A drug-loaded microsphere for interventional treatment of liver cancer and its preparation method

Abstract

This invention relates to the field of pharmaceutical formulation technology, specifically to a drug-loaded microsphere for interventional treatment of liver cancer and its preparation method. The raw materials for preparing the drug-loaded microspheres include the following components in parts by weight: sodium cantharidate 2-3 parts, lecithin 4-7 parts, cholesterol 0.02-0.04 parts, 1,2-propanediol 20-30 parts, acrylamide 4-6 parts, allyl alcohol-folic acid 3-4.5 parts, acrylic acid-camptothecin 3-5 parts, and benzoyl peroxide 0.1-0.15 parts. The drug-loaded microspheres prepared by this invention have good anti-liver cancer efficacy, low toxicity and side effects, and high bioavailability.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to a drug-loaded microsphere for interventional treatment of liver cancer and its preparation method. Background Technology

[0002] Currently, treatment methods for liver cancer include three main therapies: surgery, chemotherapy, and radiotherapy, as well as newer methods such as targeted therapy, immunotherapy, and minimally invasive interventional therapy. Surgery is suitable for early-stage patients without metastasis, but carries the risk of reduced angiogenesis inhibitors after primary lesion removal, potentially promoting tumor regeneration and metastasis. Furthermore, fatal liver failure after hepatectomy is a significant complication. Radiotherapy effectively kills cancer cells, but radiation lacks tissue specificity and selectivity, resulting in significant toxic side effects. Chemotherapy is an important treatment for cancer, but most chemotherapy drugs are toxic to both normal and cancer cells; the specificity of tumor structure limits the effectiveness of chemotherapy to only 2-5% of its drugs. Drugs cannot penetrate the tumor, resulting in poor efficacy and easy development of drug resistance. The remnants of dead cancer cells during chemotherapy can stimulate the expression of tumor-related factors. Most existing targeted drugs can only partially block the proliferation pathway of cancer cells, and combining drugs or increasing the dosage will increase toxic side effects and easily lead to recurrence and drug resistance. Immunotherapy is a new method in recent years, but the treatment response rate is low. Minimally invasive interventional therapy, by embolizing the arteries in the tumor area to block nutrition and blood supply and "starve" the tumor, and at the same time deliver drugs to the tumor in a targeted manner, achieves the synergistic effect of targeted chemotherapy and embolization, and has become an important cancer treatment in recent years. Summary of the Invention

[0003] To address the shortcomings of existing technologies, this invention proposes a drug-loaded microsphere for interventional treatment of liver cancer and its preparation method.

[0004] This invention is achieved through the following technical solution:

[0005] A drug-loaded microsphere for interventional treatment of liver cancer, the raw materials for preparation include the following components in parts by weight: sodium cantharidate 2-3 parts, lecithin 4-7 parts, cholesterol 0.02-0.04 parts, 1,2-propanediol 20-30 parts, acrylamide 4-6 parts, allyl alcohol-folic acid 3-4.5 parts, acrylic acid-camptothecin 3-5 parts, and benzoyl peroxide 0.1-0.15 parts.

[0006] Furthermore, the raw materials for preparing the allyl alcohol-folic acid include the following components in parts by weight: 3-6 parts folic acid, 1.5-3 parts allyl alcohol, 1.8-3.5 parts 1-hydroxybenzotriazole (HOBt), and 2.7-5 parts N-N'-dicyclohexylcarbodiimide (DCC).

[0007] Furthermore, the method for preparing the allyl alcohol-folic acid includes the following steps:

[0008] (1) Dissolve folic acid in dimethyl sulfoxide, add 1-hydroxybenzotriazole and N-N'-dicyclohexylcarbodiimide, stir at 60-70℃ and 100-200 rpm for 30-40 min, and continue stirring at room temperature for 2-3 h to obtain an activated folic acid solution.

[0009] (2) Dissolve allyl alcohol in dimethyl sulfoxide to obtain an allyl alcohol solution. Mix the allyl alcohol solution with the activated folic acid obtained in step (1). Under nitrogen protection, stir the mixture at 50-60℃ and 200-300 rpm for 12-14 h. Cool to room temperature, centrifuge at 8000 rpm for 15-20 min, wash the precipitate with deionized water, and dry it under vacuum at 60-70℃ to obtain allyl alcohol-folic acid.

