S-type heterojunction piezoelectric nano-enzyme BTO-atFe-Cu as well as preparation method and application thereof

Abstract

The invention discloses an S-type heterojunction piezoelectric nano-enzyme BTO-Fe-Cu and a preparation method and application thereof, and belongs to the technical field of tumor treatment, and the preparation method comprises the following steps: step 1, synthesizing BTO; and step 2, synthesizing the S-type heterojunction piezoelectric nano enzyme BTO-atFe-Cu. According to the preparation method, typical piezoelectric semiconductor barium titanate is compounded with metal nano-enzyme MIL-100 (Fe), and the piezoelectric composite nano-enzyme BTO-atFe-Cu with Fe / Cu double active centers is successfully constructed through Cu doping engineering. Energy bands are adjusted through doping of metal ions, the problem that the energy bands are not matched is solved, and copper-iron death is successfully coordinated; meanwhile, the low-efficiency Type-I heterojunction piezoelectric nano-enzyme is converted into the high-efficiency Type-S heterojunction piezoelectric nano-enzyme through Cu doping, and the separation efficiency of electron-hole pairs is greatly improved, so that the ROS (reactive oxygen species) generation capability under ultrasonic stimulation is remarkably enhanced, the catalytic activity of the piezoelectric nano-enzyme is improved, and the catalytic efficiency is further improved.

Description

Technical Field

[0001] The present invention relates to the technical field of tumor treatment, and particularly to an S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu, its preparation method and application. Background Art

[0002] Cancer has become the number one killer of human health in the 21st century. Currently, the tumor treatment methods used clinically mainly include surgical treatment, chemotherapy, and radiotherapy. However, surgical treatment requires the resection of the diseased part at an early stage and cannot completely remove cancer cells. It is invasive and cancer is prone to recurrence; radiotherapy or chemotherapy uses high-energy rays or drugs to kill cancer cells while also damaging normal cells, with obvious side effects and easy to generate treatment resistance. These three treatment methods all have certain defects in clinical cancer treatment, and there is an urgent need to develop new treatment strategies to improve the treatment effect of cancer.

[0003] With the development of nanotechnology, the strategy of using nanomaterials to treat tumors has shown great application potential in clinical cancer treatment. Among them, piezoelectric catalysis therapy, as an emerging tumor treatment method, uses the charges generated by piezoelectric semiconductor materials under mechanical stress to catalyze chemical reactions, and achieves the purpose of killing tumor cells by generating high-energy reactive oxygen species. It avoids the invasiveness of surgical treatment and overcomes the inaccuracy and side effects of traditional chemotherapy or radiotherapy, so it shows good application prospects in tumor treatment. A variety of representative piezoelectric materials, such as barium titanate (BaTiO3); lithium niobate (LiNbO3); cadmium telluride (CdTe), etc., have also been applied in tumor catalytic therapy. However, common piezoelectric semiconductors have problems of low electron-hole separation efficiency and easy recombination, resulting in low efficiency of reactive oxygen species generation in tumor cells, and thus affecting the catalytic treatment efficiency.

[0004] Previous studies have reported that the combination of piezoelectric semiconductors and nanozymes can significantly improve the separation efficiency of electrons and holes by forming heterostructures, providing a new idea for improving the generation efficiency of reactive oxygen species in piezoelectric semiconductors. In addition, the enzymatic catalytic activity of nanozymes can further enhance the tumor treatment effect in cooperation with the piezocatalytic activity of piezoelectric semiconductors. For example, the metal nanozyme MIL-100(Fe) can degrade to produce ferric ions in the tumor microenvironment, trigger the Fenton reaction of iron, catalyze the production of reactive oxygen species and induce ferroptosis of cells, and combine with piezoelectric semiconductors to generate an intracellular reactive oxygen storm, significantly improving the therapeutic effect of piezocatalysis. However, both piezoelectric semiconductors and nanozyme materials have fixed valence band systems, and there is often a problem of band mismatch, which greatly limits the combined use of piezoelectric semiconductors and nanozymes. Inspired by natural enzymes with metal dual active centers, the construction of bimetallic active center nanozymes using metal ion doping engineering can achieve fine regulation of the energy bands of nanozymes and change the type of heterojunction. The doping of metal ions regulates the energy bands and changes the type of heterojunction, converting it from a type I / II heterojunction with low catalytic efficiency to an S / Z type heterojunction, thereby improving the catalytic efficiency.

