JP2013256405A - Ni-Zn-BASED FERRITE MAGNETIC NANOPARTICLE FOR THERMOTHERAPY, AND DRUG-BOUND COMPLEX FOR THERMOTHERAPY USING THE SAME - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide Ni-Zn-based ferrite magnetic nanoparticles for thermotherapy having a small change of a temperature rise at an application time of an external magnetic field even when a particle size is changed, and to provide a drug-bound complex for thermotherapy using the same.SOLUTION: In Ni-Zn-based ferrite magnetic nanoparticles for thermotherapy having a core comprising NiZnFeO(0.2≤i≤0.6) magnetic nanoparticles and a shell comprising amorphous SiOfor covering the core, the average particle size is 10-20 nm, and a temperature rise is 4-15°C at the application time of an external magnetic field under the condition of an AC magnetic field frequency of 15 kHz and an AC magnetic field intensity of 210 Oe.

Description

  The present invention relates to a ferrite magnetic nanoparticle and a drug-binding complex using the same.

Nanometer-scale ultrafine particles bring about new and unique physical properties that have not been available in the past, and high performance as functional materials can be expected. Therefore, various substances have been studied. In particular, when the magnetic material is made fine particles, single domain particles having no domain wall are generated, and the coercive force is expected to increase.
As such fine particles, the present inventors have reported Zn-based ferrite magnetic nano particles having a high saturation magnetic moment (see Patent Document 1). Further, the present inventors have magnetite magnetic nanoparticles surface coated with SiO _2, in which (see Patent Document 2) reports a technique of introducing a functional group through a SiO _2. With this functional group, it is possible to easily modify the magnetic fine particles with a drug or the like and to easily take the magnetic fine particles into cells or tissues.
Furthermore, when applying an external magnetic field to the Co—Ti-based ferrite magnetic nanoparticle, the present inventors can obtain a temperature increase of about 20 ° C., and these particles can be applied to cancer thermotherapy (hyperthermia). (See Non-Patent Document 1). Here, hyperthermia is a treatment method in which cancer cells are locally heated and killed without adversely affecting healthy cells. Generally, cancer cells are said to die at 42 to 43 ° C. or higher.

JP 2006-069830 A JP 2007-269770 A

Y. Ichiyanagi et al., Thermochimica Acta, 532 (2012) 123-126.

However, in the case of the ferrite magnetic nanoparticles described in Non-Patent Documents 1 and 2, there is a problem that the rising temperature when an external magnetic field is applied varies greatly depending on the particle size. And, since it is difficult to control the particle size of ferrite magnetic nanoparticles in a narrow range, fine particles with a certain particle size distribution can be obtained, but when the particle size changes, the temperature rise when an external magnetic field is applied changes, Overheating the affected area may harm healthy cells.
Accordingly, an object of the present invention is to provide a Ni-Zn ferrite magnetic nanoparticle for thermotherapy with a small change in temperature rise when an external magnetic field is applied even if the particle size changes, and a drug-binding complex for thermotherapy using the same. Is to provide.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that Ni—Zn ferrite magnetic nanoparticles having a specific composition and particle size range have an elevated temperature when an external magnetic field is applied even if the particle size changes. It was found that this change is small and suitable for thermotherapy.
That is, the Ni—Zn-based ferrite magnetic nanoparticle for thermotherapy of the present invention includes a core made of Ni _(1-i) Zn _i Fe ₂ O ₄ (0.2 ≦ i ≦ 0.6) magnetic nanoparticle, and the core A shell made of amorphous SiO ₂ covering the substrate, the average particle size is 10 to 20 nm, the alternating magnetic field frequency is 15 kHz, the alternating magnetic field strength is 210 Oe, and the temperature rise when applying an external magnetic field is 4 to 4 15 ° C.

When the average particle diameter is constant, it is preferable that a value obtained by dividing the maximum value of the rising temperature when the external magnetic field is applied by the minimum value is 3.0 or less.
Furthermore, it is preferable to have a functional group covalently introduced on the surface of the shell.
The functional group is preferably at least one selected from the group consisting of an amino group, an isocyanate group, a mercapto group, a vinyl group, an epoxy group, a methacryloxy group, a ureido group, a chloropropyl group, and a sulfide group.

