A porphyrin-based metal organic framework sonosensitizer and its preparation method and application

Abstract

The present invention relates to a kind of porphyrin-based metal organic framework sonosensitizer and its preparation method and application, the preparation method includes:With porphyrin ligand, metal source, auxiliary agent and organic solvent as preparation raw material, carried out coordination reaction by hydrothermal method and obtained;The porphyrin ligand is tetra-(carboxylphenyl) porphine, the metal source is ytterbium ion salt or its hydrate, and the auxiliary agent is benzoic acid and polyvinylpyrrolidone. The present invention successfully prepares Yb-TCPP sonosensitizer using solvent thermal method, and I / II type ROS can be produced simultaneously under ultrasound;And Au / Yb-TCPP nanosonosensitizer is obtained by in situ growth Au nanoparticles, it has shorter band gap and abundant oxygen vacancy defects, promotes electron-hole separation and suppresses its recombination under ultrasound, can enhance the generation of I / II type ROS, while Au / Yb-TCPP has catalase-like activity, can react with hydrogen peroxide to realize self-oxygenation, alleviate the impact brought by hypoxic tumor microenvironment, and then enhance SDT efficiency.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine and relates to a porphyrin-based metal organic framework sonosensitizer and a preparation method and application thereof. Background Art

[0002] Cancer, with its difficult treatment and cure, high metastasis rate, and high mortality rate, has become one of the leading causes of death that endangers human health. However, existing treatments such as radiotherapy, chemotherapy, and surgical resection have significant adverse reactions such as systemic toxicity and tissue damage. In recent years, with the development of nanotechnology and nanomedicine, some new non-invasive treatments have gradually emerged and been vigorously developed. Sonodynamic therapy (SDT) is a therapeutic strategy that kills cancer cells by repeatedly irradiating the tumor site with low-intensity, short-term ultrasound. It has the advantages of high tissue penetration depth and low adverse reactions and is effectively used in the treatment of deep tumors. However, the unique hypoxic microenvironment and low ROS quantum yield of tumors limit the clinical application of sonodynamic therapy. Therefore, it is of great significance to develop new nanosonosensitizers with high ROS quantum yield and overcoming the hypoxic microenvironment to improve the efficacy of sonodynamic therapy.

[0003] Porphyrin has excellent biomedical properties such as excellent photophysical / chemical properties, effective scavenging ability, low toxicity and long Stokes shift. As a type II sonosensitizer, it is used in tumor photodynamic and sonodynamic therapy. Metal-organic framework materials using porphyrin as an organic ligand can achieve high sonosensitizer loading and stable diffusion of ROS through adjustable size and structure, effectively avoiding the self-explosion effect between sonosensitizer molecules, and are widely used in sonodynamic therapy. In addition, with the help of the lower energy gap of metal clusters and the electron transfer between organic ligands → metal ions, porphyrin-based metal-organic framework materials can produce hydroxyl radicals (·OH) and superoxide anions (O2 ·- However, overcoming the tumor hypoxic microenvironment and improving the ROS quantum yield remain key issues that need to be addressed in sonodynamic therapy. Summary of the Invention

[0004] In view of the deficiencies in the prior art, the object of the present invention is to provide a porphyrin-based metal-organic framework sonosensitizer and its preparation method and application, specifically to provide a porphyrin-based metal-organic framework sonosensitizer and its preparation method, a type I / II active oxygen dual-synergistic self-generated oxygen porphyrin-based metal-organic framework sonosensitizer and its preparation method, as well as the application of the above products.

[0005] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0006] In a first aspect, the present invention provides a method for preparing a porphyrin-based metal-organic framework sonosensitizer, the preparation method comprising: using a porphyrin ligand, a metal source, an auxiliary agent and an organic solvent as preparation raw materials, and carrying out a coordination reaction by a hydrothermal method to obtain the sonosensitizer; the porphyrin ligand is meso-tetrakis(carboxyphenyl)porphine, the metal source is an ytterbium ion salt or its hydrate, and the auxiliary agent is benzoic acid and polyvinylpyrrolidone.

