20.1,4.8Hz,16H),3.75(dt,J=17.0,4.8Hz,16H),3.45(d,J=15.4Hz,24H).

[0067] like Figure 5 As shown, the mass spectrum data of photosensitizer MTAB is: MALDI-MS: C 104 H 106 BF2N7O 16 [M] + Theoretical value is 1758.8, measured value is 1759.6.

[0068] The absorption and emission spectra of the photosensitizer MTAB are as follows: Figure 6 As shown, the maximum absorption peak of the photosensitizer MTAB is located at 843 nm, and the maximum emission peak is located at 1002 nm.

[0069] Example 3

[0070] Application of aza-BODIPY-based near-infrared zone II type I photosensitizer in the preparation of optical nanodiagnostic and therapeutic agents

[0071] 1 mg of photosensitizer OTAB and 1 mg of photosensitizer MTAB were added to 1 mL of tetrahydrofuran, and 10 mg of distearoylphosphatidylethanolamine-polyethylene glycol 2000-targeted transmembrane peptide cRGD cyclic peptide (DSPE-PEG 2000-cRGD), mixed evenly, the resulting mixture was added dropwise to 10 mL of deionized water under ultrasonic conditions, and ultrafiltration and centrifugation (5000 rpm, 15 min each time) were performed three times to obtain optical nano-diagnostic and therapeutic agents cRGD@OTAB NPs and cRGD@MTAB NPs, respectively.

[0072] Various performance tests were performed on the cRGD@OTAB NPs and cRGD@MTAB NPs. The specific tests are as follows:

[0073] 1. Photodynamic performance test

[0074] The photodynamic properties of cRGD@OTAB NPs and cRGD@MTAB NPs were tested by using superoxide anion probe dihydrorhodamine 123 (DHR123) and singlet oxygen probe 9,10-anthracenediyl-bis(methylene)dicarboxylic acid (ABDA), respectively. 2 ) laser irradiation, and record the changes in the fluorescence spectrum and absorption spectrum of the solution.

[0075] like Figure 7 As shown in (a), the fluorescence intensity of the DHR123 solution containing cRGD@OTAB NPs is positively correlated with time; Figure 7 As shown in (b), the absorption intensity of the ABDA solution containing cRGD@OTAB NPs hardly changes, indicating that cRGD@OTAB NPs generate superoxide anions via the type I photodynamic pathway, rather than the type II photodynamic pathway.

[0076] like Figure 8 As shown in (a), the fluorescence intensity of the DHR123 solution containing cRGD@MTAB NPs is positively correlated with time; Figure 8 As shown in (b), the absorption intensity of the ABDA solution containing cRGD@MTAB NPs remained almost unchanged, indicating that cRGD@MTAB NPs produced superoxide anions via the type I photodynamic pathway, rather than the type II photodynamic pathway.

[0077] 2. Photothermal performance test

[0078] cRGD@OTAB NPs were added to deionized water to prepare cRGD@OTAB NPs solutions with concentrations of 10, 20, 30, 40, and 50 μg / mL, respectively. 2 mL of cRGD@OTAB NPs solution was placed in a cuvette and subjected to a 1.0 W / cm 2 ) laser irradiation and record the change of solution temperature over time.

[0079] like Figure 9As shown in the figure, the temperature increase of the solution is proportional to the concentration of cRGD@OTAB NPs, indicating that the cRGD@OTAB NPs solution has good photothermal properties.

[0080] 3. Extracorporeal phototherapy effect test

[0081] The MTT method was used to evaluate the cytotoxicity of cRGD@OTAB NPs on murine breast cancer 4T1 tumor cells. First, the cells were seeded in a 96-well plate at a density of 8000 per well and cultured until the cells adhered. Then, the old culture medium was replaced with 100 μL of fresh culture medium containing different concentrations of cRGD@OTAB NPs, and the culture was continued in a CO2 incubator for 24 hours. After that, 10 μL of MTT was added to each well, and the culture medium was removed after 4 hours of culture. 100 μL of DMSO was added to each well, shaken for 10 minutes, and the absorbance of each well at 570 nm was measured on a microplate reader. For the phototoxicity of cRGD@OTAB NPs, the cells were incubated with different concentrations of cRGD@OTAB NPs for 12 hours and then irradiated with an 808 nm laser (1.0 W / cm 2 ) for 5 min, and then continue to culture for 24 h, and finally measure cell viability using the standard MTT method. Figure 10 .

[0082] like Figure 10 As shown in the figure, in the absence of light, the survival rate of 4T1 cells incubated with cRGD@OTAB NPs was above 80%, indicating that cRGD@OTAB NPs have good biocompatibility. Under 808nm laser irradiation, when the concentration of cRGD@OTABNPs was 25μg / mL, the cell viability dropped to 8%, indicating that cRGD@OTAB NPs can kill tumor cells synergistically through photothermal and photodynamic therapy, with significant cancer therapeutic effects.

