Porphyrin oxygen-carrying polymer sound-sensitive agent as well as preparation method and application thereof

Abstract

The invention relates to the technical field of nano biomedicine, in particular to a porphyrin oxygen-carrying polymer sound-sensitive agent as well as a preparation method and application thereof, and the porphyrin oxygen-carrying polymer sound-sensitive agent takes porphyrin as a main body structure and takes polyheptafluorobutyramide as a polymeric side chain. The polyheptafluorobutyramide contained in the porphyrin oxygen-carrying polymer sonosensitizer can carry oxygen, the perfluoroalkyl modified polymer can release oxygen explosively under the activation of ultrasonic waves, and the visible light triggered perfluoroalkyl modified polymer can increase oxygen supply to relieve tumor hypoxia and reverse a hypoxia microenvironment, so that the oxygen-sensitive effect of the porphyrin oxygen-carrying polymer sonosensitizer is improved, and the oxygen-sensitive effect of the porphyrin oxygen-carrying polymer sonosensitizer is improved. The generation of active oxygen in the SDT process is enhanced, the accumulation efficiency of the tumor site is further improved, the effect of SDT tumor treatment is improved, and the method becomes an effective method for enhancing hypoxia tumor chemoacoustic dynamics treatment.

Description

Technical Field

[0001] The present invention relates to the technical field of nano-biomedicine, and in particular to a porphyrin oxygen-carrying polymer sonosensitizer, a preparation method and an application thereof. Background Art

[0002] Currently, traditional cancer treatments such as chemotherapy, radiotherapy, and surgery, while effective to a certain extent, have significant drawbacks. While chemotherapy drugs kill cancer cells, they can also damage normal cells, leading to a series of serious side effects such as nausea, vomiting, hair loss, and decreased immunity, significantly impacting patients' quality of life. Radiotherapy, when used locally, can cause radiation damage to surrounding normal tissues, with long-term effects potentially leading to tissue fibrosis and dysfunction. Surgery, on the other hand, is highly invasive and requires a long recovery time. Furthermore, for some advanced or metastatic cancers, surgery is difficult to completely eliminate cancer cells, making recurrence and metastasis highly likely. Therefore, there is an urgent need to find safer and more effective cancer treatments.

[0003] Sonodynamic therapy (SDT), a novel tumor treatment, has garnered widespread attention in recent years. It achieves localized destruction of tumor tissue through the interaction of sound waves and nanomaterials, offering advantages such as targeted delivery, minimal trauma, and reusability. Compared to traditional tumor treatments, SDT not only directly kills tumor cells but also stimulates the body's immune response, enhancing anti-tumor immunity. This improves therapeutic efficacy while minimizing damage and side effects.

[0004] Organic sonosensitizers are key components in SDT. They are activated by ultrasound irradiation and produce ROS (reactive oxygen species) via sonoluminescence or sonochemical pyrolysis, thereby exerting a killing effect on tumor cells. Generally, photosensitizers can be used as sonosensitizers. The molecular design of sonosensitizers is mostly derived from photosensitizers and is mainly divided into four categories: porphyrin derivatives, cyanine derivatives, other small molecule sonosensitizers, and semiconductor polymers. Compared with inorganic nanomaterials, organic sonosensitizers have high biocompatibility, excellent biodegradability, significant tumor targeting and accumulation potential, and are easily metabolized from the liver or kidneys in living mice, showing strong potential for biomedical applications.

[0005] Porphyrins and their derivatives, due to their excellent photosensitizing activity, are widely used as first-generation photosensitizers in photodynamic therapy and have also been extensively studied in the field of sonodynamic therapy. Common porphyrin-derived sonosensitizers include protoporphyrin (IX), hematoporphyrin (HP), hematoporphyrin monomethyl ether (HP), dihydrochlorin e6 (Ce6), Ce6-C15-ethyl ester, verteporfin, temoporfin, mesoporphyrin sodium (DVDMS), 5-aminolevulinic acid (5-ALA), and phthalocyanine-artesunate conjugates. These sonosensitizers have similar 18-carbon aromatic macrocyclic carbon core structures and can generate ROS under ultrasound irradiation. However, they generally have some problems, such as poor water solubility, which leads to poor dispersion in the physiological environment, affecting their effect on tumor tissue; higher biosafety issues, which may cause potential harm to normal tissues of the body; low tumor targeting accumulation ability, which makes it difficult to efficiently enrich at the tumor site, limiting the effect of sonodynamic therapy and greatly hindering their widespread application in SDT. Summary of the Invention

[0006] The purpose of the present invention is to provide a porphyrin-based oxygen-carrying polymer sonosensitizer and its preparation method and application, so as to solve the shortcomings of existing porphyrin-derived sonosensitizers in SDT applications and improve the tumor treatment effect.

