Preparation method of cisplatin chloride modified blood purification filter membrane and corresponding purification membrane

Abstract

The present invention discloses a preparation method of a cisplatin chloride modified blood purification filter membrane and a corresponding purification membrane, which belongs to the field of medical technology. The inventors of the present application have found a blood purification membrane that can provide a blood purification effect and can also achieve the anti-cancer effect by administering anti-cancer drugs through a large number of experiments. The present invention provides a method for effectively combining cisplatin with a blood purification membrane, and allowing cisplatin to be released from the blood purification filter membrane after contact with blood. Cisplatin reaches cancer cells with the blood, thereby playing an anti-cancer role. At the same time, the blood purification membrane can also remove metabolites produced in the anti-cancer process, thereby avoiding the nephrotoxicity caused by cisplatin. The method of the present invention can also increase the binding rate of cisplatin and polyethersulfone, thereby increasing the preparation yield. The cisplatin chloride modified blood purification membrane prepared by the chemical grafting method of the present invention has the effect of slowly releasing cisplatin, and is particularly suitable for blood purification treatment of tumor patients.

Description

Technical Field

[0001] The present invention relates to a method for preparing a biological material with anti-tumor performance, in particular to a method for preparing a cisplatin chloride modified blood purification filter membrane that needs to be in contact with blood. Background Art

[0002] Blood purification technologies, represented by hemodialysis, are increasingly used clinically, particularly in critical care. Malignant tumors are one of the three major killers of human health, and their incidence is increasing year by year. Tumors can easily lead to kidney damage and renal insufficiency during their development and treatment, necessitating blood purification therapy. Cancer patients receiving blood purification therapy represent a unique group, most of whom have severe and complex underlying medical conditions, compromised immunity, and a poor prognosis.

[0003] Despite significant advancements in blood purification technology, the treatment remains invasive. Cancer patients experience significantly higher rates of complications such as thrombosis, infection, and allergies during blood purification than other patients. Therefore, minimizing the use of invasive treatments (such as chemotherapy, radiotherapy, and invasive testing or treatment) is crucial for cancer patients, as long as their condition allows.

[0004] Blood purification therapy relies on a blood purification filter composed of hollow fiber membranes, most of which are artificially synthesized from polymer materials. Currently, modifications to blood purification filter membrane materials primarily focus on improving their anticoagulant, anti-inflammatory, and biocompatibility properties. For example, heparin or heparin-like molecules are coated onto dialysis membrane materials to impart anticoagulant activity; avacopan is grafted onto dialysis membrane materials to impart anti-inflammatory properties; and albumin is grafted onto dialysis membrane materials to improve biocompatibility. However, research on blood purification filter membranes with anti-tumor properties has yet to be reported. Summary of the Invention

[0005] Principle of the invention:

[0006] The inventors of the present application have noted that cisplatin is an anti-tumor chemotherapy drug with good effects and is widely used in the treatment of malignant tumors such as lung cancer, ovarian cancer, prostate cancer, testicular cancer, nasopharyngeal cancer, and esophageal cancer. Cisplatin Cisplatin is primarily administered via intravenous infusion, and nephrotoxicity is one of its most significant side effects. Clinically, to prevent cisplatin-induced kidney damage, adequate hydration is generally recommended 2 to 16 hours before and within 6 hours after administration. Despite this, some patients may experience renal impairment and may even require blood purification therapy to remove toxins and restore renal function.

[0007] The single mode of administration and nephrotoxicity are the main reasons restricting the clinical application of cisplatin.

[0008] Based on this, the inventors hope to combine the anti-cancer effects of cisplatin with its blood purification function: by combining cisplatin with a blood purification membrane, cisplatin will be released from the blood purification filter membrane after contact with blood. Cisplatin will then reach cancer cells with the blood, thereby exerting its anti-cancer effect. The blood purification process can also remove metabolic toxins. In this way, the inventors have achieved the ability to administer cisplatin during a single blood purification process (which generally lasts for several hours). This not only expands the administration methods of anti-cancer drugs, but also achieves blood purification treatment, solves the problem of nephrotoxicity during cisplatin anti-cancer treatment, and reduces the number of "invasive" treatments and medical burdens for cancer patients, achieving multiple goals at one stroke.

