CN104119474B - A kind of surface-functionalized micro-nano polymeric hollow particle and preparation method thereof - Google Patents

Abstract

The invention discloses a micro-nano polymer hollow particle, in particular a surface-functionalized micro-nano polymer hollow particle and a preparation method thereof. First, soluble polymer template particles are prepared by a simple polymerization process, and then the polymerization reaction of methylene succinic anhydride, N-vinylpyrrolidone, and cross-linking agent is initiated on the surface of the template particles to prepare a core-shell structure. Then use a good solvent for the template core to dissolve the core in the core-shell particle to prepare a hollow-structured polymer particle with uniform wall thickness and reactive groups on the surface. The inner and outer surfaces of the hollow polymer particles have reactive functional groups, which can be chemically bonded to attach and wrap specific active substances, drugs, biomolecules, tumor targeting agents, antibodies, etc., which is conducive to micro-nano polymerization Application of hollow particles in the field of biomedicine.

Description

A surface-functionalized micro-nano polymer hollow particle and its preparation method

technical field

The invention belongs to the field of new materials, and relates to a micro-nano polymer hollow particle, in particular to a surface-functionalized micro-nano polymer hollow particle and a preparation method thereof.

Background technique

Polymer hollow particles have the characteristics of low density and high specific surface area, and their hollow parts can accommodate a large number of guest molecules or large-sized guests, thus producing some peculiar properties based on the microscopic "wrapping" effect, making hollow particle materials in medicine It has important applications in many technical fields such as , biochemistry and chemical industry. In addition, the chemical composition and thickness of the shell of polymer hollow particles can be adjusted, so that many properties of hollow particles such as optical, electrical, magnetic, thermal, mechanical and other properties can be "tailored" in a wide range.

Due to its unique structure, polymer hollow particles can be used as drug carriers and drug delivery systems, and have the following advantages: (1) Passive targeting, after entering the circulatory system, can be taken up by mononuclear macrophages and reach the net Liver, spleen, lung, bone marrow, lymph and other target sites where the endothelial system is concentrated, in addition, special treatments such as surface modification or physical and chemical means can also be used to achieve active targeting effects; (2) Drugs are encapsulated in the cavity , after entering the body, controlled release and sustained release can be achieved through the pores of the matrix material or with the degradation of the matrix; (3) When applied to drugs with small therapeutic index, their toxic and side effects can be greatly reduced; (4) Drugs After being wrapped by it, it is in a relatively closed environment. Such a structure can effectively prevent the damage of external factors and enzymes in the body after administration, so as to achieve the purpose of improving drug stability.

At present, the methods for preparing hollow polymer particles include emulsion polymerization and template methods. Seed emulsion polymerization is the most studied and widely used method to prepare core-shell/hollow polymer composite particles. The basic process can be divided into the following steps: firstly, the seed emulsion is synthesized by emulsion polymerization, and then Add the second monomer into the seed emulsion for repolymerization to obtain a polymer emulsion with a core-shell structure, and finally remove the core with an appropriate solvent to obtain hollow particles. According to the different feeding methods of the second monomer, seed emulsion polymerization can be divided into four different processes: batch method, equilibrium swelling method, semi-continuous method and continuous method.

The key to the template method is the template, which generally needs to be prepared in advance. The template does not undergo chemical reactions during the entire reaction process, and the polymer is formed and shaped on the surface of the template. Therefore, the shape and size of the template directly determine the shape and size of the obtained hollow sphere, and the microsphere morphology can be adjusted by adjusting the morphology of the template. the goal of. The microencapsulated core-shell structure product is removed by an appropriate method. Caruso et al. reported the preparation of polymer hollow particles by layer-by-layer assembly method (LayerbyLayer), which is a representative system in which polyelectrolytes with opposite charges are adsorbed alternately layer by layer on the surface of a solid template through electrostatic interaction. Finally, the template is removed to obtain a hollow sphere. The advantage of the template method is that the morphology is controllable and easy to control, but the disadvantage is that the reaction conditions are relatively harsh and the stability is relatively poor, so there are few practical applications at present.

The preparation of hollow polymer particles by emulsion polymerization and template method has its own advantages. The preparation of hollow polymer particles by traditional emulsion polymerization and seed polymerization has the disadvantages of complex system composition, wide particle size distribution, and unstable product structure; the template method has the disadvantages of morphology Controllable characteristics, but usually the reaction conditions are harsh, the steps are cumbersome, and the stability is poor.

