Drug-loaded microspheres for interventional therapy of liver cancer and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to drug-loaded microspheres for interventional therapy of liver cancer and a preparation method of the drug-loaded microspheres. The drug-loaded microspheres are prepared from the following raw materials in parts by weight: 2 to 3 parts of sodium cantharidinate, 4 to 7 parts of lecithin, 0.02 to 0.04 part of cholesterol, 20 to 30 parts of 1, 2-propylene glycol, 4 to 6 parts of acrylamide, 3 to 4.5 parts of allyl alcohol-folic acid, 3 to 5 parts of acrylic acid-camptothecin and 0.1 to 0.15 part of benzoyl peroxide. The prepared drug-loaded microspheres are good in anti-liver cancer effect, small in toxic and side effects and high in bioavailability.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a drug-loaded microsphere for interventional treatment of liver cancer and a preparation method thereof. Background Art

[0002] At present, the treatment methods for liver cancer include surgery, chemotherapy and radiotherapy, as well as new methods such as targeted, immune and minimally invasive intervention. Among them, surgery is suitable for early patients without metastasis, but there is a risk of tumor regeneration and metastasis due to the reduction of angiogenesis inhibitors after resection of the primary lesion; in addition, fatal liver failure after liver resection is also an important complication; radiotherapy can effectively kill cancer cells, but radiation has no tissue specificity and selectivity and has great toxic side effects; chemotherapy is an important means of treating cancer, but most chemotherapy drugs are toxic to both normal cells and cancer cells, and tumor structure specificity means that only 2-5% of the drugs are effective. The remains of dead cancer cells during chemotherapy will stimulate the expression of factors related to tumor growth; most of the existing targeted drugs can only partially block the proliferation pathways of cancer cells, and combined use of drugs or increased dosages will increase toxic side effects, and easily cause recurrence and drug resistance; immunotherapy is a new method in recent years, but the treatment response rate is low; minimally invasive interventions "starve" the tumor by embolizing the arteries in the tumor area to block nutrition and blood supply, and at the same time deliver drugs to the tumor in a targeted manner to achieve a synergistic effect of targeted chemotherapy and embolism, becoming an important cancer treatment in recent years. Summary of the invention

[0003] In view of the deficiencies of the prior art, the present invention proposes a drug-loaded microsphere for interventional treatment of liver cancer and a preparation method thereof.

[0004] The present invention is achieved through the following technical solutions: A drug-loaded microsphere for interventional treatment of liver cancer. The preparation raw materials include the following components in parts by weight: 2-3 parts of sodium cantharidin, 4-7 parts of lecithin, 0.02-0.04 parts of cholesterol, 20-30 parts of 1,2-propylene glycol, 4-6 parts of acrylamide, 3-4.5 parts of acrylol-folic acid, 3-5 parts of acrylic acid-camptothecin, and 0.1-0.15 parts of benzoyl peroxide.

[0005] Furthermore, the raw materials for preparing the acryl alcohol-folic acid include the following components in parts by weight: 3-6 parts of folic acid, 1.5-3 parts of acryl alcohol, 1.8-3.5 parts of 1-hydroxybenzotriazole (HOBt), and 2.7-5 parts of N-N'-dicyclohexylcarbodiimide (DCC).

[0006] Furthermore, the preparation method of propylene glycol-folic acid comprises the following steps: (1) Dissolve folic acid in dimethyl sulfoxide, add 1-hydroxybenzotriazole and N-N'-dicyclohexylcarbodiimide, stir at 60-70°C 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; (2) dissolving allyl alcohol in dimethyl sulfoxide to obtain an allyl alcohol solution, mixing the allyl alcohol solution with the activated folic acid obtained in step (1), stirring and reacting at 50-60° C. and 200-300 rpm for 12-14 h under nitrogen protection, cooling to room temperature, centrifuging at 8000 rpm for 15-20 min, washing the precipitate with deionized water, and vacuum drying at 60-70° C. to obtain allyl alcohol-folic acid.

[0007] Furthermore, in step (1), the mass concentration of folic acid in dimethyl sulfoxide is 0.1 g / mL.

[0008] Furthermore, in step (2), the mass concentration of the acryl alcohol in dimethyl sulfoxide is 0.1 g / mL.

[0009] 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).