[0007] The present invention first utilizes the electron transfer effect between organic ligands and metal ions, uses meso-tetra(carboxyphenyl)porphine, ytterbium ion salt or its hydrate, benzoic acid, polyvinylpyrrolidone and organic solvent as preparation raw materials, and successfully prepares a porphyrin-based metal organic framework sonosensitizer by solvothermal method. The preparation method is simple and can simultaneously generate type I / II ROS (including singlet oxygen ( 1 O2), hydroxyl radicals (·OH) and superoxide anions (O2 ·- )), which has excellent anti-tumor effect when used in tumor sonodynamic therapy.

[0008] Preferably, the organic solvent includes N,N-dimethylformamide, dimethyl sulfoxide and anhydrous ethanol.

[0009] Preferably, the mass fraction of the anhydrous ethanol in the reaction system is 66-70%, for example, 66%, 67%, 68%, 69%, 70%, etc.

[0010] Preferably, the coordination reaction is carried out at 80-100°C (e.g., 80°C, 85°C, 88°C, 90°C, 92°C, 95°C, 100°C, etc.) for 2-8h (e.g., 2h, 3h, 4h, 5h, 6h, 7h, 8h, etc.).

[0011] Preferably, the molar ratio of the metal source to the porphyrin ligand is (2-4):(1-3), for example, 2:1, 1:1, 2:3, 3:1, 3:2, 4:1, 4:3, etc.

[0012] Further preferably, the preparation method comprises:

[0013] A dimethyl sulfoxide solution of the porphyrin ligand, an N,N-dimethylformamide solution of the metal source, an N,N-dimethylformamide solution of polyvinyl pyrrolidone, and an anhydrous ethanol solution of benzoic acid are mixed, and a coordination reaction is carried out at 80-100°C (for example, 80°C, 85°C, 88°C, 90°C, 92°C, 95°C, 100°C, etc.) for 2-8h (for example, 2h, 3h, 4h, 5h, 6h, 7h, 8h, etc.) to obtain the porphyrin-based metal organic framework sonosensitizer.

[0014] In a second aspect, the present invention provides a porphyrin-based metal organic framework sonosensitizer prepared according to the preparation method described in the first aspect, which is recorded as Yb-TCPP. The porphyrin-based metal organic framework sonosensitizer has a sheet structure and has the ability to simultaneously generate type I ROS and type II ROS.

[0015] The size of the porphyrin-based metal organic framework sonosensitizer is approximately between 130-170 nm.

[0016] In a third aspect, the present invention provides a method for preparing a type I / II active oxygen dual-synergistic self-generated oxygen-porphyrin-based metal-organic framework sonosensitizer, the preparation method comprising:

[0017] The porphyrin-based metal organic framework sonosensitizer described in the second aspect and a gold source are mixed in an aqueous solution, and the mixture is reduced with a reducing agent to obtain the product.

[0018] Furthermore, the present invention addresses the problems of low ROS quantum yield during sonodynamic therapy and the impact of the tumor hypoxic microenvironment on the efficacy of sonodynamic therapy (SDT). A new type of sonosensitizer is constructed by in situ growing gold nanoparticles inside Yb-TCPP. The sonosensitizer has a short band gap and abundant oxygen vacancy defects. It promotes electron-hole separation and inhibits their recombination under ultrasound, can simultaneously enhance the quantum yield of type I / II ROS, and also has catalase-like activity. It can react with hydrogen peroxide to achieve self-oxygen production, alleviate the impact of the hypoxic tumor microenvironment, and thereby enhance the efficiency of SDT.

[0019] Preferably, the gold source is chloroauric acid or its hydrate.

[0020] Preferably, the gold source is chloroauric acid hexahydrate.

[0021] Preferably, the molar ratio of the porphyrin-based metal organic framework sonosensitizer to the gold source is (1-5):(1-10), for example, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 2:5, 1:2, 2:3, 1:1, 3:2, 2:1, 3:1, 4:1, 5:1, etc.

[0022] Preferably, the mixing is carried out under stirring conditions for 18-30 hours, for example, 18 hours, 20 hours, 22 hours, 24 hours, 25 hours, 26 hours, 28 hours, 30 hours, etc.

[0023] Preferably, the mixture is washed with ultrapure water before the reduction.

[0024] Preferably, the reducing agent is sodium borohydride.

[0025] Preferably, the reduction is carried out under stirring conditions.

