CN111617256B - Doxorubicin drug carrier La/Tm-MOFs@SiO 2 Preparation method and application of composite material - Google Patents
Doxorubicin drug carrier La/Tm-MOFs@SiO 2 Preparation method and application of composite material Download PDFInfo
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- 239000012621 metal-organic framework Substances 0.000 title claims abstract description 145
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 title claims abstract description 135
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- WYTZZXDRDKSJID-UHFFFAOYSA-N (3-aminopropyl)triethoxysilane Chemical compound CCO[Si](OCC)(OCC)CCCN WYTZZXDRDKSJID-UHFFFAOYSA-N 0.000 claims abstract description 10
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 claims abstract description 10
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Abstract
The invention belongs to the field of biomedical materials, and in particular discloses an doxorubicin drug carrier La/Tm-MOFs@SiO 2 Preparation method and application of composite material, and La/Tm-MOFs@SiO 2 The drug carrier is of a core-shell structure, wherein the inner core is composed of La/Tm-MOFs, the outer shell is amino silicon dioxide, and the preparation method of the drug carrier comprises the following steps: and (3) taking lanthanum nitrate, thulium chloride and trimesic acid solution to react for 12-30 hours at 100-150 ℃, preparing La/Tm-MOFs co-doped with rare earth ions, dissolving the La/Tm-MOFs and CTAB in absolute ethyl alcohol, deionized water, ammonia water and diethyl ether, stirring, quickly dripping the mixed solution of TEOS and APTES, continuously stirring, adding 37% HCl, stopping alkalization reaction, centrifuging, washing and drying to obtain La/Tm-MOFs nano particles wrapped by amino silicon dioxide. The La/Tm-MOFs coated by the aminated silica can be used as a carrier of the doxorubicin, and the release of the doxorubicin can be monitored in real time through the change of the up-conversion fluorescence intensity of the material and the doxorubicin. The preparation method is simple and convenient to operate, so that the preparation cost is low.
Description
Technical Field
The invention belongs to the field of biomedical materials, and in particular relates to an doxorubicin drug carrier La/Tm-MOFs@SiO 2 A preparation method and application of the composite material.
Background
With the rapid development of biological material science, clinical medicine and pharmacy, medical biological materials are called drug carriers. The medicine is a carrier for the medicine to enter the human body, so that the medicine can better enter key parts of the human body to play a role. The medicine is loaded on a proper carrier, so that the controlled release, absorption and metabolism of medicine molecules in a human body can be improved, the utilization rate of the medicine is obviously improved, and side effects caused by overhigh medicine concentration are prevented. In the development and clinical application of anticancer drugs, the therapeutic effect is directly related to the drug concentration-time correlation of the drug in the tissue. Traditional methods for assaying drug concentration in cells and tissues are overly complex, such as High Performance Liquid Chromatography (HPLC), radiolabeling and detection, histological and immunohistochemical analysis. However, conventional analysis and detection methods may not provide accurate information in real time without radiation because the test sample must be tested in vitro. In addition, because in-vivo and in-vitro detection methods may not completely reflect in-vivo behaviors of drug delivery, it is important to design a visual drug carrier capable of clearly detecting specific behaviors of a drug release process and controlling a drug release function, and the visual drug carrier is gradually valued.
Metal Organic Frameworks (MOFs) are a periodic network structure of three-dimensional porous materials, a broad class of crystalline materials. The high porosity and the large specific surface area of MOFs material make the drug loading capacity of the MOFs material as a drug carrier larger, and also provide important guarantee for the development of MOFs material in the fields of drug carriers and drug release.
Disclosure of Invention
In order to solve the problems, one of the purposes of the invention is to provide a La/Tm-MOFs composite material coated by amination silica of an doxorubicin drug carrier, which is simply named La/Tm-MOFs@SiO 2 La/Tm-MOFs refer to La 3+ And Tm 3+ Co-doping the formed hetero-metal ions La/Tm-MOFs, said La/Tm-MOFs@SiO 2 The core is of a core-shell structure, the inner core is composed of La/Tm-MOFs, the outer shell is of aminated silicon dioxide, the inner core is of a porous structure, the particle size of La/Tm-MOFs particles is about 200-500nm, the thickness of the outer shell is 10-30nm, and the La/Tm-MOFs@SiO is prepared by the method 2 As a drug carrier, not only doxorubicin can be subjected toThe controlled release (can specifically release the drug under acidic conditions), and the release of the drug can be monitored in real time by the unique change of the up-conversion fluorescence intensity generated by the action of the controlled release drug and doxorubicin, so that the visual observation can be carried out on the controlled release process of the drug.