[0083] 4. In vivo diagnostic and therapeutic effect testing

[0084] (1) In vivo tumor imaging: A near-infrared two-zone in vivo imaging system was used to test cRGD@OTAB NPs and monitor the in vivo fluorescence signal at different times (0, 3, 6, 9, 12, 24, and 48 h). 4T1 tumor-bearing Balb / c female mice were selected for in vivo imaging monitoring. When the tumor grew to ≈100 mm 3 When cRGD@OTAB NPs were injected into the tail vein of mice, the near-infrared zone II images of the tumor were quickly captured.

[0085] like Figure 11 As shown in Figure 3, the fluorescence intensity of cRGD@OTAB NPs at the tumor site gradually increased over time and reached a peak at 12 h, which is also the optimal treatment time for subsequent phototherapy.

[0086] (2) In vivo anti-tumor test: Balb / c female mice were used as research subjects to establish a 4T1 tumor-bearing mouse model. The 4T1 tumor-bearing mice were divided into 4 groups and injected with PBS and cRGD@OTAB NPs via the tail vein. 12 hours after injection, the light-irradiated group received 808 nm laser (0.8 W / cm 2 Tumor volume changes were monitored every two days to evaluate the therapeutic outcome during the treatment period.

[0087] like Figure 12 As shown in the data, the tumors in the non-laser-irradiated PBS, cRGD@OTAB NPs group, and the laser-irradiated PBS group grew rapidly, with almost no anti-tumor effect, while the anti-tumor inhibition rate of the laser-irradiated cRGD@OTAB NPs group reached 87.87% on day 16, indicating that cRGD@OTAB NPs have excellent anti-tumor ability under light irradiation.

Claims

1. A near-infrared II type I photosensitizer based on aza-BODIPY, characterized in that: The structural formula of the photosensitizer is shown below: Where R is selected from Any one of, m is an integer from 0 to 19, R1 is selected from CH3, OCH3, Cl, Br, I, N3, NH2, Any one of, X is selected from any one of Cl, Br, I.

2. A method for preparing a near-infrared II type I photosensitizer based on aza-BODIPY according to claim 1, characterized in that: The steps include: Step 1: Add the iodinated aromatic hydrocarbon represented by Formula I, p-aminoacetophenone, cuprous iodide, 1,10-phenanthroline, and potassium hydroxide to dry toluene, reflux and stir at 100-120°C for 24-36 hours, and separate and purify to obtain compound 1; Step 2: Phosphorus oxychloride is added dropwise to a DMF solution of the triphenylamine derivative represented by Formula II, and the mixture is stirred under reflux at 90-100°C for 3-6 hours, and then separated and purified to obtain compound 2; Step 3: Compound 1 and compound 2 are added to ethanol, and sodium hydroxide is added, and the mixture is stirred at room temperature for 8 to 12 hours, and then separated and purified to obtain compound 3; Step 4: Add compound 3, nitromethane, diethylamine, and sodium hydroxide to ethanol, reflux and stir at 90-100° C. for 12-18 hours, and separate and purify to obtain compound 4; Step 5: Add compound 4 and ammonium acetate to n-butanol, reflux and stir at 105-115°C for 12-18 hours, and separate and purify to obtain compound 5; Step 6: Add compound 5, anhydrous N,N-diisopropylethylamine, and boron trifluoride etherate to ultra-dry dichloromethane, stir at room temperature under nitrogen atmosphere for 8-12 hours, and separate and purify to obtain the target product; 3. The method for preparing the near-infrared II type I photosensitizer based on aza-BODIPY according to claim 2, characterized in that: In step 1, the molar ratio of the iodinated aromatic hydrocarbon to p-aminoacetophenone, cuprous iodide, 1,10-phenanthroline, and potassium hydroxide is 2-3:1:0.15-0.3:0.2-0.3:7-8.

4. The method for preparing the near-infrared II type I photosensitizer based on aza-BODIPY according to claim 2, characterized in that: In step 2, the molar ratio of the triphenylamine derivative to phosphorus oxychloride is 1:1.3-2.

0.

5. The method for preparing a near-infrared II type I photosensitizer based on aza-BODIPY according to claim 2, characterized in that: In step 3, the molar ratio of compound 1 to compound 2 and sodium hydroxide is 1:1-1.3:12-14.

6. The method for preparing a near-infrared II type I photosensitizer based on aza-BODIPY according to claim 2, characterized in that: In step 4, the molar ratio of the compound 3 to nitromethane, diethylamine, and sodium hydroxide is 1:8-12:9-12:0.2-0.

5.

7. The method for preparing a near-infrared II type I photosensitizer based on aza-BODIPY according to claim 2, characterized in that: In step 5, the molar ratio of compound 4 to ammonium acetate is 1:25-30.

8. The method for preparing a near-infrared II type I photosensitizer based on aza-BODIPY according to claim 2, characterized in that: In step 6, the molar ratio of the compound 5 to boron trifluoride etherate and anhydrous N,N-diisopropylethylamine is 1:18-22:18-25.

9. Use of the near-infrared II type I photosensitizer based on aza-BODIPY according to claim 1 in the preparation of optical nanodiagnostic and therapeutic agents.

Images