CN115389659A - Cell membrane bonded magnetic carbon sphere composite material and preparation method and application thereof - Google Patents
Cell membrane bonded magnetic carbon sphere composite material and preparation method and application thereof Download PDFInfo
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- CN115389659A CN115389659A CN202211010609.8A CN202211010609A CN115389659A CN 115389659 A CN115389659 A CN 115389659A CN 202211010609 A CN202211010609 A CN 202211010609A CN 115389659 A CN115389659 A CN 115389659A
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- cell membrane
- magnetic carbon
- carbon sphere
- composite material
- magnetic
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Abstract
The invention belongs to the technical field of materials science and the like, and relates to a cell membrane bonded magnetic carbon sphere composite material, and a preparation method and application thereof. The composite material is prepared by activating carboxyl on the surface of a magnetic carbon sphere with a carboxyl activating reagent to obtain an activated magnetic carbon sphere, and then reacting the activated magnetic carbon sphere with a cell membrane to obtain the high-stability cell membrane bonded magnetic carbon sphere. On the basis of keeping the original easy separation of magnetic nanoparticles, the cell membrane bonded magnetic carbon sphere material provided by the invention introduces the hydrothermal carbon layer on the surface of the magnetic sphere, so that the chemical stability and the hydrophilicity of the carrier material are obviously improved, and simultaneously, the surface of the magnetic carbon sphere is subjected to carboxyl activation so that the magnetic carbon sphere material can be bonded with a cell membrane, the bonding strength of the material and the cell membrane is increased, the stability and the reusability of a cell membrane bionic material are comprehensively improved, and a new technical means is provided for the development of medicaments. The invention has important significance for safety evaluation of medicaments and discovery of new medicament lead compounds.
Description
Technical Field
The invention belongs to the technical fields of materials science, analytical chemistry, cell biology, receptor pharmacology and the like, and relates to a high-stability reusable high-stability cell membrane bonded magnetic carbon sphere bionic composite material, and a preparation method and application thereof.
Background
The clarification of the material basis of the efficacy of traditional Chinese medicine is an important content of the modernization of traditional Chinese medicine. The chemical components of the traditional Chinese medicine are very complex, most of the components are constant and small, which are obtained by separating and performing activity screening through the traditional chromatographic method, trace and trace components are not studied sufficiently, and some trace components have very strong pharmacological activity and are screened out in the research. How to rapidly identify active ingredients (particularly trace and trace ingredients) in a traditional Chinese medicine compound is an important problem to be solved urgently in the field.
The cell membrane fishing technology is a leading hot spot technology used for screening active ingredients of traditional Chinese medicines (compound). The main principle of the technology is that magnetic particles are used as a cell membrane immobilized matrix, active ingredients of the medicine are selectively extracted through the affinity between a membrane receptor and a target object, and then an acetic acid solution is used for elution, so that the rapid separation and analysis of the pharmacodynamic substances of the traditional Chinese medicine are realized (chem. Compared with the cell membrane chromatography, the cell membrane fishing technology does not need column loading and column balancing processes, and has the advantages of simplicity, convenience, rapidness and low requirement on equipment; meanwhile, the technology is used as a solid phase extraction method, and can be used for pre-enriching specific components, so that the method is more favorable for rapid separation and analysis of trace active ingredients of the traditional Chinese medicine.
The immobilized matrix used in the current cell membrane fishing technology is mainly Fe 3 O 4 Magnetic nanoparticles and their embedded composites (e.g. carbon nanotubes and graphene), however Fe 3 O 4 Insufficient chemical stability of the nanoparticles: on one hand, the membrane is easily oxidized by oxygen when exposed to air (Angew. Chem. Int. Ed.2007,46, 1222-1244) and is also easily corroded by acidic eluent (colloid. Surface. A2021, 616, 126333), so that the surface property of the membrane is changed and the magnetism of the membrane is reduced, which is quite unfavorable for the repeated use and stable analysis of the cell membrane composite material. On the other hand, at present, the magnetic matrix mainly carries cell membranes in a non-covalent bond (such as physical adsorption) mode, the interaction between the carried matrix and the cell membranes is weak, and the cell membranes are easy to fall off in the processes of extraction, elution and the like (chem.eng.j.2019, 364, 269-279), so that the stability of the cell membrane composite material is further reduced, the recycling rate is low, and the recycling effect is poor.