The second object of the present invention is to provide the La/Tm-MOFs@SiO 2 The preparation method of (2) comprises the following steps:
(1) Preparing La/Tm-MOFs material;
(2) Dissolving Cetyl Trimethyl Ammonium Bromide (CTAB) and La/Tm-MOFs prepared in the step (1) in absolute ethyl alcohol, sequentially adding deionized water, ammonia water and diethyl ether after ultrasonic dissolution, stirring for 0.4-1.0 h, then quickly dripping a mixed solution of Tetraethoxysilane (TEOS) and 3-aminopropyl triethoxysilane (APTES), continuously stirring for 2-5 h, then adding 37wt% HCl, stopping alkalization reaction, centrifuging, washing until an eluate is neutral, and drying to obtain an aminated silica coated La/Tm-MOFs composite material;
the addition ratio of the hexadecyl trimethyl ammonium bromide, the La/Tm-MOFs material, the deionized water, the ammonia water, the diethyl ether, the tetraethoxysilane and the 3-aminopropyl triethoxysilane in the step (2) is (200-400) mg: (100-175) mg: (60-80) mL: (1-2) mL: (10-30) mL: (2-4) mL: (100-300) mu L.
The ammonia water is 15wt% ammonia water.
The addition ratio of the cetyl trimethyl ammonium bromide and the absolute ethyl alcohol is (200-400) mg: (10-20) mL.
The drying temperature in the step (2) is 40-60 ℃.
The preparation method of the La/Tm-MOFs material in the step (1) comprises the following steps:
respectively dissolving lanthanum nitrate and thulium chloride in deionized water, dissolving trimesic acid in absolute ethyl alcohol, uniformly mixing a lanthanum nitrate aqueous solution, a thulium chloride aqueous solution and a trimesic acid ethanol solution to obtain a white solution, then reacting for 12-30 hours at 100-150 ℃ (preferably, reacting for 24 hours at 140 ℃), centrifuging, washing and drying to obtain the La/Tm-MOFs material.
The dosage ratio of the lanthanum nitrate, the thulium chloride, the trimesic acid, the total amount of deionized water and the absolute ethyl alcohol in the step (1) is as follows: (200-300) mg: (15-30) mg: (100-300) mg: (10-30) mL: (10-30) mL, preferably in an amount ratio of (200-270) mg: (15-25) mg: (125-270) mg: (10-22) mL: (10-20) mL.
The drying temperature is 40-60 ℃.
The preparation method of the invention is simple and convenient to operate, thus the preparation cost is low.
It is a third object of the present invention to provide a method of using the La/Tm-MOFs@SiO 2 。
Further, the invention provides La/Tm-MOFs@SiO particles coated with the aminated silica 2 The application of the compound as a carrier of anticancer drugs.
Further, the application is as follows: la/Tm-MOFs@SiO 2 As a pharmaceutical carrier for doxorubicin. The drug carrier specifically releases the drug under acidic conditions.
The specific method for the application is as follows: la/Tm-MOFs@SiO 2 Dispersing in medicinal solution, standing to obtain carrier dispersion, centrifuging, and drying to obtain La/Tm-MOFs@SiO carrying medicine 2 . The drug solution is 0.5g/L doxorubicin aqueous solution, and the drug loading rates of the carrier reach 22.5mg/g, 40mg/g and 57.5mg/g respectively at 24h, 48h and 72 h.
Further, the present invention also provides a method for preparing the catalyst by La/Tm-MOFs@SiO 2 The change of up-conversion fluorescence intensity acting with doxorubicin can be used for monitoring the application of drug release in real time, and visually observing the drug release process.
Compared with the prior art, the invention has the advantages that:
(1) The rare earth ion co-doped La/Tm-MOFs produce superior fluorescence when physically mixed differently from both La-MOFs and Tm-MOFs.