[0010] Further, in step (1), the folic acid concentration in dimethyl sulfoxide is 0.1 g / mL.

[0011] Further, in step (2), the mass concentration of the allyl alcohol in dimethyl sulfoxide is 0.1 g / mL.

[0012] Furthermore, the raw materials for preparing the acrylic acid-camptothecin include the following components in parts by weight: 1.2-1.6 parts of acrylic acid, 1.5-2 parts of camptothecin, 0.95-1.25 parts of 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC), and 0.6-0.8 parts of 4-dimethylaminopyridine (DAMP).

[0013] Furthermore, the preparation method of the acrylic acid-camptothecin includes the following steps:

[0014] (a) Take camptothecin, DAMP, EDC and dichloromethane and stir to mix well to obtain a mixed solution. Take acrylic acid and dichloromethane and stir to mix well. Add the mixture dropwise to the mixed solution under nitrogen protection and stir at 150-200 rpm for 12-14 h.

[0015] (b) After the reaction in step (a) is completed, dichloromethane is removed under reduced pressure, the mixture is washed with deionized water, and dried under vacuum at 40-50°C to obtain acrylic acid-camptothecin.

[0016] Further, in step (a), the mass fraction of camptothecin in dichloromethane is 0.025 g / mL.

[0017] Further, in step (a), the mass fraction of the acrylic acid in dichloromethane is 0.1 g / mL.

[0018] Furthermore, the present invention also provides a method for preparing the drug-loaded microspheres for interventional treatment of liver cancer, comprising the following steps:

[0019] S1: Add 1,2-propanediol and sodium cantharidate to ultrapure water and mix well to obtain sodium cantharidate solution. Add lecithin and cholesterol to anhydrous ethanol and mix well. Add this mixture to sodium cantharidate solution. Stir at 1300-1500 rpm for 20-25 min under nitrogen protection. Filter through a 0.22μm microporous membrane 3-4 times to obtain sodium cantharidate liposomes.

[0020] S2: Acrylamide and benzoyl peroxide were slowly added to the sodium cantharidate liposomes obtained in step S1 while stirring. The mixture was stirred at 80°C and 200-300 rpm for 2 h. Acrylic acid-camptothecin and allyl alcohol-folic acid were slowly added. The mixture was stirred at 200-300 rpm and 80°C for 3 h. The mixture was then filtered. The filter cake was washed with anhydrous ethanol and deionized water and dried under vacuum at 40°C to obtain drug-loaded microspheres for interventional treatment of liver cancer.

[0021] Further, in step S1, the mass ratio of 1,2-propanediol to ultrapure water is 1:3.

[0022] Furthermore, in step S1, the mass ratio of anhydrous ethanol to lecithin is 4:1.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] This invention provides drug-loaded microspheres for interventional treatment of liver cancer. Sodium cantharidate was prepared, and the microspheres were fabricated using polyacrylamide. Polyacrylamide contains numerous amide bonds, is water-absorbing, and exhibits swelling properties, which is beneficial for embolization therapy. The introduction of folic acid and camptothecin into the polyacrylamide enhances targeting. Camptothecin and sodium cantharidate synergistically enhance the anti-liver cancer effect. This invention also prepares acrylic acid-camptothecin. By covalently linking acrylic acid and camptothecin, camptothecin acquires double bonds and participates in the polymerization process of polyacrylamide. This successfully introduces camptothecin, with its antitumor activity, into the polyacrylamide chain of the drug-loaded microspheres, effectively improving anti-liver cancer activity and biocompatibility, and solving the problem of difficult formulation of camptothecin as a hydrophobic drug. Finally, this invention prepares folic acid-allyl alcohol. By covalently linking folic acid and allyl alcohol, folic acid is introduced into the polyacrylamide. Folic acid is highly expressed or overexpressed in tumor cells and conserved in normal cells. The introduction of folic acid can improve the targeting of the drug-loaded microspheres. Attached Figure Description

[0025] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only for this invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0026] Figure 1This is a scanning electron microscope image of the drug-loaded microspheres for interventional treatment of liver cancer as described in Embodiment 1 of the present invention;

[0027] Figure 2 This demonstrates the antitumor effects of the drug-loaded microspheres described in Examples 1-3 and Comparative Examples 1-2 of the present invention.