Disclosure of Invention
The invention aims to solve the problems in the prior art and provides a cell membrane bonded magnetic carbon sphere bionic composite material with high stability and reusability, and a preparation method and application thereof. By simple hydrothermal carbonization of Fe 3 O 4 The surface of the nano magnetic sphere is covered with a layer of hydrothermal carbon, so that the oxidation resistance, acid resistance, hydrophilicity and cell membrane combination of the magnetic sphere can be obviously improved, carboxyl with better reaction activity and cell membrane amino can be provided for amidation immobilization, the stability and reusability of the cell membrane composite material are comprehensively improved, and a new technical means is provided for the development of medicaments.
The technical scheme adopted by the invention for solving the technical problems is as follows:
the invention aims to provide a high-stability cell membrane bonded magnetic carbon sphere composite material, which is prepared by activating carboxyl on the surface of a magnetic carbon sphere by a carboxyl activating reagent to obtain an activated magnetic carbon sphere, and then reacting the activated magnetic carbon sphere with a cell membrane.
By adopting the technical scheme, a carboxyl activating reagent is adopted to activate the carboxyl on the surface of the magnetic carbon sphere, and the activated magnetic carbon sphere and free amino carried by a cell membrane are subjected to amide condensation reaction, namely the cell membrane is connected with the activated ester-based magnetic carbon sphere through a covalent bond, so that the target high-stability cell membrane bonded magnetic carbon sphere composite material is prepared; because the cell membrane and the magnetic carbon sphere in the composite material are connected through chemical bonds, the composite material has the advantages of excellent cell membrane loading and difficult falling, thereby having high stability and high recycling performance.
Preferably, the average particle size of the magnetic carbon spheres is 120-350nm, and the magnetic carbon spheres are prepared by carrying out hydrothermal reaction on magnetic spheres and glucose, wherein the magnetic spheres are Fe 3 O 4 Magnetic nanoparticles; more preferably, the mass ratio of the magnetic spheres to the glucose is 0.1-0.5; more preferably, the reaction temperature is not lower than 200 ℃ and the reaction time is not lower than 10h.
More preferably, the magnetic spheres have the particle size of 100-280nm and are Fe synthesized by carrying out solvothermal reaction on iron salt 3 O 4 Magnetic nanoparticles; more preferably, the iron salt is ferric chloride hexahydrate; more preferably, the magnetic ball is prepared by carrying out solvothermal reaction on ferric chloride hexahydrate, sodium citrate and sodium acetate by using ethylene glycol as a solvent. More preferably, the feeding mass ratio of the ferric chloride hexahydrate, the sodium citrate and the sodium acetate is 0.5-2.5; more preferably, the reaction temperature is not lower than 200 ℃ and the reaction time is not lower than 10h.
Preferably, the carboxyl activating reagent is at least one of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS), more preferably a mixture of EDC and NHS.
More preferably, the mass ratio of the magnetic carbon spheres, EDC and NHS is (1-5): (2-12): (4-24); more preferably, the activated magnetic carbon spheres are obtained by activating 10-50mg of magnetic carbon spheres with 20-120mg of EDC and 40-240mg of NHS in 0.01-0.1mol/L MES buffer.
Preferably, the ratio of the number of the cells to the number of the magnetic carbon spheres is 1 × 10 7 ～1.2×10 8 Each cell/5-50 mg magnetic carbon sphere; more preferably, the cell membrane is a cell membrane of an MC3T3-E1 cell.
Another objective of the present invention is to provide a method for preparing any one of the above cell membrane-bonded magnetic carbon sphere composite materials with high stability, comprising the following steps:
(1) Preparing magnetic spheres by a hydrothermal method, and performing hydrothermal reaction on the magnetic spheres and glucose to prepare magnetic carbon spheres;
(2) Activating the magnetic carbon spheres by a carboxyl activating reagent to obtain activated magnetic carbon spheres;
(3) The cell is broken and separated to obtain a cell membrane, and the cell membrane reacts with the activated magnetic carbon spheres to prepare the high-stability cell membrane bonded magnetic carbon sphere composite material.