[0005] Based on this, the present invention designs an S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu, its preparation method and application in tumor catalytic therapy. By doping with Cu ions, the type I / II heterojunction of the piezoelectric nanozyme is successfully transformed into an S / Z type heterojunction, greatly enhancing the tumor piezocatalytic therapy effect. And due to the presence of Fe and Cu elements, the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu also exhibits a copper-iron synergistic death effect, further enhancing the anti-tumor effect of the piezoelectric nanozyme. Summary of the Invention

[0006] Aiming at the above-mentioned shortcomings of the prior art, the present invention provides an S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu, its preparation method and application. By combining nanozymes with piezoelectric semiconductors and using doping engineering to achieve the transformation of heterostructure types, the problems of low production of reactive oxygen species and weak ferroptosis effect inside tumors are solved.

[0007] To achieve the above objectives, the present invention is realized through the following technical solutions:

[0008] A preparation method for constructing an S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu by combining nanozymes with piezoelectric semiconductors, comprising the following steps:

[0009] Step 1: Synthesize BTO, including the following steps:

[0010] Step (1): Dissolve tetrabutyl titanate and barium hydroxide monohydrate in a solvent to prepare a mixed solution;

[0011] Step (2): Stir the obtained mixed solution thoroughly, and then add aqueous ammonia solution drop by drop until the pH value of the solution reaches alkalinity;

[0012] Step (3): Subsequently, transfer the prepared mixture to an autoclave for reaction. After the reaction is completed, wash the obtained solution with acetic acid, and then wash with ethanol to remove impurities; dry the washed product overnight;

[0013] Step (4): Collect the dried powder and put it into a crucible for calcination, and then let the product cool naturally to room temperature;

[0014] Step (5): Finally, grind the calcined product into fine powder to obtain tetragonal BTO nanoparticles;

[0015] Step Two: Synthesize S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu, including the following steps:

[0016] Step a: Stir and react BTO with H2O2 to obtain BTO-OH, then wash with ultrapure water and dry in a drying oven;

[0017] Step b: Immerse BTO-OH in a solution containing ferric chloride and copper nitrate, and perform ultrasonic oscillation treatment;

[0018] Step c: Subsequently, immerse BTO-OH in a solution containing benzenetricarboxylic acid, and perform ultrasonic oscillation treatment;

[0019] Step d: Finally, wash the product with ultrapure water and dry in a drying oven to obtain S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu.

[0020] Furthermore, Step (1) is specifically: Dissolve 28 - 32 mM of tetrabutyl titanate and 43 - 47 mM of barium hydroxide monohydrate in a solvent mixture composed of 28 - 32 mL of ethanol and 18 - 22 mL of deionized water to prepare a mixed solution.

[0021] Furthermore, in Step (2), adjust the pH value of the solution to reach 10.5 - 11.5.

[0022] Furthermore, Step (3) is specifically: Subsequently, transfer the prepared mixture to a 100 mL stainless steel autoclave lined with polytetrafluoroethylene, and heat at 198 - 202 °C for 45 - 49 hours. After the reaction is completed, wash the obtained solution three times with acetic acid, and then wash with ethanol to remove impurities; dry the washed product at 75 - 85 °C overnight.

[0023] Furthermore, in Step (4), the calcination is carried out in a tube furnace, the calcination temperature is 798 - 805 °C, and it lasts for 9.5 - 10.5 hours.

