KR102385556B1 - Iron oxide magnetic particles - Google Patents

Abstract

The present invention relates to iron oxide magnetic particles containing iron oxide and MXn, wherein M is a lanthanide element and includes at least one selected from the group consisting of La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu, X includes at least one selected from the group consisting of F, Cl, Br and I, and n is an integer of 2 to 4. The iron oxide magnetic particles according to the present invention can be applied to various fields.

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.

Meanwhile, radiation or electromagnetic field-based thermal therapy 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. Heat therapy is an anticancer therapy that selectively kills cancer cells by raising the temperature of the cancer tissue and the surrounding area to about 40 to 43° C. using the difference in heat sensitivity between normal cells and 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 the magnetic particles are accumulated in the cancer tissue in the body. Therefore, research on thermotherapy using magnetic particles has received a lot of attention.

As magnetic particles for thermal treatment, iron oxide magnetic particles are mainly used. This is because the iron oxide magnetic particles are a material having an indirect band gap in which energy equal to the amount of momentum used is converted into heat and released. 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, and accordingly, exothermic properties and its magnetic properties 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 being conducted, but this also has a disadvantage in that it is difficult to apply inside the living body due to the low exothermic temperature.

In addition, rare earth metals (17 chemical elements of the periodic table, scandium (Sc) and yttrium (Y), lanthanides from lanthanum (La) to lutetium (Lu) are 15 elements), along with unique physical and chemical properties, excellent radiation Since it has absorption and shielding effects, various attempts have been made.

Non-patent literature: 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 lanthanide element, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and at least one selected from the group consisting of Lu, wherein X includes at least one selected from the group consisting of F, Cl, Br and I, wherein n is 2 to 4 Provided is an iron oxide magnetic particle that is an integer.

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.

It may have high structural stability due to the bond formed between the iron oxide and the lanthanide element-halogen compound.

1 shows the results of observation of GdI ₃ /Fe ₃ O ₄ particles prepared according to Example 3 of the present invention using a transmission electron microscope (a: transmission electron microscope (TEM) image, b: high-resolution transmission Electron microscopy (HR-TEM) image, c: EDX component analysis).
Figure 2 shows the results of observing CuI·GdI ₃ /Fe ₃ O ₄ particles prepared according to Example 14 of the present invention using a transmission electron microscope (a: transmission electron microscope (TEM) image, b: High-resolution transmission electron microscopy (HR-TEM) image, c: EDX component analysis).

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 lanthanide element, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and at least one selected from the group consisting of Lu, wherein X includes at least one selected from the group consisting of F, Cl, Br and I, wherein n is It is an integer of 2 to 4.

As used herein, the term "iron oxide" is an oxide of iron, for example, 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 (Wustite), FeO ₂ (Iron Dioxide), Fe ₄ O ₅ , Fe ₅ O ₆ , Fe ₅ O ₇ , Fe ₂₅ O ₃₂ and may include one or more selected from the group consisting of Delafossite, but is not limited thereto.

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

According to an embodiment of the present invention, M may be Gd.

In addition, the MX _n may include one or more selected from the group consisting of GdF ₂ , GdF ₃ , GdCl _{2 , GdCl 3 , GdBr 2 , GdBr 3} , GdI ₂ and GdI ₃ , preferably the MX _n may include one or more selected from the group consisting of GdF ₃ , GdCl ₃ , GdBr ₃ and GdI ₃ .

In addition, X may include a radioactive isotope of X or a mixture of radioactive isotopes of X. The term "radioisotope" refers to any 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.

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 ionic radius of the lanthanides used in the present invention is smaller than expected and regular. The lanthanide group refers to 15 elements with atomic numbers from lanthanum (La) of 57 to lutetium (Lu) of 71. All are rare earth elements, with the exception of luterium (Lu), the electrons are arranged in the f-region of the atomic orbital. In the f-region of the atomic orbital, since the inner shell of the outermost atomic shell is filled with electrons, the screening effect of the newly filled electrons is not large, and the effective nuclear charge is increased.

The occlusion effect is an effect in which the electrostatic repulsive force (repulsive force) between electrons (-) and electrons (-) in an atom weakens the attractive force between the nucleus (+) and electrons (-) of the atom. It becomes difficult to remove (increase ionization energy). As a result of intensive research, the present inventors have found that if the shielding effect is not large, the effective nuclear charge increases, so the electrons have a strong tendency to be attracted by the attraction of protons. found that there is

For example, the radius of the Ln ³⁺ (Lanthanide ion) lanthanide ion decreases regularly according to the atomic number. According to Fajans' rules, when the size of the Ln ³⁺ ion decreases, Ln(OH) In ₃ , the covalent property increases in the ionic bond between Ln ³⁺ and OH ^- ions.