Preferably, in the step (1), ferric chloride hexahydrate and sodium citrate are fully dissolved in ethylene glycol, sodium acetate is added under the conditions of heating in a water bath at 50 ℃ and stirring, and after complete dissolution, the mixture is placed into a hydrothermal reaction kettle, the reaction temperature is not lower than 200 ℃, and the reaction time is not lower than 10 hours, so that magnetic nanoparticles, namely magnetic spheres, are prepared; more preferably, the resulting material is washed several times with water and ethanol.
Preferably, in the step (1), the magnetic spheres are dispersed in ultrapure water, glucose is added, mechanical stirring is carried out until glucose particles are completely dissolved, the solution is placed into a hydrothermal reaction kettle, the reaction temperature is not lower than 200 ℃, the time is not lower than 10 hours, the magnetic carbon spheres are prepared, and more preferably, the prepared material is washed by water and ethanol for a plurality of times.
Preferably, in the step (2), the magnetic carbon spheres are dispersed in MES buffer, and EDC and NHS are added to activate the carboxyl groups, so as to prepare activated magnetic carbon spheres after the carboxyl groups are activated.
Preferably, in the step (3), the cells are cultured and collected, fully dispersed in the PBS solution, placed in an ultrasonic cell disruptor, disrupted under ice-water bath conditions of 585W, 2S for working, 5S for 15min, and separated by differential centrifugation to obtain cell membranes. More preferably, the cell is an MC3T3-E1 cell.
Preferably, in the step (3), the cell membrane is fully dispersed in the PBS solution to obtain a cell membrane suspension, the activated magnetic carbon spheres are resuspended in the cell membrane suspension, the ultrasonic treatment is performed, the shaking table is slowly shaken for not less than 12 hours, the magnet is separated, and the PBS buffer solution is rinsed for several times to obtain the high-stability cell membrane bonded magnetic carbon sphere composite material. More preferably, the temperature of the shaker is about 4 ℃.
The invention also aims to provide an application of any one of the high-stability cell membrane bonded magnetic carbon sphere composite materials, and the high-stability cell membrane bonded magnetic carbon sphere composite material is applied to the detection, screening or extraction technology of various active substances (such as flavonoids, terpenes, glycosides, lignins and the like) of natural products of traditional Chinese medicines, traditional Chinese medicine compounds and the like as a solid phase extraction material, and is more preferably used as a solid phase extraction material in a cell membrane fishing technology.
Furthermore, when the composition is used for screening the anti-osteoporosis and potential anti-osteoporosis components of the medicine, the anti-osteoporosis and potential anti-osteoporosis components can be specifically combined with the MC3T3-E1 cell membrane protein, so that the composition can be used for screening the anti-osteoporosis and potential anti-osteoporosis components of the medicine, and has important significance for the screening of the lead medicine.
The invention also aims to provide a method for screening the effective components of the traditional Chinese medicine, which comprises the following steps:
1) Adding the above high-stability cell membrane bonded magnetic carbon sphere composite material into the Chinese medicinal extractive solution, oscillating in water bath at 37 deg.C for 5-60min, separating the material with magnet, and washing with ultrapure water;
2) And eluting the composite material and the combined substances thereof by using an eluent, and analyzing the substances after the solvent is removed from the eluent to screen the effective component groups.
Preferably, the traditional Chinese medicine is a compound traditional Chinese medicine, and more preferably is a three-seed pill. More preferably, the adding amount of the composite material in the step 1) is 2-20mg of the composite material per 1mL of the traditional Chinese medicine extracting solution; more preferably, the eluent in the step 2) is 1% -20% acetic acid solution; more preferably, the analysis method in step 2) is to re-dissolve the substance in methanol, filter the substance through a 0.22 μm filter membrane, and inject the substance into an analysis instrument for analysis.
Compared with the prior art, the invention has the beneficial effects that: the existing magnetic cell membrane carrier material has poor stability, is easily oxidized by air after being placed for a long time, is easily corroded in acidic eluent, and has weak binding capacity with cell membranes, so that the magnetic carrier-cell membrane composite material has poor stability and is difficult to be repeatedly used for many times, and the practical application of the cell membrane fishing technology is not facilitated. The high-stability magnetic carbon sphere bionic material provided by the invention is prepared by wrapping magnetic particles with hydrothermal carbon with active ester groups on the surface, so that the cell membrane bonded magnetic carbon sphere material provided by the invention is characterized in that on the basis of keeping the original easy separation of magnetic nanoparticles, a hydrothermal carbon layer is introduced on the surface of a magnetic sphere, the chemical stability and the hydrophilicity of a carrier material are obviously improved, the bonding strength of the material and a cell membrane is increased, the stability and the reusability of the cell membrane bionic material are comprehensively improved, and a new technical means is provided for the development of medicaments. The invention has important significance for safety evaluation of medicaments and discovery of new medicament lead compounds.
