KR20220095107A - Iron oxide magnetic particles - Google Patents

Abstract

The present invention relates to iron oxide magnetic particles comprising iron oxide and MX_n, wherein the M is a transition metal comprising electrons in a 6p orbital on a periodic table and includes at least one selected from a group consisting of Tl, Pb, Bi, and Po, the X includes at least one selected from a group consisting of F, Cl, Br and I, and the n is an integer of 1 to 6.

Description

Magnetic iron oxide particles {IRON OXIDE MAGNETIC PARTICLES}

The present invention relates to iron oxide magnetic particles.

Magnetic particles have been widely used in biomedical fields including cell labeling, magnetic resonance imaging (MRI), drug delivery, and thermotherapy. Among various types of magnetic particles, superparamagnetic iron oxide magnetic particles have been widely studied in the biomedical field because of their high magnetic susceptibility and superparamagnetism.

In addition, since the magnetic particles have a characteristic of generating heat when radiation or a magnetic field is applied, a magnetic carrier, magnetic or radiation for a contrast agent in magnetic resonance imaging (MRI) or drug delivery in the field of nanomedicine. It can also be used for basal hyperthermia and the like.

In the field of imaging, iron oxide has been proposed as a negative contrast agent as a superparamagnetic contrast agent. However, the iron oxide particles have a strong hydrophobic attraction, so that aggregation occurs well to form a cluster, or when exposed to a living environment, biodegradation may occur rapidly. In addition, if the structure of the iron oxide particles is not sufficiently stable, the original structure may change, so that the magnetic properties may be changed and may be toxic. On the other hand, iodine is proposed as a positive contrast agent, but when it is used at high concentrations to enhance the contrast effect, liver/kidney toxicity occurs, so a formulation technology that increases the content per volume of the contrast medium has been introduced.

로 올려 암 세포를 선택적으로 사멸시키는 항암요법이다. 암 세포 주변에 자성 입자를 주입하여 외부에서 자기장을 걸어주면 자성 입자에서 열이 발생하여 짧은 시간에 암 세포를 사멸시킬 수 있다. 자기장은 피부 조직에 의해 영향을 받지 않아 침투 깊이의 제한이 없기 때문에 자성 입자가 신체 내 암 조직에 축적되어 있을 때에 선택적으로 열을 가할 수 있다. 따라서 자성 입자를 이용한 온열 치료 연구는 많은 관심을 받아왔다.On the other hand, radiation or electromagnetic field-based thermal treatment has been proposed to compensate for the limitations of existing cancer treatment methods (Wust et al. Lancet Oncology, 2002, 3:487-497). One of the unique characteristics of cancer cells is that their ability to adapt to heat is markedly inferior compared to normal cells. Hyperthermic therapy uses the difference in heat sensitivity between normal cells and cancer cells to reduce the temperature of the cancer tissue and its surroundings by about 40 to 43

It is an anticancer therapy that selectively kills cancer cells. If magnetic particles are injected around the cancer cells and a magnetic field is applied from the outside, heat is generated from the magnetic particles and the cancer cells can be killed in a short time. Since the magnetic field is not affected by the skin tissue and there is no limit to the penetration depth, heat can be selectively applied when magnetic particles are accumulated in cancer tissue in the body. Therefore, research on thermotherapy using magnetic particles has received a lot of attention.

As the magnetic particles for thermal treatment, iron oxide magnetic particles are mainly used. This is because the magnetic iron oxide particles are a material having an indirect band gap in which energy equal to the amount of momentum used is converted into heat and emitted. Among them, Fe ₃ O ₄ (magnetite) or a-Fe (ferrite)-based Magnetic particles have biocompatibility, heat inducibility, chemical stability and unique magnetic properties. Because of these characteristics, research is being actively conducted as a magnetic heating element for thermal treatment of iron oxide magnetic particles, and it has been approved for medical use by the US FDA. By the way, among the iron oxide magnetic particles, Fe ₃ O ₄ particles are nano-sized and their crystal phase is easily changed to α-Fe ₂ O ₃ , γ-Fe ₃ O ₃ , etc. depending on the conditions of the surrounding environment. There is a disadvantage in that the ability to generate heat decreases due to the change in enemy characteristics. As other materials, studies on MFe ₂ O ₄ (M=Co,Ni,Mg) particles of the Co, Ni, Mg series are in progress, but this also has a disadvantage in that it is difficult to apply inside the living body due to the low exothermic temperature.