The thermotherapy drug-binding complex of the present invention comprises the thermotherapy Ni—Zn-based ferrite magnetic nanoparticle according to claim 3 or 4 and a drug, and the functional group and the drug are bound to each other. .
The drug-binding complex for thermotherapy of the present invention comprises the Ni-Zn ferrite magnetic nanoparticles for thermotherapy according to claim 3 or 4, and a ligand that specifically interacts with a desired substance, The functional group and the ligand are bonded.

  According to the present invention, there is provided a Ni—Zn-based ferrite magnetic nanoparticle for thermotherapy, and a drug-binding complex for thermotherapy using the same, which has a small change in rising temperature when an external magnetic field is applied even if the particle size changes. can get.

It is a figure which shows the temperature rise of the Ni-Zn type ferrite magnetic nanoparticle at the time of an external magnetic field application. It is a schematic diagram which shows the structure of a Ni-Zn type ferrite magnetic nanoparticle. It is a figure which shows the temperature change of the alternating current magnetic susceptibility imaginary part of a Ni-Zn type ferrite magnetic nanoparticle. It is another figure which shows the temperature rise of the Ni-Zn type ferrite magnetic nanoparticle at the time of an external magnetic field application.

Hereinafter, embodiments of the present invention will be described.
Ni-Zn based ferrite magnetic nanoparticles for thermotherapy according to an embodiment of the present invention have Ni _(1-i) Zn _i Fe ₂ O ₄ (0.2 ≦ i ≦ 0.6) having an average particle size of 10 to 20 nm. It has a core made of magnetic nanoparticles and a shell made of amorphous SiO ₂ covering the core.

<Core of magnetic nanoparticle>
The composition of the magnetic nanoparticle as the core is Ni _(1-i) Zn _i Fe ₂ O ₄ (0.2 ≦ i ≦ 0.6). When i is less than 0.2, and when i exceeds 0.6, as shown in FIG. 1, the temperature rise when applying an external magnetic field is less than 4 ° C., which is not suitable for thermotherapy. Here, the external magnetic field has an alternating magnetic field frequency of 15 kHz and an alternating magnetic field strength of 210 Oe. The elevated temperature is a value when the core is covered with the shell.
In particular, when 0.2 ≦ i ≦ 0.4, the rising temperature when applying an external magnetic field is 5 to 15 ° C., and when the body temperature is 37 ° C., the local temperature rises to 42 ° C. or higher. Suitable for hyperthermia. In the present invention, the absolute value of the rising temperature when an external magnetic field is applied is not necessarily important, and it is important that the change in the rising temperature is small when the particle size of the magnetic nanoparticle varies within the above range. This is because the absolute value of the rising temperature itself can be changed by changing the conditions of the external magnetic field.
As shown in Table 1 described later, the magnetic nanoparticle of the present invention has a small change in rising temperature when an external magnetic field is applied even when the particle size varies within the above range, and the maximum value of the rising temperature is divided by the minimum value. The value obtained is 3.0 or less in any composition. For this reason, the magnetic nanoparticles have a particle size distribution of a predetermined width, and even if the particle size changes, the rising temperature does not become excessively high when an external magnetic field is applied, and the affected area is overheated and harms healthy cells. Can be suppressed.

<Shell made of amorphous SiO ₂ >
The shell is an amorphous silica network (network-like film) covering the core, and can be formed by the following wet method, for example, as described in Patent Document 1 above.
That is, a solution containing a hydrate of Ni halide, a solution containing a hydrate of Zn halide, a solution containing a hydrate of Fe halide, and a hydrate of Na ₂ SiO ₃ When the precipitate formed by uniformly mixing with the solution containing it is fired, as shown in FIG. 2, a structure is obtained in which the magnetic nanoparticles are held in a state separated by a network film (shell) of amorphous SiO ₂ . Here, as shown in FIG. 2, examples of the “network film” include those in which amorphous SiO ₂ surrounds individual magnetic nanoparticles and continuous amorphous SiO _2, but are not limited thereto. .
Specifically, the shell (structure including the core) can be manufactured, for example, as follows with respect to the composition of Ni _(1-i) Zn _i Fe ₂ O ₄ . First, NiCl ₂ · 6H ₂ O aqueous solution, ZnCl ₂ aqueous solution, FeCl ₂ · 4H ₂ O aqueous solution, and Na ₂ SiO ₃ · 9H ₂ O aqueous solution are added at a molar ratio of (1-i): i: 2: 3. And mixing and standing. After wet mixing and repeatedly washing the resulting precipitate, it is dried in a constant temperature bath of about 350K. Further, the precipitate is fired for 10 hours in an electric furnace in an air atmosphere in a temperature range of 873 to 1373K.
Here, the obtained precipitate is washed and then dried to form a glassy lump. This is pulverized and then fired in an air atmosphere to convert the magnetic nanoparticles of the metal hydroxide {Ni _(1-i) Zn _i Fe} _x (OH) _x into the metal oxide Ni _(1-i) Zn. _i Change to Fe ₂ O ₄ magnetic nanoparticles. By optimizing the firing temperature at this time, a magnetic nanoparticle dispersion in which individual magnetic nanoparticles are held in a state separated by an amorphous SiO ₂ network film is obtained. The firing time is preferably 3 hours or longer.

