Biodegradable Manganese-Based Sonosensitizer, Its Preparation Method and Application

Abstract

The present invention discloses a biodegradable manganese-based sonosensitizer, a preparation method thereof and an application. The preparation method includes: performing a first reaction on a first mixed reaction system containing a first precursor, oleic acid, oleylamine and a high-boiling organic solvent; in a protective atmosphere, performing a second reaction on the mixture obtained after the first reaction ends with a second precursor and modifying polyethylene glycol to obtain a biodegradable manganese-based sonosensitizer with a perovskite structure. Compared with the existing commercial inorganic sonosensitizer titanium dioxide, the manganese-based sonosensitizer prepared by the present invention has a better sonosensitization effect; moreover, due to the characteristics of its perovskite structure itself, it can be biodegradable, avoiding toxicity caused by long-term residue in the body, and is a new type of highly efficient and low-toxic sonosensitizer.

Description

Technical Field

[0001] The present invention relates to a sonosensitizer, and particularly to a biodegradable manganese-based sonosensitizer, its preparation method and application, belonging to the technical field of functional inorganic nanomaterials. Background Art

[0002] Sonodynamic therapy (SDT) is a new type of tumor treatment method that focuses ultrasound on tumor or bacterial lesion sites to activate sonosensitizers or sonosensitizing drugs to generate reactive oxygen species (ROS) to kill tumors or bacteria. Compared with phototherapy, sonodynamic therapy has deeper tissue penetration, is non-invasive and effective for various types of tumors and bacterial lesions, and has gradually become a research hotspot in recent years.

[0003] Sonosensitizers are mainly divided into organic and inorganic types. Organic sonosensitizers represented by porphyrins and their derivatives usually have good biocompatibility and potential clinical application value. However, the poor water solubility, poor stability, phototoxicity and short blood circulation time of such sonosensitizers make it impossible to achieve good therapeutic effects. Inorganic sonosensitizers represented by titanium dioxide have received the favor of researchers due to their lower phototoxicity and better chemical stability. However, inorganic sonosensitizers are usually difficult to degrade after playing their therapeutic role in the body and are likely to cause long-term toxicity in the body. Therefore, it is particularly important to develop biodegradable inorganic sonosensitizers. Summary of the Invention

[0004] The main object of the present invention is to provide a biodegradable manganese-based sonosensitizer, its preparation method and application to overcome the deficiencies in the prior art.

[0005] To achieve the foregoing invention object, the technical solutions adopted by the present invention include:

[0006] An embodiment of the present invention provides a preparation method of a biodegradable manganese-based sonosensitizer, which includes:

[0007] Performing a first reaction on a first mixed reaction system containing a first precursor, oleic acid, oleylamine and a high-boiling organic solvent;

[0008] Performing a second reaction on the mixture obtained after the first reaction and a second precursor in a protective atmosphere to obtain a biodegradable manganese-based sonosensitizer.

[0009] An embodiment of the present invention also provides a biodegradable manganese-based sonosensitizer prepared by the foregoing preparation method, which has a perovskite structure and can degrade in the presence of moisture.

[0010] Furthermore, an embodiment of the present invention also provides the application of the foregoing biodegradable manganese-based sonosensitizer in the fields of preparing antibacterial products or drugs for sonodynamic therapy of tumors, etc.

[0011] Compared with the prior art, the advantages of the present invention include:

[0012] 1) The manganese-based sonosensitizer constructed in the present invention, due to the characteristics of its perovskite-type structure, will degrade after exerting the sonodynamic therapy effect in vivo and finally be excreted from the body through feces, avoiding the toxicity caused by long-term presence in the body;

[0013] 2) The perovskite-type manganese-based sonosensitizer constructed in the present invention has a narrow bandgap, and electron-hole pairs are easily separated under the excitation of ultrasound; at the same time, the abundant oxygen vacancies can act as electron traps to prevent the recombination of electrons and holes. Therefore, it has good sonosensitization effect, and its sonodynamic effect is not affected by degradation within a certain period of time. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] 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 recorded in the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0015] Figure 1 It is a schematic diagram of the biodegradable manganese-based sonosensitizer and its application in a typical embodiment of the present invention;

