CN111001009A - VB2Preparation method and application of drug carrier - Google Patents

VB2Preparation method and application of drug carrier Download PDF

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CN111001009A
CN111001009A CN201911385185.1A CN201911385185A CN111001009A CN 111001009 A CN111001009 A CN 111001009A CN 201911385185 A CN201911385185 A CN 201911385185A CN 111001009 A CN111001009 A CN 111001009A
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solution
cmcs
cqds
preparation
drug carrier
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CN111001009B (en
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熊春华
金良梅
张建勇
陆海霞
修丽丽
姚彩萍
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Zhejiang Gongshang University
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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    • A61K49/00—Preparations for testing in vivo
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    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0065—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle
    • A61K49/0067—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle quantum dots, fluorescent nanocrystals
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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    • C01B32/00—Carbon; Compounds thereof
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    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
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    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
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    • C08K3/18—Oxygen-containing compounds, e.g. metal carbonyls
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    • C08K3/18—Oxygen-containing compounds, e.g. metal carbonyls
    • C08K3/20—Oxides; Hydroxides
    • C08K3/22—Oxides; Hydroxides of metals
    • C08K2003/2265—Oxides; Hydroxides of metals of iron
    • C08K2003/2275—Ferroso-ferric oxide (Fe3O4)
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    • C08K2201/00—Specific properties of additives
    • C08K2201/01—Magnetic additives

Abstract

The invention discloses a VB2The preparation method of the drug carrier comprises the following steps: in deionized water, sealing ascorbic acid and diethylenetriamine, carbonizing, centrifuging the obtained reaction liquid, filtering and dialyzing to obtain a nitrogen-doped carbon quantum dot AT-CQDs solution; by using carboxymethyl chitosan and Fe3O4Preparation of Fe3O4-a CMCS composite; nitrogen-doped carbon quantum dot AT-CQDs solution and Fe3O4Preparation of CMCS suspension to obtain Fe3O4-CMCS @ AT-CQDs composite material as VB2Drug carrier, embedding vitamin B2. The drug carrier provided by the invention has fluorescence and magnetic responsiveness, and can be applied to a drug targeting delivery system.

Description

VB2Preparation method and application of drug carrier
Technical Field
The invention belongs to the field of food engineering, and particularly relates to a method for preparing novel VB2Methods for drug carriers and uses thereof.
Background
Breakthrough in nanotechnology makes it possible to integrate nanoparticles of different functions into a single hybrid nanostructure, thus constituting multifunctional nanosensors, carriers and probes with great potential in life sciences. The magnetic fluorescent composite material is generally a composite material in which a magnetic nanomaterial with magnetic responsiveness and a fluorescent nanomaterial rich in fluorescence are physically or chemically connected together. The magnetic fluorescent particles are combined with magnetic and fluorescent substances, and have the functions of fluorescence, magnetic response and physical surface.
Vitamin B2(VB2) Is one of 13 basic vitamins of human body, and is an important component of the auxiliary group of yellow enzymes in the organism. VB2Can promote the development and regeneration of human cells, is also essential for the normal growth of hair and nails, can better prevent perioral diseases and periocular diseases, and has certain improvement effect on vision. However, many active ingredients lack bioavailability by oral administration due to poor solubility and permeability in the intestinal tract.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for preparing novel VB2A method of drug carrier.