The invention proposes a preparation method of template particles and hollow particles with simple process, and obtains a micro-nano polymer hollow particle having both highly reactive acid anhydride groups and highly complexing pyrrolidone groups.

Contents of the invention

The purpose of the present invention is to overcome the shortcomings of the existing micro-nano polymer hollow particles and their preparation methods, and provide a surface-functionalized micro-nano polymer hollow particle and a simple preparation method.

The particle size of the hollow polymer particles is uniform and controllable, and the wall thickness of the hollow particles can be regulated through various process parameters.

The inner and outer surfaces of the hollow polymer particles have reactive functional groups, which can be chemically bonded to attach and wrap specific active substances, drugs, biomolecules, tumor targeting agents, antibodies, etc., which is conducive to micro-nano polymerization Application of hollow particles in the field of biomedicine.

The present invention provides following technical scheme:

First, soluble polymer template particles are prepared by a simple polymerization process, and then seed polymerization is initiated on the surface of the template particles to prepare polymer particles with a core-shell structure, and then the core-shell particles are dissolved in a good solvent for the template core. The inner core can prepare hollow polymer particles with uniform wall thickness and reactive groups on the surface.

A surface-functionalized micro-nano polymer hollow particle, the polymer hollow particle comprises the following structural units:

Where n is 10-10000, preferably 100-1000.

Preferably, the above-mentioned structural units are connected into a cross-linked structure through a cross-linking agent.

The chemical structure of the hollow polymer particles contains both acid anhydride groups and pyrrolidone groups.

The acid anhydride group has high reactivity and can undergo reactions such as hydrolysis, saponification, esterification, acylation, and amidation.

The pyrrolidone group has complexation reactivity, and can carry out coordination complexation with transition metals containing empty orbitals, charge-absorbing halogens, drug molecules, and the like.

The copolymerized macromolecule micro-nano hollow particle containing acid anhydride group and pyrrolidone group is a polymer hollow particle with a new chemical composition, the inner and outer surfaces of the cavity of the particle contain highly reactive acid anhydride group and pyrrolidone group, These functional chemical groups can undergo a series of chemical and biochemical follow-up reactions, which provide great convenience for the post-functionalization of polymer hollow particles such as chemical modification, biological modification, and drug complexation. Therefore, they are widely used in the field of biomedicine It has broad application value.

A method for preparing surface-functionalized micro-nano polymer hollow particles, the preparation method comprising the following steps, preferably simultaneously comprising the following steps:

1. Preparation of soluble polymer template particles;

2. Prepare shell monomer, polymerization initiator and solvent, then add template particles, ultrasonically disperse and mix well;

3. Nitrogen to remove oxygen, and then put into a constant temperature water bath to heat to initiate polymerization;

4. After the reaction is completed, the product is separated by a high-speed centrifuge;

5. Put the centrifuged product into excess acetone for ultrasonic vibration, centrifuge, wash, repeat more than three times, and extract all the core templates to obtain hollow polymer microspheres;

6. Put it in a vacuum oven and dry it at 60°C to constant weight;

Wherein, the method for preparing soluble polymer template particles comprises the following steps, preferably simultaneously comprising the following steps:

(i) Template particle monomers, polymerization initiators, and solvents are fed into a reactor equipped with a nitrogen conduit, a condenser, an agitator, and a thermometer at one time according to a set ratio, fully dissolved and mixed uniformly;

(ii) Nitrogen and oxygen discharge for 30 minutes, heat the solution system in a constant temperature water bath at a temperature of 45-120°C, time of 5-600 minutes, stirring rate of 0-500rpm;

(iii) After the reaction is completed, after ultrasonic vibration for 30 minutes, the high-speed centrifuge is separated at a speed of 5000-12000 rpm; the centrifuged product is washed with the solvent described in step (1), centrifuged and washed again, and repeated 3-5 times;

(iv) redispersing the final centrifuged product in the solvent described in step (1) by ultrasonic vibration to obtain a dispersion system of polymer template particles, which is ready for use.

The template particles are selected from the polymerization products of the following template particle monomers: (a) maleic anhydride and (b) methyl acrylate, ethyl acrylate, butyl acrylate, vinyl acetate, styrene, methacrylate hydroxy At least one of ethyl ester, vinylpyrrolidone, cyanoacrylate, acrylic acid, methacrylic acid, and acrylamide. Maleic anhydride concentration is 0.1%-25%, preferably 1%-10%; (b) concentration is 0.1%-25%, preferably 1%-10%.