[0016] Figure 2 It is a transmission electron microscope image of the unmodified biodegradable manganese-based sonosensitizer prepared in Example 1 of the present invention;

[0017] Figure 3 It is a particle size diagram of the unmodified biodegradable manganese-based sonosensitizer prepared in Example 1 of the present invention;

[0018] Figure 4 It is a transmission electron microscope image of the biodegradable manganese-based sonosensitizer modified with polyethylene glycol prepared in Example 1 of the present invention;

[0019] Figure 5 It is an X-ray diffraction pattern of the biodegradable manganese-based sonosensitizer prepared in Example 1 of the present invention;

[0020] Figure 6 It is a rate diagram of the biodegradable manganese-based sonosensitizer prepared in Example 1 of the present invention oxidizing the DPBF probe under ultrasound, and a comparison diagram with pure water and commercial titanium dioxide;

[0021] Figure 7 It is a transmission electron microscope image of the biodegradable manganese-based sonosensitizer prepared in Example 1 of the present invention at different times under the conditions of the presence and absence of moisture;

[0022] Figure 8 This is a graph showing the change in the tumor volume of mice during sonodynamic therapy using the prepared biodegradable manganese-based sonosensitizer in Example 1 of the present invention;

[0023] Figure 9 This is a result graph of the amounts of the biodegradable manganese-based sonosensitizer excreted by mice through feces and urine respectively in Example 1 of the present invention. Detailed implementation manners

[0024] In order to solve the above existing problems, through long-term research and a large number of practices, the inventors of this case were able to propose the technical solution of the present invention. It mainly provides a preparation method of a biodegradable manganese-based sonosensitizer. This sonosensitizer has a perovskite-type structure. Due to its structural characteristics, this sonosensitizer can degrade in the presence of moisture and will not affect the sonodynamic therapy effect within a certain period of time. The following will further explain the technical solution, its implementation process, principle, etc.

[0025] A biodegradable manganese-based sonosensitizer provided in one aspect of the embodiments of the present invention has a perovskite-type structure, and the surface modification with polyethylene glycol makes it have good water solubility.

[0026] Further, the biodegradable manganese-based sonosensitizer is prepared by a first precursor (manganese precursor) and a second precursor (vanadium precursor). The two form nanoparticles through high-temperature thermal decomposition in an organic phase, and polyethylene glycol is surface-modified by the ligand exchange method.

[0027] The manganese-based sonosensitizer provided by the present invention has a better sonosensitization effect; and due to the characteristics of its perovskite-type structure itself, it can be biodegradable, avoiding the toxicity caused by long-term residue in the body, and it is a new type of highly efficient and low-toxic sonosensitizer.

[0028] A preparation method of a biodegradable manganese-based sonosensitizer provided in another aspect of the embodiments of the present invention includes:

[0029] Carrying out a first reaction on a first mixed reaction system containing a first precursor, oleic acid, oleylamine, and a high-boiling organic solvent;

[0030] In a protective atmosphere, carrying out a second reaction on the mixture obtained after the first reaction ends with a second precursor to obtain a biodegradable manganese-based sonosensitizer.

[0031] In some embodiments, the first precursor is a manganese precursor, mainly including oleates, and preferably may include manganese oleate, but is not limited thereto.

[0032] In some embodiments, the high-boiling organic solvent includes any one of dibenzyl ether, 1-octadecene, etc., but is not limited thereto.

[0033] In some embodiments, the volume ratio of the high-boiling organic solvent, oleic acid and oleylamine is 18-20:0.5-1:0.5:1.

[0034] In some embodiments, the preparation method specifically includes: heating a first mixed reaction system containing a first precursor, oleic acid, oleylamine and a high-boiling organic solvent to above 100°C, preferably 100-120°C, removing water and oxygen, and performing a first reaction for 2-4 h.

[0035] Among them, when adding the first precursor to pump out water and oxygen, the temperature needs to be maintained above 100°C.

