Multilayered heteropolymer microspheres and methods of making and using the same
The method for preparing multilayer heterogeneous polymer microspheres in one step solves the problems of complex synthesis and high cost in existing technologies, and realizes the simple and rapid preparation and regioselective adsorption of multilayer polymer microspheres, which are suitable for bioseparation detection and disease monitoring.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2026-01-04
- Publication Date
- 2026-03-24
AI Technical Summary
Existing methods for synthesizing multilayer polymer microspheres are complex and costly, making it difficult to achieve efficient and low-cost preparation, and their application in the preparation of magnetic beads is limited.
Multilayer heterogeneous polymer microspheres were prepared using a one-step method. The hydrophobic polymer microspheres were mixed with a surfactant solution, and hydrophilic monomers, hydrophobic monomers, crosslinking agents and magnetic nanoparticles were added to induce swelling and crosslinking polymerization, forming microspheres with more than three heterogeneous layers. The degree of phase separation was controlled to manage the differences in layers and polarity.
A simple and rapid preparation of multilayer heteropolymer microspheres has been achieved, which can selectively adsorb different dyes in a regional manner. They are suitable for biological separation and detection and disease monitoring, and have broad prospects for industrial application.
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Figure CN121449817B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of polymer microspheres, specifically relating to a multilayer heterogeneous polymer microsphere, its preparation method, and its application. Background Technology
[0002] Multilayer polymer microspheres are promising functional materials that, due to their inherent differences in physicochemical environments, can achieve phased drug release, tumor detection, imaging, and sensing. Currently, multilayer polymer microspheres can be synthesized using template-based or template-free methods. For example, using polystyrene particles as templates, silica / polydiallyldimethylammonium chloride hybrid multilayer polymer microspheres can be synthesized through layer-by-layer stacking, and triblock copolymers poly(ethylene oxide)-b-poly(4-vinylpyridine)-b-polystyrene can be self-assembled into trilayer nanospheres. However, these methods neglect the regulation of phase behavior between polymers and typically require multiple reaction steps, resulting in complex operations and high costs. Furthermore, magnetic beads obtained by magnetically functionalizing polymer microspheres are important bioseparation materials with significant applications in respiratory diseases and cancer detection, and multilayer polymer microspheres show great promise in magnetic bead preparation. Therefore, there is an urgent need to develop a one-step synthesis method for multilayer polymer microspheres to achieve efficient and low-cost synthesis. Summary of the Invention
[0003] To address the technical problems existing in the prior art, the first objective of this invention is to provide a method for preparing multilayer heterogeneous polymer microspheres.
[0004] The second objective of this invention is to provide a multilayer heterogeneous polymer microsphere.
[0005] A third objective of this invention is to provide an application of the multilayer heterogeneous polymer microspheres described above in the selective adsorption of dye regions and the preparation of bio-separation and detection products.
[0006] To achieve the first objective mentioned above, the present invention adopts the following technical solution:
[0007] This invention discloses a method for preparing multilayer heterogeneous polymer microspheres, comprising the following steps:
[0008] Hydrophobic polymer microspheres were dispersed in a surfactant solution and mixed with a first oil-in-water emulsion for a single swelling process to obtain a mixture.
[0009] A second oil-in-water emulsion comprising a hydrophilic monomer, a first hydrophobic monomer, a second hydrophobic monomer, a crosslinking agent, an initiator, and optionally geomagnetic nanoparticles is added to the mixture for secondary swelling.
[0010] Crosslinking polymerization was carried out under an inert atmosphere. After the reaction was completed, the mixture was centrifuged and washed to obtain multilayer heterogeneous polymer microspheres with more than three layers of heterostructure.
[0011] It should be noted that the addition of magnetic nanoparticles is arbitrary. Technicians can choose to add them or not according to the application requirements. When no magnetic nanoparticles are added, the prepared multilayer heteropolymer microspheres are not magnetic, and vice versa.
[0012] The hydrophilic monomer is selected from one or more of 4-vinylbenzoic acid, acrylic acid, 4-vinylphenylboronic acid, and N,N,N-trimethylvinylbenzoic acid ammonium chloride;
[0013] The first hydrophobic monomer is styrene;
[0014] The second hydrophobic monomer is selected from one or more of the following: methyl methacrylate, ethyl methacrylate, propyl methacrylate, n-butyl methacrylate, isobutyl methacrylate, tert-butyl methacrylate, n-hexyl methacrylate, 2-ethylhexyl methacrylate, phenyl methacrylate, benzyl methacrylate, 2,2,2-trifluoroethyl methacrylate, 2,2,3,3,3-pentafluoropropyl methacrylate, 2,2,3,3,4,4,4-heptafluorobutyl methacrylate, methyl acrylate, ethyl acrylate, n-butyl acrylate, isobutyl acrylate, tert-butyl acrylate, and n-hexyl acrylate.
[0015] In the preparation method of this invention, a block copolymer or gradient copolymer is formed during polymerization through polymerization-induced phase separation. The polymer segments are rearranged to form multilayer heterogeneous polymer microspheres. By changing the type and amount of the second hydrophobic monomer, the degree of phase separation between polymers is controlled. When the degree of phase separation is low, a three-layer structure (hydrophobic core-intermediate layer-hydrophilic layer) is formed, where the intermediate layer is the region containing the second hydrophobic monomer. When the compatibility is high, a structure with more than three layers is formed (e.g., hydrophobic core-transition layer-intermediate layer-hydrophilic layer, hydrophobic core-intermediate layer-transition layer-hydrophilic layer, or hydrophobic core-transition layer-intermediate layer-transition layer-hydrophilic layer, etc.). Unlike the intermediate layer, the transition layer is a mixed region formed by different monomer combinations, containing not only the second hydrophobic monomer but also a hydrophilic monomer or the first hydrophobic monomer. The position of the transition layer (between the intermediate layer and the hydrophilic layer or between the intermediate layer and the hydrophobic layer) is determined by the different components. The hydrophobic core possesses strong hydrophobicity and low polarity, enabling it to adsorb low-polarity oil-soluble dyes. The intermediate and transition layers exhibit weak hydrophobicity and high polarity, allowing them to adsorb strongly polar oil-soluble dyes. The hydrophilic layer, on the outermost layer, adsorbs water-soluble dyes. Furthermore, by endowing the multilayer heteropolymer microspheres with magnetism, they hold promise for wide applications in the field of biomolecular separation and detection, such as respiratory disease monitoring and cancer screening.
[0016] Furthermore, the volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:0.1-5, preferably 1:0.25-2.25; for example, the volume ratio of the first hydrophobic monomer to the second hydrophobic monomer can be 1:0.25, 1:0.5, 1:0.75, 1:1, 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.25, etc. Research has found that by adjusting the type and amount of the first and second hydrophobic monomers, the number of heterogeneous layers in the multilayer heteropolymer microspheres can be precisely controlled, providing conditions for subsequent applications of regioselective adsorption.
