KR20210049695A - Magnetic-Optical Composite Nanoparticles - Google Patents

Abstract

The present invention relates to a nanoparticle having a magnetic-optical composite structure. The nanoparticle having a magnetic-optical composite structure comprises: quantum dots having a fluorescence signal; precious metal nanoparticles having metal-enhanced fluorescence (MEF) characteristics; and magnetic nanoparticles. Accordingly, with the nanoparticle, fluorescence signal suppression can be overcome, and improved biomolecule or biomaterial detection capability can be provided.

Description

Magnetic-Optical Composite Nanoparticles

The present invention relates to magnetic-optical composite nanoparticles, which are composed of magnetic nanoparticles and heterogeneous nanoparticles to realize both magnetic and optical functions, a method of manufacturing the same, and detection of a specific material using the same.

In more detail, it provides a platform for manufacturing magnetic-optical composite nanoparticles of various configurations, magnetic separation using magnetic properties of the magnetic-optical composite nanoparticles, and metal enhancement between noble metal nanoparticles and quantum dot nanoparticles. It relates to a method of manufacturing a probe for detecting biomolecules and improving optical performance using a fluorescence (MEF) phenomenon.

Existing in vitro diagnostic biomolecule detection methods include Enzyme-Linked Immunosorbent Assay (ELISA) and flow cytometry, but these are imported products, which are expensive and take a lot of time. In addition, organic phosphors have a short life time and a high probability of test errors in terms of poor stability.

In order to solve this problem, nanomaterials with high detection sensitivity have been recently used from various viewpoints. Although it is applied using up-conversion nanoparticles and quantum dots, they cannot separate molecules or proteins to be captured because they do not have magnetic properties. Therefore, there is a disadvantage in that beads having magnetic properties must be used, and the process is complicated to extract specific molecules and proteins to be captured.

Although the magnetic-optical nanoparticles in which metals and metal oxides were combined are expected to have great applicability, it is difficult to have uniform magnetic and optical properties in a single nanoparticle at the same time. The applicability is limited in that the particles cause quenching of the luminescent nanostructures.

In the present invention, after chemically bonding the noble metal nanoparticles to the magnetic nanoparticle-first ceramic core-shell nanoparticle surface, a second ceramic shell is formed and quantum dot nanoparticles are chemically bonded thereon to prepare a magnetic-optical composite functional nanoparticle. Provides a way to do it. In addition, the luminous efficiency of the quantum dots is improved by using the metal-enhanced fluorescence (MEF) of the magnetic-optical composite nanoparticles, and the target cells are imaged using the improved luminescence signal. In addition, a biomaterial is quantitatively analyzed using the magnetic-optical composite nanoparticles and detected through a colorimetric assay.

1. Korean Patent Application Publication No. 10-1304427

An object of the present invention is to provide a magnetic-optical composite nanoparticle composed of quantum dot nanoparticles, noble metal nanoparticles, and magnetic nanoparticles having a fluorescent signal, and a method of manufacturing the same.

In addition, an object of the present invention is to overcome the suppression of light emission signals of quantum dot nanoparticles by magnetic nanoparticles using the magnetic-optical composite nanoparticles, and to provide an ability to detect biomolecules or biomaterials.

The present invention comprises the steps of preparing a core-shell nanoparticle by forming a first ceramic shell on the magnetic nanoparticles;

Preparing core-shell nanoparticles to which noble metal nanoparticles are attached by attaching noble metal nanoparticles to the first shell surface of the core-shell nanoparticles;

Forming a second ceramic shell surrounding the core-shell nanoparticles to which the noble metal nanoparticles are attached to prepare core-double-shell nanoparticles; And

It provides a method of manufacturing a magnetic-optical composite nanoparticle comprising the step of preparing a magnetic-optical composite nanoparticle by attaching the quantum dot nanoparticle to the second shell surface of the core-double-shell nanoparticle.

In addition, the present invention is manufactured by the above-described manufacturing method,

Core-shell nanoparticles including a magnetic nanoparticle core and a first ceramic shell;

Noble metal nanoparticles formed on the surface of the first ceramic shell of the core-shell nanoparticles;

A second ceramic shell surrounding the core-shell nanoparticles in which the noble metal nanoparticles are formed; And

It provides a magnetic-optical composite nanoparticles including quantum dot nanoparticles formed on the surface of the second ceramic shell.

In addition, the present invention provides an image diagnostic composition, an analyte detection kit, or a molecular diagnostic chip including magnetic-optical composite nanoparticles.

In addition, the present invention comprises the steps of functionalizing a biomolecule capable of binding to an analyte to be detected on the surface of the magnetic-optical composite nanoparticles;

Exposing the functionalized magnetic-optical composite nanoparticles to a sample containing one or more analytes; And

It provides a method of imaging or detecting an analyte comprising the step of identifying an analyte bound to magnetic-optical composite nanoparticles using photoluminescence spectroscopy.

In the present invention, magnetic-optical composite nanoparticles composed of magnetic nanoparticles, precious metal nanoparticles, and quantum dot nanoparticles are used to specifically capture and detect biomolecules or biomaterials, as well as colorimetric analysis and light emission. Quantitative analysis using signals can be performed.

Accordingly, the magnetic-optical composite nanoparticles of the present invention can be used in various biomedical fields such as disease diagnosis, cell separation, and imaging.

