阅读说明：本技术 具有改善分散性及颗粒均匀度的磁性纳米颗粒制备方法 (Method for preparing magnetic nano-particles with improved dispersibility and particle uniformity ) 是由 唐宁 张边江 陈全战 于 2019-10-15 设计创作，主要内容包括：本发明涉及一种具有改善分散性及颗粒均匀度的磁性纳米颗粒制备方法,所述方法包括以下步骤：制备包覆介孔二氧化硅的Fe<Sub>3</Sub>O<Sub>4</Sub>纳米粒子；制备表面修饰光敏剂的二氧化硅-Fe<Sub>3</Sub>O<Sub>4</Sub>纳米核粒子；制备具有改善分散性的磁性纳米颗粒。本发明所述的方法利用大分子阻聚剂和超声分散相结合的方法,有效阻止了纳米粒子之间的相互团聚,从而制备了分散性好的磁性纳米颗粒。(The invention relates to a method for preparing magnetic nano particles with improved dispersity and particle uniformity, which comprises the following steps: preparing Fe3O4 nano particles coated with mesoporous silica; preparing silicon dioxide-Fe 3O4 nanometer nuclear particles of surface modified photosensitizer; magnetic nanoparticles with improved dispersibility are prepared. The method of the invention combines the macromolecular polymerization inhibitor and the ultrasonic dispersion, effectively prevents the mutual agglomeration of the nano particles, thereby preparing the magnetic nano particles with good dispersibility.)

1. A method for preparing magnetic nanoparticles with improved dispersibility and particle uniformity, the method comprising the steps of:

(1) Preparing mesoporous silica coated Fe3O4 nanoparticles:

dispersing Fe3O4 nano particles in 0.05-0.1 wt% hydroxyethyl cellulose aqueous solution at 50-60 ℃, adjusting the pH value to 8.5-9.0, adding tetraethyl orthosilicate and ethyl acetate under the stirring state, stirring until the tetraethyl orthosilicate and the ethyl acetate are dissolved, adding 3-aminopropyl-triethoxysilane, keeping the temperature of the reaction solution at 60-65 ℃, stirring for reacting for 16-24 hours, cooling and centrifuging the product, and washing the product with ethanol to obtain the Fe3O4 nano particles with the surface coated with mesoporous silica;

(2) Preparing silicon dioxide-Fe 3O4 nano-core particles of the surface-modified photosensitizer:

S1, dispersing the Fe3O4 nano particles with the surfaces coated with the mesoporous silica in a hydroxyethyl cellulose solution to form a dispersion liquid;

S2, dispersing the photosensitizer in DMF under the condition of keeping out of the sun, combining the photosensitizer with DMF solutions of EDC and NHS, oscillating and activating at room temperature, and adding methacryloxypropyl trimethoxy silane and Fe3O4 nanoparticle-hydroxyethyl cellulose dispersion liquid of which the surface is coated with mesoporous silica into an activation system; oscillating for reaction overnight, centrifuging and discarding supernatant, washing with deionized water, and drying to obtain mesoporous silica surface modified photosensitizer Fe3O4 nanoparticles;

wherein the concentration of the hydroxyethyl cellulose aqueous solution is 0.05-0.1 wt%;

(3) Preparation of magnetic nanoparticles with improved dispersibility:

Preparing PVA/PVP composite dispersion liquid; dispersing gold nanoparticles in DMF, combining the gold nanoparticles with DMF solution of EDC and NHS, oscillating and activating for 4 hours at room temperature, and adding Fe3O4 nanoparticle dispersion liquid of the mesoporous silica surface modification photosensitizer dispersed in PVA/PVP composite dispersion liquid into an activation system; and (3) oscillating for reaction overnight, centrifuging to remove supernatant, washing with deionized water, ultrasonically dispersing in the deionized water for 15-20min, centrifuging, and drying to obtain the magnetic nanoparticles.

2. The method according to claim 1, wherein in step (1), tetraethyl orthosilicate, ethyl acetate and 3-aminopropyl-triethoxysilane are added in a volume ratio of 10-15:20-40: 1.

3. The method according to claim 1, wherein S2 of step (2) specifically includes: dissolving photosensitizer hematoporphyrin in N, N-dimethylformamide under a dark condition, adding EDC and NHS for activation for 3-4 hours, and adding Fe3O4 nano particles which are dispersed in hydroxyethyl cellulose solution and coated with mesoporous silica into an activation system, wherein the concentration of the hydroxyethyl cellulose in the hydroxyethyl cellulose solution is 0.05-0.1 wt%; and oscillating for reaction overnight, centrifuging, removing supernatant, washing with clear water, and drying to obtain the mesoporous silica surface modified photosensitizer Fe3O4 nanoparticles.

4. the method according to claim 1, wherein in step (3), the concentration of the PVA dispersion is 0.1-0.5 wt%; the PVP dispersion concentration is 0.05-0.2 wt%, preferably 0.05-0.1 wt%.