(2)La/Tm-MOFs@SiO 2 The drug loading rate which can be achieved when the drug is used as a drug carrier is extremely high. The drug loading on the first day is 22.5mg/g, the drug loading on the second day is 40mg/g, and the drug loading on the third day reaches 57.5mg/g. Because the drug carrying process is slow, the drug carrying effect is generally carried out about the third dayAnd the best is achieved. It can be seen that the material achieves a high load of doxorubicin.
(3)La/Tm-MOFs@SiO 2 Has better biocompatibility and unique pH response, so that the medicine can be released in a specific weak acid environment and is not released under alkaline conditions.
(4) By designing the core-shell material La/Tm-MOFs@SiO 2 The reaction with doxorubicin produced unique up-conversion fluorescence, and the release of doxorubicin was detected based on the up-conversion fluorescence. The fluorescence energy of the anticancer drug doxorubicin can be directly used for in vivo imaging, and can be regarded as a fluorescent dye which generates up-conversion fluorescence based on dye sensitization. The core-shell structure is designed to load doxorubicin based on different actions, so that the relationship between up-conversion fluorescence and doxorubicin can be established. The amino groups of the shell aminated porous silicon form hydrogen bonds with the amino groups and hydroxyl groups of DOX, and a large amount of doxorubicin is loaded. In a weakly acidic environment, DOX is released due to weakening of hydrogen bonding by protonation; the core MOFs supported a small amount of DOX based on adsorption, since the shell protection was essentially not released (core loading was about 10% at pH 5.8, as demonstrated by the assistance of fig. 7, released to about 10% at the end). As the protonation time is longer, the association of doxorubicin is reduced, single-molecule doxorubicin becomes more, the energy transfer effect with MOFs is enhanced, the sensitization effect becomes stronger, and the up-conversion fluorescence becomes stronger. According to the time relationship, the drug release is monitored in real time by the change of the fluorescence intensity. Therefore, la/Tm-MOFs are used as an inner core, up-conversion fluorescence is generated by the action of the La/Tm-MOFs and doxorubicin, and the aminated porous silicon is used as an outer shell to load the doxorubicin and carry out pH response release. And constructing a core-shell structure, correlating with each other through a time relationship, and detecting the release of the drug through up-conversion fluorescence.
Drawings
FIG. 1 is a fluorescent plot of La/Tm-MOFs, la-MOFs+Tm-MOFs, prepared in step 1) of example 1, under 375nm excitation.
In FIG. 2, (a), (c) are La/Tm-MOFs@SiO at 375nm and 985nm excitation, respectively 2 Fluorescence maps of the medicine before and after medicine loading under different release amounts; (b) Is a concentration curve graph prepared by taking a peak value at 585nm under 375nm excitationThe method comprises the steps of carrying out a first treatment on the surface of the (d) Is a concentration graph prepared by taking peaks at 539nm and 645nm under 985nm excitation; (e) Is a graph of the change of the time of releasing doxorubicin and the up-conversion fluorescence intensity of the material.
FIG. 3 is an SEM image (left image) and a TEM image (right image) of La/Tm-MOFs prepared in example 1.
FIG. 4 shows the La/Tm-MOFs@SiO prepared in example 1 2 Is a TEM image of (1).
FIG. 5A is an EDX diagram of La/Tm-MOFs prepared in example 1; FIG. 5B is a diagram of La/Tm-MOFs@SiO prepared in example 1 2 EDX plot of (c).
FIG. 6 is a diagram of La/Tm-MOFs@SiO in example 5, test method 1 2 Graph of drug loading over 72 hours.
Fig. 7 is a graph showing the release profile of doxorubicin in phosphate buffer solutions at ph=3.8, ph=5.8, ph=7.4 in test method 2 of example 5.
FIG. 8 is a fluorescence plot of doxorubicin at various pH values.
Detailed Description
The applicant will now make further details of the technical solutions and advantageous effects of the present invention with reference to specific examples, but it should be understood that the following examples should not be construed to limit the scope of protection claimed in the present application to any extent.
