JP2010208875A - Magnetic hollow particle and method for producing the same - Google Patents

Abstract

An object of the present invention is to provide a magnetic hollow particle capable of freely controlling the particle diameter and the film thickness of the outer shell, and excellent in dispersibility, and a method for producing the same.
A negatively charged magnetic particle having a particle diameter of 6 nm or less is charged and adsorbed in a single layer on the surface of a positively charged spherical template particle having a particle diameter of 100 nm or less. By heating this with an aqueous phase under pressure, the magnetic particles are firmly fused together to form an outer shell. Magnetic hollow particles are produced by washing and eluting the remaining components inside the outer shell.
[Selection] Figure 1

Description

  The present invention relates to a magnetic hollow particle, and more particularly, to a magnetic hollow particle having excellent dispersibility and a method for producing the magnetic hollow particle, in which the particle diameter and the film thickness of the outer shell can be freely controlled.

  In recent years, it has been studied to use magnetic hollow particles as microcapsules. For example, by filling a drug in the hollow part, it can be used as a carrier for drug delivery, or by filling a gas such as chlorofluorocarbon. It has been studied to use it as a contrast agent when capturing a sound wave reflection image. Furthermore, using the magnetocaloric effect has been studied for application to hyperthermia treatment of cancer.

  Various methods have been studied for producing magnetic hollow particles. JP 2000-34582 A (Patent Document 1) forms a coating layer of iron oxide on the surface of template particles by dispersing spherical polymer particles as a template in an aqueous solution of iron salt and hydrolyzing the iron salt. Then, a method for producing a magnetic hollow particle by drying and firing this is disclosed.

  However, in the method of Patent Document 1, it is difficult to control the film thickness of the outer shell of the hollow particles, and generally the film thickness tends to increase. In addition, the shape and volume of the hollow portion varied. Furthermore, many of the particle diameters were as large as about 400 to 600 nm.

  On the other hand, Japanese Patent Laid-Open No. 2000-203810 (Patent Document 2) forms a W / O type emulsion having an appropriate water droplet diameter by adding an organic solvent to an aqueous solution of a metal salt as an alternative method not using a template. And the method of producing the magnetic hollow particle which has an outer shell with a film thickness of 20 nm or less by spraying and baking the said emulsion is disclosed. According to the method of Patent Document 2, it is recognized that the film thickness becomes thin and the hollow part becomes a beautiful spherical shape, but it is still difficult to control the film thickness and particle diameter of the outer shell of the hollow particles. Many of the particle sizes were on the order of micrometers.

  Furthermore, Japanese Patent Application Laid-Open No. 5-138209 (Patent Document 3) discloses that template particles made of a polymer and metal particles having a particle size of 1/5 or less of the particle size of the template particles are stirred at high speed in an air stream. A method for producing magnetic hollow particles by colliding metal particles with the surface of template particles to form a coating layer and then heating and firing the coating layer is disclosed. However, even in the method of Patent Document 3, it is difficult to make hollow particles fine, and many of the particle diameters are on the order of micrometers.

  When considering further application development of magnetic hollow particles, minimization of the particle diameter is one important concern, but as described above, the particles can be obtained by any of the methods disclosed in Patent Documents 1 to 3. It was very difficult to freely control and produce magnetic hollow particles having a diameter of 100 nm or less.

  In addition, the magnetic hollow particles are required to have high dispersibility in their use. In the methods disclosed in Patent Documents 1 to 3, there is a step of firing at a high temperature in order to obtain the strength of the outer shell of the hollow particles. Since it is essential, there is a problem that the particles are aggregated in the firing step and the dispersibility is deteriorated. In addition, the magnetic hollow particles according to the conventional method have a problem of aggregation due to spontaneous magnetization. That is, when the film thickness of the outer shell of the magnetic hollow particle is 20 nm or more, the magnetic hollow particle itself has spontaneous magnetization, so that there is a problem that the magnetic attraction acts between the particles and the dispersibility deteriorates.

JP 2000-34582 A JP 2000-203810 A JP-A-5-138209

  The present invention has been made in view of the above-described problems in the prior art, and the present invention provides a magnetic hollow particle that can freely control the particle diameter and the thickness of the outer shell, and has excellent dispersibility, and a method for producing the same. The purpose is to provide.