[0007] To achieve the above objectives, the present invention provides a porphyrin-based oxygen-carrying polymer sonosensitizer, which has porphyrin as the main structure and polyheptafluorobutyramide as the polymer side chain. The specific structural formula is as follows:

[0008]

[0009] Wherein, m is the degree of polymerization, m=40~60.

[0010] The porphyrin-based oxygen-carrying polymer sonosensitizer of the present invention has a porphyrin main structure that provides a sonodynamic effect. It contains polymeric side chains that are used to modify oxygen-carrying perfluorocompounds to enhance the sonodynamic effect. The heptafluorobutyramide on the side chain is covalently linked to the polymer side end, forming a polyheptafluorobutyramide that can carry oxygen. Under ultrasound activation, the perfluoroalkyl-containing polymer undergoes a change, resulting in an explosive release of oxygen. This process helps enhance the effectiveness of sonodynamic therapy for tumors. When triggered by visible light, it can increase oxygen supply, alleviate tumor hypoxia, reverse the hypoxic microenvironment, enhance the production of ROS during SDT, and improve the accumulation efficiency at the tumor site, thereby enhancing the effectiveness of SDT for tumor treatment.

[0011] The present invention also provides a method for preparing the above-mentioned porphyrin oxygen-carrying polymer sonosensitizer, comprising the following steps:

[0012] S1. In a light-proof environment, a porphine monomer, triethylamine, and 2-bromoisobutyryl bromide are mixed with a solvent and reacted under nitrogen protection to prepare molecule 1;

[0013] S2. In a light-proof environment, molecule 1 and N-succinimidyl acrylate are mixed with a solvent, and then a catalyst is added. N,N,N',N",N"-pentamethyldiethylenetriamine is added under nitrogen protection to carry out an atom transfer radical polymerization reaction to prepare polymer 1;

[0014] S3. In a light-proof condition, polymer 1 and heptafluorobutyramide were added to a solvent, and triethylamine was added under nitrogen protection to carry out an amidation reaction to prepare polymer 2, i.e., a porphyrin-based oxygen-carrying polymer sonosensitizer.

[0015] Preferably, the molar ratio of the porphine monomer, triethylamine and 2-bromoisobutyryl bromide in S1 is 1:8:15.

[0016] Preferably, the solvent in S1 is dichloromethane, the reaction temperature is 25° C., and the reaction time is 48 h.

[0017] Preferably, the molar ratio of molecule 1 to acrylate-N-succinimide ester in S2 is 1:50-200.

[0018] Preferably, the solvent in S2 is anisole and the catalyst is cuprous bromide.

[0019] Preferably, the reaction temperature of the atom transfer radical polymerization reaction in S2 is 80-100° C., and the reaction time is 9-12 h.

[0020] Preferably, the molar ratio of polymer 1 to heptafluorobutyramide in S3 is 1:1.2.

[0021] Preferably, the solvent in S3 is N,N-dimethylformamide, the reaction temperature of the amidation reaction is 35-60° C., and the reaction time is 24-60 h.

[0022] The present invention also provides an application of the porphyrin oxygen-carrying polymer sonosensitizer, which is used in a targeted sonosensitizer complex for sonodynamic therapy.