[0017] The following provides examples of some combinations of the first and second hydrophobic monomers that were tried during the research process.
[0018] Furthermore, the first hydrophobic monomer and the second hydrophobic monomer are selected from a combination of one of the following to obtain polymer microspheres with a three-layer heterostructure:
[0019] 1) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from methyl methacrylate, and the volume ratio of the first hydrophobic monomer and the second hydrophobic monomer is 1:0.25-1.25; for example, 1:0.25, 1:0.5, 1:0.75, 1:1, 1:1.25, etc.
[0020] 2) The first hydrophobic monomer is styrene, and the second hydrophobic monomer is selected from ethyl methacrylate. The volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:0.25-1.75; for example, 1:0.25, 1:0.5, 1:0.75, 1:1, 1:1.25, 1:1.5, 1:1.75, etc.
[0021] 3) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from propyl methacrylate, and the volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:0.25-0.5; for example, 1:0.25, 1:0.5, etc.
[0022] 4) The first hydrophobic monomer is styrene, and the second hydrophobic monomer is selected from n-hexyl methacrylate and / or 2-ethylhexyl methacrylate. The volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:0.25-2.25; for example, 1:0.25, 1:0.5, 1:0.75, 1:1, 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.25, etc.
[0023] 5) The first hydrophobic monomer is styrene, and the second hydrophobic monomer is selected from phenyl methacrylate and / or benzyl methacrylate, and the volume ratio of the first hydrophobic monomer and the second hydrophobic monomer is 1:0.25.
[0024] Furthermore, the first hydrophobic monomer and the second hydrophobic monomer are selected from one of the following combinations to obtain polymer microspheres with a four-layer heterostructure:
[0025] 1) The first hydrophobic monomer is styrene, and the second hydrophobic monomer is selected from ethyl methacrylate. The volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:2-2.25; for example, 1:2, 1:2.25, etc.
[0026] 2) The first hydrophobic monomer is styrene, and the second hydrophobic monomer is selected from propyl methacrylate. The volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:0.75-1.5; for example, 1:0.75, 1:1, 1:1.25, 1:1.5, etc.
[0027] 3) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from n-butyl methacrylate, and the volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:0.25-1.75; for example, 1:0.25, 1:0.5, 1:0.75, 1:1, 1:1.25, 1:1.5, 1:1.75, etc.
[0028] 4) The first hydrophobic monomer is styrene, and the second hydrophobic monomer is selected from phenyl methacrylate. The volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:0.5-2.25; for example, 1:0.5, 1:0.75, 1:1, 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.25, etc.
[0029] 5) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from benzyl methacrylate, and the volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:0.5;
[0030] 6) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from tert-butyl methacrylate, and the volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:0.75-2.25.
[0031] Furthermore, the first and second hydrophobic monomers are selected from one of the following combinations to obtain polymer microspheres with a 5-layer heterostructure:
[0032] 1) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from propyl methacrylate, and the volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:1.75-2.25; for example, 1:1.75, 1:2, 1:2.25, etc.
[0033] 2) The first hydrophobic monomer is styrene, and the second hydrophobic monomer is selected from n-butyl methacrylate. The volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:2-2.25; for example, 1:2, 1:2.25, etc.
[0034] 3) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from benzyl methacrylate, and the volume ratio of the first hydrophobic monomer and the second hydrophobic monomer is 1:0.75-1.5; for example, 1:0.75, 1:1, 1:1.25, 1:1.5, etc.
[0035] Furthermore, the mass-to-volume ratio of the hydrophilic monomer to the first hydrophobic monomer is 100-1000 mg:1 ml; for example, the mass-to-volume ratio of the hydrophilic monomer to the first hydrophobic monomer can be 100 mg:1 ml, 200 mg:1 ml, 300 mg:1 ml, 400 mg:1 ml, 500 mg:1 ml, 600 mg:1 ml, 700 mg:1 ml, 800 mg:1 ml, 900 mg:1 ml, 1000 mg:1 ml, etc.
[0036] Furthermore, the mass-to-volume ratio of the hydrophobic polymer microspheres to the first hydrophobic monomer is 50-200 mg:1 ml; exemplaryly, the mass-to-volume ratio of the hydrophobic polymer microspheres to the first monomer can be 50 mg:1 ml, 60 mg:1 ml, 70 mg:1 ml, 80 mg:1 ml, 90 mg:1 ml, 100 mg:1 ml, 120 mg:1 ml, 140 mg:1 ml, 160 mg:1 ml, 180 mg:1 ml, 200 mg:1 ml, etc.
[0037] Furthermore, the mass-to-volume ratio of the hydrophobic polymer microspheres to the second hydrophobic monomer is 100mg:0.25-2.25ml; exemplaryly, the mass-to-volume ratio of the hydrophobic polymer microspheres to the second hydrophobic monomer can be 100mg:0.25ml, 100mg:0.5ml, 100mg:0.75ml, 100mg:1ml, 100mg:1.25ml, 100mg:1.5ml, 100mg:1.75ml, 100mg:2ml, 100mg:2.25ml, etc.
[0038] Furthermore, in the first oil-in-water emulsion, the aqueous phase is a surfactant solution, and the oil phase is an organic solvent, with a volume ratio of 1-30 mL:50 μL. Exemplarily, the volume ratio can be 1 ml:50 μl, 2 ml:50 μl, 5 ml:50 μl, 10 ml:50 μl, 15 ml:50 μl, 20 ml:50 μl, 25 ml:50 μl, 30 ml:50 μl, etc. It should be noted that the surfactant derived from the aqueous phase of the first oil-in-water emulsion and the surfactant solution used to disperse the hydrophobic polymer microspheres can be formulated using the same surfactant, or different surfactants of the same type, such as both anionic or nonionic surfactants. Of course, the surfactant derived from the aqueous phase of the second oil-in-water emulsion also follows this formulation requirement.
[0039] Furthermore, in the second oil-in-water emulsion, the aqueous phase is a surfactant solution containing hydrophilic monomers, and the oil phase is an organic solvent containing a first hydrophobic monomer, a second hydrophobic monomer, a crosslinking agent, an initiator, and optionally magnetic nanoparticles. The volume ratio of the aqueous phase to the oil phase is 10:1.25-5. For example, the volume ratio of the aqueous phase to the oil phase can be 10:1.25, 10:1.5, 10:1.75, 10:2, 10:2.25, 10:2.5, 10:2.75, 10:3, 10:3.25, 10:3.5, 10:3.75, 10:4, 10:4.25, 10:4.5, 10:4.75, 10:5, etc.
[0040] Furthermore, in the second oil-in-water emulsion, the concentration of the hydrophilic monomer in the aqueous phase is 10-100 mg / ml; for example, the concentration of the hydrophilic monomer in the aqueous phase can be 10 mg / ml, 20 mg / ml, 30 mg / ml, 40 mg / ml, 50 mg / ml, 60 mg / ml, 70 mg / ml, 80 mg / ml, 90 mg / ml, 100 mg / ml, etc.