Wust et al. Lancet Oncology, 2002, 3:487-497.

An object of the present invention is to provide magnetic iron oxide particles that can be used in various fields.

In order to solve the above problems, the present invention provides magnetic iron oxide particles containing iron oxide and MX _n , wherein M is a transition metal containing electrons in a 6p orbital on the periodic table, one selected from the group consisting of Tl, Pb, Bi and Po. It provides at least one species selected from the group consisting of F, Cl, Br and I, and wherein n is an integer of 1 to 6, wherein X is an iron oxide magnetic particle.

The magnetic iron oxide particles of the present invention may have high reactivity to stimuli introduced from the outside, such as radiation, magnetic fields, and radio waves.

In addition, by using the contrast agent containing the iron oxide magnetic particles, it can be applied to various imaging devices, and sufficient images can be obtained by administering a small dose.

The magnetic iron oxide particles of the present invention may have high structural stability due to a bond formed between iron oxide and a transition metal element including an electron in a 5d orbital-halogen compound.

Hereinafter, various embodiments of the present invention will be described with reference to the accompanying drawings. It should be understood that the present invention is not limited to specific embodiments, and includes various modifications, equivalents and/or alternatives of the embodiments of the present invention. In connection with the description of the drawings, like reference numerals may be used for like components.

In this document, expressions such as "have", "may have", "includes", or "may include" indicate the presence of a corresponding characteristic (eg, a numerical value, function, operation, or component such as a part). and does not exclude the presence of additional features.

In this document, expressions such as “A or B”, “at least one of A or/and B”, or “one or more of A or/and B” may include all possible combinations of the items listed together. . For example, "A or B", "at least one of A and B", or "at least one of A or B" means (1) includes at least one A, (2) includes at least one B; Or (3) it may refer to all cases including both at least one A and at least one B.

The expression "configured to (or configured to)" used in this document, depending on the context, for example, "suitable for (Suitable for)", "having the capacity to" It can be used interchangeably with "," "Designed to", "Adapted to", "Made to", or "Capable of". The term "configured (or set up to)" does not necessarily mean only "specifically designed to".

Terms used in this document are only used to describe specific embodiments, and may not be intended to limit the scope of other embodiments. The singular expression may include the plural expression unless the context clearly dictates otherwise. Terms used herein, including technical or scientific terms, may have the same meanings as commonly understood by one of ordinary skill in the art described in this document. Among the terms used in this document, terms defined in a general dictionary may be interpreted with the same or similar meaning as the meaning in the context of the related art, and unless explicitly defined in this document, have an ideal or excessively formal meaning. not interpreted In some cases, even terms defined in this document cannot be construed to exclude embodiments of the present document.

The embodiments disclosed in this document are presented for explanation and understanding of the disclosed and technical content, and do not limit the scope of the present invention. Accordingly, the scope of this document should be construed to include all modifications or various other embodiments based on the technical spirit of the present invention.

Hereinafter, preferred embodiments of the present invention will be described in detail. Prior to this, the terms or words used in the present specification and claims should not be construed as being limited to conventional or dictionary meanings, and the inventor should properly understand the concept of the term in order to best describe his invention. Based on the principle that it can be defined, it should be interpreted as meaning and concept consistent with the technical idea of the present invention.

Accordingly, the configuration of the embodiments described in the present specification are only some of the most preferred embodiments of the present invention and do not represent all the technical spirit of the present invention, so various equivalents and modifications that can be substituted for them at the time of the present application It should be understood that there may be

Throughout the specification, when a part "includes" a certain element, it means that other elements may be further included, rather than excluding other elements, unless otherwise stated.

In one aspect of the present disclosure, the term "about" is used to include errors in manufacturing processes included in specific values or slight numerical adjustments falling within the scope of the technical spirit of the present disclosure. For example, the term “about” means a range of ±10%, ±5% in one aspect, and ±2% in another aspect of the value to which it refers.

Hereinafter, the present invention will be specifically described.