[0023] Beneficial effects of the present invention:

[0024] (1) The porphyrin-based oxygen-carrying polymer sonosensitizer of the present invention has a porphyrin main structure to provide sonodynamic effects, contains polymer side chains to modify oxygen-carrying perfluoro compounds, and improves the sonodynamic effects. The heptafluorobutyramide on the side chain is connected to the side end of the polymer by a covalent bond. The contained polyheptafluorobutyramide can not only carry oxygen, but also the perfluoroalkyl modified polymer can explosively release oxygen under the activation of ultrasound. The perfluoroalkyl modified polymer triggered by visible light increases oxygen supply to alleviate tumor hypoxia, reverses the hypoxic microenvironment, enhances the generation of reactive oxygen species during SDT, further improves the accumulation efficiency of the tumor site, and improves the effect of SDT in treating tumors;

[0025] (2) The preparation method of the porphyrin oxygen-carrying polymer sonosensitizer of the present invention has clear steps, mild reaction conditions, easy operation and control, and is suitable for large-scale preparation;

[0026] (3) The porphyrin-based oxygen-carrying polymer sonosensitizer of the present invention has the advantages of improving tumor targeting enrichment, alleviating hypoxia, and increasing oxygen supply when used in SDT to treat tumors, and is expected to become an effective method for enhancing chemosonic dynamics therapy of hypoxic tumors.

[0027] The technical solution of the present invention is further described in detail below through the accompanying drawings and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 is the absorption spectrum of molecule 1 prepared in Example 1 of the present invention;

[0029] Figure 2 is the absorption spectrum of polymer 2 prepared in Example 1 of the present invention;

[0030] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of molecule 1 prepared in Example 1 of the present invention;

[0031] Figure 4 is the hydrogen nuclear magnetic resonance spectrum of polymer 1 prepared in Example 1 of the present invention;

[0032] Figure 5 is the hydrogen nuclear magnetic resonance spectrum of polymer 2 prepared in Example 1 of the present invention;

[0033] Figure 6 fluorine spectrum of polymer 2 prepared in Example 1 of the present invention;

[0034] Figure 7 is the oxygen loading diagram of polymer 2 prepared in Example 1 of the present invention;

[0035] Figure 8 is the sonodynamic diagram of the reference molecule DPBF of the present invention;

[0036] Figure 9 is the sonodynamic diagram of polymer 2 prepared in Example 1 of the present invention;

[0037] Figure 10 This is the sonodynamic diagram of polymer 2 after oxygen loading obtained in Example 1 of the present invention;

[0038] Figure 11 This is a cell survival rate graph showing the cytotoxicity of the targeted porphyrin-based oxygen-carrying small molecule sonosensitizer prepared in Example 1 of the present invention to mouse breast cancer cells. DETAILED DESCRIPTION

[0039] The present invention is further described below with reference to the accompanying drawings and examples. Unless otherwise defined, technical or scientific terms used herein shall have the same meanings as those commonly understood by persons of ordinary skill in the art to which the present invention pertains. The above-mentioned features or features described in the specific examples of the present invention may be combined in any manner. These specific examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention.

[0040] The present invention provides a porphyrin-based oxygen-carrying polymer sonosensitizer, which has porphyrin as the main structure and polyheptafluorobutyramide as the polymer side chain. The specific structural formula is as follows:

[0041]

[0042] Wherein, m is the degree of polymerization, m=40~60.

[0043] The present invention also provides a method for preparing the above-mentioned porphyrin oxygen-carrying polymer sonosensitizer, comprising the following steps:

[0044] S1. In a light-proof environment, a porphine monomer, triethylamine, and 2-bromoisobutyryl bromide are mixed with a solvent and reacted under nitrogen protection to prepare molecule 1;

[0045] S2. In a light-proof environment, molecule 1 and N-succinimidyl acrylate are mixed with a solvent, and then a catalyst is added. N,N,N',N",N"-pentamethyldiethylenetriamine is added under nitrogen protection to carry out an atom transfer radical polymerization reaction to prepare polymer 1;

[0046] S3. In a light-proof condition, polymer 1 and heptafluorobutyramide were added to a solvent, and triethylamine was added under nitrogen protection to carry out an amidation reaction to prepare polymer 2, i.e., a porphyrin-based oxygen-carrying polymer sonosensitizer.

[0047] In some embodiments of the present invention, the specific structural formula of molecule 1 in S1 is as follows:

[0048]

[0049] In some embodiments of the present invention, the specific structural formula of polymer 1 in S2 is as follows:

[0050]

[0051] Preferably, the molar ratio of the porphine monomer, triethylamine and 2-bromoisobutyryl bromide in S1 is 1:8:15.