[0041] Furthermore, the mass-to-volume ratio of the magnetic nanoparticles to the first hydrophobic monomer is 1-50 mg:1 mL; exemplaryly, the mass-to-volume ratio of the magnetic nanoparticles to the first hydrophobic monomer can be 1 mg:1 mL, 5 mg:1 mL, 10 mg:1 mL, 15 mg:1 mL, 20 mg:1 mL, 25 mg:1 mL, 30 mg:1 mL, 35 mg:1 mL, 40 mg:1 mL, 45 mg:1 mL, 50 mg:1 mL, etc.
[0042] Furthermore, the temperature of the first swelling is 20-60℃, and the time is 10-30h.
[0043] Furthermore, the temperature for the secondary swelling is 20-60℃, and the time is 2-12h.
[0044] Furthermore, the crosslinking polymerization is carried out at a temperature of 50-90°C for a time of 5-30 hours.
[0045] Furthermore, the organic solvent is selected from one or more of 1-chlorododecane, toluene, ethyl acetate, dichloromethane, chloroform, dimethyl sulfoxide, and methanol.
[0046] Furthermore, the crosslinking agent is selected from 2-vinylbenzene. In one specific embodiment, the volume ratio of the crosslinking agent to the first hydrophobic monomer is 1-5:100.
[0047] Furthermore, the initiator is selected from azo initiators, such as azobisisobutyronitrile (AIBN).
[0048] Furthermore, the surfactant is sodium dodecyl sulfate and / or polyvinyl alcohol.
[0049] Furthermore, the concentration of the surfactant solution is 0.1-2 wt%; for example, the concentration of the surfactant in the aqueous phase can be 0.1 wt%, 0.25 wt%, 0.5 wt%, 0.75 wt%, 1 wt%, 1.25 wt%, 1.5 wt%, 1.75 wt%, 2 wt%, etc.
[0050] Furthermore, the hydrophobic polymer microspheres are polystyrene microspheres and / or polymethyl methacrylate microspheres.
[0051] Furthermore, the magnetic nanoparticles are iron oxide magnetic nanoparticles with a particle size of 1-20 nm.
[0052] To achieve the second objective mentioned above, the present invention adopts the following technical solution:
[0053] This invention discloses a multilayer heterogeneous polymer microsphere prepared by the preparation method described above;
[0054] The multilayer heterogeneous polymer microspheres have a heterogeneous structure with three or more layers, which, from the inside out, sequentially include...
[0055] The hydrophobic region is composed of a strongly hydrophobic polymer core;
[0056] The intermediate zone comprises an intermediate layer and optionally one or more transition layers; and
[0057] The hydrophilic zone consists of a single-layer structure with strong hydrophilicity and a fractal structure.
[0058] It should be noted that the heterogeneous structure of the multilayer heterogeneous polymer microspheres provided by this invention is tunable. Although the required properties of the core and shell regions of the multilayer heterogeneous polymer microspheres are relatively fixed, and they are usually formed as single-layer structures, those skilled in the art can adjust the types and amounts of the first and second hydrophobic monomers during the preparation process, thereby forming one or more heterogeneous structures in the middle region of the multilayer heterogeneous polymer microspheres. Ultimately, the multilayer heterogeneous polymer microspheres can contain 3, 4, 5, or more layers of heterogeneous structures, with clear interfaces between different layers. Due to the polarity differences between the layers of the multilayer heterogeneous polymer microspheres, regional selective adsorption of different fluorescent dye molecules and the recycling and reuse of chemicals can be achieved.
[0059] Furthermore, the particle size of the multilayer heteropolymer microspheres is between 3 and 10 μm.
[0060] To achieve the third objective mentioned above, the present invention adopts the following technical solution:
[0061] This invention discloses an application of the multilayer heteropolymer microspheres described above in the regioselective adsorption of dyes and the preparation of bioassay products. The following application exemplifies the use of the multilayer heteropolymer microspheres in the regioselective adsorption of dyes. In this application scenario, the multilayer heteropolymer microspheres are not required to be magnetic. The application further includes:
[0062] A suspension containing multilayer heterogeneous polymer microspheres is mixed with a test sample containing dye, and stirred for a period of time to achieve regional selective adsorption of different dyes.
[0063] The dyes include water-soluble dyes and / or oil-soluble dyes, and the oil-soluble dyes include first polar dyes and / or second polar dyes.
[0064] The hydrophilic region of the multilayer heteropolymer microspheres adsorbs water-soluble dyes, the middle region of the multilayer heteropolymer microspheres adsorbs a first polar dye, and the hydrophobic region of the multilayer heteropolymer microspheres adsorbs a second polar dye.
[0065] Furthermore, the water-soluble dye includes one or more of the following: Rhodamine b, fluorescein isothiocyanate, Texas Red, Cy3, Cy5, Cy7, DAPI, phenolphthalein, methyl red, bromothymol blue, tartrazine, sunset yellow, carmine, brilliant blue, Congo red, and methyl orange.
[0066] The first polar dye includes one or more of coumarin 6, Nile Red, coumarin 153, and BODIPY;
[0067] The second polar dye includes one or more of 9-vinylanthracene, Disperse Red 60, indanthrene blue, Disperse Blue 56, Solvent Red 26, Sudan Red, Phthalocyanine Blue, Anthrone, and Alizarin.
[0068] Furthermore, the mass ratio of the multilayer heteropolymer microspheres to the dye is 1-100:1; for example, the mass ratio of the multilayer heteropolymer microspheres to the dye can be 1:1, 5:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1, 65:1, 70:1, 75:1, 80:1, 85:1, 90:1, 95:1, 100:1, etc.
[0069] The beneficial effects of this invention are as follows:
[0070] This invention provides a multilayer heterogeneous polymer microsphere, its preparation method, and its applications. The multilayer heterogeneous polymer microsphere has a heterogeneous structure with three or more layers, distinct interfaces between different layers, and polarity differences between the layers. This facilitates the regioselective adsorption of different fluorescent dye molecules; that is, water-soluble dyes are easily adsorbed into the outer shell region of the multilayer heterogeneous polymer microsphere, strongly hydrophobic dyes or second-polar dyes are easily adsorbed into the core region of the multilayer heterogeneous polymer microsphere, and first-polar dyes are easily adsorbed into the middle region of the multilayer heterogeneous polymer microsphere.
[0071] Furthermore, these multilayer heteropolymer microspheres offer the advantage of adjustable layer number, size, and composition per layer. By controlling the types and amounts of the hydrophilic monomer, the first hydrophobic monomer, and the second hydrophobic monomer during the preparation process, the number and size of the multilayer heteropolymer microspheres can be effectively controlled. Currently, in the experimental stage, multilayer heteropolymer microspheres with a maximum of 5 heterostructures can be prepared. Combined with the properties imparted to different layers, regioselective adsorption of dye molecules can be achieved. The preparation method provided by this invention is simple and rapid, enabling one-step preparation, facilitating large-scale production, and showing broad prospects for industrial application.