[0028] Figure 3 Organ toxicity of the drug-loaded microspheres described in Example 1 and Comparative Examples 1-2 of this invention;

[0029] Figure 4 This is a test graph showing the cumulative drug release rate of the drug-loaded microspheres described in Example 1 of the present invention. Detailed Implementation

[0030] To make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to specific embodiments, but the present invention is not limited to the following embodiments.

[0031] It should be noted that, unless otherwise specified, all chemical reagents involved in this invention were purchased through commercial channels.

[0032] Example 1: A drug-loaded microsphere for interventional treatment of liver cancer, the raw materials for preparation include the following components in parts by weight: 3 parts sodium cantharidate, 7 parts lecithin, 0.04 parts cholesterol, 30 parts 1,2-propanediol, 6 parts acrylamide, 4.5 parts allyl alcohol-folic acid, 5 parts acrylic acid-camptothecin, and 0.15 parts benzoyl peroxide.

[0033] The raw materials for preparing allyl alcohol-folic acid include the following components in parts by weight: 6 parts folic acid, 3 parts allyl alcohol, 3.5 parts HOBt, and 5 parts DCC.

[0034] The preparation method of allyl alcohol-folic acid includes the following steps:

[0035] (1) Dissolve 6 g of folic acid in 60 mL of dimethyl sulfoxide, add 3.5 g of HOBt and 5 g of DCC, stir at 70℃ and 200 rpm for 40 min, and continue stirring at room temperature for 3 h to obtain an activated folic acid solution.

[0036] (2) Dissolve 3 g of allyl alcohol in 30 g of dimethyl sulfoxide to obtain an allyl alcohol solution. Mix the allyl alcohol solution with the activated folic acid obtained in step (1). Under nitrogen protection, stir the reaction at 60°C and 300 rpm for 14 h. Cool to room temperature, centrifuge at 8000 rpm for 20 min, wash the precipitate with deionized water, and dry it under vacuum at 70°C to obtain allyl alcohol-folic acid.

[0037] The raw materials for preparing acrylic acid-camptothecin include the following components in parts by weight: 1.6 parts acrylic acid, 2 parts camptothecin, 1.25 parts EDC, and 0.8 parts DAMP.

[0038] The preparation method of acrylic acid-camptothecin includes the following steps:

[0039] (a) Take 4 g camptothecin, 1.6 g DAMP, 2.5 g EDC and 160 mL dichloromethane and stir to obtain a mixed solution. Take 3.2 g acrylic acid and 32 mL dichloromethane and stir to obtain a mixed solution. Add the mixed solution dropwise under nitrogen protection and stir at 200 rpm for 14 h.

[0040] (b) After the reaction in step (a) is completed, dichloromethane is removed under reduced pressure, the mixture is washed with deionized water, and dried under vacuum at 50°C to obtain acrylic acid-camptothecin.

[0041] This embodiment also provides a method for preparing the drug-loaded microspheres for interventional treatment of liver cancer, including the following steps:

[0042] S1: Add 30 g of 1,2-propanediol and 3 g of sodium cantharidate to 90 g of ultrapure water and mix well to obtain sodium cantharidate solution. Add 7 g of lecithin and 0.04 g of cholesterol to 28 g of anhydrous ethanol and mix well. Add this mixture to the sodium cantharidate solution. Stir at 1500 rpm for 25 min under nitrogen protection. Filter the mixture through a 0.22 μm microporous membrane 4 times to obtain sodium cantharidate liposomes.

[0043] S2: While stirring, slowly add 6 g of acrylamide and 0.15 g of benzoyl peroxide to the sodium cantharidate liposomes obtained in step S1. Stir and react at 80℃ and 300 rpm for 2 h. Slowly add 5 g of acrylic acid-camptothecin and 4.5 g of allyl alcohol-folic acid. React at 300 rpm and 80℃ for 3 h. Filter, wash the filter cake with anhydrous ethanol and deionized water, and vacuum dry at 40℃ to obtain drug-loaded microspheres for interventional treatment of liver cancer. Scanning electron microscopy image as shown. Figure 1 As shown.

[0044] Example 2: A drug-loaded microsphere for interventional treatment of liver cancer, the raw materials for preparation include the following components in parts by weight: 2 parts sodium cantharidate, 4 parts lecithin, 0.02 parts cholesterol, 20 parts 1,2-propanediol, 4 parts acrylamide, 3 parts allyl alcohol-folic acid, 3 parts acrylic acid-camptothecin, and 0.1 parts benzoyl peroxide.

