Polyether modified porphyrin alkali metal salt as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of porphyrin. The structural formula of the polyether modified porphyrin alkali metal salt is # imgabs0 #, R1 represents C1-C60 straight chain or branched chain alkyl, and-CH2-in the R1 can be optionally substituted by oxygen to form an ether group; m is alkali metal. The invention also discloses a preparation method of the porphyrin alkali metal salt. The invention also relates to application of the polyether modified porphyrin alkali metal salt. The method is used for solving the problems that the ether group modified porphyrin branched chain can effectively improve the acoustic sensitivity, but the water solubility is poor, and the toxicity is increased under high concentration.

Description

Technical Field

[0001] The present invention belongs to the field of porphyrin technology, and specifically relates to a polyether-modified porphyrin alkali metal salt and a method for preparing the polyether-modified porphyrin alkali metal salt. The present invention also relates to the application of the polyether-modified porphyrin alkali metal salt. Background Art

[0002] Sonodynamic therapy (SDT) has attracted widespread attention in the treatment of diseases such as cancer and atherosclerosis, as well as in medical imaging. SDT is a treatment related to photodynamic therapy (PDT), but it uses sound waves instead of light to activate sonosensitizers for precise tumor treatment.

[0003] Sonosensitizers are a class of molecules with specific pharmacological activities that release reactive oxygen species (ROS) in response to sound wave stimulation. These ROS can be used to destroy abnormal cells, such as cancer cells. Sonosensitizers play a key role in this therapy because their selectivity, efficacy, and toxicity directly influence the effectiveness of treatment. In the current technological context, sonosensitizers are primarily divided into two categories: non-organic sonosensitizers and organic sonosensitizers.

[0004] Non-organic sonosensitizers: This category includes a range of non-organic substances, such as TiO2 nanoparticles and silicon nanoparticles. Although they can induce cell damage under ultrasound stimulation, they face challenges such as low efficiency, limited biocompatibility, and non-biodegradability, which limit their feasibility in clinical applications. Therefore, there is a need to identify more efficient and safer sonosensitizers to enhance the efficacy of sonodynamic therapy.

[0005] Organic sonosensitizers: Organic sonosensitizers are another class of sonosensitizers. They have well-defined molecular structures and can be precisely designed and produced on a large scale through synthesis. Compared with non-organic sonosensitizers, organic sonosensitizers have better tissue compatibility and biodegradability, making them potential candidates for sonodynamic therapy. However, organic sonosensitizers also have some limitations, such as limited cell killing effects after acoustic stimulation. Therefore, it is necessary to find ways to improve organic sonosensitizers to enhance their sonodynamic therapeutic effects.

[0006] Porphyrin sonosensitizers: Porphyrin compounds are among the earliest sonosensitizers used in sonodynamic therapy. Based on the basic structure of porphyrin, these sonosensitizers have been derived into a variety of improved sonosensitizers, such as protoporphyrin IX and hematoporphyrin monomethyl ether. These porphyrin derivatives exhibit improved selectivity and superior anti-tumor efficacy compared to first-generation hematoporphyrins. Furthermore, some researchers have enhanced the sonodynamic therapeutic effect and sonosensitivity of porphyrin sonosensitizers by introducing metal coordination atoms or nanoparticles.

[0007] Previous studies by our research group have shown that ether-modified porphyrin side chains can effectively improve sonosensitivity, but they have problems with poor water solubility and increased toxicity at high concentrations, which also limits their application. Summary of the Invention

[0008] The first object of the present invention is to provide a polyether-modified porphyrin alkali metal salt to solve the problem that ether-modified porphyrin side chains can effectively improve sonosensitivity, but have poor water solubility and increased toxicity at high concentrations.

[0009] In order to solve the above technical problems, the present invention adopts the following technical solution: a polyether-modified porphyrin alkali metal salt, characterized in that the polyether-modified porphyrin alkali metal salt has the structural formula:

[0010]

[0011] Wherein, R1 represents a C1-C60 straight-chain or branched alkyl group, wherein -CH2- can be optionally substituted by an oxy group to form an ether group; and M is an alkali metal.

