Auxiliary agent of slow-release anti-cancer drug and preparation method of auxiliary agent

Abstract

The invention discloses an auxiliary agent of a slow-release anti-cancer drug and a preparation method of the auxiliary agent. The preparation method comprises the following steps: S1, preparing mesoporous alumina; s2, preparation of pretreated mesoporous alumina; s3, preparation of organic mesoporous alumina; s4, preparing modified mesoporous alumina; and S5, preparing the anti-cancer drug auxiliary agent. According to the anti-cancer drug adjuvant with the slow release function, the multifunctional anti-cancer drug adjuvant is prepared through multi-step surface modification, the adjuvant has the excellent effects of a mesoporous structure, cyclodextrin inclusion, folic acid targeting, drug absorption promotion and the like, efficient loading and controllable release of drugs can be achieved, and the anti-cancer drug adjuvant with the slow release function can be used for preparing the anti-cancer drug adjuvant with the slow release function. The active targeting and drug absorption promoting capabilities are also realized, so that the treatment effect of the anti-cancer drug is improved, and the bioavailability of the anti-cancer drug is improved.

Description

[0001] This application is a divisional application. The application number of the original application is 202411846909.9, and the original application date is December 16, 2024. The entire content of the original application is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the technical field of drug carriers, and specifically relates to an adjuvant for sustained-release anticancer drugs and a preparation method thereof. Background Art

[0003] A drug sustained-release material, i.e., a drug sustained-release carrier material, is a carrier for small molecule drugs during the slow release process of drugs and is an important part of a drug sustained-release system. Generally, the release rate and drug efficacy of drugs are regulated by controlling the structural changes of the drug carrier material. Currently, polymer carrier materials are generally commonly used for drug sustained-release carrier materials, and the commonly used polymer carrier materials include natural polymer carrier materials and synthetic polymer carrier materials.

[0004] Developing effective drug carriers to reduce the inherent adverse reactions of chemotherapy drugs and improve the treatment effect has become one of the key issues in cancer treatment. Currently, in order to enhance the enhanced permeability and retention effect, drug nanocarriers have been developed to improve the accumulation of drugs in the tumor region, and the nanocarriers include polymer vesicles, micelles, polymer nanoparticles, inorganic nanoparticles, and hybrid porous solids.

[0005] Chinese Patent Application CN108078939A discloses an anticancer drug carrier preparation and its application. In the present invention, succinic anhydride, wolfberry polysaccharide, and α-linolenic acid are used as reaction raw materials. First, succinic anhydride and wolfberry polysaccharide are reacted under alkaline conditions, and the reactants are put into a dimethyl sulfoxide solvent and activated under the action of N,N'-carbonyldiimidazole. The activated substance and α-linolenic acid are further subjected to an esterification reaction. The obtained target product has high mechanical strength, good stability, and excellent biocompatibility. The prepared drug carrier is applied to the loading of hydrophobic tumor drugs to improve the bioavailability of tumor drugs. However, the loading capacity and sustained-release stability of this carrier still need to be further improved. Summary of the Invention

[0006] Aiming at the deficiencies of the prior art, the purpose of the present invention is to provide an adjuvant for anticancer drugs with a sustained-release function and a preparation method thereof. The adjuvant for anticancer drugs has a large drug loading capacity, and at the same time, the release of the drug is stable, improving the bioavailability of the drug.

[0007] To achieve the above purpose, the present invention provides the following technical solutions: A preparation method of an adjuvant for anticancer drugs with a sustained-release function, comprising the following steps: S1. Preparation of mesoporous alumina; S2. Preparation of pretreated mesoporous alumina: Add mesoporous alumina to an ethanol aqueous solution, then add γ-glycidoxypropyltrimethoxysilane, and carry out a stirring reaction. After the reaction is completed, filter, wash, and dry to obtain pretreated mesoporous alumina; S3. Preparation of organic mesoporous alumina: Add the pretreated mesoporous alumina in step S2 to DMF, then add hydroxypropyl cyclodextrin and triethylamine, and carry out a heating reaction under nitrogen protection. After the reaction is completed, filter, wash, and dry to obtain organic mesoporous alumina; S4. Preparation of modified mesoporous alumina: Add 3-mercaptopropionic acid and folic acid to a DMF solution, then add EDC and NHS, and carry out stirring activation. After the activation is completed, add the organic mesoporous alumina in step S3, and carry out an esterification reaction under nitrogen protection. After the reaction is completed, filter, wash, and dry to obtain modified mesoporous alumina; S5. Preparation of an anticancer drug adjuvant: Add the modified mesoporous alumina in step S4 to DMF, then add 8-shogaol and azobisisobutyronitrile, and carry out a constant-temperature reaction. After the reaction is completed, filter, wash, and dry to obtain the anticancer drug adjuvant.