[0010] Furthermore, the preparation method of acrylic acid-camptothecin comprises the following steps: (a) Mix camptothecin, DAMP, EDC and dichloromethane to obtain a mixed solution, mix acrylic acid and dichloromethane to obtain a mixed solution, add acrylic acid dropwise to the mixed solution under nitrogen protection, and stir at 150-200 rpm for 12-14 h; (b) After the reaction in step (a) is completed, dichloromethane is removed under reduced pressure, the mixture is washed with deionized water, and vacuum dried at 40-50° C. to obtain acrylic acid-camptothecin.

[0011] Furthermore, in step (a), the mass fraction of camptothecin in dichloromethane is 0.025 g / mL.

[0012] Furthermore, in step (a), the mass fraction of acrylic acid in dichloromethane is 0.1 g / mL.

[0013] Furthermore, the present invention also provides a method for preparing the drug-loaded microspheres for interventional treatment of liver cancer, comprising the following steps: S1: Add 1,2-propylene glycol and sodium cantharidate into ultrapure water and mix well to obtain a sodium cantharidate solution; add lecithin and cholesterol into anhydrous ethanol and mix well; add the mixture into the sodium cantharidate solution; stir at 1300-1500 rpm for 20-25 min under nitrogen protection; filter through a 0.22 μm microporous filter membrane for 3-4 times to obtain sodium cantharidate liposomes; S2: Slowly add acrylamide to the sodium cantharidin liposomes obtained in step S1 while stirring, add benzoyl peroxide, stir and react at 80°C and 200-300 rpm for 2 h, slowly add acrylic acid-camptothecin and acrylol-folic acid, react at 200-300 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.

[0014] Furthermore, in step S1, the mass ratio of 1,2-propylene glycol to ultrapure water is 1:3.

[0015] Furthermore, in step S1, the mass ratio of anhydrous ethanol to lecithin is 4:1.

[0016] Compared with the prior art, the present invention has the following beneficial effects: The present invention provides a drug-loaded microsphere for interventional treatment of liver cancer, sodium cantharidin is prepared, and polyacrylamide is used to prepare the drug-loaded microsphere. Polyacrylamide contains a large number of amide bonds, can absorb water, has water absorption and swelling, is conducive to embolization therapy, and introduces folic acid and camptothecin into polyacrylamide, which can enhance targeting, and camptothecin and sodium cantharidin synergize to enhance the anti-liver cancer effect. The present invention prepares acrylic acid-camptothecin, and by covalently linking acrylic acid and camptothecin, camptothecin has a double bond, participates in the polymerization process of polyacrylamide, and successfully introduces camptothecin with anti-tumor activity into the polyacrylamide chain of the drug-loaded microsphere, effectively improves the anti-liver cancer activity, improves biocompatibility, and solves the problem of difficulty in configuring camptothecin as a hydrophobic drug. The present invention prepares folic acid-propenol, covalently links folic acid and propenol, introduces folic acid into polyacrylamide, folic acid is highly expressed or overexpressed in tumor cells, and conservatively expressed in normal cells, and the introduction of folic acid can improve the targeting of drug-loaded microspheres. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] In order to more clearly illustrate the technical solutions in the present invention or the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings in the following description are only for the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0018] Figure 1This is a scanning electron microscope image of the drug-loaded microspheres for interventional treatment of liver cancer described in Example 1 of the present invention; Figure 2 The anti-tumor effects of the drug-loaded microspheres described in Examples 1-3 and Comparative Examples 1-2 of the present invention; Figure 3 The organ toxicity of the drug-loaded microspheres described in Example 1 and Comparative Examples 1-2 of the present invention; Figure 4 This is a test chart of the cumulative drug release rate of the drug-loaded microspheres described in Example 1 of the present invention. DETAILED DESCRIPTION

[0019] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments, but the present invention is not limited to the following embodiments.

[0020] It should be noted that, unless otherwise specified, the chemical reagents involved in the present invention were purchased through commercial channels.

[0021] Example 1: A drug-loaded microsphere for interventional treatment of liver cancer, the preparation raw materials include the following components in parts by weight: 3 parts of sodium cantharidin, 7 parts of lecithin, 0.04 parts of cholesterol, 30 parts of 1,2-propylene glycol, 6 parts of acrylamide, 4.5 parts of acrylamide-folic acid, 5 parts of acrylic acid-camptothecin, and 0.15 parts of benzoyl peroxide.