In Figure 1 (a) is a schematic diagram of the manufacturing process of a magnetic-optical composite nanoparticle composed of iron oxide nanoparticles, gold nanoparticles, and cadmium selenide quantum dot nanoparticles having an amplified light emission signal of quantum dots and nanoparticles prepared in each process. A transmission electron microscopy (TEM) photograph of the particles is shown.
In Figure 1 (b) is a strategy for amplifying the intensity of the fluorescence signal using MEF by plasmonic nanoparticles such as precious metal nanoparticles, and in the process, the fluorescence signal intensity by adjusting the distance between the precious metal nanoparticle and the quantum dot nanoparticle. It is a schematic diagram showing the process of maximizing the amplification of
In FIG. 2 (a) is a schematic diagram and a transmission electron microscope photograph showing a change in thickness of a second silica shell according to the amount of a silica precursor.
In Figure 2 (b) is a graph showing the result of measuring the thickness of the second silica shell of the magnetic-optical composite nanoparticles prepared in Example.
In Figure 3 (a) is a transmission electron micrograph of a manganese-doped zinc sulfide quantum dot and a cadmium selenide quantum dot, a transmission electron micrograph of the magnetic-optical composite nanoparticles prepared in Example, and a photoluminescence spectrometer (Photoluminescence, PL). ) Shows the fluorescence signal.
In FIG. 3, (b) shows a transmission electron microscope photograph and an energy dispersive spectroscopy (EDS) photograph of the magnetic-optical composite nanoparticles prepared in Example.
In Figure 4 (a) is a schematic diagram and transmission of the magnetic-optical nanoparticles (Bare without Au) prepared in Comparative Example and the magnetic-optical composite nanoparticles (having a difference in the thickness of the second ceramic shell) prepared in Example Shows an electron microscope picture.
In FIG. 4 (b) is measured by a dynamic light scattering (DLS) in order to confirm the increase in the size of the nanoparticles according to the thickness of the second silica shell of the magnetic-optical composite nanoparticles prepared in Example. It shows the microfluidic size (a result of the change in particle size distribution), and (c) shows the result of measuring the change of the PL intensity according to the thickness of the second silica shell by photoluminescence spectroscopy of a fluorescence microscope.
In FIG. 5, (a) is a schematic diagram showing a process of specifically detecting and imaging cancer cells with magnetic-optical composite nanoparticles to which cyclic arginine-glycine-aspartic acid tripeptide (cRGD) is attached.
In Figure 5, (b) is a fluorescence microscope of brain tumor cells (U87MG cells) and breast cancer cells (MCF7 cells) using magnetic-optical composite nanoparticles to which cyclic arginine-glycine-aspartic acid tripeptide (cRGD) is attached. Shows the result of imaging with. At this time, brain tumor cells have a high level of expression of cRGD-binding receptors (integrin, integrin) on the cell surface, and breast cancer cells have a low level of integrin expression on the surface.
In Figure 6 (a) is a schematic diagram showing the process of modifying the antibody to the magnetic-optical complex structure nanoparticles and magnetically separating the antigen accordingly and detecting fluorescence, (b) is a magnetic-optical complex in which the influenza A antibody is surface functionalized The results of confirming the intensity of the light emission signal at the same time as the immunochromatographic rapid test (colorimetric analysis) according to the concentration of influenza A virus using structural nanoparticles are shown.

Hereinafter, the present invention will be described in detail.

The present invention relates to a method of manufacturing a magnetic-optical composite nanoparticle, wherein the magnetic-optical composite nanoparticle according to the present invention comprises (A) a core-shell nanoparticle by forming a first ceramic shell on the magnetic nanoparticle. A step (hereinafter, a core-shell nanoparticle manufacturing step);

(B) preparing core-shell nanoparticles with noble metal nanoparticles attached by attaching noble metal nanoparticles to the first shell surface of the core-shell nanoparticles (hereinafter, core-shell nanoparticles with noble metal nanoparticles attached thereto) Manufacturing step);

(C) forming a second ceramic shell surrounding the core-shell nanoparticles to which the noble metal nanoparticles are attached to prepare a core-double-shell nanoparticle (hereinafter, a core-double-shell nanoparticle manufacturing step); And

(D) attaching quantum dot nanoparticles to the second shell surface of the core-double-shell nanoparticles to prepare magnetic-optical composite nanoparticles (hereinafter, magnetic-optical composite nanoparticle manufacturing step). have.

In the present invention, the (A) core-shell nanoparticle manufacturing step is a step of preparing a magnetic nanoparticle-ceramic core-shell nanoparticle by forming a first ceramic shell on the magnetic nanoparticle.

The step may be performed by mixing the ceramic precursor solution with the first solution including magnetic nanoparticles, and through the step, a second solution including the first core-shell nanoparticles may be prepared.

In one embodiment, the magnetic nanoparticles form the core of the core-shell nanoparticle. The magnetic nanoparticles may be metal oxide nanoparticles, and the metal oxides are FeO, Fe ₂ O ₃ , Fe ₃ O ₄ , CoFe ₂ O ₄ , NiFe ₂ O ₄ , MnFe ₂ O ₄ , TiO ₂ , ZrO ₂ , It may be at least one selected from the group consisting of _{CeO 2} , Al ₂ O _{3 and MgO.} In the present invention, magnetism may be imparted to the magnetic-optical composite nanoparticles finally prepared by using the metal oxide.

The magnetic nanoparticles may be composed of a cluster or self-assembly of magnetic nanoparticles.

The average particle diameter of the magnetic nanoparticles, clusters, or self-assembly is not limited as long as it is larger than the noble metal nanoparticles and quantum dot nanoparticles to be described later, but may be, for example, 10 to 500 nm. In addition, the magnetic nanoparticles, clusters, or self-assembly may be spherical. In the present invention, the term'spherical' may encompass not only the mathematical definition of a three-dimensional shape consisting of all points at the same distance from one point, but also those having an apparently rounded shape.

In one embodiment, the first ceramic shell may serve to protect magnetic nanoparticles.

The ceramic may include at least one selected from the group consisting of silica, titania, zirconia, alumina, and zeolite, and in the present invention, silica may be used to form a silica shell.

The thickness of the first ceramic shell is not particularly limited, and for example, the thickness of the shell may be adjusted to 1 to 100 nm, 5 to 50 nm, or 1 to 20 nm.

In one embodiment, the first ceramic shell may be formed through a reaction of magnetic nanoparticles and a ceramic precursor. At this time, an alkoxy compound may be used as the ceramic precursor, and specifically, at least one selected from the group consisting of tetraethyl orthosilicate (TEOS) and tetramethyl orthosilicate (TMOS) may be used.

In the present invention, (B) core-shell nanoparticles with noble metal nanoparticles are attached to the core-shell nanoparticles prepared in step (A) by attaching noble metal nanoparticles to the core-shell nanoparticles prepared in step (A). It is a step of manufacturing. In the present invention, core-shell nanoparticles to which noble metal nanoparticles are attached may be expressed as metal-enhanced fluorescent template nanoparticles.

In the present invention, the step (B) includes the steps of introducing a functional group to the surface of the first ceramic shell of the core-shell nanoparticles; And

It may include the step of bonding the noble metal nanoparticles to the functional group.

In addition, step (B) in the present invention includes the steps of introducing a functional group to the surface of the first ceramic shell of the core-shell nanoparticles;

Bonding a noble metal nanoparticle seed to the functional group; And

It may include the step of preparing the noble metal nanoparticles by growing the noble metal nanoparticle seed bound to the functional group.

Specifically, in step (B), a third solution containing core-shell nanoparticles having a functional group introduced into the surface of the first ceramic shell by adding a functional group-containing compound to the second solution prepared in step (A) is prepared. can do.

In addition, a solution 4-1 including core-shell nanoparticles to which noble metal nanoparticles are attached may be prepared by adding a noble metal nanoparticle solution to the third solution. Alternatively, a solution including core-shell nanoparticles with noble metal nanoparticle seeds attached may be prepared by adding a noble metal nanoparticle seed solution to the third solution, and noble metal nanoparticles by adding a noble metal ion precursor solution to the solution By growing the seed into nanoparticles, a solution 4-2 including core-shell nanoparticles in which the grown noble metal nanoparticles are formed may be prepared.

In one embodiment, the type of the noble metal is not particularly limited, and may be, for example, gold, silver, platinum, copper, or an alloy thereof.