[0036] In some embodiments, the second precursor is a vanadium precursor, mainly including chlorides, preferably including vanadium tetrachloride, etc., but not limited thereto.

[0037] Furthermore, the molar ratio range of the first precursor to the second precursor is 1:1.9-1:1.5.

[0038] Furthermore, the protective atmosphere can be an argon atmosphere, but not limited thereto.

[0039] In some embodiments, the preparation method specifically includes: in a protective atmosphere, heating the mixture obtained after the end of the first reaction to above 260°C, preferably 260-320°C, and then adding the second precursor to perform a second reaction for more than 60 min, preferably 60-120 min.

[0040] Furthermore, the reaction time after adding the second precursor must be more than 60 minutes.

[0041] Furthermore, the whole system should be anhydrous and anaerobic, and the reaction should be carried out under the protection of an inert gas atmosphere (such as an argon atmosphere).

[0042] Furthermore, the temperature when adding the second precursor must be maintained above 260°C.

[0043] In some embodiments, the preparation method may further include: modifying polyethylene glycol on the surface of the product obtained from the second reaction by ligand exchange to obtain a biodegradable manganese-based sonosensitizer with surface-modified polyethylene glycol. In the present invention, modifying polyethylene glycol on the surface of the product changes the sonosensitizer from hydrophobic to hydrophilic, enabling it to be dispersed in the solution, so that the performance of generating reactive oxygen species in the solution phase can be tested subsequently.

[0044] Furthermore, the preparation method specifically may include: first precipitating the product obtained after the end of the second reaction with a polar solvent, then centrifuging, and modifying polyethylene glycol on the surface of the product by ligand exchange.

[0045] Among some embodiments, the mass ratio of the modified polyethylene glycol used in the ligand exchange method to the product should be above 2:1 (greater than or equal to 2:1). The reaction temperature of the ligand exchange method is 50 - 55 °C or room temperature according to different solvents, and the reaction time is 8 - 12 h. For example, when the solvent used in the ligand exchange method is dichloromethane, the reaction is carried out at room temperature. When tetrahydrofuran is used, the reaction is carried out at 50 - 55 °C.

[0046] Furthermore, the modified polyethylene glycol used in the ligand exchange method includes any one of 3,4-dihydroxyphenylacetamide polyethylene glycol, polyethylene glycol grafted maleic anhydride-1-octadecene, etc., but is not limited thereto.

[0047] Furthermore, the polar solvents for precipitating the manganese-based sonosensitizer include ethanol and / or acetone, etc., but are not limited thereto.

[0048] Furthermore, the volume ratio of the polar solvent to the reaction system of the second reaction should be greater than 10:1.

[0049] Among some more specific embodiments, the preparation method of the biodegradable manganese-based sonosensitizer mainly includes the following steps:

[0050] (1) First, mix the first precursor with oleic acid, oleylamine, and a high-boiling organic solvent, heat in an oil bath to 100 - 120 °C to pump out water and oxygen, and maintain for 2 - 4 hours;

[0051] (2) Under argon protection, continue to heat the above system to 260 - 320 °C, add the second precursor, and react for 60 - 120 minutes to obtain the biodegradable manganese-based sonosensitizer;

[0052] (3) Finally, precipitate the sonosensitizer with a polar solvent and then centrifuge, and modify the surface with polyethylene glycol through the ligand exchange method to change it from hydrophobic to hydrophilic.

[0053] In summary, when the present invention prepares the biodegradable manganese-based sonosensitizer, the two precursors thermally decompose to form amorphous aggregates under high-temperature conditions, and the two continue to fuse to form dot-like seeds, which further grow to form a perovskite-type sonosensitizer, and then the surface is modified with polyethylene glycol through the ligand exchange method to change it from hydrophobic to hydrophilic. This sonosensitizer can degrade in the presence of moisture and has no effect on the sonosensitization effect within a certain time.