[0026] Preferably, the reduction time is 5-30 min, for example, 5 min, 7 min, 8 min, 10 min, 15 min, 20 min, 22 min, 25 min, 30 min, etc.

[0027] In the fourth aspect, the present invention provides a type I / II reactive oxygen dual-synergistic self-generated porphyrin-based metal-organic framework sonosensitizer prepared according to the preparation method described in the third aspect, which is recorded as Au / Yb-TCPP. The type I / II reactive oxygen dual-synergistic self-generated porphyrin-based metal-organic framework sonosensitizer has hydrogen peroxide nanozyme activity and the performance of improving the yield of type I / II reactive oxygen.

[0028] The size of the type I / II active oxygen dual-synergistic self-generated oxygen-porphyrin-based metal organic framework sonosensitizer is approximately between 80 and 120 nm.

[0029] In a fifth aspect, the present invention provides the use of the porphyrin-based metal organic framework sonosensitizer described in the second aspect or the type I / II active oxygen dual-synergistic self-generated oxygen porphyrin-based metal organic framework sonosensitizer described in the fourth aspect in the preparation of anti-tumor drugs or anti-tumor materials.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] The present invention successfully prepared Yb-TCPP sonosensitizer using a solvothermal method, which can simultaneously generate type I / II ROS (including singlet oxygen, superoxide anions, and hydroxyl radicals) under ultrasound; and obtained Au / Yb-TCPP nanosonosensitizer by in situ growth of Au nanoparticles, which has a short band gap and abundant oxygen vacancy defects, promotes electron-hole separation and inhibits their recombination under ultrasound, while enhancing the production of type I / II ROS. Au / Yb-TCPP also has catalase-like activity, which can react with hydrogen peroxide to achieve self-oxygenation, alleviate the effects of hypoxic tumor microenvironment, and thus enhance SDT efficiency. The sonosensitizer involved in the present invention is simple to prepare, can simultaneously and efficiently generate multiple ROS, and has the ability to improve the hypoxic tumor microenvironment, and is expected to be applied in the field of biomedicine. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 TEM image of the Yb-TCPP sonosensitizer prepared in Example 1;

[0033] Figure 2 is a TEM image of the Au / Yb-TCPP sonosensitizer prepared in Example 2;

[0034] Figure 3 1 is an EDS element spectrum characterization diagram of the Au / Yb-TCPP sonosensitizer prepared in Example 2;

[0035] Figure 41 is the X-ray diffraction pattern of the Yb-TCPP sonosensitizer prepared in Example 1 and the Au / Yb-TCPP sonosensitizer prepared in Example 2;

[0036] Figure 5 1 is an X-ray photoelectron spectrum of the Yb-TCPP sonosensitizer prepared in Example 1 and the Au / Yb-TCPP sonosensitizer prepared in Example 2;

[0037] Figure 6 is the Au 4f orbital X-ray photoelectron spectrum of the Au / Yb-TCPP sonosensitizer prepared in Example 2;

[0038] Figure 7 Graphs showing the generation levels of singlet oxygen type II ROS during sonication of the Yb-TCPP sonosensitizer prepared in Example 1 and the Au / Yb-TCPP sonosensitizer prepared in Example 2, wherein a, b, and c are the singlet oxygen generation levels and total ratios of Yb-TCPP and Au / Yb-TCPP over sonication time, respectively;

[0039] Figure 8 1 is a graph showing the level of generation of type I ROS superoxide anions during sonication of the Yb-TCPP sonosensitizer prepared in Example 1 and the Au / Yb-TCPP sonosensitizer prepared in Example 2, wherein a, b, and c are the level and total ratio of superoxide anions generated by Yb-TCPP and Au / Yb-TCPP over sonication time, respectively;

[0040] Figure 9 1 is a graph showing the generation level of type I ROS hydroxyl radicals during the sonication of the Yb-TCPP sonosensitizer prepared in Example 1 and the Au / Yb-TCPP sonosensitizer prepared in Example 2, wherein a, b, and c are the generation level and total ratio of hydroxyl radicals of Yb-TCPP and Au / Yb-TCPP over sonication time, respectively;

[0041] Figure 10 1 is a graph showing the bandgap semiconductor width of the Yb-TCPP sonosensitizer prepared in Example 1 and the Au / Yb-TCPP sonosensitizer prepared in Example 2;

