CN112694577A - Imprinted mesoporous material and preparation method and application thereof - Google Patents
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Abstract
The invention discloses a printThe mesoporous material is mesoporous SiO with the outer diameter of 100-200 nm and subjected to C ═ C surface modification and sialic acid surface imprinting treatment2And (3) granules. The preparation method comprises the following steps: firstly preparing mesoporous SiO2Then using mesoporous SiO modified by surface double bond2The nanospheres are used as carriers, sialic acid to be detected is used as template molecules to prepare mesoporous silicon-based molecularly imprinted microspheres, and then the template molecules are removed through dialysis under acidic conditions to prepare the molecularly imprinted microspheres. Then embedding the tumor therapeutic drug adriamycin into the pore canal of the microsphere by a solvent infiltration method for tumor targeted therapy. The imprinted mesoporous material can directly reach the focus of infection by loading a medicament, has the effect of killing cancer cells and the effect of causing cancer cell apoptosis, and achieves the aim of targeted treatment of tumors.
Description
Technical Field
The invention relates to a imprinted mesoporous material, a preparation method and application thereof, and belongs to the technical field of research and development and preparation of tumor cell targeted drugs.
Background
The liver is one of the good parts of the tumor, benign tumors are less common, and metastatic tumors are more in malignant tumors. Primary tumors can occur in the hepatocyte cell lines, bile duct epithelium, blood vessels or other mesoderm tissues, with metastatic tumors being mostly metastatic cancers and rarely metastatic sarcomas. Since the liver is the largest parenchymal organ of the human body and plays a role in various important metabolic functions of the human body, once malignant tumors occur in the liver, serious life-threatening consequences can be caused. The liver has abundant blood supply, is closely related to important blood vessels of a human body, and has hidden and rapid growth of malignant liver tumor, so that the treatment is very difficult, and the overall curative effect and prognosis are not very ideal.
Doxorubicin (DOX) is one of the most commonly used anticancer drugs, especially metastatic cancer cells. However, gastrointestinal reactions, cardiac toxicity and other drug side effects caused by non-specificity due to cytotoxicity limit the effectiveness of clinical treatments. The chemotherapeutic drug combined with the nano-carrier can control the release of the therapeutic agent in the blood transportation process, so that the therapeutic agent is released after reaching cancer tissues. Therefore, adverse reactions can be reduced while enhancing anticancer effects. Due to mesoporous SiO2The particles have a high specific surface area and an ordered mesoporous structure, which makes it possible to perform effective drug delivery.
The molecular imprinting technology is a technology for preparing a high molecular polymer material with specific affinity and recognition capability for target molecules. The molecularly imprinted polymer prepared by the traditional method has the defects of high extraction difficulty of target molecules, low adsorption capacity, poor dynamic performance and the like due to a highly crosslinked structure. Target molecules are imprinted on the surface of a carrier material, so that the adsorption capacity and the kinetic performance of the molecularly imprinted polymer can be greatly improved, and the molecularly imprinted polymer can be used for controlled release of targeted anticancer drugs, ocular peptide drugs, oral insulin and enantioselective racemate drugs. The mesoporous silica has the advantages of large specific surface area, simple and convenient modification, good stability, high mechanical strength and the like, and is very suitable for being used as a carrier material of a surface molecularly imprinted polymer. However, in the prior art, no imprinted mesoporous material which is mild, good in biocompatibility and widely applicable exists.
Disclosure of Invention
One of the purposes of the present invention is to provide a trace mesoporous material. The specific technical scheme is as follows:
the imprinted mesoporous material is mesoporous SiO subjected to C ═ C surface modification and sialic acid surface imprinting treatment2Particles, the outer diameter of the particles is 100-200 nm.
