Mesoporous polymer microspheres, and preparation method and application thereof

Abstract

The present application relates to the technical field of high polymer material, and particularly relates to a kind of mesoporous polymer microspheres and its preparation method and application, the present application is prepared by method in the case where not using surfactant cetyltrimethylammonium bromide (CTAC), and the structure of the hollow mesoporous microspheres can be controlled, and the functionalized microspheres can be modified, the -OH contained on the surface of the microspheres is oxidized to-COOH under the action of concentrated sulfuric acid and ammonium persulfate, then reacts with methoxypolyethylene glycol amine to make-COOH graft PEG-NH2 functional group, effectively improve the hydrophilicity of the material, enhance the drug loading performance of sample to doxorubicin (DOX), by changing the volume ratio of water and ethanol in solvent, obtain 3 groups of polymer microspheres with different particle sizes, the results show that, solvent has significant influence on microsphere particle size in the reaction process, the volume ratio of ethanol and water is from 4:19, 8:19 to 16:19, the particle size of microsphere is continuously increased, and the drug loading is also increased.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of high polymer materials, in particular to a mesoporous polymer microsphere and a preparation method and application thereof. BACKGROUND

[0002] Developing new functional materials with specific micro-nano structures has always been an important topic of concern for researchers, and porous organic polymers are a new type of porous material formed by periodic units. They have a series of advantages such as stable physical and chemical properties, developed pore structure, modifiable surface properties, and good biocompatibility, and show promising application prospects in the field of drug loading and release.

[0003] With the development and application of different structures and properties of materials, the types of porous organic polymer materials are increasing, the performance of the materials is continuously improved, and the application range is increasingly expanding. Based on the differences in synthesis methods at different stages, the preparation of porous organic polymers mainly includes the following three methods: (1) post-crosslinking of polymer precursors containing functional groups; (2) one-step self-condensation of functionalized small molecule monomers; (3) "weaving" of rigid aromatic monomers through external crosslinking agents. At present, the synthesis of porous organic polymers still faces many challenges, such as complex preparation process and unsatisfactory drug loading performance, so the low-cost and high-performance preparation of porous organic polymers is still a difficult problem to solve. SUMMARY

[0004] In view of the deficiencies of the prior art, the purpose of the present application is to provide a mesoporous polymer microsphere and a preparation method and application thereof. The present application prepares structure-controllable and function-modifiable hollow mesoporous microspheres without using the surfactant cetyltrimethylammonium bromide (CTAC) by The -OH contained on the surface of the microspheres is oxidized to -COOH under the action of concentrated sulfuric acid and ammonium persulfate, and then reacts with methoxypolyethylene glycol amine to graft PEG-NH2 functional groups on the -COOH, effectively improving the hydrophilicity of the material and enhancing the drug loading performance of the sample on doxorubicin.

[0005] To solve the above technical problems, the technical scheme adopted by the present application is as follows:

[0006] A preparation method of a mesoporous polymer microsphere, comprising the following steps:

[0007] Ammonia and m-diphenol are added to a mixture of ethanol and water and stirred to obtain a mixed solution. Tetraethyl silicate and formaldehyde are added dropwise to the mixed solution to obtain a turbid solution, which is then subjected to a heating reaction. The product after the heating reaction is subjected to post-treatment to obtain a first product;

[0008] The first product is added to a mixture containing ammonium persulfate, concentrated sulfuric acid and water, and after reaction, the second product is obtained by post-treatment.

[0009] The second product is added into a phosphate buffer containing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, and then reacted with methoxypolyethylene glycol amine to obtain the mesoporous polymer microspheres.

[0010] In the preferred embodiment of the present application, the volume ratio of ethanol to deionized water in the mixture of ethanol and deionized water is 4-16:19.

[0011] In the preferred embodiment of the present application, the volume ratio of the ammonia water to ethanol is 1:40-160, the mass-volume ratio of the resorcinol to ethanol is 2g:40-160mL, and the volume ratio of the silicon acid polyvinyl ester, formaldehyde and ammonia water is 7.2:2.8:1.