[0022] The raw materials for preparing propylene alcohol-folic acid include the following components in parts by weight: 6 parts of folic acid, 3 parts of propylene alcohol, 3.5 parts of HOBt and 5 parts of DCC.

[0023] The preparation method of propylene glycol-folic acid comprises the following steps: (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°C and 200 rpm for 40 min, and continue stirring at room temperature for 3 h to obtain an activated folic acid solution; (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), and react at 60° C. and 300 rpm for 14 h under nitrogen protection, cool to room temperature, centrifuge at 8000 rpm for 20 min, wash the precipitate with deionized water, and dry in vacuo at 70° C. to obtain allyl alcohol-folic acid.

[0024] The raw materials for preparing acrylic acid-camptothecin include the following components in parts by weight: 1.6 parts of acrylic acid, 2 parts of camptothecin, 1.25 parts of EDC, and 0.8 parts of DAMP.

[0025] The preparation method of acrylic acid-camptothecin comprises the following steps: (a) 4 g of camptothecin, 1.6 g of DAMP, 2.5 g of EDC were mixed with 160 mL of dichloromethane to obtain a mixed solution. 3.2 g of acrylic acid was mixed with 32 mL of dichloromethane and added dropwise to the mixed solution under nitrogen protection. The mixture was stirred at 200 rpm for 14 h. (b) After the reaction in step (a) is completed, dichloromethane is removed under reduced pressure, the product is washed with deionized water, and dried under vacuum at 50° C. to obtain acrylic acid-camptothecin.

[0026] This embodiment also provides a method for preparing the drug-loaded microspheres for interventional treatment of liver cancer, comprising the following steps: S1: Add 30 g 1,2-propylene glycol and 3 g sodium cantharidate to 90 g ultrapure water and mix well to obtain a sodium cantharidate solution; add 7 g lecithin and 0.04 g cholesterol to 28 g anhydrous ethanol and mix well; add the mixture to the sodium cantharidate solution; stir at 1500 rpm for 25 min under nitrogen protection; filter through a 0.22 μm microporous filter membrane for 4 times to obtain sodium cantharidate liposomes; S2: Slowly add 6 g of acrylamide to the sodium cantharidin liposomes obtained in step S1 while stirring, add 0.15 g of benzoyl peroxide, stir and react at 80°C and 300 rpm for 2 h, slowly add 5 g of acrylic acid-camptothecin and 4.5 g of acryl alcohol-folic acid, react at 300 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. The scanning electron microscope image is as shown in Figure 1 shown.

[0027] Example 2: A drug-loaded microsphere for interventional treatment of liver cancer, the preparation raw materials include the following components in parts by weight: 2 parts of sodium cantharidin, 4 parts of lecithin, 0.02 parts of cholesterol, 20 parts of 1,2-propylene glycol, 4 parts of acrylamide, 3 parts of acrylol-folic acid, 3 parts of acrylic acid-camptothecin, and 0.1 parts of benzoyl peroxide.

[0028] The raw materials for preparing allyl alcohol-folic acid include the following components in parts by weight: 3 parts of folic acid, 1.5 parts of allyl alcohol, 1.8 parts of HOBt and 2.7 parts of DCC.

[0029] The preparation method of propylene glycol-folic acid comprises the following steps: (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°C and 100 rpm for 30 min, and continue stirring at room temperature for 2 h to obtain an activated folic acid solution; (2) Dissolve 1.5 g of propylene glycol in 15 mL of dimethyl sulfoxide to obtain an propylene glycol solution, mix the propylene glycol solution with the activated folic acid obtained in step (1), and react at 50° C. and 200 rpm under nitrogen protection for 12 h. Cool to room temperature, centrifuge at 8000 rpm for 15 min, wash the precipitate with deionized water, and dry in vacuo at 60° C. to obtain propylene glycol-folic acid.

[0030] The raw materials for preparing acrylic acid-camptothecin include the following components in parts by weight: 1.2 parts of acrylic acid, 1.5 parts of camptothecin, 0.95 parts of EDC, and 0.6 parts of DAMP.

[0031] The preparation method of acrylic acid-camptothecin comprises the following steps: (a) 3 g of camptothecin, 1.2 g of DAMP, and 1.9 g of EDC were mixed with 120 mL of dichloromethane to obtain a mixed solution. 2.4 g of acrylic acid was mixed with 24 mL of dichloromethane and added dropwise to the mixed solution under nitrogen protection. The mixture was stirred at 150 rpm for 12 h. (b) After the reaction in step (a) is completed, dichloromethane is removed under reduced pressure, the product is washed with deionized water, and vacuum dried at 40° C. to obtain acrylic acid-camptothecin.