  The present inventors diligently studied magnetic hollow particles that can freely control the particle diameter and the thickness of the outer shell and that are excellent in dispersibility. As a result, negatively charged magnetic particles with a particle diameter of 3 to 6 nm are charged and adsorbed in a single layer on the surface of the positively charged spherical template particles, and this is pressure-heated in an aqueous phase, The inventors have found a phenomenon in which the magnetic particles forming the outer shell are firmly bonded to each other, and have reached the present invention.

  That is, according to the present invention, there are provided magnetic hollow particles having a particle diameter of 100 nm or less, comprising an outer shell formed by fusing magnetic particles and a spherical hollow portion. In the present invention, the thickness of the outer shell can be 10 nm or less, and the second magnetic particles can be included in the hollow portion. Moreover, in this invention, the 2nd magnetic particle can be included in the said hollow part, and the said magnetic particle can be made into a magnetite particle. Furthermore, in the present invention, the outer shell can be a single-layer film of the magnetic particles, and the outer shell can be a multilayer film in which the single-layer films of the magnetic particles are stacked. .

  Further, according to the present invention, a positively charged dispersion of spherical template particles and a negatively charged dispersion of magnetic particles having a particle diameter of 6 nm or less are mixed, and the surface of the template particles is mixed. Including a step of adsorbing the magnetic particles in a single layer to form a template-magnetic particle composite, a step of pressure heating the template-magnetic particle composite in an aqueous phase, and a step of eluting the template particles. A method for producing magnetic hollow particles is provided. In the present invention, the heating temperature in the heating step may be 150 ° C. to 200 ° C. In the present invention, the template-magnetic particle composite dispersion and the cationic polymer solution are mixed, and the cationic polymer is adsorbed on the surface of the template-magnetic particle composite to form the template-magnetic particle-cation. Mixing the template-magnetic particle-cationic polymer composite dispersion and the magnetic particle dispersion to form a surface of the template-magnetic particle-cationic polymer composite. A step of adsorbing the magnetic particles in a single layer. Further, in the present invention, the template particles can contain second ferrite particles, the magnetic particles can be magnetite particles, and the template particles can be silica particles.

  As described above, according to the present invention, there are provided magnetic hollow particles that can freely control the particle diameter and the thickness of the outer shell, and that are excellent in dispersibility, and a method for producing the same.

The conceptual diagram for demonstrating the manufacturing method of the magnetic hollow particle of 1st Embodiment. The conceptual diagram for demonstrating the manufacturing method of the magnetic hollow particle of 2nd Embodiment. The conceptual diagram for demonstrating the manufacturing method of the magnetic hollow particle of 3rd Embodiment. TEM image of sample 1. TEM image of sample 2. TEM image of sample 3. The figure which shows the weight conversion distribution of the particle size of the sample 3. FIG. TEM images of sample 2 magnetic hollow particles before and after evacuation. The figure which shows an ultrasonic reflection image. The graph which shows the temperature change at the time of applying an alternating current magnetic field to the aqueous dispersion liquid of the sample 3. FIG.

  Hereinafter, the present invention will be described with reference to embodiments shown in the drawings, but the present invention is not limited to the embodiments shown in the drawings. In each drawing referred to below, common elements are denoted by the same reference numerals, and description thereof is omitted as appropriate. In addition, “average particle diameter” used in the following description refers to number average.

  FIG. 1 is a conceptual diagram for explaining a method for producing a magnetic hollow particle 100 according to the first embodiment of the present invention. In the present embodiment, first, spherical particles having a uniform particle diameter are prepared as templates. Fig.1 (a) shows the silica particle 10 which is a template in this embodiment. The particle diameter of the silica particles 10 can be selected as appropriate. In the present embodiment, the average particle diameter of the silica particles 10 is set to 100 nm or less, so that it is difficult to produce the magnetic particles by the conventional method. Particles can be made. In this embodiment, the average particle diameter of the silica particles 10 can be 100 nm or less, can be 80 nm or less, and can be 50 nm or less.

  Next, in this embodiment, the surface of the template (silica particles 10) is modified so as to be positively charged in the aqueous phase. In the present embodiment, for example, the surface of the silica particles 10 can be modified by coating the surface of the silica particles 10 with the cationic silane coupling agent 12. In the present embodiment, examples of the cationic silane coupling agent 12 include silane coupling agents having an amino group or an imino group, such as 3-aminopropyltrimethoxysilane, 3-aminopropyltriethoxysilane, N-2- (aminoethyl) -3-aminopropyltriethoxysilane, N-2- (aminoethyl) -3-aminopropyltrimethoxysilane, N-2- (aminoethyl) -3-aminopropylmethyldimethoxysilane Etc. In the following description, the silica particles 10 modified with the cationic silane coupling agent 12 are referred to as modified silica particles 14.