[0012] In the preferred embodiment of the present application, the mass-volume ratio of ammonium persulfate, concentrated sulfuric acid and water in the mixed solution of ammonium persulfate, concentrated sulfuric acid and water is 1-1.5g:0.5-0.8mL:10-15mL.

[0013] In the preferred embodiment of the present application, the mass ratio of the product one to ammonium persulfate is 0.1-0.3:1-1.5.

[0014] In the preferred embodiment of the present application, the mass ratio of the product two to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide is 4-6:6-8:2-5.

[0015] In the preferred embodiment of the present application, the mass ratio of the methoxypolyethylene glycol amine to the product two is 1-3:2-5.

[0016] In the preferred embodiment of the present application, the post-treatment operation for obtaining the first product is cooling the product after the heating reaction to room temperature, centrifugal separation to obtain a solid, washing and drying, and then adding HF solution and stirring; the post-treatment operation for obtaining the second product is heating refluxing the product after the reaction, filtering, washing, and drying, wherein the heating refluxing temperature is 50-80℃, the heating refluxing time is 1-3h, the drying temperature is 60-90℃, and the drying time is 6-12h.

[0017] The second object of the present application is to provide the mesoporous polymer microspheres prepared by the preparation method as described in any one of the above.

[0018] The third object of the present application is to provide the application of the mesoporous polymer microspheres as described above in loading hydrophilic drugs.

[0019] In the preferred embodiment of the present application, the hydrophilic drug is doxorubicin.

[0020] Compared with the prior art, the present application has the beneficial effects that:

[0021] 1、The present application prepares a hydrophilic material without using the surfactant cetyltrimethylammonium bromide (CTAC) by selecting appropriate reaction monomers, optimizes the preparation conditions, synthesizes a precursor, and then introduces polyethylene glycol to improve the surface activity and biocompatibility thereof; the present application prepares a hollow mesoporous microsphere with controllable structure and modified function by The -OH contained on the surface of the hollow mesoporous microsphere is oxidized into -COOH under the action of concentrated sulfuric acid and ammonium persulfate, and then reacts with methoxypolyethylene glycol amine to graft the PEG-NH2 functional group on the -COOH, so that the hydrophilicity of the material is effectively improved, and the drug loading performance of the sample on doxorubicin (DOX) is enhanced.

[0022] 2、The present application obtains three groups of polymer microspheres with different particle sizes by changing the volume ratio of water and ethanol in the solvent; with the increase of the ethanol concentration, the particle size of the microspheres continuously increases, and the drug loading capacity also increases; this is because before the introduction of polyethylene glycol, the surface of the microspheres is hydrophobic; with the increase of the ethanol concentration, the hydrophilicity of the sample is enhanced; in a certain region, the number of assembled samples is reduced, the size of the microspheres is also increased, and the drug loading capacity is also increased; in the in-vitro dissolution experiment, compared with the neutral environment, the cumulative release rate of the doxorubicin attached to the sample in the acidic environment reaches 87.89%; and the raw materials of the preparation method of the present application are easy to obtain, the cost is low, and the reaction can be carried out under relatively mild conditions.

[0023] 3、The preparation method of the present application is simple, does not need to use complex precursor building units and expensive transition metal catalysts, and can be carried out under mild conditions, and has good drug loading performance. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 The present application is a synthesis route map;

[0025] Figure 2 The present application is a sample prepared by Example 1 of the present application. 13 The present application is a sample prepared by Example 1 of the present application.

[0026] Figure 3 The present application is a sample prepared by Example 1 of the present application.

[0027] Figure 4 The present application is a sample prepared by Example 1 of the present application. (a) Nitrogen adsorption-desorption isotherm; (b) DFT pore size distribution of the sample prepared by Example 1 of the present application.

[0028] Figure 5 The present application is a sample prepared by Example 3 of the present application.