[0009] However, one difficulty in solving this problem is that cisplatin is a three-dimensional metallic platinum structure, which is not easy to combine with the organic materials commonly used in blood purification membranes. On the other hand, the combination process of cisplatin and organic materials must be reversible after contact with blood, that is, cisplatin needs to be and easily released from the organic material.

[0010] To address this problem, the inventors of this application conducted extensive experiments and ultimately found a method for preparing a purification membrane that can effectively combine cisplatin with an organic purification membrane and easily release it into the blood, thereby increasing the binding rate and achieving an anti-cancer effect.

[0011] Specifically, the present invention provides a method for preparing a cisplatin chloride modified blood purification filter membrane, the method comprising:

[0012] Step (1) constructing a vacuum and anhydrous reaction space, filling the reaction space with nitrogen, dissolving freeze-dried polyethersulfone in an ultra-dry organic solvent, and stirring thoroughly to obtain a polyethersulfone solution, preparing anhydrous aluminum chloride and acetyl chloride under vacuum and anhydrous conditions, and then mixing the polyethersulfone solution with the anhydrous aluminum chloride and acetyl chloride, reacting for a predetermined time, and drying to obtain acetylated polyethersulfone;

[0013] Step (2) taking the acetylated polyethersulfone and fully dissolving it in an ultra-dry organic solvent, then sequentially adding potassium permanganate, sodium hydroxide, and double-distilled water, reacting for a predetermined time, preparing a dilute hydrochloric acid solution with a pH of 1, and slowly pouring the obtained dark yellow liquid into the prepared dilute hydrochloric acid solution, and the precipitated white cloudy precipitate is the carboxylated polyethersulfone;

[0014] Step (3) dissolving the carboxylated polyethersulfone in an ultra-dry organic solvent, adding thionyl chloride and mixing, washing the reaction product, and vacuum drying to constant weight to obtain chlorinated polyethersulfone;

[0015] Step (4) dissolving cisplatin in double-distilled water, adding hydrogen peroxide, reacting at 50° C. in the dark for 1 h, repeatedly washing the reaction product with double-distilled water, and vacuum drying to constant weight to obtain oxidized cisplatin;

[0016] Step (5) dissolving the products obtained in step (3) and step (4) in an ultra-dry thionyl chloride organic solvent to carry out a grafting reaction at a reaction temperature of 25° C. in the dark for 12 h, and vacuum drying to constant weight to obtain cisplatin chloride modified polyethersulfone.

[0017] Step (6) dissolving the cisplatin chloride modified polyethersulfone and polyethersulfone in an ultra-dry organic solvent to prepare an 18% solution, and adopting an immersion precipitation phase conversion method to prepare a cisplatin chloride modified polyethersulfone blood purification filter membrane.

[0018] In a preferred implementation, in step (1), the reaction temperature is 80-100°C, in step (2), the reaction temperature is 80-90°C, the reaction is carried out for 3-5 hours, and then cooled to room temperature, and in step (3), the reaction temperature is 40°C, and the reaction is carried out for 3-5 hours.

[0019] In a preferred implementation, in step (5), the reaction temperature is 20-40°C, preferably 25-30°C.

[0020] In a preferred implementation, the mass ratio of each substance is as follows:

[0021] In step 1, the ratio of polyethersulfone to acetyl chloride is 1 to 3; in step 2, the ratio of potassium permanganate to sodium hydroxide is 1 to 6; in step 3, the ratio of carboxylated polyethersulfone to thionyl chloride is 1 to 4; in step 4, the ratio of cisplatin to hydrogen peroxide is 1:10; in step 5, the ratio of acylated polyethersulfone to oxidized cisplatin is 3 to 1; and in step 6, the mass fraction of modified polyethersulfone is 15% to 30%.

[0022] In a preferred implementation, the ultra-dry organic solvent includes at least one of N-methylpyrrolidone, N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, and chloroform.

[0023] On the other hand, the present invention provides a cisplatin chloride modified blood purification filter membrane, which includes an acyl chloride molecular layer grafted on a biological material and cisplatin grafted on the acyl chloride group. The cisplatin chloride modified blood purification filter membrane is prepared using the described method.

