KR20190096807A - Radioisotope-containiing metal layered double hydroxide composite, preparing method of the same, and uses of the same - Google Patents

Abstract

The present application relates to: radioisotope-containing metal bilayer hydroxide hybrids comprising radioisotopes located within and/or between lattice of metal bilayer hydroxides; a method for manufacturing the radioisotope-containing metal bilayer hydroxide hybrids; and a use of the radioisotope-containing metal bilayer hydroxide hybrids for diagnosing and/or treating cancer.

Description

RADIOISOTOPE-CONTAINIING METAL LAYERED DOUBLE HYDROXIDE COMPOSITE, PREPARING METHOD OF THE SAME, AND USES OF THE SAME}

The present application is directed to radioisotope-containing metal bilayer hydroxide hybrids comprising radioisotopes located within and / or between layers of a lattice of metal bilayer hydroxides, methods of making the radioisotope-containing metal bilayer hydroxide hybrids, and Radioisotope-containing metal double layer hydroxide hybrids for cancer diagnosis and / or cancer treatment.

In the treatment of cancer, surgery to remove the tumor at a glance, anticancer drug treatment for the invisible metastatic cancer treatment, and radiation therapy for the long-term function and appearance of the cancer-generating site are used. . However, in the case of surgery, the possibility of recurrence is high because of the invasive nature of the surrounding tissues. The anticancer drug treatment, which is effective for treating metastatic tumors, has difficulty in treating the visible tumors.

The use of radioisotopes in the medical field is on the rise, due to the expansion of the use of gamma cameras and positron emission tomography (PET) cameras. BACKGROUND OF THE INVENTION The development of materials and methods that can be diagnosed by administering radioisotopes into the body is progressing in various ways, and the role of radioisotopes in cancer diagnosis and treatment is becoming important.

Examples of cancer treatment with radioisotopes are typically glass microspheres containing the yttrium-90 (Y-90, ⁹⁰ Y) that emits the pure β-emissions under the trade name TheraSphere® (MDS Nordion, Inc.). It has been used for the treatment of patients with tumors in the liver. J. Vasc. Interv. Radiol. 13, 223 (2002), “Yttrium-90 Microspheres: Radiation Therapy for Unresectable Liver Cancer,” showed that ⁹⁰ Y-containing microsphere compounds may increase patient survival in non-resectable liver cancer treatment. Glass microspheres used as carriers of yttrium-90 are very insoluble and relatively resistant to radiation damage, but have the major drawback that they remain in vivo after their half-life with non-biodegradable materials in vivo. In another example, J. Nucl. Med. 54, 2093 (2013), "In Vivo Dosimetry Based on SPECT and MR Imaging of ¹⁶⁶ Ho-Microspheres for Treatment of Liver Malignancies," uses polymer-based holmium-166-poly-L-la instead of glass microspheres. ¹⁶⁶ Ho-poly (L-lactic acid) microspheres were applied to liver cancer treatment using single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). It has been shown that the overall information being treated can be traced efficiently. However, the microsphere used has a disadvantage that it requires a technical skill to be injected into the vicinity of the affected area by using a catheter to the tumor proximity vessel as a particle characteristic of several tens of micro-size, and does not reach the capillaries.

Korean Patent Application Publication No. 10-2014-0092226, "Capture of Radionuclides in Nanoparticle Compositions," describes copper-61 (Cu-61, ⁶¹ Cu) and copper- as new diagnostic tools utilizing positron emission tomography (PET) imaging technology. Diagnostic compounds have been developed that include encapsulated nanometer-sized metal entities of radioactive isotopes such as 64 (Cu-64, ⁶⁴ Cu), ie new liposome compositions. However, compared to glass microspheres, the particles are nanometer-sized to facilitate intravenous injection into the body and have biodegradable properties, but chelates can be combined with radioisotopes to capture radioisotopes in liposomes. Wrapping in liposomes and using the principles of osmotic pressure requires a rather complex process to capture radioisotopes into liposomes.

In order to solve the above-mentioned, there is a need for development of a substance that is highly selective for cancer cells, harmless to the human body, and radioactive isotopes that can be released in vitro without remaining in the living body, and a method for efficiently preparing the same.

