Preparation method of cis-platinum acylating chloride modified blood purification filter membrane and corresponding purification membrane

Abstract

The invention discloses a preparation method of a cis-platinum acylating chloride modified blood purification filter membrane and a corresponding purification membrane, and belongs to the technical field of medicines. The inventor of the application finds a blood purification membrane which can provide a blood purification effect and can also achieve an anti-cancer effect through administration of anti-cancer drugs through a large number of experiments and explorations. The cis-platinum can be effectively combined with the blood purification membrane, the cis-platinum is released from the blood purification filter membrane after being in contact with blood, the cis-platinum reaches cancer cells along with the blood to achieve the anti-cancer effect, meanwhile, the blood purification membrane can also remove metabolites generated in the anti-cancer process, and the anti-cancer effect is achieved. According to the preparation method and the corresponding purification membrane, the binding rate of cis-platinum and polyether sulfone can be increased, and the preparation yield is increased. The cis-platinum acylating chloride modified blood purification membrane prepared by a chemical grafting method has the effect of slowly releasing cis-platinum, and is particularly suitable for blood purification treatment of tumor patients.

Description

Technical Field

[0001] The 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 which needs to be in contact with blood. Background Art

[0002] Blood purification technology represented by hemodialysis is increasingly used in clinical practice, especially in the treatment of critical illnesses. Malignant tumors are one of the three major killers that endanger human health, and the incidence rate is increasing year by year. Tumors are prone to cause kidney damage and renal insufficiency during their occurrence, development and treatment, and blood purification treatment is required. Tumor patients who receive blood purification treatment are a special group, most of whom have severe and complex underlying diseases, low immunity, and poor prognosis.

[0003] Although blood purification technology has made great progress, its treatment is still "invasive". The incidence of complications such as thrombosis, infection, and allergies in cancer patients during blood purification treatment is significantly higher than that of other patients. Therefore, it is very necessary to minimize the "damaging" treatment methods (such as chemotherapy, radiotherapy, invasive examinations or treatments) for cancer patients as much as possible, provided that the condition allows.

[0004] Blood purification therapy requires a blood purification filter composed of hollow fiber filter membranes, and most blood purification membranes are artificially synthesized from polymer materials. At present, the modification of blood purification filter membrane materials is mainly focused on improving their anticoagulant, anti-inflammatory properties and biocompatibility: for example, coating heparin or heparin-like molecules on dialysis membrane materials to make them have anticoagulant activity; grafting Avacopan on dialysis membrane materials to make them have anti-inflammatory effects; grafting albumin on dialysis membrane materials to improve their biocompatibility. However, research on blood purification filter membranes with anti-tumor effects has not been reported. Summary of the invention

[0005] Principle of the invention:

[0006] The inventors of the present application have noticed 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, esophageal cancer, etc. Cisplatin Cisplatin is mainly administered by intravenous drip, and nephrotoxicity is one of the most important side effects of cisplatin. In clinical practice, in order to avoid cisplatin-induced kidney damage, it is usually recommended to fully hydrate 2 to 16 hours before and within 6 hours after administration. Despite this, some patients still experience renal damage and even need blood purification treatment to remove toxins and save renal function.

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

[0008] Based on this, the inventor hopes to combine the anti-cancer effect of cisplatin with the blood purification function: combine cisplatin with the blood purification membrane, release cisplatin from the blood purification filter membrane after contact with blood, and reach cancer cells with blood to play an anti-cancer role, and metabolic toxins can also be removed during the blood purification process. In this way, the inventor has achieved the administration of cisplatin in a single blood purification process (generally lasting several hours), which not only expands the administration method of anti-cancer drugs, but also achieves blood purification treatment, solves the problem of nephrotoxicity in the anti-cancer treatment process of cisplatin, and reduces the number of "damaging" treatments and medical burdens of tumor patients, killing two birds with one stone.

[0009] However, one difficulty in solving this problem is that cisplatin is a three-dimensional metal 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 is easily released from the organic material.