[0072] Furthermore, when multilayer heterogeneous polymer microspheres are magnetic, they may have potential applications in areas such as biomolecular separation and detection, disease screening and diagnosis. Attached Figure Description
[0073] The specific embodiments of the present invention will be described in further detail below with reference to the accompanying drawings.
[0074] Figure 1 This is a transmission electron microscope (TEM) image of the three-layer heterogeneous polymer microspheres prepared in Example 1 of the present invention.
[0075] Figure 2This is a transmission electron microscope (TEM) image of the four-layer heterogeneous polymer microspheres prepared in Example 2 of the present invention.
[0076] Figure 3 This is a transmission electron microscope (TEM) image of the 5-layer heteropolymer microspheres prepared in Example 3 of the present invention.
[0077] Figure 4 This is a laser confocal image of the dye-selective adsorption region of the 5-layer heteropolymer microspheres prepared in Example 3 of the present invention.
[0078] Figure 5 This is a transmission electron microscope (TEM) image of the three-layer heterogeneous polymer microspheres (magnetic) prepared in Example 9 of the present invention. Detailed Implementation
[0079] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments and accompanying drawings, further clarifies the invention. Those skilled in the art should understand that the specific description below is illustrative rather than restrictive and should not be construed as limiting the scope of protection of the present invention.
[0080] In this invention, the preparation methods are all conventional unless otherwise specified, and the raw materials used can be obtained from publicly available commercial sources or prepared according to existing technology unless otherwise specified.
[0081] Unless otherwise specified, no magnetic particles were added during the preparation of the multilayer heteropolymer microspheres in the following experiments.
[0082] Example 1
[0083] a) 150 mg of seed polystyrene microspheres were dispersed in 15 mL of sodium dodecyl sulfate aqueous solution (concentration 0.25%), and mixed with the first oil-in-water emulsion (aqueous phase: sodium dodecyl sulfate aqueous solution, concentration 0.25%, 7.5 mL; oil phase: 1-chlorododecane, 75 μL). The mixture was stirred and swollen in a flask at 50 °C for 15 hours to obtain the mixture.
[0084] b) Prepare a second oil-in-water emulsion, wherein the aqueous phase is an aqueous solution of sodium dodecyl sulfate (0.25% concentration, 15 mL) containing 4-vinylbenzoic acid (1.05 g), and the oil phase contains styrene (1.5 mL), propyl methacrylate (0.5 mL), 2-vinylbenzene (40 μL) and azobisisobutyronitrile (40 mg).
[0085] c) Mix the mixture with the second oil-in-water emulsion and continue to swell at 50 °C for 10 hours;
[0086] d) Purge with nitrogen to remove oxygen for 10 min, then stir and react at 80 °C for 20 hours under inert conditions;
[0087] e) After the reaction is complete, centrifuge the mixture and wash it three times with water to obtain white three-layer heterogeneous polymer microspheres.
[0088] Microsphere structure characterized by TEM (see Figure 1 The prepared three-layer heteropolymer microspheres exhibit a distinct three-layer structure, with the dark-colored middle portion being a hydrophobic core (corresponding to...). Figure 1 (ICP No. 11), the outermost part with a fractal structure is a hydrophilic shell (corresponding to...) Figure 1 (Issue No. 13), the dense part between the two parts is the intermediate layer (corresponding to) Figure 1 (Number 12), with clear boundaries and microspheres with a diameter of about 3.5 μm.
[0089] Example 2
[0090] a) 200 mg of seed polystyrene microspheres were dispersed in 30 mL of sodium dodecyl sulfate aqueous solution (concentration 0.15%), and mixed with the first oil-in-water emulsion (aqueous phase: sodium dodecyl sulfate aqueous solution, concentration 0.15%, 15 mL; oil phase: 1-chlorododecane, 100 μL). The mixture was stirred and swollen in a flask at 45 °C for 10 hours to obtain the mixture.
[0091] b) Prepare a second oil-in-water emulsion, wherein the aqueous phase is an aqueous solution of sodium dodecyl sulfate (0.15%, 30 mL) containing sodium 4-vinylbenzoate (1.5 g), and the oil phase contains styrene (2 mL), phenyl methacrylate (4 mL), 2-vinylbenzene (60 μL) and azobisisobutyronitrile (50 mg).
[0092] c) Mix the mixture with the second oil-in-water emulsion and continue to swell at 45 °C for 10 hours;
[0093] d) Purge with nitrogen to remove oxygen for 10 min, then stir and react at 75 °C for 18 hours under inert conditions;
[0094] e) After the reaction is complete, centrifuge the mixture and wash it three times with water to obtain white 4-layer heterogeneous polymer microspheres.
[0095] The internal structure of the microspheres was characterized by TEM (see [link]). Figure 2 The prepared four-layer heteropolymer microspheres exhibit a distinct four-layer structure, with the dark-colored central portion being a hydrophobic core (corresponding to...). Figure 2 (ICP No. 21) The outermost part with a fractal structure is a hydrophilic shell (corresponding to...) Figure 2 (Number 24), the brighter part near the core is the intermediate layer containing the second monomer (corresponding to) Figure 2 (Number 22), the brighter part near the outer shell is the transition layer (corresponding to) Figure 2(Number 23), with clear boundaries and microspheres with a diameter of about 4 μm.
[0096] Example 3
[0097] a) 100 mg of seed polystyrene microspheres were dispersed in 10 mL of sodium dodecyl sulfate aqueous solution (concentration 0.2%), and mixed with the first oil-in-water emulsion (aqueous phase: sodium dodecyl sulfate aqueous solution, concentration 0.2%, 5 mL; oil phase: 1-chlorododecane, 25 μL). The mixture was stirred and swollen in a flask at 35 °C for 25 hours to obtain the mixture.
[0098] b) Prepare a second oil-in-water emulsion, wherein the aqueous phase is an aqueous solution of sodium dodecyl sulfate (0.2%, 7.5 mL) containing sodium 4-vinylbenzoate (400 mg), and the oil phase contains styrene (0.5 mL), benzyl methacrylate (0.75 mL), 2-vinylbenzene (15 μL) and azobisisobutyronitrile (15 mg).
[0099] c) Mix the mixture with the second oil-in-water emulsion and continue to swell at 35 °C for 8 hours;
[0100] d) Purge with nitrogen to remove oxygen for 10 min, then stir and react at 80 °C for 25 hours under inert conditions;
[0101] e) After the reaction is complete, centrifuge the mixture and wash it three times with water to obtain white 5-layer heteropolymer microspheres.