[0052] In some embodiments of the present invention, the porphine monomer in S1 is 5,10,15,20-tetrakis(4-hydroxyphenyl)-2H,24H-porphine.

[0053] In some embodiments of the present invention, in S1, the porphine monomer is first added to a solvent to completely dissolve it, and then vacuum-treated. Then, triethylamine is added, and after stirring at room temperature for 30 minutes, 2-bromoisobutyryl bromide is added.

[0054] Preferably, the solvent in S1 is dichloromethane, the reaction temperature is 25° C., and the reaction time is 48 h.

[0055] In some embodiments of the present invention, the amount of dichloromethane in S1 is 20 mL.

[0056] In some embodiments of the present invention, the reaction process of S1 is as follows:

[0057]

[0058] In some embodiments of the present invention, after S1 completes the reaction, the reaction is quenched with water, extracted with dichloromethane, and the product is dried by spin drying and then purified by chromatography to obtain molecule 1. The present invention does not limit the developing solvent used for purification, and any solvent known to those skilled in the art can be used.

[0059] Preferably, the molar ratio of molecule 1 to acrylate-N-succinimide ester in S2 is 1:50-200.

[0060] In some embodiments of the present invention, the molar ratio of molecule 1 to N-succinimidyl acrylate is 1:60.

[0061] In some embodiments of the present invention, the reaction process of S2 is as follows:

[0062]

[0063] Preferably, the solvent in S2 is anisole and the catalyst is cuprous bromide.

[0064] Preferably, the reaction temperature of the atom transfer radical polymerization reaction in S2 is 80-100° C., and the reaction time is 9-12 h.

[0065] In some embodiments of the present invention, the reaction temperature of the atom transfer radical polymerization reaction in S2 is 90° C. and the reaction time is 12 h.

[0066] In some embodiments of the present invention, after the reaction S2 is completed, the product is filtered using an organic filter membrane and then repeatedly precipitated in diethyl ether to obtain polymer 1. The present invention does not limit the number of precipitations, and any number known to those skilled in the art can be used.

[0067] Preferably, the molar ratio of polymer 1 to heptafluorobutyramide in S3 is 1:1.2.

[0068] In some embodiments of the present invention, the reaction process of S3 is as follows:

[0069]

[0070] Preferably, the solvent in S3 is N,N-dimethylformamide (in DMF), the reaction temperature of the amidation reaction is 35-60° C., and the reaction time is 24-60 h.

[0071] In some embodiments of the present invention, the reaction temperature of the amidation reaction in S3 is 50° C., and the reaction time is 48 h.

[0072] In some embodiments of the present invention, after the reaction in S3 is completed, the product is filtered using an organic filter membrane and then repeatedly precipitated in diethyl ether to obtain polymer 2. The present invention does not limit the number of precipitations, and any number known to those skilled in the art can be used.

[0073] The present invention also provides an application of the porphyrin oxygen-carrying polymer sonosensitizer, which is used in a targeted sonosensitizer complex for sonodynamic therapy.

[0074] Example 1

[0075] The present invention provides a method for preparing a porphyrin-based oxygen-carrying polymer sonosensitizer, comprising the following steps:

[0076] S1. In a light-proof environment, the acceptor molecule 5,10,15,20-tetrakis(4-hydroxyphenyl)-2H,24H-porphine (100 mg, 0.1 mM) was dissolved in 20 mL of dichloromethane in a reaction tube and vacuum-treated. Then, the donor molecule triethylamine (240 mg, 1.5 mM) was added. After stirring at room temperature for 30 min, the donor molecule 2-bromoisobutyryl bromide (270 mg, 0.8 Mm) was added. The mixture was reacted at 25°C under nitrogen protection for 48 hours. Finally, the reaction was quenched with water. After extraction with dichloromethane, the product was spin-dried and then purified by chromatography to obtain the molecule 1.