[0029] Figure 6Adsorption kinetics curve of the sample prepared for the present embodiment 3;

[0030] Figure 7 Release kinetics curve of the sample prepared for the present embodiment 3. DETAILED DESCRIPTION

[0031] The technical solutions in the embodiments of the present application will be described clearly and completely in the following with reference to the embodiments of the present application, preferred embodiments and the accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments of the present application, all other embodiments obtained by those skilled in the art without creative work fall within the scope of protection of the present application.

[0032] It should be noted that all the professional terms used in the present application are only for the purpose of describing the specific embodiments, and are not intended to limit the protection scope of the present application. Unless otherwise specified, the various raw materials, reagents, instruments and equipment used in the following embodiments of the present application can be purchased from the market or prepared by the existing method.

[0033] The synthetic route of DLU-31-PEG prepared by the present application is shown in the following formula (I). Figure 1 The present application aims at the defects in the prior art that the synthesis reaction of the porous organic polymer often needs to use complex precursor building units, expensive transition metal catalysts, and needs to be carried out under relatively harsh conditions, and the drug loading capacity is unsatisfactory. Therefore, a low-cost and high-performance hollow polymer microsphere and a preparation method and application thereof are proposed. The present application researches from the aspects of design, synthesis, characterization and performance determination of drug carriers, develops a new functional porous organic polymer and investigates its application performance in drug loading and controlled release. By selecting appropriate reaction monomers, without using cetyltrimethylammonium bromide (CTAC) as a surfactant, optimizing the preparation conditions, synthesizing the precursor, then introducing polyethylene glycol to improve the surface activity and biocompatibility, and by the method, the hollow mesoporous microspheres with controllable structure and modified function are prepared. The -OH on the surface of the microspheres is oxidized to -COOH under the action of concentrated sulfuric acid and ammonium persulfate, and then reacts with methoxypolyethylene glycol amine to graft PEG-NH2 functional groups on the -COOH, which effectively improves the hydrophilicity of the material and enhances the drug loading performance of the sample to doxorubicin (DOX).

[0034] Embodiment 1

[0035] A preparation method of a mesoporous polymer microsphere DLU-31-PEG, comprising the following steps:

[0036] (1) Preparation of DLU-31: Take ethanol 40 mL, deionized water 190 mL, and place them in a 500 mL round-bottom flask. After mixing and stirring, add 1 mL of ammonia water, and stir at 25°C for 30 min. Then add 2 g of m-diphenol, and after complete dissolution, the solution is light yellow. Continue stirring for 30 min to obtain a mixed solution. Slowly add 7.2 mL of template agent tetraethyl orthosilicate (TEOS) and 2.8 mL of formaldehyde to the mixed solution, and the solution gradually turns into a milky white turbidity. Increase the temperature to 55°C, and adjust the rotation speed to 240 r / min. React for 24 h, and the solution gradually turns pink with precipitate generated. After the reaction is completed, cool to room temperature, centrifuge, and obtain a light yellow solid. Wash with a large amount of deionized water and ethanol to remove unreacted monomers, dry in a drying box at 60°C, then add 50 mL of a 10% HF solution dropwise, and stir for 24 h to remove the SiO2core. The prepared product is named as DLU-31;

[0037] (2) Carboxylation of DLU-31: Take 0.2 g of DLU-31 and add it to a mixed solution containing 1.36 g of ammonium persulfate, 0.64 mL of concentrated sulfuric acid, and 12 mL of H2O. Heat to reflux at 60°C for 3 h. After the reaction is completed, cool, filter, and wash with a large amount of ethanol and deionized water until the filtrate is neutral. Dry at 60°C under vacuum for 12 h. The product is named as DLU-31-COOH;

[0038] (3) Preparation of DLU-31-PEG: Take 50 mg of DLU-31-COOH and add it to a PBS buffer (pH = 7.4, 20 mL) containing 70 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 40 mg of N-hydroxysuccinimide (NHS). Stir for 1 h to activate the carboxyl group, then add 25 mg of methoxypolyethylene glycol amine, and stir at room temperature for 12 h. Filter, wash with ethanol and water, and dry in a vacuum drying oven at 60°C to obtain mesoporous polymer microspheres, which are recorded as DLU-31-PEG.