In the present invention, through the step of introducing a functional group to the surface of the first ceramic shell of the core-shell nanoparticle, the functional group is introduced to the surface of the first ceramic shell of the core-shell nanoparticle, and the functional group is a noble metal nanoparticle or a noble metal nanoparticle. It can form multiple bonds with the seed.

In one embodiment, the functional group may be selected from the group consisting of an amine group (-NH), a thiol group (-SH), a carboxyl group (-COOH), a hydroxyl group (-OH), and dopamine. Specifically, the functional group may be an amine group, and an amine group may be introduced into the shell surface by reacting the core-shell nanoparticles with the amine group-containing compound.

In the step of coupling the noble metal nanoparticles to the functional group of the present invention and the noble metal nanoparticle seed to the functional group, the functional group forms a bond with the noble metal nanoparticle or the noble metal nanoparticle seed, and is formed on the core-shell nanoparticle. Noble metal nanoparticles or noble metal nanoparticle seeds may be attached.

At this time, the noble metal nanoparticles or the noble metal nanoparticle seeds may be prepared through a general manufacturing method in the art, and specifically, may be synthesized in an aqueous solution using a noble metal ion precursor solution and a reducing agent. It can be prepared as a noble metal nanoparticle or a noble metal nanoparticle seed by changing conditions such as the noble metal ion precursor, the type and concentration of the reducing agent, and the reaction temperature.

When gold is used as a noble metal, gold chloride trihydrate (HAuCl ₄ 3H ₂ O), potassium gold (III) chloride, K (AuCl ₄ ), and potassium dicyanoaurate are used as gold ion precursors. , KAu (CN) ₂ ) can be used at least one selected from the group consisting of, and when using silver as a noble metal, silver nitrate (AgNO ₃ ) as a silver ion precursor, and potassium silver cyanide (Potassium dicyanoaurate, KAg (CN)) ₂ ) and silver acetate may be used. When platinum is used as a noble metal, potassium tetrachloroplatinate (K ₂ PtCl ₄ ), platinum chloride (platinum chloride PtCl ₄ ) and chloroplatinic acid (hexachloroplatinic acid, H ₂ PtCl ₆ ) can be used, and when using copper as a noble metal, copper nitrate hydrate (Cu(NO ₃ )) as a precursor of copper ions ₂ · 3H ₂ O) and copper sulfate pentahydrate (CuSO ₄ · 5H ₂ O) can be used at least one selected from the group consisting of, and when palladium is used as a noble metal, palladium acetylacetonate ( palladium acetylacetonate), palladium chloride (PdCl ₂ ), and palladium nitrate (palladium nitrate hydrate, Pd(NO ₃ ) ₂ ·H ₂ O). In addition, as a reducing agent, sodium citrate (Na ₃ Cit), sodium borohydrate (NaBH ₄ ), hydroquinone, sodium ascorbate, and hydroxyl amine. One or more selected from the group can be used.

In addition, the synthesis may be carried out in the presence of a stabilizer, and at this time, as a stabilizer, at least one selected from the group consisting of PVP (polyvinylpyrrolidone), sodium citrate (trisodium citrate), and SDS (sodium dodecyl sulfate) may be used. have. In addition, the synthesis may be carried out by using a magnetic nucleation inhibitor or the like, and potassium iodide may be used as the magnetic nucleation inhibitor of gold, and acetonitrile may be used as the magnetic nucleation inhibitor of silver.

The reducing agent not only acts as a reducing agent for reducing the noble metal in the aqueous solution, but also may impart a negative charge around the synthesized noble metal nanoparticles. Therefore, the reduced noble metal nanoparticles or noble metal nanoparticle seeds are well dispersed in the aqueous solution due to the surface negative charge, and can be strongly bonded to meet functional groups such as amine groups. Therefore, the noble metal nanoparticles or the noble metal nanoparticle seeds form a strong bond with the functional groups on the surface of the ceramic shell of the core-shell nanoparticles, and attach or grow the noble metal nanoparticles to the core-shell nanoparticles to form a metal enhanced fluorescent template nanoparticle. Can be manufactured.

In one embodiment, after reacting the core-shell nanoparticles into which the functional group has been introduced with the noble metal nanoparticles, a stabilizer may be further treated, and at this time, the above-described type of stabilizer may be used without limitation.

In the present invention, when the noble metal nanoparticle seed is used, the step of preparing the noble metal nanoparticle by growing the noble metal nanoparticle seed bound to the functional group may be further performed.

The above step may be performed by adding a noble metal ion precursor solution to a solution containing core-shell nanoparticles to which noble metal nanoparticle seeds are attached. Through the above step, a noble metal nanoparticle seed may be used as a seed, and the seed may be grown as a nanoparticle, and the size and optical properties of the nanoparticle may be improved. In this case, the noble metal ion precursor used in the production of the seed may be used as the noble metal ion precursor, and the aforementioned type may be used as a reducing agent. In addition, it is possible to additionally use stabilizers of the type described above.

The noble metal nanoparticle seed is grown by attaching the noble metal nanoparticle seed to the ceramic surface of the core-shell nanoparticle, and then growing, so that the noble metal nanoparticle grows in contact with the ceramic surface. It has an easy advantage. In addition, when the noble metal nanoparticles are grown, networking between the nanoparticles may occur, forming a robust structure that can never be separated from the ceramic surface.

In one embodiment, the average particle diameter of the noble metal nanoparticles or the grown noble metal nanoparticles may be 5 to 50 nm. In the above range, a wavelength range in which metal-enhanced fluorescence is possible can be adjusted.

In the present invention, the (C) core-double-shell nanoparticle manufacturing step is a step of preparing a core-double-shell nanoparticle by forming a second ceramic shell surrounding the core-shell nanoparticle to which the noble metal nanoparticle is attached.

The step may be performed by mixing the ceramic shell precursor solution with the 4-1 solution or the 4-2 solution prepared in step (B), and the core-double-shell nanoparticles in which the second ceramic shell is formed through the above step It is possible to prepare a fifth solution containing.

In one embodiment, the second ceramic shell serves to protect the core-shell nanoparticles to which the noble metal nanoparticles are attached, that is, the metal-enhanced fluorescent template nanoparticles, and at the same time adjust the distance between the noble metal nanoparticles and the quantum dot nanoparticles to be attached later. It can play a regulating role.

The ceramic may be used without limitation in the above-described type in the first ceramic shell, and for example, at least one selected from the group consisting of silica, titania, alumina, zirconia, and zeolite may be used. In the present invention, silica may be used to form the second ceramic shell.

In one embodiment, the second ceramic shell may be formed through a reaction of a core-shell nanoparticle to which noble metal nanoparticles are attached and a ceramic precursor. At this time, an alkoxy compound may be used as the ceramic precursor, and specifically, at least one selected from the group consisting of tetraethyl orthosilicate (TEOS) and tetramethyl orthosilicate (TMOS) may be used. In the present invention, the thickness of the secondary ceramic shell can be adjusted by varying the content of the precursor.