Drawings
FIG. 1 is a schematic diagram of a process for preparing a cell membrane-bonded magnetic carbon sphere biomimetic material according to the present invention;
FIG. 2Fe 3 O 4 A graph comparing the magnetic response time of Magnetic Spheres (MNs) and Magnetic Carbon Spheres (MHCNs) with the change of the standing time;
FIG. 3 is a graph comparing water dispersibility of MNs and MHCNs as a function of time;
figure 4 acid resistance test (pH = 1) comparison graph of MNs and MHCNs;
FIG. 5 scanning electron micrographs of MNs (a), MHCNs (b) and cell membrane-bonded magnetic carbon spheres (CM-MHCNs) (c);
FIG. 6 infrared spectra of MNs, MHCNs and CM-MHCNs;
FIG. 7 is a graph comparing the stability of the amount of cell membrane-bound CM/MNs, CM/MHCNs and CM-MHCNs with time;
FIG. 8 is a graph comparing the binding amount of cnidiadin by CM/MNs, CM/MHCNs and CM-MHCNs with the number of uses;
FIG. 9 chromatogram of the original liquid of SANZIWAN Chinese medicinal composition (A) and the extract of CM-MHCNs (B).
Detailed Description
The technical solution of the present invention is further specifically described below by using specific embodiments and with reference to the accompanying drawings.
The invention provides a high-stability cell membrane bonded magnetic carbon sphere material and a preparation method thereof. The magnetic carbon spheres are prepared and activated through hydrothermal reaction of magnetic particles and glucose, cell membranes are prepared from cells which grow adherently and meet technical requirements through digestion, crushing and differential centrifugation, the activated magnetic carbon spheres and the cell membranes are fully mixed, and the cell membranes are wrapped on the surfaces of the magnetic carbon spheres by utilizing covalent connection of activated groups carried by the magnetic carbon spheres and free groups of the cell membranes, so that the cell membrane bonded magnetic carbon sphere composite material with high stability and recycling is obtained. The cell membrane bonded magnetic carbon sphere can obviously prolong the service life of the material, provides a new technical means for drug development, and has important significance.
The preparation method of the cell membrane bonded magnetic carbon sphere composite material comprises the following operations:
1) Preparation of magnetic carbon spheres
Ultrasonically dissolving ferric chloride hexahydrate and sodium citrate in ethylene glycol, adding sodium acetate, magnetically stirring until the sodium chloride and the sodium citrate are completely dissolved, and carrying out hydrothermal reaction for 10 hours at the temperature of 200 ℃ to obtain the magnetic nanoparticles. The obtained magnetic nanoparticles were washed several times with ultrapure water and absolute ethanol, and finally dispersed in ultrapure water. And (3) adding anhydrous glucose into the magnetic nanoparticle suspension, mechanically stirring to completely dissolve the glucose, performing hydrothermal reaction at 200 ℃ for 10 hours to obtain magnetic carbon spheres, removing the carbon spheres which are not wrapped with the magnetic nanoparticles by using a gravity settling method, washing for a plurality of times by using ultrapure water and absolute ethyl alcohol, and drying. Preferably, the feeding mass ratio of the ferric chloride hexahydrate, the sodium citrate and the sodium acetate is 0.5-2.5; the mass ratio of the magnetic ball to the glucose is 0.1-0.5.
The preparation method of the magnetic carbon sphere is one embodiment of the source of the magnetic carbon sphere of the present invention, but is not limited to the magnetic carbon sphere obtained by the preparation method of the present invention, and the magnetic carbon sphere having characteristics similar to those of the magnetic carbon sphere of the present invention (i.e., the surface has functional groups such as carboxyl groups for activation) can be used as the magnetic carbon sphere of the present invention.