In order to solve the above technical problems, the present invention provides a VB2The preparation method of the drug carrier comprises the following steps:
1) and preparing a carbon quantum dot:
1.1) dissolving 0.5g of ascorbic acid (vitamin C) in 15 +/-2 mL of deionized water, adding 0.25-1 mL (preferably 0.5mL) of diethylenetriamine serving as a nitrogen source, and uniformly stirring;
1.2) sealing the solution (clear transparent solution) obtained in the step 1.1), and carbonizing the solution at 160-200 ℃ for 2-6 h (preferably carbonizing the solution at 180 ℃ for 4 h);
1.3) cooling the product obtained in the step 1.2 (cooling to room temperature), centrifuging, and filtering the supernatant obtained by centrifuging; dialyzing the filtrate for 10-14 h by using a dialysis bag with the interception amount of 3500Da, wherein the obtained liquid (namely the intercepted liquid in the dialysis bag) obtained by dialysis is a nitrogen-doped carbon quantum dot AT-CQDs solution;
2) preparation of Fe3O4-CMCS：
Dissolving 0.5g of carboxymethyl chitosan in (50 +/-10) mL of deionized water to obtain solution A; 0.2g of Fe3O4Mixing with (50 +/-10) mL of deionized water, and performing ultrasonic dispersion (for about 10-15 min) to obtain a solution B;
uniformly mixing the solution A and the solution B, and reacting at 70 +/-10 ℃ for 2 +/-0.5 h; cooling the obtained reaction solution (cooling to room temperature), separating magnetic hysteresis (permanent magnet hysteresis separation), washing the separated magnetic substance, and vacuum dryingTo obtain Fe3O4-CMCS composite (particulate);
3)、Fe3O4preparation of CMCS @ AT-CQDs composite:
mixing Fe3O4Ultrasonic dispersion of-CMCS composite material (granular) in PBS buffer solution with pH 7.4 to prepare Fe of 10mg/mL3O4-a CMCS suspension;
dissolving (2 +/-0.5) mg of activating agent in 1-5 mL of nitrogen-doped carbon quantum dot AT-CQDs solution, and activating AT (37 +/-5) DEG for (30 +/-5) min; 1ml of Fe was added thereto3O4A CMCS suspension is reacted for 12 to 48 hours at a temperature of between 25 and 60 ℃ (preferably for 24 hours at a temperature of between 37 ℃); after the reaction is completed, magnetic hysteresis separation (permanent magnet hysteresis separation) is carried out, and the magnetic substance obtained by separation is washed and then dried in vacuum to obtain VB2Fe of drug carrier3O4-CMCS @ AT-CQDs composite.
VB as the invention2Improvement of the preparation method of the drug carrier: the activating agent in the step 3) is EDC.
VB as the invention2The preparation method of the drug carrier is further improved: in the step 3), the magnetic material obtained by separation is washed by deionized water and then dried in vacuum to obtain the magnetic material which can be used as VB2Fe of drug carrier3O4-CMCS @ AT-CQDs composite.
VB as the invention2The preparation method of the drug carrier is further improved: in the step 3), Fe is added3O4The CMCS suspension was reacted at 37 ℃ for 24 h.
VB as the invention2The preparation method of the drug carrier is further improved: in the step 1.3), the supernatant obtained by centrifugation is filtered through a 0.45 μm microporous membrane, thereby realizing filtration.
VB as the invention2The preparation method of the drug carrier is further improved:
in the step 1.1), the dosage of the diethylenetriamine is 0.5 mL;
in the step 1.2), carbonization is carried out for 4 hours at 180 ℃.
VB as the invention2The preparation method of the drug carrier is further improved:
in the step 2), after the solution A and the solution B are mixed, firstly carrying out ultrasonic treatment for 3-5 min, and then oscillating the mixture in a shaking table for 0.5 +/-0.1 h, so that the solution A and the solution B are uniformly mixed.
VB as the invention2The preparation method of the drug carrier is further improved:
in the step 2), the magnetic substance obtained by separation is washed by absolute ethyl alcohol and deionized water respectively, and then is dried in vacuum to obtain Fe3O4CMCS composite (granular).
The invention also provides VB prepared by the method2Use of a pharmaceutical carrier characterized by: vitamin B embedding2。
VB as the invention2Improvement of the use of pharmaceutical carriers: mixing Fe3O4the-CMCS @ AT-CQDs composite material is prepared into Fe with the concentration of 10mg/mL by using PBS solution with the pH value of 7.43O4-CMCS @ AT-CQDs solution;
3mgVB2Dissolved in 10mL of a 0.1mol/LHCL solution, and 2mL of Fe was added3O4-CMCS @ AT-CQDs solution; reacting for 2 hours in a constant temperature shaking table at 37 ℃ under the condition of keeping out of the light, thereby leading VB2Uniformly dispersing to form the magnetic fluorescent bifunctional drug-loaded microsphere.
The invention has the following technical advantages:
1. the method of the invention can be used for preparing novel bifunctional composite material (Fe)3O4-CMCS @ AT-CQDs composite material), which has good thermal stability, magnetic property, fluorescence property and other properties.
The fluorescence is good, the mark is obvious, and the tracking of the medicine in vivo is facilitated; the magnetic property is good, and the separation can be carried out through an external magnetic field, so that the retention time of the medicine in the body is reduced; thereby improving the utilization rate of the medicine and reducing the cytotoxicity.