Wherein, the shell monomer is selected from: methylene succinic anhydride, N-vinylpyrrolidone, and crosslinking agent. Preferably, the shell monomer consists of methylene succinic anhydride, N-vinylpyrrolidone and a crosslinking agent.

Wherein, the range of the usage ratio among methylene succinic anhydride, N-vinylpyrrolidone and crosslinking agent is: (2-4): (1-2): (1-2). Preferably, the range of the amount ratio among methylene succinic anhydride, N-vinylpyrrolidone and crosslinking agent is: (2-3):(1-1.5):(1-1.5). The inventors of the present application unexpectedly found that micro-nano polymer gel particles can be obtained when the ratio of the three is within the aforementioned range, and the particles have good sphericity and uniform particle size.

Among them, the cross-linking agent is a molecule with two or more polymerizable structures, such molecules include but not limited to: divinylbenzene, ethylene glycol dimethacrylate, N,N'-methylenebisacrylamide, Polyethylene glycol diacrylate.

The content of the shell monomer accounts for 1%-50% of the total amount of the solution, preferably 5%-20%; wherein, the content of the crosslinking agent accounts for 0.1%-15% of the total amount of other monomers, preferably 1%-10%.

Wherein, in the preparation method of the surface-functionalized micro-nano polymer hollow particles, the polymerization initiator is selected from thermal polymerization initiators known to those skilled in the art, such initiators include but are not limited to: Cumene hydroperoxide, tert-butyl hydroperoxide, dicumyl peroxide, di-tert-butyl peroxide, lauryl peroxide, dibenzoyl peroxide, tert-butyl peroxybenzoate, peroxide At least one of diisopropyl oxydicarbonate, dicyclohexyl peroxydicarbonate, azobisisobutyronitrile and azobisisoheptanonitrile.

The initiator content accounts for 0.01%-0.5% of the total solution, preferably 0.01%-0.1%.

Described solvent is selected from: formate, ethyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, pentyl acetate, isopentyl acetate, benzyl acetate, methyl propionate, ethyl propionate , Butyl propionate, Methyl butyrate, Ethyl butyrate, Butyl butyrate, Isoamyl butyrate, Methyl benzoate, Ethyl benzoate, Propyl benzoate, Butyl benzoate, Isobenzoate At least one or a combination of pentyl esters, methyl phenylacetate, ethyl phenylacetate, acetone, methyl ethyl ketone, n-hexane, and cyclohexane.

Preferably, the solvent is composed of organic acid alkyl esters, ketones, and alkanes.

Preferably, the range of the usage ratio among organic acid alkyl esters, ketones and alkanes is: (5-8):(1-3):(1-2). Preferably, the range of the usage ratio among organic acid alkyl esters, ketones and alkanes is: (6-7):(1-2):(1-1.5). More preferably, the solvent consists of butyl acetate, cyclohexanone and cyclohexane in a ratio of 6:1:1.

It should be noted that this polymerization reaction system can also react normally and obtain micro-nano polymer hollow particles without the addition of stabilizers.

The stirring rate is 0-500rpm, that is, when the stirring rate is 0, the polymer latex particles can also be reacted and prepared normally. Compared with the reaction under stirring conditions, the shape and size of the particles will be different. This is another characteristic of the process for preparing hollow polymer particles of the present invention.

In the preparation method of a surface-functionalized micro-nano polymer hollow particle of the present invention, before the reaction, the monomer, the polymerization initiator, and the optional stabilizer are dissolved in a solvent, and the polymer template particles are uniformly dispersed in the solvent ; After the polymerization reaction is initiated, copolymerized polymer oligomers are generated in the system, cross-linking reactions occur between these oligomers, and larger sheet structures are formed after coagulation and precipitation; then, these sheet-like structures are adsorbed on the surface of template particles The core-shell particles are deposited on the surface of the template under the action of the template particles; as the template particles continue to absorb oligomers and sheet-like structures from the reaction system, the particle size of the core-shell particles continues to increase until the monomer is exhausted and the reaction ends .

During the reaction process, cross-linking reactions are also continuously carried out inside the cross-linked sheet-like structure and between the sheets, so that the outer shell of the microsphere forms an overall structure with a high degree of cross-linking.

Since the outer shell of the particle is formed by superimposing cross-linked sheet structures, there are abundant pores between the sheet structures. This microscopic sheet gap provides a channel for the molecular chain of the template particle to be dissolved by the solvent, and provides a pathway for the drug to dissolve. The adsorption and release of molecules and biomolecules provide a channel, which is beneficial to the application of hollow particles in the field of biomedicine.