[0102] The internal structure of the microspheres was characterized by TEM (see [link]). Figure 3 The prepared 5-layer heteropolymer microspheres exhibit a distinct five-layer structure with clear boundaries. The dark-colored central portion is the hydrophobic core (corresponding to...). Figure 3 (No. 31) The outermost part with a fractal structure is a hydrophilic shell (corresponding to...) Figure 3 (Number 35), the brighter part is the intermediate layer containing the second monomer (corresponding to) Figure 3 (Number 33), the dark gray area near the kernel is the transition layer (corresponding to...) Figure 3 (Number 32), the light gray part near the outer shell is the transition layer (corresponding to) Figure 3 (No. 34), the microspheres have a particle size of about 5 μm.
[0103] Example 4
[0104] a) 100 mg of seed polystyrene microspheres were dispersed in 50 mL of sodium dodecyl sulfate aqueous solution (concentration 0.2%), and mixed with the first oil-in-water emulsion (aqueous phase: sodium dodecyl sulfate aqueous solution, concentration 0.2%, 5 mL; oil phase: 1-chlorododecane, 200 μL). The mixture was stirred and swollen in a flask at 35 °C for 30 hours to obtain the mixture.
[0105] b) Prepare a second oil-in-water emulsion, wherein the aqueous phase is an aqueous solution of sodium dodecyl sulfate (0.2% concentration, 8 mL) containing N,N,N-trimethylvinylbenzene ammonium chloride (800 mg), and the oil phase contains styrene (1 mL), propyl methacrylate (1.5 mL), 2-vinylbenzene (200 μL) and azobisisobutyronitrile (100 mg).
[0106] c) Mix the mixture with the second oil-in-water emulsion and continue to swell at 35 °C for 10 hours;
[0107] d) Purge with nitrogen to remove oxygen for 5 min, then stir and react at 68 °C for 15 hours under inert conditions;
[0108] e) After the reaction is complete, the mixture is centrifuged and washed three times with water to obtain white 4-layer heterogeneous polymer microspheres with the same structure as in Example 2.
[0109] Example 5
[0110] a) 100 mg of seed polystyrene microspheres were dispersed in 5 mL of polyvinyl alcohol aqueous solution (concentration 0.5%), and mixed with the first oil-in-water emulsion (aqueous phase: polyvinyl alcohol aqueous solution, concentration 0.5%, 3 mL; oil phase: 1-chlorododecane, 10 μL). The mixture was stirred and swollen in a flask at 40 °C for 18 hours to obtain the mixture.
[0111] b) Prepare a second oil-in-water emulsion, wherein the aqueous phase is a polyvinyl alcohol aqueous solution (concentration 0.5%, 15 mL) containing sodium 4-vinylbenzoate (800 mg), and the oil phase contains styrene (1.5 mL), methyl methacrylate (1.5 mL), 2-vinylbenzene (50 μL) and azobisisobutyronitrile (25 mg).
[0112] c) Mix the mixture with the second oil-in-water emulsion and continue to swell at 40 °C for 10 hours;
[0113] d) Purge with nitrogen for 5 min to remove oxygen, then stir and react at 70 °C for 15 hours under inert conditions;
[0114] e) After the reaction is complete, the mixture is centrifuged and washed three times with water to obtain white three-layer heterogeneous polymer microspheres with the same structure as in Example 1.
[0115] Example 6
[0116] a) 250 mg of seed polystyrene microspheres were dispersed in 30 mL of sodium dodecyl sulfate aqueous solution (concentration 0.4%), and mixed with the first oil-in-water emulsion (aqueous phase: sodium dodecyl sulfate aqueous solution, concentration 0.4%, 20 mL; oil phase: 1-chlorododecane, 200 μL), and stirred and swollen in a flask at 35 °C for 20 hours.
[0117] b) Prepare a second oil-in-water emulsion, wherein the aqueous phase is an aqueous solution of sodium dodecyl sulfate containing acrylic acid (3 g) (concentration 0.4%, 30 mL), and the oil phase contains styrene (3 mL), phenyl methacrylate (2 mL), 2-vinylbenzene (100 μL) and azobisisobutyronitrile (125 mg).
[0118] c) Mix the mixture with the second oil-in-water emulsion and continue to swell at 35 °C for 8 hours;
[0119] d) Purge with nitrogen to remove oxygen for 10 min, then stir and react at 75 °C for 25 hours under inert conditions;
[0120] e) After the reaction is complete, the mixture is centrifuged and washed three times with water to obtain white 4-layer heterogeneous polymer microspheres with the same structure as in Example 2.
[0121] Example 7
[0122] a) 100 mg of seed polystyrene microspheres were dispersed in 5 mL of sodium dodecyl sulfate aqueous solution (concentration 0.5%), and mixed with the first oil-in-water emulsion (aqueous phase: sodium dodecyl sulfate aqueous solution, concentration 0.5%, 5 mL; oil phase: 1-chlorododecane, 30 μL), and stirred and swollen in a flask at 45 °C for 18 hours.
[0123] b) Prepare a second oil-in-water emulsion, wherein the aqueous phase is an aqueous solution of sodium dodecyl sulfate (0.5%, 8 mL) containing sodium 4-vinylbenzoate (200 mg), and the oil phase contains styrene (1 mL), n-hexyl methacrylate (2 mL), 2-vinylbenzene (30 μL) and azobisisobutyronitrile (10 mg).
[0124] c) Mix the mixture with the second oil-in-water emulsion and continue to swell at 45 °C for 8 hours;
[0125] d) Purge with nitrogen to remove oxygen for 10 min, then stir and react at 80 °C for 25 hours under inert conditions;
[0126] e) After the reaction is complete, the mixture is centrifuged and washed three times with water to obtain white three-layer heterogeneous polymer microspheres with the same structure as in Example 1.
[0127] Example 8
[0128] a) 150 mg of seed polystyrene microspheres were dispersed in 5 mL of polyvinyl alcohol aqueous solution (concentration 1%), and mixed with the first oil-in-water emulsion (aqueous phase: polyvinyl alcohol aqueous solution, concentration 0.35%, 5 mL; oil phase: 1-chlorododecane, 25 μL), and stirred and swollen in a flask at 35 °C for 25 hours.
[0129] b) Prepare a second oil-in-water emulsion, wherein the aqueous phase is a polyvinyl alcohol aqueous solution (1% concentration, 7.5 mL) containing sodium 4-vinylbenzoate (400 mg), and the oil phase contains styrene (1 mL), benzyl methacrylate (0.75 mL), 2-vinylbenzene (15 μL) and azobisisobutyronitrile (15 mg).
[0130] c) Mix the mixture with the second oil-in-water emulsion and continue to swell at 35 °C for 8 hours;
[0131] d) Purge with nitrogen to remove oxygen for 10 min, then stir and react at 70 °C for 15 hours under inert conditions;
[0132] e) After the reaction is complete, the mixture is centrifuged and washed three times with water to obtain white 5-layer heterogeneous polymer microspheres with the same structure as in Example 3.