[0012] The present invention solves some limiting problems of current sonosensitizer types through salt-modified polyether branched porphyrin derivatives, improves the efficacy and feasibility of sonodynamic therapy, and thus provides a better choice for clinical treatment.

[0013] The second object of the present invention is to provide a method for preparing a polyether-modified porphyrin alkali metal salt, which is characterized by comprising the following steps:

[0014] (1) Dissolving compound 1 in a hydrogen bromide / acetic acid solution under a nitrogen atmosphere, and then stirring and dissolving the mixture; vacuum treatment to remove volatile substances to obtain compound 2;

[0015] (2) Compound 2 was dissolved by adding R1-OH, and then concentrated sulfuric acid was slowly added. The reaction mixture was stirred under nitrogen. The solution was extracted with ethyl acetate, and then water was added. The organic layer was washed with distilled water, and then the volatile solvent was removed under low pressure. Compound 3 was separated by silica gel column chromatography.

[0016] (3) Compound 3 is added with M-OH to form alkaline conditions. After the reaction, the product is dried with anhydrous sodium sulfite, concentrated under vacuum and then purified by chromatography to obtain compound 4, i.e., a polyether-modified porphyrin alkali metal salt;

[0017] The reaction equation is as follows:

[0018]

[0019] In order to solve the above technical problems, the present invention adopts the following technical solution, wherein the stirring time in step (1) is 40-60 hours.

[0020] In order to solve the above technical problems, the present invention adopts the following technical solution, wherein the stirring time in step (2) is 60-70 hours.

[0021] To solve the above technical problems, the present invention adopts the following technical solution: the mass volume ratio of the compound 1:33% hydrogen bromide / acetic acid solution is 1:(50-150), wherein the 33% hydrogen bromide / acetic acid solution is a mass volume ratio, that is, 33 grams of hydrogen bromide is added to 100 ml of acetic acid.

[0022] To solve the above technical problems, the present invention adopts the following technical solution, wherein the mass volume ratio of the compound 2 to R1-OH is 1:(50-300), and the volume ratio of R1-OH to concentrated sulfuric acid is (300-600):1.

[0023] In order to solve the above technical problems, the present invention adopts the following technical solution: the compound 3 is dissolved in M-OH, and the concentration of M-OH is in the range of 0.01 mol / L to saturation concentration.

[0024] The third object of the present invention is to provide a use of a polyether-modified porphyrin alkali metal salt in a sonosensitizer.

[0025] In order to reduce the side effects of sonodynamic therapy, it is necessary to develop sonosensitizers that can be activated at lower ultrasound intensities. This will help reduce the risk of normal tissue damage and improve the safety and acceptability of treatment. In addition, by adjusting and enhancing the water solubility of drugs, the present invention of porphyrin sonosensitizers improves the ultrasound activation intensity required for the sonosensitizer by modifying the side chain structure of the porphyrin derivative by ether groups in the early stage, and then enhances its water solubility by modifying it with alkali metal salts in the later stage, further enhancing the sonodynamic effect while reducing the toxic side effects of the drug. This is an important improvement. This improvement helps to reduce the risk of normal tissue damage, increase the utilization rate of drugs, increase the threshold of drug concentration that can be used, and at the same time enhance the cell-killing effect of sonodynamic therapy. Therefore, this technical improvement has important application significance for improving the safety and efficacy of sonodynamic therapy.

[0026] The present invention improves the ultrasound sensitivity of sonosensitizers: In the closest prior art, sonosensitizers typically require high ultrasound intensities to be activated during sonodynamic therapy, potentially causing damage to normal tissue. One of the objectives of the present invention is to reduce the acoustic activation intensity of sonosensitizers, enabling them to generate reactive oxygen species even at lower ultrasound intensities, thereby improving ultrasound sensitivity.

[0027] This invention enhances cell-killing efficacy: In addition to improving ultrasound sensitivity, the present invention also aims to achieve a stronger cell-killing effect. The improved sonosensitizer, upon ultrasound stimulation, produces reactive oxygen species in tumor cells, thereby achieving a cell-killing effect. This task involves refining the molecular structure and properties of the sonosensitizer to ensure its greater efficacy in treatment.