In one embodiment, the thickness of the second ceramic shell is 5 nm to 100 nm, 5 to 50 nm, or 5 to 20 nm, and noble metal nanoparticles may be included in the second ceramic shell.

In the present invention, (D) the magnetic-optical composite nanoparticle manufacturing step is a step of preparing a magnetic-optical composite nanoparticle by attaching the quantum dot nanoparticle to the second shell surface of the core-double-shell nanoparticle.

Specifically, the step may be performed by adding a functional group-containing compound to the fifth solution prepared in step (C), and through the step, a sixth step comprising nanoparticles having a functional group introduced into the surface of the second ceramic shell. Solutions can be prepared. In addition, a seventh solution including magnetic-optical composite nanoparticles may be prepared by adding quantum dot nanoparticles to the sixth solution.

In the present invention, step (D) includes introducing a functional group to the surface of the second ceramic shell; And it may include the step of bonding the quantum dot nanoparticles to the functional group.

In one embodiment, the functional group may be selected from the group consisting of a thiol group (-SH), an amine group (-NH2), a carboxyl group (-COOH), and a hydroxyl group (-OH). Specifically, the functional group may be a thiol group, and a thiol group may be introduced into the shell surface by reacting a core-double-shell nanoparticle with a thiol group-containing compound.

In one embodiment, the functional group is strongly bonded to the quantum dot nanoparticles, and the quantum dot nanoparticles may be attached to the core-double-shell nanoparticles.

In one embodiment, the quantum dot nanoparticles are cadmium selenide (CdSe), cadmium sulfide (CdS), zinc oxide (ZnO), zinc selenide (ZnSe), zinc sulfide (ZnS) and zinc sulfide doped with manganese (Mn-doped). ZnS), indium phosphide (InP), and cesium lead halide (CsPbBr ₃ , CsPbI ₃ ) may include at least one selected from the group consisting of quantum dots.

These quantum dot nanoparticles may be prepared through a general manufacturing method in the art, and specifically, may be synthesized using a quantum dot ion precursor, a reducing agent, and a stabilizer on an organic solvent. At this time, the quantum dot ion may be zinc, sulfur, manganese, cadmium, selenium, indium, phosphorus, cesium, lead, bromine, or iodine.

One or more selected from the group consisting of zinc chloride dehydrate (ZnCl2), zinc acetate, and zinc nitrate may be used as the zinc ion precursor, and sulfur powder as a sulfur ion precursor And one or more selected from the group consisting of dodecyl mercaptan (1-dodecanethiol) may be used, and one or more selected from the group consisting of manganese chloride and manganese nitrate may be used as a manganese ion precursor. , One or more selected from the group consisting of cadmium oxide and cadmium chloride may be used as a cadmium ion precursor, and a group consisting of selenium powder and selenium oxide as a selenium ion precursor One or more selected from the group may be used, and one or more selected from the group consisting of indium acetate, indium chloride, and indium fluoride may be used as the indium ion precursor. Tris (trimethylsilyl) phosphine may be used, and at least one selected from the group consisting of cesium bromide and cesium iodide may be used as a cesium ion precursor, and lead bromide ( lead bromide) and lead iodide. In addition, as a reducing agent and a stabilizer, at least one selected from the group consisting of dibenzylamine, oleylamine, oleic acid, and octadecylamine may be used. ), dimethylformamide (DMF), and at least one selected from the group consisting of toluene.

In one embodiment, the size of the quantum dot nanoparticles may be 3 to 15 nm.

In addition, the present invention relates to magnetic-optical composite nanoparticles. Magnetic-optical composite nanoparticles according to the present invention can be prepared by the above-described manufacturing method.

Magnetic-optical composite nanoparticles according to the present invention include a core-shell nanoparticle including a magnetic nanoparticle core and a first ceramic shell;

Noble metal nanoparticles formed on the surface of the first ceramic shell of the core-shell nanoparticles;

A second ceramic shell surrounding the core-shell nanoparticles in which the noble metal nanoparticles are formed; And

It may include quantum dot nanoparticles formed on the surface of the second ceramic shell.

The magnetic-optical composite nanoparticles according to the present invention may simultaneously implement magnetic and optical functions, including magnetic nanoparticles, precious metal nanoparticles, and quantum dot nanoparticles.

In one embodiment, the noble metal nanoparticles bonded to the surface of the core-shell nanoparticles may be included in the second ceramic shell. Therefore, the quantum dot nanoparticles may be located outside the noble metal nanoparticles bonded to the core-shell nanoparticle surface.

In particular, in the present invention, optical performance may be improved by using a metal-enhanced fluorescence (MEF) phenomenon between noble metal nanoparticles and quantum dot nanoparticles. Metal-enhanced fluorescence (MEF) is a phenomenon in which the luminous efficiency increases when a specific metal and a phosphor are connected by a covalent or non-covalent bond with a certain distance between them and emits light that is brighter than the maximum value of the self-brightness originally possessed by the phosphor. it means. In the present invention, the luminous efficiency of the quantum dot nanoparticles can be improved through metal-enhanced fluorescence (MEF) between the noble metal nanoparticles and the quantum dot nanoparticles having fluorescence characteristics, and the target cells can be imaged using the improved luminescence signal. In particular, in the present invention, the luminescence characteristics of the quantum dot nanoparticles can be adjusted according to the purpose of use by adjusting the distance between the noble metal nanoparticles and the quantum dot nanoparticles through the second ceramic shell.

In addition, the present invention relates to an image diagnostic composition, an analyte detection kit, or a molecular diagnostic chip comprising the above-described magnetic-optical composite nanoparticles.

In addition, the present invention comprises the steps of functionalizing a biomolecule capable of binding to an analyte to be detected on the surface of a magnetic-optical composite nanomaterial particle;

Exposing the functionalized magnetic-optical composite nanoparticles to a sample containing one or more analytes; And

It relates to a method of imaging or detecting an analyte, comprising the step of identifying an analyte bound to magnetic-optical composite nanoparticles using photoluminescence spectroscopy.

The magnetic-optical composite nanoparticles according to the present invention are functionalized biomolecules capable of recognizing an analyte to be detected, and thus can be used as a probe that can be applied to detect various target biomolecules.