Lanthanum nitrate used in the following of this embodiment is La (NO) 3 ) 3 ·6H 2 O, the thulium chloride used is TmCl 3 ·6H 2 O。
The preparation method of La-MOFs comprises the following steps: 250mg of lanthanum nitrate is weighed and dissolved in 20mL of deionized water, 250mg of trimesic acid is weighed and dissolved in 20mL of absolute ethyl alcohol, the lanthanum nitrate solution and the trimesic acid solution are uniformly mixed to obtain a white solution, then the white solution reacts for 24 hours at 140 ℃, the precipitate is separated by a centrifuge, and the precipitate is repeatedly washed 3 times by deionized water and absolute ethyl alcohol (washing sequence: deionized water, absolute ethyl alcohol and deionized water) and centrifuged. And then placing the mixture in an oven for drying at 50 ℃ to obtain the La-MOFs material.
The preparation method of the Tm-MOFs comprises the following steps: 25mg of thulium chloride is weighed and dissolved in 20mL of deionized water, 250mg of trimesic acid is weighed and dissolved in 20mL of absolute ethyl alcohol, thulium chloride solution and trimesic acid solution are uniformly mixed to obtain white solution, then the white solution reacts for 24 hours at 140 ℃, precipitate is separated by a centrifuge, and the precipitate is repeatedly washed 3 times by deionized water and absolute ethyl alcohol (washing sequence: deionized water, absolute ethyl alcohol and deionized water) and centrifuged. And then placing the mixture in an oven for drying at 50 ℃ to obtain the Tm-MOFs material.
The preparation method of La-MOFs+Tm-MOFs comprises the following steps: the La-MOFs material (150 mg) and the Tm-MOFs material (20 mg) obtained above were dissolved in deionized water (20 mL) respectively, mixed, and then dried in an oven at 50℃to obtain La-MOFs+Tm-MOFs materials.
Example 1
Aminated silica coated La/Tm-MOFs (La/Tm-MOFs@SiO) 2 ) The preparation method of the preparation method comprises the following steps in sequence:
1) 250mg of lanthanum nitrate and 20mg of thulium chloride are weighed and dissolved in 20mL of deionized water, 250mg of trimesic acid is weighed and dissolved in 20mL of absolute ethyl alcohol, three solutions of lanthanum nitrate solution, thulium chloride solution and trimesic acid solution are uniformly mixed to obtain a white solution, then the white solution is reacted for 24 hours at 140 ℃, cooled to room temperature, precipitate is separated by a centrifuge, and the precipitate is repeatedly washed with deionized water and absolute ethyl alcohol for 3 times (washing sequence: deionized water, absolute ethanol, deionized water, as in the examples below, not described in detail) and centrifuging the precipitate. And then placing the mixture in an oven for drying at 60 ℃ to obtain the La/Tm-MOFs material.
2) 400mg of cetyltrimethylammonium bromide and 150mg of La/Tm-MOFs prepared in the step (1) were dissolved in 20mL of absolute ethyl alcohol, after ultrasonic dissolution, 80mL of deionized water, 1mL of ammonia water and 20mL of diethyl ether were sequentially added, stirred for 0.5h, and then a mixture of 3mL of tetraethoxysilane and 0.1mL of 3-aminopropyl triethoxysilane was rapidly dropped (1 min was completed). Stirring was continued for 4h, then 1mL 37wt% HCl was added and the basification was stopped. Centrifuging at 4200rpm for 12min, washing the precipitate with deionized water, anhydrous ethanol and acetone mixture respectively for 3 times, and oven drying at 60deg.C to obtain aminated silica coated La/Tm-MOFs composite material, denoted as La/Tm-MOFs@SiO 2 -1。
FIG. 1 shows the results of the excitation of La-MOFs, tm-MOFs, la-MOFs+Tm-MOFs at 375nm,fluorescence profile of La/Tm-MOFs prepared in example 1 step 1). Tm-MOFs have no fluorescence peak; la-MOFs have a weaker fluorescence peak. The two MOFs were physically mixed together and only La-MOFs showed fluorescence since Tm-MOFs did not fluoresce. But contrast La 3+ And Tm 3+ The hetero-metal ion MOFs formed by co-doping has a strong fluorescence peak at 480 nm. Description of La 3+ And Tm 3+ The hetero-metal ions La/Tm-MOFs formed by co-doping are a new MOFs, not a simple mixture of two MOFs.