[0028] This invention studies novel sonosensitizers: It also proposes a method for modifying porphyrin derivatives to produce novel sonosensitizers. These novel sonosensitizers, while exhibiting minimal cellular toxicity, can generate reactive oxygen species through ultrasound stimulation and kill tumor cells. Therefore, one of the objectives is to lay the experimental and theoretical foundation for the development of more novel, highly effective sonosensitizers with anti-tumor effects.

[0029] In summary, the compounds of this invention are ether-modified side-chain porphyrin salts, a class of water-soluble, stable porphyrin derivatives. These compounds enhance the ultrasound sensitivity of sonosensitizers, raise the threshold for safe drug concentrations, and strengthen their cell-killing effects. They also provide a foundation for the development of novel sonosensitizers. These objectives aim to promote innovation in sonodynamic therapy, improve therapeutic efficacy, and reduce adverse effects on patients, paving the way for safer and more effective treatments. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 A toxicity comparison was conducted between the representative drug of the present invention and ether-modified branched-chain porphyrin derivatives of non-metallic base salts and protoporphyrin IX. The results showed that the representative drug of the present invention and protoporphyrin IX had no obvious toxic damage to human lung cancer PC-9 cells at different concentrations. The ether-modified branched-chain porphyrin derivatives of non-metallic base salts had little toxicity at low concentrations, but increased toxicity at high concentrations.

[0031] Figure 2 The sonodynamic efficacy of the representative drug of the present invention was compared with that of ether-modified branched-chain porphyrin derivatives of non-metallic base salts and protoporphyrin IX. The results showed that neither the drug alone nor ultrasound treatment alone had a significant killing effect on human lung cancer cells. The representative drug of the present invention had a better cell-killing effect under ultrasound than the ether-modified branched-chain porphyrin derivatives of non-metallic base salts and the existing sonosensitizer protoporphyrin IX.

[0032] Figure 3 The detection results of intracellular ROS in different treatment groups of the representative drug of the present invention showed that neither the drug alone nor ultrasound produced obvious ROS, while the drug produced obvious ROS in the cells after ultrasound stimulation. DETAILED DESCRIPTION

[0033] The present invention will be further explained below with reference to the accompanying drawings and specific embodiments.

[0034] Comparative Example 1

[0035] The sonosensitizer protoporphyrin IX is available from aladdin; product number: P103197; it is insoluble in water.

[0036] Comparative Example 2

[0037] The synthetic route of reference example 2 is as follows:

[0038]

[0039] Synthesis of compound 3: According to the literature [Chen Junlei, Zhao Ming, Shi Zhichun, Li Jun, Zhang Shujun. Synthesis of sonosensitizer DEG. Chinese Journal of Pharmaceutical Industry, 2019, 50(4):399-402.], hemin (2.0 g, 3.3 mmol) was added to a 100 mL reaction bottle, and HBr-AcOH (30.0 mL, 33%) was added. Under nitrogen protection, the reaction was carried out at room temperature for 42.0 h, and the mixture was concentrated under reduced pressure to obtain the crude product of compound 2. The crude product of compound 2 was dissolved in diethylene glycol (30.0 mL) and concentrated sulfuric acid (0.25 mL, 98%) was added dropwise. The reaction was carried out at room temperature for 71.0 h. The reaction progress was monitored by thin layer chromatography during the reaction. The reaction solution was extracted with ethyl acetate (150 mL × 3), and the organic phase was washed sequentially with saturated aqueous sodium chloride solution (200.0 mL × 2) and deionized water (200 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and then separated and purified by silica gel column chromatography [eluent: V ethyl acetate / V n-hexane = 9 / 1] to give a purple solid oily liquid (2.2 g, 68.8%). Its structure was identified by ESI-MS, NMR, IR, and UV-vis.