[0024] In another preferred implementation, the biomaterial is a polymer material, metal, or 3D printing material that can be used in the medical field and is soluble in organic solvents but insoluble in water.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] Through extensive experiments, the present invention broadens the administration methods for cisplatin, enabling a novel chemotherapy treatment for cancer patients requiring blood purification, allowing simultaneous administration of the anticancer drug cisplatin during blood purification. Furthermore, the present invention addresses the difficulty in binding cisplatin to polyethersulfone, improving both the yield and the grafting efficiency of blood purification filter membranes composed of cisplatin grafted onto polyethersulfone.

[0027] The method of the present invention first prepares polyethersulfone chloride, then oxidizes cisplatin. The polyethersulfone chloride and oxidized cisplatin then react to graft cisplatin onto the polyethersulfone membrane. During blood purification therapy, cisplatin dissociates from the polyethersulfone membrane, simultaneously purifying blood and providing anti-tumor effects. This invention is the first to propose a technique for preparing a blood purification filter membrane with anti-tumor effects, particularly suitable for blood purification therapy for cancer patients.

[0028] The present invention has mild reaction conditions, requires low-cost polymer materials, reagents, and drugs, and is economical and environmentally friendly. The entire modification process is simple and easy to carry out, suitable for industrial production and easy to promote. The modified blood purification filter membrane also has anti-tumor effects and has great application prospects.

[0029] The blood purification filter membrane modified by the method provided by the present invention has grafted drug molecules that still have good anti-tumor effects, while the bulk properties of the polymer material are not significantly affected.

[0030] The cisplatin chloride-modified polyethersulfone membrane of the present invention, upon contact with blood and entry into cells, undergoes two electron reduction reactions of the Pt(IV) complex under the action of a cellular reducing agent, such as glutathione or ascorbic acid, thereby regenerating the original square planar Pt(II) cisplatin drug and releasing two polyethersulfone ligands. This causes cisplatin to dissociate from the membrane material and slowly release it, allowing cancer patients to receive anti-tumor treatment while undergoing blood purification. This cisplatin chloride-modified blood purification filter membrane has both blood purification and anti-tumor effects, thereby reducing the number of "invasive" treatments and the medical burden on cancer patients, achieving a "three-pronged" effect and benefiting cancer patients requiring blood purification treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 Schematic diagram showing the anti-tumor mechanism of cisplatin chloride-modified polyethersulfone blood purification filter membrane.

[0032] Figure 2 The following is a reaction formula for preparing polyethersulfone chlorinated.

[0033] Figure 3 The reaction formula for the preparation of oxidized cisplatin is shown.

[0034] Figure 4The preparation of cisplatin chloride modified polyethersulfone blood purification filter membrane and the cisplatin release reaction formula are shown. DETAILED DESCRIPTION

[0035] The present invention will be described in detail below with reference to the accompanying drawings and embodiments thereof, but the protection scope of the present invention is not limited to the scope of the embodiments described herein.

[0036] Example 1

[0037] ① Weigh 10g of freeze-dried PES and put it into a 250ml round-bottom flask. Use a vacuum pump to evacuate and fill it with nitrogen. Draw 50ml of N-methylpyrrolidone ultra-dry solvent and inject it into the round-bottom flask. Heat and stir for 15 minutes. It can be seen that polyethersulfone is completely dissolved in N-methylpyrrolidone ultra-dry solvent to form a homogeneous solution. Place the constructed reaction system in a 0℃ water bath, and quickly add 4g of anhydrous aluminum chloride, 8ml of acetyl chloride, and 20ml of N-methylpyrrolidone ultra-dry solvent to the reaction system. Adjust the temperature of the reaction system to 60℃ and react for 4h. After the reaction is completed, cool to room temperature and slowly pour the solution into double-distilled water to obtain a brown solid. Repeatedly wash with double-distilled water several times to remove residual solvents. Vacuum dry at 60℃ to constant weight to obtain acetylated polyethersulfone. The reaction process is as follows Figure 2 shown.