In this way, one Ni—Zn ferrite magnetic nanoparticle is in a state in which one or more cores are included in the shell, and the average particle diameter of the entire inclusion structure is determined as Ni—Zn ferrite. The average particle size of the magnetic nanoparticle is taken.
The average particle diameter of the Ni—Zn-based ferrite magnetic nanoparticles can be calculated from the half-value diffraction angle width of the powder X-ray diffraction peak using the Debye-Scherrer formula, for example. Furthermore, the inventor measured the diameters of a plurality of fine particles with a transmission electron microscope image, and confirmed that the calculated values coincided with high accuracy.
In addition, when the magnetic nanoparticles are produced by firing the precipitate obtained by the above-described wet method, the higher the firing temperature and the longer the firing time, the larger the magnetic nanoparticles grow and the larger the particle size. Therefore, the particle size of the magnetic nanoparticles can be controlled by adjusting the firing temperature or firing time.

The reason why the average particle diameter of the Ni—Zn-based ferrite magnetic nanoparticles is 10 to 20 nm is that the average particle diameter of less than 10 nm is practically difficult to produce, and the temperature rising effect by applying an external magnetic field is also inferior. In addition, those having an average particle diameter exceeding 20 nm are difficult to manufacture practically, and amorphous SiO ₂ is crystallized, so that it is difficult to obtain magnetic nano-particles contained in SiO _2. .

  The Ni—Zn-based ferrite magnetic nanoparticle for thermotherapy according to an embodiment of the present invention is manufactured and stored as an intermediate in a powder state in which a core is covered with a shell, or in a state in which a functional group is introduced on the surface of the shell. Then, a drug or a ligand is bonded to a functional group according to the subject of hyperthermia to become a medicine.

<Functional group>
Examples of the functional group include at least one selected from the group consisting of an amino group, an isocyanate group, a mercapto group, a vinyl group, an epoxy group, a methacryloxy group, a ureido group, a chloropropyl group, and a sulfide group. These functional groups can be introduced covalently through, for example, a silane coupling agent.
As described above, the silane coupling agent preferably has a functional group having reactivity or affinity that can form a complex with a drug or a ligand. For example, as the silane coupling agent used for introducing an amino group, any compound having this functional group may be used. Specifically, 3-aminopropyltriethoxysilane (γ-APTES), N-2 (aminoethyl) 3-aminopropylmethyldimethoxysilane, N-2 (aminoethyl) 3-aminopropyltrimethoxysilane, N-2 (aminoethyl) 3-aminopropyltriethoxysilane, 3-aminopropyltri Mention may be made of methoxysilane, 3-triethoxysilyl-N- (1,3-dimethyl-butylidene) propylamine, N-phenyl-3-aminopropyltrimethoxysilane. In particular, γ-APTES is preferably used.

As the silane coupling agent used for introducing an isocyanate group, any compound having this functional group may be used, and specific examples include 3-isocyanatopropyltriethoxysilane.
As the silane coupling agent used for introducing a mercapto group, any compound having this functional group may be used, and specific examples include 3-mercaptopropylmethyldimethoxysilane and 3-mercaptopropyltrimethoxysilane. Can be mentioned.
The silane coupling agent used for introducing the vinyl group may be any compound having this functional group, and specifically, vinyltrichlorosilane, vinyltrimethoxysilane, vinyltriethoxysilane. Can be mentioned.
Furthermore, as the silane coupling agent used for introducing the epoxy group, any compound having this functional group may be used. Specifically, 2- (3,4-epoxycyclohexyl) ethyltrimethoxy Examples include silane, 3-glycidoxypropyltrimethoxysilane, 3-glycidoxypropylmethyldiethoxysilane, 3-glycidoxypropyltriethoxysilane, and styryl p-styryltrimethoxysilane.