  In the present embodiment, magnetic particles that are components of the outer shell of the magnetic hollow particles are also prepared. FIG. 1B shows the magnetic particle 16 in the present embodiment. In the present embodiment, examples of the magnetic particles 16 include magnetite particles. In the present embodiment, it is desirable that the average particle diameter of the magnetic particles 16 be 6 nm or less. The reason for this will be described in detail later.

  Next, in the present embodiment, the surfaces of the magnetic particles 16 are modified so as to be negatively charged in the aqueous phase. In the present embodiment, the surface of the magnetic particle 16 can be modified by coating the surface of the magnetic particle 16 with the molecule 18 having an anionic functional group. Specifically, a temporary coating substance such as thiomalic acid is added to a non-polar solvent dispersion of magnetic particles coated with long-chain fatty acids such as oleic acid, and the fatty acid on the particle surface is replaced with a temporary coating substance. To do. Subsequently, the magnetic particles coated with the temporary coating material are added to the aqueous dispersion of molecules having an anionic functional group, and the temporary coating material on the particle surface is exchanged with molecules having an anionic functional group. Thus, surface modification can be performed. The surface modification method described above in the present embodiment is described in detail in Japanese Patent Application No. 2007-194233, which is an earlier application of the present applicant.

  In the present embodiment, examples of the molecule 18 having an anionic functional group include low-molecular carboxylic acids, and examples thereof include citric acid and dimercaptosuccinic acid. In the following description, the magnetic particle 16 modified with the molecule 18 having an anionic functional group is referred to as the modified magnetic particle 20.

  Next, in the present embodiment, the modified silica particles 14 and the modified magnetic particles 20 prepared by the above-described procedure are mixed in an aqueous phase, whereby the modified magnetic particles 20 are charged and adsorbed on the surface of the modified silica particles 14. Here, when the cationic functional group such as an amino group present on the surface of the modified silica particle 14 receives hydrogen ions in the aqueous phase, the surface is positively charged, and the cation present on the surface of the modified magnetic particle 20. When the functional functional group releases hydrogen ions in the aqueous phase, its surface is negatively charged. However, the amount of positive charges of the modified silica particles 14 increases as the pH region decreases, whereas the amount of negative charges of the modified magnetic particles 20 increases as the pH region increases. Therefore, in the present embodiment, it is preferable to adjust the pH range of the aqueous phase to 5 to 6 in order to maximize the adsorption efficiency of both.

  FIG. 1C shows a state in which the modified magnetic particles 20 are uniformly charged and adsorbed on the surface of the modified silica particles 14. In the present embodiment, as shown in FIG. 1C, the electrostatic attractive force generated between the modified silica particle 14 and the modified magnetic particle 20 is maximized under the above-mentioned optimum pH condition. The particles 20 are strongly attracted to the surface of the modified silica particles 14 and adsorb evenly. Furthermore, since the modified magnetic particle 20 (that is, the magnetic particle 16) is a fine particle having a particle diameter of 6 nm or less, a dense coating layer 22 composed of the modified magnetic particle 20 is formed on the surface of the modified silica particle 14. In the present embodiment, the coating layer 22 is formed as a single layer of the modified magnetic particles 20. In the following description, the modified silica particle 14 coated with the modified magnetic particle 20 is referred to as a silica particle-magnetic particle composite 30.

  Next, the process of firmly fusing the particles of the magnetic particles 16 constituting the coating layer 22 of the silica particle-magnetic particle composite 30 adjusted by the above-described procedure will be described. In the present embodiment, the particles of the magnetic particles 16 are fused by pressure heating in the aqueous phase without firing the silica particle-magnetic particle composite 30. In the present embodiment, for example, the container containing the silica particle-magnetic particle composite 30 aqueous dispersion is placed in a pressure-resistant container and sealed, and pressure heating is performed by heating the container in an oven or the like. Can do. In the present embodiment, the temperature condition for pressure heating can be set to 150 to 200 ° C.

  In the present embodiment, the reason why the particle diameter of the magnetic particles 16 is 6 nm or less is explained below. If the magnetic particles have a particle diameter exceeding 6 nm, sufficient fusion between the particles does not occur only by pressure heating in the aqueous phase, and in order to obtain the necessary and sufficient strength of the outer shell, As in the method, it is necessary to further fire this at a high temperature. However, the firing inevitably causes aggregation of the hollow particles, and as a result, the dispersibility is inevitably deteriorated.

