Method for producing ferrite quantum dots and method for producing aqueous dispersion of ferrite quantum dots

Abstract

To provide a method for producing a new ferrite quantum dot different from a conventional one.SOLUTION: A method for producing ferrite quantum dots, the method comprising the steps of preparing a mixed solution in which at least ferrous hydroxide is present in water at 0 °C or higher and 30 °C or lower, preparing a green rust-containing suspension by oxidizing the mixed solution to form green rust crystals in the mixed solution, synthesizing ferrite quantum dots in the suspension by raising the temperature of the suspension to 50 °C or higher and 100 °C or lower in an oxygen-free stream, and collecting the ferrite quantum dots in the suspension.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing ferrite quantum dots and a method for producing an aqueous dispersion of ferrite quantum dots. [Background technology]

[0002] Magnetic nanoparticles (MNPs) are expected to be applied to various fields as follows (for example, Non-Patent Document 1 and Non-Patent Document 2).

[0003] [Dual-mode magnetic hyperthermia and magnetic particle imaging (MPI) using magnetic nanoparticles] Magnetic nanoparticles are actually used in medical applications such as cancer hyperthermia and magnetic particle imaging (MPI).

[0004] [Dual-mode magnetic hyperthermia and MNP] Magnetic nanoparticle (MNP) heating systems have attracted increasing attention as a technology for precisely controlling biological systems by controlling magnetic effects in space and time in hyperthermia and cell signaling. In particular, cutting-edge research is being conducted into highly effective biomedical applications, such as dual-mode magnetic hyperthermia (magnetic heat-induced drug delivery and magnetic thermal control of cellular activity). Against this background, the development of advanced design concepts for tuning the magnetism that directly affects the heating properties of nanoparticles is becoming increasingly important. The development of MNPs for optimizing heating is required through the design of MNPs with improved heating efficiency.

[0005] [Magnetic heating of nanoparticles] Magnetic heating of nanoparticles is achieved by converting external electromagnetic energy into an alternating magnetic field (AMF) via Rhineel-Brown relaxation. This magnetic heating method has no penetration depth limitations, and tissue attenuation does not occur when the AMF is used as a heat dissipation process. Furthermore, local temperature can be remotely and precisely controlled with nanoscale spatial resolution. Because MNPs and biomolecules (e.g., membrane proteins, DNA, etc.) have similar sizes, it is possible to specifically activate or stimulate target molecules with molecular-level precision.

[0006] [Magnetic heating and cancer hyperthermia] Magnetic heating is currently the most widely studied therapeutic approach for cancer treatment, specifically magnetic hyperthermia, a type of hyperthermia treatment. Heat emitted from MNPs can induce a heat shock response in tumor cells, destroying them through a series of biochemical reactions. Furthermore, heat has also been used to support the therapeutic effects of other treatments by reducing the ability of cancer cells to recover from anticancer activity. Its great potential has been demonstrated in clinical use, particularly for prostate cancer and glioma, without substantial side effects. More recently, MNPs have begun to be used as effective tools to stimulate thermoresponsive components in various biological systems, including magnetically triggered cargo delivery, activation of thermosensitive membrane receptors, and cellular signaling for gene expression and protein production.

[0007] [Development of superparamagnetic MNPs with optimized heating efficiency] There are various types of magnetic materials, among which ferromagnetic materials such as metal particles can be excellent energy conversion materials that generate large amounts of heat. However, despite their high heating efficiency, they have low stability in aqueous conditions, and due to their inherent magnetic properties (magnetic coercivity), they have the problem of causing particle aggregation when exposed to an external magnetic field. For this reason, superparamagnetic MNPs (materials that are less likely to cause unintended aggregation) are used, but they have the opposite problem of relatively low heat generation efficiency, which needs to be resolved. For example, the limit of the permissible magnetic field strength for biological organs (4.5 × 10 8Considering the A / m·s (known as the “Brzezowicz criterion”) and the injectable dose of MNPs, the development of superparamagnetic MNPs with optimized heating efficiency is highly required to achieve the desired results.

[0008] [Design and synthesis of MNPs with improved heat generation] The design and synthesis of MNPs with improved heat generation capabilities must take into account the theoretical mechanisms underlying the magnetic heating process. However, the key nanomagnetic parameters that govern the heating efficiency of nanomaterials, such as magnetic anisotropy (K), saturation magnetization (MS), and MNP size, must be considered. Varying these parameters allows for tailoring the heating profile of MNPs. Single-core MNPs, such as those made of iron oxide ferrites (Fe3O4 and γ-Fe2O3), metal-doped ferrites, and metal alloys, have been developed over the past few decades. Recently, core-shell MNPs, consisting of two types of MNPs, have attracted attention due to their novel advantages over single-core MNPs. The synergistic magnetic behavior at the core-shell interface can be flexibly and systematically manipulated by varying core-shell parameters (e.g., core-shell volume ratio, core-shell interface, structure, and core-shell composition). The core-shell architecture has emerged as a powerful tool for designing nanoparticles for maximum heating power. By utilizing the properties of each magnetic component, conflicting technological demands for magnetic properties can be met.