In addition, as the silane coupling agent used for introducing a methacryloxy group, any compound having this functional group may be used. Specifically, 3-methacryloxypropylmethyldimethoxysilane, 3-methacryloxy Mention may be made of propyltrimethoxysilane, 3-methacryloxypropylmethyldiethoxysilane, 3-methacryloxypropyltriethoxysilane, acryloxy-3-acryloxypropyltrimethoxysilane.
As the silane coupling agent used for introducing the ureido group, any compound having this functional group may be used, and specific examples include 3-ureidopropyltriethoxysilane.
As the silane coupling agent used for introducing the chloropropyl group, any compound having this functional group may be used, and specific examples include 3-chloropropyltrimethoxysilane.
As a silane coupling agent used for introducing a sulfide group, any compound having this functional group may be used, and specific examples thereof include bis (triethoxysilylpropyl) tetrasulfide.

Hereinafter, the introduction of the functional group through the silane coupling agent as described above may be referred to as “silanization” or “silanization treatment”.
Before performing the silanization treatment, it is preferable that the surface of the magnetic ultra-nano fine particles is washed to remove organic substances and expose many hydroxyl groups that can react with the silane coupling agent on the fine particle surfaces. Specifically, cleaning with an organic solvent such as ethanol, UV cleaning (JP-A-1-146330), plasma treatment, and the like can be given.

<Drug-binding complex for thermotherapy>
The drug-binding complex for thermotherapy according to the embodiment of the present invention has Ni—Zn-based ferrite magnetic nanoparticles and a drug, and a drug or a ligand is bonded via a functional group. Here, the bond between the magnetic nanoparticle and the drug or ligand via the functional group may be any bond such as a covalent bond, an ionic bond, or a hydrogen bond.
Examples of the drug include drugs for treating cancer cells, cells and tissues in the body, which are the targets of thermotherapy. The type of the drug is not particularly limited as long as it does not impair the formation and stability of the complex, but nucleic acids, polynucleotides, genes and analogs thereof, glycosaminoglycans and derivatives thereof, oligosaccharides, polysaccharides and derivatives thereof, Examples include vitamins and derivatives thereof, physiologically active substances such as proteins and peptides, and low molecular weight compounds having pharmacological activity. More specifically, anticancer agents, antibiotics, enzyme agents, antioxidants, lipid action inhibitors, hormones Agent, anti-inflammatory agent, steroid agent, vasodilator, angiotensin receptor antagonist, angiotensin converting enzyme inhibitor, smooth muscle cell proliferation / migration inhibitor, platelet aggregation inhibitor, anticoagulant, chemical mediator release inhibitor , Vascular endothelial cell proliferation or inhibitor, aldose reductase inhibitor, mesangial cell proliferation Harm agents, lipoxygenase inhibitors, immunosuppressants, immunostimulants, antiviral agents, Maillard reaction inhibitors, amyloidosis inhibitors, NOS inhibitors include AGEs (Advanced glycation endproducts) inhibitors and drugs radical scavenger.

  The type of ligand is not particularly limited as long as it has a specific interaction with a desired substance. For example, proteins such as transferrin, CEA, EGF, and AFP; peptides such as insulin; monoclonal antibodies and the like Low molecular weight compounds such as antibodies such as tumor antigens, hormones, transmitters, carbohydrates such as Lewis X and ganglioside, amino acids and derivatives thereof, vitamins such as folic acid, and derivatives thereof. The ligand exemplified above may be used as a whole, or a fragment obtained by enzyme treatment or the like may be used. Further, it may be an artificially synthesized peptide or peptide derivative. The ligand is preferably an antibody, and when used for humans, a mouse-human chimeric antibody, a humanized antibody, or a human antibody is more preferable.

After administration of the drug combination complex for thermotherapy to a human or non-human subject, magnetism is concentrated from outside the body at a site where a predetermined tissue or cell is present, and the complex is accumulated or retained at the site. In this way, when a predetermined external magnetic field is further applied from outside the tissue or cell into which the thermotherapy drug-binding complex has been incorporated, the temperature of the thermotherapy drug-binding complex increases within the tissue or cell, and Heat treatment is performed at
For example, because folate receptors are present in excess in cancer cells, administration of a hyperthermia drug-binding complex with folic acid bound as a ligand and magnetically accumulating it in cancer tissue will cause the cancer cells to be used for thermotherapy. The drug binding complex will be selectively incorporated.
Finally, when the drug-binding complex for thermotherapy after thermotherapy is magnetically adsorbed and collected from the tissue or the cell, the cell or tissue is not damaged.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples.