[0054] The perovskite-type manganese-based sonosensitizer constructed by the present invention has a narrow bandgap, and electrons and holes are easily separated under the excitation of ultrasound; at the same time, the abundant oxygen vacancies present can act as electron traps to prevent the recombination of electrons and holes. Therefore, it has a good sonosensitization effect, and its sonodynamic effect is not affected by degradation within a certain time.

[0055] Another aspect of the embodiment of the present invention also provides a biodegradable manganese-based sonosensitizer prepared by the aforementioned preparation method.

[0056] Among them, the particle size of the biodegradable manganese-based sonosensitizer is 4.4 - 5 nm.

[0057] Furthermore, the particle size of the biodegradable manganese-based sonosensitizer surface-modified with polyethylene glycol is 10 - 12 nm.

[0058] Another aspect of the embodiment of the present invention also provides the application of the biodegradable manganese-based sonosensitizer, which can be applied to the preparation of antibacterial products or drugs for sonodynamic therapy of tumors and other fields.

[0059] Among them, the parameters of the ultrasonic device used in sonodynamic therapy are 20 kHz - 60 kHz, 1.5 - 3.0 W / cm 2 , and the duty cycle is 40% - 50%.

[0060] The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments. This embodiment is implemented on the premise of the technical solution of the present invention, and the detailed implementation manners and specific operation processes are given. However, the protection scope of the present invention is not limited to the following embodiments. Therefore, the specific functional details disclosed herein should not be construed as restrictive, but only as the basis of the claims and as a representative basis for teaching those skilled in the art to adopt the present invention in any appropriate detailed embodiment in different ways.

[0061] The present invention uses 1,3-diphenylisobenzofuran (DPBF) as a probe to detect the generation of reactive oxygen species. The more the characteristic absorption at 416 nm decreases, the more DPBF is oxidized, and the more reactive oxygen species are generated by the material.

[0062] Example 1

[0063] The preparation of the biodegradable manganese-based sonosensitizer in this example includes the following steps:

[0064] (1) Mix 0.62 g of manganese oleate, 1 mL of oleic acid, 1 mL of oleylamine, and 20 mL of dibenzyl ether, heat to 120 °C, and pump water and air with a vacuum pump for 2 hours;

[0065] (2) Continue to heat the above system to 260 °C, add 200 μL of vanadium tetrachloride, and continue to react for 60 minutes to obtain a perovskite-type manganese vanadate sonosensitizer;

[0066] (3) Finally, precipitate the product with ethanol, then centrifuge, and wash it three times with ethanol and n-hexane;

[0067] (4) Add 5 mg of the product and 10 mg of 3,4-dihydroxyphenylacetamide polyethylene glycol into 10 mL of tetrahydrofuran, stir overnight (12 h) at 50 °C, and precipitate with 100 mL of anhydrous ether to obtain a perovskite-type manganese vanadate sonosensitizer with surface-modified polyethylene glycol.

[0068] The application schematic diagram of the biodegradable manganese-based sonosensitizer in this example is as Figure 1 shown.

[0069] Figure 2 This is the transmission electron microscopy image of the unmodified polyethylene glycol biodegradable manganese-based sonosensitizer prepared in this example. It can be seen from Figure 2 that the sonosensitizer is a nanometer particle with uniform morphology.

[0070] Figure 3 This is the particle size distribution diagram of the unmodified polyethylene glycol biodegradable manganese-based sonosensitizer prepared in this example. It can be seen from Figure 3 that the particle size of the sonosensitizer is about 4.4 nm, which is basically consistent with the Figure 2 result of the electron microscopy image.

[0071] Figure 4 This is the transmission electron microscopy image of the polyethylene glycol-modified biodegradable manganese-based sonosensitizer prepared in this example. It can be seen from Figure 4 that the particle size of the sonosensitizer increases to about 10 nm after being modified with polyethylene glycol.

[0072] Figure 5 This is the X-ray diffraction pattern of the biodegradable manganese-based sonosensitizer prepared in this example. It can be seen from Figure 4 that the sonosensitizer has a perovskite-type structure.