[0077] S2. In a light-proof environment, molecule 1 (100 mg) and acrylic acid-N-succinimide ester (796 mg, 5.24 mM) were dissolved in 2 mL of anisole in a reaction tube, and then CuBr catalyst was added. N,N,N',N",N"-pentamethyldiethylenetriamine (200 μL) was added as a ligand under nitrogen protection, and the reaction was carried out at 90°C for 12 hours. After the reaction was completed, the solid catalyst was removed by filtration with an organic filter membrane, and then the mixture was repeatedly precipitated in ether to obtain a reddish-brown conjugated main chain polymer substituted with acrylic acid-N-succinimide ester side chains, polymer 1 (900 mg).

[0078] S3. Under light-shielding conditions, polymer 1 (300 mg) and heptafluorobutyramide (1.75 mmol) were dissolved in 5 mL of DMF, triethylamine (1.75 mmol) was added under nitrogen protection, and the mixture was stirred at 50°C for 48 h. After the reaction, the solid catalyst was removed by filtration using an organic filter membrane, and the mixture was repeatedly precipitated in ether to obtain polymer 2, i.e., a porphyrin-based oxygen-carrying polymer sonosensitizer.

[0079] Example 2

[0080] The present invention provides a method for preparing a porphyrin-based oxygen-carrying polymer sonosensitizer, comprising the following steps:

[0081] S1. In a light-proof environment, the acceptor molecule 5,10,15,20-tetrakis(4-hydroxyphenyl)-2H,24H-porphine (100 mg, 0.1 mM) was dissolved in 20 mL of dichloromethane in a reaction tube and vacuum-treated. Then, the donor molecule triethylamine (240 mg, 1.5 mM) was added. After stirring at room temperature for 30 min, the donor molecule 2-bromoisobutyryl bromide (270 mg, 0.8 Mm) was added. The mixture was reacted at 25°C under nitrogen protection for 48 hours. Finally, the reaction was quenched with water. After extraction with dichloromethane, the product was spin-dried and then purified by chromatography to obtain the molecule 1.

[0082] S2. In a light-proof environment, molecule 1 (100 mg) and acrylic acid-N-succinimide ester (796 mg, 5.24 mM) were dissolved in 2 mL of anisole in a reaction tube, and then CuBr catalyst was added. N,N,N',N",N"-pentamethyldiethylenetriamine (200 μL) was added as a ligand under nitrogen protection, and the reaction was carried out at 80°C for 12 h. After the reaction was completed, the solid catalyst was removed by filtration with an organic filter membrane, and then the mixture was repeatedly precipitated in diethyl ether to obtain a reddish-brown conjugated main chain polymer substituted with acrylic acid-N-succinimide ester side chains, polymer 1 (900 mg).

[0083] S3. Under light-shielding conditions, polymer 1 (300 mg) and heptafluorobutyramide (1.75 mmol) were dissolved in 5 mL of DMF, triethylamine (1.75 mmol) was added under nitrogen protection, and the mixture was stirred at 35°C for 60 h. After the reaction, the solid catalyst was removed by filtration using an organic filter membrane, and the mixture was repeatedly precipitated in ether to obtain polymer 2, i.e., a porphyrin-based oxygen-carrying polymer sonosensitizer.

[0084] Example 3

[0085] The present invention provides a method for preparing a porphyrin-based oxygen-carrying polymer sonosensitizer, comprising the following steps:

[0086] S1. In a light-proof environment, the acceptor molecule 5,10,15,20-tetrakis(4-hydroxyphenyl)-2H,24H-porphine (100 mg, 0.1 mM) was dissolved in 20 mL of dichloromethane in a reaction tube and vacuum-treated. Then, the donor molecule triethylamine (240 mg, 1.5 mM) was added. After stirring at room temperature for 30 min, the donor molecule 2-bromoisobutyryl bromide (270 mg, 0.8 Mm) was added. The mixture was reacted at 25°C under nitrogen protection for 48 hours. Finally, the reaction was quenched with water. After extraction with dichloromethane, the product was spin-dried and then purified by chromatography to obtain the molecule 1.