When this is applied to the iron oxide magnetic particles of the present invention, the lanthanum element-halogen compound is bound to iron oxide by a stronger covalent property rather than an ionic bond, so that the particles are not decomposed even in a magnetic field or a strong frequency, even when applied to the human body. It is possible to ensure stability not to be decomposed. Also, according to the present invention, magnetic properties can be enhanced by including metal cations such as Cu and lanthanum in iron oxide. According to another embodiment of the present invention, the magnetic iron oxide particles may further include a heavy atom-halogen compound. can The term "heavy atom" refers to, for example, Mn, Co, Cu, Se, Sr, Mo, Ru, Rh, Pd, Ag, Cd, Sn, Ba, Ta, W, Re, Os, Ir, Pt, Au, Hg, atoms heavier than B (boron), such as Tl and Pb, but are not limited thereto. Specifically, it may further include at least one selected from the group consisting of CuF, CuCl, CuBr and CuI.

As an example of a lanternium element, Gd has an atomic radius of 0.18 nm, whereas, as an example of a heavy atomic element, Cu has an atomic radius of 0.128 nm, so that Gd is about 1.5 times that of Cu has the size of

Presumably, when the iron oxide contains the lanthanum element-halogen compound according to the present invention, the lanthanum element-halogen compound is disposed in the iron oxide as primary particles, and may have gaps (pores/pores). In addition, when a heavy atom-halogen compound having a relatively smaller size than the primary particles is disposed in the iron oxide as secondary particles, the lanthanum element-halogen compound can fill the gap between the primary particles, resulting in the expansion and contraction of the particles. It can absorb distortion by buffering it. 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 lanthanum element-halogen compound and the heavy atom-halogen compound included in the magnetic iron oxide particles 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 magnetic iron oxide particles may be coated with a hydrophilic or charged ligand or polymer. The hydrophilic ligand 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 ligand 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 ligand, and hyaluronidase or collagenase may be used to enhance penetration into cells. can be used, but is not limited thereto.

The iron oxide contained in the iron oxide magnetic particles of the present invention may be derived from a complex of iron and at least one compound selected from the group consisting of an aliphatic hydrocarbon acid salt having 4 to 25 carbon atoms and an amine compound.

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 two or more mixed acid salts.

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).

The content of MX _n in the magnetic iron oxide particles may be calculated during the manufacturing process of the magnetic iron oxide particles according to an embodiment of the present invention. After iron forms a complex with at least one compound selected from the group consisting of an aliphatic hydrocarbon acid salt of 4 to 25 carbon atoms and an amine compound, the complex forms iron oxide through a series of processes, and MX _n is bonded to the formed iron oxide The content of MX _n to be added when making the mixture may be based on 100 mol% of the total of the complex.

The magnetic iron oxide particles of the present invention contain the MX _n in an amount of about 1 to 13 mol%, based on 100 mol% of the total of the complex of iron and one or more compounds selected from the group consisting of aliphatic hydrocarbon salts having 4 to 25 carbon atoms and amine-based compounds, preferably Preferably from about 1 to 6 mol%, more preferably from about 3 to 6 mol% is prepared.

In one embodiment, the iron oxide magnetic particles may be included in a weight ratio of MX _n to iron oxide, 1:0.005 to 0.08, preferably 1: 0.01 to 0.08 (the ratio is ICP, a metal content analysis equipment) (Inductively coupled plasma) based on Mass Spectroscopy results). By being included within the above range, it is possible to secure excellent non-loss power, and it is also possible to secure a high temperature change under an external alternating magnetic field or when irradiated with radiation.

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.

In one embodiment, the average particle diameter (d50) of the magnetic iron oxide particles can be adjusted according to the administration method, administration location, and the organ to be diagnosed. For example, when having a size of 0.1 to 100 nm, when the average particle diameter (d50) is 15 nm or less, intravenous injection is preferable, and when the average particle diameter (d50) is more than 15 nm, intralesional, Intratumor injection may be preferred.

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.

In the case of a lanthanide element-halogen compound such as MX _n of the present invention, it not only increases the strength of magnetization by bonding with iron oxide as 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 final iron oxide-based 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 lanthanum group element-halogen 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 as a contrast agent, or may be used as a radiotherapy or thermal treatment to kill cancer cells.