  With regard to this point, as a result of intensive studies, the present inventors have determined that magnetic particles having a particle diameter of 6 nm or less are heated between the magnetic particles by pressure heating in a water phase at a temperature of 150 ° C. or higher. It has been found that strong fusion occurs and the same strength as that obtained by firing is realized. In this embodiment, in order to cause fusion between the magnetic particles 16, the particle diameter is preferably 6 nm or less, and more preferably 5 nm or less. In practice, available fine magnetic particles having a particle diameter of 3 to 6 nm can be used.

  In the above-described pressure heating process, the magnetic particles 16 are firmly fused between the particles to form an outer shell, and the components constituting the modified silica particles 14 and the anionic functional groups that have covered the magnetic particles 16 are coated. Molecules 18 having a thermal decomposition, many of which elute out of the outer shell. Further, after this pressure heating step, the magnetic hollow particles 100 of this embodiment are produced by completely eluting components other than the magnetic particles 16 remaining inside by a washing step using an appropriate solvent. . In this embodiment, since silica particles are used as a template, it is not necessary to use an organic solvent for cleaning the inside of the particles, and it is not necessary to pay attention to the residual organic solvent.

  FIG.1 (d) shows the magnetic hollow particle 100 of this embodiment. As shown in FIG. 1 (d), the hollow portion 104, which is a cavity formed inside the outer shell 102 of the magnetic hollow particle 100, has a clean spherical shape corresponding to the shape of the original template (silica particle 12). ing. That is, in this embodiment, since the outer shell shrinks or deforms due to firing does not occur, the shape and volume of the hollow portion 104 are uniquely determined by the shape and volume of the original template. Therefore, in the present embodiment, it is possible to control the shape and volume of the hollow portion 102 by selecting the shape and volume of the original template. When the magnetic hollow particle 100 is used as a microcapsule for drug delivery, it is very beneficial that its volume can be freely controlled.

  In the present embodiment, the outer shell 102 of the magnetic hollow particle 100 is formed as a single layer film of the magnetic particle 16 as shown in FIG. Therefore, in the present embodiment, the film thickness of the outer shell 102 of the magnetic hollow particle 100 is uniquely determined by the particle diameter of the magnetic particle 16. Therefore, in the present embodiment, the film thickness of the outer shell 102 can be controlled by selecting the size of the particle diameter of the magnetic particles 16. Furthermore, in the present invention, in order to increase the strength of the outer shell of the magnetic hollow particles, the film thickness can be controlled to be larger. Hereinafter, this point will be described with reference to FIG.

  FIG. 2 is a conceptual diagram for explaining a method for producing a magnetic hollow particle 200 according to the second embodiment of the present invention. As shown in FIG. 2 (a), in the present embodiment, after the silica particle-magnetic particle composite 30 is produced by the above-described method described with reference to FIGS. 1 (a) to (c), Is mixed with the cationic polymer 32 in the aqueous phase. The cationic polymer 32 receives hydrogen ions in the aqueous phase and is positively charged, and is charged and adsorbed on the surface of the silica particle-magnetic particle composite 30 that is negatively charged in the same aqueous phase. As a result, as shown in FIG. 2B, the outermost surface of the silica particle-magnetic particle composite 30 is covered with the cationic polymer 32 and is positively charged. In the present embodiment, examples of the cationic polymer 32 include a polymer having an amino group or an imino group in the side chain or main chain, and examples thereof include polyethyleneimine, polyvinylamine, and polyallylamine.

  In the present embodiment, the silica particle-magnetic particle composite 30 (hereinafter referred to as silica particle-magnetic particle-cationic polymer composite 40) coated with the cationic polymer 32 and the negatively charged modification are further included. Magnetic particles 20 are mixed in an aqueous phase. As a result, as shown in FIG. 2C, the modified magnetic particles 20 are charged and adsorbed on the outermost surface of the silica particle-magnetic particle-cationic polymer composite 40, and the second coating layer 42 is formed. The Thereafter, this is heated under pressure and washed by the same method as described above for the magnetic hollow particles 100, whereby the magnetic hollow particles 200 of the present embodiment are produced.