FIG. 3 is an SEM and TEM image of La/Tm-MOFs prepared in example 1, and it can be seen that: the La/Tm-MOFs particles have a size of about 200-500nm.
FIG. 4 shows the La/Tm-MOFs@SiO prepared in example 1 2 TEM images of the material, it can be seen that: la/Tm-MOFs@SiO 2 Has obvious core-shell structure. The particle size of the La/Tm-MOFs particles of the inner core is about 200-500nm, siO of the outer shell 2 Is 15-20nm thick.
FIG. 5A is an EDX diagram of La/Tm-MOFs prepared in example 1, FIG. 5B is an EDX diagram of La/Tm-MOFs@SiO prepared in example 1 2 In the EDX diagram of (2), la/Tm-MOFs@SiO 2 The Si is agglomerated together but is seen to be the outermost layer, which can be explained by La/Tm-MOFs@SiO 2 Is of a core-shell structure.
Example 2
Aminated silica coated La/Tm-MOFs (La/Tm-MOFs@SiO) 2 ) The preparation method of the preparation method comprises the following steps in sequence:
1) 270mg of lanthanum nitrate and 18mg of thulium chloride are weighed and dissolved in 22mL of deionized water, 225mg of trimesic acid is weighed and dissolved in 15mL of absolute ethyl alcohol, three solutions of lanthanum nitrate solution, thulium chloride solution and trimesic acid solution are uniformly mixed to obtain a white solution, then the white solution is reacted for 24 hours at 140 ℃, cooled to room temperature, precipitate is separated by a centrifuge, and the precipitate is repeatedly washed for 3 times by the deionized water and the absolute ethyl alcohol and centrifuged. And then placing the mixture in an oven for drying at 60 ℃ to obtain the La/Tm-MOFs material.
2) 380mg of cetyltrimethylammonium bromide and 175mg of La/Tm-MOFs prepared in the step (1) are dissolved in 18mL of absolute ethyl alcohol, and 70mL of deionized water is sequentially added after ultrasonic dissolution1.5mL of ammonia water and 22mL of diethyl ether were stirred for 0.5h, and then a mixture of 2mL of ethyl orthosilicate and 0.2mL of 3-aminopropyl triethoxysilane was rapidly dropped (1 min was over). Stirring was continued for 4h, then 1mL 37wt% HCl was added and the basification was stopped. Centrifuging at 4200rpm for 12min, washing the precipitate with deionized water, anhydrous ethanol and acetone mixture respectively for 3 times, and oven drying at 60deg.C to obtain aminated silica coated La/Tm-MOFs composite material, denoted as La/Tm-MOFs@SiO 2 -2。
Example 3
Aminated silica coated La/Tm-MOFs (La/Tm-MOFs@SiO) 2 ) The preparation method of the preparation method comprises the following steps in sequence:
1) 225mg of lanthanum nitrate and 25mg of thulium chloride are weighed and dissolved in 15mL of deionized water, 270mg of trimesic acid is weighed and dissolved in 18mL of absolute ethyl alcohol, three solutions of lanthanum nitrate solution, thulium chloride solution and trimesic acid solution are uniformly mixed to obtain a white solution, then the white solution is reacted for 24 hours at 140 ℃, cooled to room temperature, precipitate is separated by a centrifuge, and the precipitate is repeatedly washed for 3 times by the deionized water and the absolute ethyl alcohol and centrifuged. And then placing the mixture in an oven for drying at 60 ℃ to obtain the La/Tm-MOFs material.