5. The method according to claim 1, wherein in the step (3), the gold nanoparticles have a particle size of 2-5 nm.

6. Use of magnetic nanoparticles prepared according to the process of claims 1 to 5 as contrast agents for nuclear magnetic resonance.

Technical Field

The invention belongs to the technical field of magnetic resonance nano materials, and particularly relates to a preparation method of magnetic nano particles for magnetic resonance imaging.

Background

In 1973, since Lauterbour first applied Magnetic Resonance Imaging (MRI) to human body diagnosis, the technology has been rapidly developed and widely applied in the fields of biology, medicine and the like. MRI has been widely used for imaging the head, nervous system, abdomen and blood vessels of the human body, is particularly effective for detecting tissue necrosis, ischemia and various malignant lesions, and enables early diagnosis and monitoring of the metabolism of the circulatory system of the human body.

Magnetic nanomaterials have found wide application in magnetic recording, magnetic probes, etc. due to their unique magnetic properties on a nanoscale. In recent years, the application of magnetic nanoparticles has been expanded to medical fields such as magnetic resonance imaging, bio-separation, and magnetic hyperthermia.

Patent document CN201910230788.8 discloses a core-shell type magnetic nanomaterial, which is prepared according to the following principle: methacrylic acid and the surface of the Fe3O4 nano particle form a coordination reaction, methacrylic acid is anchored on the surface of the Fe3O4 particle, konjac glucomannan, methacrylic acid, a cross-linking agent, an initiator and a template are added, and the micro-spherical magnetic particle is directly polymerized by a graft copolymerization method. When the Fe3O4 magnetic nanoparticles are surface-polymerized with high molecular materials, the biocompatibility of the nanoparticles can be improved, but the finally formed spherical particles influence the high relaxation rate.

Photodynamic Therapy (PDT) is a new technology for disease diagnosis and treatment using Photodynamic effect, and its action is based on Photodynamic effect. This is a photosensitizing reaction with biological effects involving oxygen molecules. The process is that the laser irradiation with specific wavelength excites the photosensitizer absorbed by the tissue, the photosensitizer in excited state transfers the energy to the surrounding oxygen to generate singlet oxygen with strong activity, and the singlet oxygen makes the adjacent biological macromolecules generate oxidation reaction to generate cytotoxicity, thereby causing cell damage and death. Until now, a plurality of hospitals adopt photodynamic therapy to diagnose and treat tumors clinically, and the photodynamic therapy is closer to minimally invasive therapy, so that the photodynamic therapy is more suitable for treating brain tumors.

Patent document CN201510351730.0 discloses a core-shell structured nanocomposite, which uses a BaGdF5 nanocrystal as a core and mesoporous silica as a shell, and modifies a photosensitizer dihydroxysilicon phthalocyanine and a targeting agent hyaluronic acid on the surface of the mesoporous silica. The nano composite material has the functions of nuclear magnetic angiography, CT angiography, photothermal therapy and photodynamic therapy.

the inventor provides a magnetic nano material in another patent application, wherein a photosensitive material is connected to the surface of a Fe3O4 nano particle with the surface coated with mesoporous silica, and a gold nano particle with a certain particle size is embedded on the surface of the mesoporous silica material, and the gold nano particle can enhance the photodynamic therapy effect under the excitation light with a certain wavelength.

However, the nanoparticles prepared by the method have the defects of poor particle dispersity (adhesion phenomenon) and low particle size uniformity, so that the performance of the nanoparticles in application is insufficient.

this is because the prepared nanoparticles have an agglomeration phenomenon in the process of preparing the nanocomposite because of the large specific surface and high surface energy of the nanoparticles. Although the surface of the nano particles is coated by adopting a surface coating modification method, the agglomeration effect of the nano particles is weakened; however, steric repulsion is generated by the coating, which is not enough to achieve the purpose of preventing agglomeration.

Therefore, only by solving the problem of particle agglomeration of the nano material, the nano material has excellent dispersibility and particle uniformity, the special nano effect can be fully exerted in the application, and the performance of the nano material can be greatly improved.

Disclosure of Invention

The object of the present invention is to provide a method for preparing magnetic nanoparticles with improved dispersibility and particle uniformity; so as to solve the problem of particle agglomeration of the nano material, and ensure that the nano material has excellent dispersibility and particle uniformity.

The purpose of the invention is realized by the following technical scheme.

A method for preparing magnetic nanoparticles with improved dispersibility and particle uniformity comprises the following steps.

(1) Preparing mesoporous silica coated Fe3O4 nanoparticles:

Dispersing Fe3O4 nano particles in 0.05-0.1 wt% hydroxyethyl cellulose aqueous solution at 50-60 ℃, adjusting the pH value to 8.5-9.0, adding tetraethyl orthosilicate and ethyl acetate under the stirring state, stirring until the tetraethyl orthosilicate and the ethyl acetate are dissolved, adding 3-aminopropyl-triethoxysilane, keeping the temperature of the reaction solution at 60-65 ℃, stirring for reacting for 16-24 hours, cooling and centrifuging the product, and washing with ethanol to obtain the Fe3O4 nano particles with the surface coated with mesoporous silica.