[0024] Further, step two, synthesizing the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu, includes the following steps:

[0025] Step a: Stir 95 - 103 mg of BTO with 9.5 - 10.8 M H2O2 at 42 - 47 °C for 5 - 7 hours to obtain BTO-OH, then wash it with ultrapure water and dry it in an oven.

[0026] Step b: Immerse 98 - 103 mg of BTO-OH into a 9 - 11 mL solution containing 52 - 55 mg of ferric chloride and 160 - 164 mg of copper nitrate, and perform ultrasonic oscillation treatment.

[0027] Step c: Subsequently, immerse BTO-OH into a 9 - 10 mL solution containing 42 - 47 mg of benzenetricarboxylic acid, and perform ultrasonic oscillation treatment.

[0028] Step d: Finally, wash the product with ultrapure water and dry it in an oven to obtain the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu.

[0029] Further, in steps a and d, wash with ultrapure water three times.

[0030] Further, the ultrasonic oscillation treatment time is 8 - 12 minutes.

[0031] To better achieve the object of the present invention, the present invention also provides an S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu prepared according to the described preparation method.

[0032] To better achieve the object of the present invention, the present invention also provides an application of the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu in tumor treatment.

[0033] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. The present invention uses the typical piezoelectric semiconductor barium titanate and the metal nanozyme MIL-100(Fe), and through Cu doping engineering, successfully constructs the piezoelectric nanozyme BTO@Fe-Cu with Fe / Cu dual active centers. By doping metal ions to adjust the energy band, the problem of energy band mismatch is solved, and ferroptosis is successfully synergized; at the same time, Cu doping transforms the inefficient Type-I heterojunction into an efficient Type-S heterojunction, greatly improving the separation efficiency of electron-hole pairs, thus significantly enhancing the ROS (reactive oxygen species) generation ability under ultrasonic stimulation, improving the catalytic activity of the nanozyme, and further improving the catalytic efficiency.

[0034] 2. In the present invention, a heterojunction structure (BTO@Fe-Cu) is formed by BTO (barium titanate) and MIL-100(Fe, Cu). Under exogenous stimuli (ultrasound), the heterojunction structure enables the separation of electrons and holes. The holes can directly catalyze water to generate hydroxyl radicals, accelerating the ferroptosis process. Excessive hydroxyl radicals can also induce apoptosis, generating a reactive oxygen species storm in tumor cells and promoting apoptosis. After the death of tumor cells, antigens are released, promoting the maturation of DC cells, thereby stimulating T cells to play a role and enhancing immunogenic cell death. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings.

[0036] Figure 1 Schematic diagram of the principle of the preparation method of the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu of the present invention; in the figure, Hydrothermal: hydrothermal synthesis method.

[0037] Figure 2 Schematic diagram of the application of the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu of the present invention in tumor treatment.

[0038] In the figure, DLAT aggregation: DLAT aggregation; Cuproptosis: cuproptosis; GSH: glutathione; GPX4: antioxidant enzyme that can catalyze the reduction of glutathione; LPO: lipid peroxidation; Ferroptosis: ferroptosis; POD: peroxidase; Apoptosis: apoptosis; h+: holes;.OH: hydroxyl radicals; Enhanced Immunotherapy Efficacy: enhanced immunotherapy effect; Dying tumor cells: dying cancer cells; Immatured DC: immature DC cells; Matured DC: mature DC cells; T Cells: T cells (an immune cell).

[0039] Figure 3 Results of characterizing BTO, BTO-OH, BTO@Fe, and BTO@Fe-Cu prepared in Example 3 using a transmission electron microscope.

[0040] Figure 4 Results of measuring the average hydrodynamic diameter of the nanomaterials prepared in Example 3 using a dynamic light scattering instrument (DLS).

[0041] Figure 5 Results of measuring the Zeta potential of the nanomaterials obtained in each stage of Example 3 using a dynamic light scattering instrument (DLS).

[0042] Figure 6 It is a treatment plan diagram.