[0073] Using DPBF as a probe to detect reactive oxygen species, investigate the ability of the biodegradable manganese-based sonosensitizer prepared in this example to generate reactive oxygen species under ultrasonic conditions. The ultrasonic conditions used are 40 kHz, 3 W / cm 2 , 50% duty cycle, and the total ultrasonic radiation time is 10 minutes. Figure 6 This is the rate graph of the biodegradable manganese-based sonosensitizer prepared in this example to oxidize DPBF under ultrasonic conditions, and it is compared with pure water and commercial titanium dioxide. It can be seen from Figure 6 that the biodegradable manganese-based sonosensitizer prepared in this example can effectively oxidize DPBF under ultrasonic conditions, and the oxidation rate is faster than that of pure water and commercial titanium dioxide, indicating that the sonosensitization efficiency of this biodegradable manganese-based sonosensitizer is higher than that of commercial titanium dioxide.

[0074] Figure 7TEM images of the biodegradable manganese-based sonosensitizer prepared in this example at different times in the presence and absence of moisture. It can be seen from Figure 7 that in the presence of moisture, the manganese-based sonosensitizer begins to degrade significantly on the fourth day, while in the dry condition, no significant degradation occurs within 15 days.

[0075] The biodegradable manganese-based sonosensitizer prepared in this example was injected into tumor-bearing mice via the tail vein. Sonodynamic therapy was performed 8 hours after the injection of the material on the first and second days, respectively. The ultrasonic parameters were 40 kHz, 3.0 W / cm 2 , 50% duty cycle, and each ultrasonic treatment lasted for 5 minutes. The experimental design included control group 1 (untreated), control group 2 (manganese-based sonosensitizer alone), control group 3 (ultrasound alone), and experimental group 4 (manganese-based sonosensitizer + ultrasound). Figure 8 shows the changes in tumor volume of mice in each group during sonodynamic therapy. The experimental results show that compared with other control groups, the tumor growth of mice in the manganese-based sonosensitizer + ultrasound group was more significantly inhibited.

[0076] A certain amount of the biodegradable manganese-based sonosensitizer prepared in this example was injected into mice via the tail vein. The mice were placed in a mouse metabolic cage, and their feces and urine were collected daily for 15 days. After nitrification, the manganese content in them was determined by inductively coupled plasma mass spectrometry (ICP-MS) to determine the amount of manganese-based sonosensitizer excreted through feces and urine. Figure 9 shows the amount of the biodegradable manganese-based sonosensitizer prepared in this example excreted by mice through feces and urine respectively. It can be seen from Figure 9 that the manganese-based sonosensitizer is mainly excreted through feces.

[0077] Example 2

[0078] The preparation of the biodegradable manganese-based sonosensitizer in this example includes the following steps:

[0079] (1) Mix 0.62 g of manganese oleate, 1 mL of oleic acid, 1 mL of oleylamine, and 20 mL of 1-octadecene, heat to 120 °C, and pump water and air with a vacuum pump for 2 hours;

[0080] (2) Continue to heat the above system to 320 °C, add 200 μL of vanadium tetrachloride, and continue to react for 60 minutes to obtain a perovskite-type manganese vanadate sonosensitizer;

[0081] (3) Finally, precipitate the product with ethanol, then centrifuge, and wash it three times with ethanol and n-hexane;

[0082] (4) Add 5 mg of the product and 10 mg of 3,4-dihydroxyphenylacetamide polyethylene glycol to 10 mL of tetrahydrofuran, stir overnight at 50 °C, and precipitate with 100 mL of anhydrous ether to obtain a perovskite-type manganese vanadate sonosensitizer with surface-modified polyethylene glycol.

[0083] Using DPBF as a probe to detect the generation of reactive oxygen species, the ability of the biodegradable manganese-based sonosensitizer prepared in this example to generate reactive oxygen species under ultrasonic conditions was detected. The ultrasonic conditions were 40 kHz, 3 W / cm 2 , 50% duty cycle, and the total ultrasonic time was 10 minutes. The results showed that they were basically the same as those in Example 1.