[0045] The raw materials for preparing allyl alcohol-folic acid include the following components in parts by weight: 3 parts folic acid, 1.5 parts allyl alcohol, 1.8 parts HOBt, and 2.7 parts DCC.

[0046] The preparation method of allyl alcohol-folic acid includes the following steps:

[0047] (1) Dissolve 3 g of folic acid in 30 mL of dimethyl sulfoxide, add 1.8 g of HOBt and 2.7 g of DCC, stir at 60℃ and 100 rpm for 30 min, and continue stirring at room temperature for 2 h to obtain an activated folic acid solution.

[0048] (2) Dissolve 1.5 g of allyl alcohol in 15 mL of dimethyl sulfoxide to obtain an allyl alcohol solution. Mix the allyl alcohol solution with the activated folic acid obtained in step (1). Under nitrogen protection, stir the mixture at 50 °C and 200 rpm for 12 h. Cool to room temperature, centrifuge at 8000 rpm for 15 min, wash the precipitate with deionized water, and dry it under vacuum at 60 °C to obtain allyl alcohol-folic acid.

[0049] The raw materials for preparing acrylic acid-camptothecin include the following components in parts by weight: 1.2 parts acrylic acid, 1.5 parts camptothecin, 0.95 parts EDC, and 0.6 parts DAMP.

[0050] The preparation method of acrylic acid-camptothecin includes the following steps:

[0051] (a) Take 3 g camptothecin, 1.2 g DAMP, 1.9 g EDC and 120 mL dichloromethane and stir to mix well to obtain a mixed solution. Take 2.4 g acrylic acid and 24 mL dichloromethane and stir to mix well. Add the mixture dropwise to the mixed solution under nitrogen protection and stir at 150 rpm for 12 h.

[0052] (b) After the reaction in step (a) is completed, dichloromethane is removed under reduced pressure, the mixture is washed with deionized water, and dried under vacuum at 40°C to obtain acrylic acid-camptothecin.

[0053] This embodiment also provides a method for preparing the drug-loaded microspheres for interventional treatment of liver cancer, including the following steps:

[0054] S1: Add 20 g of 1,2-propanediol and 2 g of sodium cantharidate to 60 g of ultrapure water and mix well to obtain sodium cantharidate solution. Add 4 g of lecithin and 0.02 g of cholesterol to 16 g of anhydrous ethanol and mix well. Add this mixture to the sodium cantharidate solution. Stir at 1300 rpm for 20 min under nitrogen protection. Filter the mixture three times through a 0.22 μm microporous membrane to obtain sodium cantharidate liposomes.

[0055] S2: While stirring, slowly add 4 g of acrylamide and 0.1 g of benzoyl peroxide to the sodium cantharidate liposomes obtained in step S1. Stir and react for 2 h at 80 °C and 200 rpm. Slowly add 3 g of acrylic acid-camptothecin and 3 g of allyl alcohol-folic acid. React for 3 h at 200 rpm and 80 °C. Filter the mixture. Wash the filter cake with anhydrous ethanol and deionized water. Dry it under vacuum at 40 °C to obtain drug-loaded microspheres for interventional treatment of liver cancer.

[0056] Example 3: A drug-loaded microsphere for interventional treatment of liver cancer, the raw materials for preparation include the following components in parts by weight: 2.5 parts sodium cantharidate, 6 parts lecithin, 0.03 parts cholesterol, 25 parts 1,2-propanediol, 5 parts acrylamide, 4 parts allyl alcohol-folic acid, 4 parts acrylic acid-camptothecin, and 0.12 parts benzoyl peroxide.

[0057] The raw materials for preparing allyl alcohol-folic acid include the following components in parts by weight: 5 parts folic acid, 2 parts allyl alcohol, 2 parts HOBt, and 4 parts DCC.

[0058] The preparation method of allyl alcohol-folic acid includes the following steps:

[0059] (1) Dissolve 5 g of folic acid in 50 mL of dimethyl sulfoxide, add 2 g of HOBt and 4 g of DCC, stir at 65℃ and 150 rpm for 35 min, and continue stirring at room temperature for 2.5 h to obtain an activated folic acid solution.

[0060] (2) Dissolve 2 g of allyl alcohol in 20 mL of dimethyl sulfoxide to obtain an allyl alcohol solution. Mix the allyl alcohol solution with the activated folic acid obtained in step (1). Under nitrogen protection, stir the reaction at 55 °C and 250 rpm for 13 h. Cool to room temperature, centrifuge at 8000 rpm for 18 min, wash the precipitate with deionized water, and dry it under vacuum at 65 °C to obtain allyl alcohol-folic acid.