[0010] To address this problem, the inventors of this application conducted a large number of experiments and finally found a method for preparing a purification membrane that can effectively combine cisplatin with an organic purification membrane and easily release it in 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 the freeze-dried polyethersulfone in an ultra-dry organic solvent, and stirring well 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 deionized 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 cloud-like precipitate is the carboxylated polyethersulfone;

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

[0015] Step (4) dissolving cisplatin in double distilled water, adding hydrogen peroxide, reacting at a temperature of 50° C., reacting 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 product obtained in step (3) and step (4) in an ultra-dry thionyl chloride organic solvent to carry out a grafting reaction at a temperature of 25° C. in a dark environment 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 using 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, polyethersulfone:acetyl chloride=1-3; in step 2, potassium permanganate:sodium hydroxide=1-6; in step 3, carboxylated polyethersulfone:dichlorothionyl=1-4; in step 4, cisplatin:hydrogen peroxide=1:10; in step 5, acyl chloride polyethersulfone:oxidized cisplatin=3-1; in step 6, the mass fraction of modified polyethersulfone is 15%-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 by the described method.

[0024] In another preferred implementation, the biomaterial is a polymer material or 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] The present invention has broadened the administration method of cisplatin through a large number of experiments, and has realized a new treatment method for cancer patients who need blood purification, which can be used to administer cisplatin anticancer drugs while purifying blood to achieve chemotherapy. In addition, the present invention solves the problem that cisplatin and polyethersulfone are not easy to combine, and improves the preparation yield of the blood purification filter membrane composed of cisplatin grafted on polyethersulfone and the grafting efficiency of cisplatin.

[0027] The method of the present invention first prepares polyethersulfone chloride, then oxidizes cisplatin, and then reacts polyethersulfone chloride with oxidized cisplatin, thereby grafting cisplatin on the polyethersulfone membrane. When blood purification treatment is performed, cisplatin dissociates from the polyethersulfone membrane, and simultaneously plays a role in blood purification and anti-tumor. The present invention first proposes a blood purification filter membrane preparation technology with anti-tumor effect, which is particularly suitable for blood purification treatment of tumor patients.

[0028] The present invention has mild reaction conditions, low cost of required polymer materials, reagents and drugs, and is economical and environmentally friendly; the entire modification process is simple and easy to implement, 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 grafted drug molecules of the blood purification filter membrane modified by the method provided by the present invention still have good anti-tumor effects, and the bulk properties of the polymer material are not significantly affected.

[0030] After the acyl chloride cisplatin modified polyethersulfone membrane of the present invention comes into contact with blood, once it enters the cell, the Pt(IV) complex will undergo two electron reduction reactions under the action of a cell reducing agent such as glutathione or ascorbic acid, thereby regenerating the original square plane Pt(II) cisplatin drug and releasing two polyethersulfone ligands. This causes cisplatin to dissociate from the membrane material and slowly release, allowing tumor patients to receive anti-tumor treatment while undergoing blood purification. This acyl chloride cisplatin modified blood purification filter membrane has both blood purification function and anti-tumor effect, thereby reducing the number of "damaging" treatments and medical burdens for tumor patients, having the effect of "killing three birds with one stone", and is good news for the majority of tumor patients who need to receive 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 with acyl chloride.

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

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

[0035] The present invention will be described in detail below in conjunction with 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, and vacuum dry at 60℃ to constant weight to obtain acetylated polyethersulfone. The reaction process is as follows Figure 2 shown.

[0038] ② Weigh 10g of acetylated polyethersulfone and dissolve it in 50ml of N-methylpyrrolidone. Stir magnetically at room temperature for 15min 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 sequence. Adjust the temperature of the reaction system to 60℃ and react for 4h. After the reaction is completed, cool it to room temperature and pour it into a dilute hydrochloric acid solution with a pH of 1. A white cloudy precipitate can be seen. Place it in a refrigerator at 4℃ for 4h, filter it, and vacuum dry it at 60℃ to obtain carboxylated polyethersulfone.