[0084] Example 3

[0085] The preparation of the biodegradable manganese-based sonosensitizer in this example includes the following steps:

[0086] (1) Mix 0.62 g of manganese oleate, 1 mL of oleic acid, 1 mL of oleylamine, and 20 mL of dibenzyl ether, heat to 100 °C, and pump water and air with a vacuum pump for 2 hours;

[0087] (2) Continue to heat the above system to 260 °C, add 200 μL of vanadium tetrachloride, and continue to react for 60 minutes to obtain a perovskite-type manganese vanadate sonosensitizer;

[0088] (3) Finally, precipitate the product with ethanol, then centrifuge, and wash three times with ethanol and n-hexane;

[0089] (4) Add 5 mg of the product and 10 mg of 3,4-dihydroxyphenylacetamide polyethylene glycol to 10 mL of tetrahydrofuran, stir overnight at 50 °C, and precipitate with 100 mL of anhydrous ether to obtain a perovskite-type manganese vanadate sonosensitizer with surface-modified polyethylene glycol.

[0090] Using DPBF as a probe to detect the generation of reactive oxygen species, the ability of the biodegradable manganese-based sonosensitizer prepared in this example to generate reactive oxygen species under ultrasonic conditions was detected. The ultrasonic conditions were 40 kHz, 3 W / cm 2 , 50% duty cycle, and the total ultrasonic time was 10 minutes. The results showed that they were basically the same as those in Example 1.

[0091] Example 4

[0092] The preparation of the biodegradable manganese-based sonosensitizer in this example includes the following steps:

[0093] (1) Mix 0.62 g of manganese oleate, 0.8 mL of oleic acid, 0.6 mL of oleylamine, and 19 mL of dibenzyl ether, heat to 120 °C, and pump water and air with a vacuum pump for 2 hours;

[0094] (2) Heat the above system to 260 °C, add 200 μL of vanadium tetrachloride, and continue the reaction for 120 minutes to obtain a perovskite-type manganese vanadate sonosensitizer;

[0095] (3) Finally, precipitate the product with ethanol, then centrifuge, and wash it three times with ethanol and n-hexane;

[0096] (4) Add 5 mg of the product and 15 mg of 3,4-dihydroxyphenylacetamide polyethylene glycol to 10 mL of tetrahydrofuran, stir overnight at 50 °C, and precipitate with 100 mL of anhydrous ether to obtain a perovskite-type manganese vanadate sonosensitizer with surface-modified polyethylene glycol.

[0097] Using DPBF as a probe to detect the generation of reactive oxygen species, the ability of the biodegradable manganese-based sonosensitizer prepared in this example to generate reactive oxygen species under ultrasonic conditions was detected. The ultrasonic conditions were 40 kHz, 3 W / cm 2 , 50% duty cycle, and the total ultrasonic time was 10 minutes. The results showed that they were basically the same as those in Example 1.

[0098] Example 5

[0099] The preparation of the biodegradable manganese-based sonosensitizer in this example includes the following steps:

[0100] (1) Mix 0.62 g of manganese oleate, 0.5 mL of oleic acid, 0.5 mL of oleylamine, and 18 mL of dibenzyl ether, heat to 120 °C, and pump out water with a vacuum pump for 3 hours;

[0101] (2) Heat the above system to 260 °C, add 200 μL of vanadium tetrachloride, and continue the reaction for 60 minutes to obtain a perovskite-type manganese vanadate sonosensitizer;

[0102] (3) Finally, precipitate the product with ethanol, then centrifuge, and wash it three times with ethanol and n-hexane;

[0103] (4) Add 5 mg of the product and 10 mg of 3,4-dihydroxyphenylacetamide polyethylene glycol to 10 mL of tetrahydrofuran, stir at 55 °C for 8 h, and precipitate with 100 mL of anhydrous ether to obtain a perovskite-type manganese vanadate sonosensitizer with surface-modified polyethylene glycol.

[0104] Using DPBF as a probe to detect the generation of reactive oxygen species, the ability of the biodegradable manganese-based sonosensitizer prepared in this example to generate reactive oxygen species under ultrasonic conditions was detected. The ultrasonic conditions were 60 kHz, 1.5 W / cm 2 , 40% duty cycle, and the total ultrasonic time was 10 minutes. The results showed that they were basically the same as those in Example 1.