[0061] The raw materials for preparing acrylic acid-camptothecin include the following components in parts by weight: 1.5 parts acrylic acid, 1.8 parts camptothecin, 1 part EDC, and 0.7 parts DAMP.

[0062] The preparation method of acrylic acid-camptothecin includes the following steps:

[0063] (a) Take 3.6 g camptothecin, 1.4 g DAMP, 2 g EDC and 144 mL dichloromethane and stir to mix well to obtain a mixed solution. Take 3 g acrylic acid and 30 mL dichloromethane and stir to mix well. Add the mixture dropwise to the mixed solution under nitrogen protection and stir at 180 rpm for 13 h.

[0064] (b) After the reaction in step (a) is completed, dichloromethane is removed under reduced pressure, the mixture is washed with deionized water, and dried under vacuum at 45°C to obtain acrylic acid-camptothecin.

[0065] This embodiment also provides a method for preparing the drug-loaded microspheres for interventional treatment of liver cancer, including the following steps:

[0066] S1: Add 25 g of 1,2-propanediol and 2.5 g of sodium cantharidate to 75 g of ultrapure water and mix well to obtain sodium cantharidate solution. Add 6 g of lecithin and 0.03 g of cholesterol to 24 g of anhydrous ethanol and mix well. Add this mixture to the sodium cantharidate solution. Stir at 1400 rpm for 22 min under nitrogen protection. Filter the mixture through a 0.22 μm microporous membrane 4 times to obtain sodium cantharidate liposomes.

[0067] S2: While stirring, slowly add 5 g of acrylamide and 0.12 g of benzoyl peroxide to the sodium cantharidate liposomes obtained in step S1. Stir and react at 80°C and 250 rpm for 2 h. Slowly add 4 g of acrylic acid-camptothecin and 4 g of allyl alcohol-folic acid. React at 250 rpm and 80°C for 3 h. Filter, wash the filter cake with anhydrous ethanol and deionized water, and vacuum dry at 40°C to obtain drug-loaded microspheres for interventional treatment of liver cancer.

[0068] The only difference between Comparative Example 1 and Example 1 is that allyl alcohol-folic acid is replaced with acrylamide.

[0069] The only difference between Comparative Example 2 and Example 1 is that acrylic acid-camptothecin is replaced with acrylamide.

[0070] Example 1: Eight-week-old (220-240 g) male SD rats were used. After one week of acclimatization in the SPF animal room, inoculation with orthotopic tumors was initiated. An orthotopic liver tumor model was established by surgically injecting N1S1 hepatocellular carcinoma cells into the rat liver. N1S1 cell culture dishes were removed from the constant-temperature cell culture incubator (5% CO2, 37℃), the liquid was aspirated, centrifuged to remove the supernatant, washed with PBS to remove dead cells and other impurities, and the cell pellet was resuspended in IMDM complete culture medium. 18 μL of the original cell culture was added to 2 μL of 0.4% trypan blue for cell counting. A certain amount of matrix gel was aspirated and mixed with the N1S1 cell pellet to obtain an N1S1 cell-Matrix gel suspension. 50 μL of the N1S1 cell-Matrix gel suspension (1×10⁻⁶) was drawn using a 1 mL insulin injection. 7(N1S1 cells) were placed on crushed ice for later use. Male rats were anesthetized with an anesthetic and placed in a supine position with their limbs fixed on a rat board. The rat's abdomen was shaved and disinfected with iodine. A 2 cm incision was made one finger's width below the right rib on the right side of the abdominal midline. The epidermis, muscle, and peritoneum were gradually incised. A sterile cotton swab was used to expose the right lobe of the liver to the field of vision. The right lobe of the liver was slowly and gently pulled. An insulin needle containing N1S1 cell-Matrix glue suspension was slowly inserted into the liver tissue. The N1S1 cell-Matrix glue suspension was pushed in. The insulin needle was withdrawn and pressure was applied with a cotton swab to stop bleeding. After confirming that there was no leakage of cell fluid and no local bleeding, the liver was returned to the abdominal cavity and the abdomen was closed by suturing layer by layer. Postoperative observation of rat recovery and vital signs was conducted, ensuring normal food and water intake. After tumor implantation, rats were randomly divided into groups of five, with each group marked with the group, injection time, cell type, and quantity. Seven days after inoculation, 1 mg of microsphere powder was dispersed and mixed in 0.3 mL of 3% carboxymethyl cellulose solution. A carboxymethyl cellulose solution without added microspheres served as the control group. The normal group did not undergo liver cancer modeling. Using an equal volume of carboxymethyl cellulose solution, rats were anesthetized and fixed on the operating table. The abdomen was shaved to expose the epidermis, disinfected with iodine, and the abdomen was opened layer by layer. The fascia at the common hepatic artery was dissected, and the blood vessels were freed. Carboxymethyl cellulose solution, with or without microspheres, was administered via a PE 10 catheter through the common hepatic artery. 0.1 mL of saline was used to push out any remaining solution in the catheter. The blood vessels were ligated, and the layers were sutured and disinfected. After the anesthetic wore off, rats were ensured to have normal food and water intake upon recovery. Tumor size was recorded every 3 days. Results are as follows: Figure 2 As shown. Rats were sacrificed 14 days later, and their hearts, lungs, and kidneys were dissected, weighed, and organ coefficients were calculated, as shown. Figure 3 As shown.