[0133] Comparative Example 1
[0134] a) Disperse 100 mg of seed polystyrene microspheres in 10 mL of polyvinyl alcohol aqueous solution (concentration 1%), mix with the first oil-in-water emulsion (aqueous phase: polyvinyl alcohol aqueous solution, concentration 0.35%, 5 mL, oil phase: 1-chlorododecane, 25 μL), and stir and swell in a flask at 35 °C for 25 hours.
[0135] b) Prepare a second oil-in-water emulsion, wherein the aqueous phase is a polyvinyl alcohol aqueous solution (1% concentration, 7.5 mL) containing sodium 4-vinylbenzoate (400 mg), and the oil phase contains styrene (0.5 mL), methyl methacrylate (3 mL), 2-vinylbenzene (15 μL) and azobisisobutyronitrile (15 mg).
[0136] c) Mix the mixture with the second oil-in-water emulsion and continue to swell at 35 °C for 8 hours;
[0137] d) Purge with nitrogen to remove oxygen for 10 min, then stir and react at 70 °C for 15 hours under inert conditions;
[0138] e) After the reaction is complete, centrifuge the mixture. Microspheres cannot be obtained; only a gel-like substance can be obtained.
[0139] Comparative Example 2
[0140] a) Disperse 100 mg of seed polystyrene microspheres in 20 mL of polyvinyl alcohol aqueous solution (concentration 1%), mix with the first oil-in-water emulsion (aqueous phase: polyvinyl alcohol aqueous solution, concentration 0.35%, 5 mL, oil phase: 1-chlorododecane, 25 μL), and stir and swell in a flask at 35 °C for 25 hours.
[0141] b) Prepare a second oil-in-water emulsion, wherein the aqueous phase is a polyvinyl alcohol aqueous solution (1% concentration, 7.5 mL) containing sodium 4-vinylbenzoate (1000 mg), and the oil phase contains styrene (0.5 mL), benzyl methacrylate (3 mL), 2-vinylbenzene (15 μL) and azobisisobutyronitrile (15 mg).
[0142] c) Mix the mixture with the second oil-in-water emulsion and continue to swell at 35 °C for 8 hours;
[0143] d) Purge with nitrogen to remove oxygen for 10 min, then stir and react at 70 °C for 15 hours under inert conditions;
[0144] e) After the reaction is complete, centrifuge the mixture and wash it three times with water to obtain white polymer microspheres with a multinucleated structure.
[0145] Test Example 1
[0146] a) The multilayer heterogeneous polymer microspheres obtained in Example 3 were formulated into a suspension (concentration 100 mg / mL, 5 mL) and mixed with a first oil-in-water emulsion containing dye (aqueous phase: 0.25% sodium dodecyl sulfate aqueous solution containing rhodamine b (20 ppm), oil phase: containing 9-vinylanthracene (20 ppm), coumarin 6 (20 ppm) and ethyl acetate (4 μL)). The mixture was stirred at 400 rpm for 20 hours at room temperature.
[0147] b) Prepare a second oil-in-water emulsion, with the aqueous phase being a 0.25% aqueous solution of sodium dodecyl sulfate containing rhodamine b (20 ppm) and the oil phase being toluene (4 μL). Mix with the mixture from step a) and stir at 400 rpm for 20 hours at room temperature.
[0148] c) After the dye adsorption is complete, centrifugation yields a pink solid and a clear, transparent supernatant.
[0149] Laser confocal microscopy characterization of the dye adsorption on the microspheres revealed that the three dyes were distributed in the hydrophobic, intermediate, and hydrophilic regions of the microspheres, achieving regioselective adsorption. The results are as follows: Figure 4 As shown in the figure, the hydrophobic region adsorbs blue 9-vinylanthracene, the middle region adsorbs green coumarin 6, and the outermost hydrophilic region adsorbs red rhodamine b.
[0150] Test Example 2
[0151] a) The multilayer heterogeneous polymer microspheres from Example 2 were formulated into a suspension (concentration 50 mg / mL, 10 mL) and mixed with a first oil-in-water emulsion containing dye (aqueous phase: 1% aqueous solution of polyvinyl alcohol containing rhodamine b (40 ppm), oil phase: containing 9-vinylanthracene (40 ppm), coumarin 6 (40 ppm), and toluene (4 μL)). The mixture was stirred at 200 rpm for 25 hours at room temperature.
[0152] b) Prepare a second oil-in-water emulsion, with the aqueous phase being a 1% aqueous solution of polyvinyl alcohol containing rhodamine b (40 ppm) and the oil phase being dichloromethane (4 μL). Mix with the mixture from step a) and stir at 200 rpm for 25 hours at room temperature.
[0153] c) After the dye adsorption is complete, centrifugation yields a pink solid and a clear, transparent supernatant.
[0154] Laser confocal microscopy characterization of the dye adsorption on the microspheres revealed that the three dyes were distributed at different locations on the microspheres, achieving regional selective adsorption. Specifically, the hydrophobic region adsorbed blue 9-vinylanthracene, the middle region adsorbed green coumarin 6, and the outermost hydrophilic region adsorbed red rhodamine b.
[0155] Test Example 3
[0156] a) The multilayer heterogeneous polymer microspheres from Example 2 were formulated into a suspension (concentration 10 mg / mL, 20 mL), and mixed with a first oil-in-water emulsion containing dye (aqueous phase: 0.5% aqueous solution of polyvinyl alcohol containing rhodamine b (5 ppm), oil phase: containing 9-vinylanthracene (5 ppm), coumarin 6 (5 ppm), and dichloromethane (10 μL)). The mixture was stirred at 500 rpm for 10 hours at room temperature.
[0157] b) Prepare a second oil-in-water emulsion, with the aqueous phase being a 0.5% aqueous solution of polyvinyl alcohol containing rhodamine b (5 ppm) and the oil phase being dichloromethane (10 μL). Mix with the mixture from step a) and stir at 500 rpm for 10 hours at room temperature.
[0158] c) After the dye adsorption is complete, centrifugation yields a pink solid and a clear, transparent supernatant.
[0159] Laser confocal microscopy characterization of the dye adsorption on the microspheres revealed that the three dyes were distributed at different locations on the microspheres, achieving regional selective adsorption. Specifically, the hydrophobic region adsorbed blue 9-vinylanthracene, the middle region adsorbed green coumarin 6, and the outermost hydrophilic region adsorbed red rhodamine b.
[0160] Test Example 4
[0161] a) The multilayer heterogeneous polymer microspheres from Example 1 were formulated into a suspension (concentration 100 mg / mL, 15 mL) and mixed with a first oil-in-water emulsion containing dye (aqueous phase: a mixed aqueous solution of polyvinyl alcohol and sodium dodecyl sulfate containing rhodamine b (10 ppm) (0.8%), oil phase: containing 9-vinylanthracene (10 ppm), coumarin 6 (10 ppm), and chloroform (2 μL)). The mixture was stirred at 400 rpm for 10 hours at room temperature.