2. The composite material is used for embedding nutrients, and a target can be transported to a specific position by the aid of a carrier for controlled release.
In conclusion, the invention designs a green and simple synthesis method, prepares and obtains the drug carrier with fluorescence and magnetic responsiveness, and becomes one of the most promising applications of a novel drug targeting delivery system.
Drawings
The following describes embodiments of the present invention in further detail with reference to the accompanying drawings.
FIG. 1 is an infrared spectrum of ascorbic acid (a), AA-CQDs (b), AT-CQDs (c);
FIG. 2 is a UV absorption spectrum of ascorbic acid (a), diethylenetriamine (b) and AT-CQDs (c);
FIG. 3 is a graph showing the change of fluorescence intensity of AT-CQDs with excitation time;
FIG. 4 is Fe3O4(a)、Fe3O4-CMCS(b)、Fe3O4-thermogravimetric curves of CMCS @ AT-CQDs (c);
FIG. 5 shows AT-CQDs (a), Fe3O4-fluorescence spectra of CMCS @ AT-CQDs (b);
FIG. 6 is Fe3O4(a)、Fe3O4CMCS (b) with Fe3O4-hysteresis loop of CMCS @ AT-cqds (c);
FIG. 7 is a standard curve of VB 2;
FIG. 8 is a graph showing the release profile of drug-loaded microspheres in simulated gastrointestinal fluids;
FIG. 9 shows the effect of different amounts of diethylenetriamine on the fluorescence intensity of AT-CQDs;
FIG. 10 is a graph showing the effect of reaction temperature on the fluorescence intensity of AT-CQDs;
FIG. 11 is a graph showing the effect of reaction time on the fluorescence intensity of AT-CQDs;
FIG. 12 is the reaction volume ratio over Fe3O4-effect of CMCS @ AT-CQDs fluorescence intensity;
FIG. 13 is reaction temperature vs. Fe3O4-effect of CMCS @ AT-CQDs fluorescence intensity;
FIG. 14 is reaction time vs. Fe3O4-effect of CMCS @ AT-CQDs fluorescence intensity;
FIG. 15 shows the effect of drug loading on drug-loaded microspheres and encapsulation efficiency;
FIG. 16 is Fe3O4-effect of CMCS @ AT-CQDs addition on drug loaded microspheres addition.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:
example 1, preparation of a carbon quantum dot, the following steps were performed in order:
1) 0.5g of ascorbic acid (vitamin C) is weighed and dissolved in 15mL of deionized water, 0.5mL of diethylenetriamine serving as a nitrogen source is added, and the mixture is stirred uniformly to obtain a clear and transparent solution.
2) Transferring the solution (clear transparent solution) obtained in the step 1) into a 50mL polytetrafluoroethylene lining reaction kettle, sealing, putting into an electric heating constant-temperature air blast drying oven, and carbonizing at 180 ℃ for 4 hours; after the reaction is finished, the reaction kettle is naturally cooled to room temperature.
3) And centrifuging the reaction product obtained in the step 2) for 15min AT 6000r/min, taking supernatant, performing vacuum filtration through a 0.45-micron microporous filter membrane, dialyzing the obtained filtrate for 12h by using a dialysis bag with the interception amount of 3500Da, wherein the obtained liquid (namely the intercepted liquid in the dialysis bag) obtained by dialysis is a nitrogen-doped carbon quantum dot AT-CQDs solution.
4) And vacuum drying the nitrogen-doped carbon quantum dot AT-CQDs solution AT 50 ℃ to constant weight to obtain the nitrogen-doped carbon quantum dot AT-CQDs.
The invention uses a Fourier infrared spectrometer to carry out structural characterization on nitrogen-doped carbon quantum dots AT-CQDs:
FIG. 1 is an infrared spectrum of ascorbic acid, carbon quantum dots AA-CQDs and nitrogen-doped carbon quantum dots AT-CQDs, respectively. In the original ascorbic acid, a plurality of impurity peaks exist, and after the ascorbic acid is carbonized into carbon quantum dots, a series of obvious characteristic peaks appear, and the structure is more single. Among AA-CQDs, 3371cm-1 is a stretching vibration peak attributed to-OH, 1617cm-1 and 1400cm-1 are a symmetric vibration peak and an antisymmetric vibration peak, respectively, of-COOH, and the stretching vibration peak position of the carbonyl group appears at 1709 cm-1. For nitrogen-doped carbon quantum dots AT-CQDs, the absorption peak AT 3281cm-1 is from-OH and NHx, the absorption peak AT 1347cm-1 is obvious and corresponds to C-O-C in epoxy groups, and the stretching vibration peak of C ═ O appears AT 1629cm-1, and is displaced compared with 1617cm-1 of AA-CQDs, and the intensity is obviously enhanced. From the above analysis, AT-CQDs have been shown to be rich in hydrophilic groups, hydroxyl and carboxyl, thereby attaching water solubility to the carbon-amido quantum dots.