After centrifuging the above-mentioned core-shell particles, put them into excess acetone for ultrasonic vibration, acetone enters the interior of the core-shell particles through the pores, dissolves the template particles in the center, centrifuges, washes, and repeats three times, the core template can be completely dissolved. Finally, surface-functionalized micro-nano polymer hollow particles are obtained.

Compared with the micro-nano polymer hollow particles prepared by other methods, the shell of the hollow particle is a highly cross-linked lamellar superimposed integrated structure, and the shell is thicker, which can maintain the same shape in a dry state without collapsing Phenomenon.

A surface-functionalized micro-nano polymer hollow particle and its preparation method disclosed in the above technical solution have the following advantages:

1) The copolymerized macromolecular micro-nano hollow particles prepared by the present invention are hollow particles of a novel chemical composition, and the inner and outer surfaces of the cavity of the particles contain highly reactive acid anhydride groups and pyrrolidone groups. These functional chemical groups A series of chemical and biochemical follow-up reactions can occur, which provides great convenience for the post-functionalization of polymer hollow particles such as chemical modification, biological modification, and drug complexation, so it has broad application value in the field of biomedicine.

2) The shell of the hollow particles is a highly cross-linked lamellar superimposed structure. The shell is thicker and can keep its shape in a dry state without collapsing. Moreover, there are abundant pores between the lamellar structures. It provides a channel for the adsorption and release of drug molecules and biomolecules.

3) The preparation process of the micro-nano polymer hollow particles of the present invention is simple, the core template used is easy to prepare and easy to dissolve and remove, the particle size of the hollow particles can be regulated by various process parameters, and the particle size is uniform.

The surface-functionalized micro-nano polymer hollow particles provided by the invention can be used in biomedical fields such as drug carriers, targeted preparations, cancer diagnosis, hepatitis detection, protein separation, cell separation, and immune absorption.

Description of drawings

FIG. 1 is a transmission electron micrograph of template particles of Example 1. FIG.

FIG. 2 is a transmission electron micrograph of template particles of Example 2. FIG.

FIG. 3 is a transmission electron micrograph of template particles of Example 3. FIG.

FIG. 4 is a transmission electron micrograph of template particles of Example 4. FIG.

FIG. 5 is a transmission electron micrograph of the hollow polymer particles of Example 5. FIG.

FIG. 6 is a transmission electron micrograph of the hollow polymer particles of Example 6. FIG.

FIG. 7 is a transmission electron micrograph of the hollow polymer particles of Example 7. FIG.

FIG. 8 is a transmission electron micrograph of the hollow polymer particles of Example 8. FIG.

detailed description

The technical solutions of the present invention will be described in further detail below in conjunction with the accompanying drawings and examples. The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention.

1-4 are transmission electron micrographs of template particles in the preparation process of a surface-functionalized micro-nano polymer hollow particle of the present invention. The template particles have good sphericity, uniform particle size, and are close to monodispersity.

Figures 5-8 are transmission electron micrographs of a surface-functionalized micro-nano polymer hollow particle of the present invention. The polymer hollow particle is still spherical, the shell structure is complete, the wall thickness can be adjusted, and the particle size is uniform, close to a single particle. dispersion.

The preparation method of micro/nano polymer hollow particles: firstly, soluble polymer template particles are prepared. The template particle monomer, thermal decomposition initiator, and solvent are fed into the reactor equipped with nitrogen conduit, condenser, stirrer and thermometer at one time according to the set ratio, fully dissolved and mixed evenly. Wherein, the template particle monomer is selected from: (a) maleic anhydride and (b) methyl acrylate, ethyl acrylate, butyl acrylate, vinyl acetate, styrene, hydroxyethyl methacrylate, ethylene At least one of pyrrolidone, cyanoacrylate, acrylic acid, methacrylic acid, and acrylamide, maleic anhydride concentration 0.1%-25%, preferably 1%-10%, (b) type monomer concentration 0.1% -25%, preferably 1%-10%; Wherein, the thermal initiator is selected from cumene hydroperoxide, tert-butyl hydroperoxide, dicumyl peroxide, ditert-butyl peroxide, peroxide Lauroyl, dibenzoyl peroxide, tert-butyl peroxybenzoate, diisopropyl peroxydicarbonate, dicyclohexyl peroxydicarbonate, azobisisobutyronitrile, azobisisoheptyl At least one of nitriles, the initiator content accounts for 0.1%-3% of the total amount of monomers, preferably 0.5%-1%; wherein, the solvent is selected from formate, ethyl acetate, butyl acetate, isoacetic acid Butyl, sec-butyl acetate, amyl acetate, isopentyl acetate, benzyl acetate, methyl propionate, ethyl propionate, butyl propionate, methyl butyrate, ethyl butyrate, butyrate , isoamyl butyrate, methyl benzoate, ethyl benzoate, propyl benzoate, butyl benzoate, isoamyl benzoate, methyl phenylacetate, ethyl phenylacetate, acetone, methyl ethyl ketone, n-hexane, At least one or a combination of cyclohexane. Nitrogen and oxygen removal for 30 minutes, heat the solution system in a constant temperature water bath, temperature 45-120 ° C, time 5-600 min, stirring speed 0-500 rpm; 12000rpm; the centrifuged product is washed with the solvent described in step (1), centrifuged again, washed, and repeated 3-5 times; the final centrifuged product is redispersed in the solvent described in step (1) by ultrasonic vibration to obtain high Dispersion system of molecular template particles, ready for use.