[0039] Example 2

[0040] A method for preparing mesoporous polymer microspheres DLU-32-PEG, comprising the following steps:

[0041] (1) Preparation of DLU-32: Take 80 mL of ethanol and 190 mL of deionized water, and place them in a 500 mL round-bottom flask. After mixing and stirring, add 1 mL of ammonia water, and stir at 25°C for 30 min. Then add 2 g of m-diphenol, and after complete dissolution, the solution is light yellow. Continue stirring for 30 min to obtain a mixed solution. Slowly add 7.2 mL of template agent tetraethyl orthosilicate (TEOS) and 2.8 mL of formaldehyde to the mixed solution, and the solution gradually turns into a milky white turbidity. Increase the temperature to 55°C, and adjust the rotation speed to 240 r / min. React for 24 h, and the solution gradually turns pink and has a precipitate generated. After the reaction is completed, cool to room temperature, and centrifugally separate to obtain a light yellow solid. Wash with a large amount of deionized water and ethanol to remove unreacted monomers, dry in a drying box at 60°C, and then add a 10% HF solution dropwise. Stir for 24 h to remove the SiO2 core, and prepare DLU-32.

[0042] (2) Carboxylation of DLU-32: Take 0.2 g of DLU-32 and add it to a mixed solution containing 1.36 g of ammonium persulfate, 0.64 mL of concentrated sulfuric acid, and 12 mL of H2O. Heat to reflux at 60°C for 3 h. After the reaction is completed, cool, filter, and wash with a large amount of ethanol / deionized water until the filtrate is neutral. Dry at 60°C under vacuum for 12 h to prepare DLU-32-COOH.

[0043] (3) Preparation of DLU-31-PEG: Take 50 mg of DLU-32-COOH and add it to a PBS buffer (pH = 7.4, 20 mL) containing 70 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 40 mg of N-hydroxysuccinimide (NHS). Stir for 1 h to activate the carboxyl group, and then add 25 mg of methoxypolyethylene glycol amine. Stir at room temperature for 12 h, filter, and sufficiently wash with ethanol / water. Dry in a vacuum drying oven at 60°C to obtain mesoporous polymer microspheres, which are recorded as DLU-32-PEG.

[0044] Example 3

[0045] A method for preparing mesoporous polymer microspheres DLU-33-PEG, comprising the following steps:

[0046] (1) Preparation of DLU-33: Take ethanol 160 mL, deionized water 190 mL, put into a 500 mL round-bottom flask, after mixing and stirring, add ammonia water 1 mL, stir at 25°C for 30 min, then add m-diphenol 2 g, completely dissolved, the solution is light yellow, continue to stir for 30 min, get the mixed solution, slowly drop the template agent tetraethyl orthosilicate (TEOS) 7.2 mL, formaldehyde 2.8 mL into the mixed solution, the solution gradually turns into milky white turbidity, increase the temperature to 55°C, adjust the rotation speed to 240 r / min, react for 24 h, the solution gradually turns into pink and precipitate is generated, after the reaction is completed, cool to room temperature, centrifugal separation, get light yellow solid, wash with a large amount of deionized water, ethanol to remove unreacted monomers, dry in a drying oven at 60°C, then drop the HF solution with a concentration of 10%, stir for 24 h, remove the SiO2core, prepare DLU-33;

[0047] (2) Carboxylation of DLU-33: Take 0.2 g of DLU-31 and add it into a mixed solution containing 1.36 g of ammonium persulfate, 0.64 mL of concentrated sulfuric acid and 12 mL of H2O, heat under reflux at 60°C for 3 h, after the reaction is completed, cool, filter, wash with a large amount of ethanol / deionized water until the filtrate is neutral, dry at 60°C under vacuum for 12 h, prepare DLU-33-COOH;

[0048] (3) Preparation of DLU-33-PEG: Take 50 mg of DLU-31-COOH and add it into PBS buffer (pH = 7.4, 20 mL) containing 70 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 40 mg of N-hydroxysuccinimide (NHS), stir for 1 h to activate the carboxyl group, then add 25 mg of methoxypolyethylene glycol amine, stir at room temperature for 12 h, filter, wash with ethanol / water, dry in a vacuum drying oven at 60°C to prepare mesoporous polymer microspheres, marked as DLU-33-PEG.