[0043] Figure 7 They are pictures of tumors after different treatments.

[0044] Figure 8 It is a curve graph of the change in the tumor volume of mice in different treatment groups.

[0045] Figure 9 It is a curve graph of the change in the body weight of mice in different treatment groups. Detailed implementation manners

[0046] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0047] Explanation of technical terms:

[0048] BTO: Barium titanate, which is a piezoelectric semiconductor and is widely used in the field of photocatalysis. Piezoelectric semiconductors can generate charges when subjected to mechanical pressure.

[0049] MIL-100(Fe, Cu): Iron-based nanozyme doped with copper. MIL-100(Fe), as a representative iron-based nanozyme, is often used in tumor treatment to induce ferroptosis in tumor cells. After doping with copper, another way to promote cell death, namely cuproptosis, will be introduced. The combination of the two causes stronger ferroptosis in tumor cells and further enhances apoptosis in cells.

[0050] Heterojunction: The interfacial region formed by the contact of two different semiconductors. Usually, the conditions for forming a heterojunction are that the two semiconductors have similar crystal structures, similar atomic spacings, and thermal expansion coefficients.

[0051] Example 1: In some embodiments, please refer to Figures 1 - 2 in the accompanying drawings of the specification. The preparation method of the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu constructed by combining a nanozyme and a piezoelectric semiconductor includes the following steps:

[0052] Step 1. Synthesize BTO (barium titanate), including the following steps:

[0053] Step (1): Dissolve 28 mM of tetrabutyl titanate and 43 mM of barium hydroxide monohydrate in a solvent mixture composed of 28 mL of ethanol and 18 mL of deionized water to prepare a mixed solution;

[0054] Step (2): Stir the obtained mixed solution thoroughly, and then dropwise add ammonia water until the pH value of the solution reaches 10.5;

[0055] Step (3): Subsequently, transfer the prepared mixture to a 100 mL stainless steel autoclave lined with polytetrafluoroethylene and heat it at 198 °C for 45 hours. After the reaction is completed, wash the obtained solution three times with acetic acid, and then wash it with ethanol to remove impurities; dry the washed product overnight at 75 °C;

[0056] Step (4): Collect the dried powder and put it into a crucible for calcination. The calcination is carried out in a tubular furnace at a calcination temperature of 798 °C for 9.5 hours, and then let the product cool naturally to room temperature;

[0057] Step (5): Finally, grind the calcined product into fine powder to obtain tetragonal BTO nanoparticles.

[0058] Step 2. Synthesize S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu, including the following steps:

[0059] Step a: Stir 95 mg of BTO and 9.5 M H2O2 at 42 °C for 5 hours to obtain BTO-OH, then wash it three times with ultrapure water and dry it in a drying oven;

[0060] Step b: Immerse 98 mg of BTO-OH into a 9 mL solution containing 52 mg of ferric chloride and 160 mg of copper nitrate, and ultrasonically vibrate for 8 minutes;

[0061] Step c: Subsequently, immerse BTO-OH into a 9 mL solution containing 42 mg of benzene-1,3,5-tricarboxylic acid, ultrasonically vibrate for 8 minutes, and repeat five times;

[0062] Step d: Finally, wash the product three times with ultrapure water and dry it in a drying oven to obtain S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu.

[0063] Example 2: In some embodiments, refer to Figures 1 - 2 , the preparation method of S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu constructed by combining nanozyme and piezoelectric semiconductor, including the following steps:

[0064] Step 1. Synthesize BTO (barium titanate), including the following steps:

[0065] Step (1): Dissolve 32 mM of titanium butoxide and 47 mM of barium hydroxide monohydrate in a solvent mixture consisting of 32 mL of ethanol and 22 mL of deionized water to prepare a mixed solution;

[0066] Step (2): Stir the obtained mixed solution thoroughly, and then add aqueous ammonia solution drop by drop until the pH value of the solution reaches 11.5;