The iron oxide magnetic particle according to an embodiment of the present invention is an iron oxide magnetic particle comprising iron oxide and MX _n , wherein M is a transition metal having an electron in a 6p orbital on the periodic table, and is a group consisting of Tl, Pb, Bi and Po. Including one or more selected from, wherein X includes one or more selected from the group consisting of F, Cl, Br and I, wherein n is an integer of 1 to 6.

The term “iron oxide” refers to oxides of iron, eg, iron oxides are Fe ₁₃ O ₁₉ , Fe ₃ O ₄ (magnetite), γ-Fe ₂ O ₃ (maghemite) and α-Fe ₂ O ₃ (hematite), β -Fe ₂ O ₃ (beta phase), ε-Fe ₂ O ₃ (epsilon phase), FeO (Wstite), FeO ₂ (Iron Dioxide), Fe ₄ O ₅ , Fe ₅ O ₆ , Fe ₅ O ₇ , Fe ₂₅ O ₃₂ , It may include one or more selected from the group consisting of ferrite-based (Ferrite type) and delafossite (Delafossite), but is not limited thereto.

The iron oxide magnetic particles, specifically, as particles containing MX _n in the iron oxide particles, have magnetism, and amplify the contrast effect of the iron oxide under various radiation conditions or a magnetic field having a relatively low intensity and/or low frequency of an alternating magnetic field. have.

In addition, X may include a radioactive isotope of X or a mixture of radioactive isotopes of X. Specifically, it refers to a compound in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of fluorine such as ¹⁸ F; isotopes of chlorine such as ³⁶ Cl; isotopes of bromine, such as ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br; And isotopes of iodine, for example, ¹²³ I, ¹²⁴ I, ¹²⁵ I and ¹³¹ I refers to those containing alone or in mixture.

In addition, the MX _n may include at least one selected from the group consisting of BiF _{3 , BiCl 3 , BiBr 3 , and} BiI ₃ .

According to the present invention, the meaning that MX _n is included in the iron oxide particles means that between the iron oxide particles and MX _n A physical or chemical bond may be formed. Specifically, MX _n may be disposed between iron oxide particles, and iron oxide and MX _n may be bonded through hydrogen bonding _. It may be formed by introducing a doping method such as a process or an ion implantation process, or may include forming iron oxide crystal nuclei inside MX _n to form a shell structure.

The magnetic iron oxide particles may have an average particle diameter (d50) of 0.1 nm to 1 μm. When the size of the magnetic iron oxide particles has an average particle diameter (d50) of 0.1 nm to 100 nm, it can be used as a component of a contrast agent, an anticancer agent, a thermotherapy agent, and a radiotherapy agent, and the size of the iron oxide magnetic particle is 100 nm If it is exceeded, it can be applied to various in vitro medical fields.

M used in the present invention is a post-transition metal containing electrons in 6p orbital on the periodic table, and refers to four elements including Tl, Pb, Bi and Po. In particular, Bi has the strongest diamagnetism among 　metals. Among metals, it has the lowest thermal conductivity after mercury and has the lowest electrical conductivity among all metals. Bi, which does not contain lead, has high stability, so the compound is used in cosmetics and medical treatment.

When this is applied to the iron oxide magnetic particles of the present invention, it is bound to the iron oxide in a trivalent form, so that it is not decomposed from the particles in a magnetic field or a strong frequency, so that it is not decomposed even when applied to the human body can be secured. In addition, according to the present invention, by including metal cations such as Cu and lanthanum in iron oxide, magnetic properties may be further strengthened.

According to another embodiment of the present invention, the magnetic iron oxide particles may further include a heavy atom-halogen compound. The term "heavy atom" refers to a heavier atom than B (boron), such as, for example, Mn, Co, Cu, Se, Sr, Mo, Ru, Rh, Pd, Ag, Cd, Sn, Ba, Tl, Pb. Atoms include, but are not limited to. Specifically, it may further include at least one selected from the group consisting of CuF, CuCl, CuBr and CuI.

Presumably, when the iron oxide contains the post-transition metal-halogen compound containing electrons in the 6p orbital according to the present invention, the post-transition metal-halogen compound containing electrons in the 6p orbital is disposed in the iron oxide as primary particles, and , may have gaps (pores/pores). And, when the heavy atom-halogen compound, which is relatively smaller in size than the primary particle, is disposed in the iron oxide as secondary particles, the gap between the primary particles made of the halogen compound and the post-transition metal containing electrons in the 6p orbital is filled. It can absorb and absorb the distortion caused by the expansion and contraction of the particles. As a result, it is believed that the iron oxide magnetic particles are less likely to be destroyed or crystal broken, and as a result, the halogen compound is less likely to be separated from the particles, and as a result, the stability of the iron oxide magnetic particles can be improved.