[0040] Comparative Example 2, Synthesis of Compound 4: Compound 3 (284.7 mg, 0.3 mmol) was added to a 50 mL reaction flask, and a THF / H2O (V / V=1 / 1, 15.0 mL) mixed solvent was added. After stirring for complete dissolution, sodium hydroxide (43.1 mg, 1.1 mmol) was added and reacted at room temperature for 25.0 h. The reaction progress was monitored by thin layer chromatography during the reaction. After concentration under reduced pressure, the mixture was acidified with acetic acid aqueous solution (volume fraction 20.0%) for 40.0 min. Deionized water (250.0 mL) was added and extracted with ethyl acetate (150.0 mL×3). The organic phases were combined and concentrated under reduced pressure and recrystallized from dichloromethane-n-hexane to obtain purple crystals (224.9 mg, 97.4%). Its structure was identified by ESI-MS, NMR, IR, and UV-vis.

[0041] Example 1

[0042] Compound 1: purchased from Sigma-Aldrich, product number: 51280.

[0043] 33% hydrogen bromide / acetic acid: Tokyo Chemical Industry Co., Ltd. (Shanghai), product number: H0182-100G.

[0044] Ethylene glycol: Sigma-Aldrich, Catalog No. 324558.

[0045] Concentrated sulfuric acid: Sigma-Aldrich, Cat. No. 543827.

[0046] Ethyl acetate: Sigma-Aldrich, Cat. No. L092004.

[0047] Sodium hydroxide: Chinese medicine, product number: 10019718.

[0048] Anhydrous sodium sulfite: Chinese medicine, product number: C219270250.

[0049] Mixer: Gongyi Yuhua Instrument Co., Ltd., model SZCL-2A.

[0050] Silica gel: General-reagent, G72651B.

[0051] Vacuum pump: Suzhou Kress Instrument Co., Ltd., SHK-IIIS.

[0052] 1.1 Weigh 1g of compound 1 and dissolve it in 10mL of 33% hydrogen bromide / acetic acid solution in a nitrogen atmosphere. The resulting mixture is stirred and dissolved for 40 hours. Vacuum remove the volatile substances to obtain compound 2. Continue to add 50mL of ethylene glycol to dissolve it, then slowly add 0.1mL of concentrated sulfuric acid, and continue stirring the reactants under nitrogen for 60 hours. The solution is extracted with ethyl acetate and water is added. After washing the organic layer with distilled water, the volatile solvent is removed again at a low pressure of 20kPa, and the residue is separated by silica gel column chromatography to obtain compound 3. 100mg of compound 3 is continued to be added to 10mL of sodium hydroxide, and after the reaction, it is dried with anhydrous sodium sulfite. The obtained organic phase material is concentrated at a vacuum low pressure of 1kPa and then chromatographically purified to obtain compound 4, which is a representative drug.

[0053] Representative drug synthesis routes are as follows:

[0054]

[0055] 1.2 Performance Testing

[0056] 1.2.1 Detection of cell proliferation ability / toxicity

[0057] The experiment used CCK-8 (Cell Counting Kit-8) reagent to detect cell proliferation and toxicity. First, human lung cancer cells (PC-9 cells) in the logarithmic growth phase were digested with trypsin. After digestion was terminated with serum-containing medium, the cells were transferred to a centrifuge tube and centrifuged at 1000 rpm for 5 minutes. The supernatant was discarded, and the cells were resuspended in culture medium and counted. The cells were diluted according to the results. The final cell density was 1×10 4 / mL and seeded into 96-well plates. Each group of samples included a blank control and 7 drug concentration groups. 24 hours after cell inoculation, carefully aspirate the culture medium in each well, add drug-free culture medium to the blank group, and add culture medium with drug concentrations of 64, 32, 16, 8, 4, 2, and 1 μg / mL to the experimental group. Return the 96-well plate to the cell culture incubator and culture for 24 hours. Then aspirate the culture medium again, add culture medium containing CCK-8 reagent, and continue incubating in the cell culture incubator for 3 hours. Then take it out and put it into the microplate reader for detection at a detection wavelength of 450nm. The cell viability is calculated according to the following formula:

[0058] Cell survival rate (%) = (OD value of drug group - OD value of blank group) / (OD value of control group - OD value of blank group) × 100%

[0059] The results are as follows Figure 2 As shown, compared with the control sonosensitizer (Control Example 2), the representative drug of the present invention has similar toxicity to PPIX (refer to data reported in previous literature), and is better than Control Example 2, that is, it has almost no obvious cytotoxicity to human lung cancer cells.