[0087] S2. In a light-proof environment, molecule 1 (100 mg) and acrylic acid-N-succinimide ester (796 mg, 5.24 mM) were dissolved in 2 mL of anisole in a reaction tube, and then CuBr catalyst was added. N,N,N',N",N"-pentamethyldiethylenetriamine (200 μL) was added as a ligand under nitrogen protection, and the reaction was carried out at 100°C for 9 h. After the reaction was completed, the solid catalyst was removed by filtration with an organic filter membrane, and then the mixture was repeatedly precipitated in ether to obtain a reddish-brown conjugated main chain polymer substituted with acrylic acid-N-succinimide ester side chains, polymer 1 (900 mg).

[0088] S3. Under light-shielding conditions, polymer 1 (300 mg) and heptafluorobutyramide (1.75 mmol) were dissolved in 5 mL of DMF, triethylamine (1.75 mmol) was added under nitrogen protection, and the mixture was stirred at 60°C for 24 h. After the reaction, the solid catalyst was removed by filtration using an organic filter membrane, and the mixture was repeatedly precipitated in ether to prepare polymer 2, i.e., a porphyrin-based oxygen-carrying polymer sonosensitizer.

[0089] Characterization experiments and performance testing

[0090] The organic solution of molecule 1 and polymer 2 in Example 1 was prepared using dichloromethane as an organic solvent, and its absorption spectrum was tested. The molecule 1, polymer 1 and polymer 2 prepared in Example 1 were subjected to nuclear magnetic resonance detection. The results are as follows: Figure 1-5 shown.

[0091] from Figure 1 From the absorption spectrum, we can see that the absorption peak of molecule 1 is located in the 500nm band; Figure 3 The H NMR spectrum of can show characteristic proton signals with the same structure as molecule 1, which shows that Example 1 successfully prepared molecule 1.

[0092] from Figure 2 From the absorption spectrum, we can see that the absorption peak of polymer 2 is located in the 550nm band; Figure 5The H NMR spectrum of can show characteristic proton signals with the same structure as polymer 2, which shows that polymer 2 was successfully prepared in Example 1.

[0093] from Figure 4 The H NMR spectrum of can show characteristic proton signals with the same structure as polymer 1, which shows that polymer 1 was successfully prepared in Example 1.

[0094] Fluorine spectrum detection: The polymer 2 prepared in Example 1 was subjected to fluorine spectrum detection to obtain the fluorine spectrum of polymer 2, as shown in FIG. Figure 6 As shown, the corresponding characteristic signals can be seen, indicating that heptafluorobutamide has been successfully connected to the side end of the polymer through a covalent bond, and its chemical structure has not been significantly damaged during the synthesis process, ensuring the functional integrity of polyheptafluorobutamide, helping to ensure the reliability of its oxygen carrying and oxygen release properties, thereby improving the stability of the therapeutic effect.

[0095] Oxygen loading test: The oxygen loading test was performed on the polymer 2 prepared in Example 1, with water as the control group, and the oxygen loading diagram of the polymer 2 was obtained, as shown in FIG. Figure 7 As shown in the figure, polymer 2 has oxygen-carrying capacity. After being loaded with oxygen, polymer 2 can store and slowly release oxygen, indicating that it has good oxygen-carrying performance and good stability. This shows that the polyheptafluorobutyramide side chain has successfully played the role of carrying oxygen, providing a material basis for alleviating tumor hypoxia in subsequent sonodynamic therapy, helping to enhance the production of reactive oxygen species and improve the treatment effect.

[0096] Acoustic dynamics test: a saturated solution of the reference molecule DPBF was prepared with ethanol as solvent and its acoustic dynamics was tested as a comparison reference. The results are as follows: Figure 8 As shown; with ethanol: water = 1: 1 solvent preparation of polymer 2 in Example 1 organic solution, test the sonic dynamics, the results are as follows Figure 9 As shown; Also using ethanol: water = 1:1 as solvent, the organic solution of polymer 2 after oxygen loading was prepared and the sonic dynamics was tested. The results are as follows Figure 10 shown.

[0097] By comparison Figures 8-10 It can be seen that different substances (DPBF, polymer 2, polymer 2+oxygen) have different sonodynamic effects at the same time (5 minutes). DPBF, as a reference molecule, can be used as a reference standard for sonodynamic effects. Compared with DPBF, the sonodynamic effect reduction ratio of polymer 2 is 7%, which has obvious sonodynamic effects. The sonodynamic effect reduction ratio of polymer 2+oxygen after oxygen loading is 24%, and the sonodynamic effect is more obvious, which is beneficial to improving the effect of sonodynamic therapy.