[0008] Preferably, the preparation method of the mesoporous alumina in step S1 is specifically as follows: Add cetyltrimethylammonium bromide to deionized water, stir to dissolve, then add aluminum nitrate, stir evenly, add urea, and carry out a hydrothermal reaction. After the reaction is completed, carry out aging, then filter, wash, dry, and calcine to obtain the mesoporous alumina.

[0009] Preferably, the mass ratio of cetyltrimethylammonium bromide, deionized water, aluminum nitrate, and urea is 6-8:300-400:25-30:12-16. The temperature of the hydrothermal reaction is 120-140 °C, and the time is 6-9 h; the temperature of the aging is 70-80 °C, and the time is 10-15 h; the temperature of the calcination is 500-600 °C, and the time is 3-4 h.

[0010] In the present invention, mesoporous alumina is prepared by hydrothermal method. Mesoporous alumina has characteristics such as a high specific surface area, a large pore volume, a controllable pore size distribution, a suitable surface acidity, and good thermal stability, which can effectively improve the drug loading capacity of the adjuvant.

[0011] Preferably, the mass concentration of ethanol in the ethanol aqueous solution in step S2 is 70-80%, the mass ratio of the mesoporous alumina to γ-glycidoxypropyltrimethoxysilane is 50:10-14, the temperature of the stirring reaction is 70-75 °C, and the time is 4-6 h.

[0012] In the present invention, γ-glycidoxypropyltrimethoxysilane is used to modify the surface of mesoporous alumina, thereby introducing epoxy groups onto the alumina surface, which is beneficial to the subsequent reactions.

[0013] Preferably, in step S3, the mass ratio of the pretreated mesoporous alumina, hydroxypropyl cyclodextrin, and triethylamine is 50:12 - 18:0.5 - 1, the temperature of the heating reaction is 60 - 70 °C, and the time is 3 - 5 h.

[0014] In the present invention, hydroxypropyl cyclodextrin is introduced onto the alumina by means of covalent bonds. Cyclodextrin has a hydrophobic inner cavity, which can, on the one hand, encapsulate drug molecules to improve the solubility of the drugs, and on the other hand, also has the function of drug slow release, enabling the drugs to be released steadily.

[0015] Preferably, in step S4, the mass ratio of 3-mercaptopropionic acid, folic acid, EDC, NHS, and the organic mesoporous alumina is 10 - 13:5 - 7:10 - 15:13 - 18:50 - 60.

[0016] Preferably, in step S4, the temperature of the stirring activation is 20 - 30 °C, the rotation speed is 150 - 200 r / min, and the time is 1 - 2 h; the temperature of the esterification reaction is 40 - 50 °C, and the time is 3 - 4 h.

[0017] In the present invention, through the esterification reaction of the carboxyl groups in 3-mercaptopropionic acid and folic acid with the hydroxyl groups in hydroxypropyl cyclodextrin, 3-mercaptopropionic acid and folic acid are introduced onto the alumina carrier. Folic acid can bind to the overexpressed folic acid receptors on the surface of cancer cells, endowing the adjuvant with targeting properties, and the sulfhydryl group in 3-mercaptopropionic acid is beneficial to the subsequent reactions.

[0018] Preferably, in step S5, the mass ratio of the modified mesoporous alumina, 8-shogaol, and azobisisobutyronitrile is 50 - 60:4 - 7:0.5 - 1.

[0019] Preferably, in step S5, the temperature of the constant temperature reaction is 60 - 70 °C, and the time is 1 - 2 h.

[0020] In the present invention, through the thiol-ene reaction, 8-shogaol is introduced onto the alumina carrier. 8-Shogaol has strong antioxidant and anti-inflammatory effects, which can improve the stability of anticancer drugs. At the same time, 8-shogaol has moderate lipophilicity and can interact with the phospholipid bilayer of cell membranes, temporarily changing the fluidity and permeability of cell membranes, thereby promoting the absorption of drug molecules and improving the bioavailability of drugs, enhancing the drug delivery effect of the adjuvant.

[0021] The present invention also protects an anticancer drug adjuvant with a slow release function prepared by the method as described above.

[0022] Compared with the prior art, the present invention has the following beneficial effects: (1) The anti-cancer drug adjuvant with a sustained-release function provided by the present invention is prepared into a multifunctional anti-cancer drug adjuvant through multi-step surface modification. This adjuvant has excellent mesoporous structure, cyclodextrin inclusion, folic acid targeting, and drug absorption promotion effects. It can not only achieve high-efficiency drug loading and controlled release, but also has the ability of active targeting and drug absorption promotion, thereby improving the therapeutic effect of anti-cancer drugs and the bioavailability of anti-cancer drugs.