Description of the drawings: the preparation method of the carbon quantum dot AA-CQDs comprises the following steps: the use of diethylenetriamine as nitrogen source in step 2) is eliminated with respect to example 1, the rest being equivalent to example 1; obtaining carbon quantum dots AA-CQDs.
FIG. 2 shows the UV absorption spectrum of ascorbic acid, diethylenetriamine and AT-CQDs, and it can be seen from FIG. 2 that nitrogen-doped carbon quantum dots AT-CQDs show a distinct optical absorption capability in the UV-visible region and extend to the visible region. A weak shoulder appears at 210nm, which is sp2Pi-pi of hybridized C ═ C bond*Electron transition of (3). In addition, a maximum absorption peak exists at 336nm, corresponding to the n-pi transition of C ═ O. And the ascorbic acid and the diethylenetriamine have no absorption peaks at the two positions, which indicates that a new substance is generated in the synthesis process.
Performance test 1 photostability
The experimental method comprises the following steps: the nitrogen-doped carbon quantum dot AT-CQDs solution (with the concentration of 0.1mg/mL and diluted by deionized water) is placed in a refrigerator with the temperature of 4 ℃ for sealed storage, and the fluorescence intensity of the solution is measured by a fluorescence spectrophotometer every 2 days AT the excitation wavelength of 370 nm.
The results obtained are shown in FIG. 3. As can be seen from FIG. 3, the fluorescence intensity of the nitrogen-doped carbon quantum dot AT-CQDs solution is reduced to a small extent with the time, which indicates that the carbon quantum dot has strong light stability. After two weeks, the fluorescence intensity of the carbon quantum dots remained substantially unchanged. After 1 month, the fluorescence intensity was measured and it was found that 28% of the initial fluorescence intensity was lost. The experiments show that the carbon quantum dots prepared by the method have good photobleaching performance, can be subjected to long-time detection and surface modification, and can be applied to biochemical detection.
Example 2 preparation of magnetic fluorescent bifunctional composite Material
1) Dissolving 0.5g of carboxymethyl chitosan in 50mL of deionized water, and uniformly stirring to prepare solution A;
weighing 0.2gFe3O4Mixing with 50mL of deionized water, and ultrasonically dispersing for 10min to prepare a solution B;
mixing the A, B solutions, continuing to perform ultrasonic treatment for 5min, then placing the mixture in a shaking table to oscillate for 0.5h, and then placing the mixture in a 70 ℃ water bath to react for 2 h; cooling to room temperature after reaction, separating with permanent magnet, washing the separated magnetic substance with anhydrous ethanol and deionized water for several times, and vacuum drying (drying at 50 deg.C to constant weight) to obtain Fe3O4CMCS composite (granular).
2) And the obtained Fe3O4Ultrasonic dispersion of-CMCS composite material (granular) in PBS buffer solution with pH 7.4 to prepare Fe of 10mg/mL3O4-a CMCS suspension;
weighing 2mg of activator EDC, dissolving in 5mL of nitrogen-doped carbon quantum dot AT-CQDs solution (obtained in step 3 of example 1), and activating AT 37 ℃ for 30 min; 1ml of Fe was added thereto3O4-CMCS suspension, placed in a constant temperature shaker at 37 ℃ for 24h reaction; after the reaction is finished, after the hysteresis separation of the permanent magnet, the magnetic substance obtained by separation is washed for a plurality of times by deionized water and dried in vacuum (dried to constant weight at 50 ℃) to obtain Fe3O4-CMCS @ AT-CQDs composite.
EDC, i.e., 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
Performance test 2 thermal stability
And (3) adopting a thermogravimetric/differential scanning calorimetry synchronous analyzer to carry out determination and analysis on the relationship of temperature to mass fraction on Fe3O4-CMCS @ AT-CQDs.