[0105] Example 6

[0106] The preparation of the biodegradable manganese-based sonosensitizer in this example includes the following steps:

[0107] (1) Mix 0.62 g of manganese oleate, 1 mL of oleic acid, 1 mL of oleylamine, and 20 mL of dibenzyl ether, heat to 120 °C, and pump out water and air with a vacuum pump for 4 hours;

[0108] (2) Continue to heat the above system to 260 °C, add 200 μL of vanadium tetrachloride, and continue to react for 60 minutes to obtain a perovskite-type manganese vanadate sonosensitizer;

[0109] (3) Finally, precipitate the product with ethanol, then centrifuge, and wash three times with ethanol and n-hexane;

[0110] (4) Add 5 mg of the product and 25 mg of 3,4-dihydroxyphenylacetamide polyethylene glycol to 10 mL of tetrahydrofuran, stir at 50 °C for 10 h, and precipitate with 100 mL of anhydrous ether to obtain a perovskite-type manganese vanadate sonosensitizer with surface-modified polyethylene glycol.

[0111] Using DPBF as a probe to detect the generation of reactive oxygen species, the ability of the biodegradable manganese-based sonosensitizer prepared in this example to generate reactive oxygen species under ultrasonic conditions was detected. The ultrasonic conditions were 20 kHz, 3 W / cm 2 , 50% duty cycle, and the total ultrasonic time was 10 minutes. The results showed that they were basically the same as those in Example 1.

[0112] Example 7

[0113] The preparation of the biodegradable manganese-based sonosensitizer in this example includes the following steps:

[0114] (1) Mix 0.62 g of manganese oleate, 1 mL of oleic acid, 1 mL of oleylamine, and 20 mL of dibenzyl ether, heat to 120 °C, and pump out water and air with a vacuum pump for 2 hours;

[0115] (2) Continue to heat the above system to 260 °C, add 200 μL of vanadium tetrachloride, and continue to react for 60 minutes to obtain a perovskite-type manganese vanadate sonosensitizer;

[0116] (3) Finally, precipitate the product with ethanol, then centrifuge, and wash three times with ethanol and n-hexane;

[0117] (4) Add 5 mg of the product and 20 mg of polyethylene glycol-grafted maleic anhydride-1-octadecene to 10 mL of dichloromethane, stir overnight at room temperature, and rotary evaporate to remove the solvent dichloromethane to obtain a perovskite-type manganese vanadate sonosensitizer with surface-modified polyethylene glycol.

[0118] Using DPBF as a probe to detect the generation of reactive oxygen species, the ability of the biodegradable manganese-based sonosensitizer prepared in this example to generate reactive oxygen species under ultrasonic conditions was detected. The ultrasonic conditions were 40 kHz, 3 W / cm 2 , 50% duty cycle, and the total ultrasonic time was 10 minutes. The results showed that they were basically the same as those in Example 1.

[0119] Example 8

[0120] The preparation of the biodegradable manganese-based sonosensitizer in this example includes the following steps:

[0121] (1) Mix 0.62 g of manganese oleate, 1 mL of oleic acid, 1 mL of oleylamine, and 20 mL of dibenzyl ether, heat to 110 °C, pump water and air with a vacuum pump, and maintain for 2 hours;

[0122] (2) Continue to heat the above system to 280 °C, add 200 μL of vanadium tetrachloride, and continue to react for 80 minutes to obtain a perovskite-type manganese vanadate sonosensitizer;

[0123] (3) Finally, precipitate the product with acetone, then centrifuge, and wash it three times with acetone and n-hexane;

[0124] (4) Add 5 mg of the product and 10 mg of 3,4-dihydroxyphenylacetamide polyethylene glycol to 10 mL of tetrahydrofuran, stir overnight at 50 °C, and precipitate with 100 mL of anhydrous ether to obtain a perovskite-type manganese vanadate sonosensitizer with surface-modified polyethylene glycol.