[0032] This embodiment also provides a method for preparing the drug-loaded microspheres for interventional treatment of liver cancer, comprising the following steps: S1: Add 20 g 1,2-propylene glycol and 2 g sodium cantharidate to 60 g ultrapure water and mix well to obtain a sodium cantharidate solution; add 4 g lecithin and 0.02 g cholesterol to 16 g anhydrous ethanol and mix well; add the mixture to the sodium cantharidate solution; stir at 1300 rpm for 20 min under nitrogen protection; filter through a 0.22 μm microporous filter membrane for 3 times to obtain sodium cantharidate liposomes; S2: Slowly add 4 g acrylamide to the sodium cantharidin liposomes obtained in step S1 while stirring, add 0.1 g benzoyl peroxide, stir and react at 80°C and 200 rpm for 2 h, slowly add 3 g acrylic acid-camptothecin and 3 g acryl alcohol-folic acid, react at 200 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.

[0033] Example 3: A drug-loaded microsphere for interventional treatment of liver cancer, the preparation raw materials include the following components in parts by weight: 2.5 parts of sodium cantharidin, 6 parts of lecithin, 0.03 parts of cholesterol, 25 parts of 1,2-propylene glycol, 5 parts of acrylamide, 4 parts of acrylol-folic acid, 4 parts of acrylic acid-camptothecin, and 0.12 parts of benzoyl peroxide.

[0034] The raw materials for preparing propylene alcohol-folic acid include the following components in parts by weight: 5 parts of folic acid, 2 parts of propylene alcohol, 2 parts of HOBt and 4 parts of DCC.

[0035] The preparation method of propylene glycol-folic acid comprises the following steps: (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°C and 150 rpm for 35 min, and continue stirring at room temperature for 2.5 h to obtain an activated folic acid solution; (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), stir and react at 55° C. and 250 rpm for 13 h under nitrogen protection, cool to room temperature, centrifuge at 8000 rpm for 18 min, wash the precipitate with deionized water, and dry in vacuo at 65° C. to obtain allyl alcohol-folic acid.

[0036] The raw materials for preparing acrylic acid-camptothecin include the following components in parts by weight: 1.5 parts of acrylic acid, 1.8 parts of camptothecin, 1 part of EDC, and 0.7 parts of DAMP.

[0037] The preparation method of acrylic acid-camptothecin comprises the following steps: (a) 3.6 g camptothecin, 1.4 g DAMP, 2 g EDC were mixed with 144 mL dichloromethane to obtain a mixed solution, 3 g acrylic acid was mixed with 30 mL dichloromethane, and then added dropwise to the mixed solution under nitrogen protection, and the reaction was stirred at 180 rpm for 13 h; (b) After the reaction in step (a) is completed, dichloromethane is removed under reduced pressure, the product is washed with deionized water, and dried under vacuum at 45° C. to obtain acrylic acid-camptothecin.

[0038] This embodiment also provides a method for preparing the drug-loaded microspheres for interventional treatment of liver cancer, comprising the following steps: S1: Add 25 g 1,2-propylene glycol and 2.5 g sodium cantharidate to 75 g ultrapure water and mix well to obtain a sodium cantharidate solution; add 6 g lecithin and 0.03 g cholesterol to 24 g anhydrous ethanol and mix well; add the mixture to the sodium cantharidate solution; stir at 1400 rpm for 22 min under nitrogen protection; filter through a 0.22 μm microporous filter membrane for 4 times to obtain sodium cantharidate liposomes; S2: Slowly add 5 g acrylamide to the sodium cantharidin liposomes obtained in step S1 while stirring, add 0.12 g benzoyl peroxide, stir and react at 80°C and 250 rpm for 2 h, slowly add 4 g acrylic acid-camptothecin and 4 g acryl 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.

[0039] The difference between Comparative Example 1 and Example 1 is that acrylamide is used instead of propylene glycol-folic acid.

[0040] The difference between Comparative Example 2 and Example 1 is that acrylic acid-camptothecin is replaced by acrylamide.