In one embodiment, the analyte to be detected is amino acid, peptide, polypeptide, protein, glycoprotein, lipoprotein, nucleoside, nucleotide, oligonucleotide, nucleic acid, sugar, carbohydrate, oligosaccharide, polysaccharide, fatty acid , Lipids, hormones, metabolites, cytokines, chemokines, receptors, neurotransmitters, antigens, allergens, antibodies, substrates, metabolites, cofactors, inhibitors, drugs, pharmaceuticals, nutrients, prions, toxins, poisons, explosives, It may be an insecticide, a chemical inorganic agent, a biohazard agent, a radioisotope, a vitamin, a heterocyclic aromatic compound, a carcinogen, a mutagenic agent, an anesthetic agent, an amphetamine, barbiturate, a hallucinogen, a waste or a contaminant. In addition, when the analyte is a nucleic acid, the nucleic acid may include genes, viral RNA and DNA, bacterial DNA, fungal DNA, mammalian DNA, cDNA, mRNA, RNA and DNA fragments, oligonucleotides, synthetic oligonucleotides, modified oligonucleotides, single It may be a nucleic acid of both stranded and double stranded, natural and synthetic.

In one embodiment, a biomolecule capable of recognizing an analyte and capable of binding to the surface of the composite nanoparticle according to the present invention is an antibody, antibody fragment, genetically engineered antibody, single chain antibody, receptor protein, binding protein, It may be an enzyme, inhibitor protein, lectin, cell adhesion protein, oligonucleotide, polynucleotide, nucleic acid or aptamer.

Photoluminescence spectroscopy using magnetic-optical composite nanoparticles according to the invention can show a stronger signal intensity due to the interaction between the noble metal part of the nanoparticles and the quantum dots, so it can be detected even when the amount of analyte is small. This could be possible. In addition, magnetic separation of analytes bound to magnetic-optical composite nanoparticles is possible by using magnetic properties, and can be used for very high sensitivity biomolecular analysis, and is also very useful as an in vitro diagnostic and imaging technology.

Hereinafter, the present invention will be described in more detail through examples. It is obvious that these examples are only for the purpose of describing the present invention easily, and that the scope of the present invention is not limited to the examples presented.

Example

Example 1. Preparation of magnetic-optical composite nanoparticles

1) Magnetite (Fe ₃ O ₄ ) Synthesis of nanoparticles

The synthesis of iron oxide, specifically magnetite (Fe ₃ O ₄ ) nanoparticles, was performed through a polyol method.

Iron chloride hexahydrate (FeCl ₃ 6H ₂ O) is an iron ion precursor, ethylene glycol (EG) is a reducing agent and solvent, sodium acetate (NaOAc), H ₂ O is hydrolyzed. It was used as an adjuvant to help.

In 50 mL of EG, FeCl3·6H ₂ O 2 mmol, NaOAc 6 mmol, H ₂ O 150 mmol were added, and then placed in a 3-neck flask, and then rapidly heated to 200° C. for 15 minutes while mechanically stirring. The reaction time was maintained at 3 hours and 30 minutes, cooled, washed with ethanol, and dispersed in ethanol (preparation of the first solution).

2) Gold nanoparticle or gold nanoparticle seed synthesis

In the synthesis of gold nanoparticles, gold chloride trihydrate (HAuCl ₄ 3H ₂ O) was used as a gold ion precursor, sodium citrate (Na ₃ Cit) was used as a reducing agent and stabilizer, and H ₂ O as a solvent. .

HAuCl ₄ · 3H ₂ O 1 mM 100 mL was heated to 100° C., and then, while magnetic stirring was maintained, _{10 mL of Na 3} Cit 38.8 mM was injected. The reaction proceeded for 1 hour, cooled to room temperature, and stored at room temperature.

In addition, in the synthesis of gold nanoparticle seeds, HAuCl ₄ · 3H ₂ O was used as a gold ion precursor, sodium borohydrate (NaBH ₄ ) was used as a reducing agent, Na ₃ Cit was used as a stabilizer, and H ₂ O was used as a solvent.

In H ₂ O 50 mL HAuCl ₄ · 3H ₂ O Point the concentration of the concentration of 0.25 mM, Na ₃ Cit of a 0.25 mM, were added to 1.5 mL of 0.1M NaBH _4. It was reacted for 6 hours while maintaining magnetic stirring at room temperature.

3) Preparation of core-shell nanoparticles with gold nanoparticles attached

First, a silica shell was formed on the iron oxide nanoparticles using the Stober method.

Ethanol and water (H ₂ O) are solvents, ammonium hydroxide solution (NH ₄ OH) is a catalyst, tetraethyl orthosilicate (TEOS) is a silica precursor, polyvinylpyrrolidone (PVP). ) Was used as a stabilizer.

Ethanol 60 mL, H ₂ O 9 mL, and NH ₄ OH 3 mL were mixed. 30 mg (first solution) of iron oxide nanoparticles was added to the solution. After adding 0.060 mL of TEOS to a homogeneous mixed solution in which iron oxide nanoparticles were mixed, the mixture was shaken at room temperature for 2 hours. Then, it was washed with ethanol and dispersed in 12 mL of ethanol. Through this, iron oxide nanoparticles-silica core-shell nanoparticles were synthesized (preparation of a second solution).

Gold nanoparticles or gold nanoparticle seeds were attached to the iron oxide nanoparticles-silica core-shell nanoparticles.

First, iron oxide nanoparticles-silica core-shell nanoparticles were functionalized.

(3-Aminopropyl)triethoxysilane (APTES) was used _{as a precursor of an amine group (-NH 2} ), and 2-propanol was used as a solvent.

The second solution, iron oxide nanoparticles-silica core-shell nanoparticles, containing 4 mL of ethanol was substituted with 10 mL of 2-propanol, and 0.10 mL of APTES was added and shaken. It was at 80 ℃ after sonic treatment (sonication) for 4 hours, washed with H ₂ O and dispersed in 5 mL H ₂ O (3 solution, Ltd.).

5 mL of a third solution containing iron oxide nanoparticles-silica core-shell nanoparticles functionalized on the surface of the amine group and 25 mL of a gold nanoparticle solution or a gold nanoparticle seed solution were mixed and shaken for 16 hours. _{And after the post-treatment, 20 mL of H 2} O in which PVP was dissolved in 1 wt% was added as a stabilizer and shaken evenly. Then, H ₂ O and washed by dispersion in 20 mL (4-1 solution prepared / gold nano-particle solution was used) in H ₂ O.

When the gold nanoparticle seed solution was used, gold nanoparticle seeds attached to the surface were grown into gold nanoparticles.

PVP was used as a stabilizer, ascorbic acid (L-ascorbic acid) was used as a reducing agent, and tetrachloride hydrate (HAuCl ₄ ·3H ₂ O) was used as a gold ion precursor.

After adding 10 mg of iron oxide-silica core-shell nanoparticles with gold nanoparticle seeds attached to _{200 mL of H 2} O containing 1 wt% PVP, 4 mL of 20 mM ascorbic acid aqueous solution was added and shaken to be uniformly mixed. Then, 6 mL of 5 mM HAuCl ₄ ·3H ₂ O aqueous solution was divided into 6 portions at 10 minute intervals. It reacted for 1 hour while shaking at room temperature. Washed with H ₂ O and ethanol, and dispersed in 20 mL of ethanol (preparation of solution 4-2).