[0067] Step (3): Subsequently, transfer the prepared mixture to a 100 mL stainless steel autoclave lined with polytetrafluoroethylene, and heat it at 202 °C for 49 hours. After the reaction is completed, wash the obtained solution three times with acetic acid, and then wash it with ethanol to remove impurities; dry the washed product overnight at 85 °C;

[0068] Step (4): Collect the dried powder and put it into a crucible for calcination. The calcination is carried out in a tube furnace at a calcination temperature of 805 °C for 10.5 hours, and then let the product cool naturally to room temperature;

[0069] Step (5): Finally, grind the calcined product into fine powder to obtain tetragonal BTO nanoparticles.

[0070] Step Two: Synthesize S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu, including the following steps:

[0071] Step a: Stir 103 mg of BTO with 10.8 M H2O2 at 47 °C for 7 hours to obtain BTO-OH, then wash it three times with ultrapure water and dry it in a drying oven;

[0072] Step b: Immerse 103 mg of BTO-OH in an 11 mL solution containing 55 mg of ferric chloride and 164 mg of copper nitrate, and ultrasonically vibrate for 12 minutes;

[0073] Step c: Subsequently, immerse BTO-OH in a 10 mL solution containing 47 mg of benzenetricarboxylic acid, ultrasonically vibrate for 12 minutes, and repeat five times;

[0074] Step d: Finally, wash the product three times with ultrapure water and dry it in a drying oven to obtain S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu.

[0075] Example Three: In some embodiments, please refer to the Figures 1 - 2 , preparation method of nanozyme combined with piezoelectric semiconductor to construct S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu, including the following steps:

[0076] Step One: Synthesize BTO (barium titanate), including the following steps:

[0077] Step (1): Dissolve 30 mM of tetrabutyl titanate and 45 mM of barium hydroxide monohydrate in a solvent mixture consisting of 30 mL of ethanol and 20 mL of deionized water to prepare a mixed solution;

[0078] Step (2): Stir the obtained mixed solution thoroughly, and then dropwise add an ammonia water solution until the pH value of the solution reaches 11;

[0079] Step (3): Subsequently, transfer the prepared mixture to a 100 mL stainless-steel autoclave lined with polytetrafluoroethylene, and heat it at 200 °C for 48 hours. After the reaction is completed, wash the obtained solution three times with acetic acid, and then wash it with ethanol to remove impurities; dry the washed product overnight at 80 °C;

[0080] Step (4): Collect the dried powder and put it into a crucible for calcination. The calcination is carried out in a tube furnace at a calcination temperature of 800 °C for 10 hours, and then let the product cool naturally to room temperature;

[0081] Step (5): Finally, grind the calcined product into fine powder to obtain tetragonal BTO nanoparticles.

[0082] Step 2. Synthesis of S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu, including the following steps:

[0083] Step a: Stir 100 mg of BTO with 10 M H2O2 at 45 °C for 6 hours to obtain BTO-OH, then wash it three times with ultrapure water and dry it in a drying oven;

[0084] Step b: Immerse 100 mg of BTO-OH in a 10 mL solution containing 54 mg of ferric chloride and 162 mg of copper nitrate, and ultrasonically vibrate for 10 minutes;

[0085] Step c: Subsequently, immerse BTO-OH in a 10 mL solution containing 45 mg of benzenetricarboxylic acid, ultrasonically vibrate for 10 minutes, and repeat five times;

[0086] Step d: Finally, wash the product three times with ultrapure water and dry it in a drying oven to obtain S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu.

[0087] The present invention utilizes typical piezoelectric semiconductor barium titanate and metal nanozyme MIL-100(Fe), and through Cu doping engineering, successfully constructs a piezoelectric nanozyme BTO@Fe-Cu with Fe / Cu dual active centers. By doping metal ions to adjust the energy band, the problem of energy band mismatch is solved, and ferroptosis and cuproptosis are successfully synergized; at the same time, Cu doping transforms the inefficient Type-I heterojunction into an efficient Type-S heterojunction, greatly improving the separation efficiency of electron-hole pairs, thereby significantly enhancing the ROS (reactive oxygen species) generation ability under ultrasonic stimulation, improving the catalytic activity of the nanozyme, and further improving the catalytic efficiency.