The second purpose of the invention is to provide a preparation method of the imprinted mesoporous material. The specific technical scheme is as follows:
the preparation method of the imprinted mesoporous material comprises the following steps:
(1) mesoporous SiO2Preparation of
The pore-foaming agents of Cetyl Trimethyl Ammonium Bromide (CTAB) and ammonium fluoride (NHF)4) Dispersing in deionized water, slowly adding Tetraethoxysilane (TEOS), reacting for 1-3 h at 70-100 ℃, repeatedly washing with deionized water and ethanol, centrifuging, and drying to obtain complete SiO2Particles of said SiO2Dispersing the particles in ethanol, adding hydrochloric acid, refluxing for 18-36 h at 70-100 ℃, repeatedly washing and centrifuging by using deionized water and ethanol, and removing the pore-forming agent eluted to prepare the mesoporous SiO2Particles;
(2) mesoporous SiO2Modified by silanization (MSNs)
Making mesoporous SiO2The particles are uniformly dispersed in ethanol to form mesoporous SiO2Reacting the ethanol solution of the particles with 3- (methacryloyloxy) propyltrimethoxysilane (MPTS) and ethanol at 40-60 ℃ for 8-18 h, then repeatedly centrifuging and washing the mixture by deionized water and ethanol to remove unreacted components, and drying the product to obtain the C ═ C surface modified mesoporous SiO2Particles;
(3) preparation of sialic acid surface imprinted mesoporous SiO2Particle (MIP-MSNs)
Adding the C ═ C surface modified mesoporous SiO obtained in the previous step into a reaction vessel2The preparation method comprises the steps of carrying out ultrasonic dispersion on particles, Phosphate Buffer Solution (PBS), Sialic Acid (SA), 3-methylacrylamidophenylboronic acid (MAPBA), N-isopropylacrylamide (NIPAM), acrylamide (AAM), N- (3-aminopropyl) methacrylamide hydrochloride and N, N ' -methylene Bisacrylamide (BIS) uniformly, then carrying out magnetic stirring at room temperature, introducing argon gas into a reaction system while adding Ammonium Persulfate Solution (APS) and N, N, N ', N ' -tetramethylethylenediamine solution (TMEDA), placing the reaction vessel in a water bath at 35-40 ℃ for reaction for 12-36 h, carrying out centrifugal collection and dialysis, and carrying out centrifugal collection on particles again to obtain mesoporous SiO (silicon dioxide) with sialic acid surface imprinted2Particles (MIP-MSNs);
in the step (1), the proportions of hexadecyl trimethyl ammonium bromide, ammonium fluoride, ethyl orthosilicate, ethanol and hydrochloric acid are (400-) - (500 mg): (700-) - (800 mg): (2-3mL): (90-110mL): (1.5-3 mL);
mesoporous SiO in step (2)2The proportion of the particles, the total amount of ethanol and the 3- (methacryloyloxy) propyltrimethoxysilane is (450-500mg): (50-70mL): 1-3 mL);
in the step (3), C ═ C surface modified mesoporous SiO2The ratio of particles, phosphate buffer, sialic acid, 3-methacrylamidophenylboronic acid, N-isopropylacrylamide, acrylamide, N- (3-aminopropyl) methacrylamide hydrochloride, N, N ' -methylenebisacrylamide, ammonium persulfate, N, N, N ', N ' -tetramethylethylenediamine was (450-500mg), (25-35mL), (15-20mg), (10-13mg), (80-85mg), (23-27mg), (10-12mg), (6-10mg), (45-55 μ L) and (95-105 μ L).
Preferably, the magnetic stirring time in the step (3) is 2-6 h.
Preferably, the argon is introduced in the step (3) for 20-60 min.
The invention also aims to provide application of the imprinted mesoporous material. The specific technical scheme is as follows:
the imprinted mesoporous material is applied to tumor cell targeted drug delivery.
Preferably, the tumor cell targeting drug is doxorubicin.
More preferably, the method of application comprises the steps of: mesoporous SiO imprinted on sialic acid surface by solvent permeation method2Dissolving the particles and adriamycin in phosphate buffer solution, magnetically stirring at room temperature to completely mix, centrifuging to remove supernatant, collecting particles, and making into adriamycin-loaded nanoparticles for targeted therapy of tumor cells; the sialic acid surface imprinted mesoporous SiO2The proportion of the particles, the adriamycin and the phosphate buffer solution is (15-25mg): (3-7mg): 8-12 mL.
More preferably, the magnetic stirring time is 5-20 h.
The invention has the advantages of
The invention provides a molecular imprinting material-sialic acid surface imprinted mesoporous SiO2Particles (MIP-MSNs) in C ═ C modified mesoporous SiO2The surface of the particle is grafted with a molecular imprinting polymer layer, and an imprinting process is carried out on the surface of the mesoporous silicon dioxide, so that the synthesized imprinting material has a larger specific surface area, a higher mass transfer rate, more surface imprinting active sites are exposed, and the selectivity is improved. The surface imprinting layer plugs the adriamycin in the mesopores, and releases the adriamycin when being combined with tumor cells, so that the imprinted mesoporous material loaded with the drug (such as the adriamycin) can directly reach focuses, has the effect of killing cancer cells and the effect of causing cancer cell apoptosis, and achieves the aim of targeted treatment of tumors.