Then, prepare a solution of shell monomer, polymerization initiator, and solvent, and mix it evenly with the dispersion system of the above-mentioned template particles; pass nitrogen to remove oxygen for 20-30 minutes, put it in a constant temperature water bath and heat to initiate polymerization reaction, the temperature is 45-120 ° C, time 180-600min, stirring rate 0-450rpm; after the reaction is completed, the product is separated by a high-speed centrifuge at a speed of 5000-12000rpm; the centrifuged product is placed in excess acetone and ultrasonically oscillated for 30 minutes, then centrifuged, washed, and repeated three times to extract all the kernels template to obtain hollow polymer microspheres; put them into a vacuum oven, and dry them at a temperature of 60° C. to constant weight.

Wherein, the shell monomer is selected from: methylene succinic anhydride, N-vinylpyrrolidone, and crosslinking agent. Preferably, the shell monomer consists of methylene succinic anhydride, N-vinylpyrrolidone and a crosslinking agent.

Wherein, the range of the usage ratio among methylene succinic anhydride, N-vinylpyrrolidone and crosslinking agent is: (2-4): (1-2): (1-2). Preferably, the range of the amount ratio among methylene succinic anhydride, N-vinylpyrrolidone and crosslinking agent is: (2-3):(1-1.5):(1-1.5). The inventors of the present application unexpectedly found that micro-nano polymer gel particles can be obtained when the ratio of the three is within the aforementioned range, and the particles have good sphericity and uniform particle size.

Among them, the cross-linking agent is a molecule with two or more polymerizable structures, such molecules include but not limited to: divinylbenzene, ethylene glycol dimethacrylate, N,N'-methylenebisacrylamide, Polyethylene glycol diacrylate.

The content of the shell monomer accounts for 1%-50% of the total amount of the solution, preferably 5%-20%; wherein, the content of the crosslinking agent accounts for 0.1%-15% of the total amount of other monomers, preferably 1%-10%.

Wherein, in the preparation method of the surface-functionalized micro-nano polymer hollow particles, the polymerization initiator is selected from thermal polymerization initiators known to those skilled in the art, such initiators include but are not limited to: Cumene hydroperoxide, tert-butyl hydroperoxide, dicumyl peroxide, di-tert-butyl peroxide, lauryl peroxide, dibenzoyl peroxide, tert-butyl peroxybenzoate, peroxide At least one of diisopropyl oxydicarbonate, dicyclohexyl peroxydicarbonate, azobisisobutyronitrile and azobisisoheptanonitrile.

The initiator content accounts for 0.01%-0.5% of the total solution, preferably 0.01%-0.1%.

Described solvent is selected from: formate, ethyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, pentyl acetate, isopentyl acetate, benzyl acetate, methyl propionate, ethyl propionate , Butyl propionate, Methyl butyrate, Ethyl butyrate, Butyl butyrate, Isoamyl butyrate, Methyl benzoate, Ethyl benzoate, Propyl benzoate, Butyl benzoate, Isobenzoate At least one or a combination of pentyl esters, methyl phenylacetate, ethyl phenylacetate, acetone, methyl ethyl ketone, n-hexane, and cyclohexane.

Preferably, the solvent is composed of organic acid alkyl esters, ketones, and alkanes.

Preferably, the range of the usage ratio among organic acid alkyl esters, ketones and alkanes is: (5-8):(1-3):(1-2). Preferably, the range of the usage ratio among organic acid alkyl esters, ketones and alkanes is: (6-7):(1-2):(1-1.5). More preferably, the solvent consists of butyl acetate, cyclohexanone and cyclohexane in a ratio of 6:1:1.