[0060] 1.2.2 Drug efficacy testing

[0061] First, the culture medium of human lung cancer cells in the culture flask was carefully aspirated with a pipette, and replaced with medium containing and without drugs (concentration 4 μg / mL) and labeled. The cells were returned to the incubator for 2 hours, digested with trypsin and resuspended. After cell counting, the cells were diluted to 1×10 6 The cells were placed in a polystyrene dish at a density of 1 mL / mL and ultrasonically irradiated. After ultrasonic irradiation, 200 μL of the cells were homogenized and added to a 96-well plate. Culture medium containing CCK-8 reagent was added and the cells were incubated in a cell culture incubator for 3 hours. The cells were then removed and analyzed using a microplate reader at a wavelength of 450 nm. The cell viability was calculated using the following formula:

[0062] Cell survival rate (%) = (OD value of drug group - OD value of blank group) / (OD value of control group - OD value of blank group) × 100%

[0063] The results showed that compared with the existing control sonosensitizer, the representative drug of the present invention, porphyrin sodium salt with an added ether group, had a better tumor cell killing effect.

[0064] 1.2.3 Reactive oxygen species detection

[0065] This study uses the intracellular reactive oxygen species (ROS) fluorescent probe 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA) to monitor intracellular ROS levels. Brief description of the assay process: Dissolve DCFH-DA in DMSO to a 10 mM stock solution, store at -20°C in the dark, and dilute 1:1000 in serum-free 1640 medium to a final concentration of 10 μmol / L.

[0066] The cells in the logarithmic growth phase were digested and centrifuged, then resuspended in culture medium and counted. Culture medium was added to dilute the cells to 1×10 5 / mL concentration and seeded in a 35 mm culture dish. After being placed in a cell culture incubator for 24 hours, the culture medium was carefully aspirated and replaced with a diluted DCFH-DA solution (only serum-free culture medium was added to the negative control group). After further culture for 30 minutes, the culture medium was removed and washed three times with serum-free 1640 culture medium. The culture medium was replaced with a culture medium containing or not containing the representative drug of the present invention. After further incubation for 2 hours, ultrasonic irradiation was performed. After ultrasonic irradiation, the cells were washed twice with PBS and observed under a fluorescence microscope, and the results were recorded.

[0067] The results of the active oxygen detection showed that the drug of the present invention alone or ultrasound alone could not release a large amount of active oxygen, but the drug could generate a large amount of active oxygen after ultrasound excitation and was captured by the active oxygen detection fluorescent probe in the cells.

[0068] All of the above results demonstrate that the ether-modified porphyrin derivatives of the present invention have very low toxicity and exhibit a stronger tumor-killing effect under equivalent ultrasound conditions. Furthermore, the drugs of the present invention generate a large amount of reactive oxygen species upon ultrasound excitation. This provides a better option for the future development of new sonosensitizers.

[0069] 1.2.4 Water solubility test

[0070] The compounds synthesized in the present invention were compared with protoporphyrin IX and ether-modified branched porphyrin derivatives of non-metallic base salts according to the relevant methods of the Chinese Pharmacopoeia (2010 edition). The results showed that the structures of the compounds synthesized in the present invention were easily soluble in water, while the structures of protoporphyrin IX and ether-modified branched porphyrin derivatives of non-metallic base salts were almost insoluble in water.

[0071] Example 2

[0072] Weigh 1.5g of compound 1 and dissolve it in 30mL of 33% hydrogen bromide / acetic acid solution in a nitrogen atmosphere. The resulting mixture is stirred and dissolved for 50 hours. Vacuum remove the volatile substances to obtain compound 2. Continue to add 150mL of ethylene glycol to dissolve it, then slowly add 0.5mL of concentrated sulfuric acid, and continue stirring the reactants under nitrogen for 65 hours. The solution is extracted with ethyl acetate and water is added. Add an equal volume of water to wash the organic layer, and repeat this step twice to remove the unreacted etherifying agent and sulfuric acid. Remove the volatile solvent at a low pressure of 50kPa, and the residue is separated by silica gel column chromatography to obtain compound 3. 125mg of compound 3 is continued to be added to 25mL of sodium hydroxide, and after the reaction, it is dried with anhydrous sodium sulfite. The obtained organic phase material is concentrated at a vacuum low pressure of 5kPa and then chromatographically purified to obtain compound 4, which is a representative drug.