  FIG.2 (d) shows the magnetic hollow particle 200 of this embodiment. As shown in FIG. 2D, the outer shell 202 of the magnetic hollow particle 200 is formed as a two-layer film of the magnetic particle 16. Here, the film thickness of the outer shell 202 of the magnetic hollow particle 200 is defined as a thickness twice as large as the particle diameter of the magnetic particle 16. Furthermore, in the present embodiment, by repeating the procedure shown in FIGS. 2A and 2B, a single layer film made of the magnetic particles 16 is laminated one by one, and the outer shell 202 of the magnetic hollow particles 200 is magnetically bonded. It can be formed as a laminated film in which single-layer films of particles 16 are laminated. In other words, since the film thickness of the outer shell of the magnetic hollow particles can be defined as N times the particle diameter of the magnetic particle 16, the film thickness of the outer shell can be accurately controlled.

In the present embodiment, it is preferable to control the film thickness so as to achieve a necessary and sufficient strength according to the application and the magnetic hollow particles themselves do not have spontaneous magnetization. The film thickness of the hollow particles can be 20 nm or less, can be 10 nm or less, and can be 5 nm or less. As described above, the magnetic hollow particles of the present invention have excellent dispersibility and excellent strength because they do not have spontaneous magnetization. In addition, since there is little variation in the particle diameter and the shape and volume of the hollow part, it is useful for applications that require quantitativeness such as medication.

Next, the magnetic hollow particle 300 which is the third embodiment of the present invention suitable for the application of hyperthermia will be described below. FIG. 3 is a conceptual diagram for explaining a method for producing a magnetic hollow particle 300 according to the third embodiment of the present invention. FIG. 3A shows silica particles 50 that are templates in the present embodiment. The manufacturing method of the magnetic hollow particle 300 is different from the procedure described with reference to FIG. 1 only in that the silica particle 50 serving as a template is formed including the second magnetic particle 52. About other than, it can produce by the method similar to having mentioned above.

  That is, as shown in FIG. 3A, the surface of the silica particles 50 is modified with the cationic silane coupling agent 12 to form modified silica particles 54, and then mixed with the modified magnetic particles 20 in the aqueous phase. Is done. As a result, as shown in FIG. 3B, the modified magnetic particles 20 are charged and adsorbed on the surfaces of the modified silica particles 54 to form the coating layer 22. Then, the magnetic hollow particle 300 of this embodiment is produced by pressure-heating and washing the silica particle-magnetic particle composite body 60.

  FIG. 3C shows the magnetic hollow particle 300 of the present embodiment. As shown in FIG. 3C, the magnetic hollow particle 300 of the present embodiment encloses the spherical second magnetic particle 52 in a hollow portion 104 formed inside the outer shell 102 so as to be freely movable. . When the particle diameter of the magnetic particles 52 has a certain size, the magnetocaloric effect necessary and sufficient for the application of hyperthermia is ensured. The magnetic particles 52 contained in the silica particles 50 may be made of the same material as the magnetic particles 16 constituting the outer shell 102 or may be made of another material. The particle diameter of the magnetic particles 52 can be about 30 to 70% of the particle diameter of the silica particles 50, and preferably about 50 to 70%.

  Hereinafter, although the magnetic hollow particle of this invention is demonstrated more concretely using an Example, this invention is not limited to the Example mentioned later.

(1) Production of magnetic iron oxide hollow particles (production of citric acid-coated magnetite particles)
An iron-oleic acid complex salt is prepared by reacting iron chloride with sodium oleate, and a mixture of this and oleic acid is dissolved in octadecene at room temperature, and the temperature is raised to 320 ° C. at a constant rate for 90 minutes. After reacting at 30 ° C. for 30 minutes, the mixture was cooled to room temperature to obtain oleic acid-coated magnetite particles having an average particle diameter of about 6 nm and a uniform particle diameter. A solution obtained by dissolving 0.324 g of thiomalic acid (manufactured by Tokyo Chemical Industry Co., Ltd., Mw = 150.15) in 4 ml of dimethyl sulfoxide was added to 16 ml of the toluene dispersion of this oleic acid-coated magnetite particle, and sonication was performed for 4 hours (ultrasonic wave) Treatment), and then washed with 2-methoxyethanol to obtain thiomalic acid-coated magnetite particles.

  After adding 0.415 g of anhydrous citric acid (manufactured by Kishida Chemical Co., Mw = 192.13) in ultrapure water and adjusting the pH to 7 to 20 ml of the thiomalic acid-coated magnetite particles, By washing with 4-dioxane, a citric acid-coated magnetite particle dispersion was obtained. The obtained particles were observed with a transmission electron microscope (TEM), and the average particle diameter was determined. As a result, a value of about 5 nm was obtained.