[0071] Figure 2 The results showed that the tumor size in Examples 1-3 and Comparative Examples 1-2 was significantly reduced, indicating that the drug-loaded microspheres could effectively fight tumors. The anti-tumor effect of Examples 1-3 was better than that of Comparative Examples 1-2. Comparative Example 1 did not contain folic acid, resulting in decreased targeting, and Comparative Example 2 did not contain camptothecin, resulting in decreased anti-tumor effect. When organs are toxic, pathological changes occur, causing changes in organ weight, such as... Figure 3 The results showed that, compared with the normal group, the lung and kidney coefficients of the other groups of mice did not change significantly. The heart coefficient of the control group was significantly reduced. In contrast, Example 1 and Comparative Examples 1-2 significantly increased the heart coefficient to normal levels, effectively preventing cardiac atrophy and lesions. The effect of Example 1 was better than that of Comparative Examples 1-2. Comparative Example 1 did not add folic acid, resulting in decreased targeting. Comparative Example 2 did not add camptothecin, resulting in decreased synergistic toxicity reduction.

[0072] Experimental Example 2: 300 mg of the drug-loaded microspheres obtained in Example 1 were thoroughly mixed with 25 mL of physiological saline and allowed to stand. At 0 h, 3 h, 6 h, 12 h, 24 h, and 36 h, 1 mL of the supernatant was collected each time, with the same volume of fresh physiological saline added to maintain a constant overall volume. The sample was filtered through a 0.22 μm microporous membrane, and 20 μL of the filtrate was used to determine the sodium cantharidate content using high-performance liquid chromatography (HPLC). The cumulative drug release amount was obtained, and the cumulative drug release rate was calculated. The results are as follows: Figure 4 As shown.

[0073] Figure 4 The results showed that the drug-loaded microspheres for interventional treatment of liver cancer of the present invention have significant sustained-release drug release behavior. The drug is released slowly, so it can release the drug slowly locally, thereby continuously and targetedly delivering the drug to tumor cells to exert a good local targeted treatment effect on tumors and reduce systemic toxic side effects.

[0074] Experimental Example 3: 50 mg of the microsphere sample prepared in Examples 1-3 of this invention was accurately weighed and placed in physiological saline at 37℃. After shaking for 30 seconds, the sample was allowed to stand, and the suspension time of the microspheres was recorded (until complete separation was observed by the naked eye). After 20 minutes, the sample was removed, the surface water was wiped off with filter paper, and the mass was quickly weighed using an electronic balance. The water absorption swelling rate (WSR) was calculated according to the following formula: WSR = [(W2-W1) / W1] × 100%, where W2 is the mass of the microspheres after water absorption, and W1 is the mass of the microspheres in the dry state. The results are shown in Table 1.

[0075] Table 1:

[0076] Hover time (s) 20 min swelling rate Example 1 119.7 57.13 Example 2 120.1 56.98 Example 3 119.5 57.39

[0077] Table 1 shows that the drug-loaded microspheres of the present invention are easily dispersed and do not adhere in physiological saline, with a suspension time of 2 min, indicating good dispersibility; the water absorption and swelling rate of the microspheres after 20 min is more than 55%, which has a good water absorption and swelling effect, further ensuring the effect of tumor vascular embolization.