2) Activation of magnetic carbon spheres
Dispersing magnetic carbon spheres in MES buffer solution, adding EDC and NHS, performing ultrasonic treatment, and oscillating in a 37 ℃ water bath constant temperature shaking table. Preferably, the mass ratio of the magnetic carbon spheres, EDC and NHS is (1-5): (2-12): (4-24); the MES buffer solution is 0.01-0.1mol/L MES buffer solution.
3) Preparation of cell membranes
Cells were cultured with a cell count of about 6X 10 7 Removing culture medium, washing with PBS several times, digesting with 0.25% pancreatin, centrifuging at 4 deg.C, collecting cells, resuspending with PBS to a concentration of about 3-12 × 10 7 The volume is/mL. Placing in a cell ultrasonication instrument, crushing the cells, working for 2S under the condition of 585W in ice-water bath, stopping for 5S, and standing for 15min, crushing, centrifuging at the rotation speed of 1000 Xg and the temperature of 4 ℃ for 10-15min, taking supernatant, centrifuging at the temperature of 15000 Xg and the temperature of 4 ℃ for 10-20min, wherein the precipitate is cell membrane, and suspending in PBS.
4) Preparation of cell membrane bonded magnetic carbon spheres
And (3) resuspending the activated magnetic carbon spheres in a cell membrane suspension, performing ultrasound for 10min, slowly oscillating for 12h in a shaker at 4 ℃, and fully wrapping the cell membrane and the magnetic carbon spheres by using the magnetic carbon sphere activated ester group to be connected with amino covalent bonds carried by cell membrane protein.
The high-stability cell membrane bonded magnetic carbon sphere composite material is prepared by the preparation method, has high stability and high recycling property, and can be recycled. Meanwhile, the invention also provides an application method of applying the high-stability cell membrane bonded magnetic carbon sphere composite material as a solid phase extraction material to medicine extraction, and the application method has great significance for research and development in the field of medicines, treatment in the field of diseases and the like.
The present invention will be described in further detail with reference to specific examples, but it should be understood that the described examples are only a part of the examples of the present invention, and not all of the examples. The description is illustrative of the invention and is not to be construed as limiting.
Example 1
Osteoporosis is a systemic bone disease in which bone density and bone quality are reduced due to various causes, bone microstructures are destroyed, bone brittleness is increased, and thus fracture is likely to occur. The underlying cause of this disease is usually due to the fact that osteoclastic bone resorption is greater than osteoblastic bone formation. The MC3T3-E1 cell membrane bonded magnetic carbon sphere material prepared by the invention can stably and efficiently screen effective components acting on MC3T3-E1 cells in the medicine, and has important significance for treating osteoporosis.
The preparation of the MC3T3-E1 cell membrane bonded magnetic carbon spheres and the application thereof in screening anti-osteoporosis effective components of the three-pill in the embodiment comprise the following operations:
1) Preparation of magnetic carbon spheres
Weighing 1.8g ferric chloride hexahydrate and 0.36g sodium citrate, ultrasonically dissolving in 50ml ethylene glycol, adding 2.4g sodium acetate at 50 deg.C, magnetically stirring for 30min, completely dissolving, and performing hydrothermal reaction at 200 deg.C for 10h to obtain 0.51g magnetic nanoparticles (magnetic spheres, see figure 5 a) with particle size of 189 nm. The obtained magnetic nanoparticles were washed with ultrapure water and absolute ethanol three times each, and finally dispersed in 20ml of ultrapure water. And (3) adding 1.8g of anhydrous glucose into the 10ml of magnetic nanoparticle suspension, mechanically stirring for 30min to completely dissolve the glucose, carrying out hydrothermal reaction at 200 ℃ for 10h to obtain magnetic carbon spheres, removing the carbon spheres without wrapping the magnetic particles by using a gravity settling method, washing the carbon spheres with ultrapure water and absolute ethyl alcohol for three times, and drying to obtain 0.63g of magnetic carbon spheres with the average particle size of 195nm (see figure 5 b). It can be observed by SEM that the surface roughness of the magnetic carbon spheres is significantly greater than that of the magnetic spheres. The appearance of Fe on the surface of the magnetic carbon sphere can be observed by the infrared spectrum of FIG. 6 3 O 4 C = O (1702 cm) not present in magnetic sphere -1 Absorption peak) and C-O group (1330 cm) -1 Absorption peak) indicating that the magnetic sphere produces a hydrothermal carbon layer on the surface after reacting with glucose. These surface groups (such as carboxyl, etc.) lay the foundation for subsequent activation and covalent bonding modification of cell membranes.