[0023] (2) The anti-cancer drug adjuvant with a sustained-release function provided by the present invention uses cetyltrimethylammonium bromide as a template agent to prepare mesoporous alumina through a hydrothermal reaction. The obtained mesoporous alumina carrier has a regular mesoporous structure and a large specific surface area, providing a good foundation for subsequent functional modification and drug loading; subsequently, epoxy groups are introduced on the surface of the mesoporous alumina, which not only enhances the chemical stability of the alumina carrier, but also provides sufficient reaction sites for subsequent functional modification.

[0024] (3) The anti-cancer drug adjuvant with a sustained-release function provided by the present invention reacts the organic mesoporous alumina with hydroxypropyl cyclodextrin. The hydrophobic inner cavity of the cyclodextrin molecule can form an inclusion complex with the drug molecule, and this host-guest interaction realizes the controlled release of the drug and effectively prolongs the in vivo circulation time of the drug; subsequently, the modified mesoporous alumina is reacted with 3-mercaptopropionic acid and folic acid, and the folic acid molecule is grafted onto the carrier in the form of a covalent bond, enabling the carrier to have the ability to recognize the overexpressed folic acid receptor on the surface of cancer cells, thereby realizing the active targeting of tumor tissues and improving the enrichment efficiency of the drug at the lesion site. At the same time, the mercapto group introduced in 3-mercaptopropionic acid is beneficial for subsequent reactions; finally, the modified mesoporous alumina is reacted with 8-shogaol. On the one hand, 8-shogaol can effectively scavenge the free radicals generated during drug delivery, protect the drug molecule from oxidative damage, and improve the stability of the drug delivery system. On the other hand, it can enhance cell permeability and improve the absorption rate of the drug at the targeting site, thereby improving the cell uptake efficiency, bioavailability, and therapeutic effect of the drug. Description of the Drawings

[0025] Figure 1 It is a cumulative release rate graph of different groups of anti-cancer drug adjuvants loaded with anti-cancer drugs in a simulated small intestine environment. Detailed Embodiments

[0026] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0027] Example 1 A preparation method of an anticancer drug adjuvant with a sustained-release function includes the following steps: S1. Preparation of mesoporous alumina: Add 7 g of cetyltrimethylammonium bromide to 350 g of deionized water, stir to dissolve, then add 28 g of aluminum nitrate, stir evenly, add 14 g of urea, carry out hydrothermal reaction at 130 °C for 8 h, after the reaction is completed, age at 75 °C for 13 h, then filter, wash, dry, and calcine at 550 °C for 3.5 h to obtain mesoporous alumina; S2. Preparation of pretreated mesoporous alumina: Add 50 g of mesoporous alumina to 800 mL of an ethanol aqueous solution (the mass concentration of ethanol is 75%), then add 12 g of γ-glycidyletheroxypropyltrimethoxysilane, stir and react at 72 °C for 5 h, after the reaction is completed, filter, wash, dry to obtain pretreated mesoporous alumina; S3. Preparation of organically modified mesoporous alumina: Add 50 g of the pretreated mesoporous alumina in step S2 to 700 mL of DMF, then add 15 g of hydroxypropyl cyclodextrin and 0.8 g of triethylamine, react at 65 °C for 4 h under nitrogen protection, after the reaction is completed, filter, wash, dry to obtain organically modified mesoporous alumina; S4. Preparation of modified mesoporous alumina: Add 12 g of 3-mercaptopropionic acid and 6 g of folic acid to 800 mL of a DMF solution, then add 13 g of EDC and 16 g of NHS, stir and activate at a rotation speed of 180 r / min and a temperature of 25 °C for 1.5 h, after the activation is completed, add 55 g of the organically modified mesoporous alumina in step S3, react at 45 °C for 3.5 h under nitrogen protection, after the reaction is completed, filter, wash, dry to obtain modified mesoporous alumina; S5. Preparation of the anticancer drug adjuvant: Add 55 g of the modified mesoporous alumina in step S4 to 800 mL of DMF, then add 6 g of 8-shogaol and 0.8 g of azobisisobutyronitrile, react at a constant temperature of 65 °C for 1.5 h, after the reaction is completed, filter, wash, dry to obtain the anticancer drug adjuvant.