2) 355mg of cetyltrimethylammonium bromide and 165mg of La/Tm-MOFs prepared in the step (1) are dissolved in 15mL of absolute ethyl alcohol, 77mL of deionized water, 1.8mL of ammonia water and 15mL of diethyl ether are sequentially added after ultrasonic dissolution, the mixture is stirred for 0.5h, and then a mixture of 2.5mL of tetraethoxysilane and 0.25mL of 3-aminopropyl triethoxysilane is rapidly dripped (dripping is completed for 1 min). Stirring was continued for 4h, then 1mL 37wt% HCl was added and the basification was stopped. Centrifuging at 4200rpm for 12min, washing the precipitate with deionized water, anhydrous ethanol and acetone mixture respectively for 3 times, and oven drying at 60deg.C to obtain aminated silica coated La/Tm-MOFs composite material, denoted as La/Tm-MOFs@SiO 2 -3。
Example 4
Aminated silica coated La/Tm-MOFs (La/Tm-MOFs@SiO) 2 ) The preparation method of the preparation method comprises the following steps in sequence:
1) 200mg of lanthanum nitrate and 15mg of thulium chloride are weighed and dissolved in 10mL of deionized water, 125mg of trimesic acid is weighed and dissolved in 10mL of absolute ethyl alcohol, three solutions of lanthanum nitrate solution, thulium chloride solution and trimesic acid solution are uniformly mixed to obtain a white solution, then the white solution is reacted for 24 hours at 140 ℃, cooled to room temperature, precipitate is separated by a centrifuge, and the precipitate is repeatedly washed for 3 times by the deionized water and the absolute ethyl alcohol and centrifuged. And then placing the mixture in an oven for drying at 60 ℃ to obtain the La/Tm-MOFs material.
2) 200mg of cetyltrimethylammonium bromide and 100mg of La/Tm-MOFs prepared in the step (1) were dissolved in 10mL of absolute ethyl alcohol, 60mL of deionized water, 2mL of ammonia water and 10mL of diethyl ether were sequentially added after ultrasonic dissolution, and stirred for 0.5h, and then a mixture of 3.5mL of tetraethoxysilane and 0.1mL of 3-aminopropyl triethoxysilane was rapidly dropped (1 min was dropped). Stirring was continued for 4h, then 1mL 37wt% HCl was added and the basification was stopped. Centrifuging at 4200rpm for 12min, washing the precipitate with deionized water, anhydrous ethanol and acetone mixture respectively for 3 times, and oven drying at 60deg.C to obtain aminated silica coated La/Tm-MOFs composite material, denoted as La/Tm-MOFs@SiO 2 -4。
Example 5
La/Tm-MOFs@SiO prepared in example 1 below 2 For the La/Tm-MOFs@SiO of the present invention, example 1 2 The purpose of (2) is described in detail.
La/Tm-MOFs@SiO of the present invention 2 Efficacy test as a drug doxorubicin carrier.
The phosphate buffer solution used in the test, ph=3.8, consisted of 7.1mL, 0.2mol/L Na 2 HPO 4 The solution is mixed with 12.9mL of 0.1mol/L citric acid solution; the phosphate buffer solution with pH=5.8 consists of 12.1mL of Na with a concentration of 0.2mol/L 2 HPO 4 The solution is mixed with 7.9mL of 0.1mol/L citric acid solution; the phosphate buffer solution with pH=7.4 consists of 18.2mL of Na with a concentration of 0.2mol/L 2 HPO 4 The solution was mixed with 1.8mL of a 0.1mol/L citric acid solution.
The test method comprises the following steps:
1. 20mL of an aqueous solution of doxorubicin at 0.5g/L was prepared, to which 0.2g of the aminated silica-coated La/Tm-MOFs complex prepared in example 1 was addedMixing materials, standing for 3 days, centrifuging, and oven drying the centrifuged solid at 60deg.C for 6 hr to obtain doxorubicin-loaded La/Tm-MOFs@SiO 2 . Measuring absorbance of the supernatant liquid when standing for 24 hours, and measuring absorbance of the supernatant liquid every 24 hours to measure the concentration of doxorubicin in the supernatant liquid, thereby obtaining La/Tm-MOFs@SiO prepared in example 1 in 24 hours, 48 hours and 72 hours 2 As shown in FIG. 6, the drug loading of doxorubicin increases with the increase of drug loading time, and the drug loading amounts at 24h, 48h and 72h reach 22.5mg/g, 40mg/g and 57.5mg/g respectively.