Respectively taking 5mg of prepared Fe3O4 magnetic spheres (magnetic nanoparticles) and magnetic carbon spheres, performing ultrasonic treatment for 30min to respectively disperse the magnetic spheres and the magnetic carbon spheres in 10mL of deionized water to prepare 0.5mg/mL of magnetic sphere suspension and magnetic carbon sphere suspension, standing in air at 4 ℃, and finding that after standing for 5 days and 10 days, the magnetic response time of the magnetic carbon spheres is not obviously changed, and the magnetic response time of the magnetic spheres is obviously increased from 14s to 27s and 38s, which indicates that the magnetism of the magnetic spheres is obviously reduced (see figure 2).
By repeating the above operation and observing the sedimentation of the suspension after 14h and 48h (see fig. 3), the sedimentation velocity of the magnetic carbon spheres is obviously lower than that of the magnetic spheres, and the magnetic carbon spheres have better dispersibility, which indicates stronger hydrophilicity.
Then, respectively taking 10mL of a suspension of 0.5mg/mL magnetic spheres and a suspension of magnetic carbon spheres, adjusting the pH =1 of the solution, standing for 3 days to find that the magnetic response time of the magnetic carbon spheres is not obviously changed, the solution is clear, the magnetic spheres cannot be completely separated, keeping the magnetic field for 5min, still dispersing particles in the solution, and the solution is brown (see figure 4), which indicates that the magnetic carbon spheres can resist strong acid corrosion and the magnetic spheres cannot. The test result shows that compared with the magnetic spheres, the magnetic carbon spheres have better magnetic stability, hydrophilicity (water dispersibility) and acid resistance, and are suitable for further preparing the stable bionic composite material.
2) Activation of magnetic carbon spheres
The dried 20mg magnetic carbon spheres were dispersed in 20mL 0.1M MES buffer, 80mg EDC,120mg NHS, ultrasonic 15s, shaking in 37 ℃ water bath constant temperature shaker for 15min, washed three times with ultrapure water, and the product was dispersed in 3mL PBS.
3) Preparation of cell membranes
The invention selects MC3T3-E1 cells to prepare MC3T3-E1 cell membrane bonded magnetic carbon spheres. MC3T3-E1 cells were taken and counted at 6X 10 7 At one time, the culture medium is removed, PBS is rinsed for 3 times, 0.25% pancreatin is added to digest the adherently growing MC3T3-E1 cells, the cells are collected by centrifugation for 5min at 1000rpm/min at 4 ℃, and 2mL PBS is used for resuspension. Placing in a cell ultrasonic disruptor to disrupt MC3T3-E1 cells, centrifuging at 1000 Xg rotation speed and 4 ℃ for 10min, taking supernatant, centrifuging at 15000 Xg 4 ℃ for 10min to obtain precipitate which is MC3T3-E1 cell membrane, and suspending in 3mL PBS.
4) Preparation of cell membrane bonded magnetic carbon sphere
Mixing the activated magnetic carbon sphere suspension obtained in the step 2) with the cell membrane suspension obtained in the step 3), ultrasonically dispersing for 10min, and standing overnight in a shaking table at 4 ℃, wherein the standing overnight time is 12h generallyAnd carrying out chemical bond connection on the cell membrane by using the magnetic carbon sphere activating group to ensure that the cell membrane is fully bonded with the magnetic carbon sphere, so that the cell membrane is stably wrapped on the magnetic carbon sphere to obtain the target high-stability cell membrane bonded magnetic carbon sphere composite material. The SEM image of the obtained composite material is shown in figure 5c, the average particle size is 199nm, the surface roughness is obviously reduced compared with that of the magnetic spheres and the magnetic carbon spheres, and the surface is smooth. With the combination of figure 6, compared with magnetic carbon sphere MHCNs, the infrared absorption peaks of C-H and C-O groups on the surface of the composite material CM-MHCNs are obviously enhanced, the absorption peak of Fe-O groups is obviously reduced, and ester groups (1743 CM) are newly appeared -1 ) Absorption peak. These results indicate that the cell membrane has been successfully bonded to the surface of the magnetic carbon sphere.