(Preparation of template particles)
In a water bath set at 40 ° C., 50 ml of ethanol and 2.5 ml of tetraethoxysilane (TEOS) were mixed in a glass flask, and 10 ml of 3% aqueous ammonia solution was added thereto while stirring. After stirring in a 45 ° C. water bath for 2 hours, 100 ml of ultrapure water was added to the reaction solution (silica particles dispersed), and ethanol in the reaction solution was removed using an evaporator. The reaction solution substituted in water by the procedure described above was dialyzed with ultrapure water to obtain silica particles having an average particle diameter of 50 nm dispersed in ultrapure water (hereinafter referred to as silica particles A). In the same procedure (however, the stirring temperature was 40 ° C.), silica particles having an average particle diameter of 100 nm (hereinafter referred to as silica particles B) were obtained.

(Preparation of magnetic particle-containing template particles)
Citric acid-coated citric acid-coated particles having an average particle diameter of 20 nm prepared by the same procedure as described above were dispersed in a mixed solution of ethanol and water (volume ratio 1: 1). Tetraethoxysilane (TEOS, Si (OC ₂ H ₅ ) ₄ ) is added to the dispersion, followed by addition of a 28% aqueous ammonia solution and reaction at room temperature. The surface of the magnetite particles coated with citric acid is hydrolyzed with TEOS. It was coated with silica produced by decomposition. As a result, magnetite particle-containing silica particles having an average particle size of 100 nm (hereinafter referred to as silica particles C) were obtained.

(Amination of template particles)
After 1 g of silica particles A having an average particle diameter of 50 nm were dispersed in 20 ml of ultrapure water, the pH of this silica particle aqueous dispersion was adjusted to 3 or less using hydrochloric acid. On the other hand, 1.8 ml of 3-aminopropyltrimethoxysilane, which is a silane coupling agent, 1.7 ml of 6N hydrochloric acid, and 2 ml of ultrapure water are mixed, and the mixture is added to the silica particle aqueous dispersion prepared in the above-described procedure. The mixture was stirred vigorously while slowly adding.

  While continuing stirring, 25 ml of ethanol was added to the silica particle aqueous dispersion, and then the pH was adjusted to 5.5 using an aqueous sodium hydroxide solution. This silica particle aqueous dispersion was placed in a 70 ° C. water bath and further stirred for 4 hours to aminate the surface of the silica particles. Hereinafter, this dispersion is referred to as “aminated silica particle aqueous dispersion”.

  Next, this aminated silica particle aqueous dispersion was transferred from the water bath to a centrifuge tube, centrifuged at 20,000 G for 15 min., And the supernatant was discarded. Wash the remaining aminated silica particles by adding 20 ml of acetic acid solution at pH 2 to re-disperse the particles, then centrifuge at 20,000 G for 15 min. The precipitate of aminated silica particles finally obtained (hereinafter referred to as aminated silica particles A) was re-dispersed in a pH 2 acetic acid solution and stored. In the same procedure, silica particle B was aminated (hereinafter referred to as aminated silica particle B), and silica particle C enclosing magnetite particles was aminated in the same procedure (hereinafter aminated silica particle). Referred to as C).

(Single layer coating with magnetite particles)
The acetic acid solution in which 50 mg of aminated silica particles A were dispersed was transferred to a centrifuge tube, centrifuged at 20,000 G for 15 min., And the supernatant was discarded. Add 1 ml of ultrapure water to the precipitate of the remaining aminated silica particles to re-disperse the particles, and repeat the washing with ultrapure water three times by centrifugation at 20,000 G for 15 min. The precipitate of the aminated silica particles thus obtained was dispersed in 35 ml of ultrapure water, and the pH of the aqueous dispersion of aminated silica particles was adjusted to 5.

  On the other hand, 100 mg of citric acid-coated magnetite particles having an average particle diameter of 5 nm prepared by the above-described procedure was dispersed in 10 ml of ultrapure water to adjust the pH to 5. Hereinafter, this dispersion is referred to as “magnetite particle aqueous dispersion”. Add the aminated silica particle aqueous dispersion prepared in the above procedure to 10 ml of this magnetite particle aqueous dispersion and stir for 5 min., Then apply ultrasonic treatment for 30 sec. And stir for another 5 min. And transferred to a centrifuge tube and centrifuged at 20,000 G for 15 min. The precipitate of the magnetite silica composite particles obtained by discarding the supernatant was dispersed and stored in 10 ml of ultrapure water. The aminated silica particles C were also coated with magnetite particles in the same procedure. Here, a sample in which silica particles A are coated with magnetite particles is referred to as sample 1, and a sample in which silica particles C are coated with magnetite particles is referred to as sample 3 below.