[0049] Example 4

[0050] A method for preparing mesoporous polymer microspheres DLU-31-PEG, comprising the following steps:

[0051] (1) Preparation of DLU-31: Take 40 mL of ethanol and 190 mL of deionized water, and place them in a 500 mL round-bottom flask. After mixing and stirring, add 1 mL of ammonia water, and stir at 25°C for 30 min. Then add 2 g of m-diphenol, and after complete dissolution, the solution is light yellow. Continue stirring for 30 min to obtain a mixed solution. Slowly add 7.2 mL of template agent tetraethyl orthosilicate (TEOS) and 2.8 mL of formaldehyde to the mixed solution, and the solution gradually turns into a milky white turbidity. Increase the temperature to 55°C, and adjust the rotation speed to 240 r / min. React for 24 h, and the solution gradually turns pink and has a precipitate generated. After the reaction is completed, cool to room temperature, and centrifugally separate to obtain a light yellow solid. Wash with a large amount of deionized water and ethanol to remove unreacted monomers, dry in a drying box at 60°C, then add a 10% HF solution dropwise, and stir for 24 h to remove the SiO2 core, thereby preparing DLU-31.

[0052] (2) Carboxylation of DLU-31: Take 0.1 g of DLU-31 and add it to a mixed solution containing 1.0 g of ammonium persulfate, 0.5 mL of concentrated sulfuric acid, and 10 mL of H2O. Heat to reflux at 50°C for 2 h. After the reaction is completed, cool, filter, and wash with a large amount of ethanol / deionized water until the filtrate is neutral. Dry at 75°C under vacuum for 10 h to prepare DLU-31-COOH.

[0053] (3) Preparation of DLU-31-PEG: Take 40 mg of DLU-31-COOH and add it to a PBS buffer (pH = 7.4, 20 mL) containing 60 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 20 mg of N-hydroxysuccinimide (NHS). Stir for 1 h to activate the carboxyl group, then add 20 mg of methoxypolyethylene glycol amine, and stir at room temperature for 12 h. Filter, wash with ethanol / water, and dry in a vacuum drying oven at 60°C to obtain mesoporous polymer microspheres.

[0054] Example 5

[0055] A method for preparing mesoporous polymer microspheres DLU-31-PEG, comprising the following steps:

[0056] (1) Preparation of DLU-31: Take ethanol 40 mL, deionized water 190 mL, put into a 500 mL round bottom flask, after mixing and stirring, add ammonia water 1 mL, stir at 25°C for 30 min, then add m-diphenol 2 g, completely dissolved, the solution is light yellow, continue to stir for 30 min, get the mixed solution, slowly drop the template agent tetraethyl orthosilicate (TEOS) 7.2 mL, formaldehyde 2.8 mL into the mixed solution, the solution gradually turns into milky white turbidity, increase the temperature to 55°C, adjust the rotation speed to 240 r / min, react for 24 h, the solution gradually turns into pink and precipitate is generated, after the reaction is completed, cool to room temperature, centrifugal separation, get light yellow solid, wash with a large amount of deionized water, ethanol to remove unreacted monomer, dry in a drying box at 60°C, then drop the HF solution with a concentration of 10%, stir for 24 h, remove the SiO2 core, prepare DLU-31;