<Production of Ni-Zn ferrite magnetic nanoparticles>
NiCl ₂ · 6H ₂ O aqueous solution, ZnCl ₂ aqueous solution, FeCl ₂ · 4H ₂ O aqueous solution, and Na ₂ SiO ₃ · 9H ₂ O aqueous solution as a molar ratio of (1-i): i: 2: 3 at room temperature Mix with stirring in a container with a stirrer and mix uniformly for 5 to 10 hours, then leave for 24 to 48 hours, or centrifuge for 10 to 30 minutes using a centrifuge. A precipitate formed therein. This precipitate was washed with pure water. This washing operation was performed until the concentration of impurities contained in the washing water became 1/1000 or less of the initial value, and then dried in a constant temperature bath of about 350 K, whereby a glassy lump was obtained. This glassy lump was put in a mortar and pulverized into a powder.

The obtained powder is baked in an electric furnace in the air at a temperature range of 873 to 1373 K for 10 hours in the air, so that each Ni _(1-i) Zn _i Fe ₂ O ₄ magnetic nanoparticle becomes amorphous SiO _2. A magnetic nanoparticle dispersion held in a state of being separated by a network film was obtained.
Confirmation that individual magnetic nanoparticles are held in a state of being separated by the amorphous SiO ₂ mesh film, magnetic nanoparticulate dispersion magnetic nanoparticles and amorphous SiO ₂ in the composition according to the measurement of powder X-ray diffraction pattern of And the presence of an amorphous SiO ₂ layer between the magnetic nanoparticles by transmission electron microscopic image, and Fe atoms in the magnetic nanoparticles by X-ray absorption fine structure measurement It was confirmed by confirming that no Si atom was present in the adjacent region, that is, that amorphous SiO ₂ was present outside the magnetic nanoparticle. When the average particle diameter of the magnetic nanoparticles was calculated from the half-value diffraction angle width of the X-ray diffraction peak using the Debye-Scherrer equation, the values shown in Table 1 were obtained. Further, when the maximum particle size of the magnetic nanoparticles was measured from the transmission electron microscope image, it was larger than the average particle size.
The particle size of the sample (the magnetic nanoparticle) was adjusted by controlling the firing temperature within the above range. In addition, a particle size becomes large, so that a calcination temperature is high.

  Further, magnetic measurements (AC magnetic susceptibility) of magnetic nanoparticles having an average particle diameter of about 13 nm and different compositions (values i) were performed using a SQUID magnetometer at a temperature of 1233 K. Magnetization is measured with a SQUID magnetometer (superconducting quantum interference device: MPMS manufactured by Quantum Design) on a powder sample of magnetic nano-particles, with an AC frequency f = 100 Hz, an AC magnetic field H = 1 Oe, and a temperature range of 5K to Measured at 300K. The powder sample was put in an acrylic sample case with an inner diameter of 4 mm, fixed with (Apiezon grease) Kimwipe, and then attached to a SQUID sample holder.

The obtained results are shown in FIG. As shown in FIG. 3, it was found that the maximum magnetization (alternating magnetic susceptibility imaginary part) increases with increasing i = 0 to 0.4, and further decreases with increasing i. Moreover, it was found that the nano-particles have almost no holding power and are superparamagnetic.
Furthermore, from FIG. 3, at room temperature, the value of the imaginary part of the AC magnetic susceptibility was highest when i = 0.4. Here, the heat generation mechanism due to magnetic relaxation loss is expressed by the formula: P = π × μ ₀ × χ ”× f × H ² (where P: heat dissipation amount (W), μ ₀ : permeability of vacuum (H / m ), Χ ″: AC magnetic susceptibility imaginary part (emu / g), f: AC magnetic field frequency (Hz), H: AC magnetic field strength (Oe)). Therefore, in an alternating magnetic field, the amount of heat generated by magnetic relaxation loss is maximized when i = 0.4.
In addition, since the imaginary part (that is, χ ″: imaginary part of AC magnetic susceptibility) in the component whose phase is delayed by 90 degrees from the alternating magnetic field is a parameter related to Neel relaxation, the temperature at which χ ″ is maximum releases the heat most. Will show points.