5) Screening target components in Chinese medicinal extractive solution by using high-stability cell membrane bonded magnetic carbon sphere composite material
Incubating the high-stability cell membrane bonded magnetic carbon sphere composite material prepared in the step 4) in 10mL of three-seed pill extracting solution at constant temperature of 37 ℃, and oscillating and incubating for 15min. Magnet separation, and elution with 15% acetic acid eluent for 5 times, each time for 2min. Mixing eluates, rotary evaporating, redissolving in 0.5mL methanol, filtering with 0.22 μm filter membrane, injecting into analytical instrument, and screening effective constituent group;
wherein, the preparation of the three-seed pill extracting solution comprises the following steps: 5g of each of the three traditional Chinese medicines of the dodder, the schisandra chinensis and the fructus cnidii are taken, 100ml of 90 percent ethanol is condensed and refluxed for 2h at the temperature of 85 ℃ for twice, the two filtrates are combined, and the mixture is rotationally steamed and redissolved in 10ml of ultrapure water.
Chromatographic conditions are as follows:
liquid phase, waters ACQUITY UPLC H-CLASS ultra-performance liquid chromatography
Mobile phase: a:0.1% formic acid, B acetonitrile
Flow rate: 0.2mL/min
And (3) chromatographic column: ACQUITY UPLC
BEHC18 1.7μm
Sample preparation: a: specifically binding MC3T3-E1 cell membrane bonded magnetic carbon spheres with the extract of the three-seed pill, and eluting the components; b: sanzi Wan extract
Column temperature: 35 deg.C
Detection wavelength: 270nm
The detection results are shown in fig. 9: the MC3T3-E1 cell membrane bonded magnetic carbon sphere material prepared by the invention is totally separated and identified from the three-seed pill extracting solution (sample A) into 19 types, wherein the representative components of the 19 types are 13 types, and the separation and identification effects of the three-seed pill extracting solution (sample B) are obviously higher.
Screening results
The MC3T3-E1 cell membrane bonded magnetic carbon sphere material prepared by the invention is characterized in that 13 representative components are screened from a three-seed pill extracting solution, and are hyperin R1, beta-sitosterol R2, quercetin R3, kaempferol R4, bergapten R5, imperatorin R6, apigenin R7, diosmetin R8, imperatorin R9, cnidium lactone R10, schisandrin R11, schizandrin A R12 and schisandrin B R13 respectively through ultra-performance liquid chromatography analysis and mass spectrometry identification. The 13 components have been reported to have anti-osteoporosis effect.
Test example 1
To test the stability of the cell Membrane-bonded magnetic carbon sphere composites (CM-MHCNs), fe was prepared 3 O 4 Magnetic beads adsorbing cell membrane composites (CM/MNs) and magnetic carbon beads adsorbing cell membrane composites (CM/MHCNs) were used for comparison. CM/MNs preparation and related parameters example steps 1), 3) and 4) were followed, except that step 4) "activated magnetic carbon spheres" was replaced by "Fe 3 O 4 A magnetic ball ". CM/MHCNs preparation and related parameters were as in example steps 1), 3) and 4), except that step 4) "activated magnetic carbon spheres" was replaced with "magnetic carbon spheres". The three composites were then left to stand in 5mL PBS at 4 deg.C, and the relative content (mg/g) of the remaining protein on the composites was determined by a protein assay kit as a function of the number of days of standing, with the results shown in FIG. 7. The amount of membrane protein (cell membrane) immobilized by CM-MHCNs is obviously higher than that of CM/MNs and CM/MHCNs, and does not change greatly with time, after 6 days, 80.6% of initial protein amount still remains, and the membrane protein immobilization amount of CM/MNs and CM/MHCNs is greatly reduced with time, after 6 days, it is only equal to 42.3% and 19.7% of initial value, and it shows that the cell membrane prepared by said inventionThe bonded magnetic carbon sphere composite material has excellent stability.