[0041] Experimental Example 1: Take 8-week-old (220-240 g) male SD rats; after one week of adaptation in the SPF animal room, start inoculating orthotopic tumors; through surgical operation, inject N1S1 liver cancer cells into the rat liver to establish an orthotopic liver tumor model. Take out the N1S1 cell culture dish from the constant temperature cell culture incubator (5% CO2, 37°C), aspirate the liquid and centrifuge to remove the upper culture medium, wash with PBS, remove impurities such as dead cells, and then add IMDM complete culture medium to resuspend the cell pellet, take 18 μL of cell stock solution and add 2 μL of 0.4% trypan blue cell counting, draw a certain amount of matrix gel and N1S1 cell pellet to suspend to obtain N1S1 cell-matrix gel suspension; 1 mL insulin needle extracts 50 μL N1S1 cell-matrix gel suspension (1×10 7Cells) were placed on crushed ice for later use. Male rats were anesthetized with anesthetics and placed in a supine position with four limbs fixed on a mouse board; the rats' abdomens were shaved and disinfected with iodine, and an incision of about 2 cm was made at the right side of the ribs below the midline of the abdomen. The epidermis, muscles, and peritoneum were gradually cut open, and the right lobe of the liver was exposed to the visual field with a sterile cotton swab. The right lobe of the liver was slowly pulled gently, and the insulin needle containing the N1S1 cell-matrix gel suspension was slowly inserted into the liver tissue, and the N1S1 cell-matrix gel suspension was pushed in. The insulin needle was pulled out and pressed 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 sutured layer by layer. The recovery and life status of the rats were observed after surgery to ensure normal diet and water intake. After tumor implantation, the rats were randomly divided into groups, with 5 rats in each group. The groups, injection time, injected cell type and number were marked on the mouse cages. Seven days after inoculation, 1 mg of microsphere powder was first dispersed and mixed in 0.3 mL of 3% carboxymethyl cellulose solution for standby use. The carboxymethyl cellulose solution without drug-loaded microspheres was used as the control group. The normal group did not undergo liver cancer modeling. An equal amount of carboxymethyl cellulose solution was used. The rats were anesthetized and fixed on the operating table. The abdomen was shaved to expose the epidermis, and the rats were wiped and disinfected with iodine. The surgical instruments were opened layer by layer, the fascia at the common hepatic artery was peeled off, the blood vessels were freed, and the carboxymethyl cellulose solution containing or not containing microsphere material was injected through the hepatic artery through a PE 10 catheter. The residual liquid in the catheter was then pushed with 0.1 mL of normal saline, the blood vessels were ligated, and the layers were sutured and disinfected. After the anesthetic expired, normal diet and water intake were ensured after recovery. The tumor size was recorded every 3 days thereafter. The results are shown in Figure 2 After 14 days, the rats were killed, the heart, lungs, and kidneys were removed and weighed, and the organ coefficient was calculated, as shown in Figure 3 shown.

[0042] Figure 2 The results showed that the tumor sizes of Examples 1-3 and Comparative Examples 1-2 were significantly reduced, indicating that the drug-loaded microspheres can effectively fight tumors. The anti-tumor effects of Examples 1-3 were better than those of Comparative Examples 1-2. Comparative Example 1 did not add folic acid, and the targeting was reduced. Comparative Example 2 did not add camptothecin, and the anti-tumor effect was reduced. When organs are poisoned, pathological changes will occur, causing changes in organ weight, such as Figure 3 The results showed that compared with the normal group, the lung coefficient and kidney coefficient 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 were able to significantly increase the heart coefficient to a normal level, effectively preventing heart atrophy and pathology. The effect of Example 1 was better than that of Comparative Examples 1-2. Comparative Example 1 did not add folic acid, and the targeting was reduced. Comparative Example 2 did not add camptothecin, and the synergistic attenuation effect was reduced.

[0043] Experimental Example 2: Take 300 mg of the drug-loaded microspheres obtained in Example 1, mix them thoroughly with 25 mL of normal saline and let them stand. Take 1 mL of the supernatant at 0 h, 3 h, 6 h, 12 h, 24 h and 36 h, and add the same volume of fresh normal saline each time 1 mL of the supernatant is taken so that the volume of the whole system remains unchanged. Pass the sample through a 0.22 μm microporous filter membrane, take 20 μL of the filtrate and use a high performance liquid chromatography (HPLC) to determine the content of sodium cantharidin, obtain the cumulative release of the drug, and calculate the cumulative release rate of the drug. The results are as follows: Figure 4 shown.