[0162] b) Prepare a second oil-in-water emulsion, wherein the aqueous phase is a mixed aqueous solution (0.8%) of polyvinyl alcohol and sodium dodecyl sulfate containing rhodamine b (10 ppm), and the oil phase is toluene (2 μL). Mix with the mixture from step a) and stir at 400 rpm for 10 hours at room temperature.
[0163] c) After the dye adsorption is complete, centrifugation yields a pink solid and a clear, transparent supernatant.
[0164] Laser confocal microscopy characterization of the dye adsorption on the microspheres revealed that the three dyes were distributed at different locations on the microspheres, achieving regional selective adsorption. Specifically, the hydrophobic region adsorbed blue 9-vinylanthracene, the middle region adsorbed green coumarin 6, and the outermost hydrophilic region adsorbed red rhodamine b.
[0165] Test Example 5
[0166] a) The multilayer heterogeneous polymer microspheres from Example 1 were formulated into a suspension (50 mg / mL, 5 mL) and mixed with a first oil-in-water emulsion containing dye (aqueous phase: a mixed aqueous solution of polyvinyl alcohol and sodium dodecyl sulfate containing rhodamine b (30 ppm) (0.8%), oil phase: containing 9-vinylanthracene (30 ppm), coumarin 6 (30 ppm), and dimethyl sulfoxide (2 μL)). The mixture was stirred at 500 rpm for 8 hours at room temperature.
[0167] b) Prepare a second oil-in-water emulsion, with the aqueous phase being a mixed aqueous solution (0.8%) of polyvinyl alcohol and sodium dodecyl sulfate containing rhodamine b (30 ppm) and the oil phase being dimethyl sulfoxide (4 μL). Mix with the mixture from step a) and stir at 500 rpm for 8 hours at room temperature.
[0168] c) After the dye adsorption is complete, centrifugation yields a pink solid and a clear, transparent supernatant.
[0169] Laser confocal microscopy characterization of the dye adsorption on the microspheres revealed that the three dyes were distributed at different locations on the microspheres, achieving regional selective adsorption. Specifically, the hydrophobic region adsorbed blue 9-vinylanthracene, the middle region adsorbed green coumarin 6, and the outermost hydrophilic region adsorbed red rhodamine b.
[0170] Test Example 6
[0171] a) The multilayer heterogeneous polymer microspheres from Example 1 were formulated into a suspension (concentration 100 mg / mL, 5 mL) and mixed with a first oil-in-water emulsion containing dye (aqueous phase: 0.8% aqueous solution of sodium dodecyl sulfate containing FITC (30 ppm), oil phase: containing 9-vinylanthracene (30 ppm), Cy3 (30 ppm), and dimethyl sulfoxide (2 μL)). The mixture was stirred at 500 rpm for 8 hours at room temperature.
[0172] b) Prepare a second oil-in-water emulsion, with the aqueous phase being an aqueous solution of sodium dodecyl sulfate (0.8%) containing FITC (30 ppm) and the oil phase being dimethyl sulfoxide (4 μL). Mix with the mixture from step a) and stir at 500 rpm for 8 hours at room temperature.
[0173] c) After the dye adsorption is complete, centrifugation yields a green solid and a clear, transparent supernatant.
[0174] Laser confocal microscopy characterization of the dye adsorption on the microspheres revealed that the three dyes were distributed at different locations on the microspheres, achieving regional selective adsorption. Specifically, the hydrophobic region adsorbed 9-vinylanthracene (blue), the middle region adsorbed Cy3 (red), and the outermost hydrophilic region adsorbed FITC (green).
[0175] Example 9
[0176] a) 100 mg of seed polystyrene microspheres were dispersed in 5 mL of polyvinyl alcohol aqueous solution (concentration 0.5%), and mixed with the first oil-in-water emulsion (aqueous phase: polyvinyl alcohol aqueous solution, concentration 0.5%, 10 mL; oil phase: 1-chlorododecane, 10 μL). The mixture was stirred and swollen in a flask at 40 °C for 18 hours to obtain the mixture.
[0177] b) Prepare a second oil-in-water emulsion, wherein the aqueous phase is a polyvinyl alcohol aqueous solution containing sodium 4-vinylbenzoate (800 mg) (concentration 0.5%, 15 mL), and the oil phase contains styrene (1 mL), propyl methacrylate (1 mL), 2-vinylbenzene (50 μL), azobisisobutyronitrile (25 mg), dichloromethane (0.5 mL) and magnetite nanoparticles (50 mg).
[0178] c) Mix the mixture with the second oil-in-water emulsion and continue to swell at 40 °C for 10 hours;
[0179] d) Purge with nitrogen for 5 min to remove oxygen, then stir and react at 70 °C for 15 hours;
[0180] e) After the reaction is complete, centrifuge the above mixture and wash it three times with water to obtain brown, four-layered heteropolymer microspheres containing magnetic nanoparticles (magnetic), the structure of which is as follows. Figure 5 .
[0181] The structure of the microspheres (magnetic) was characterized by TEM (see [reference]). Figure 5 The prepared four-layer heteropolymer microspheres (magnetic) exhibit a distinct four-layer structure, with the dark-colored central portion being a hydrophobic core (corresponding to...). Figure 5 (No. 51), the outermost part with a fractal structure is a hydrophilic shell (corresponding to...) Figure 5 (Issue No. 54), the dense part between the two parts is the intermediate layer (corresponding to) Figure 5 (No. 53) and transition layer (corresponding to) Figure 5 (No. 52), with clear boundaries, nanoparticles are present in the middle layer (indicated by the arrow), and the microspheres (magnetic) have a particle size of about 4 μm.
[0182] Due to the enhanced magnetism of the four-layer heteropolymer microspheres, they have wide applications in the field of biomolecular separation and detection, such as respiratory disease monitoring and cancer screening.
[0183] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. For those skilled in the art, other variations or modifications can be made based on the above description. It is impossible to exhaustively list all the implementation methods here. All obvious variations or modifications derived from the technical solutions of the present invention are still within the protection scope of the present invention.
