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

Abstract

[Problem] To provide a novel method of producing ferrite quantum dots that is different from conventional methods. [Solution] This method of producing ferrite quantum dots comprises: a step for preparing a mixed solution containing at least iron(II) hydroxide in water at 0°C to 30°C; a step for oxidizing the mixed solution to form green rust crystals in the mixed solution, thereby preparing a green rust-containing suspension; a step for raising the temperature of the suspension to at least 50°C but not over 100°C in an oxygen-free gas stream, thereby synthesizing the ferrite quantum dots in the suspension; and a step for recovering the ferrite quantum dots that are in the suspension.

Description

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

[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.

[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 MNPs] Magnetic nanoparticle (MNP) heating systems have attracted increasing attention as a technology for precisely controlling biological systems through spatiotemporal control of magnetic effects in hyperthermia and cell signaling. In particular, cutting-edge research is being conducted into highly effective biomedical applications, such as dual-mode magnetic hyperthermia (magnetically induced drug delivery and magnetically controlled cell activity). Against this background, the development of advanced design concepts for tuning the magnetic properties of nanoparticles, which directly affect their heating properties, is becoming increasingly important. The development of MNPs with improved heating efficiency is required to optimize heating.

[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 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.) are similar in size, it is possible to specifically activate or stimulate target molecules with molecular-level precision.

[0006] Magnetic Heating and Cancer Hyperthermia Magnetic heating, a type of cancer hyperthermia, is the most advanced therapeutic approach. 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. Clinical use, particularly in prostate cancer and glioma, has demonstrated its great potential without substantial side effects. More recently, MNPs have begun to be used as effective tools to stimulate heat-responsive 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. While there are many types of magnetic materials, ferromagnetic materials, such as metal particles, can be excellent energy conversion materials capable of generating large amounts of heat. However, despite their high heating efficiency, they suffer from poor stability in aqueous conditions and, due to their inherent magnetic properties (magnetic coercivity), can cause particle aggregation when exposed to an external magnetic field. Therefore, superparamagnetic MNPs (materials that are less susceptible to unintended aggregation) are used. However, these materials suffer from relatively low heating efficiency, which is a challenge that needs to be addressed. For example, considering the limit on the magnetic field strength tolerated by biological organs (4.5 × 10 A / m s, known as the "Brezovich criterion") and the injectable dose of MNPs, the development of superparamagnetic MNPs with optimized heating efficiency is highly desirable to achieve desired results.

[0008] Design and Synthesis of MNPs with Enhanced Heating Capabilities While the theoretical mechanisms underlying the magnetic heating process must be considered, the design and synthesis of MNPs with enhanced heat generation primarily requires consideration of key nanomagnetic parameters that govern the heating efficiency of nanomaterials, such as magnetic anisotropy (K), saturation magnetization (MS), and MNP size. Varying these parameters allows for tailoring of the MNP heating profile. 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 several 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 characteristics of each magnetic component, it is possible to satisfy conflicting technical requirements for magnetic properties.

[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 used in 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 shape of these particles has the following relationship with magnetic relaxation. Magnetic nanoparticles with different shapes, such as single-core, multi-core, and chain-like structures, have different magnetic anisotropy due to the influence of dipole interactions caused by AC magnetization, with multi-core structures showing reduced magnetic anisotropy and chain-like structures showing 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 in five different structures—single-core (S1 superparamagnetic), multi-core (S2), nanoflower (S3), ferromagnetic single-core (S4), and cubic (S5)—S4 and S5 exhibited coercive force, making them difficult to use for therapeutic purposes. Furthermore, while S1, S2, and S3 are superparamagnetic and exhibit no coercive force, the multi-core and nanoflower structures of S2 and S3 effectively increase the core particle size and increase the anisotropy energy, even though the aggregation of nanoparticles reduces the magnetic anisotropy. Similarly, the anisotropy energy increases with increasing particle size in core-shell architectures.

[0011] Abstracts of the 44th Annual Meeting of the Magnetic Society of Japan (2020) Evaluation of Magnetic Relaxation Dependent on the Structure of Magnetic Nanoparticles Nanotoday Volume 13, April 2017, Pages 61-76, Recent advances of magneto-thermal capabilities of nanoparticles: From design principles to biomedical applications

[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 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, quantum dots must be increased in particle size 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.

[0015] In order to achieve the above object, the present invention provides a method for producing ferrite quantum dots, comprising 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.

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

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

[0025] The present invention provides a method for producing ferrite quantum dots, comprising 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 ferrites produced by the present invention include not only those consisting only of iron and oxygen, but also ferrites containing other metals besides iron and oxygen and represented by the general formula MFe2O4 (where M is a divalent transition metal ion). The divalent transition metal ion can be Fe2+, Zn2+, Co2+, etc.

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

[0028] First, a mixed solution is prepared by adding at least ferrous hydroxide to water at a temperature of 0°C to 30°C (Step 1). By adding divalent transition metal ions other than iron, a ferrite containing metals other than iron and oxygen can be prepared. In particular, 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. During this oxidation, some of the Fe2+ is oxidized to form an intermediate in which Fe2+ and Fe3+ 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 aligned and aggregated in the step of synthesizing the ferrite quantum dots in step 3. This alignment 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 with a uniform particle size (primary particle size), such as 2 to 5 nm, can be obtained. By either associating or aggregating these primary particles, agglomerates with a uniform particle size, such as 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, these sizes allow them to 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, it is possible to synthesize stable ferrite quantum dots in which the divalent iron ions are not easily oxidized by air.

[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 ranging from several to several tens of nanometers (preferably 2 to 10 nm, with 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, quantum dots with uniform particle size but varying in size by several nanometers can be synthesized.

[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 has been achieved 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 from local areas 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 series 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. This will contribute to the advancement of medical technology and enable early and accurate diagnosis. Magnetic heating cancer hyperthermia treatment will be extremely effective (it will only be useful when combined with the inventive step described above in (1)).

[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 water (previously degassed with oxygen by passing N gas through it) at 25°C. The pH was adjusted to 8.5 with 0.05 M NaOH aqueous solution under an N gas atmosphere to prepare a hydroxide suspension (a mixture containing ferrous hydroxide and zinc co-hydroxide). This suspension was then immersed in a 90°C hot water bath, and the suspension was heated to 75°C for 3 minutes to react (oxidize). The reaction was then stopped by immersing in 4°C cold water. 50 ml of 0.01 M sodium acetate (pH 3.5) solution (4°C) was added to dissolve and recover the reaction residue. The precipitate was then collected by settling under an N atmosphere and dispersed in 2 L of water degassed with N gas. The precipitate, which had aggregated due to orientation association, was then collected using a centrifuge. XRD analysis of this recovered material confirmed that the zinc ferrite crystals were oriented in the

[110] plane. Furthermore, from a transmission electron microscope photograph of the crystals, it was observed that the zinc ferrite crystal particles of the quantum dots had a particle diameter of 5 nm, and that 3 to 10 particles were 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 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.

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

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

4. A method for producing an aqueous dispersion of ferrite quantum dots, comprising the steps of: mixing ferrite quantum dots produced by the method for producing ferrite quantum dots according to any one of claims 1 to 3 with water; and dispersing the ferrite quantum dots mixed in the water using ultrasound to prepare a dispersion of the ferrite quantum dots.

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.