[0125] Using DPBF as a probe to detect the generation of reactive oxygen species, the ability of the biodegradable manganese-based sonosensitizer prepared in this example to generate reactive oxygen species under ultrasonic conditions was detected. The ultrasonic conditions were 40 kHz, 3 W / cm 2 , 50% duty cycle, and the total ultrasonic time was 10 minutes. The results showed that they were basically the same as those in Example 1.

[0126] In addition, the inventors of this case also referred to the foregoing examples, and conducted tests with other raw materials, process operations, and process conditions described in this specification, and all obtained relatively ideal results.

[0127] Although the present invention has been described with reference to the illustrative embodiments, those skilled in the art will understand that various other changes, omissions, and / or additions can be made without departing from the spirit and scope of the present invention, and the elements of the embodiments can be replaced with substantial equivalents. Additionally, many modifications can be made without departing from the scope of the present invention to adapt a particular situation or material to the teachings of the present invention. Therefore, the present invention is not intended to be limited to the specific embodiments disclosed for carrying out the present invention, but is intended to include all embodiments that fall within the scope of the appended claims.

Claims

1. A preparation method of a biodegradable manganese-based sonosensitizer, characterized in that, comprising: heating a first mixed reaction system containing a first precursor, oleic acid, oleylamine and a high-boiling organic solvent to 100-120 °C, removing water and oxygen, and carrying out a first reaction for 2-4 h, wherein the first precursor is manganese precursor manganese oleate; in a protective atmosphere, heating the mixture obtained after the end of the first reaction to 260-320 °C, and then adding a second precursor to carry out a second reaction for 60-120 min to obtain a biodegradable manganese-based sonosensitizer, wherein the second precursor is vanadium tetrachloride; the molar ratio of the first precursor to the second precursor is 1:1.9-1:1.5; the biodegradable manganese-based sonosensitizer has a perovskite structure and can degrade in the presence of moisture, wherein the particle size of the biodegradable manganese-based sonosensitizer is 4.4-5 nm.

2. The preparation method according to claim 1, characterized in that: the high-boiling organic solvent is selected from any one of dibenzyl ether and 1-octadecene.

3. The preparation method according to claim 1, characterized in that: the volume ratio of the high-boiling organic solvent, oleic acid and oleylamine is 18-20:0.5-1:0.5-1.

4. The preparation method according to claim 1, characterized in that: the protective atmosphere is an inert gas atmosphere.

5. The preparation method according to claim 4, characterized in that: the protective atmosphere is an argon atmosphere.

6. The preparation method according to claim 1, characterized in that, the preparation method further comprises: modifying polyethylene glycol on the surface of the product obtained from the second reaction by a ligand exchange method to obtain a biodegradable manganese-based sonosensitizer with surface-modified polyethylene glycol.

7. The preparation method according to claim 6, characterized in that, the preparation method specifically comprises: first precipitating the product obtained after the end of the second reaction with a polar solvent, then centrifuging, and modifying polyethylene glycol on the surface of the product by a ligand exchange method, wherein the mass ratio of the modified polyethylene glycol to the product used in the ligand exchange method is more than 2:1, the reaction temperature used in the ligand exchange method is 50-55 °C or room temperature, and the reaction time is 8-12 h.

8. The preparation method according to claim 7, characterized in that: the modified polyethylene glycol is selected from any one of 3,4-dihydroxyphenylacetamide polyethylene glycol and polyethylene glycol grafted maleic anhydride-1-octadecene, and the polar solvent is selected from ethanol and / or acetone.

9. The preparation method according to claim 7, characterized in that: the volume ratio of the polar solvent to the reaction system of the second reaction is greater than 10:

1.

10. The preparation method according to claim 6, characterized in that: the particle size of the biodegradable manganese-based sonosensitizer with surface-modified polyethylene glycol is 10-12 nm.

11. Application of the biodegradable manganese-based sonosensitizer prepared by the preparation method according to any one of claims 1-10 in the preparation of antibacterial products or in the preparation of drugs for sonodynamic therapy of tumors.

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