The weight ratio of the transition metal-halogen compound including electrons in the 5d orbital included in the magnetic iron oxide particles to the heavy atom-halogen compound may be 1:0.2 to 1:1.5. What is included within the above range can most effectively fill the gaps between the particles, so that the effect of buffering and absorbing the distortion caused by expansion and contraction can be excellently secured.

In one embodiment, in the magnetic iron oxide particles, at least a portion of the surface of the iron oxide particles may be coated with a hydrophilic polymer. The hydrophilic polymer may be introduced to increase solubility and stabilization of the magnetic iron oxide particles in water according to an embodiment, or to enhance targeting or penetration into specific cells such as cancer cells. Such a hydrophilic polymer may preferably have biocompatibility, for example, polyethylene glycol, polyethyleneamine, polyethyleneimine, polyacrylic acid, polymaleic anhydride, polyvinyl alcohol, polyvinylpyrrolidone, polyvinylamine, poly Acrylamide, polyethylene glycol, phosphoric acid-polyethylene glycol, polybutylene terephthalate, polylactic acid, polytrimethylene carbonate, polydioxanone, polypropylene oxide, polyhydroxyethyl methacrylate, starch, dextran derivatives, sulfonic acid It may include at least one selected from the group consisting of amino acids, sulfonic acid peptides, silica and polypeptides, but is not limited thereto. If necessary, when targeting cancer cells, a peptide or protein containing folic acid, transferrin or RGD may be used as the hydrophilic polymer, and hyaluronidase or collagenase may be used to enhance cell penetration. can be used, but is not limited thereto.

In one embodiment, the iron oxide may be derived from a complex of iron and at least one compound selected from the group consisting of aliphatic hydrocarbon salts and amine compounds having 4 to 25 carbon atoms. Examples of the aliphatic hydrocarbon acid salts having 4 to 25 carbon atoms include butyrate, valerate, caproate, enanthate, caprylic acid, pelargonate, caprate, laurate, myristic acid salt, pentadecylate, and acetic acid. Salt, palmitate, palmitoleate, margarate, stearate, oleate, bacinate, linoleate, (9,12,15)-linoleate, (6,9,12)-linoleate, eleoste Arate, tuberculostearate, racidate, arachidonic acid salt, behenate, lignocerate, nerbonate, cerotate, montanate, melisate and peptide salt containing one or more amino acids It may include one or more selected from the group consisting of. These 　 compounds may be used alone or in the form of a mixed acid salt of two or more.

The metal component of the aliphatic hydrocarbon salt having 4 to 25 carbon atoms may include at least one selected from the group consisting of calcium, sodium, potassium and magnesium.

Examples of the amine compound include methylamine, ethylamine, propylamine, isopropylamine, butylamine, amylamine, hexylamine, octylamine, 2-ethylhexylamine, nonylamine, decylamine, laurylamine, pentadecyl Amine, cetylamine, stearylamine and cyclohexylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diamylamine, dioctylamine, di(2-ethylhexyl)amine didecylamine, dilaurylamine, dicetylamine, distearylamine, methylstearylamine, ethylstearylamine and butylstearylamine, triethylamine, triamylamine, trihexylamine and trioctylamine; triallylamine and oleylamine, laurylaniline, stearylaniline, triphenylamine, N,N-dimethylaniline and dimethylbenzylaniline, monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol; Diethylenetriamine, triethylenetetramine, tetraethylenepentaamine, benzylamine, diethylaminopropylamine, xylylenediamine, ethylenediamine, hexamethylenediamine, dodecamethylenediamine, dimethylethylene Diamine, triethylenediamine, guanidine, diphenylguanidine, N,N,N',N'-tetramethyl-1,3-butanediamine, N,N,N',N'-tetramethylethylenediamine , 2,4,6-tris(dimethylaminomethyl)phenol, morpholine, N-methylmorpholine, 2-ethyl-4-methylimidazole and 1,8-diazabicyclo (5,4,0) It may include one or more selected from the group consisting of undecene-7 (DBU).