[0057] (2) Carboxylation of DLU-31: Take 0.3 g of DLU-31 and add it into a mixed solution containing 1.5 g of ammonium persulfate, 0.8 mL of concentrated sulfuric acid and 15 mL of H2O, heat and reflux at 75°C for 1 h, after the reaction is completed, cool, filter, wash with a large amount of ethanol / deionized water until the filtrate is neutral, vacuum dry at 90°C for 6 h, prepare DLU-31-COOH;

[0058] (3) Preparation of DLU-31-PEG: Take 60 mg of DLU-31-COOH and add it into PBS buffer (pH = 7.4, 20 mL) containing 80 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 50 mg of N-hydroxysuccinimide (NHS), stir for 1 h to activate the carboxyl group, then add 36 mg of methoxy polyethylene glycol amine, stir at room temperature for 12 h, filter, wash with ethanol / water, dry in a vacuum drying oven at 60°C to prepare mesoporous polymer microspheres.

[0059] Result analysis

[0060] Figure 2 (a) The infrared spectrum of the sample prepared in Example 1 of the present application is shown in the figure, a new characteristic peak appears at 1500 cm -1 in the infrared spectrum of DLU-31-PEG, which is the stretching vibration of amide, indicating the successful introduction of PEG-NH2 in DLU-31, the peak at 3451 cm -1 is the stretching vibration of -OH, the peak at 1601 cm -1 is the stretching vibration of C=C on the benzene ring, the peaks at 1359 cm -1 and 1062 cm -1 are respectively attributed to the bending vibration of -CH2 and the bending vibration of -OH; Figure 2(b) the sample prepared in Example 1 of the present application 13 The C NMR spectrum of DLU-31-PEG is shown in the figure. The peaks at 14 ppm and 27 ppm in the C NMR spectrum are methyl carbon and methylene carbon, the peak at 114.7 ppm is the ortho carbon of the hydroxyl group on the benzene ring, and the peak at 133 ppm is the carbon on the benzene ring connected to the carbonyl group. The peak at 181 ppm in DLU-31-COOH is attributed to the carboxyl carbon (COOH), and the characteristic peak at 172 ppm in DLU-31-PEG is the amide carbon (CONH), indicating that PEG-NH2 is grafted in the precursor. 13 The C NMR spectrum of DLU-31-PEG is shown in the figure. The peaks at 14 ppm and 27 ppm in the C NMR spectrum are methyl carbon and methylene carbon, the peak at 114.7 ppm is the ortho carbon of the hydroxyl group on the benzene ring, and the peak at 133 ppm is the carbon on the benzene ring connected to the carbonyl group. The peak at 181 ppm in DLU-31-COOH is attributed to the carboxyl carbon (COOH), and the characteristic peak at 172 ppm in DLU-31-PEG is the amide carbon (CONH), indicating that PEG-NH2 is grafted in the precursor.

[0061] Figure 3 The SEM images of the samples prepared in Examples 1-3 of the present application are shown in the figure. It can be seen from the figure that the samples are uniform spherical structures. The average particle size of the DLU-31-PEG sample prepared in Example 1 is about 0.8 um, the average particle size of the DLU-32-PEG sample prepared in Example 2 is about 1.2 um, and the average particle size of the DLU-33-PEG sample prepared in Example 3 is 2.4 um. The color of the outer edge of the material is darker, and the color of the inside is lighter, indicating that the sample is a hollow sphere, and the spherical structure of the sample is maintained after the etching of the HF solution.

[0062] Figure 4 The (a) nitrogen adsorption-desorption isotherm and (b) DET pore size distribution of the sample prepared in the present application at 77k are shown in the figure. It can be seen that the nitrogen adsorption-desorption curve of DLU-31-PEG is a typical type IV adsorption isotherm. In the relative pressure range of 0.5-0.9, capillary condensation phenomenon occurs, and there is a clear hysteresis loop, indicating the presence of mesoporous structure. In the low pressure region, the isotherm rises gently with increasing pressure, indicating that there are fewer microporous structures. In the high pressure region, the isotherm rises rapidly with increasing pressure, indicating that there are some macroporous structures in the sample. The sample is mainly mesoporous structure, and there are a small part of macroporous size. Macroporous is beneficial to the diffusion of DOX in the sample. The BET specific surface area of the sample DLU-31-PEG is 131 m 2 / g, and the total pore volume is 0.24 cm 3 / g.