[0038] ② Dissolve 10g of acetylated polyethersulfone in 50ml of N-methylpyrrolidone and stir magnetically at room temperature for 15 minutes to obtain a homogeneous solution. Add 0.8g of potassium permanganate, 2.4g of sodium hydroxide, 9g of double-distilled water, and 40ml of N-methylpyrrolidone in that order. Adjust the reaction temperature to 60°C and allow to react for 4 hours. After the reaction is complete, cool to room temperature and pour into a dilute hydrochloric acid solution (pH = 1). A white, cloudy precipitate will form. Refrigerate in a 4°C refrigerator for 4 hours, filter, and vacuum dry at 60°C to obtain the carboxylated polyethersulfone.

[0039] ③ Dissolve 10g of carboxylated polyethersulfone in 50ml of N,N-dimethylformamide and stir magnetically at room temperature for 15 minutes to obtain a homogeneous solution. Add 3.6ml (0.8 equivalents) of thionyl chloride and adjust the reaction temperature to 25°C for 4 hours. After the reaction, cool to room temperature, rinse several times with ethanol, and dry under vacuum at 60°C to obtain the chlorinated polyethersulfone.

[0040] ④ Dissolve 3g of cisplatin in 200ml of double-distilled water, add 150mL of 30% hydrogen peroxide (10 times excess) while stirring, adjust the temperature of the reaction system to 20℃, and react for 1h in the dark. After the solution turns light yellow and dissolves, filter it while hot, then place the filtrate in a 4℃ refrigerator for recrystallization for about 4h, filter it, and wash it with cold water, cold ether, and cold ethanol for about three times to finally obtain light yellow crystals of oxidized cisplatin. Dry the sample in a vacuum in the dark. The reaction process of this step is as follows: Figure 3 shown.

[0041] ⑤ Take 1g of polyethersulfone chloride and 0.5g of cisplatin oxide and dissolve them in 80ml of ultra-dry N,N-dimethylformamide to make the compound evenly suspended. Adjust the temperature of the reaction system to 25℃ and react in the dark for 12h. After the reaction is completed, filter the reaction solution through diatomaceous earth and freeze-dry the filtrate using a vacuum freeze dryer. After the filtrate is freeze-dried, wash it 3 times with 5mL of dichloromethane and 40mL of anhydrous ether respectively, collect the product by centrifugation, and finally dry it in vacuum at room temperature to obtain a gray solid cisplatin chloride modified polyethersulfone. The process is as follows: Figure 4 The yield was determined by measuring the ratio of the total mass of the reaction products to the total mass of the starting materials, and the yield was approximately 68%.

[0042] ⑥ Take 0.2g of cisplatin chloride modified polyethersulfone and 1g of polyethersulfone and dissolve them in 5.5ml of N-methylpyrrolidone solvent to make an 18% solution. Use the immersion precipitation phase conversion method to prepare a cisplatin chloride modified polyethersulfone blood purification filter membrane.

[0043] Verification of grafting:

[0044] The unused blood purification membrane was soaked in physiological saline for 5-10 hours, and the filtrate was collected for later use. The used blood purification membrane was soaked in the same physiological saline for 5-10 hours, and the filtrate was collected. The content of metallic platinum in the filtrate was then detected by metal analysis spectroscopy. No metallic platinum peak was detected in the filtrate before use, but a metallic platinum peak was detected in the filtrate after use, proving that cisplatin has been successfully grafted to the purification membrane and can be released.

[0045] like Figure 4 As shown in the lower half, upon contact with blood, the polyethersulfone membrane modified with cisplatin chloride of the present invention, once inside cells, undergoes a two-electron reduction reaction under the action of cellular reducing agents such as glutathione or ascorbic acid, regenerating the original square planar Pt(II) cisplatin drug and releasing two polyethersulfone ligands. This results in cisplatin dissociating from the membrane material and slowly releasing it, allowing cancer patients to receive anti-tumor treatment while undergoing blood purification.