In the magnetic iron oxide particles of the present invention, the mol% of MX _n is about 1 to 13 mol%, preferably about 1 to 8, compared to the complex of iron and at least one compound selected from the group consisting of aliphatic hydrocarbons and aliphatic-amines. It can be prepared by adjusting to mol%.

In one embodiment, the iron oxide magnetic particles may be included in a weight ratio of MX _n based on iron oxide, 1:0.005 to 0.06, preferably 1: 0.01 to 0.06. The ratio may be measured using (Inductively coupled plasma) Mass Spectroscopy, which is a metal content analysis equipment. In the magnetic iron oxide particles of the present invention, MX _n is included within the above range, so that an excellent non-loss force can be secured, and a high temperature change can be ensured under an external alternating magnetic field or when irradiated with radiation.

The magnetic iron oxide particles as described above have high reactivity to stimuli introduced from the outside, such as radiation, magnetic field, and radio waves, and can secure high non-loss power, and thus can be effectively used for thermal treatment, which will be described later.

Presumably, in the case of a compound such as MX _n of the present invention, it not only increases the strength of magnetization by bonding with iron oxide, which is a magnetic substance, but also increases the size or total amount of electromagnetic field energy that the compound can absorb. It is possible to increase the amount of thermal energy emitted from the underlying magnetic particles. This is not only in the existing high frequency (200 kHz or more) band, but also in the electromagnetic field energy environment of relatively low and medium frequency (50 Hz ~ 200 kHz) band, higher thermal energy emission (conversion) efficiency (ILP: Intrinsic loss power) compared to the existing iron oxide-based magnetic particles ) can be improved or increased.

In addition, by using the contrast agent containing the iron oxide magnetic particles, it can be applied to various imaging devices, and sufficient images can be obtained by administering a small dose.

Furthermore, since it has high structural stability by the bond formed between iron oxide and the MX _n compound, there is no concern about side effects that may be caused by each component, and the toxicity is low, so it can be safely applied to the human body.

The magnetic iron oxide particles according to an embodiment of the present invention may be used for radiation therapy or thermal therapy for the death of cancer cells.

Since the magnetic iron oxide particles according to the present invention have magnetism, they can be usefully used in a diagnostic method using magnetic properties.

According to an embodiment of the present invention, (a) administering a composition comprising the iron oxide magnetic particles to a patient suspected of cancer, and (b) the presence or absence of the magnetic particles injected into the patient using a magnetic resonance device It provides a method for diagnosing cancer, comprising the step of detecting When the magnetic particles according to the present invention are administered, for example, the contrast between the lesion and the normal tissue is clearly enhanced in the MRI T1- and T2-weighted images, thereby confirming the visible contrast effect. When the magnetic iron oxide particles of the present invention are administered, cancer diagnosis can be performed without additional administration of an additional contrast agent, so that the diagnosis and treatment of cancer can be performed simultaneously with the magnetic iron oxide particles of the present invention.

When a cancer cell targeting material or penetration enhancing material is bound to the magnetic iron oxide particles of the present invention, thermal diagnosis and treatment can be more efficiently performed under an external alternating magnetic field or under irradiation with radiation.

The magnetic iron oxide particles used in the contrast agent composition include 0.1 to 15 wt%, 1 to 15 wt%, 1 to 10 wt%, 3 to 10 wt%, or 4 to 8 wt% of the magnetic iron oxide particles relative to the total amount of the contrast agent composition. may be included.

When the magnetic iron oxide particles are included within the above range, the magnetic iron oxide particles are discharged outside the body without being accumulated in the body, thereby remarkably reducing toxicity as a contrast agent.

In one embodiment, the contrast agent may exhibit a contrast effect in a magnetic field having a frequency of 1 kHz to 1 MHz or less or an intensity of 20 Oe (1.6 kA/m) to 200 Oe (16 kA/m) or less. have. The alternating magnetic field irradiated after administering the contrast agent to the subject may have a frequency of 1 kHz to 1 MHz, or a frequency of 30 kHz to 120 kHz. In general, in order to change the spin state from a singlet to a triplet, an alternating magnetic field of 1 MHz or more must be applied. In addition, the alternating magnetic field is 20 Oe (1.6 kA/m) to 200 Oe (16.0 kA/m), 80 Oe (6.4 kA/m) to 160 Oe (12.7 kA/m), or 140 Oe (11.1 kA/m) It may have a magnetic field strength. The contrast agent according to an embodiment is useful in that it can be used even in an alternating magnetic field of a low magnetic field strength and/or frequency, which is relatively harmless to the human body, unlike the conventional high-energy method.