FIG. 4 shows magnetic Fe3O4 nanoparticles (a) and Fe3O4CMCS (b) and Fe3O4Thermogravimetric curves of CMCS @ AT-CQDs (c), it can be seen from FIG. 4 that two weight loss processes occur in the sample from room temperature to 600 ℃. The first degradation process occurs before 200 ℃ and changes more slowly, which is caused by the evaporation of adsorbed water on the physical surface of each complex, Fe3O4The mass loss rate of-CMCS @ AT-CQDs is 0.8 percent. The second mass loss process occurs in the temperature range of 200-460 ℃, and the mass loss rate of Fe3O4-CMCS @ AT-CQDs AT this stage is 23.8%, which is caused by the decomposition of the carboxymethyl chitosan coated on the magnetic nanoparticles and the connected carbon quantum dots under the action of heat. After about 460 ℃, the mass tends to be stable and no longer decreases, and the remaining substance is mostly inorganic Fe3O4The organic matter has been completely decomposed.
Performance test 3 fluorescent Properties
Carbon quantum dots AT-CQDs and Fe measured AT an excitation wavelength of 370nm and an incidence and emission slit width of 10nm3O4-fluorescence spectrum of CMCS @ AT-CQDs complex. As shown in FIG. 5, the emission peak of AT-CQDs is AT 443nm, while Fe3O4Emission peak position of-CMCS @ AT-CQDs AT 438nm, and Fe3O4The fluorescence emission spectra of the CMCS are symmetrically distributed before and after connection, and the half-peak width is relatively widened. From the comparison of the fluorescence intensities of the two, the complex Fe3O4The fluorescence intensity of-CMCS @ AT-CQDs is reduced slightly compared with that of pure AT-CQDs quantum dots, and the spectrum is blue-shifted by 5nm, indicating that Fe3O4the-CMCS @ AT-CQDs still have stronger fluorescence.
Performance test 4 magnetic Properties
FIG. 6 shows the measurement of Fe in sample (a) by a vibrating sample magnetometer at room temperature of 300K3O4、(b)Fe3O4CMCS with (c) Fe3O4Hysteresis loop of-CMCS @ AT-CQDs, magnetic Fe3O4The magnetic strength of the magnetic material is related to the size of the magnetic material and the surface environment. It can be seen from fig. 6 that the magnetic strength of the three samples gradually increases with the increase of the magnetic field, and finally reaches saturation, while the magnetic strength decreases with the decrease of the magnetic field, and the three samples have no remanence and hysteresis. The magnetic hysteresis loop is symmetrically distributed with the coordinate center when passing through the origin, and the distribution of the graph shows that the magnetic hysteresis loop, the magnetic hysteresis loop and the coordinate center have superparamagnetism and zero coercive force. Pure Fe3O4The saturation magnetization of the magnetic material is 79.61emu/g, and the magnetic compound Fe is modified by carboxymethyl chitosan3O4Saturation magnetization of CMCS66.91emu/g, because of pure Fe3O4Indicating that the non-magnetic substance was grafted, resulting in a decrease in saturation magnetization thereof. Then connected with carbon quantum dots, because a large amount of other nonmagnetic groups are possibly attached, the magnetic shielding effect is caused, and Fe3O4The saturation magnetization of-CMCS @ AT-CQDs was further reduced to 58.24 emu/g. The magnetic fluorescent composite microsphere still has stronger magnetic responsiveness on the whole and can play an important role in the field of biomedicine.
Example 3 vitamin B2Determination of embedding rate and drug-loading rate
Fe prepared in example 23O4the-CMCS @ AT-CQDs composite material is prepared into Fe with the concentration of 10mg/mL by using PBS solution with the pH value of 7.43O4-CMCS @ AT-CQDs solution;
accurately weighing 3mgVB2Completely dissolved in 10mL of 0.1mol/L HCl solution, and 2mL of Fe was added3O4-CMCS @ AT-CQDs solution; reacting for 2 hours in a constant temperature shaking table at 37 ℃ under the condition of keeping out of the light, thereby leading VB2Uniformly dispersing to form the magnetic fluorescent bifunctional drug-loaded microsphere.