It should be noted that this polymerization reaction system can also react normally and obtain micro-nano polymer hollow particles without the addition of stabilizers.

The stirring rate is 0-500rpm, that is, when the stirring rate is 0, the polymer latex particles can also be reacted and prepared normally. Compared with the reaction under stirring conditions, the shape and size of the particles will be different. This is another characteristic of the process for preparing hollow polymer particles of the present invention.

The micro-nano polymer gel particles obtained under different preparation conditions were observed with HITACHIH-800 transmission electron microscope. Disperse and dilute the product after centrifugation and washing with a solvent, vibrate ultrasonically for 15 minutes, then use a dropper to draw a small amount of sample and drop it on the copper grid of the electron microscope, and let it dry naturally. The copper mesh has been covered with polyvinyl butyral support film, and the surface has been sprayed with carbon.

The particle size and particle size distribution of the polymer gel particles were measured with a MalvemMastersize2000 laser particle size analyzer. Disperse and dilute the product after centrifugation and washing with a solvent (the dilution rate is more than 1000 times), fully vibrate in an ultrasonic generator to disperse the particles, and then carry out instrumental analysis. The data statistical analysis method is as follows:

${\mathrm{<span\; class="notranslate">\; d</span>}}_{\mathrm{<span\; class="notranslate">\; no</span>}}<span\; class="notranslate">\; =</span>\underset{\mathrm{<span\; class="notranslate">\; i</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 1</span>}}{\overset{\mathrm{<span\; class="notranslate">\; no</span>}}{\mathrm{<span\; class="notranslate">\; \&Sigma;</span>}}}{\mathrm{<span\; class="notranslate">\; d</span>}}_{\mathrm{<span\; class="notranslate">\; i</span>}}<span\; class="notranslate">\; /</span>\mathrm{<span\; class="notranslate">\; no</span>}$

${\mathrm{<span\; class="notranslate">\; d</span>}}_{\mathrm{<span\; class="notranslate">\; w</span>}}<span\; class="notranslate">\; =</span>\underset{\mathrm{<span\; class="notranslate">\; i</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 1</span>}}{\overset{\mathrm{<span\; class="notranslate">\; no</span>}}{\mathrm{<span\; class="notranslate">\; \&Sigma;</span>}}}{\mathrm{<span\; class="notranslate">\; d</span>}}_{\mathrm{<span\; class="notranslate">\; i</span>}}^{\mathrm{<span\; class="notranslate">\; 4</span>}}<span\; class="notranslate">\; /</span>\underset{\mathrm{<span\; class="notranslate">\; i</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 1</span>}}{\overset{\mathrm{<span\; class="notranslate">\; no</span>}}{\mathrm{<span\; class="notranslate">\; \&Sigma;</span>}}}{\mathrm{<span\; class="notranslate">\; d</span>}}_{\mathrm{<span\; class="notranslate">\; i</span>}}^{\mathrm{<span\; class="notranslate">\; 3</span>}}$

PDI＝ _dw / _dn

In the formula, d _i - single microsphere particle size; d _n - microsphere number average particle size; d _w - microsphere weight average particle size; n - sample volume; PDI - particle size distribution index.

Example 1

Template particle preparation

Maleic anhydride 2g, vinyl acetate 1.8g, benzoyl peroxide 0.03g, butyl acetate 92mL; nitrogen deoxygenation for 30min; water bath heating to initiate polymerization, temperature 80°C, time 350min; reaction product was centrifuged Separate at 5000rpm, wash with butyl acetate three times, and redisperse in butyl acetate by ultrasonic vibration to obtain a dispersion system of polymer template particles.

The transmission electron microscope photo of the prepared template particles is shown in Fig. 1, the template particle particle size is 208nm, the particle size distribution coefficient is 1.04, close to monodispersity.

Example 2

Template particle preparation

Maleic anhydride 2.4g, vinyl acetate 2g, azobisisobutyronitrile 0.02g, isoamyl acetate 86mL; nitrogen deoxygenation for 30min; water bath heating to initiate polymerization, temperature 65°C, time 600min; The centrifuge was separated at 5000 rpm, washed with isoamyl acetate three times, and redispersed in isoamyl acetate by ultrasonic vibration to obtain a dispersion system of polymer template particles.

The transmission electron micrograph of the prepared template particles is shown in Fig. 2. The template particles have a particle size of 220nm and a particle size distribution coefficient of 1.05, which is close to monodispersity.