[0088] Example 4: In some embodiments, the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu prepared in Example 1 of the present invention can be used in tumor treatment. The BTO@Fe-Cu nanoparticles are injected into the body through the tail vein and enter tumor cells through blood circulation. In tumor cells, the trivalent iron ions and divalent copper ions in the Fe and Cu dual active centers will be reduced to divalent iron ions and monovalent copper ions by glutathione, the content of glutathione decreases, and the content of lipid peroxides increases. Divalent iron and monovalent copper catalyze hydrogen peroxide to generate free radicals, thereby inducing ferroptosis. Fdx1 (a reductase, the direct target of Elesclomol, as an upstream regulator of protein lipoylation modification, on the one hand, participates in regulating the lipoylation of proteins (including DLAT); on the other hand, Fdx1 reduces Cu 2+ to more toxic Cu + , resulting in the inhibition of Fe-S cluster protein synthesis and inducing cell death) will reduce divalent copper ions to monovalent copper ions and catalyze DLAT (a protein present in cells), etc., to undergo lipoylation. Monovalent copper ions will further bind to the lipoylated site of DLAT, causing DLAT to oligomerize, thereby causing cuproptosis in cells.

[0089] The present invention forms a heterojunction structure (BTO@Fe-Cu) through BTO (barium titanate) and MIL-100(Fe, Cu). Under external stimulation (ultrasound), the heterojunction structure enables the separation of electrons and holes. The holes can directly catalyze water to generate hydroxyl radicals, accelerating the ferroptosis process. Excessive hydroxyl radicals will also induce apoptosis, generating a reactive oxygen species storm in tumor cells and promoting apoptosis. After tumor cells die, antigens will be released, promoting the maturation of DC cells, thereby stimulating T cells to play a role and enhancing immunogenic cell death.

[0090] Experimental Example 1: Verification of the related properties of the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu

[0091] The BTO, BTO-OH, BTO@Fe, and BTO@Fe-Cu prepared in Example 3 were characterized using a transmission electron microscope. The results are as Figure 3 shown, indicating that the particle sizes of the nanoparticles at each stage are all around 100 nm. In the figure, A, BTO; B, BTO-OH; C, BTO@Fe; D, BTO@Fe-Cu.

[0092] The average hydrodynamic diameter of the nanomaterials prepared in Example 3 was measured using a dynamic light scattering instrument (DLS). The results are as Figure 4 shown. In the figure, A, BTO; B, BTO@Fe; C, BTO@Fe-Cu.

[0093] The Zeta potential of the nanomaterials prepared at each stage in Example 3 was measured using a dynamic light scattering instrument (DLS). The results are as Figure 5 shown, and the potential of BTO@Fe-Cu is -20.5 mV.

[0094] Experimental Example 2: Verification of the in vivo anti-tumor efficacy of nanomaterials under ultrasonic action

[0095] Method: Tumors were inoculated at the right hind leg groin of each male BALB / C mouse, and 4T1 cells were inoculated into each mouse. When the tumor reached 100 mm 3 , treatment began; the 4T1 tumor-bearing mice were divided into eight groups (n = 5 in each group). Subsequently, each group was treated according to the following protocol: (i) control group PBS, (ii) BTO, (iii) BTO@Fe, (iv) BTO@Fe-Cu, (v) ultrasound (US), (vi) US + BTO, (vii) US + BTO@Fe, (viii) US + BTO@Fe-Cu. The drug concentration was 10 mg / kg, and the ultrasonic parameters were 1.0 MHz, 1.0 W / cm 2 , 5 min, and 50% duty cycle. The nanomaterials were injected on day 0 and day 3, and ultrasonic treatment was performed 4 hours after injection. Subsequently, ultrasonic treatment was performed on day 1, day 2, day 4, and day 5 respectively. The body weight and tumor volume of the mice were recorded every two days. The results are as Figures 7 - 9 shown. Among them, Figure 6 is the treatment protocol diagram, Figure 7 is the picture of the tumor after different treatments, Figure 8 is the curve graph of the change in the tumor volume of mice in different treatment groups, Figure 9 is the curve graph of the change in the body weight of mice in different treatment groups. The results show that the growth of the tumor in the mice treated with the combination of ultrasound and the present invention was significantly inhibited, and good tumor treatment effects were achieved.