[0098] Cytotoxicity test: Polymer 2 of Example 1 was prepared into cell culture fluid with different concentration gradients (the highest polymer concentration was 2 mg / mL), and cultured with mouse breast cancer cells for 4 hours. CCK-8 reagent was added, and the cell survival rate was calculated by measuring the absorbance at 450 nm. The results are as follows: Figure 11 As shown, it can be seen that polymer 2 has very low toxicity to breast cancer cells, indicating that the porphyrin-based oxygen-carrying polymer sonosensitizer prepared by the present invention has good biocompatibility, which makes it less harmful to normal cells when used for tumor treatment, thereby improving the safety and feasibility of sonodynamic therapy.

[0099] Therefore, the porphyrin-based oxygen-carrying polymer sonosensitizer provided by the present invention can effectively bind and store oxygen, has good acoustic response characteristics, good biocompatibility and stability, can enhance the killing effect of sonodynamic therapy on tumor cells, meet the needs of different tumor treatments, and is expected to become a new and efficient tumor treatment drug.

[0100] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit the same. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that they can still modify or replace the technical solutions of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A porphyrin-based oxygen-carrying polymer sonosensitizer, characterized in that: The main structure is porphyrin, and the side chain is polyheptafluorobutyramide. The specific structural formula is as follows: Wherein, m is the degree of polymerization, m=40~60.

2. A method for preparing the porphyrin oxygen-carrying polymer sonosensitizer according to claim 1, characterized in that: The following steps are included: S1. In a light-proof environment, a porphine monomer, triethylamine, and 2-bromoisobutyryl bromide are mixed with a solvent and reacted under nitrogen protection to prepare molecule 1; S2. In a light-proof environment, molecule 1 and N-succinimidyl acrylate are mixed with a solvent, and then a catalyst is added. N,N,N',N",N"-pentamethyldiethylenetriamine is added under nitrogen protection to carry out an atom transfer radical polymerization reaction to prepare polymer 1; S3. In a light-proof condition, polymer 1 and heptafluorobutyramide were added to a solvent, and triethylamine was added under nitrogen protection to carry out an amidation reaction to prepare polymer 2, i.e., a porphyrin-based oxygen-carrying polymer sonosensitizer.

3. The method for preparing a porphyrin-based oxygen-carrying polymer sonosensitizer according to claim 2, wherein: The molar ratio of porphine monomer, triethylamine and 2-bromoisobutyryl bromide in S1 is 1:8:

15.

4. The method for preparing a porphyrin-based oxygen-carrying polymer sonosensitizer according to claim 2, wherein: The solvent in S1 is dichloromethane, the reaction temperature is 25°C, and the reaction time is 48 h.

5. The method for preparing a porphyrin-based oxygen-carrying polymer sonosensitizer according to claim 2, wherein: The molar ratio of molecule 1 to N-succinimidyl acrylate in S2 is 1:50-200.

6. The method for preparing a porphyrin-based oxygen-carrying polymer sonosensitizer according to claim 2, wherein: In S2, the solvent is anisole and the catalyst is cuprous bromide.

7. The method for preparing a porphyrin-based oxygen-carrying polymer sonosensitizer according to claim 2, wherein: The reaction temperature of the atom transfer radical polymerization reaction in S2 is 80-100°C, and the reaction time is 9-12h.

8. The method for preparing a porphyrin-based oxygen-carrying polymer sonosensitizer according to claim 2, wherein: The molar ratio of polymer 1 to heptafluorobutyramide in S3 is 1:1.

2.

9. The method for preparing a porphyrin-based oxygen-carrying polymer sonosensitizer according to claim 2, wherein: The solvent in S3 is N,N-dimethylformamide, the reaction temperature of the amidation reaction is 35-60° C., and the reaction time is 24-60 h.

10. A use of the porphyrin oxygen-carrying polymer sonosensitizer according to claim 1, characterized in that: Used in targeted sonosensitizer complexes for sonodynamic therapy.

Images