Claims
1. A method for preparing multilayer heterogeneous polymer microspheres, characterized in that, Includes the following steps: Hydrophobic polymer microspheres were dispersed in a surfactant solution and mixed with a first oil-in-water emulsion for a single swelling process to obtain a mixture. A second oil-in-water emulsion comprising a hydrophilic monomer, a first hydrophobic monomer, a second hydrophobic monomer, a crosslinking agent, an initiator, and optionally geomagnetic nanoparticles is added to the mixture for secondary swelling. Crosslinking polymerization was carried out under an inert atmosphere. After the reaction was completed, the mixture was centrifuged and washed to obtain multilayer heterogeneous polymer microspheres with more than three layers of heterostructure. The hydrophilic monomer is selected from one or more of 4-vinylbenzoic acid, acrylic acid, 4-vinylphenylboronic acid, and N,N,N-trimethylvinylbenzoic acid ammonium chloride; The first hydrophobic monomer is styrene; The second hydrophobic monomer is selected from one or more of the following: methyl methacrylate, ethyl methacrylate, propyl methacrylate, n-butyl methacrylate, isobutyl methacrylate, tert-butyl methacrylate, n-hexyl methacrylate, 2-ethylhexyl methacrylate, phenyl methacrylate, benzyl methacrylate, 2,2,2-trifluoroethyl methacrylate, 2,2,3,3,3-pentafluoropropyl methacrylate, 2,2,3,3,4,4,4-heptafluorobutyl methacrylate, methyl acrylate, ethyl acrylate, n-butyl acrylate, isobutyl acrylate, tert-butyl acrylate, and n-hexyl acrylate. The volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:0.1-5; The mass-to-volume ratio of the hydrophilic monomer to the first hydrophobic monomer is 100-1000 mg: 1 mL; The mass-to-volume ratio of the hydrophobic polymer microspheres and the second hydrophobic monomer is 100 mg: 0.25-2.25 mL; In the first oil-in-water emulsion, the aqueous phase is a surfactant solution, the oil phase is an organic solvent, and the volume ratio of the aqueous phase to the oil phase is 1-30 mL:50 μL.
2. The preparation method according to claim 1, characterized in that, The aqueous phase of the second oil-in-water emulsion is a surfactant solution containing hydrophilic monomers, and the oil phase is an organic solvent containing a first hydrophobic monomer, a second hydrophobic monomer, a crosslinking agent, an initiator, and optionally geomagnetic nanoparticles. The volume ratio of the aqueous phase to the oil phase is 10:1.25-5. In the second oil-in-water emulsion, the concentration of the hydrophilic monomer in the aqueous phase is 10-100 mg / mL.
3. The preparation method according to claim 1, characterized in that, The first and second hydrophobic monomers are selected from a combination of one of the following to obtain polymer microspheres with a three-layer heterostructure: 1) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from methyl methacrylate, and the volume ratio of the first hydrophobic monomer and the second hydrophobic monomer is 1:0.25-1.25; 2) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from ethyl methacrylate, and the volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:0.25-1.75; 3) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from propyl methacrylate, and the volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:0.25-0.5; 4) The first hydrophobic monomer is styrene, and the second hydrophobic monomer is selected from n-hexyl methacrylate and / or 2-ethylhexyl methacrylate, and the volume ratio of the first hydrophobic monomer and the second hydrophobic monomer is 1:0.25-2.25; 5) The first hydrophobic monomer is styrene, and the second hydrophobic monomer is selected from phenyl methacrylate and / or benzyl methacrylate, and the volume ratio of the first hydrophobic monomer and the second hydrophobic monomer is 1:0.
25.
4. The preparation method according to claim 1, characterized in that, The first and second hydrophobic monomers are selected from one of the following combinations to obtain polymer microspheres with a four-layer heterostructure: 1) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from ethyl methacrylate, and the volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:2-2.25; 2) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from propyl methacrylate, and the volume ratio of the first hydrophobic monomer and the second hydrophobic monomer is 1:0.75-1.5; 3) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from n-butyl methacrylate, and the volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:0.25-1.75; 4) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from phenyl methacrylate, and the volume ratio of the first hydrophobic monomer and the second hydrophobic monomer is 1:0.5-2.25; 5) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from benzyl methacrylate, and the volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:0.5; 6) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from tert-butyl methacrylate, and the volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:0.75-2.
25.
5. The preparation method according to claim 1, characterized in that, The first and second hydrophobic monomers are selected from one of the following combinations to obtain polymer microspheres with a 5-layer heterostructure: 1) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from propyl methacrylate, and the volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:1.75-2.25; 2) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from n-butyl methacrylate, and the volume ratio of the first hydrophobic monomer to the second hydrophobic monomer is 1:2-2.25; 3) The first hydrophobic monomer is styrene, the second hydrophobic monomer is selected from benzyl methacrylate, and the volume ratio of the first hydrophobic monomer and the second hydrophobic monomer is 1:0.75-1.
5.
6. The preparation method according to claim 1, characterized in that, The temperature of the first swelling is 20-60℃, and the time is 10-30h; The secondary swelling temperature is 20-60℃, and the time is 2-12h; The cross-linking polymerization is carried out at a temperature of 50-90℃ for 5-30 hours.
7. The preparation method according to any one of claims 1-6, characterized in that, The surfactant is sodium dodecyl sulfate and / or polyvinyl alcohol; the concentration of the surfactant solution is 0.1-2 wt%; The hydrophobic polymer microspheres are polystyrene microspheres and / or polymethyl methacrylate microspheres; The magnetic nanoparticles are iron oxide magnetic nanoparticles with a particle size of 1-20 nm.
8. A multilayer heterogeneous polymer microsphere, characterized in that, It was prepared by the preparation method according to any one of claims 1-7; The multilayer heterogeneous polymer microspheres have a heterogeneous structure with three or more layers, which, from the inside out, sequentially include... The hydrophobic region is composed of a hydrophobic polymer core; The intermediate zone comprises an intermediate layer and optionally one or more transition layers; and The hydrophilic zone consists of a single hydrophilic layer and has a fractal structure.
9. The application of the multilayer heterogeneous polymer microspheres as described in claim 8 in the regioselective adsorption of dyes and the preparation of bioseparation and detection products, characterized in that, The application further includes: A suspension containing multilayer heterogeneous polymer microspheres is mixed with a test sample containing dye, and stirred for a period of time to achieve regional selective adsorption of different dyes. The dyes include water-soluble dyes and / or oil-soluble dyes, and the oil-soluble dyes include first polar dyes and / or second polar dyes. The hydrophilic region of the multilayer heteropolymer microspheres adsorbs water-soluble dyes, the middle region of the multilayer heteropolymer microspheres adsorbs a first polar dye, and the hydrophobic region of the multilayer heteropolymer microspheres adsorbs a second polar dye.
10. The application according to claim 9, characterized in that, The water-soluble dyes include one or more of the following: Rhodamine b, fluorescein isothiocyanate, Texas Red, Cy3, Cy5, Cy7, DAPI, phenolphthalein, methyl red, bromothymol blue, tartrazine, sunset yellow, carmine, brilliant blue, Congo red, and methyl orange. The first polar dye includes one or more of coumarin 6, Nile Red, coumarin 153, and BODIPY; The second polar dye includes one or more of 9-vinylanthracene, Disperse Red 60, indanthrene blue, Disperse Blue 56, Solvent Red 26, Sudan Red, Phthalocyanine Blue, Anthrone, and Alizarin.
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