[0028] Example 2 A preparation method of an anticancer drug adjuvant with a sustained-release function includes the following steps: S1. Preparation of mesoporous alumina: Add 7 g of cetyltrimethylammonium bromide to 350 g of deionized water, stir to dissolve, then add 27 g of aluminum nitrate, stir evenly and then add 14 g of urea. Perform hydrothermal reaction at 130 °C for 7 h. After the reaction is completed, age at 75 °C for 12 h, then filter, wash, dry, and calcine at 550 °C for 3.5 h to obtain mesoporous alumina; S2. Preparation of pretreated mesoporous alumina: Add 50 g of mesoporous alumina to 800 mL of an ethanol aqueous solution (the mass concentration of ethanol is 75%), then add 12 g of γ-glycidoxypropyltrimethoxysilane, and stir and react at 72 °C for 5 h. After the reaction is completed, filter, wash, dry to obtain pretreated mesoporous alumina; S3. Preparation of organic mesoporous alumina: Add 50 g of the pretreated mesoporous alumina in step S2 to 700 mL of DMF, then add 14 g of hydroxypropyl cyclodextrin and 0.7 g of triethylamine, and react at 65 °C for 4 h under nitrogen protection. After the reaction is completed, filter, wash, dry to obtain organic mesoporous alumina; S4. Preparation of modified mesoporous alumina: Add 11 g of 3-mercaptopropionic acid and 6 g of folic acid to 800 mL of DMF solution, then add 12 g of EDC and 15 g of NHS, and stir and activate at a rotation speed of 170 r / min and a temperature of 25 °C for 1.5 h. After the activation is completed, add 55 g of the organic mesoporous alumina in step S3, and react at 45 °C for 3.5 h under nitrogen protection. After the reaction is completed, filter, wash, dry to obtain modified mesoporous alumina; S5. Preparation of an anticancer drug adjuvant: Add 55 g of the modified mesoporous alumina in step S4 to 800 mL of DMF, then add 5 g of 8-shogaol and 0.7 g of azobisisobutyronitrile, and react at a constant temperature of 65 °C for 1.5 h. After the reaction is completed, filter, wash, dry to obtain the anticancer drug adjuvant.

[0029] Example 3 A preparation method of an anticancer drug adjuvant with a sustained-release function, comprising the following steps: S1. Preparation of mesoporous alumina: Add 6 g of cetyltrimethylammonium bromide to 300 g of deionized water, stir to dissolve, then add 25 g of aluminum nitrate, stir evenly and then add 12 g of urea. Perform hydrothermal reaction at 120 °C for 9 h. After the reaction is completed, age at 70 °C for 15 h, then filter, wash, dry, and calcine at 500 °C for 4 h to obtain mesoporous alumina; S2. Preparation of pretreated mesoporous alumina: Add 50 g of mesoporous alumina to 800 mL of an ethanol aqueous solution (the mass concentration of ethanol is 70%), then add 10 g of γ-glycidoxypropyltrimethoxysilane, and stir and react at 70 °C for 6 h. After the reaction is completed, filter, wash, dry to obtain pretreated mesoporous alumina; S3. Preparation of organic mesoporous alumina: Add 50 g of the pretreated mesoporous alumina in step S2 into 700 mL of DMF, then add 12 g of hydroxypropyl cyclodextrin and 0.5 g of triethylamine, react at 60 °C for 5 h under nitrogen protection, filter, wash, and dry after the reaction to obtain organic mesoporous alumina; S4. Preparation of modified mesoporous alumina: Add 10 g of 3-mercaptopropionic acid and 5 g of folic acid into 800 mL of DMF solution, then add 10 g of EDC and 13 g of NHS, stir and activate at a rotation speed of 150 r / min and a temperature of 20 °C for 2 h. After activation, add 50 g of the organic mesoporous alumina in step S3, react at 40 °C for 4 h under nitrogen protection, filter, wash, and dry after the reaction to obtain modified mesoporous alumina; S5. Preparation of anticancer drug adjuvant: Add 50 g of the modified mesoporous alumina in step S4 into 800 mL of DMF, then add 4 g of 8-shogaol and 0.5 g of azobisisobutyronitrile, react at a constant temperature of 60 °C for 2 h, filter, wash, and dry after the reaction to obtain the anticancer drug adjuvant.