[0009] However, this core-shell architecture has several drawbacks, including a complex synthesis method, the need to use toxic metals as materials, and the inability to easily excrete them from the body or from local areas.

[0010] [Evaluation of the shape and magnetic relaxation of magnetic nanoparticles for magnetic heating cancer hyperthermia and magnetic particle imaging (MPI)] Magnetic nanoparticles are important therapeutic materials used in magnetic heating cancer hyperthermia and magnetic particle imaging (MPI), and the following relationship exists between the shape of these particles and magnetic relaxation. Magnetic nanoparticles with different shapes, such as single-core, multi-core, and chain-like structures, exhibit different magnetic anisotropy due to the influence of dipole interactions caused by AC magnetization, with multi-core structures exhibiting reduced magnetic anisotropy and chain-like structures exhibiting increased magnetic anisotropy. Furthermore, during the magnetization relaxation process when a fast-responding pulsed magnetic field is applied, a two-stage relaxation phenomenon can be analyzed, in which Brownian relaxation occurs after Néel relaxation. This analysis revealed that for five different structures—single-core (S1 superparamagnetic), multi-core (S2), nanoflower (S3), ferromagnetic single-core (S4), and cubic (S5)—S4 and S5 exhibit coercivity, making them difficult to use for therapeutic purposes. While S1, S2, and S3 are superparamagnetic and exhibit no coercivity, the multi-core and nanoflower structures of S2 and S3 effectively increase the core size and increase the anisotropy energy, even though the magnetic anisotropy decreases with the aggregation of nanoparticles. Similarly, the anisotropy energy increases with increasing particle size in core-shell architectures. [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] Abstracts of the 44th Annual Meeting of the Magnetic Society of Japan (2020) Evaluation of magnetic relaxation dependent on the structure of magnetic nanoparticles [Non-patent document 2] Nanotoday Volume 13, April 2017, Pages 61-76, Recent advances of magneto-thermal capabilities of nanoparticles: From design principles to biomedical applications Summary of the Invention [Problem to be solved by the invention]

[0012] In order to enhance the magnetocaloric effect and the contrast effect of MPI, it is necessary to increase the anisotropy energy of magnetic nanoparticles. Furthermore, in terms of treatment and diagnosis, the materials must be safe and healthy and easy to excrete from the body. While magnetic treatment and diagnosis are effective, the health and safety of the materials and their ease of excretion from the body are currently major issues that need to be resolved. To increase the anisotropy, the quantum dot particle size must be increased to approximately 100 nm. However, particles larger than 50 nm are difficult to excrete from the body. Therefore, increasing the particle size to increase the anisotropy energy contradicts the ease of excretion from the body, making this issue extremely difficult to resolve.

[0013] As a result of extensive research aimed at solving these contradictory problems, the present inventors have found the following solution.

[0014] That is, an object of the present invention is to provide a novel method for producing ferrite quantum dots that is different from conventional methods. [Means for solving the problem]

[0015] In order to achieve the above object, the present invention provides a method for producing ferrite quantum dots, which includes the steps of: preparing a mixed solution containing at least ferrous hydroxide in water at a temperature of 0°C to 30°C; oxidizing the mixed solution to form green rust crystals in the mixed solution, thereby preparing a green rust-containing suspension; raising the temperature of the suspension to 50°C to 100°C in an oxygen-free air stream, thereby synthesizing the ferrite quantum dots in the suspension; and recovering the ferrite quantum dots in the suspension.

[0016] Such a method for producing ferrite quantum dots is a novel and simple method for producing ferrite quantum dots.

[0017] In this case, the ferrite quantum dots can be oriented and associated in the step of synthesizing the ferrite quantum dots. Also, the ferrite quantum dots can be aggregated and precipitated in the step of synthesizing the ferrite quantum dots.

[0018] In the method for producing ferrite quantum dots of the present invention, such association and condensation methods can be employed to obtain agglomerated particles.

[0019] The present invention also provides a method for producing an aqueous dispersion of ferrite quantum dots, comprising the steps of: mixing ferrite quantum dots produced by any of the above-described methods for producing ferrite quantum dots with water; and dispersing the ferrite quantum dots mixed in the water using ultrasonic waves to prepare the dispersion of the ferrite quantum dots.