Example 3

Template particle preparation

Maleic anhydride 3g, styrene 2.8g, azobisisobutyronitrile 0.04g, isobutyl acetate 90mL; nitrogen deoxygenation for 30min; water bath heating to initiate polymerization reaction, temperature 75°C, time 480min; reaction product was centrifuged The machine was separated at 5000 rpm, washed three times with isobutyl acetate, and redispersed in isoamyl acetate by ultrasonic vibration to obtain a dispersion system of polymer template particles.

The transmission electron micrograph of the prepared template particles is shown in Fig. 3. The template particles have a particle size of 232nm and a particle size distribution coefficient of 1.06, which is close to monodispersity.

Example 4

Template particle preparation

Maleic anhydride 2.6g, styrene 3.2g, benzoyl peroxide 0.05g, isoamyl acetate 85mL; nitrogen deoxygenation 30min; water bath heating to initiate polymerization, temperature 85 ℃, time 600min; reaction product was centrifuged The machine was separated at 5000 rpm, washed with isoamyl acetate three times, and redispersed in isoamyl acetate by ultrasonic vibration to obtain a dispersion system of polymer template particles.

The transmission electron microscope photo of the prepared template particles is shown in Fig. 4, the template particle diameter is 210nm, the particle diameter distribution coefficient is 1.06, close to monodispersity.

Example 5

Preparation of hollow particles

Add 1.6 g of methylene succinic anhydride, 0.65 g of N-vinylpyrrolidone, 1.1 g of divinylbenzene, 0.03 g of dibenzoyl peroxide, 60 mL of butyl acetate into the template particle dispersion system of Example 1, and Hexanone 10mL, n-hexane 10mL; Nitrogen deoxygenation 30min, heating in a constant temperature water bath to initiate polymerization, temperature 85°C, reaction 8h to end; The product was separated with a centrifuge at 5000rpm; The centrifuged product was placed in excess acetone and ultrasonically oscillated After 30 minutes, centrifugation and washing were repeated three times to extract all the core templates to obtain hollow polymer microspheres; put them into a vacuum oven and dry them at 60°C until they reached a constant weight.

The transmission electron micrograph of the obtained hollow particles is shown in Fig. 5, the average particle diameter of the particles is 246nm, the particle size distribution index is 1.05, and the wall thickness of the hollow particles is 15nm.

Example 6

Preparation of hollow particles

Using the template particles of Example 2, other conditions are the same as in Example 5, except that the amounts of the shell monomer methylene succinic anhydride, N-vinylpyrrolidone, and divinylbenzene are respectively 3.5g, 1.5g, 2.2g.

The transmission electron micrograph of gained hollow particle is shown in Fig. 6, and the average particle diameter of particle is 272nm, and particle size distribution index is 1.07, and the wall thickness of hollow particle is 27nm, shows that along with the increase of shell monomer concentration, the wall thickness of hollow particle Increase.

Example 7

Preparation of hollow particles

The template particles of Example 3 were used, and other conditions were the same as in Example 5, except that the mixed solvent used was composed of 65 mL of isoamyl acetate, 12 mL of cyclohexanone, and 15 mL of n-hexane.

The transmission electron micrograph of gained hollow particle is shown in Fig. 7, and the average particle diameter of particle is 283nm, and particle size distribution index is 1.06, and the wall thickness of hollow particle is 32nm, shows that by changing the kind and the proportioning of reaction solvent, can regulate and control the hollow particle wall thickness.

Example 8

Preparation of hollow particles

Using the template particles of Example 4, other conditions are the same as in Example 5, except that the shell monomer used and the amount thereof are: 5.6 g of methylene succinic anhydride, 3.2 g of N-vinylpyrrolidone, polyethylene glycol Alcohol diacrylate 2.8g.

The transmission electron micrograph of gained hollow particle is shown in Fig. 8, and the average particle diameter of particle is 306nm, and particle size distribution index is 1.08, and the wall thickness of hollow particle is 45nm, shows that changing the kind of cross-linking agent can still obtain hollow particle, and along with The wall thickness of hollow particles increases with the increase of shell monomer concentration.

Comparative example 1

Other conditions are the same as in Example 5, except that the shell monomer does not contain divinylbenzene as a crosslinking agent. The results show that the obtained reaction product is a polymer colloidal substance, and hollow particles cannot be obtained.

Comparative example 2

Other conditions were the same as in Example 5, except that the amounts of methylene succinic anhydride, N-vinylpyrrolidone, and divinylbenzene were 3.5 g, 1.5 g, and 0.3 g, respectively. The results show that the obtained reaction product contains polymer colloidal substances, and a small amount of hollow particles are incomplete, indicating that the amount of crosslinking agent is very important to the stability of the shell.