And (3) carrying out magnetic hysteresis and centrifugal separation on the product obtained by the reaction, measuring a light absorption value of the liquid by using an ultraviolet spectrophotometer, washing the magnetic material obtained by separation by using deionized water and absolute ethyl alcohol for a plurality of times in sequence, and carrying out vacuum drying for 24 hours at the temperature of 50 ℃. And calculating the encapsulation efficiency and the drug loading rate of the microspheres according to a standard curve and a formula.
The actual dosage of the microspheres is the addition amount of the reacted traditional Chinese medicine-the mass of the traditional Chinese medicine in the filtrate;
Figure BDA0002343396420000071
the results obtained were: 3mg of vitamin B2And when Fe3O4-CMCS @ AT-CQDs is 2mL, the drug loading rate reaches 12.02 percent, and the encapsulation rate is 64.56 percent.
Measurement of VB2 Standard Curve: 0.5mg/mL VB is accurately prepared by taking 0.1mol/L HCL solution as a solvent2The solution was used as a mother solution, and 1mL, 2mL, 2.5mL, 3mL, 3.5mL, and 4mL of the mother solution were measured in a 10mL volumetric flaskSix solutions with different concentrations of 0.05mg/mL, 0.1mg/mL, 0.125mg/mL, 0.15mg/mL, 0.175mg/mL and 0.2mg/mL were prepared as standard solutions. Measuring absorbance at maximum wavelength of 444nm with ultraviolet spectrophotometer using 0.1mol/L HCl solution as blank solution, performing parallel determination for 3 times, plotting absorbance at maximum wavelength as ordinate and VB2 standard solution concentration as abscissa to obtain VB2The standard working curve with absorbance is shown in FIG. 7. To obtain VB2The linear regression equation at 0.1mol/LHCL solution is A-12.092C +0.0487 (R)2＝0.9956)。
Example 4 simulation of Release behavior in gastrointestinal fluids 3mgVB2Dissolving in 10mL of 0.1mol/L HCL solution, and transferring the above 400uL mother solution to 2mL of Fe3O4Adding 2mL of artificial gastric and intestinal juice into the-CMCS @ AT-CQD solution, reacting AT constant temperature of 37 ℃ in the dark, taking out 1mL of reaction solution every 30min, centrifuging, taking supernatant, taking 0.1mol/L of HCL solution as blank liquid, measuring absorbance under an ultraviolet spectrophotometer AT the wavelength of 444nm, and calculating VB in the reaction medium by using a standard curve of the absorbance and the mass concentration2And (3) plotting a release-time curve.
As can be seen from FIG. 8, in the simulated artificial gastric juice with pH of 1.2, the release rate of VB2 reaches 26.67 percent within 0.5 h; the release of VB2 appears in burst release until 3.0h, the release is increased to 71.79%, and the release trend is gradually gentle after 3h, which is attributed to that the acid medium in gastric juice starts to permeate into the interior through the pores of the microspheres, so that the embedded VB2 is gradually dissolved in the acid medium and is smoothly released from the pores, and the purpose of slow release is achieved. Similarly, in the simulated artificial intestinal juice with the pH value of 7.4, the slow release efficiency is not greatly different in the first 0.5h, the release rate is about 28 percent, and VB is generated within 3h along with the prolonging of the slow release time2A burst effect occurs because of VB2Is a pH responsive substance (pKa)1＝1.7，pKa210.2), VB in simulated artificial intestinal fluid at pH 7.42Has an isoelectric point of 6.0 and is negatively charged. And Fe3O4The carboxyl groups in the structure of the CMCS @ AT-CQDs synthetic substance are mostly ionized and exist in a carboxylate form,the composite material is charged with negative electricity, and has strong repulsion action of the same charge, so that the molecular chain of the synthetic material of Fe3O4-CMCS @ AT-CQDs extends to the periphery, and the carboxylate anions can be combined with water molecules in a hydrogen bond form to cause Fe3O4Swelling of-CMCS @ AT-CQDs composite microspheres with increased Fe due to repulsion between carboxylate groups3O4-size of microporous structure on CMCS @ AT-CQDs composite microsphere surface, VB2The slow release process can be completed by the flow out from the enlarged micropores and the diffusion from the inside of the synthetic substance to the medium with pH 7.4. Comparison within the same 3h, VB2The release rate in the simulated artificial intestinal fluid reaches 86.59 percent, which indicates that Fe3O4-CMCS @ AT-CQDs vs VB2The release rate of the drug entrapped in intestinal fluid is significantly higher than that in the stomach. After 3h, the release rate gradually leveled off, the initial VB2The sustained release occurs in Fe3O4Surface of the-CMCS @ AT-CQDs synthetic substance due to the reaction Medium and Fe3O4VB on the surface of the-CMCS @ AT-CQDs synthetic substance2With a certain concentration difference following VB2The concentration of vitamin B2 in the composite microspheres is gradually reduced, and VB in a release medium2The concentration is gradually increased, so that VB between the synthetic substance and the simulated intestinal fluid medium2The concentration gradient gradually decreases, resulting in VB2The slow release rate is gradually reduced, and the release curve is gradually gentle.