[0030] Example 4 A preparation method of an anticancer drug adjuvant with a sustained-release function, comprising the following steps: S1. Preparation of mesoporous alumina: Add 8 g of cetyltrimethylammonium bromide into 400 g of deionized water, stir and dissolve, then add 30 g of aluminum nitrate, stir evenly, add 16 g of urea, carry out hydrothermal reaction at 140 °C for 6 h, age at 80 °C for 10 h, then filter, wash, and dry, and calcine at 600 °C for 3 h to obtain mesoporous alumina; S2. Preparation of pretreated mesoporous alumina: Add 50 g of mesoporous alumina into 800 mL of ethanol aqueous solution (the mass concentration of ethanol is 80%), then add 14 g of γ-glycidoxypropyltrimethoxysilane, stir and react at 75 °C for 4 h, filter, wash, and dry after the reaction to obtain pretreated mesoporous alumina; S3. Preparation of organic mesoporous alumina: Add 50 g of the pretreated mesoporous alumina in step S2 into 700 mL of DMF, then add 18 g of hydroxypropyl cyclodextrin and 1 g of triethylamine, react at 70 °C for 3 h under nitrogen protection, filter, wash, and dry after the reaction to obtain organic mesoporous alumina; S4. Preparation of modified mesoporous alumina: Add 13 g of 3-mercaptopropionic acid and 7 g of folic acid into 800 mL of DMF solution, then add 15 g of EDC and 18 g of NHS, stir and activate for 1 h at a rotation speed of 200 r / min and a temperature of 30 °C. After activation, add 60 g of the organic mesoporous alumina in step S3, react at 50 °C for 3 h under nitrogen protection. After the reaction is completed, filter, wash, and dry to obtain the modified mesoporous alumina; S5. Preparation of the anticancer drug adjuvant: Add 60 g of the modified mesoporous alumina in step S4 into 800 mL of DMF, then add 7 g of 8-shogaol and 1 g of azobisisobutyronitrile, react at a constant temperature of 70 °C for 1 h. After the reaction is completed, filter, wash, and dry to obtain the anticancer drug adjuvant.

[0031] Comparative Example 1 A preparation method of an anticancer drug adjuvant with a sustained-release function includes the following steps: S1. Preparation of mesoporous alumina: Add 7 g of cetyltrimethylammonium bromide into 350 g of deionized water, stir to dissolve, then add 28 g of aluminum nitrate, stir evenly and then add 14 g of urea, carry out hydrothermal reaction at 130 °C for 8 h. After the reaction is completed, age at 75 °C for 13 h, then filter, wash, and dry, and calcine at 550 °C for 3.5 h to obtain mesoporous alumina; S2. Preparation of pretreated mesoporous alumina: Add 50 g of mesoporous alumina into 800 mL of an ethanol aqueous solution (the mass concentration of ethanol is 75%), then add 12 g of γ-glycidoxypropyltrimethoxysilane, stir and react at 72 °C for 5 h. After the reaction is completed, filter, wash, and dry to obtain the pretreated mesoporous alumina; S3. Preparation of modified mesoporous alumina: Add 12 g of 3-mercaptopropionic acid and 6 g of folic acid into 800 mL of DMF solution, then add 13 g of EDC and 16 g of NHS, stir and activate at a rotation speed of 180 r / min and a temperature of 25 °C for 1.5 h. After activation, add 55 g of the pretreated mesoporous alumina in step S2, react at 45 °C for 3.5 h under nitrogen protection. After the reaction is completed, filter, wash, and dry to obtain the modified mesoporous alumina; S4. Preparation of the anticancer drug adjuvant: Add 55 g of the modified mesoporous alumina in step S3 into 800 mL of DMF, then add 6 g of 8-shogaol and 0.8 g of azobisisobutyronitrile, react at a constant temperature of 65 °C for 1.5 h. After the reaction is completed, filter, wash, and dry to obtain the anticancer drug adjuvant.

[0032] Compared with Example 1, hydroxypropyl cyclodextrin was not introduced in this comparative example.

[0033] Comparative Example 2 A preparation method of an anti-cancer drug adjuvant with a sustained-release function, comprising the following steps: S1. Preparation of mesoporous alumina: Add 7 g of cetyltrimethylammonium bromide to 350 g of deionized water, stir to dissolve, then add 28 g of aluminum nitrate, stir evenly, add 14 g of urea, carry out hydrothermal reaction at 130 °C for 8 h, after the reaction is completed, age at 75 °C for 13 h, then filter, wash, dry, and calcine at 550 °C for 3.5 h to obtain mesoporous alumina; S2. Preparation of pretreated mesoporous alumina: Add 50 g of mesoporous alumina to 800 mL of an ethanol aqueous solution (the mass concentration of ethanol is 75%), then add 12 g of γ-glycidoxypropyltrimethoxysilane, stir and react at 72 °C for 5 h, after the reaction is completed, filter, wash, dry to obtain pretreated mesoporous alumina; S3. Preparation of organic mesoporous alumina: Add 50 g of the pretreated mesoporous alumina in step S2 to 700 mL of DMF, then add 15 g of hydroxypropyl cyclodextrin and 0.8 g of triethylamine, react at 65 °C for 4 h under nitrogen protection, after the reaction is completed, filter, wash, dry to obtain organic mesoporous alumina; S4. Preparation of modified mesoporous alumina: Add 6 g of folic acid to 800 mL of DMF solution, then add 13 g of EDC and 16 g of NHS, stir and activate at a rotation speed of 180 r / min and a temperature of 25 °C for 1.5 h, after the activation is completed, add 55 g of the organic mesoporous alumina in step S3, react at 45 °C for 3.5 h under nitrogen protection, after the reaction is completed, filter, wash, dry to obtain modified mesoporous alumina; S5. Preparation of the anti-cancer drug adjuvant: Add 55 g of the modified mesoporous alumina in step S4 to 800 mL of DMF, then add 6 g of 8-shogaol, carry out constant-temperature oscillation at 65 °C for 1.5 h, after the reaction is completed, filter, wash, dry to obtain the anti-cancer drug adjuvant.