[0046] Example 2

[0047] ① Weigh 10g of freeze-dried PES into a 250ml round-bottom flask. Evacuate with a vacuum pump and fill with nitrogen. Pipette 50ml of N-methylpyrrolidone into the flask and heat with stirring for 15 minutes. Polyethersulfone should dissolve completely in the N-methylpyrrolidone to form a homogeneous solution. Place the reaction system in a 0°C water bath. Quickly add 5.5g of anhydrous aluminum trichloride, 8ml of acetyl chloride, and 20ml of N-methylpyrrolidone. Adjust the reaction temperature to 90°C and allow the reaction to proceed for 2 hours. After the reaction is complete, cool to room temperature and slowly pour the solution into deionized water to yield a brown solid. Rinse the solid several times with deionized water to remove any residual solvent. Dry the solid under vacuum at 60°C to a constant weight to obtain acetylated polyethersulfone.

[0048] ② Dissolve 10g of acetylated polyethersulfone in 50ml of N-methylpyrrolidone and stir magnetically at room temperature for 15 minutes to obtain a homogeneous solution. Add 1.2g of potassium permanganate, 3.7g of sodium hydroxide, 9g of double-distilled water, and 40ml of N-methylpyrrolidone in that order. Adjust the reaction temperature to 80°C and allow to react for 4 hours. After the reaction is complete, cool to room temperature and pour into a dilute hydrochloric acid solution (pH = 1). A white, cloudy precipitate will form. Refrigerate in a 4°C refrigerator for 4 hours, filter, and vacuum dry at 60°C to obtain the carboxylated polyethersulfone.

[0049] ③ Dissolve 10g of carboxylated polyethersulfone in 50ml of N,N-dimethylformamide and stir magnetically at room temperature for 15 minutes to obtain a homogeneous solution. Add 5ml (1.1 equivalents) of thionyl chloride and adjust the reaction temperature to 40°C for 4 hours. After the reaction, cool to room temperature, rinse several times with ethanol, and dry under vacuum at 60°C to obtain the chlorinated polyethersulfone.

[0050] ④ Dissolve 3g of cisplatin in 200ml of double-distilled water. Add 150ml of 30% hydrogen peroxide (10-fold excess) while stirring. Adjust the reaction temperature to 50°C and react for 1 hour in the dark. Once the solution turns light yellow and dissolves, filter it while hot. Place the filtrate in a 4°C refrigerator for recrystallization for approximately 4 hours. Filter and wash three times with cold water, cold ether, and cold ethanol to obtain pale yellow cisplatin oxide crystals. Dry the sample in a vacuum oven in the dark.

[0051] ⑤ Dissolve 1g of polyethersulfone chloride and 1g of cisplatin oxide in 80ml of ultra-dry N,N-dimethylformamide to homogenize the mixture. Adjust the reaction system temperature to 25°C and incubate in the dark for 12 hours. After completion, filter the reaction mixture through diatomaceous earth and lyophilize the filtrate using a vacuum freeze dryer. After lyophilization, wash the filtrate three times with 5ml of dichloromethane and 40ml of anhydrous ether, respectively. Collect the product by centrifugation and finally dry it under vacuum at room temperature to obtain a gray solid, cisplatin chloride-modified polyethersulfone. The yield is determined by measuring the total mass of the reaction product to the total mass of the starting materials, which is approximately 71%.

[0052] ⑥ Take 0.5g of cisplatin chloride modified polyethersulfone and 1g of polyethersulfone and dissolve them in 6.8ml of N-methylpyrrolidone solvent to make an 18% solution. Use the immersion precipitation phase conversion method to prepare a cisplatin chloride modified polyethersulfone blood purification filter membrane.

[0053] Example 3

[0054] ① Weigh 10g of freeze-dried PES into a 250ml round-bottom flask. Evacuate with a vacuum pump and fill with nitrogen. Pipette 50ml of N-methylpyrrolidone into the flask and heat with stirring for 15 minutes. Polyethersulfone should dissolve completely in the N-methylpyrrolidone to form a homogeneous solution. Place the reaction system in a 0°C water bath. Quickly add 5.5g of anhydrous aluminum trichloride, 8ml of acetyl chloride, and 20ml of N-methylpyrrolidone. Adjust the temperature of the reaction system to 100°C and allow the reaction to proceed for 12 hours. After the reaction is complete, cool to room temperature and slowly pour the solution into deionized water to obtain a brown solid. Rinse the solid several times with deionized water to remove any residual solvent. Dry the solid under vacuum at 60°C to a constant weight to obtain acetylated polyethersulfone.