According to an embodiment of the present invention, the composition for bio-imaging including the above-described iron oxide magnetic particles may be used. 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 one embodiment of the present invention, the present invention provides the steps of (a) administering a composition containing the magnetic iron oxide particles to a patient suspected of having cancer, and (b) the presence of the magnetic iron oxide particles in the patient's body using a magnetic resonance device. It provides a method for diagnosing cancer, comprising the step of detecting the presence or absence. When the magnetic iron oxide 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 a separate 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 iron oxide magnetic particles of the present invention, thermal diagnosis and treatment can be more efficiently performed under an external alternating magnetic field or under irradiation.

In one embodiment, when the magnetic iron oxide particles of the present invention are included in the contrast agent composition, the magnetic iron oxide particles of the present invention are 0.1 to 15 wt%, 1 to 15 wt%, 1 to 10 wt%, based on 100 wt% of the contrast agent composition %, 3 to 10% by weight, or 4 to 8% by weight.

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. there is. 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 containing the iron oxide magnetic particles of the present invention has no limitation on devices applicable for imaging diagnosis. Since the contrast agent containing the magnetic iron oxide particles of the present invention has both a negative contrast agent and a positive contrast agent component, it has high contrast and thus exhibits an excellent contrast effect. In particular, it 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 to be 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 contrast agent containing the magnetic iron oxide particles of the present invention, it shows a value of about 50-100HU based on 1mg.

The present invention provides CT imaging effects as well as 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. Unrestricted by the devices that can be used as contrast agents can be very useful when complex tests are required. 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 is complexly applicable to various devices, this inconvenience can be improved.

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

The cancer is stomach 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, prostate cancer , bone cancer, skin cancer, blood cancer, kidney 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. there is.

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

As mentioned above, the contrast agent containing the magnetic iron oxide particles 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. As cancer hyperthermia, there is systemic hyperthermia, which increases the cancer treatment effect in combination with radiation therapy/drug therapy. Local heat treatment is available.

As described above, 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, the magnetic iron oxide particles according to the present invention, due to the effect of amplifying the internal quantum efficiency of the iron oxide due to the difference in dielectric constant or electron capacitance due to the halogen group to which it is attached, efficient heat generation when used in thermotherapy using an external alternating magnetic field or radiation equipment brings the result of Accordingly, it is possible to dramatically lower the concentration of particles injected into the body compared to the existing iron oxide particles, and thereby, the problems of bioaccumulation and toxicity can be significantly improved. 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.

Example

Examples 1 to 15: MX _n Synthesis of iron oxide magnetic particles containing

(a) iron-oleic acid or iron-oleylamine complex synthesis

FeCl ₃ .6H ₂ O and sodium oleate (28 mmol) (Examples 1 to 5 and 11 to 15) or oleylamine (28 mmol) (Examples 6 to 10), 200 ml of hexane, 100 ml of ethanol, and 100 ml of deionized water were mixed and reacted with vigorous stirring at 110° C. for 6 hours. After the reaction solution was cooled to room temperature, the transparent lower layer was removed using a separatory funnel, 100 ml of water was mixed with the brown upper organic layer, and shaken, and the lower water layer was removed again. This was repeated 3 times. The remaining brown organic layer was transferred to a beaker and heated at 110° C. for 4 hours to evaporate hexane.

(b) MX _n Synthesis of iron oxide magnetic particles containing

4.5 g (5 mmol) of the iron-oleic acid complex prepared in (a) above and 1.7 g (6 mmol) of oleic acid were mixed (Examples 1 to 5 and 11 to 15), or the iron-oleic acid complex prepared in (a) above 4.208 g (5 mmol) of the ylamine complex and 1.6 g (6 mmol) of oleylamine were mixed (Examples 6 to 10). And, the types and contents of MX _n in Tables 1 and 2 below were mixed with 7 ml of 1-eicosene and 13 ml of dibenzyl ether, respectively. The mixture was placed in a round bottom flask and gas and moisture were removed in a vacuum at 90° C. for about 30 minutes. Nitrogen was injected and the temperature was raised to 200 °C. Thereafter, the temperature was raised to 310°C at a rate of 3.3°C/min and reacted for 60 minutes. After cooling the reaction solution, it was transferred to a 50 ml conical tube, 30 ml of ethanol and hexane were injected in a 1:1 ratio, and then centrifuged to precipitate particles. The precipitated particles were washed with 10 ml of hexane and 5 ml of ethanol, and then the obtained precipitate was dispersed in toluene or hexane. Here, dibenzyl ether is decomposed into benzyl aldehyde and toluene at a temperature of 150 ° C. or higher, and hydrogen between iron oxo (-Fe-O-Fe-) and a lanthanide element-halogen compound (MX _n ) by radicals generated from the aldehyde Helps form bonds and participates in crystal formation. The size of the prepared particles was about 6-7 nm.