Comparative example 1-1, the amount of the nitrogen source diethylenetriamine added in step 1) of example 1 was changed from 0.5mL to: 0mL, 0.25mL, 0.5mL, 0.75mL, 1.0mL, the remainder being equivalent to example 1. A comparison of the results obtained is shown in FIG. 9. From FIG. 9, it is found that the fluorescence intensity is maximum at 0.5 mL.
Comparative examples 1-2, the reaction time in step 1) of example 1 was changed from 180 ℃ to 160 ℃, 170 ℃, 190 ℃, 200 ℃ respectively; the rest is equivalent to embodiment 1. A comparison of the results obtained is shown in FIG. 10. From this FIG. 10, it can be seen that the fluorescence intensity at 180 ℃ is the maximum.
Comparative examples 1 to 3, the reaction time in step 1) of example 1 was changed from 4h to 2h, 3h, 5h and 6h, respectively, and the rest was identical to example 1. A comparison of the results obtained is shown in FIG. 11. From FIG. 11, it can be seen that the fluorescence intensity was maximum at 4 h.
Comparative example 2-1, nitrogen-doped carbon quantum dot AT-CQDs solution in step 2) of example 2: fe3O4The volume ratio of the CMCS suspension was changed from 5:1 to: 1:1, 2:1, 3:1, 4:1, the remainder being identical to example 2. A comparison of the results obtained is shown in FIG. 12. From this FIG. 12, it is understood that the fluorescence intensity is maximum at a volume ratio of 5: 1.
Comparative example 2-2, the reaction time in step 2) of example 2 was changed from 37 ℃ to 25 ℃, 50 ℃ and 60 ℃, respectively; the rest is equivalent to example 2. A comparison of the results obtained is shown in FIG. 13. From FIG. 13, it can be seen that the fluorescence intensity was the maximum at 37 ℃.
Comparative examples 2-3, the reaction time in step 2) of example 2 was changed from 24h to 12h, 36h and 48h, respectively, and the rest was the same as example 2. A comparison of the results obtained is shown in FIG. 14. From FIG. 14, it can be seen that the fluorescence intensity was maximum at 24 hours.
Comparative example 3-1, the amount of the drug added in example 3 was changed from 3mg to: 1mg, 2mg, 4mg, 5mg, and the rest is the same as example 3. A comparison of the results obtained is shown in FIG. 15. From fig. 15, it can be seen that the encapsulation efficiency and the loading amount are the best when the drug is added in an amount of 3 mg.
Comparative example 3-2, example 3 Fe in step 1)3O4The addition amount of the-CMCS @ AT-CQDs solution is changed from 2mL to: 1mL, 3mL, 4mL, 5mL, and the remainder was the same as in example 3. A comparison of the results obtained is shown in FIG. 16. From FIG. 16, Fe is known3O4The encapsulation efficiency and the load capacity are optimal when the dosage of the-CMCS @ AT-CQDs solution is 2 mL.
Finally, it is also noted that the above-mentioned lists merely illustrate a few specific embodiments of the invention. It is obvious that the invention is not limited to the above embodiments, but that many variations are possible. All modifications which can be derived or suggested by a person skilled in the art from the disclosure of the present invention are to be considered within the scope of the invention.