2. Doxorubicin-loaded La/Tm-mofs@sio was studied at 37 ℃, ph=3.8, ph=5.8, ph=7.4, respectively 2 The specific experimental procedure is as follows:
firstly, preparing phosphate buffer solution with pH=3.8, and then weighing 0.5g of prepared La/Tm-MOFs@SiO carrying doxorubicin 2 Dispersing in 10mL of phosphate buffer solution with pH=3.8, transferring to a dialysis bag (Kw=14000), clamping two ends of a bag opening of the dialysis bag by clamps, placing the dialysis bag in a beaker filled with 200mL of phosphate buffer solution with pH=3.8, adding a stirrer into the beaker, placing the beaker on a magnetic stirrer, stirring, taking 3mL of buffer solution in the beaker every half hour to measure the absorbance, pouring the buffer solution back into the beaker again, measuring the absorbance every 1 hour when the data change is not large, measuring the absorbance every 6 hours when the data change is not large, and then adjusting the detection interval time according to the change value of the absorbance until the absorbance value is not changed. And calculating the content of the released doxorubicin in the beaker according to a standard curve regression equation obtained by a standard curve method of an ultraviolet spectrophotometer. Plotting the time interval and the accumulated drug release rate to obtain the release curve of the doxorubicin in the phosphate buffer solution with pH=3.8. The above buffer solution was changed to a phosphate buffer solution having ph=5.8 and ph=7.4, and a release profile of doxorubicin in the phosphate buffer solution having ph=5.8 and ph=7.4 was obtained.
Doxorubicin-loaded La/Tm-mofs@sio 2 The release curve of the doxorubicin is shown in FIG. 7, and it can be seen from FIG. 7 that La/Tm-MOFs@SiO carrying doxorubicin 2 High release of doxorubicin under acidic conditionRelease efficiency, i.e. easier release of the loaded drug under acidic conditions. Based on the pH difference between cancer cells and normal cells, the carrier can specifically release the medicine in an acidic environment, can provide a basis for reducing the damage to the normal cells in actual treatment, and provides an effective actual reference basis for an anticancer tumor medicine loading system.
3. The fluorescence change of doxorubicin at different pH was studied at 37 ℃, ph=3.8, ph=5.8, ph=7.4, respectively, with the following experimental steps:
preparing 0.5g/L of doxorubicin aqueous solution and phosphate buffer solution with pH=3.8, adding 20mL of doxorubicin aqueous solution into 10mL of phosphate buffer solution with pH=3.8, uniformly mixing, and measuring the fluorescence intensity. The buffer solution is changed into phosphate buffer solution with pH=5.8 and pH=7.4, and the fluorescence spectrum of the doxorubicin at different pH values is obtained. As the pH decreases, the fluorescence intensity of doxorubicin increases, because protonation reduces the association of DOX, thereby making the particle size of doxorubicin smaller. I.e., under protonation conditions, more single molecule DOX is present, thereby sensitizing La/Tm-MOFs to up-conversion fluorescence.
The fluorescence patterns of doxorubicin at different pH values are shown in FIG. 8, and it can be seen from FIG. 8 that the positions of doxorubicin fluorescence peaks at different pH values are not changed.
4. 20mL of an aqueous solution of doxorubicin at 0.5g/L was prepared, to which 0.2g of the aminated silica-coated La/Tm-MOFs composite prepared in example 1 was added to prepare a solution, and the solution was left in a dark place for 72 hours, and the fluorescence intensity thereof was measured. La/Tm-MOFs@SiO prepared in example 1 2 The fluorescence spectrum of 375nm excitation before and after drug loading is shown in FIG. 2 (a). La/Tm-MOFs@SiO before drug loading 2 Only 480nm has a distinct fluorescence peak, which is consistent with the La/Tm-MOFs fluorescence peak shown in FIG. 1, and after the porous silicon amide is coated, the La/Tm-MOFs fluorescence performance is not affected. After drug loading, there were two distinct fluorescence peaks at 585nm and 637nm (consistent with that of doxorubicin). And with the release of doxorubicin drug, the fluorescence intensities of 585nm and 637nm were gradually decreased. The fluorescence intensity at 585nm was plotted against the amount of doxorubicin released, as shown in FIG. 2 (b). Thus can pass through 585nmAnd judging the release condition of the medicine by the degree of weakening the fluorescence intensity.