Comparative example 3

Other conditions were the same as in Example 5, except that the mixed solvent used consisted of: 80 mL of cyclohexanone, 15 mL of n-hexane, and no butyl acetate. The results show that the obtained reaction product is a polymer colloidal substance, and hollow particles cannot be obtained. It shows that the solvent type and ratio are very important to the formation of hollow particles.

Comparative example 4

Other conditions were the same as in Example 5, except that the mixed solvent used consisted of: 65 mL of butyl acetate, 12 mL of cyclohexanone, and no n-hexane. The results show that the obtained reaction product contains polymer colloidal substances, and a small amount of hollow particles are incomplete, indicating that the type and ratio of solvents are very important for the formation of complete hollow particles.

Comparative example 5

Other conditions were the same as in Example 5, except that the mixed solvent used consisted of: 65 mL of butyl acetate, 15 mL of n-hexane, and no cyclohexanone. The results show that the obtained reaction product contains polymer colloidal substances, and there are a small amount of hollow particles but incomplete, indicating that the solvent type and ratio are very important for the formation of complete hollow particles.

It should be pointed out that the specific embodiments described above can enable those skilled in the art to understand the innovative invention more comprehensively, but it does not limit the innovative invention in any way. Therefore, although this specification has described the innovative invention in detail through the embodiments, those skilled in the art should understand that all technical solutions and improvements thereof that do not depart from the spirit and scope of the innovative invention should be included in the Among the protection scope of this innovative invention patent.

Claims (5)

1. a surface functionalized micro-nano polymer hollow particle, the chemical structure of the polymer hollow particle comprises the following structural units: Wherein, n=10-10000; The above-mentioned structural units are connected into a cross-linked structure by a cross-linking agent; The chemical structure of the hollow polymer particles contains both acid anhydride groups and pyrrolidone groups; The acid anhydride group has high reactivity and can undergo hydrolysis, saponification, esterification, acylation and amidation reactions; The pyrrolidone group has complexation reaction activity, and can carry out coordination complexation with transition metals containing empty orbitals, electric-absorbing halogens, and drug molecules; And, the hollow polymer particles are prepared through the following steps: (1) preparing soluble polymer template particles; (2) Prepare a solution of shell monomer, polymerization initiator and solvent, then add template particles, ultrasonically disperse, and mix uniformly; (3) nitrogen deoxygenation, then put into a constant temperature water bath and heat to initiate polymerization; (4) the reaction is completed, and the product is separated with a high-speed centrifuge; (5) Put the centrifuged product into excess acetone for ultrasonic vibration, centrifuge, wash, repeat more than three times, extract all inner core templates, and obtain hollow polymer microspheres; (6) put into vacuum oven, dry to constant weight at 60 ℃ of temperature; The shell monomer in the above-mentioned steps comprises methylene succinic anhydride, N-vinylpyrrolidone and crosslinking agent simultaneously, and between methylenesuccinic anhydride, N-vinylpyrrolidone and crosslinking agent The dosage ratio range is: (2～3): (1～2): (1～2); the solvent is composed of the organic It is composed of acid alkyl esters, ketones and alkanes. 2. a kind of surface functionalized micro-nano polymer hollow particle as claimed in claim 1, described soluble polymer template particle is selected from the polymerization product of following monomer: (a) maleic anhydride and (b) At least one of methyl acrylate, ethyl acrylate, butyl acrylate, vinyl acetate, styrene, hydroxyethyl methacrylate, vinylpyrrolidone, cyanoacrylate, acrylic acid, methacrylic acid, and acrylamide. 3. a kind of surface functionalized micro-nano polymer hollow particle as claimed in claim 1, in the described shell monomer, between methylene succinic anhydride, N-vinylpyrrolidone, cross-linking agent three The dosage ratio range is: (2～3):(1～1.5):(1～1.5). 4. a kind of surface functionalized micro-nano polymer hollow particles as claimed in claim 1, the cross-linking agent is a molecule with more than two polymerizable structures, selected from divinylbenzene, ethylene dimethacrylate Glycol esters, N,N'-methylenebisacrylamide, polyethylene glycol diacrylate. 5. A surface-functionalized micro-nano polymer hollow particle as claimed in claim 1, wherein the solvent is composed of butyl acetate, cyclohexanone and cyclohexane in a ratio of 6:1:1.