[0042] Figure 11 1 is a photoluminescence spectrum of the Yb-TCPP sonosensitizer prepared in Example 1 and the Au / Yb-TCPP sonosensitizer prepared in Example 2;

[0043] Figure 12 1 is the electron paramagnetic resonance spectrum of the Yb-TCPP sonosensitizer prepared in Example 1 and the Au / Yb-TCPP sonosensitizer prepared in Example 2;

[0044] Figure 131S orbital X-ray photoelectron spectra of the Yb-TCPP sonosensitizer prepared in Example 1 and the Au / Yb-TCPP sonosensitizer prepared in Example 2;

[0045] Figure 14 Graph showing the evaluation results of the hypoxia mitigation ability of the Yb-TCPP sonosensitizer prepared in Example 1 and the Au / Yb-TCPP sonosensitizer prepared in Example 2, wherein a represents the quenching of the hypoxia probe by binding to oxygen molecules, b represents the specific fluorescence intensity, and F1, F2, and F3 represent the PBS group, the Yb-TCPP group, and the Au / Yb-TCPP group, respectively;

[0046] Figure 15 1 is a graph showing the evaluation results of the oxygen production levels of the Yb-TCPP sonosensitizer prepared in Example 1 and the Au / Yb-TCPP sonosensitizer prepared in Example 2;

[0047] Figure 16 14-day treatment of tumor-bearing mice with the Yb-TCPP sonosensitizer prepared in Example 1 and the Au / Yb-TCPP sonosensitizer prepared in Example 2;

[0048] Figure 17 14 days after treatment with the Yb-TCPP sonosensitizer prepared in Example 1 and the Au / Yb-TCPP sonosensitizer prepared in Example 2, the tumor mass results of mice in different groups were shown. DETAILED DESCRIPTION

[0049] The technical solution of the present invention is further described below by way of specific embodiments. It should be understood by those skilled in the art that the embodiments are merely to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0050] Example 1

[0051] This embodiment provides a porphyrin-based metal organic framework sonosensitizer (denoted as Yb-TCPP), and its preparation method is as follows:

[0052] A certain amount of meso-tetrakis(4-carboxyphenyl)porphine was weighed and added to dimethyl sulfoxide, and stirred evenly to prepare a precursor solution with a concentration of 10 mM. A certain amount of ytterbium chloride hexahydrate and polyvinylpyrrolidone (10k) were respectively added to N,N-dimethylformamide and stirred evenly to a concentration of 10 mM and 0.4 M, respectively. Benzoic acid was fully dissolved in anhydrous ethanol solution at a concentration of 10 mM.

[0053] Subsequently, 2 mL of ytterbium chloride hexahydrate solution, 2 mL of polyvinylpyrrolidone solution, 1 mL of meso-tetrakis(4-carboxyphenyl)porphine solution, 0.5 mL of benzoic acid solution, and 10 mL of anhydrous ethanol were added to a 20 mL scintillation vial. The solution was thoroughly mixed and heated in a 90°C oven for 2 hours. After the reaction was complete, the temperature was cooled to 25°C and the product was washed with N,N-dimethylformamide and ethanol to obtain a porphyrin-based metal-organic framework sonosensitizer.

[0054] Example 2

[0055] This embodiment provides a type I / II active oxygen dual-synergistic self-generated oxygen porphyrin-based metal organic framework sonosensitizer (denoted as Au / Yb-TCPP), the preparation method of which is as follows:

[0056] Before the reaction, all glassware and rotors were soaked in aqua regia overnight and washed. Take 10mL of 0.2mM Yb-TCPP solution (solvent is water), add 500 microliters of 10mM chloroauric acid solution, and stir vigorously for 24 hours in the dark. Then centrifuge and wash once with ultrapure water to remove excess gold ions, add 250 microliters of 0.1M sodium borohydride solution, and stir vigorously for 5 minutes. After the reaction is completed, centrifuge and wash twice, and disperse in ultrapure water.