(Multi-layer coating with magnetite particles)
After adding a solution of 500 mg of polyethyleneimine having a molecular weight of 600 in 10 ml of ultrapure water to 10 ml of a dispersion of silica particles B (average particle size 100 nm) coated with magnetite particles, stirring for 5 min. Then, the mixture was subjected to ultrasonic treatment for 30 sec., Further stirred for 5 min, transferred to a centrifuge tube, and centrifuged at 20,000 G for 15 min. The precipitate obtained by discarding the supernatant was dispersed in 10 ml of ultrapure water, and the pH was adjusted to 5.

  This dispersion was added to 10 ml of an aqueous magnetite particle dispersion and stirred for 5 min., Then sonicated for 30 sec., Stirred for another 5 min., Transferred to a centrifuge tube, and 15 min. At 20,000 G. Centrifuged. The supernatant obtained by discarding the supernatant was dispersed in 35 ml of ultrapure water and stored. This is referred to as sample 3 below.

(Pressure heating process)
Transfer 35 ml of each sample prepared in the above procedure to a 40 ml Teflon (registered trademark) container, place the Teflon (registered trademark) container in a stainless steel pressure-resistant container, place it in an oven, and place it at 200 ° C. Heated for hours.

(Template elution process)
After pressure heating, the particles in the dispersion liquid of each sample were magnetically collected by a magnet. The collected particles were washed with an aqueous sodium hydroxide solution to elute the silica remaining inside the particles. Specifically, after the dispersed particles were dispersed in 10 ml of 1N aqueous sodium hydroxide solution, the mixture was stirred at room temperature for 4 hours, and then the particles were magnetically recovered and the supernatant was discarded. And the process of magnetic recovery again was repeated 3 times. The finally obtained particles were dispersed and stored in ultrapure water as a final sample.

(2) Photographing by TEM A TEM image of magnetic iron oxide hollow particles was observed for each sample of this example. 4, 5, and 6 show TEM images of Sample 1, Sample 2, and Sample 3, respectively. As a result of obtaining the average particle size of each sample from the TEM image, sample 1 has a uniform particle size of about 50 nm as shown in FIG. 4, and samples 2 and 3 are shown in FIGS. Thus, the particles had a uniform particle size of about 100 nm. Samples 1 and 3 were found to have a single layer structure in which the outer shell was made of magnetite particles, and sample 2 was found to have a two layer structure in which the outer shell was made of magnetite particles. Furthermore, all of Samples 1 to 3 had a spherical shape with a clean outer shape and hollow portion.

(3) Verification of dispersibility After the sample 3 was dispersed and washed in ultrapure water, it was dispersed again in ultrapure water and the dispersibility was evaluated. The evaluation of dispersibility was performed based on the measurement result of the weight conversion distribution of the particle diameter using the dynamic light scattering method. FPAR-1000 (Otsuka Electronics Co., Ltd.) was used for measurement of the weight conversion distribution of particle diameter. FIG. 7 shows the measurement result of the weight-converted distribution of the particle diameter of Sample 3. As shown in FIG. 7, Sample 3 showed a unimodal distribution in the range of 203.9 ± 51.7 nm, and good dispersibility was recognized.

(4) Verification of ultrasonic contrast effect The aqueous dispersion of sample 3 was transferred to an Eppendorf tube with a volume of 2 ml, magnetic hollow particles were magnetically recovered, and the supernatant was discarded. The Eppendorf tube is placed in a 100 ml separable flask, sealed, and immersed in a 60 ° C water bath. Water remaining inside the hollow particles was evaporated.

  After stopping the diagram pump, 1 ml of 2H, 3H-decafluoropentane, an alternative fluorocarbon, was injected from the mouth of the flask closed with a rubber stopper using a syringe. Thereafter, the Eppendorf tube was taken out from the separable flask, 1 ml of ultrapure water was added thereto to disperse the hollow particles, and ultrasonic contrast was performed using UF-550XTD manufactured by Fukuda Denshi.

  8 shows a TEM image of the magnetic hollow particles of Sample 2, FIG. 8 (a) shows a TEM image of the magnetic hollow particles before evacuation, and FIG. 8 (b) shows evacuation. Then, a TEM image of magnetic hollow particles in which chlorofluorocarbon is enclosed in the hollow part is shown. As shown in FIG. 8, after vacuuming, the outer shell of the magnetic hollow particles was not damaged, and there was no change in the shape before and after vacuuming. From this result, it was shown that the outer shell of the magnetic hollow particle of this example has a necessary and sufficient strength.