4) Formation of a second silica shell on the surface of core-shell nanoparticles (metal-enhanced fluorescent template nanoparticles) with gold nanoparticles attached (core-double-shell nanoparticle production)

A silica shell was formed in a solution (solution 4-1 or solution 4-2) containing metal-enhanced fluorescent template nanoparticles, which are iron oxide-silica core-shell nanoparticles to which gold nanoparticles are bound, using a stover method.

Ethanol and water (H ₂ O) were used as a solvent, aqueous ammonia (NH ₄ OH) as a catalyst, and tetraethyl orthosilicate (TEOS) as a silica precursor.

1 mL of ethanol, 0.15 mL of _{H 2 O, and 0.1 mL of NH 4} OH were mixed. 0.5 mg of metal-enhanced fluorescent template nanoparticles were added to the solution. Metal-enhanced fluorescence template Add 0.001 to 0.006 mL of TEOS 0.001 mL per 10 minutes to obtain the desired silica thickness (3 nm, 5 nm, 10 nm, 20 nm, 30 nm and 35 nm) in a homogeneous mixed solution mixed with nanoparticles. After putting it in, it was shaken at room temperature. Then, it was washed with ethanol and dispersed in 10 mL of ethanol (preparation of the fifth solution).

In the present invention, FIG. 2 is a schematic diagram showing a change in the thickness of a second silica shell according to the amount of orthosilicate (TEOS), a transmission electron microscope photograph (a), and a graph showing the result of measuring the thickness of the second silica shell (b) to be. In FIG. 2, metal-enhanced fluorescent template nanoparticles were prepared using the 4-2 solution.

5) Functionalization of the second silica shell surface of core-double-shell nanoparticles

In order to attach the quantum dots, the second silica shell surface of the core-double-shell nanoparticles was functionalized.

(3-Mercatopropyl)-trimethoxysilane (MPTS) was used as a precursor of a thiol group (-SH), and ethanol was used as a solvent.

0.50 mL of MPTS was added to 10 mL of ethanol containing the fifth solution, core-double-shell nanoparticles, and shaken. The reaction proceeded at 25° C. for 16 hours. Washed with ethanol, and dispersed in 1 mL of ethanol (preparation of solution 6).

6) Manganese (Mn) doped zinc sulfide (ZnS) quantum dot nanoparticles and cadmium selenide (CdSe) nanoparticle synthesis

In the synthesis of manganese-doped zinc sulfide quantum dot nanoparticles, zinc chloride (ZnCl ₂ ) is a zinc ion precursor, sulfur powder is a sulfur ion precursor, and manganese chloride (MnCl ₂ ) is manganese. As an ion precursor, dibenzylamine was used as a solvent and a reducing agent.

ZnCl ₂ 0,4 g, MnCl ₂ 20 mg, sulfur powder 0.6 g was added to 54 mL of dibenzylamine, and magnetic stirring was performed. Rapidly heated from 25° C. to 120° C. for 10 minutes, and the reaction time was maintained for 1 hour. Then, it was rapidly heated to 260° C. for 15 minutes, and the reaction time was maintained. The temperature was lowered to 150° C. in a room temperature atmosphere, and a mixed solution of 0.4 g of _{ZnCl 2 and 5 mL of dibenzylamine was added.} Then, it was rapidly heated to 260° C. for 15 minutes, and the reaction was maintained for 15 minutes. After cooling the reaction-completed solution in a room temperature atmosphere, 5 mL of oleylamine was added to stabilize it. Then, it was washed with ethanol and dispersed in chloroform.

In the synthesis of cadmium selenide quantum dot nanoparticles, cadmium oxide (CdO) is a cadmium ion precursor, octadecene (ODE) is a non-coordinating solvent, oleic acid (OA) is a surfactant, and octadecylamine ( octadecylamine (ODA) was used as a stabilizer, selenium (Se) was used as a selenium ion precursor, and trioctylphosphine (TOP) was used as a coordination solvent for selenium.

After dissolving 0.26 g of CdO in 40 mL of ODE in a three-necked flask, 2 mL of OA was injected. Under a nitrogen atmosphere, the mixed solution was rapidly heated to 160° C. within 10 minutes and held for 1 hour. Then, it was heated rapidly to 260° C. within 10 minutes, in the process the solution became transparent. After maintaining at 260°C for 30 minutes, it was naturally cooled to 200°C. 3 g of ODA was injected into the mixed solution and rapidly heated to 300° C. within 10 minutes. When the solution reached 300° C., 0.78 g of Se was dissolved in 5 mL of TOP, and then injected into the mixed solution, followed by reacting for 5 minutes to prepare cadmium selenide quantum dots. After cooling rapidly to room temperature, it _{was washed with chloroform (CHCl 3} ) and ethanol, and dispersed in chloroform.

7) Preparation of magnetic-optical composite nanoparticles

In this step, when using zinc sulfide quantum dots doped with manganese, solution 4-2 was used, and when cadmium selenide quantum dots were used, solution 4-1 was used.

The sixth solution, 1 mL of ethanol containing core-double-shell nanoparticles with functionalized thiol groups, was shaken with 0.2 mL (10 mg/mL) of chloroform containing manganese-doped zinc sulfide quantum dots or cadmium selenide quantum dots. . The reaction was carried out at 25° C. for 16 hours. Thereafter, magnetic separation was performed to remove non-stick quantum dots to prepare magnetic-optical composite nanoparticles and dispersed in 2 mL of ethanol (preparation of solution 7).

Comparative Example 1.

Steps 3) to 5) of Example 1 were not performed, and steps 6) to 7) were performed in the same manner to prepare magnetic-optical nanoparticles that do not contain noble metal (gold) nanoparticles.

Experimental Example 1. Physical properties of magnetic-optical composite nanoparticles

In Figure 1 (a) shows a schematic diagram of a manufacturing process (step) of a magnetic-optical composite nanoparticle according to the present invention and a transmission electron microscope (TEM) photograph at each step.

In addition, (b) uses a phenomenon in which metal-enhanced fluorescence (MEF) appears when a fluorescent signal is generated around plasmonic nanoparticles such as gold nanoparticles, and is applied to magnetic-optical composite nanoparticles to prevent quantum dot nanoparticles. It is a schematic diagram showing that the fluorescence signal is increased. In the present invention, the fluorescence signal can be maximized by adjusting the distance between the noble metal nanoparticles and the quantum dot nanoparticles using the thickness of the second silica shell.

In Figure 3 (a) shows a transmission electron micrograph of the zinc sulfide quantum dot nanoparticles doped with manganese and the cadmium selenide nanoparticles, and also the transmission electron micrograph of the magnetic-optical composite nanoparticles prepared in Example The results measured by photoluminescence (PL) are shown. The left graph was measured with a wavelength of 310 nm, and the right graph was measured with a wavelength of 532 nm.