[0078] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of the invention (including the claims) is limited to these examples; within the framework of the invention, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of the different aspects of the invention as described above, which are not provided in the details for the sake of brevity.

[0079] This invention is intended to cover all such substitutions, modifications, and variations that fall within the broad scope of the appended claims. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this invention should be included within the scope of protection of this invention.

Claims

1. A drug-loaded microsphere for interventional treatment of liver cancer, characterized in that, The raw materials for preparation include the following components in parts by weight: sodium cantharidate 2-3 parts, lecithin 4-7 parts, cholesterol 0.02-0.04 parts, 1,2-propanediol 20-30 parts, acrylamide 4-6 parts, allyl alcohol-folic acid 3-4.5 parts, acrylic acid-camptothecin 3-5 parts, and benzoyl peroxide 0.1-0.15 parts; The raw materials for preparing the allyl alcohol-folic acid include the following components in parts by weight: 3-6 parts folic acid, 1.5-3 parts allyl alcohol, 1.8-3.5 parts HOBt, and 2.7-5 parts DCC. The method for preparing the allyl alcohol-folic acid includes the following steps: (1) Dissolve folic acid in dimethyl sulfoxide, add HOBt and DCC, stir at 60-70℃, and continue stirring at room temperature to obtain an activated folic acid solution. (2) Dissolve allyl alcohol in dimethyl sulfoxide to obtain an allyl alcohol solution. Mix the allyl alcohol solution with the activated folic acid obtained in step (1). Stir the reaction under nitrogen protection, cool, centrifuge, wash the precipitate with deionized water, and dry under vacuum to obtain allyl alcohol-folic acid. The raw materials for preparing acrylic acid-camptothecin include the following components in parts by weight: 1.2-1.6 parts acrylic acid, 1.5-2 parts camptothecin, 0.95-1.25 parts EDC, and 0.6-0.8 parts 4-dimethylaminopyridine; The preparation method of the acrylic acid-camptothecin includes the following steps: (a) Take camptothecin, 4-dimethylaminopyridine, EDC and dichloromethane and stir to mix well to obtain a mixed solution. Take acrylic acid and dichloromethane and stir to mix well. Add the acrylic acid dropwise to the mixed solution under nitrogen protection and stir to react. (b) After the reaction in step (a) is completed, dichloromethane is removed under reduced pressure, the mixture is washed with deionized water and dried under vacuum to obtain acrylic acid-camptothecin.

2. The drug-loaded microspheres for interventional treatment of liver cancer according to claim 1, characterized in that, In step (1), the folic acid concentration in dimethyl sulfoxide is 0.1 g / mL.

3. The drug-loaded microspheres for interventional treatment of liver cancer according to claim 2, characterized in that, In step (2), the mass concentration of the allyl alcohol in dimethyl sulfoxide is 0.1 g / mL.

4. The drug-loaded microspheres for interventional treatment of liver cancer according to claim 3, characterized in that, In step (a), the mass fraction of camptothecin in dichloromethane is 0.025 g / mL; the mass fraction of acrylic acid in dichloromethane is 0.1 g / mL.

5. A method for preparing drug-loaded microspheres for interventional treatment of liver cancer as described in any one of claims 1-4, characterized in that, Includes the following steps: S1: Add 1,2-propanediol and sodium cantharidate to ultrapure water and mix well to obtain sodium cantharidate solution. Add lecithin and cholesterol to anhydrous ethanol and mix well. Add this mixture to sodium cantharidate solution and stir under nitrogen protection. Filter through a microporous membrane to obtain sodium cantharidate liposomes. S2: Acrylamide and benzoyl peroxide are added to the sodium cantharidate liposomes obtained in step S1 while stirring. The mixture is stirred and reacted. Acrylic acid-camptothecin and allyl alcohol-folic acid are added and stirred and reacted. The mixture is then filtered. The filter cake is washed with anhydrous ethanol and deionized water and dried under vacuum to obtain drug-loaded microspheres for interventional treatment of liver cancer.

6. The method for preparing drug-loaded microspheres for interventional treatment of liver cancer according to claim 5, characterized in that, In step S1, the mass ratio of 1,2-propanediol to ultrapure water is 1:3; The mass ratio of anhydrous ethanol to lecithin is 4:1.

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