  FIG. 9 shows a captured ultrasonic reflection image. FIG. 9A shows an image of the aqueous dispersion of sample 2 before the chlorofluorocarbon sealing process, and FIG. 9B shows the aqueous dispersion of sample 2 after the chlorofluorocarbon sealing process. As is clear from comparison between FIGS. 9A and 9B, the image of sample 2 after the fluorocarbon encapsulation treatment shows a clear contrast, and the fluorocarbon in the hollow portion of the magnetic hollow particles of the present example. Was shown to be securely encapsulated.

(5) Verification of magnetocaloric effect Sample 3 was dispersed in 0.7 ml of ultrapure water, placed in a measurement cell, and set in a coil. While an AC magnetic field having a frequency of 900 kHz was generated from the coil, a fiber thermometer was inserted into the particle dispersion in the cell, and the temperature change was monitored.

  FIG. 10 is a graph showing a temperature change when an AC magnetic field is applied to the aqueous dispersion of sample 3. As shown in FIG. 10, the temperature of the ultrapure water in which the sample 3 is dispersed begins to rise at a stretch when an alternating magnetic field is applied, and the temperature at which cancer cells are said to die when about 800 seconds elapse ( It was shown that the magnetic iron oxide hollow particles of this example are applicable to hyperthermia.

  As described above, according to the present invention, there are provided magnetic hollow particles that can freely control the particle diameter and the film thickness of the outer shell, and are excellent in dispersibility, and a method for producing the same. By the present invention, further application development of magnetic hollow particles is expected.

DESCRIPTION OF SYMBOLS 10 ... Silica particle, 12 ... Cationic silane coupling agent, 14 ... Modified silica particle, 16 ... Magnetic particle, 18 ... Molecule which has anionic functional group, 20 ... Modified magnetic particle, 22 ... Covering layer, 30 ... Silica particle -Magnetic particle composite, 32 ... Cationic polymer, 40 ... Silica particle-Magnetic particle-Cationic polymer composite, 42 ... Second coating layer, 50 ... Silica particle, 52 ... Second magnetic particle, 54 ... Modification Silica particles, 100 ... magnetic hollow particles, 102 ... outer shell, 104 ... hollow part, 200 ... magnetic hollow particle, 202 ... outer shell, 300 ... magnetic hollow particle

Claims (12)

  A magnetic hollow particle having a particle diameter of 100 nm or less, comprising an outer shell formed by fusing magnetic particles and a spherical hollow portion.   The magnetic hollow particle according to claim 1, wherein the outer shell has a film thickness of 10 nm or less.   The magnetic hollow particle according to claim 1 or 2, wherein the second magnetic particle is included in the hollow portion.   The magnetic hollow particle according to claim 1, wherein the magnetic particle is a magnetite particle. The magnetic hollow particle according to any one of claims 1 to 4, wherein the outer shell is a single layer film of the magnetic particle. The magnetic hollow particle according to any one of claims 1 to 4, wherein the outer shell is a laminated film in which single-layer films of the magnetic particles are laminated. A positively charged dispersion of spherical template particles is mixed with a negatively charged dispersion of magnetic particles having a particle diameter of 6 nm or less, and the magnetic particles are adsorbed on the surface of the template particles in a single layer. Forming a template-magnetic particle composite,
Pressure-heating the template-magnetic particle composite in an aqueous phase;
Eluting the template particles;
A method for producing magnetic hollow particles.   The manufacturing method according to claim 7, wherein a heating temperature in the heating step is 150 ° C to 200 ° C. The template-magnetic particle composite dispersion and the cationic polymer solution are mixed, and the cationic polymer is adsorbed on the surface of the template-magnetic particle composite to form a template-magnetic particle-cationic polymer composite. Process,
A step of mixing the template-magnetic particle-cationic polymer complex dispersion and the magnetic particle dispersion to adsorb the magnetic particles on the surface of the template-magnetic particle-cationic polymer complex in a single layer. The manufacturing method according to claim 7 or 8, further comprising:   The manufacturing method according to any one of claims 7 to 9, wherein the template particles contain second ferrite particles.   The manufacturing method according to claim 7, wherein the magnetic particles are magnetite particles. The manufacturing method according to claim 7, wherein the template particles are silica particles.