J. Phys. Chem. C, 114, 734 (2010), Synthesis and characterization of dual radiolabeled layered double hydroxide nanoparticles for use in in-vitro and in-vivo nanotoxiclology studies, is a radioactive isotope used in SPECT imaging. -57, ⁵⁷ Co) and gallium-67 (Ga-57, ⁶⁷ Ga) metal bilayer hydroxide containing two types of radioisotope can be applied to biocompatible metal bilayer hydroxide by confirming its stability with pH change. Showed. However, the initial reaction time between the radioactive isotope and the metal elements constituting the metal double layer hydroxide is too short, and thus, there is a disadvantage in that a process of removing the unreacted radioisotope is present in the solution. In another example, the "Chelator-free labeling of layered double hydroxide nanoparticles for in Vivo PET imaging," published in Scientific Reports, 5, 16930 (2015), uses a radioactive isotope, copper-64 (Cu-64, ⁶⁴ Cu), as a metal bilayer. By attaching to the hydroxide surface and confirming by PET image, it showed that the metal double layer hydroxide containing radioisotope can be applied as a radiographic imaging material. However, ⁶⁴ Cu adhesion efficiency (labeling efficiency) in the ⁶⁴ Cu closed with a metallic double layer hydroxide finished in the way presented in this technology is very low as 16.6%. In another technique, ⁶⁴ Cu deposition efficiency improved to 59.0% when ⁶⁴ Cu was deposited after coating on metal bilayer hydroxide with bovine serum albumin (BSA), but still not high efficiency. The degree of penetration into cells by attaching radioisotope ⁵⁷ Co, which is capable of SPECT imaging, to metal bilayer hydroxides in "Radioisotope Co-57 incorporated layered double hydroxide nanoparticles as a cancer imaging agent", published in RSC adv., 6, 48415 (2016). By confirming the degree of biodistribution to liver, kidney, pancreas and tumor, the possibility of radiation diagnosis using metal double layer hydroxide was again confirmed. However, as in the previous experiments, the adhesion efficiency of ⁵⁷ Co in the metal double layer hydroxide was measured as low as 27%. Therefore, there is a need to develop a metal double layer hydroxide capable of stably supporting radioisotopes while having high labeling efficiency.

The present application is directed to radioisotope-containing metal bilayer hydroxide hybrids comprising radioisotopes located within and / or between layers of a lattice of metal bilayer hydroxides, methods of making the radioisotope-containing metal bilayer hydroxide hybrids, and It is intended to provide a use for radiodiagnosis and / or cancer treatment of radioisotope-containing metal bilayer hydroxide hybrids.

However, the problem to be solved by the present application is not limited to the above-mentioned problem, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

A first aspect of the present disclosure provides a radioisotope-containing metal bilayer hydroxide hybrid comprising radioisotopes located within and / or between layers of a lattice of metal bilayer hydroxides.

According to a second aspect of the present disclosure, after mixing an aqueous solution including metal salts including metal-based elements forming a metal double layer hydroxide and an aqueous solution including at least one radioisotope, reacting the mixed solution by a base solution ; And hydrothermally synthesizing the mixed solution to form a metal bilayer hydroxide comprising the radioisotope in the lattice and / or between the layers, providing a method for producing a radioisotope-containing metal bilayer hydroxide hybrid.

According to a third aspect of the present disclosure, after mixing an aqueous solution including metal salts including metal-based elements forming a metal double layer hydroxide and an aqueous solution including at least one radioisotope, reacting the mixed solution by a base solution ; Hydrothermally synthesizing the reacted mixed solution to form a metal bilayer hydroxide comprising the radioisotope in a lattice and / or between layers; And ion of radioisotopes, chelates containing radioisotopes, or polyatomic ions comprising radioisotopes between layers of metal bilayer hydroxides containing the formed radioisotopes in a lattice and / or between layers. Provided is a method of making a radioisotope-containing metal bilayer hydroxide hybrid, comprising the step of intercalating by.

In embodiments herein, a radioisotope-containing metal bilayer hydroxide hybrid and a radioisotope-containing metal bilayer hydroxide hybrid, comprising radioisotopes located within and / or between layers of a lattice of metal bilayer hydroxides. It provides a method for producing.

In embodiments of the present invention, the radioisotope being used for cancer diagnosis, cancer treatment, or cancer diagnosis and cancer treatment is stably included in the lattice and / or between layers of the metal double layer hydroxide, or the metal double layer hydroxide By including chelates or polyatomic ions containing radioisotopes between layers, the labeling efficiency of radioisotopes can be enhanced, and targeted to cancer cells selectively to enhance concentration on cancer cells, and cell membranes against cancer cells. Highly permeable and biocompatible radioisotope-containing metal bilayer hydroxide hybrids can be prepared.