  Next, the amount of heat generated when an external magnetic field was applied to each magnetic nanoparticle was measured. First, when a magnetic nanoparticle powder sample (initial temperature 15 ° C.) is placed in a cylindrical AC magnetic field generator and an external magnetic field of f = 15 kHz and H = 210 Oe is applied for 5 minutes, The temperature rise from the sample temperature was measured. As the thermometer, an optical fiber thermometer not affected by the magnetic field was used. Moreover, although the alternating magnetic field was applied with the coil wound on the outer side of the said cylindrical body, the coil was fully cooled and heat-insulated, and the emitted-heat amount from a coil was distinguished from temperature measurement.

  The obtained results are shown in FIGS. FIG. 4 shows the results when the average particle size of the magnetic nanoparticles is about 13 nm.

In Examples 1 to 3 where 0.2 ≦ i ≦ 0.6, the rising temperature when an external magnetic field is applied is 4 to 15 ° C., and even if the particle size changes, the rising temperature changes when an external magnetic field is applied Is suitable for thermotherapy applications. In particular, in the case of Examples 1 and 2 where 0.2 ≦ i ≦ 0.4, the rising temperature when applying an external magnetic field is 5 to 15 ° C., and the local temperature is 42 ° C. or higher when the body temperature is 37 ° C. Therefore, it is more suitable for hyperthermia.
In addition, as shown in Table 1, in each example, even when the particle diameter fluctuates in the above range, the change in the rising temperature when the external magnetic field is applied is small, and the value obtained by dividing the maximum value of the rising temperature by the minimum value. Is 3.0 or less in any composition. For this reason, the magnetic nanoparticles have a particle size distribution of a predetermined width, and even if the particle size changes, the rising temperature does not become excessively high when an external magnetic field is applied, and the affected area is overheated and harms healthy cells. Can be suppressed.

On the other hand, in the case of Comparative Example 1 in which i is less than 0.2 and in the case of Comparative Example 2 in which i exceeds 0.6, the temperature rise during application of the external magnetic field is less than 4 ° C., which may not be suitable for thermotherapy. all right.
In Comparative Examples 3 and 4 using Co—Zn-based ferrite magnetic nanoparticles and Comparative Example 5 using Fe—Zn-based ferrite magnetic nanoparticles, the temperature rise when applying an external magnetic field is 15 depending on the particle size. It exceeded ℃. For this reason, in the case of Comparative Examples 3 to 5, when the particle size changes, the rising temperature becomes excessively high when an external magnetic field is applied, and the affected area may be overheated, which may harm healthy cells. In Comparative Examples 3 to 5, the value obtained by dividing the maximum value of the rising temperature by the minimum value greatly exceeded 3.0.

Claims (6)

A core comprising Ni _(1-i) Zn _i Fe ₂ O ₄ (0.2 ≦ i ≦ 0.6) magnetic nanoparticles,
A shell made of amorphous SiO ₂ covering the core,
The average particle size is 10-20 nm,
Ni-Zn ferrite magnetic nanoparticles for thermotherapy having an AC magnetic field frequency of 15 kHz and an AC magnetic field strength of 210 Oe and an elevated temperature when an external magnetic field is applied is 4 to 15 ° C.   2. The Ni—Zn ferrite for thermotherapy according to claim 1, wherein a value obtained by dividing the maximum value of the elevated temperature when the external magnetic field is applied by the minimum value is 3.0 or less when the average particle diameter is constant. Magnetic nanoparticles.   The Ni-Zn ferrite magnetic nanoparticle for thermotherapy according to claim 1 or 2, further comprising a functional group covalently introduced onto the surface of the shell.   The functional group is at least one selected from the group consisting of an amino group, an isocyanate group, a mercapto group, a vinyl group, an epoxy group, a methacryloxy group, a ureido group, a chloropropyl group, and a sulfide group. Ni-Zn ferrite magnetic nanoparticles for thermotherapy according to claim 1.   5. A thermotherapy drug-binding complex comprising the thermotherapy Ni—Zn-based ferrite magnetic nanoparticles according to claim 3 or 4 and a drug, wherein the functional group and the drug are bonded to each other.   The thermotherapy comprising the Ni—Zn-based ferrite magnetic nanoparticles for thermotherapy according to claim 3 or 4 and a ligand that specifically interacts with a desired substance, wherein the functional group and the ligand are bound to each other. Therapeutic drug binding complex.