[0034] Compared with Example 1, in this comparative example, 3-mercaptopropionic acid was not added in step S4, and 8-shogaol was introduced onto the mesoporous alumina by the adsorption method in step S5.

[0035] Comparative Example 3 A preparation method of an anti-cancer drug adjuvant with a sustained-release function, comprising the following steps: S1. Preparation of mesoporous alumina: Add 7 g of cetyltrimethylammonium bromide to 350 g of deionized water, stir to dissolve, then add 28 g of aluminum nitrate, stir evenly, add 14 g of urea, carry out hydrothermal reaction at 130 °C for 8 h, after the reaction is completed, age at 75 °C for 13 h, then filter, wash, dry, and calcine at 550 °C for 3.5 h to obtain mesoporous alumina; S2. Preparation of pretreated mesoporous alumina: Add 50 g of mesoporous alumina to 800 mL of an ethanol aqueous solution (the mass concentration of ethanol is 75%), then add 12 g of γ-glycidoxypropyltrimethoxysilane, and stir and react at 72 °C for 5 h. After the reaction is completed, filter, wash, and dry to obtain pretreated mesoporous alumina; S3. Preparation of organic mesoporous alumina: Add 50 g of the pretreated mesoporous alumina in step S2 to 700 mL of DMF, then add 15 g of hydroxypropyl cyclodextrin and 0.8 g of triethylamine, and react at 65 °C for 4 h under nitrogen protection. After the reaction is completed, filter, wash, and dry to obtain organic mesoporous alumina; S4. Preparation of modified mesoporous alumina: Add 12 g of 3-mercaptopropionic acid and 6 g of folic acid to 800 mL of a DMF solution, then add 13 g of EDC and 16 g of NHS, and stir and activate at a rotation speed of 180 r / min and a temperature of 25 °C for 1.5 h. After the activation is completed, add 55 g of the organic mesoporous alumina in step S3, and react at 45 °C for 3.5 h under nitrogen protection. After the reaction is completed, filter, wash, and dry to obtain the anticancer drug adjuvant.

[0036] Compared with Example 1, 8-gingerol was not introduced in this comparative example.

[0037] Perform a drug loading test on the anticancer drug adjuvants prepared in Examples 1-4 and Comparative Examples 1-3 as follows: 1. Drug loading amount test Add the anticancer drug adjuvants (100 mg) prepared in Examples 1-4 and Comparative Examples 1-3 to the anticancer drug solution (20 mL, 5 mg / mL, an ethanol solution of paclitaxel) respectively, adsorb at 60 °C and a rotation speed of 160 rpm for 8 h, centrifuge to take the supernatant, and measure the concentration of the drug in the supernatant by ultraviolet spectrophotometry to indirectly determine the drug loading amount of the anticancer drug adjuvant on the drug. Drug loading rate (%) = (m 0 - m 1 ) / m 2 ×100%, where m 0 is the mass (mg) of the anticancer drug, m 1 is the mass (mg) of the anticancer drug in the supernatant, and m 2 is the mass (mg) of the anticancer drug adjuvant. The test results are shown in Table 1 below.

[0038] 2. In vitro release study of the drug By dialysis method, the drug-loaded anti-cancer drug adjuvants prepared in Example 1 and Comparative Examples 1-2 above were subjected to in vitro release experiments at physiological temperature of 37 °C. Phosphate buffer (pH = 6.8) was used to simulate the intestinal environment. 100 mg of the above drug-loaded sample was placed in a dialysis bag (1000 Da), and the dialysis bag was immersed in a beaker containing 60.0 mL of PBS buffer. A magnetic stirrer was used to stir at a constant speed under the condition of 100 rpm. At regular intervals, 3.0 mL of the release medium was taken out, and at the same time, the same volume of fresh release medium was added to the beaker. The absorbance of the drug was measured by an ultraviolet spectrophotometer, and then the cumulative release rate of the drug was calculated. The results are as Figure 1 .