note iron complex
(g iron-oleic acid or iron oleylamine content) mx _n class
(content g) Weight ratio of MX _n based on iron composite (input amount in manufacturing) Weight ratio of MX _n based on iron oxide (after material formation, analysis value: based on ICP) Example 1 4.501g
(5 mmol) GdI ₃ 0.022 g
(0.042 mmol) 0.005 0.0045 Example 2 4.501 g (5 mmol) GdI ₃ 0.135 g
(0.250 mmol) 0.030 0.028
Example 3 4.501 g (5 mmol) GdI ₃ 0.270 g
(0.501 mmol) 0.060 0.057 Example 4 4.501 g (5 mmol) GdI ₃ 0.022 g
(0.040 mmol) 0.005 0.003 Example 5 4.501 g (5 mmol) GdI ₃ 0.45 g
(0.836 mmol) 0.100 0.091 Example 6 4.208 g (5 mmol) GdI ₃ 0.022 g (0.0.042 mmol) 0.005 0.0045 Example 7 4.208 g (5 mmol) GdI ₃ 0.135 g (0.250 mmol) 0.030 0.029 Example 8 4.208 g (5 mmol) GdI ₃ 0.270 g (0.501 mmol) 0.060 0.059 Example 9 4.208 g (5 mmol) GdI ₃ 0.022 g (0.040 mmol) 0.005 0.004 Example 10 4.208 g (5 mmol) GdI ₃ 0.045 g (0.836 mmol) 0.100 0.097

note iron complex
(Iron-oleic acid content g) mx _n class
(content g) Weight ratio of MX _n based on iron composite (input amount in manufacturing) Weight ratio of MX _n based on iron oxide (after material formation, analysis value: based on ICP) Example 11 4.501g
(5 mmol) GdF ₃ 0.270 g
(1.260 mmol) 0.060 0.058 Example 12 4.501 g (5 mmol) GdBr ₃ 0.270 g
(0.680 mmol) 0.060 0.056 Example 13 4.501 g (5 mmol) GdCl ₃ 0.270 g
(1.024 mmol) 0.060 0.058 Example 14 4.501 g (5 mmol) GdI ₃ 0.270 g
(0.501 mmol)
CuI 0.270 g
(1.416 mmol) GdI ₃ : 0.060

CuI: 0.060 GdI ₃ : 0.058

CuI: 0.057 Example 15 4.501 g (5 mmol) GdI ₃ 0.135 g
(0.250 mmol)
0.270 g CuI
(1.461 mmol) GdI ₃ : 0.030

CuI: 0.060 GdI ₃ : 0.028

CuI: 0.057 Comparative Example 1 4.501 g (5 mmol) CuI 0.270 g
(1.416 mmol) 0.060 0.057 Comparative Example 2 4.501 g (5 mmol) 0.270 g CuBr
(1.882 mmol) 0.060 0.058

(c) Preparation of magnetic iron oxide particles coated with a hydrophilic ligand (polyacrylic acid)

After heating 2 g of polyacrylic acid and 40 ml of tetraethylene glycol at 110° C., 150 mg of the magnetic iron oxide particles containing the MX _n of the above example dispersed in 5 ml of hexane were injected with a syringe. It was stirred and reacted at 280 °C for 8 hours. After cooling the reaction solution, 20 ml of 0.01 N HCl was added, and particles attracted to the magnet were collected. After this was repeated twice, a precipitate was obtained using ethanol and finally dispersed in water.

Experimental Example: Iron oxide and MX under an external alternating magnetic field _n Analysis of temperature change according to the weight ratio of

After the particles prepared in Examples and Comparative Examples were coated with polyacrylic acid, which is a hydrophilic ligand, self-induced heating ability was tested. Examples and Comparative Examples were each diluted in deionized water to a concentration of 20 mg/ml, an alternating magnetic field was applied, and the temperature change was measured using a thermocouple (thermocouple, OSENSA, Canada). (AC frequency and magnetic field strength used: f = 108.7 kHz, H = 11.4 kA/m) The results are shown in Table 3 below.