[0057] Example 3

[0058] Morphological and structural characterization of sonosensitizers:

[0059] (1) The morphologies of the sonosensitizers prepared in Example 1 and Example 2 were characterized using a transmission electron microscope (TEM). Figure 1 and Figure 2 As shown, Figure 1 The Yb-TCPP sonosensitizer exhibits a square flake-like morphology, approximately 150 nm in size, while the Au / Yb-TCPP exhibits an elliptical morphology, slightly smaller in size. Both sonosensitizers exhibit uniform size and good dispersion. Gold nanoparticles, approximately 2-5 nm in size, can be observed on the surface and within the Au / Yb-TCPP. Furthermore, Au / Yb-TCPP exhibits etching marks, which is due to the large amount of heat released during the sodium borohydride reduction process, which causes some coordination bonds to break.

[0060] (2) The sonosensitizer prepared in Example 2 was subjected to EDS element spectrum analysis. Figure 3 As shown, it shows that the elements C, N, O, Yb and Au in Au / Yb-TCPP are evenly distributed.

[0061] (3) The crystal structures of the sonosensitizers prepared in Example 1 and Example 2 were analyzed by powder X-ray diffraction (XRD). Figure 4As shown, the (111) peak located at 35-40 degrees and the (200) peak near 45 degrees indicate that zero-valent Au is loaded on Yb-TCPP.

[0062] (4) The sonosensitizers prepared in Example 1 and Example 2 were analyzed using X-ray photoelectron spectroscopy (XPS). Figure 5 As shown in Figure 1, the four peaks observed at 183.5, 285.4, 399, and 532 eV belong to Yb 4d, C 1s, N 1s, and O 1s, respectively. The local magnified image of the X-ray photoelectron spectroscopy (XPS) is shown in Figure 1. Figure 6 As shown in Figure 3, after loading Au, the XPS pattern of Au / Yb-TCPP showed a peak belonging to Au 4f at 84.8 eV, proving the successful loading of Au.

[0063] Example 4

[0064] Characterization of the sonodynamic properties of sonosensitizers:

[0065] In order to verify the sonodynamic performance of the sonosensitizers prepared in Example 1 and Example 2, different fluorescent probes were used to detect the generation level of type I / II ROS during the sonodynamic process. Singlet oxygen detection reagent (SOSG), dihydrorhodamine 123 (DHR123) and terephthalic acid (TA) were used to detect singlet oxygen. 1 O2, superoxide anion O2 ·- and hydroxyl radical·OH three types of ROS.

[0066] Type II ROS singlet oxygen 1 The test results of O2 are as follows Figure 7 As shown, type I ROS superoxide anion O2 ·- The test results are as follows Figure 8 As shown in the figure, the test results of type I ROS hydroxyl radical OH are as follows Figure 9 The results show that Yb-TCPP can simultaneously produce type I / II ROS under ultrasound irradiation, and produce a higher level of ROS for sonodynamic therapy. After 4 minutes of ultrasound, the three ROS production rates of the Au / Yb-TCPP group increased by 1.49 ( 1 O2), 1.68(·OH) and 1.8(O2 ·- This indicates that after Au modification, Au / Yb-TCPP simultaneously enhances the production of type I / II ROS and sonodynamic therapeutic properties.

[0067] To explore the potential reasons for the improvement in ROS efficiency, Yb-TCPP and Au / Yb-TCPP were tested using UV-visible diffuse reflectance (UV-vis DRS) spectra. The Kubelka-Munk (KM) law was used to infer the absorption of the two sonosensitizers from the reflectance spectra, and finally the Tauc plot formula was used to calculate the band gap (Eg) of Yb-TCPP and Au / Yb-TCPP. Figure 10 As shown in Figure 2, the band gaps of Yb-TCPP and Au / Yb-TCPP are 1.72 eV and 1.66 eV, respectively, obtained through reverse deduction. The band gap of Yb-TCPP MOF decreases after loading Au, indicating that Au / Yb-TCPP has better electron-hole separation ability. Under external excitation, the electrons and holes of Au / Yb-TCPP are more easily separated.

[0068] However, in actual situations, electrons and holes can recombine rapidly in a short time, so photoluminescence spectroscopy was used to characterize the recombination ability of electrons and holes in Yb-TCPP and Au / Yb-TCPP. Figure 11 As shown in Figure 3, the photoluminescence spectrum absorption intensity of Au / Yb-TCPP decreased by 42.2% compared with Yb-TCPP, which indicates that after loading Au, Au / Yb-TCPP can effectively suppress electron-hole recombination.