[0044] Figure 4 The results show that the drug-loaded microspheres for interventional treatment of liver cancer of the present invention have significant sustained-release drug release behavior, and the drug release is slow. Therefore, the drug can be slowly released locally, thereby continuously delivering the drug to tumor cells to play a good local targeted treatment effect for tumors and reduce systemic toxic side effects.

[0045] Experimental Example 3: Weigh 50 mg of the microsphere sample prepared in Examples 1-3 of the present invention, accurately weigh it, place it in 37°C physiological saline and shake it for 30 seconds, then let it stand, record the suspension time of the microsphere (until it is completely stratified by naked eye); take it out after 20 minutes, wipe off the water on the surface with filter paper, quickly weigh it with an electronic balance, and calculate the water absorption expansion rate (WSR) according to the following formula: WSR=[(W2-W1) / W1]×100%, where W2 is the mass of the microsphere after water absorption, and W1 is the mass of the microsphere in the dry state. The results are shown in Table 1.

[0046] Table 1: Suspension time(s) 20 min swelling rate Example 1 119.7 57.13 Example 2 120.1 56.98 Example 3 119.5 57.39 The results in Table 1 show that the drug-loaded microspheres of the present invention are easily dispersed in physiological saline without adhesion, and the suspension time is 2 minutes, indicating that they have good dispersibility; the water absorption and expansion rate of the microspheres in 20 minutes is more than 55%, which has good water absorption and expansion effect, further ensuring the effect of tumor vascular embolization.

[0047] Those skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of the present invention (including the claims) is limited to these examples. Under the concept of the present invention, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of the different aspects of the present invention as described above, which are not provided in detail for the sake of simplicity.

[0048] The present 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 the present invention should be included in the scope of protection of the present invention.

Claims

1. A drug-loaded microsphere for interventional treatment of liver cancer, characterized in that: The preparation raw materials include the following components in parts by weight: 2-3 parts of sodium cantharidinate, 4-7 parts of lecithin, 0.02-0.04 parts of cholesterol, 20-30 parts of 1,2-propylene glycol, 4-6 parts of acrylamide, 3-4.5 parts of acrylol-folic acid, 3-5 parts of acrylic acid-camptothecin, and 0.1-0.15 parts of benzoyl peroxide; The raw materials for preparing the propylene alcohol-folic acid include the following components in parts by weight: 3-6 parts of folic acid, 1.5-3 parts of propylene alcohol, 1.8-3.5 parts of HOBt, and 2.7-5 parts of DCC; The preparation method of propylene glycol-folic acid comprises the following steps: (1) Dissolve folic acid in dimethyl sulfoxide, add HOBt and DCC, stir at 60-70°C, and continue stirring at room temperature to obtain an activated folic acid solution; (2) dissolving allyl alcohol in dimethyl sulfoxide to obtain an allyl alcohol solution, mixing the allyl alcohol solution with the activated folic acid obtained in step (1), stirring and reacting under nitrogen protection, cooling, centrifuging, washing the precipitate with deionized water, and vacuum drying 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 of acrylic acid, 1.5-2 parts of camptothecin, 0.95-1.25 parts of EDC, and 0.6-0.8 parts of DAMP; The preparation method of acrylic acid-camptothecin comprises the following steps: (a) Mix camptothecin, DAMP, EDC and dichloromethane to obtain a mixed solution, mix acrylic acid and dichloromethane to obtain a mixed solution, add 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 product is washed with deionized water, and vacuum dried 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 mass concentration of folic acid 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 acryl 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 claimed in claims 1-4, characterized in that: The following steps are involved: S1: adding 1,2-propylene glycol and sodium cantharidate to ultrapure water and mixing them to obtain a sodium cantharidate solution; adding lecithin and cholesterol to anhydrous ethanol and mixing them to obtain a sodium cantharidate solution; adding the mixture to the sodium cantharidate solution; stirring the mixture under nitrogen protection; and filtering the mixture through a microporous filter membrane to obtain sodium cantharidate liposomes; S2: Add acrylamide to the sodium cantharidin liposomes obtained in step S1 while stirring, add benzoyl peroxide, stir to react, add acrylic acid-camptothecin and acrylol-folic acid, stir to react, filter, wash the filter cake with anhydrous ethanol and deionized water, and vacuum dry 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-propylene glycol to ultrapure water is 1:3; The mass ratio of anhydrous ethanol to lecithin is 4:1.

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