However, it is difficult to avoid interference of autofluorescence by ordinary fluorescence, and interference of ordinary fluorescence can be avoided by up-converting fluorescence. La/Tm-MOFs@SiO 2 Adriamycin-loaded, after excitation at 985nm, produces strong fluorescence at 539nm, 645nm, as shown in FIG. 2 (c). The up-conversion fluorescence intensity of the fluorescent dye is enhanced along with the release of the drug. The up-conversion fluorescence intensity at 539nm and 645nm was plotted against the amount of doxorubicin released, as shown in FIG. 2 (d). The fluorescence intensity is proportional to the released amount of doxorubicin. Then pass La/Tm-MOFs@SiO 2 The change of the up-conversion fluorescence can detect the release of the doxorubicin, thus providing possibility for real-time monitoring of the administration process of the anticancer drug and having the capability of visual observation on the release of the drug. The time of doxorubicin release and the change in up-conversion fluorescence intensity of the material are shown in fig. 2 (e), and the drug release is monitored in real time by the change in up-conversion fluorescence intensity according to the time relationship.
Claims (7)
1. A composite La/Tm-MOFs coated by amino silicon dioxide and loaded with doxorubicin is characterized in that the La/Tm-MOFs coated by amino silicon dioxide is of a core-shell structure, the inner core is composed of La/Tm-MOFs with particle size of 200-500nm, the outer shell is amino silicon dioxide with thickness of 10-30nm, and the La/Tm-MOFs refer to La 3+ And Tm 3+ Co-doping the formed hetero-metal ions MOFs.
2. The doxorubicin-loaded aminated silica-coated La/Tm-MOFs composite according to claim 1, wherein the preparation method of the aminated silica-coated La/Tm-MOFs composite comprises the steps of:
(1) Preparing La/Tm-MOFs materials:
respectively dissolving lanthanum nitrate and thulium chloride in deionized water, dissolving trimesic acid in absolute ethyl alcohol, uniformly mixing a lanthanum nitrate aqueous solution, a thulium chloride aqueous solution and a trimesic acid ethanol solution to obtain a white solution, reacting for 12-30 hours at 100-150 ℃, centrifuging, washing and drying to obtain a La/Tm-MOFs material;
(2) Dissolving cetyl trimethyl ammonium bromide and La/Tm-MOFs in absolute ethyl alcohol, sequentially adding deionized water, ammonia water and diethyl ether after ultrasonic dissolution, stirring for 0.4-1.0 h, then rapidly dripping the mixed solution of tetraethoxysilane and 3-aminopropyl triethoxysilane, continuously stirring for 2-5 h, then adding 37wt% HCl, stopping alkalization reaction, centrifuging, washing and drying to obtain the La/Tm-MOFs composite material wrapped by the amino silicon dioxide.
3. The doxorubicin-loaded aminated silica-coated La/Tm-MOFs composite according to claim 2, wherein in step (1): the dosage ratio of lanthanum nitrate, thulium chloride, trimesic acid, the total amount of deionized water and absolute ethyl alcohol is as follows: (200-300) mg: (15-30) mg: (100-300) mg: (10-30) mL: (10-30) mL.
4. A doxorubicin-loaded aminated silica-coated La/Tm-MOFs composite according to claim 3, wherein in step (2): the addition ratio of hexadecyl trimethyl ammonium bromide, la/Tm-MOFs material, deionized water, ammonia water, diethyl ether, tetraethoxysilane, 3-aminopropyl triethoxysilane and absolute ethyl alcohol is (200-400) mg: (100-175) mg: (60-80) mL: (1-2) mL: (10-30) mL: (2-4) mL: (100-300) μl: (10-20) mL.
5. The doxorubicin-loaded aminated silica-coated La/Tm-MOFs composite according to claim 4, wherein the lanthanum nitrate, thulium chloride, trimesic acid, deionized water, absolute ethanol are used in a ratio of (200-270) mg: (15-25) mg: (125-270) mg: (10-22) mL: (10-20) mL.
6. Use of the doxorubicin-loaded aminated silica-coated La/Tm-MOFs composite material according to any one of claims 1 to 5 for the preparation of anticancer drugs.
7. According to claim 6The application is characterized in that the catalyst is prepared by La/Tm-MOFs@SiO 2 The change in up-conversion fluorescence intensity with doxorubicin was used to monitor drug release in real time.
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