[0063] DOX loading performance research

[0064] (1) Adsorption isotherm

[0065] The adsorption equilibrium data of DOX in DLU-33-PEG was analyzed by Langmuir, Freundlich and Temkin models, Figure 5 The adsorption isotherm of DLU-33-PEG. From Figure 5From Table 1, the experimental data fitted Langmuir model well, which indicated that Langmuir model was suitable to describe the adsorption process of DOX onto DLU-33-PEG. It could be inferred that the adsorption process was monolayer adsorption and occurred on a uniform surface. The maximum adsorption capacity of DLU-33-PEG for DOX was 117.31 mg / g, while the adsorption capacity of the existing cuprous oxide / phenylacetylene copper composite catalyst for tetracycline was only 99 mg / g. The nF value was 4.55, which was greater than 1, when the experimental data was fitted Freundlich model. It indicated that the adsorption process was mainly physical adsorption. In Temkin model, the bT value was 123.76, which was greater than 1. It indicated that the adsorption was an exothermic process.

[0066] Table 1 Langmuir, Freundlich and Temkin isotherm model related parameters

[0067]

[0068]

[0069] (2) Adsorption kinetics

[0070] The adsorption data was analyzed by three different kinetic models, namely pseudo-first order, pseudo-second order and Elovich equation, Figure 6 The kinetic curves of DOX adsorption onto DLU-33-PEG were shown in Table 2. The results of Pseudo-first order model were not ideal, which indicated that the model was not suitable to describe the adsorption process of DOX onto DLU-33-PEG. The R 2 of Pseudo-second order was 0.9, which was better. The experimental results showed that the initial adsorption rate increased with the increase of the initial concentration of DOX. In addition, the results of Elovich model were better, and the R 2 was 0.96, which indicated that the surface of the adsorbent was energy inhomogeneous.

[0071] Table 2 The kinetic curves of DOX adsorption onto DLU-33-PEG

[0072]

[0073] (3) Release kinetics

[0074] Figure 7The release kinetics curve of DLU-33-PEG is shown in the figure, and it can be seen that when the pH of the system is 5.5 and the time T is 36h, the cumulative release rate of the sample DLU-33-PEG is 87.89%. When the pH of the system is 7.4 and T is 36h, the cumulative release rate is 48.95%. It can be seen that after the introduction of PEG, the sample can be quickly released in the acidic pseudo-tumor microenvironment, and slowly released in the normal cells (pH is 7.4). The experimental data is substituted into the first-order model for fitting, and the R 2 of pH=5.5 and pH=7.4 is 0.87 and 0.98, respectively, which has good correlation, indicating that the sample mainly coexists with mesoporous and microporous structures. In summary, the prepared DLU-33-PEG can realize the effective loading and release of DOX, and is expected to be used in cancer treatment system in the future.

[0075] The preparation method of Example 4-5 is the same as that of Example 1, except that the amount of raw materials and reaction conditions are changed under the condition that the experimental reaction conditions allow, but it does not affect the adsorption performance of the prepared mesoporous organic polymer microspheres, therefore, the performance of the mesoporous organic polymer microspheres prepared in Example 4-5 and Example 1 is similar, and has good drug loading performance for doxorubicin.