[0096] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. Preparation method of piezoelectric nanozyme BTO@Fe-Cu with S-type heterojunction constructed by nanozyme and piezoelectric semiconductor, characterized in that It includes the following steps: Step 1: Synthesize BTO. Step 2: Synthesize the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu, including the following steps: Step a: Stir and react BTO with H2O2 to obtain BTO-OH, then wash it with ultrapure water and dry it in a drying oven. Step b: Immerse BTO-OH in a solution containing ferric chloride and copper nitrate, and perform ultrasonic oscillation treatment. Step c: Subsequently, immerse BTO-OH in a solution containing benzenetricarboxylic acid, and perform ultrasonic oscillation treatment. Step d: Finally, wash the product with ultrapure water and dry it in a drying oven to obtain the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu.

2. The preparation method of the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu according to claim 1, characterized in that, Specifically, step (1) is as follows: Dissolve 28 - 32 mM of tetrabutyl titanate and 43 - 47 mM of barium hydroxide monohydrate in a solvent mixture composed of 28 - 32 mL of ethanol and 18 - 22 mL of deionized water to prepare a mixed solution.

3. The preparation method of the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu according to claim 2, characterized in that, In step (2), adjust the pH value of the solution to reach 10.5 - 11.

5.

4. The preparation method of the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu according to claim 3, characterized in that, Specifically, step (3) is as follows: Subsequently, transfer the prepared mixture to a 100 mL stainless steel autoclave lined with polytetrafluoroethylene, and heat it at 198 - 202 °C for 45 - 49 hours. After the reaction is completed, wash the obtained solution three times with acetic acid, and then wash it with ethanol to remove impurities; dry the washed product at 75 - 85 °C overnight.

5. The preparation method of the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu according to claim 4, wherein, In step (4), the calcination is carried out in a tube furnace, and the calcination temperature is 798 - 805 °C for 9.5 - 10.5 hours.

6. The preparation method of the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu according to claim 5, characterized in that, Step 2: Synthesize the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu, including the following steps: Step a: Stir 95 - 103 mg of BTO with 9.5 - 10.8 M H2O2 at 42 - 47 °C for 5 - 7 hours to obtain BTO-OH, then wash it with ultrapure water and dry it in a drying oven. Step b: Immerse 98 - 103 mg of BTO-OH in a 9 - 11 mL solution containing 52 - 55 mg of ferric chloride and 160 - 164 mg of copper nitrate, and perform ultrasonic oscillation treatment. Step c: Subsequently, immerse BTO-OH in a 9 - 10 mL solution containing 42 - 47 mg of benzenetricarboxylic acid, and perform ultrasonic oscillation treatment. Step d: Finally, wash the product with ultrapure water and dry it in a drying oven to obtain the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu.

7. The preparation method of the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu according to claim 6, characterized in that, In steps a and d, wash it three times with ultrapure water.

8. The preparation method of the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu according to claim 7, characterized in that, The time for ultrasonic oscillation treatment is 8 - 12 minutes.

9. An S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu prepared by the preparation method according to any one of claims 1 - 8.

10. An application of the S-type heterojunction piezoelectric nanozyme BTO@Fe-Cu according to claim 9 in tumor treatment.

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