[0055] ② Dissolve 10g of acetylated polyethersulfone in 50ml of N-methylpyrrolidone and stir magnetically at room temperature for 15 minutes to obtain a homogeneous solution. Add 1.4g of potassium permanganate, 4.4g of sodium hydroxide, 9g of double-distilled water, and 40ml of N-methylpyrrolidone in that order. Adjust the reaction temperature to 100°C and allow to react for 6 hours. After the reaction, cool to room temperature and pour into a dilute hydrochloric acid solution (pH = 2). A white, cloudy precipitate will form. Refrigerate in a 4°C refrigerator for 4 hours, filter, and vacuum dry at 60°C to obtain the carboxylated polyethersulfone.

[0056] ③ Dissolve 10g of carboxylated polyethersulfone in 50ml of N,N-dimethylformamide and stir magnetically at room temperature for 15 minutes to obtain a homogeneous solution. Add 9.1ml (2 equivalents) of thionyl chloride and adjust the reaction temperature to 40°C for 4 hours. After the reaction, cool to room temperature, rinse several times with ethanol, and dry under vacuum at 60°C to obtain the chlorinated polyethersulfone.

[0057] ④ Dissolve 3g of cisplatin in 200ml of double-distilled water. Add 150ml of 30% hydrogen peroxide (10-fold excess) while stirring. Adjust the reaction system temperature to 50°C and react for 2 hours in the dark. Once the solution turns light yellow and dissolves, filter it while hot. Place the filtrate in a 4°C refrigerator for recrystallization for approximately 4 hours. Filter and wash the filtrate three times with cold water, cold ether, and cold ethanol to obtain pale yellow crystalline cisplatin oxide. Dry the sample in a vacuum oven in the dark.

[0058] ⑤ Dissolve 1g of polyethersulfone chloride and 1.5g of cisplatin oxide in 80ml of ultra-dry N,N-dimethylformamide to homogenize the mixture. Adjust the reaction system temperature to 30°C and incubate in the dark for 18 hours. After completion, filter the reaction mixture through diatomaceous earth and lyophilize the filtrate using a vacuum freeze dryer. After lyophilization, wash the filtrate three times with 5ml of dichloromethane and 40ml of anhydrous ether, respectively. Collect the product by centrifugation and finally dry it under vacuum at room temperature to obtain a gray solid, cisplatin chloride-modified polyethersulfone. The yield is determined by measuring the total mass of the reaction product to the total mass of the starting materials, which is approximately 69%.

[0059] ⑥ Take 0.8g of cisplatin chloride modified polyethersulfone and 1g of polyethersulfone and dissolve them in 8.2ml of N-methylpyrrolidone solvent to make an 18% solution. Use the immersion precipitation phase conversion method to prepare a cisplatin chloride modified polyethersulfone blood purification filter membrane.

[0060] Comparative Example 1

[0061] ① Weigh 10g of freeze-dried PES into a 250ml round-bottom flask. Evacuate with a vacuum pump and fill with nitrogen. Pipette 50ml of N-methylpyrrolidone into the flask and heat with stirring for 15 minutes. Polyethersulfone should dissolve completely in the N-methylpyrrolidone to form a homogeneous solution. Place the reaction system in a 0°C water bath. Quickly add 4g of anhydrous aluminum trichloride, 8ml of acetyl chloride, and 20ml of N-methylpyrrolidone. Adjust the temperature of the reaction system to 60°C and allow the reaction to proceed for 4 hours. After the reaction is complete, cool to room temperature and slowly pour the solution into deionized water to yield a brown solid. Rinse the solution several times with deionized water to remove any residual solvent. Dry the solution under vacuum at 60°C to a constant weight to obtain acetylated polyethersulfone.