[0073] Please refer to Example 1 for the performance testing method of Example 2.

[0074] Example 3

[0075] Under a nitrogen atmosphere, 3 g of compound 1 was dissolved in 60 mL of 33% hydrogen bromide / acetic acid solution. The mixture was stirred and dissolved at room temperature for 60 hours to ensure complete dissolution. After the reactants were completely reacted, vacuum distillation was performed using a rotary evaporator at about 50 ° C to remove all volatile solvents and by-products to obtain a crude product compound 2. 250 mL of ethylene glycol was added to dissolve the mixture, and 1 mL of concentrated sulfuric acid was slowly added. The reactants were stirred under nitrogen for 70 hours. After the reaction, ethyl acetate was used for extraction, and an equal volume of water was added to wash the organic layer. This step was repeated twice to remove unreacted etherifying agent and sulfuric acid. All solvents were evaporated under low pressure conditions of 80 kPa, and then purified using silica gel column chromatography to collect the main part to obtain compound 3. 40 mL of sodium hydroxide was added, and after the reaction, anhydrous sodium sulfite was used for drying. The obtained organic phase was concentrated under vacuum and low pressure and then chromatographically purified to obtain compound 4, which is a representative drug.

[0076] Please refer to Example 1 for the performance testing method of Example 3.

[0077] Example 4 Comparative Example 2 and Examples 1-3 are applied to sonosensitizers

[0078] How to use sonosensitizer:

[0079] Table 1 Comparison of performance data of comparative example 2 and embodiment

[0080]

[0081] The sonosensitizer of the present invention has a well-defined molecular structure, making its synthesis and production process more controllable and reproducible. This structural precision ensures the sonosensitizer's quality and performance are stable, making it suitable for large-scale mass production. This is crucial for the widespread application of sonodynamic therapy.

[0082] The improved sonosensitizer exhibits excellent tissue compatibility, water solubility, and biodegradability: This means it has virtually no adverse reactions to patient tissues during treatment. Its good water solubility further enhances its bioavailability. Furthermore, its biodegradability ensures that the sonosensitizer is safely broken down and excreted after treatment, reducing the risk of toxicity.

[0083] Selective entry into tumor cells: The sonosensitizers of the present invention exhibit selective tumor cell entry, meaning they tend to accumulate in tumor tissue without extensively affecting normal tissue. This targeted nature helps minimize unnecessary damage to normal tissue.

[0084] This invention reduces ultrasound excitation intensity: The improved sonosensitizers offer not only significant technical advantages but also significant benefits in practice. They reduce the ultrasound excitation intensity required for sonodynamic therapy, thereby minimizing potential risks and discomfort for patients. This makes sonodynamic therapy safer and more acceptable.

[0085] This invention enhances cell-damaging effects: By improving the molecular structure of the sonosensitizer, the invention enhances the cell-damaging effect produced by the sonosensitizer after ultrasound excitation. This means that patients can achieve better therapeutic effects at lower ultrasound intensities, reducing discomfort during treatment and increasing the success rate of treatment.

[0086] Overall, the present invention offers significant advantages and benefits at both the technical and application levels. It provides a safer and more effective alternative to sonodynamic therapy, potentially improving treatment outcomes in tumor therapy and other areas while reducing patient discomfort.

[0087] The molecular structure of the sonosensitizer of the present invention has the following characteristics: (1) Ether-modified porphyrin derivative side chains: By introducing a polyether-modified porphyrin derivative side chain structure, the ultrasound activation intensity of the sonosensitizer is reduced, thereby improving sonosensitivity. This is crucial for achieving the goal of generating reactive oxygen species at lower ultrasound intensities. (2) Incorporation of alkali metal salts: The introduction of alkali metal salts into the molecule increases the water solubility of the drug and enhances its bioavailability in the body. In addition, high water solubility also helps reduce the likelihood of drug retention in the body, reducing potential adverse reactions.