The system for heating by inducing an alternating magnetic field consists of four main subsystems; (a) a variable frequency and amplitude sine wave function generator (20 MHz Vp-p, TG2000, Aim TTi, USA), (b) a power amplifier (1200Watt DC Power Supply, QPX1200SP, Aim) TTi, USA), (c) induction coil (number of revolutions: 17, diameter: 50 mm, height: 180 mm) and magnetic field generator (Magnetherm RC, nanoTherics, UK), (d) temperature change thermocouple (OSENSA, Canada) .

Temperature reached per unit time
(Standard: 1 minute)
Start measuring at 25°C Example 1 35 Example 2 58 Example 3 80 Example 4 21 Example 5 76 Example 6 25 Example 7 52 Example 8 73 Example 9 22 Example 10 71 Example 11 65 Example 12 49 Example 13 51 Example 14 92 Example 15 88 Comparative Example 1 86 Comparative Example 2 57

Experimental example: Measurement of specific loss power (SLP, specific loss power)

Since the calorific value of particles varies depending on the physical and chemical properties and the strength and frequency of the external alternating magnetic field, most of the research results show the heat generating ability of the particles as SLP and ILP. SLP is the electromagnetic force lost per unit of mass, expressed in W (watts) per kg. Since the conditions of f (frequency) and H (magnetic field strength) may be different for each experiment, the SLP value is converted into an ILP value using the formula [ILP= SLP/( f H ² )] to compare the effect of thermal treatment between particles. can be compared by

For SLP measurement, an AC magnetic field generator (Magnetherm RC, Nanotherics) of a series resonance circuit controlled by a pickup coil and an oscilloscope was used. It was measured under adiabatic conditions of f = 108.7 kHz and H = 11.4 kA/m, and the temperature was measured using an optical fiber IR probe.

SLP was measured by adjusting the particles of Examples and Comparative Examples to a concentration of 20 mg/ml. The results are shown in Table 4 below.

ILP value Example 1 1.37 Example 2 5.88 Example 3 9.50 Example 4 0.22 Example 5 8.75 Example 6 0.77 Example 7 4.99 Example 8 8.35 Example 9 0.27 Example 10 7.89 Example 11 6.83 Example 12 4.31 Example 13 4.83 Example 14 10.33 Example 15 9.95 Comparative Example 1 9.81 Comparative Example 2 5.14 control

Experimental example: In vivo (in vivo) cancer treatment effect confirmation experiment

It was confirmed that apoptosis by thermal treatment using the particles of Examples and Comparative Examples effectively occurred in vivo. After transplanting Panc-1 cells into Balb/c nude mice, when the size of the cancer tissue became about 100 mm ³ , 150 μl of an aqueous solution obtained by dispersing the compositions containing Examples 7 to 14 in deionized water) was administered subcutaneously. Then, an alternating magnetic field generator (100 kHz, 80 G) was applied for 30 minutes to perform thermal treatment, and the volume of the cancer was checked for 28 days. In the case of the control group below, the tumor size was measured when no separate treatment was performed.

The results are shown in Table 5 below.

note
(measured parking) Final tumor size after treatment (mm ³ ) (Week 0) (Week 1) (Week 2) (Week 3) (Week 4) Example 1 101 140 185 203 345 Example 2 97 74 49 43 35 Example 3 98 69 25 22 19 Example 4 100 155 284 434 624 Example 5 97 75 34 25 23 Example 6 99 153 274 425 614 Example 7 98 85 53 39 34 Example 8 98 75 41 34 35 Example 9 103 167 296 470 688 Example 10 96 74 40 35 27 Example 11 98 82 47 39 25 Example 12 99 84 55 38 35 Example 13 101 80 57 37 30 Example 14 102 60 15 13 10 Example 15 100 63 18 15 13 Comparative Example 1 98 65 21 18 15 Comparative Example 2 101 74 51 31 24 control 97 171 290 440 730

Experimental Example: Measurement of Radiation Absorption Coefficient (HU)

The radiation (X-ray) absorption coefficient (HU) was measured using the particles of Examples, Comparative Examples and Controls, and the results are shown in Table 6 below. At this time, the measuring device was a Skyscan 1172 Micro CT of Bruker, and the radiation absorption coefficient (HU) was calculated as follows.