[0069] Because sodium borohydride releases a large amount of heat energy instantaneously during the Au loading process and etches the surface of Yb-TCPP, the morphology and size of Yb-TCPP change. This process leads to the appearance of oxygen vacancies OVs defects in Yb-TCPP, thereby generating oxygen vacancies in the lattice. Therefore, the existence of OVs defects in Yb-TCPP was further confirmed by electron paramagnetic resonance spectroscopy (EPR). Figure 12 As shown in the EPR curves, both Yb-TCPP and Au / Yb-TCPP have single electron peaks, and the single electron peak intensity of Au / Yb-TCPP is higher. This indicates that more vacant oxygen appears in the Au / Yb-TCPP lattice.

[0070] like Figure 13 As shown in Figure 2, XPS analysis of the ratio of vacancy oxygen to lattice oxygen in the O1S characteristic peak of the two sonosensitizers shows that the O2 / O1 ratios of Yb-TCPP and Au / Yb-TCPP are 0.98 and 3.75, respectively. This result is consistent with the EPR curve results, further demonstrating that a large number of oxygen vacancy defects are generated during the formation of Au / Yb-TCPP, thereby improving the sonodynamic performance.

[0071] Example 5

[0072] Self-oxygenation capacity of sonosensitizers:

[0073] The hypoxic nature of tumors inhibits 1 O2 production rate and sonodynamic therapy effect. Catalase-like enzymes can react with hydrogen peroxide (H2O2) in the tumor microenvironment and produce oxygen.

[0074] The hypoxia mitigation ability of the sonosensitizers prepared in Examples 1 and 2 was tested using tris(4,7-diphenyl-1,10-phenanthroline)ruthenium(II) dichloride [Ru(dpp)3]Cl2 as a hypoxia probe incubated at 37°C for 15 minutes at a concentration of 0.1 mM hydrogen peroxide. The fluorescence intensity of the probe decreased accordingly after binding with molecular oxygen. Figure 14 As shown in the figure, after the addition of H2O2, the control group PBS (F1) and the Yb-TCPP group (F2) showed strong red fluorescence due to the inability to produce molecular oxygen. However, the fluorescence intensity of the Au / Yb-TCPP group (F3) decreased from 1.1 to 0.7, demonstrating its strong hypoxia relief ability.

[0075] Then, a dissolved oxygen meter was used to detect the oxygen production rate of each group of samples. Figure 15 As shown in the figure, the oxygen production levels of PBS, Yb-TCPP, and Au / Yb-TCPP were tested. Due to its relatively stable structure, Au / Yb-TCPP can continuously generate oxygen (8.93 mg / L) within 15 minutes. This sustained oxygen production ability can not only largely alleviate the hypoxia state in the tumor site, but also effectively promote continuous acoustic cavitation during sonodynamic therapy, thereby further enhancing the ROS quantum yield.

[0076] Example 6

[0077] Sonodynamic therapy evaluation of sonosensitizers:

[0078] (1) BALB / c female mice (4-6 weeks old) were divided into three groups, with 4 mice in each group: control group, Yb-TCPP group, and Au / Yb-TCPP group.

[0079] (2) Construction of tumor-bearing mouse model:

[0080] Take 3×10 6 4T1 cells were subcutaneously injected into the upper right thigh of mice to form tumors and establish a tumor-bearing mouse model.

[0081] (3) Intervention methods:

[0082] The 7th day after the injection of 4T1 cells was designated as day 0 of treatment, and the following interventions were initiated: mice in the control group were injected with 200 μL of PBS solution on day 0 and day 2 of treatment, and were irradiated with ultrasound for 10 minutes 48 hours after the injection; mice in the Yb-TCPP group were injected with 200 μL of Yb-TCPP solution on day 0 and day 2 of treatment, and were irradiated with ultrasound for 10 minutes 48 hours after the injection (the amount of Yb-TCPP was 2 mg / kg, and the solvent was PBS); mice in the Au / Yb-TCPP group were injected with 200 μL of Au / Yb-TCPP solution on day 0 and day 2 of treatment, and were irradiated with ultrasound for 10 minutes 48 hours after the injection (the amount of Au / Yb-TCPP was 2 mg / kg, and the solvent was PBS). The ultrasound parameters used in the experiment were: 50% duty cycle, 40 kHz, 3 W / cm 2 The tumor progression of mice was monitored by measuring tumor volume and weight, and the intervention start date was designated as day 0.