Test example 2
Reusability of CM-MHCNs was examined with osthole as a positive drug. The CM-MHCNs prepared in example one were divided into 7 parts on average, incubated in 10mL of 80mg/L osthole solution at a constant temperature of 37 ℃ and incubated for 15min with shaking. Magnet separation, 8% acetic acid eluent elution 3 times, each time for 2min. Mixing eluates, rotary evaporating, redissolving in 0.5mL methanol, filtering with 0.22 μm filter membrane, injecting into analytical instrument, and analyzing the obtained osthole amount. Samples 1, 2, 3, 4, 5, 6 and 7 were subjected to the above experimental procedures for 1, 2, 3, 4, 5, 6 and 7 times, respectively, and then the binding amount of osthole in the samples 1 to 7 times was measured by high performance liquid chromatography. The above procedure was repeated while dividing the CM/MNs and CM/MHCNs prepared in test example 1 into 7 portions as controls, respectively, to obtain the amount of osthole-binding of the three composites as a function of the number of repetitions (see FIG. 8). The result shows that the osthole binding capacity of the CM-MHCNs is obviously higher than that of the CM/MNs and the CM/MHCNs, and 82.6 percent of the initial binding capacity is still kept after 7 times of repeated use, and at the moment, the CM/MNs and the CM/MHCNs only correspond to 35.5 percent and 16.8 percent of the initial binding capacity, which indicates that the cell membrane bonded magnetic carbon spheres obtained by the invention have excellent reusability and further have excellent stability.
The results show that the MC3T3-E1 cell membrane bonded magnetic carbon spheres prepared by the method can identify the anti-osteoporosis component in the three-seed pill extracting solution, and have the advantages of long service life, good stability and reusability.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and all simple modifications, changes and equivalent structural changes made in the above embodiments according to the technical spirit of the present invention still fall within the protection scope of the technical solution of the present invention.
Claims (10)
1. The cell membrane bonded magnetic carbon sphere composite material is characterized in that the composite material is an activated magnetic carbon sphere obtained by activating carboxyl on the surface of a magnetic carbon sphere by a carboxyl activating reagent, and then the activated magnetic carbon sphere is combined with a cell membrane to obtain the cell membrane bonded magnetic carbon sphere composite material.
2. The cell membrane-bonded magnetic carbon sphere composite material of claim 1, wherein the magnetic carbon sphere is prepared by hydrothermal reaction of a magnetic sphere and glucose.
3. The cell membrane-bonded magnetic carbon sphere composite material of claim 2, wherein the magnetic sphere is synthesized from iron salt through a solvothermal reaction.
4. The cell membrane-bonded magnetic carbon sphere composite material of claim 1, wherein the carboxyl activating reagent is at least one of EDC and NHS.
5. The cell membrane-bonded magnetic carbon sphere composite material of claim 4, wherein the mass ratio of the magnetic carbon sphere, EDC and NHS is (1-5): (2-12): (4-24).
6. The cell membrane-bonded magnetic carbon sphere composite material of claim 1, wherein the ratio of the number of cells to the number of magnetic carbon spheres is 1 x 10 7 ～1.2×10 8 Each cell/5-50 mg magnetic carbon sphere.
7. The cell membrane-bonded magnetic carbon sphere composite material of claim 1, wherein the cell membrane is an MC3T3-E1 cell membrane.
8. A method for preparing the cell membrane bonded magnetic carbon sphere composite material according to any one of claims 1 to 7, which comprises the following steps:
(1) Preparing magnetic spheres by a solvothermal method, and performing hydrothermal reaction on the magnetic spheres and glucose to prepare magnetic carbon spheres;
(2) Activating the magnetic carbon spheres by a carboxyl activating reagent to obtain activated magnetic carbon spheres;
(3) The cell membrane is obtained by breaking and separating the cell, and the cell membrane reacts with the activated magnetic carbon sphere to prepare the cell membrane bonded magnetic carbon sphere composite material.
9. Use of a cell membrane-bonded magnetic carbon sphere composite material according to any one of claims 1 to 7 as a solid phase extraction material.
10. The use of claim 9, wherein the screening method for the effective components of a Chinese medicine comprises the following steps:
1) Adding the traditional Chinese medicine extract into the cell membrane bonded magnetic carbon sphere composite material, carrying out constant temperature oscillation in water bath at 37 ℃ for 5-60min, separating the composite material, and washing with ultrapure water;
2) And eluting the composite material and the combined substances thereof by using an eluent, and analyzing the substances after the solvent is removed from the eluent to screen the effective component groups.
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