[0062] ② Dissolve 10g of acetylated polyethersulfone in 50ml of N-methylpyrrolidone and stir magnetically at room temperature for 15 minutes to obtain a homogeneous solution. Add 0.8g of potassium permanganate, 2.4g of sodium hydroxide, 9g of double-distilled water, and 40ml of N-methylpyrrolidone in that order. Adjust the reaction temperature to 60°C and allow to react for 4 hours. After the reaction is complete, cool to room temperature and pour into a dilute hydrochloric acid solution (pH = 1). A white, cloudy precipitate will form. Refrigerate in a 4°C refrigerator for 4 hours, filter, and vacuum dry at 60°C to obtain the carboxylated polyethersulfone.

[0063] ③ Dissolve 10g of carboxylated polyethersulfone in 50ml of N,N-dimethylformamide and stir magnetically at room temperature for 15 minutes to obtain a homogeneous solution. Add 3.6ml (0.8 equivalents) of thionyl chloride and adjust the reaction temperature to 25°C for 4 hours. After the reaction, cool to room temperature, rinse several times with ethanol, and dry under vacuum at 60°C to obtain the chlorinated polyethersulfone.

[0064] ④ Dissolve 3g of cisplatin in 200ml of double-distilled water. Add 150ml of 30% hydrogen peroxide (10-fold excess) while stirring. Adjust the reaction system temperature to 20°C and react for 1 hour in the dark. Once the solution turns light yellow and dissolves, filter it while hot. Place the filtrate in a 4°C refrigerator for recrystallization for approximately 4 hours. Filter and wash three times with cold water, cold ether, and cold ethanol to obtain pale yellow crystalline cisplatin oxide. Dry the sample in a vacuum oven in the dark.

[0065] ⑤ Dissolve 1g of polyethersulfone chloride and 0.5g of cisplatin oxide in 80ml of ultra-dry N,N-dimethylformamide until the mixture is evenly suspended. Adjust the reaction system temperature to 10°C and incubate in the dark for 12 hours. After the reaction is complete, filter the reaction mixture through diatomaceous earth and lyophilize the filtrate using a vacuum freeze dryer. After lyophilization, wash the filtrate three times with 5ml of dichloromethane and 40ml of anhydrous ether, respectively. Collect the product by centrifugation and finally dry it in a vacuum at room temperature to obtain a gray solid, cisplatin chloride-modified polyethersulfone. The yield is approximately 32%.

[0066] ⑥ Take 0.2g of cisplatin chloride modified polyethersulfone and 1g of polyethersulfone and dissolve them in 5.5ml of N-methylpyrrolidone solvent to make an 18% solution. Use the immersion precipitation phase conversion method to prepare a cisplatin chloride modified polyethersulfone blood purification filter membrane.

[0067] Comparative Example 2

[0068] The other steps of this comparative example are the same as those of comparative example 1, except that in step ⑤, the following method is adopted:

[0069] 1g of polyethersulfone chloride and 0.5g of cisplatin oxide were dissolved in 80ml of ultra-dry N,N-dimethylformamide to achieve a uniform suspension. The reaction system was maintained at 60°C in the dark for 12 hours. After completion, the reaction solution was filtered through diatomaceous earth, and the filtrate was freeze-dried using a vacuum freeze dryer. After freeze-drying, the filtrate was washed three times with 5ml of dichloromethane and then 40ml of anhydrous ether. The product was collected by centrifugation and finally dried under vacuum at room temperature. The yield was determined by measuring the total mass of the reaction product to the total mass of the starting materials. The grafting reaction efficiency was low, with a yield of less than 30%.

[0070] By repeatedly debugging various parameters, it was determined that when the reaction system temperature in step ⑤ is between 20-40°C, especially between 25-30, the yield of modified polyethersulfone can be greatly improved. When the reaction system temperature is adjusted to below 15°C and the reaction time is 12h, the reaction yield of polyethersulfone modified with cisplatin chloride is less than 35%; under the conditions of 50-80°C, the grafting reaction cannot be carried out effectively, and the reaction yield is less than 30%.