The contrast agent of the present invention has a feature that there is no limitation in terms of devices applicable for imaging diagnosis. Since the contrast agent of the present invention has both a negative contrast agent and a positive contrast agent component, it has high contrast, thereby exhibiting an excellent contrast effect. The iron oxide contrast agent of the present invention shows a higher radiation absorption HU (hounsfield unit) value and CT contrast effect than conventional iodine-based (Iohexol or Iopamidol) or gold nano-CT contrast agents. In the case of the existing iodine-based contrast agent, it is reported that the value is about 5-50 HU based on 647 mg/ml, 3000 HU (4.6 HU based on 1 mg), and gold nanoparticles based on 1 mg. On the other hand, in the case of the magnetic iron oxide particles of the present invention, it shows a value of about 50-100HU based on 1mg.

The present invention provides not only CT imaging effects but also X-ray imaging, Magnetic Resonance Imaging (MRI), US, optical imaging, Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET), Magnetic Particle Imaging (MPI), flat panel imaging , and rigid, flexible or capsule endoscopy. Since the magnetic iron oxide particles according to the present invention can be used without limitation in various devices, for example, a patient can undergo an examination of multiple devices at once after administering one contrast agent, so that different contrast agents can be used according to conventional devices. It can reduce unnecessary time required to put For example, if CT scan and MRI scan are to be performed within a short period of time, the CT contrast agent may be mixed with the MRI contrast agent and the subject's body, making the test results unclear, and the subject administers a different contrast agent for each test The more you take it, the more likely it is to become toxic. However, since the contrast agent of the present invention can be applied to various devices in a complex manner, such inconvenience can be reduced.

Another aspect provides a composition for diagnosing cancer including a contrast agent according to an embodiment.

The cancer is gastric cancer, lung cancer, melanoma, uterine cancer, breast cancer, ovarian cancer, liver cancer, biliary tract cancer, gallbladder cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, rectal cancer, colorectal cancer, cervical cancer, brain cancer, bone cancer, skin cancer, blood cancer, kidney cancer, prostate cancer, thyroid cancer, parathyroid cancer, or ureter cancer.

The composition for diagnosing cancer may be administered to an individual in an oral or parenteral manner, and may include a pharmaceutically acceptable carrier suitable for each administration. Suitable pharmaceutically acceptable carriers and agents are described in detail in Remington's Pharmaceutical Sciences 19th ed., 1995.

When the composition for diagnosing cancer is administered orally, it may be administered in a solid preparation such as a tablet, capsule, pill, or granule, or a liquid preparation such as a liquid or suspension.

When the composition for diagnosing cancer is administered parenterally, it may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intralesional injection, intratumoral injection, or the like.

When the composition for diagnosis of cancer is administered orally or parenterally as a liquid, it can be prepared as an aqueous solution or suspension using commonly known solvents such as isotonic sodium chloride solution, Hank's solution, and Ringer's solution. have.

In one embodiment, the composition for diagnosing cancer may be used to simultaneously treat cancer.

As mentioned above, the contrast agent of the present invention can kill cancer cells by heat treatment. The term "thermal treatment" means to kill lesion cells including cancer cells by exposing body tissues to a temperature higher than normal body temperature, or to make these cells more sensitive to radiation therapy or anticancer drugs. Hyperthermia for cancer includes systemic hyperthermia, which increases the cancer treatment effect in combination with radiation therapy/drug therapy. have.

As such, thermal therapy has the advantage of reducing side effects by selectively killing cancer cells. There are problems and limitations of thermal treatment have been pointed out. In the past, the following two methods were used to solve this problem:

(a) a method of increasing the strength or frequency of an external alternating magnetic field in order to increase the heat generation phenomenon of the particles; or

(b) A method of increasing the concentration of particles injected into a living body.