[0039] ③ Weigh 10g of carboxylated polyethersulfone and dissolve it in 50ml of N,N-dimethylformamide. Stir magnetically at room temperature for 15min to obtain a homogeneous solution. Add 3.6ml (0.8 equivalent) of thionyl chloride, adjust the temperature of the reaction system to 25℃, and react for 4h. After the reaction is completed, cool to room temperature, wash repeatedly with ethanol several times, and dry in vacuum at 60℃ to obtain chlorinated polyethersulfone.

[0040] ④ Take 3g of cisplatin and dissolve it 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. When the solution turns light yellow and dissolves, filter it while hot. Then put 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. Finally, light yellow crystals of oxidized cisplatin are obtained. The sample is dried 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°C, and react for 12 hours in the dark. After the reaction is completed, filter the reaction solution through diatomaceous earth, and freeze-dry the filtrate with a vacuum freeze dryer. After the filtrate is freeze-dried, wash it three 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 is determined by measuring the total mass ratio of the reaction product to the total mass ratio of the raw materials, and the yield is about 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, and use the immersion precipitation phase conversion method to make 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 standby 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 peak of metallic platinum was detected in the filtrate before use, but a peak of metallic platinum was detected in the filtrate after use, indicating that cisplatin has been successfully grafted to the purification membrane and can be released.

[0045] like Figure 4 As shown in the lower part, after the acyl chloride cisplatin modified polyethersulfone membrane of the present invention comes into contact with blood, once it enters the cell, the Pt(IV) complex will undergo two electron reduction reactions under the action of cell reducing agents 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 be slowly released, allowing tumor patients to receive anti-tumor treatment while undergoing blood purification.

[0046] Example 2

[0047] 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 15min. It can be seen that polyethersulfone is completely dissolved in N-methylpyrrolidone ultra-dry solvent to form a homogeneous solution. Place the reaction system in a 0℃ water bath, and quickly add 5.5g 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 90℃ and react for 2h. After the reaction is completed, cool to room temperature, slowly pour the solution into double distilled water to obtain a brown solid substance, repeatedly wash with double distilled water several times to remove residual solvent, and vacuum dry at 60℃ to constant weight to obtain acetylated polyethersulfone.

[0048] ② Weigh 10g of acetylated polyethersulfone and dissolve it in 50ml of N-methylpyrrolidone. Stir magnetically at room temperature for 15min 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 sequence. Adjust the temperature of the reaction system to 80℃ and react for 4h. After the reaction is completed, cool it to room temperature and pour it into a dilute hydrochloric acid solution with a pH of 1. A white cloudy precipitate can be seen. Place it in a refrigerator at 4℃ for 4h, filter it, and vacuum dry it at 60℃ to obtain carboxylated polyethersulfone.

[0049] ③ Weigh 10g of carboxylated polyethersulfone and dissolve it in 50ml of N,N-dimethylformamide. Stir magnetically for 15min at room temperature to obtain a homogeneous solution. Add 5ml (1.1 equivalents) of thionyl chloride, adjust the temperature of the reaction system to 40℃, and react for 4h. After the reaction is completed, cool to room temperature, wash repeatedly with ethanol several times, and dry in vacuum at 60℃ to obtain chlorinated polyethersulfone.

[0050] ④ Take 3g of cisplatin and dissolve it 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 50℃ and react for 1h in the dark. When 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. Finally, pale yellow crystals of oxidized cisplatin are obtained. The sample is vacuum dried in the dark.

[0051] ⑤ Take 1g of polyethersulfone chloride and 1g 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°C, and react in the dark for 12h. After the reaction, filter the reaction solution through diatomaceous earth, and freeze-dry the filtrate with a vacuum freeze dryer. After the filtrate is freeze-dried, wash it with 5mL of dichloromethane and 40mL of anhydrous ether for 3 times, collect the product by centrifugation, and finally vacuum dry it at room temperature to obtain gray solid cisplatin chloride modified polyethersulfone. The yield is determined by measuring the total mass ratio of the reaction product to the total mass of the raw material, and the yield is about 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, and use the immersion precipitation phase conversion method to make cisplatin chloride modified polyethersulfone blood purification filter membrane.