In FIG. 3, (b) is a transmission electron microscope photograph and an energy dispersive spectroscopy (EDS) photograph of magnetic-optical composite nanoparticles prepared using zinc sulfide quantum dot nanoparticles doped with manganese. Through the energy dispersive spectroscopy photograph, it can be confirmed that magnetic nanoparticles, gold nanoparticles, and quantum dot nanoparticles exist in the magnetic-optical composite nanoparticles.

In FIGS. 3A and 3B, the thickness of the second silica shell is 10 nm.

In addition, (a) in Figure 4 is the magnetic-optical nanoparticles (Bare without Au) prepared in Comparative Example 1, and four kinds of magnetic-optical composites according to the distance between the noble metal nanoparticles and the quantum dot nanoparticles prepared in Example The schematic diagram and transmission electron micrograph of the particles of structural nanoparticles (using cadmium selenide quantum dot nanoparticles) are shown.

(b) shows the hydrodynamic size measured by a dynamic light scattering (DLS) of four types of magnetic-optical composite nanoparticles (using cadmium selenide quantum dot nanoparticles) prepared in Example. As shown in (b) of FIG. 4, it can be seen that as the thickness of the silica shell increases, the hydrodynamic size increases with the same tendency.

In addition, (c) is after drying the four types of magnetic-optical composite nanoparticles (using cadmium selenide quantum dot nanoparticles) prepared in Comparative Examples and Examples on a cover glass, and then calculating the fluorescence signal intensity. It shows the results measured by a focal Raman-fluorescence microscope (Confocal Raman Microscopy). At this time, a 40x objective lens was used and a laser wavelength of 532 nm was used. The power at the time of laser irradiation was 0.139 mW, and the acquisition time was measured as 1 second.

Based on the comparative example without noble metal nanoparticles, it can be seen that when the silica shell is as thin as 5 nm, fluorescence quenching by the precious metal nanoparticles appears, and when it reaches 10 nm, the fluorescence intensity increases due to metal-enhanced fluorescence. have. In addition, at 15 nm and 20 nm, the interaction between the noble metal nanoparticles and the fluorescent quantum dots was small, and thus it was confirmed that the results were almost similar to those of the comparative example.

Experimental Example 2. Target cell image using magnetic-optical composite nanoparticles

Surface functionalization was performed to detect biomolecules of the magnetic-optical composite nanoparticles prepared in Examples. The used magnetic-optical composite nanoparticles were prepared using cadmium selenide quantum dot nanoparticles.

First, the magnetic-optical composite nanoparticles prepared in Example were used to form a silica shell using the Stover method.

Ethanol and water (H ₂ O) were used as a solvent, aqueous ammonia (NH ₄ OH) as a catalyst, and tetraethyl orthosilicate (TEOS) as a silica precursor.

To 2 mL of ethanol, 0.15 _{mL of H 2 O and 0.05 mL of NH 4} OH were added to mix evenly, 0.001 mL of TEOS was added, and the silica shell was shaken for 2 hours. Washed with ethanol and dispersed in 20 mL of ethanol.

Then, in order to attach the biomolecules, the silica-coated magnetic-optical composite nanoparticles were functionalized.

(3-aminopropyl)triethoxysilane (APTES) as _{a precursor of amine group (-NH 2} ), sodium dodecyl sulfate (SDS) as a stabilizer, succinimidyl ester with molecular weight of 5,000 Daltons-polyethylene glycol -Carboxymethyl (Succinimidyl ester-polyethyleneglycol-carboxymethyl, SC-PEG-COOH) is used as a stabilizer for magnetic-optical complex nanoparticles and a precursor of carboxyl group (-COOH), 1-ethyl-3-(3-dimethylaminopropyl). ) Carbodiimide (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and sulfo-N-hydroxysuccinimide (sulfo-NHS) as catalysts for amide bonding, ethanol and Phosphate buffered saline (PBS) was used as a solvent, and cyclic arginine-glycine-aspartic acid tripeptide (cRGD) was used to capture integrin, a receptor expressed on the surface of cells.

0.05 mL of APTES was injected into 1 mL of the prepared nanoparticles (magnetic-optical composite nanoparticles coated with silica) and shaken for 16 hours. This _{was washed with H 2} O and dispersed in 1 mL of a 0.01% SDS solution (including 0.05 mg/mL of iron oxide nanoparticles). 0.05 mL of 1 mM SC-PEG-CM was mixed with the nanoparticle solution, and the light was blocked with aluminum foil, followed by shaking for 16 hours. Thereafter, washing with H ₂ O, which was dispersed in H ₂ O 1 mL. In this process, carboxyl groups were modified on the surface of the magnetic-optical composite nanoparticles coated with silica. 20 mM EDC and 0.05 mL of sulfo-NHS were added to the solution and shaken for 30 minutes. This was washed with PBS and dispersed in 1 mL. Then, 0.1 mL of 1 mM cRGD was mixed with the solution, and the light was blocked with aluminum foil, followed by shaking for 3 hours. After washing with H ₂ O or PBS, it was dispersed in 0.5 mL.

0.025 mL of the magnetic-optical composite nanoparticle solution functionalized with the cRGD was incubated for at least 3 hours in a glass bottom dish with 70,000 U87MG cells and 70,000 MCF7 cells attached, and fixed. I did. In addition, cell imaging was performed through confocal Raman Microscopy. At this time, a 40x objective lens was used, the laser wavelength was 532 nm, the laser power was 0.139 mW, and the acquisition time was measured as 0.035 seconds per 1 μm * 1 μm pixel.

In FIG. 5, (a) is a schematic diagram of detecting an integrin receptor present in a cell membrane of a cancer cell with a magnetic-optical composite nanoparticle functionalized with cRGD, and performing a cell image using the fluorescence properties of the quantum dot nanoparticle.

In U87MG cells with a high degree of integrin expression on the cell surface, many magnetic-optical complex nanoparticles functionalized with cRGD are attached to the cell, resulting in fluorescence on the cell surface, but MCF7 cells with a low degree of integrin expression on the cell surface. In, cRGD-functionalized magnetic-optical composite nanoparticles do not adhere to the cell surface, so that fluorescence does not appear. Therefore, it is possible to image target-specific cancer cells using the magnetic-optical composite nanoparticles according to the present invention.

Experimental Example 3. Biomaterial detection using magnetic-optical composite nanoparticles

The surface functionalization of the carboxyl group of the magnetic-optical composite nanoparticles prepared in the examples was performed by using thiol-polyethylene-carboxymethyl (SH-PEG-COOH), H ₂ O and acetone having a molecular weight of 5,000 Daltons. Proceed with a solvent. The used magnetic-optical composite nanoparticles were prepared using zinc sulfide quantum dot nanoparticles doped with manganese.