Wherein the volume ratio of tetraethyl orthosilicate to ethyl acetate to 3-aminopropyl-triethoxysilane is 10-15:20-40: 1.

(2) Preparing silicon dioxide-Fe 3O4 nano-core particles of the surface-modified photosensitizer:

Dispersing Fe3O4 nano particles with mesoporous silica coated on the surface in a hydroxyethyl cellulose solution to form a dispersion liquid; dispersing a photosensitizer in DMF (dimethyl formamide), combining the photosensitizer with DMF (dimethyl formamide) solutions of EDC and NHS (polyethylene glycol NHS), oscillating and activating at room temperature, and adding methacryloxypropyl trimethoxy silane and Fe3O4 nano particle-hydroxyethyl cellulose dispersion liquid with the surface coated with mesoporous silica into an activation system; and oscillating for reaction overnight, centrifuging, discarding the supernatant, washing with deionized water, and drying to obtain the mesoporous silica surface modified photosensitizer Fe3O4 nanoparticles.

Wherein the concentration of the hydroxyethyl cellulose aqueous solution is 0.05-0.1 wt%.

preferably, the specific preparation process comprises the following steps: dissolving photosensitizer hematoporphyrin in N, N-dimethylformamide under a dark condition, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) for activation for 3-4 hours, and adding Fe3O4 nano particles coated with mesoporous silica dispersed in hydroxyethyl cellulose solution into an activation system, wherein the hydroxyethyl cellulose concentration of the hydroxyethyl cellulose solution is 0.05-0.1 wt%; and oscillating for reaction overnight, centrifuging, removing supernatant, washing with clear water, and drying to obtain the mesoporous silica surface modified photosensitizer Fe3O4 nanoparticles.

(3) preparation of magnetic nanoparticles with improved dispersibility:

Preparing PVA/PVP composite dispersion liquid; dispersing gold nanoparticles in DMF, combining the gold nanoparticles with DMF solution of EDC and NHS, oscillating and activating for 4 hours at room temperature, and adding Fe3O4 nanoparticles of mesoporous silica surface modification photosensitizer dispersed in PVA/PVP composite dispersion liquid into an activation system; and (3) oscillating for reaction overnight, centrifuging to remove supernatant, washing with deionized water, ultrasonically dispersing in the deionized water for 15-20min, centrifuging, and drying to obtain the magnetic nanoparticles.

Wherein the concentration of the PVA dispersion liquid is 0.1-0.5 wt%.

Wherein the PVP dispersion concentration is 0.05-0.3 wt%.

Preferably, the PVP dispersion concentration is between 0.05 and 0.1 wt%.

Preferably, the particle size of the gold nanoparticles is 1-5 nm.

Further preferably, the particle size of the gold nanoparticles is 2-5 nm.

In another aspect of the present invention, there is provided a use of the magnetic nanoparticle as a nuclear magnetic resonance contrast agent, comprising: imaging and positioning the brain tumor, and performing photodynamic therapy on the brain tumor by taking the nuclear magnetic imaging as guidance.

the invention has the technical effects that:

(1) When the Fe3O4 nano particles with mesoporous silica coated on the surfaces are prepared, hydroxyethyl cellulose serving as a polymerization inhibitor is adsorbed on silica particles to generate a steric hindrance effect by taking the hydroxyethyl cellulose as an organic macromolecule, so that the further aggregation of the nano particles is effectively prevented, and the dispersibility and uniformity of the formed silica-Fe 3O4 nano particles are obviously improved; and a good matrix particle foundation is laid for the final preparation of the magnetic nanoparticles.

(2) When the final magnetic particle product is prepared, a PVA (polyvinyl alcohol)/PVP (polyvinyl pyrrolidone) composite polymerization inhibitor is adopted, wherein a large amount of free polar hydroxyl groups in PVA and metal particles form a bonding effect of chelate bonds and are tightly coated around the metal particles, so that a three-dimensional surrounding shape structure limited by organic molecule long chains is formed, the size of the formed nanoparticles is limited, and the purposes of improving the particle size uniformity and preventing adhesion are achieved.

(3) In addition, PVA and PVP molecules, especially PVP molecules, coordinate with surface atoms of the formed magnetic nanoparticles through nitrogen atoms and oxygen atoms, so that long alkane chains of molecules which are not coordinated extend to the periphery of the particles, mutual agglomeration among the nanoparticles is effectively prevented, and the magnetic nanoparticles with good dispersibility are prepared.

drawings

FIG. 1 TEM photograph of Fe3O4 nanoparticles prepared in example 1

FIG. 2 TEM photograph of magnetic nanoparticles prepared in example 3

FIG. 3 TEM photograph of magnetic nanoparticles prepared in comparative example

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.