[0053] Example 3

[0054] 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 15min. It can be seen that polyethersulfone is completely dissolved in N-methylpyrrolidone ultra-dry solvent to form a homogeneous solution. Place the built reaction system in a 0℃ water bath, and quickly add 5.5g 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 100℃ and react for 12h. After the reaction is completed, cool to room temperature, slowly pour the solution into double distilled water to obtain a brown solid substance, repeatedly wash it with double distilled water several times to remove the residual solvent, and vacuum dry it at 60℃ to constant weight to obtain acetylated polyethersulfone.

[0055] ② Weigh 10g of acetylated polyethersulfone and dissolve it in 50ml of N-methylpyrrolidone. Stir magnetically at room temperature for 15min 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 sequence. Adjust the temperature of the reaction system to 100℃ and react for 6h. After the reaction is completed, cool to room temperature and pour into a dilute hydrochloric acid solution with a pH of 2. A white cloudy precipitate can be seen. Place it in a refrigerator at 4℃ for 4h, filter it, and vacuum dry it at 60℃ to obtain carboxylated polyethersulfone.

[0056] ③ Weigh 10g of carboxylated polyethersulfone and dissolve it in 50ml of N,N-dimethylformamide. Stir magnetically for 15min at room temperature to obtain a homogeneous solution. Add 9.1ml (2 equivalents) of thionyl chloride, adjust the temperature of the reaction system to 40℃, and react for 4h. After the reaction is completed, cool to room temperature, wash repeatedly with ethanol several times, and dry in vacuum at 60℃ to obtain chlorinated polyethersulfone.

[0057] ④ Take 3g of cisplatin and dissolve it 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 50℃ and react for 2h in the dark. When 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. Finally, pale yellow crystals of oxidized cisplatin are obtained. The sample is vacuum dried in the dark.

[0058] ⑤ Take 1g of polyethersulfone chloride and 1.5g 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 30°C, and react in the dark for 18h. After the reaction, filter the reaction solution through diatomaceous earth, and freeze-dry the filtrate with a vacuum freeze dryer. After the filtrate is freeze-dried, wash it with 5mL of dichloromethane and 40mL of anhydrous ether for 3 times, collect the product by centrifugation, and finally vacuum dry it at room temperature to obtain gray solid cisplatin chloride modified polyethersulfone. The yield is determined by measuring the total mass ratio of the reaction product to the total mass of the raw material, and the yield is about 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, and use the immersion precipitation phase conversion method to make a cisplatin chloride modified polyethersulfone blood purification filter membrane.

[0060] Comparative Example 1

[0061] 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 15min. It can be seen that polyethersulfone is completely dissolved in N-methylpyrrolidone ultra-dry solvent to form a homogeneous solution. Place the built 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, slowly pour the solution into double distilled water to obtain a brown solid substance, repeatedly wash with double distilled water several times to remove residual solvent, and vacuum dry at 60℃ to constant weight to obtain acetylated polyethersulfone.

[0062] ② Weigh 10g of acetylated polyethersulfone and dissolve it in 50ml of N-methylpyrrolidone. Stir magnetically at room temperature for 15min 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 sequence. Adjust the temperature of the reaction system to 60℃ and react for 4h. After the reaction is completed, cool it to room temperature and pour it into a dilute hydrochloric acid solution with a pH of 1. A white cloudy precipitate can be seen. Place it in a refrigerator at 4℃ for 4h, filter it, and vacuum dry it at 60℃ to obtain carboxylated polyethersulfone.

[0063] ③ Weigh 10g of carboxylated polyethersulfone and dissolve it in 50ml of N,N-dimethylformamide. Stir magnetically at room temperature for 15min to obtain a homogeneous solution. Add 3.6ml (0.8 equivalent) of thionyl chloride, adjust the temperature of the reaction system to 25℃, and react for 4h. After the reaction is completed, cool to room temperature, wash repeatedly with ethanol several times, and dry in vacuum at 60℃ to obtain chlorinated polyethersulfone.