Claims (10)

1.VB2The preparation method of the drug carrier is characterized by comprising the following steps:
1) and preparing a carbon quantum dot:
1.1) dissolving 0.5g of ascorbic acid in (15 +/-2) mL of deionized water, and then adding 0.25-1 mL of diethylenetriamine serving as a nitrogen source to be uniformly stirred;
1.2) sealing the solution obtained in the step 1.1), and carbonizing the solution at 160-200 ℃ for 2-6 h;
1.3) cooling and centrifuging the product obtained in the step 1.2), and filtering the supernatant obtained by centrifuging; dialyzing the filtrate for 10-14 h by using a dialysis bag with the interception amount of 3500Da, wherein the obtained liquid after dialysis is a nitrogen-doped carbon quantum dot AT-CQDs solution;
2) preparation of Fe3O4-CMCS：
Dissolving 0.5g of carboxymethyl chitosan in (50 +/-10) mL of deionized water to obtain solution A; 0.2g of Fe3O4Mixing with (50 +/-10) mL of deionized water, and performing ultrasonic dispersion to obtain a solution B;
uniformly mixing the solution A and the solution B, and reacting at 70 +/-10 ℃ for 2 +/-0.5 h; cooling the obtained reaction solution, performing magnetic hysteresis separation, washing the separated magnetic substance, and drying in vacuum to obtain Fe3O4-a CMCS composite;
3)、Fe3O4preparation of CMCS @ AT-CQDs composite:
mixing Fe3O4the-CMCS composite material is ultrasonically dispersed in PBS buffer solution with pH of 7.4 to prepare Fe with the concentration of 10mg/mL3O4-a CMCS suspension;
dissolving (2 +/-0.5) mg of activating agent in 1-5 mL of nitrogen-doped carbon quantum dot AT-CQDs solution, and activating AT (37 +/-5) DEG for (30 +/-5) min; 1ml of Fe was added thereto3O4Reacting the CMCS suspension at 25-60 ℃ for 12-48 h; after the reaction is finished, magnetic hysteresis separation is carried out, the magnetic substance obtained after separation is washed and then dried in vacuum, and the magnetic substance which can be used as VB is obtained2Fe of drug carrier3O4-CMCS @ AT-CQDs composite.
2. VB according to claim 12The preparation method of the drug carrier is characterized by comprising the following steps: activation in the step 3)The agent is EDC.
3. VB according to claim 22The preparation method of the drug carrier is characterized by comprising the following steps: in the step 3), the magnetic material obtained by separation is washed by deionized water and then dried in vacuum to obtain the magnetic material which can be used as VB2Fe of drug carrier3O4-CMCS @ AT-CQDs composite.
4. VB according to any one of claims 1 to 32The preparation method of the drug carrier is characterized by comprising the following steps: in the step 3), Fe is added3O4The CMCS suspension was reacted at 37 ℃ for 24 h.
5. VB according to any one of claims 1 to 32The preparation method of the drug carrier is characterized by comprising the following steps: in the step 1.3), the supernatant obtained by centrifugation is filtered through a 0.45 μm microporous membrane, thereby realizing filtration.
6. VB according to claim 52The preparation method of the drug carrier is characterized by comprising the following steps:
in the step 1.1), the dosage of the diethylenetriamine is 0.5 mL;
in the step 1.2), carbonization is carried out for 4 hours at 180 ℃.
7. VB according to any one of claims 1 to 32The preparation method of the drug carrier is characterized by comprising the following steps:
in the step 2), after the solution A and the solution B are mixed, firstly carrying out ultrasonic treatment for 3-5 min, and then oscillating the mixture in a shaking table for 0.5 +/-0.1 h, so that the solution A and the solution B are uniformly mixed.
8. VB according to any one of claims 1 to 32The preparation method of the drug carrier is characterized by comprising the following steps: in the step 2), the magnetic substance obtained by separation is washed by absolute ethyl alcohol and deionized water respectively, and then is dried in vacuum to obtain Fe3O4-CMCS composite.
9. VB prepared by the method of any one of claims 1 to 82Use of a pharmaceutical carrier characterized by: vitamin B embedding2。
10. VB according to claim 92Use of a pharmaceutical carrier characterized by:
mixing Fe3O4the-CMCS @ AT-CQDs composite material is prepared into Fe with the concentration of 10mg/mL by using PBS solution with the pH value of 7.43O4-CMCS @ AT-CQDs solution;
3mgVB2Dissolved in 10mL of 0.1mol/L HCl solution, and 2mL of Fe was added3O4-CMCS @ AT-CQDs solution; reacting for 2 hours in a constant temperature shaking table at 37 ℃ under the condition of keeping out of the light, thereby leading VB2Uniformly dispersing to form the magnetic fluorescent bifunctional drug-loaded microsphere.
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