[0076] In summary, the hollow mesoporous polymer microspheres have hollow capsule and porous structure, and can be used for controlled adsorption and release system, and have attractive application potential in the field of drug loading. The hollow mesoporous microspheres with controllable structure and modified function are prepared by the method without using surfactant cetyltrimethylammonium bromide (CTAC), Under the action of concentrated sulfuric acid and ammonium persulfate, the -OH on the surface is oxidized to -COOH, and then reacted with methoxypolyethylene glycol amine to graft PEG-NH2 functional groups on the -COOH, which effectively improves the hydrophilicity of the material and enhances the drug loading performance of the sample to DOX. By changing the volume ratio of water and ethanol in the solvent, three groups of polymer microspheres with different particle sizes are obtained. The experimental results show that the solvent composition has a significant effect on the particle size of the microspheres during the reaction. The volume ratio of ethanol and water is from 4:19, 8:19 to 16:19, and the particle size of the microspheres is continuously increased, which is 0.8um, 1.2um and 2.4um respectively. This is because before the introduction of polyethylene glycol (PEG), the surface of the microspheres is hydrophobic, and with the increase of ethanol concentration, the hydrophilicity of the sample is enhanced, the number of assembled samples in a certain region is reduced, and the size of the microspheres is also increased, and the drug loading capacity is also increased (37.54mg / g, 40.94mg / g and 42.57mg / g); the drug loading capacity is determined by UV-vis method, and the calculation formula is q e = (C0-C e )*V / M, q e(mg / g) represents the loading at equilibrium; Co (mg / L) is the initial concentration of doxorubicin; C e (mg / L) is the equilibrium concentration of doxorubicin; V (mL) is the volume of the solution; M (mg) is the mass of the adsorbate, in the in vitro dissolution experiment, the cumulative release rate of doxorubicin loaded by the sample in the acidic environment reached 87.89% compared with the neutral environment.

[0077] Obviously, those skilled in the art can make various modifications and variations to the present application without departing from the spirit and scope of the present application. Thus, if these modifications and variations of the present application fall within the scope of the claims of the present application and their equivalent technologies, the present application also intends to include these modifications and variations.

Claims

1. A method for preparing mesoporous polymer microspheres, characterized in that, Includes the following steps: Using resorcinol and formaldehyde as raw materials and tetraethyl silicate as a template agent, the mixture was added to a mixed solvent containing ethanol and water. After the reaction was completed, SiO2 was removed with HF solution to obtain hollow mesoporous microspheres with -OH on the surface. Under the action of concentrated sulfuric acid and ammonium persulfate, hollow mesoporous microspheres containing -OH are oxidized into mesoporous microspheres containing -COOH. Then, methoxy polyethylene glycolamine is added to the mesoporous microspheres containing -COOH to graft PEG-NH2 functional groups onto the -COOH, thus obtaining mesoporous polymer microspheres.

2. The method for preparing mesoporous polymer microspheres according to claim 1, characterized in that, In a mixed solvent of ethanol and water, the volume ratio of ethanol to water is 4~16:

19.

3. The method for preparing mesoporous polymer microspheres according to claim 1, characterized in that, The ratio of the amount of m-diphenol, formaldehyde and tetraethyl silicate is 2 g: 2.8 mL: 7.2 mL.

4. The method for preparing mesoporous polymer microspheres according to claim 1, characterized in that, The mass ratio of the meta-diphenol to the volume of ethanol is 2 g: 40~160 mL.

5. The method for preparing mesoporous polymer microspheres according to claim 1, characterized in that, The mass ratio of ammonium persulfate to concentrated sulfuric acid is 1~1.5 g : 0.5~0.8 mL.

6. The method for preparing mesoporous polymer microspheres according to claim 1, characterized in that, The mass ratio of the methoxy polyethylene glycolamine to the volume ratio of the mixed solvent of ethanol and water is 25 mg: 40~160 mL.

7. A mesoporous polymer microsphere prepared by the preparation method according to any one of claims 1-6.

8. The mesoporous polymer microspheres according to claim 7, characterized in that, The mesoporous polymer microspheres have an average particle size of 0.8–2.4 μm and a specific surface area of ​​131 m². 2 / g, total pore volume is 0.24 cm³ 3 / g.

9. The use of the mesoporous polymer microspheres according to claim 7 or 8 in the preparation of a hydrophilic drug.

10. The application according to claim 9, characterized in that, The hydrophilic drug is doxorubicin.

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