[0020] In this way, the present invention can prepare an aqueous dispersion of ferrite quantum dots.

[0021] In this case, the ultrasonic dispersion can be carried out in the presence of a dispersant mixed in the water.

[0022] In this way, dispersion can be carried out more simply and reliably by performing dispersion using ultrasonic waves in the presence of a dispersant. [Effects of the Invention]

[0023] The present invention provides a novel and simple method for producing ferrite quantum dots, which is different from conventional methods. DETAILED DESCRIPTION OF THE INVENTION

[0024] The present invention will be described in detail below, but the present invention is not limited thereto.

[0025] The present invention relates to a method for producing ferrite quantum dots, which includes the steps of: preparing a mixed solution containing at least ferrous hydroxide in water at a temperature of 0°C to 30°C; oxidizing the mixed solution to form green rust crystals in the mixed solution to prepare a green rust-containing suspension; elevating the temperature of the suspension to 50°C to 100°C in an oxygen-free air stream to synthesize the ferrite quantum dots in the suspension; and recovering the ferrite quantum dots from the suspension. In the description of the present invention, the quantum dots are preferably less than 50 nm in size, and more preferably have a particle size of 2 to 10 nm. Furthermore, quantum dots with a particle size of 2 to 5 nm are also possible.

[0026] The present invention is a method for producing ferrite quantum dots. The ferrite produced by the present invention includes not only ferrites consisting of only iron and oxygen, but also ferrites containing other metals besides iron and oxygen and expressed by the general formula MFe2O4 (where M is a divalent transition metal ion). The divalent transition metal ion is Fe 2+ In addition, Zn 2+ , Co 2+ etc.

[0027] More specifically, this method can be performed as follows.

[0028] First, a mixed solution containing at least ferrous hydroxide is prepared in water at a temperature of 0°C to 30°C (Step 1). By adding divalent transition metal ions other than iron, ferrite containing metals other than iron and oxygen can be prepared. This mixed solution can be an aqueous solution in which the molar ratio of divalent metal ions M to Fe is M / Fe = 0 to 0.5.

[0029] Next, the mixed solution prepared in step 1 is oxidized to form green rust crystals in the mixed solution (step 2). This produces a green rust-containing suspension. 2+ Part of the Fe 2+ and Fe3+ It becomes an intermediate in which both coexist.

[0030] Next, the temperature of the green rust-containing suspension prepared in step 2 is raised to 50°C or higher and 100°C or lower in an oxygen-free air stream, thereby synthesizing ferrite quantum dots in the green rust-containing suspension (step 3). In this way, by raising the temperature of the green rust-containing suspension, quantum dots can be synthesized without an oxidation reaction.

[0031] The ferrite quantum dots can be oriented and aggregated in the step of synthesizing the ferrite quantum dots in step 3. This orientation and aggregation can be achieved by leaving the green rust-containing suspension (for example, for one day or more).

[0032] Furthermore, the ferrite quantum dots can be aggregated and precipitated in the step of synthesizing the ferrite quantum dots in step 3. This aggregation and precipitation can be carried out, for example, by evaporating the water contained in the green rust-containing suspension.

[0033] Next, the ferrite quantum dots synthesized in the green rust-containing suspension are recovered in step 3. As a recovery method, known means such as filtration and drying can be used.

[0034] The method of the present invention allows for the production of uniform quantum dots from green rust. In particular, quantum dots can be made to have a uniform particle size (primary particle size), for example, of 2 to 5 nm. By either associating or aggregating these primary particles, agglomerates with a uniform particle size, for example, 100 to 200 nm, can be obtained. These quantum dots can be magnetically guided from the bloodstream to the affected area in medical applications, and in cancerous areas, quantum dots of this size can penetrate cancer cells. Furthermore, if each nanoparticle (quantum dot) is 5 nm or smaller, they are easily excreted from the body.

[0035] Furthermore, according to the present invention, stable ferrite quantum dots in which the divalent iron ions are not easily oxidized by air can be synthesized.

[0036] The present invention further provides a method for producing an aqueous dispersion of ferrite quantum dots. This method includes a step of mixing ferrite quantum dots produced by the above-described method for producing ferrite quantum dots with water, and further includes ultrasonically dispersing the ferrite quantum dots mixed in water to prepare a dispersion of ferrite quantum dots. Here, ultrasonic dispersion can be performed in the presence of a dispersant mixed in water.

[0037] The novelty of the present invention lies in the following points.