Drawings
FIG. 1 is a scanning electron micrograph of mesoporous silica according to example 1 of the present invention;
FIG. 2 is a SEM of mesoporous silica in example 1 of the present invention;
FIG. 3 is an infrared spectrum of a mesoporous silica of example 1 of the present invention;
FIG. 4 is a graph of maximum drug loading for different doxorubicin concentrations in example 2 of the present invention.
Detailed Description
Example 1
(1) Mesoporous SiO2Preparation of
450mg of cetyltrimethylammonium bromide (CTAB) and 750mg of ammonium fluoride (NHF) were accurately weighed out4) Dispersing in 123mL deionized water, after ultrasonic dispersion, slowly adding 2.25mL tetraethyl orthosilicate (TEOS), mixing uniformly, heating to 80 ℃, and reacting for 2 h. After the reaction is finished, repeatedly washing with deionized water and ethanol to remove unreacted components and other impurities, and centrifugally drying to obtain complete SiO2And (3) granules. Drying the SiO2The particles were dispersed in 100mL of ethanol, 2mL of hydrochloric acid was added, and the mixture was refluxed at 90 ℃ for 24 hours to remove the porogen cetyltrimethylammonium bromide. After the reaction is finished, repeatedly washing and centrifuging by using deionized water and ethanol, removing the pore-forming agent under elution, and preparing the SiO with the hollow mesoporous structure2And (3) granules.
The scanning electron microscope and the transmission electron microscope examine the nano particles, and the electron microscope examination result shows that the mesoporous silica particles are uniform and consistent, the pore sizes are the same, and the distribution is uniform and consistent (as shown in fig. 1 and fig. 2).
(2) Mesoporous SiO2Modified by silanization (MSNs)
Weighing 500mg of mesoporous SiO2The particles were uniformly dispersed in 10mL of ethanol, 2mL of 3- (methacryloyloxy) propyltrimethoxysilane (MPTS), 50mL of ethanol, mesoporous SiO in a single-neck flask2The ethanol solution of the particles is reacted for 12 hours at 50 ℃. After the reaction is finished, repeatedly centrifuging and washing by deionized water and ethanol, removing unreacted components, and drying to obtain the C ═ C surface modified mesoporous SiO2And (3) granules.
(3) Sialic acid surface imprinted mesoporous SiO2Particle (MIP-MSNs)
500mg of C ═ C surface modified mesoporous SiO were added to a single neck flask2The particles, 34mL of Phosphate Buffered Saline (PBS), 18.6mg of Sialic Acid (SA), 11.4mg of 3-methacrylamidophenylboronic acid (MAPBA), 81mg of N-isopropylacrylamide (NIPAM), 25.4mg of acrylamide (AAM), 10.6mg of N- (3-aminopropyl) methacrylamide hydrochloride and 7.8mg of N, N' -methylenebisacrylamide (BIS) were ultrasonically dispersed uniformly, and then magnetically stirred at room temperature for 4 hours to allow self-assembly of the template and the functional monomer. Then, while introducing argon gas into the reaction system for 30min, 51. mu.L of an Ammonium Persulfate Solution (APS) and 102. mu.L of an N, N, N ', N' -tetramethylethylenediamine solution (TMEDA) as an initiation system were added to the reaction system. The flask was placed in a 37 ℃ water bath for 24 h. After completion of the reaction, the reaction mixture was collected by centrifugation and dialyzed against a 300000MW dialysis bag in ice water to remove the template molecules. After the template molecule is eluted, the template molecule is centrifugally collected and freeze-dried to obtain the mesoporous SiO with sialic acid surface imprinting2Particles (MIP-MSNs).
As a control, non-imprinted mesoporous SiO was prepared in the same manner without adding template sialic acid molecules2The particles (NIP-MSNs), the monomer components used and the synthesis procedure were the same as described above.
(4) Loading chemotherapeutic drugs doxorubicin (MIP-MSNs @ DOX)
Adopting a solvent permeation method to print 20mg of mesoporous SiO with sialic acid on the surface2Dissolving particles (MIP-MSNs) and 5mg of adriamycin in 10mL of phosphate buffer solution, magnetically stirring for 12h at room temperature, completely mixing, centrifuging to remove supernatant, and collecting particles to obtain the adriamycin-loaded nanoparticles.
The fourier transform infrared spectrogram shows that the surface of the mesoporous silica particle is successfully modified with C ═ C, and the surface molecularly imprinted layer is successfully grafted (as shown in fig. 3).