[0071] The present invention not only proposes for the first time the grafting of cisplatin onto a blood purification membrane and its slow release during the blood purification process, thereby changing the single administration method of cisplatin which can only be administered by intravenous drip, but also finds a narrow parameter range that can significantly improve the preparation efficiency of cisplatin chloride-modified polyethersulfone blood purification filter membrane under extremely harsh preparation conditions. This is of great significance for blood purification treatment of cancer patients and has great social and economic benefits.

[0072] Although the principles of the present invention have been described in detail above in conjunction with the preferred embodiments of the present invention, those skilled in the art should understand that the above embodiments are merely illustrative of the present invention and are not intended to limit the scope of the present invention. The details in the embodiments do not constitute a limitation on the scope of the present invention. Without departing from the spirit and scope of the present invention, any obvious changes such as equivalent transformations and simple substitutions based on the technical solution of the present invention fall within the scope of protection of the present invention.

Claims

1. A method for preparing a cisplatin chloride modified blood purification filter membrane, characterized in that: The method comprises: Step (1) constructing a vacuum, anhydrous reaction space, filling the reaction space with nitrogen, dissolving the freeze-dried polyethersulfone in an ultra-dry organic solvent, and stirring thoroughly to obtain a polyethersulfone solution, preparing anhydrous aluminum chloride and acetyl chloride under vacuum, anhydrous conditions, and then mixing the polyethersulfone solution with the anhydrous aluminum chloride and acetyl chloride, reacting for a predetermined time, and drying to obtain acetylated polyethersulfone; Step (2) fully dissolving the acetylated polyethersulfone in an ultra-dry organic solvent, then sequentially adding potassium permanganate, sodium hydroxide, and double-distilled water, reacting for a predetermined time, preparing a dilute hydrochloric acid solution with a pH of 1, and slowly pouring the obtained dark yellow liquid into the prepared dilute hydrochloric acid solution. The precipitated white cloudy precipitate is the carboxylated polyethersulfone; Step (3) dissolving the carboxylated polyethersulfone in an ultra-dry organic solvent, adding thionyl chloride and mixing, washing the reaction product, and vacuum drying to a constant weight to obtain chlorinated polyethersulfone; Step (4) dissolving cisplatin in double-distilled water, adding hydrogen peroxide, reacting at 50°C, protecting from light for 1 hour, repeatedly washing the reaction product with double-distilled water, and vacuum drying to constant weight to obtain oxidized cisplatin; Step (5) dissolving the products obtained in step (3) and step (4) in an ultra-dry thionyl chloride organic solvent, performing a grafting reaction, and vacuum drying to constant weight to obtain cisplatin chloride modified polyethersulfone. In step (5), the reaction temperature is 25-30° C., and the reaction is carried out in the dark for 12 hours. Step (6) dissolving the cisplatin chloride modified polyethersulfone and polyethersulfone in an ultra-dry organic solvent to prepare an 18% solution, and using an immersion precipitation phase conversion method to prepare a cisplatin chloride modified polyethersulfone blood purification filter membrane. The mass ratios of the substances are as follows: in step (1), polyethersulfone:acetyl chloride = 1 to 3; in step (2), potassium permanganate:sodium hydroxide = 1 to 6; in step (3), carboxylated polyethersulfone:dichlorothionyl = 1 to 4; in step (4), cisplatin:hydrogen peroxide = 1:10; in step (5), acylated polyethersulfone:oxidized cisplatin = 3 to 1; The mass fraction of the modified polyethersulfone in step (6) is 15% to 30%.

2. The preparation method according to claim 1, wherein In the step (1), the reaction temperature is 50-100°C; in the step (2), the reaction temperature is 80-90°C, the reaction is carried out for 3-5 hours, and then cooled to room temperature; in the step (3), the reaction temperature is 40°C, and the reaction is carried out for 3-5 hours.

3. The preparation method according to claim 1, wherein The ultra-dry organic solvent includes at least one of N-methylpyrrolidone, N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide and chloroform.

4. A cisplatin chloride modified blood purification filter membrane, characterized in that: The cisplatin chloride modified blood purification filter membrane comprises an acyl chloride molecular layer grafted onto a biological material and cisplatin grafted onto the acyl chloride group. The cisplatin chloride modified blood purification filter membrane is prepared by the method according to any one of claims 1 to 3.

Images