[0088] The cell-killing effect of ultrasound therapy in this invention: After ultrasound stimulation, the sonosensitizer generates reactive oxygen species, which enhances the cell-killing effect. This mechanism is the core of sonodynamic therapy and is closely related to the improved sonosensitizer structure.

[0089] The molecular structure of the sonosensitizer of the present invention—an ether-modified porphyrin derivative side chain and an alkali metal salt—protects the sonosensitizer's molecular structure, including the ether-modified porphyrin derivative side chain and the alkali metal salt. These structures are crucial to the sonosensitizer's ultrasound sensitivity and cell-killing effect, and are the core innovation of the present invention.

[0090] Application Areas of the Invention: The sonosensitizers of the present invention are not only suitable for the specific application areas listed above, but can also be widely used in various sonodynamic therapy systems, including but not limited to tumor treatment. As long as the sonosensitizers of the present invention are used in sonodynamic therapy, including the treatment of atherosclerosis, or in other fields, including sonodynamic purification, sonodynamic disinfection, sonodynamic beauty, and sonodynamic cleaning, they are all within the scope of protection of this patent.

[0091] Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art may still modify the technical solutions described in the aforementioned embodiments, or make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention, and any contents not described in detail in this specification shall belong to the prior art known to professional and technical personnel in this field.

Claims

1. A polyether-modified porphyrin alkali metal salt, characterized in that: The structural formula of the polyether-modified porphyrin alkali metal salt is: Wherein, R1 represents a C1-C60 straight-chain or branched alkyl group, wherein -CH2- can be optionally substituted by an oxy group to form an ether group; and M is an alkali metal.

2. The method for preparing the polyether-modified porphyrin alkali metal salt according to claim 1, characterized in that: The following steps are involved: (1) Dissolving compound 1 in a hydrogen bromide / acetic acid solution in a nitrogen atmosphere, and then stirring and dissolving the mixture; After vacuum treatment to remove volatile substances, compound 2 was obtained; (2) Add R1-OH to compound 2 to dissolve it, then slowly add concentrated sulfuric acid, continue stirring the reactants under nitrogen, extract the solution with ethyl acetate, and then add water; wash the organic layer with distilled water, and then remove the volatile solvent under low pressure; separate by silica gel column chromatography to obtain compound 3; (3) Compound 3 is added with M-OH to form alkaline conditions. After the reaction, the compound is dried with anhydrous sodium sulfite. The product is concentrated under vacuum and then purified by chromatography to obtain compound 4, i.e., a polyether-modified porphyrin alkali metal salt. The reaction equation is as follows:

3. The method for preparing a polyether-modified porphyrin alkali metal salt according to claim 2, characterized in that: The stirring time in step (1) is 40-60 hours.

4. The method for preparing a polyether-modified porphyrin alkali metal salt according to claim 2, characterized in that: The stirring time in step (2) is 60-70 hours.

5. The method for preparing a polyether-modified porphyrin alkali metal salt according to claim 2, characterized in that: In step (1), under a nitrogen atmosphere, compound 1 is dissolved in a 33% hydrogen bromide / acetic acid solution in a mass volume ratio of 1:(50-150).

6. The method for preparing a polyether-modified porphyrin alkali metal salt according to claim 2, characterized in that: The mass volume ratio of the compound 2 to R1-OH is 1:(50-300), and the volume ratio of R1-OH to concentrated sulfuric acid is (300-600):

1.

7. The method for preparing a polyether-modified porphyrin alkali metal salt according to claim 2, characterized in that: The compound 3 is dissolved in M-OH, and the concentration of M-OH is in the range of 0.01 mol / L to saturation concentration.

8. Use of the polyether-modified porphyrin alkali metal salt according to claim 1 or the polyether-modified porphyrin alkali metal salt obtained by the preparation method according to any one of claims 2 to 7 in sonosensitizers.

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