[0039] 3. Antioxidant research By the method of DPPH free radical scavenging activity, the anti-cancer drug adjuvants prepared in Examples 1-4 and Comparative Examples 1-3 were respectively dispersed in ethanol into a dispersion with a concentration of 1 mg / mL. The concentration of the DPPH ethanol solution was prepared into 6×10 -5 mol / L. 2.0 mL of the sample dispersion was added to 1.0 mL of the DPPH ethanol solution, and the mixture was mixed evenly by a vortex mixer and reacted in the dark for 30 min. The absorbance in the wavelength range of 450 - 650 mm was measured by an ultraviolet spectrophotometer to determine the measurement wavelength, and the absorbance of the sample was measured at this wavelength, denoted as A 1 . An equal amount of DPPH ethanol solution was used as a blank control group, and its absorbance was denoted as A 0 . The results are shown in Table 1 below.

[0040] DPPH· scavenging rate = (1 - A 1 / A 0 ) × 100% 4. The drug-loaded anti-cancer drug adjuvants prepared in Example 1 and Comparative Examples 1-3 above were subjected to an experiment on inhibiting tumor cell growth in mice, as follows: The MTT (tetrazolium salt reduction method) was used to conduct experiments on the HELA cell line. HELA cells were cultured routinely. When the cells were amplified to a certain number and in good growth state, HELA cells in the logarithmic growth phase were digested with 0.25% trypsin for 2 min, centrifuged at 1000 rpm for 5 min, the supernatant was discarded, and the cell pellet was resuspended with fresh serum-free DMEM medium to prepare a cell suspension of 1×10 6 cells / mL. Then, a syringe was used to aspirate the cell suspension, the air bubbles were discharged, and the cell suspension was injected into the left axillary subcutaneous tissue of BALB / C female mice with a body weight of about 20 - 22 g. 100 μL was inoculated into each mouse, containing about 1×10 5 cells. A total of 50 mice were inoculated. The tumor growth of the mice was observed, and the body weight of the mice was weighed regularly and the tumor size was measured. The animals had normal diet and water during the experiment.

[0041] When the tumor volume grows to 100 - 150 mm 3 At this time, the mice were randomly divided into 5 groups, with 10 nude mice in each group, namely the negative control group (saline group), Example 1 group, Comparative Example 1 group, Comparative Example 2, and Comparative Example 3. The drugs were administered once every other day. After administration, the mice were normally raised. The survival status of the mice was observed every day, the body weight of the mice was recorded every two days, and the long and short diameters of the tumors of the mice were measured with a vernier caliper to calculate the tumor volume (V).

[0042] Tumor inhibition rate = (1 - V 1 / V 2 ) × 100%, where V 1 is the tumor volume of the drug administration group on the 12th day, and V 2 is the tumor volume of the saline group on the 12th day. The results are shown in Table 2 below.

[0043] Table 1 Drug loading capacity and antioxidant properties of anticancer drug adjuvants in different groups Table 2 Tumor inhibition rates of drug-loaded anticancer drug adjuvants in different groups As can be seen from Table 1 above, the anticancer drug adjuvant prepared by the present invention has a large drug loading capacity, and at the same time has a high DPPH· scavenging rate, which can improve the stability and biological activity of the anticancer drug; as can be seen from Table 2, the drug-loaded anticancer drug adjuvant prepared by the present invention has a high tumor inhibition rate on mouse tumors, indicating that the anticancer drug adjuvant of the present invention can assist the anticancer drug to play a role and improve the bioavailability of the anticancer drug; as can be seen from Figure 1 it, the anticancer drug prepared by the present invention has a stable drug release rate and has good application prospects.

[0044] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing an adjuvant for sustained-release anticancer drugs, characterized in that: The following steps are involved: S1. Preparation of mesoporous alumina by hydrothermal method; S2, using γ-glycidyloxypropyltrimethoxysilane to modify the surface of mesoporous alumina, introducing epoxy groups on the surface of alumina, and obtaining pretreated mesoporous alumina; S3, introducing hydroxypropyl cyclodextrin having a hydrophobic inner cavity onto alumina by covalent bonding to obtain an organic mesoporous alumina; S4, introducing 3-mercaptopropionic acid and folic acid onto an alumina carrier by esterifying the carboxyl groups in 3-mercaptopropionic acid and folic acid with the hydroxyl groups in hydroxypropyl cyclodextrin to obtain modified mesoporous alumina; S5. 8-gingerol is introduced onto an alumina carrier through a mercapto-ene reaction to obtain an adjuvant for sustained-release of anticancer drugs.