Example 2
Confirming the mesoporous SiO of sialic acid surface imprinting with the same weight under different adriamycin concentration conditions2Optimal loading efficiency of particle (MIP-MSNs) nanomaterials on doxorubicin. The specific operation is briefly described as follows: uniformly dispersing 1mg of MIP-MSNs in adriamycin solutions with different concentrations, shaking and uniformly mixing at 37 DEG CAfter 24h, the mixture is centrifuged at 12000rpm for 5min, and the supernatant is taken to be used for measuring the loading efficiency of MIP-MSNs in adriamycin solutions with different concentrations by a spectrophotometer. FIG. 4 shows that at 2.5mg/mL, the MIP-MSNs loading was greatest and the centrifuged supernatant drug content was lowest (see FIG. 4).
Example 3
In vitro uptake experiments of liver cancer cells (HepG-2) to specific targeting drug-loaded MSNs systems. Doxorubicin is the most commonly used tumor chemotherapy drug, has good water solubility, and can emit red fluorescence under ultraviolet irradiation, so that the condition of nanoparticles contacting cells can be judged by observing the fluorescence intensity with the aid of a fluorescence microscope.
When the HepG-2 cells are passaged for 24 hours and the cell adherence rate reaches about 80 percent, respectively adding MIP-MSNs and NIP-MSNs loaded with the adriamycin, continuously culturing for 24 hours at 37 ℃, staining cell nuclei by using Hoechst 33342 dye, and observing the adriamycin amount of two mesoporous silicon dioxide nano materials entering the cells by using a fluorescence microscope.
Hoechst 33342 is a blue dye for staining cell nucleus, and adriamycin has the characteristic of autofluorescence and emits red fluorescence under the irradiation of ultraviolet light. The cultured liver cancer cells HepG-2 are respectively cultured with MIP-MSNs and NIP-MSNs loaded with drugs for 24h at 37 ℃, and then the amount of adriamycin entering the cells (red fluorescence intensity) is observed by a fluorescence microscope. The experimental result shows that the amount of MIP-MSNs entering the cells is obviously more than that of NIP-MSNs.
Example 4
The specific targeting drug-loaded MSNs system has the effects of inhibiting the proliferation of liver cancer cells in vitro and promoting the apoptosis. CCK-8 and apoptosis experiments are utilized to detect that after free adriamycin, mesoporous silica loaded adriamycin (MSNs-DOX) and mesoporous silica loaded adriamycin (MIP-MSNs and NIP-MSNs) with different concentrations act on tumor cells (HepG-2) for 48 hours, the survival rate and the apoptosis rate of the cells are observed, and the treatment effect of the mesoporous silica system is observed.
The results show that the toxicity of the free adriamycin on the cells is the strongest, because the free adriamycin can directly enter the cells, directly kill the cells and cause the apoptosis of normal cells. After the mesoporous silica drug-loaded system is loaded with adriamycin and enters cells, the nano particles only enter tumor cells and slowly release the adriamycin due to the encapsulation and specific recognition effects of the surface imprinting layer. The result proves that the killing effect of the mesoporous silica drug-loaded system (MIP-MSNs @ DOX) with the surface modification imprinting layer on the tumor cells is stronger than that of the unmodified mesoporous silica drug-loaded system (NIP-MSNs @ DOX).
The experimental results show that the tumor cell targeting sialic acid imprinting mesoporous silica drug delivery system has excellent in-vitro anti-liver cancer treatment effect and good biocompatibility. In addition, the system showed no significant cytotoxicity against other normal cells. Furthermore, the imprinting layer on the surface of the mesoporous silica can improve the drug intake of the liver cancer cells, and high-target therapy is realized.
Claims (8)
1. The imprinted mesoporous material is characterized by being mesoporous SiO subjected to C ═ C surface modification and sialic acid surface imprinting treatment2Particles, the outer diameter of the particles is 100-200 nm.