[0064] ④ Take 3g of cisplatin and dissolve it 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. Finally, pale yellow crystals of oxidized cisplatin are obtained. The sample is vacuum dried in the dark.

[0065] 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 10℃, and react for 12h in the dark. After the reaction, filter the reaction solution through diatomaceous earth, and freeze-dry the filtrate with a vacuum freeze dryer. After the filtrate is freeze-dried, wash it with 5mL of dichloromethane and 40mL of anhydrous ether for 3 times, collect the product by centrifugation, and finally vacuum dry it at room temperature to obtain gray solid cisplatin chloride modified polyethersulfone. The yield is measured, and the yield is about 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, and use the immersion precipitation phase conversion method to make 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] 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 60℃, and react for 12h in the dark. After the reaction, filter the reaction solution through diatomaceous earth, and freeze-dry the filtrate with a vacuum freeze dryer. After the filtrate is freeze-dried, wash it with 5mL of dichloromethane and 40mL of anhydrous ether for 3 times, collect the product by centrifugation, and finally vacuum dry it at room temperature. The yield is determined by measuring the total mass ratio of the reaction product to the total mass of the raw material. It is found that the efficiency of the grafting reaction is low, and the yield is less than 30%.

[0070] By repeatedly debugging various parameters, it was determined that in step ⑤, when the reaction system temperature 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 cisplatin chloride modified polyethersulfone 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 to graft cisplatin on a blood purification membrane and slowly release it 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 greatly 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 are 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 explanations of the exemplary implementations of the present invention, and are not intended to limit the scope of the present invention. The details in the embodiments do not constitute limitations on the scope of the present invention, and any obvious changes such as equivalent transformations, simple replacements, etc. based on the technical solution of the present invention, without departing from the spirit and scope of the present invention, fall within the protection scope 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 and anhydrous reaction space, filling the reaction space with nitrogen, dissolving the freeze-dried polyethersulfone in an ultra-dry organic solvent, and stirring the mixture 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 the mixture for a predetermined time, and drying the mixture 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 deionized 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; 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 acyl chloride polyethersulfone; Step (4) dissolving cisplatin in double distilled water, adding hydrogen peroxide, reacting at a temperature of 50° C., reacting 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; Step (5) dissolving the products obtained in step (3) and step (4) in an ultra-dry thionyl chloride organic solvent, carrying out a grafting reaction, and vacuum drying to a constant weight to obtain cisplatin chloride modified polyethersulfone.

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

3. The preparation method according to claim 1, characterized in that: 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, and in the step (3), the reaction temperature is 40°C, and the reaction is carried out for 3-5 hours.

4. The preparation method according to claim 1, characterized in that: In the step (5), the reaction temperature is 20-40°C, preferably 25-30°C, more preferably 25°C, and the reaction is carried out in the dark for 12 hours.

5. The preparation method according to claim 1, characterized in that: The mass ratios of the substances are as follows: In step 1, polyethersulfone:acetyl chloride=1-3; in step 2, potassium permanganate:sodium hydroxide=1-6; in step 3, carboxylated polyethersulfone:dichlorothionyl=1-4; in step 4, cisplatin:hydrogen peroxide=1:10; in step 5, acyl chloride polyethersulfone:oxidized cisplatin=3-1; in step 6, the mass fraction of modified polyethersulfone is 15%-30%.

6. The preparation method according to claim 1, characterized in that: The ultra-dry organic solvent includes at least one of N-methylpyrrolidone, N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide and chloroform.

7. A cisplatin chloride modified blood purification filter membrane, characterized in that: The cisplatin chloride modified blood purification filter membrane comprises an acyl chloride molecule layer grafted on a biological material and cisplatin grafted on an acyl chloride group. The cisplatin chloride modified blood purification filter membrane is prepared by the method described in any one of claims 1-6.

Images