2. The preparation method according to claim 1, characterized in that: The following steps are involved: S1. Add hexadecyltrimethylammonium bromide into deionized water, stir to dissolve, then add aluminum nitrate, stir evenly and then add urea to carry out hydrothermal reaction, age after the reaction is completed, then filter, wash, dry and calcine to obtain the mesoporous alumina; S2, adding mesoporous alumina to an ethanol aqueous solution, and then adding γ-glycidyloxypropyltrimethoxysilane, stirring to react, filtering, washing, and drying after the reaction is completed to obtain pretreated mesoporous alumina; S3, adding the pretreated mesoporous alumina in step S2 into DMF, then adding hydroxypropyl cyclodextrin and triethylamine, heating and reacting under nitrogen protection, filtering, washing and drying after the reaction is completed to obtain organic mesoporous alumina; S4, adding 3-mercaptopropionic acid and folic acid to the DMF solution, and then adding EDC and NHS, stirring and activating, adding the organic mesoporous alumina in step S3 after the activation, and performing esterification reaction under nitrogen protection, filtering, washing and drying after the reaction to obtain modified mesoporous alumina; S5, adding the modified mesoporous alumina in step S4 into DMF, and then adding 8-shogaol and azobisisobutyronitrile, and reacting at a constant temperature. After the reaction is completed, filtering, washing, and drying are performed to obtain an auxiliary agent for sustained-release anticancer drugs.

3. The preparation method according to claim 1, characterized in that: The anticancer drug is paclitaxel.

4. The preparation method according to claim 2, characterized in that: In step S1, the mass ratio of hexadecyltrimethylammonium bromide, deionized water, aluminum nitrate and urea is 6-8:300-400:25-30:12-16, the temperature of the hydrothermal reaction is 120-140°C, and the time is 6-9h; the temperature of the aging is 70-80°C, and the time is 10-15h; the temperature of the calcination is 500-600°C, and the time is 3-4h.

5. The preparation method according to claim 2, characterized in that: The mass concentration of ethanol in the ethanol aqueous solution in step S2 is 70-80%, the mass ratio of the mesoporous alumina to γ-glycidyloxypropyltrimethoxysilane is 50:10-14, the temperature of the stirring reaction is 70-75°C, and the time is 4-6h.

6. The preparation method according to claim 2, characterized in that: In step S3, the mass ratio of the pretreated mesoporous alumina, hydroxypropyl cyclodextrin and triethylamine is 50:12-18:0.5-1, the temperature of the heating reaction is 60-70° C., and the time is 3-5 hours.

7. The preparation method according to claim 2, characterized in that: In step S4, the mass ratio of 3-mercaptopropionic acid, folic acid, EDC, NHS, and organic mesoporous alumina is 10-13:5-7:10-15:13-18:50-60; the stirring activation temperature is 20-30°C, the rotation speed is 150-200r / min, and the time is 1-2h; the esterification reaction temperature is 40-50°C, and the time is 3-4h.

8. The preparation method according to claim 2, characterized in that: In step S5, the mass ratio of the modified mesoporous alumina, 8-shogaol and azobisisobutyronitrile is 50-60:4-7:0.5-1; the temperature of the isothermal reaction is 60-70° C. and the time is 1-2 hours.

9. The preparation method according to claim 2, characterized in that: In step S1, the mass ratio of hexadecyltrimethylammonium bromide, deionized water, aluminum nitrate and urea is 7:350:28:14, the temperature of the hydrothermal reaction is 130°C, and the time is 8 hours; the temperature of the aging is 75°C, and the time is 13 hours; the temperature of the calcination is 550°C, and the time is 3.5 hours; In step S2, the mass concentration of ethanol in the ethanol aqueous solution is 75%, the mass ratio of the mesoporous alumina to γ-glycidyloxypropyltrimethoxysilane is 50:12, the stirring reaction temperature is 72° C., and the reaction time is 5 hours; In step S3, the mass ratio of the pretreated mesoporous alumina, hydroxypropyl cyclodextrin and triethylamine is 50:15:0.8, the temperature of the heating reaction is 65° C., and the time is 4 hours; In step S4, the mass ratio of 3-mercaptopropionic acid, folic acid, EDC, NHS and organic mesoporous alumina is 12:6:13:16:55; the stirring activation temperature is 25°C, the speed is 180r / min, and the time is 1.5h; the esterification reaction temperature is 45°C and the time is 3.5h; In step S5, the mass ratio of the modified mesoporous alumina, 8-shogaol, and azobisisobutyronitrile is 55:6:0.8; the temperature of the isothermal reaction is 65° C., and the time is 1.5 h.

10. An anticancer drug adjuvant with sustained release function prepared by the method according to any one of claims 1 to 9, characterized in that: For extended release of paclitaxel.

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