1 mg of the magnetic-optical composite nanoparticles prepared in Example were uniformly mixed with 1 mL of chloroform containing 5 mL of acetone and 1 mM SH-PEG-COOH, and shaken for 16 hours. It washed with H ₂ O, and the mixture was dispersed in H ₂ O 5 mL. Subsequently, the influenza A antibody, which is an antibody used to detect the virus, was functionalized. _{3 mL of H 2} O containing the magnetic-optical composite nanoparticles was added to 1 mL (50 mM) of 2-(N-morpholino)ethanesulfonic acid (MES) buffer. After solvent substitution, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) (20 mM) solution 0.150 mL, sulfo-N-hydroxysuccinimide (NHS) (20 mM) solution 0.150 mL Were mixed and shaken for 30 minutes. Then, it was washed with PBS and dispersed in 1 mL of PBS. Thereafter, 0.1 mL of an influenza A antibody (0.100 g) solution was added to perform stirring for at least 16 hours. Then, it was washed with PBS and dispersed in 0.6 mL of a solution.

The magnetic-optical composite nanoparticles functionalized with the influenza A antibody were reacted with the influenza A virus. Then, it was placed in an immunochromatography rapid test (Lateral Flow Assay, LFA) and detected by colorimetric analysis.

In Figure 6 (a) is a schematic diagram of a process of fluorescence detection of a concentrated sample obtained by magnetic-optical composite nanoparticles modified with a specific antibody binding to an antigen in a sample and classifying it by magnetic separation in an LFA device .

In FIG. 6 (b) shows the result of measurement with an LFA device while controlling the concentration of influenza A antigen using magnetic-optical composite nanoparticles modified with influenza A antibody.

Through the above drawing, it can be seen that the fluorescence intensity is different depending on the infection concentration.

Claims (18)

Forming a first ceramic shell on magnetic nanoparticles to prepare core-shell nanoparticles;
Preparing core-shell nanoparticles to which noble metal nanoparticles are attached by attaching noble metal nanoparticles to the surface of the first ceramic shell of the core-shell nanoparticles;
Forming a second ceramic shell surrounding the core-shell nanoparticles to which the noble metal nanoparticles are attached to prepare core-double-shell nanoparticles; And
A method of manufacturing a magnetic-optical composite nanoparticle comprising the step of preparing a magnetic-optical composite nanoparticle by attaching the quantum dot nanoparticle to the surface of the second ceramic shell of the core-double-shell nanoparticle.
The method of claim 1,
Magnetic nanoparticles are from the group consisting of FeO, Fe ₂ O ₃ , Fe ₃ O ₄ , CoFe ₂ O ₄ , NiFe ₂ O ₄ , MnFe ₂ O ₄ , TiO ₂ , ZrO ₂ , CeO ₂ , Al ₂ O _{3 and MgO} A method of producing a magnetic-optical composite nanoparticle, which is one or more selected metal oxide nanoparticles.
The method of claim 1,
The average particle diameter of the magnetic nanoparticles is 10 to 500 nm magnetic-optical composite nanoparticles manufacturing method.
The method of claim 1,
In the first ceramic shell and the second ceramic shell, the first ceramic and the second ceramic each include at least one selected from the group consisting of silica, titania, zirconia, alumina, and zeolite. .
The method of claim 1,
The thickness of the first ceramic shell is 1 to 100 nm magnetic-optical composite structure nanoparticles manufacturing method.
The method of claim 1,
The step of preparing core-shell nanoparticles to which noble metal nanoparticles are attached is
Introducing a functional group to the shell surface of the core-shell nanoparticles; And
A method for producing magnetic-optical composite nanoparticles comprising the step of binding the noble metal nanoparticles to the functional group.
The method of claim 1,
The step of preparing core-shell nanoparticles to which noble metal nanoparticles are attached is
Introducing a functional group to the shell surface of the core-shell nanoparticles;
Bonding a noble metal nanoparticle seed to the functional group; And
A method for producing a magnetic-optical composite nanoparticle comprising the step of producing a noble metal nanoparticle by growing a noble metal nanoparticle seed bound to the functional group.
The method of claim 1,
Noble metal is gold, silver, platinum, copper, or an alloy thereof, a method for producing magnetic-optical composite nanoparticles.
The method of claim 6 or 7,
Magnetic-optical composite nanoparticles containing at least one functional group selected from the group consisting of amine group (-NH), thiol group (-SH), carboxyl group (-COOH), hydroxyl group (-OH) and dopamine Manufacturing method.
The method of claim 6 or 7,
A method of manufacturing a magnetic-optical composite nanoparticle having an average particle diameter of 5 to 50 nm of the noble metal nanoparticles bound to the functional group or the grown noble metal nanoparticles.
The method of claim 1,
The thickness of the second ceramic shell is 5 nm to 100 nm,
A method of manufacturing a magnetic-optical composite nanoparticle that contains noble metal nanoparticles in the second ceramic shell.
The method of claim 1
The step of attaching the quantum dot nanoparticles to the surface of the second shell ceramic of the core-double shell nanoparticles is
Introducing a functional group to the surface of the second ceramic shell; And
Magnetic-optical composite nanoparticles manufacturing method comprising the step of coupling the quantum dot nanoparticles to the functional group.
The method of claim 12,
Magnetic-optical composite nanoparticles containing at least one functional group selected from the group consisting of amine group (-NH), thiol group (-SH), carboxyl group (-COOH), hydroxyl group (-OH) and dopamine Manufacturing method.
The method of claim 1,
Quantum dot nanoparticles include cadmium selenide (CdSe), cadmium sulfide (CdS), zinc oxide (ZnO), zinc selenide (ZnSe), zinc sulfide (ZnS), manganese-doped zinc sulfide (Mn-doped ZnS), ignition Indium (InP) and cesium lead halide (CsPbBr ₃ , CsPbI ₃ ) Magnetic-optical composite nanoparticles manufacturing method comprising at least one selected from the group consisting of quantum dots.
Core-shell nanoparticles including a magnetic nanoparticle core and a first ceramic shell;
Noble metal nanoparticles formed on the surface of the first ceramic shell of the core-shell nanoparticles;
A second ceramic shell surrounding the core-shell nanoparticles in which the noble metal nanoparticles are formed; And
Magnetic-optical composite nanoparticles comprising quantum dot nanoparticles formed on the surface of the second ceramic shell.
The method of claim 15,
Quantum dot nanoparticles are magnetic-optical composite nanoparticles that are located outside of the noble metal nanoparticles bonded to the core-shell nanoparticle surface.
The composition for image diagnosis, an analyte detection kit, or a molecular diagnosis chip comprising the magnetic-optical composite nanoparticles according to claim 15.
Functionalizing a biomolecule capable of binding to an analyte to be detected on the surface of the magnetic-optical composite nanoparticle according to claim 15;
Exposing the functionalized magnetic-optical composite nanoparticles to a sample containing one or more analytes; And
A method of imaging or detecting an analyte comprising the step of identifying an analyte bound to magnetic-optical composite nanoparticles using photoluminescence spectroscopy.

Images