[0083] Experimental results: The changes in tumor volume of each group of tumor-bearing mice are as follows: Figure 16 The changes of tumor weight in each group of tumor-bearing mice are shown in Figure 17 The tumors in the control group grew rapidly. After ultrasound treatment, the tumors in the Yb-TCPP and Au / Yb-TCPP groups were significantly inhibited, with the Au / Yb-TCPP group showing a superior effect (p < 0.001). This indicates that the material's kinetic efficacy was significantly enhanced by addressing the hypoxia problem and increasing ROS generation capacity.

[0084] The applicant declares that the present invention is illustrated by the above-described embodiments, but the present invention is not limited to the above-described embodiments. This does not mean that the present invention must rely on the above-described embodiments in order to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent replacements for raw materials in the present invention, additions of auxiliary ingredients, and selection of specific methods, etc., fall within the scope of protection and disclosure of the present invention.

[0085] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.

[0086] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A method for preparing a porphyrin-based metal organic framework sonosensitizer, characterized in that: The preparation method comprises: using a porphyrin ligand, a metal source, an auxiliary agent and an organic solvent as preparation raw materials, and carrying out a coordination reaction by a hydrothermal method to obtain the porphyrin; the porphyrin ligand is meso-tetrakis(carboxyphenyl)porphine, the metal source is an ytterbium ion salt or a hydrate thereof, and the auxiliary agent is benzoic acid and polyvinylpyrrolidone; and the molar ratio of the metal source to the porphyrin ligand is (2-4):(1-3).

2. The method for preparing a porphyrin-based metal organic framework sonosensitizer according to claim 1, wherein: The organic solvent includes N,N-dimethylformamide, dimethyl sulfoxide and anhydrous ethanol; The mass fraction of the anhydrous ethanol in the reaction system is 66-70%.

3. The method for preparing a porphyrin-based metal organic framework sonosensitizer according to claim 1 or 2, wherein: The coordination reaction is carried out at 80-100° C. for 2-8 h.

4. The method for preparing a porphyrin-based metal organic framework sonosensitizer according to claim 1, wherein: The preparation method comprises: A dimethyl sulfoxide solution of the porphyrin ligand, an N,N-dimethylformamide solution of a metal source, an N,N-dimethylformamide solution of polyvinyl pyrrolidone, and an anhydrous ethanol solution of benzoic acid are mixed, and a coordination reaction is carried out at 80-100° C. for 2-8 h to obtain the porphyrin-based metal organic framework sonosensitizer.

5. The porphyrin-based metal organic framework sonosensitizer prepared by the preparation method according to any one of claims 1 to 4, characterized in that: The porphyrin-based metal organic framework sonosensitizer has a sheet structure and has the ability to simultaneously generate type I ROS and type II ROS.

6. A method for preparing a type I / II active oxygen dual-synergistic self-generated oxygen-porphyrin-based metal-organic framework sonosensitizer, characterized in that: The preparation method comprises: The porphyrin-based metal organic framework sonosensitizer according to claim 5 and a gold source are mixed in an aqueous solution, and the mixture is reduced by a reducing agent to obtain the product.

7. The preparation method according to claim 6, characterized in that The gold source is chloroauric acid or its hydrate; The molar ratio of the porphyrin-based metal organic framework sonosensitizer to the gold source is (1-5):(1-10); The mixing is carried out under stirring for 18-30 hours; The mixture was washed with ultrapure water before the reduction.

8. The preparation method according to claim 6 or 7, characterized in that The reducing agent is sodium borohydride; The reduction is carried out under stirring conditions; The reduction time is 5-30 min.

9. Use of the porphyrin-based metal organic framework sonosensitizer according to claim 5 or the type I / II active oxygen dual-synergistic self-generated porphyrin-based metal organic framework sonosensitizer prepared by the preparation method according to any one of claims 6 to 8 in the preparation of anti-tumor drugs or anti-tumor materials.

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