CT Hounsfield Unit (HU, X-ray absorption coefficient)

(μ (linear attenuation coefficient): Relative linear attenuation coefficient)

note Radiation absorption coefficient (HU) per unit weight (based on 1mg) Example 1 58 Example 2 85 Example 3 94 Example 4 7 Example 5 96 Example 6 65 Example 7 81 Example 8 92 Example 9 8 Example 10 96 Example 11 6 Example 12 8 Example 13 15 Example 14 103 Example 15 100 Comparative Example 1 97 Comparative Example 2 18 Control 1 (iron oxide Fe ₃ O ₄ , see reference: Sci Rep., 8, 12706 (2018) about 10

Experimental Example: Thermogravimetric (TGA) analysis of magnetic iron oxide particles

In order to investigate the thermal stability of the magnetic iron oxide particles of the present invention (purpose: to check how stably the halogen elements are combined in the iron oxide magnetic particles), a thermogravometric analysis (thermogravometric analysis, TGA) was performed. Specifically, the particles of Examples, Comparative Examples and Controls were compared by measuring TGA at a rate of 20/min under nitrogen up to 200°C. The results are shown in Table 7.

note Weight reduction ratio (%) Example 1 5 Example 2 5 Example 3 2 Example 4 5 Example 5 2 Example 6 4 Example 7 4 Example 8 2 Example 9 6 Example 10 2 Example 11 7 Example 12 5 Example 13 5 Example 14 One Example 15 2 Comparative Example 1 3 Comparative Example 2 6 Control 1 (Iron Oxide Fe ₃ O ₄ ) 15 Control 2 (iron oxide-KI 6 wt% doping) 17 Control 3 (iron oxide- MgI ₂ 6 wt% doping) 13

Experimental Example: Microwave Stability Analysis of Magnetic Iron Oxide Particles

The particles of the Examples, Comparative Examples and Controls were irradiated for 15 minutes each at 2,400 to 2,500 MHz and 1000 W conditions using a microwave device manufactured by CEM Corporation in the United States. After microwave irradiation, the content of halogen elements was measured in a prodigy High Dispersion ICP measuring instrument equipped with a halogen option from A Teledyne Leeman Labs, and it was confirmed whether the particles were decayed. The results are shown in Table 8.

note Measured Halogen Elements (ppm) Example 1 13 Example 2 14 Example 3 7 Example 4 13 Example 5 7 Example 6 11 Example 7 12 Example 8 7 Example 9 15 Example 10 6 Example 11 16 Example 12 14 Example 13 15 Example 14 2 Example 15 4 Comparative Example 1 25 Comparative Example 2 30 Control 1 (Iron Oxide Fe ₃ O ₄ ) 0 Control 2 (iron oxide-KI 6 wt% doping) 65 Control 3 (iron oxide- MgI ₂ 6 wt% doping) 57

Claims (16)

An iron oxide magnetic particle comprising iron oxide and MX _n , wherein MX _n is GdCl ₃ , GdBr ₃ , and GdI ₃ At least one selected from the group consisting of,
The iron oxide magnetic particles include MX _n in a weight ratio of 1: 0.005 to 0.8 based on iron oxide.
delete delete delete delete The method according to claim 1,
Wherein X is a radioactive isotope or radioactive isotope mixture of X magnetic iron oxide particles.
The method according to claim 1,
The magnetic iron oxide particles further include at least one selected from the group consisting of CuF, CuCl, CuBr and CuI.
The method according to claim 1,
and at least a portion of a surface of the iron oxide magnetic particle is further coated with a hydrophilic ligand.
The method according to claim 1,
The iron oxide is magnetic iron oxide 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 (W

stite), FeO ₂ (Iron Dioxide), Fe ₄ O ₅ , Fe ₅ O ₆ , Fe ₅ O ₇ , and Fe ₂₅ O ₃₂ Magnetic iron oxide particles comprising at least one selected from the group consisting of.
9. The method of claim 8,
The hydrophilic ligand is polyethylene glycol, polyethyleneamine, polyethyleneimine, polyacrylic acid, polymaleic anhydride, polyvinyl alcohol, polyvinylpyrrolidone, polyvinylamine, polyacrylamide, polyethyleneglycol, phosphoric acid-polyethyleneglycol, 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.
delete 10. The method of claim 9,
The MX _n is iron oxide magnetic particles that are included in an amount of 1 to 13 mol% based on 100 mol% of the complex of iron and one or more compounds selected from the group consisting of an aliphatic hydrocarbon acid salt of 4 to 25 carbon atoms and an amine compound. .
The method according to claim 1,
The particles are magnetic iron oxide particles having a diameter of 3 nm to 100 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).

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