However, (a) the method of increasing the strength or frequency of the external alternating magnetic field can cause red spots around the skin and slight burns, wounds, inflammation, necrosis, etc. to appear in areas with a lot of fat, and not only cancer tissue but also normal tissue cells It can also lead to damage or weaken the immune system. In addition, since this method cannot avoid side effects due to harm to the human body, its use is prohibited for pregnant women, patients with severe inflammation, patients with cardiac pacemakers, and patients with severe pleural fluid and ascites. As an alternative, (b) the method of increasing the concentration of particles injected into the body increases the probability of particle accumulation in the body, and toxicity problems occur due to the chemical composition of the particle surface.

However, due to the effect of amplifying the internal quantum efficiency of iron oxide due to the difference in the dielectric constant or electron capacitance caused by the halogen group, the magnetic iron oxide particles in the present invention result in efficient heat generation when used in thermotherapy using an external alternating magnetic field or radiation equipment. Accordingly, it is possible to significantly lower the concentration of particles injected into the body compared to the existing iron oxide-based particles, thereby greatly improving the problem of bioaccumulation and toxicity. In conclusion, the present invention can remarkably overcome the disadvantages of the prior art in which use of iron oxide magnetic particles is limited due to low calorific value despite advantages of biocompatibility, chemical stability, and magnetic properties.

Hereinafter, examples and the like will be described in detail to help the understanding of the present invention. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be construed as being limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.

Claims (11)

An iron oxide magnetic particle comprising iron oxide and MX _n ,
M is a transition metal containing an electron in 6p orbital on the periodic table, and includes at least one selected from the group consisting of Tl, Pb, Bi and Po, and X is selected from the group consisting of F, Cl, Br and I and at least one of which is, wherein n is an integer of 1 to 6, which is an iron oxide magnetic particle.
The method according to claim 1,
Wherein X is a radioactive isotope of X or a magnetic iron oxide particle comprising a mixture of radioactive isotopes of X.
The method according to claim 1,
At least a portion of the surface of the iron oxide particles is further coated with a hydrophilic polymer to form a composite iron oxide magnetic particles.
The method according to claim 1,
The iron oxide precursor is iron oxide magnetic particles derived from a complex of iron and at least one compound selected from the group consisting of aliphatic hydrocarbon salts and amine compounds having 4 to 25 carbon atoms.
The method according to claim 1,
The iron oxide is Fe ₁₃ O ₁₉ , Fe ₃ O ₄ (magnetite), γ-Fe ₂ O ₃ (maghemite) and α-Fe ₂ O ₃ (hematite), β-Fe ₂ O ₃ (beta phase), ε-Fe ₂ O ₃ (epsilon phase), FeO (Wstite), FeO ₂ (Iron Dioxide), Fe ₄ O ₅ , Fe ₅ O ₆ , Fe ₅ O ₇ , Fe ₂₅ O ₃₂ , Ferrite type and delafoxite (Delafossite) magnetic iron oxide particles comprising at least one selected from the group consisting of.
4. The method according to claim 3,
The hydrophilic polymer is polyethylene glycol, polyethyleneamine, polyethyleneimine, polyacrylic acid, polymaleic anhydride, polyvinyl alcohol, polyvinylpyrrolidone, polyvinylamine, polyacrylamide, polyethylene glycol, phosphoric acid-polyethylene glycol, polybutylene terephthalate, polylactic acid, polytrimethylene carbonate, polydioxanone, polypropylene oxide, polyhydroxyethyl methacrylate, starch, dextran derivatives, sulfonic acid amino acids, sulfonic acid peptides, silica and polypeptides selected from the group consisting of An iron oxide magnetic particle comprising at least one.
The method according to claim 1,
The iron oxide magnetic particles include MX _n in a weight ratio of 1: 0.005 to 0.1 based on iron oxide.
The method according to claim 1,
The particles are magnetic iron oxide particles having a diameter of 0.1 nm to 1000 nm.
The method according to claim 1,
The iron oxide magnetic particles are magnetic iron oxide particles used at a frequency of 1 kHz to 1 MHz.
The method according to claim 1,
The iron oxide magnetic particles are used in a magnetic field having an intensity of 20 Oe (1.6 kA/m) to 200 Oe (16.0 kA/m).
The method according to claim 1,
The iron oxide magnetic particles are iron oxide magnetic particles used in radiation.