[0038] (1) While it is known to synthesize ferrite particles (e.g., on the order of micrometers) from green rust crystals, a method for synthesizing quantum dots with sizes of several to several tens of nanometers (preferably 2 to 10 nm, and a maximum of less than 50 nm) is novel. Because the size of quantum dots can be finely adjusted to within a range of several to several tens of nanometers in a reaction time of 2 to 3 minutes, it is possible to synthesize quantum dots with uniform particle size but with sizes varied in units of several nanometers.

[0039] (2) The alignment and association of quantum dots is a highly advanced colloidal chemical technique, which requires a very high and sharp particle size distribution of the quantum dots. This invention has achieved this for the first time with ferrite quantum dots. In the example, a particle size of 5 nm was achieved.

[0040] (3) The phenomenon of orienting and associating quantum dots by leaving the precipitate for a long period of time (for example, one day or more) after the reaction is a novel phenomenon discovered for the first time in the present invention.

[0041] The inventive step of the present invention is as follows.

[0042] (1) The individual oriented and associated single crystals are superparamagnetic quantum dot crystal particles of several to several tens of nanometers (preferably 2 to 10 nm, and a maximum of less than 50 nm). Since such nanoparticles of less than 50 nanometers are known to be easily excreted from the body and locally when used in medical diagnosis, the quantum dot magnetic nanoparticles synthesized by the method of the present invention are excellent in terms of ease of excretion from the body.

[0043] (2) Superparamagnetic quantum dots measuring several to several tens of nanometers are aligned and associated in a chain of 3 to 10 pieces (10 to 100 nm), resulting in a nanorod shape with 3 to 10 times greater anisotropy energy, significantly enhancing the magnetothermal effect and MPI contrast effect. This will enhance the usefulness of conventional magnetic nanoparticles in treatment and diagnosis, contributing to the advancement of medical technology and enabling early and accurate diagnosis. Magnetic heating cancer hyperthermia treatment will be extremely effective (it will only be useful when combined with the advancement described above in (1)). [Example]

[0044] More specific examples of the present invention will now be described.

[0045] [Example 1] First, 3 g of ferrous sulfate was dissolved in 150 ml of zinc chloride (Zn / Fe = 0.01) at 25°C in water (previously degassed with oxygen through a nitrogen gas flow). The pH was adjusted to 8.5 with 0.05 M NaOH under a nitrogen atmosphere to prepare a hydroxide suspension (a mixture containing ferrous hydroxide and zinc co-hydroxide). The suspension was then immersed in a 90°C hot water bath and heated to 75°C for 3 minutes to react (oxidize). The reaction was then stopped by immersion in 4°C cold water. The reaction residue was dissolved and recovered by adding 50 ml of 0.01 M sodium acetate (pH 3.5) solution (4°C). The precipitate was then collected under a nitrogen atmosphere and dispersed in 2 L of water degassed with nitrogen gas. The precipitate, which had aggregated due to orientational association, was then collected by centrifugation. XRD analysis of the recovered material confirmed that the zinc ferrite crystals were oriented and associated with a

[0110] pattern. Furthermore, from a transmission electron microscope photograph of the crystals, it was observed that the zinc ferrite quantum dots had a crystal particle diameter of 5 nm, with 3 to 10 particles oriented and associated, forming aggregates.

[0046] The present invention is not limited to the above-described embodiments. The above-described embodiments are merely examples, and any configuration that is substantially identical to the technical idea described in the claims of the present invention and that provides similar effects is included within the technical scope of the present invention.

Claims

1. A method for producing ferrite quantum dots, comprising: preparing a mixed solution containing at least ferrous hydroxide in water at a temperature of 0°C or higher and 30°C or lower; oxidizing the mixed solution to form green rust crystals in the mixed solution, thereby preparing a green rust-containing suspension; a step of synthesizing the ferrite quantum dots in the suspension by raising the temperature of the suspension to 50°C or more and 100°C or less in an oxygen-free air stream; recovering the ferrite quantum dots in the suspension; A method for producing ferrite quantum dots, comprising:

2. 2. The method for producing ferrite quantum dots according to claim 1, wherein the ferrite quantum dots are oriented and associated in the step of synthesizing the ferrite quantum dots.

3. 2. The method for producing ferrite quantum dots according to claim 1, wherein the ferrite quantum dots are aggregated and precipitated in the step of synthesizing the ferrite quantum dots.

4. A process of mixing ferrite quantum dots manufactured by the method for manufacturing ferrite quantum dots according to any one of claims 1 to 3 with water; A method for producing an aqueous dispersion of ferrite quantum dots, comprising: dispersing the ferrite quantum dots mixed in water using ultrasonic waves to prepare the dispersion of the ferrite quantum dots.

5. 5. The method for producing an aqueous dispersion of ferrite quantum dots according to claim 4, wherein the ultrasonic dispersion is carried out in the presence of a dispersant mixed in the water.