2. The preparation method of the imprinted mesoporous material according to claim 1, comprising the following steps:
(1) mesoporous SiO2Preparation of
The pore-foaming agents of Cetyl Trimethyl Ammonium Bromide (CTAB) and ammonium fluoride (NHF)4) Dispersing in deionized water, slowly adding Tetraethoxysilane (TEOS), reacting for 1-3 h at 70-100 ℃, repeatedly washing with deionized water and ethanol, centrifuging, and drying to obtain complete SiO2Particles of said SiO2Dispersing the particles in ethanol, adding hydrochloric acid, refluxing for 18-36 h at 70-100 ℃, repeatedly washing and centrifuging by using deionized water and ethanol, and removing the pore-forming agent eluted to prepare the mesoporous SiO2Particles;
(2) mesoporous SiO2Modified by silanization (MSNs)
Making mesoporous SiO2The particles are uniformly dispersed in ethanol to form mesoporous SiO2Ethanol solution of the granules, mixing it with 3- (methacryloyl)Reacting oxygen) propyl trimethoxy silane (MPTS) and ethanol for 8-18 h at 40-60 ℃, then repeatedly centrifuging and washing by deionized water and ethanol, removing unreacted components, and drying to obtain C ═ C surface modified mesoporous SiO2Particles;
(3) preparation of sialic acid surface imprinted mesoporous SiO2Particle (MIP-MSNs)
Adding the C ═ C surface modified mesoporous SiO obtained in the previous step into a reaction vessel2The preparation method comprises the steps of carrying out ultrasonic dispersion on particles, Phosphate Buffer Solution (PBS), Sialic Acid (SA), 3-methylacrylamidophenylboronic acid (MAPBA), N-isopropylacrylamide (NIPAM), acrylamide (AAM), N- (3-aminopropyl) methacrylamide hydrochloride and N, N ' -methylene Bisacrylamide (BIS) uniformly, then carrying out magnetic stirring at room temperature, introducing argon gas into a reaction system while adding Ammonium Persulfate Solution (APS) and N, N, N ', N ' -tetramethylethylenediamine solution (TMEDA), placing the reaction vessel in a water bath at 35-40 ℃ for reaction for 12-36 h, carrying out centrifugal collection and dialysis, and carrying out centrifugal collection on particles again to obtain mesoporous SiO (silicon dioxide) with sialic acid surface imprinted2Particles (MIP-MSNs);
in the step (1), the proportions of hexadecyl trimethyl ammonium bromide, ammonium fluoride, ethyl orthosilicate, ethanol and hydrochloric acid are (400-) - (500 mg): (700-) - (800 mg): (2-3mL): (90-110mL): (1.5-3 mL);
mesoporous SiO in step (2)2The proportion of the particles, the total amount of ethanol and the 3- (methacryloyloxy) propyltrimethoxysilane is (450-500mg): (50-70mL): 1-3 mL);
in the step (3), C ═ C surface modified mesoporous SiO2The ratio of particles, phosphate buffer, sialic acid, 3-methacrylamidophenylboronic acid, N-isopropylacrylamide, acrylamide, N- (3-aminopropyl) methacrylamide hydrochloride, N, N ' -methylenebisacrylamide, ammonium persulfate, N, N, N ', N ' -tetramethylethylenediamine was (450-500mg), (25-35mL), (15-20mg), (10-13mg), (80-85mg), (23-27mg), (10-12mg), (6-10mg), (45-55 μ L) and (95-105 μ L).
3. The preparation method of the imprinted mesoporous material according to claim 2, wherein the magnetic stirring time in the step (3) is 2-6 h.
4. The preparation method of the imprinted mesoporous material according to claim 2, wherein the argon gas is introduced in the step (3) for 20-60 min.
5. The imprinted mesoporous material of claim 1 is applied to tumor cell targeted drug delivery.
6. The use of claim 5, wherein the tumor cell targeting drug is doxorubicin.
7. Method for application according to claim 6, characterized in that it comprises the following steps: mesoporous SiO imprinted on sialic acid surface by solvent permeation method2Dissolving the particles and adriamycin in phosphate buffer solution, magnetically stirring at room temperature to completely mix, centrifuging to remove supernatant, collecting particles, and making into adriamycin-loaded nanoparticles for targeted therapy of tumor cells; the sialic acid surface imprinted mesoporous SiO2The proportion of the particles, the adriamycin and the phosphate buffer solution is (15-25mg): (3-7mg): 8-12 mL.
8. The method of claim 8, wherein the magnetic stirring time is 5-20 hours.
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Cited By (3)
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| CN114748644A (en) * | 2022-05-20 | 2022-07-15 | 齐齐哈尔大学 | Preparation method of phycocyanin molecularly imprinted drug carrier with ZIF-8 as matrix |
| CN114796153A (en) * | 2022-03-16 | 2022-07-29 | 齐齐哈尔大学 | Preparation method of drug-loaded degradable molecularly imprinted polymer nanoparticles |
| CN115403718A (en) * | 2022-09-06 | 2022-11-29 | 河南工业大学 | Surface molecular imprinting fluorescence sensor based on aggregation-induced emission group, preparation method and application in rhodamine 6G detection |
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