In embodiments of the present invention, the radioisotope-containing metal bilayer hydroxide hybrid has the radioisotope constituting a lattice layer stably like the metal ions of the metal bilayer hydroxide, and thus included in the metal bilayer hydroxide. The labeling efficiency of the radioisotope may be improved from about 90% to about 100%, and the radioisotope may be very stable in vivo because it is stably present in the metal bilayer hydroxide lattice layer.

In embodiments herein, the radioisotope-containing metal bilayer hydroxide hybrid can provide a hybrid with low intracellular toxicity, biocompatible and capable of stably delivering radioisotopes against cancer at local sites. In addition, since it exhibits high selectivity for cancer cells, it can be applied to radiation therapy and diagnosis of tumors.

In embodiments of the present disclosure, the radioisotope-containing metal double layer hydroxide hybrid may be variously used as necessary except for a field where only radioisotopes are used alone. For example, the radioisotope-containing metal double layer hydroxide hybrid may be used for inspecting agricultural and aquatic products by using a metal double layer hydroxide that is harmless to the human body, or may be used in the field of measuring the amount of harmful substances by measuring the adsorption amount of heavy metals. It is also available for use in fertilizer testing, including ³² P in a metal double layer oxide layer with soil-like properties for fertilizer use, and furthermore, radioactive isotopes released as industrial waste to metal double layer hydroxides. It can also be used for the field of adsorption and removal.

1 (a) to 1 (c) are schematic diagrams showing the structure of a radioisotope-containing metal bilayer hydroxide hybrid in an embodiment of the present application.
FIG. 2 illustrates a process for preparing a radioisotope-containing metal bilayer hydroxide hybrid in one embodiment of the present disclosure.
3 is an X-ray diffraction pattern of a metal double layer hydroxide hybrid including non-radioactive isotope copper in one embodiment of the present disclosure.
FIG. 4 is an SEM image of metal bilayer hydroxide hybrids including non-radioactive isotope copper in one embodiment of the present disclosure. FIG.
FIG. 5 shows cytotoxicity test results (L929 cells) for metal bilayer hydroxide hybrids including non-radioactive isotope copper in one embodiment of the present disclosure.
FIG. 6 illustrates labeling efficiency of 64-copper according to the amount of radiation of copper-64 when synthesizing a metal double layer hydroxide hybrid including copper-64 in a lattice.
FIG. 7 illustrates labeling efficiency of copper-64 of metal bilayer hydroxide hybrids including copper-64 in one embodiment of the present disclosure.
FIG. 8 illustrates thin layer chromatography (TLC) evaluation of metal double layer hydroxide hybrids including copper-64 in one embodiment of the present disclosure.
9 shows 64-copper labeling stability over time in saline of metal bilayer hydroxide hybrids comprising copper-64 in one embodiment of the present disclosure.
FIG. 10 illustrates copper-64 label stability over time in various media of metal bilayer hydroxide hybrids comprising copper-64, in one embodiment of the present disclosure.
FIG. 11 shows the results of cell penetration experiments (MDA-MB-231 cells) on metal bilayer hydroxide hybrids containing radioisotope copper-64 in one embodiment of the present application.
FIG. 12 shows cytotoxicity results (MDA-MB-231 cells) for metal bilayer hydroxide hybrids with radioisotope copper-64 in one embodiment of the present disclosure.
FIG. 13 is a positron emission tomography (PET) image according to in vivo distribution over time after iv injection of a metal double layer hydroxide hybrid containing radioisotope copper-64 according to one embodiment of the present invention. The result is.
FIG. 14 shows long-term copper-64 detection curves over time after intravenous (iv) injection of metal bilayer hydroxide hybrids with radioisotope copper-64 in one embodiment of the present disclosure.
FIG. 15 shows tumor uptake over time following iv injection of metal bilayer hydroxide hybrids with radioisotope copper-64 in one embodiment of the present disclosure.
FIG. 16 shows in vivo distribution results over time after iv injection of metal bilayer hydroxide hybrids containing radioisotope copper-64 in one embodiment of the present disclosure.
FIG. 17 is an X-ray diffraction pattern of a metal double layered pure oxide surface-treated with a metal double layered hydroxide, a folate, and a polymer in which a non-radioactive isotope lutetium is included in a lattice.
FIG. 18 shows an infrared spectroscopic analysis of a metal double layer hydroxide hybrid having a non-radioactive isotope lutetium contained in a lattice and surface treated with a folate and a polymer.
FIG. 19 illustrates labeling efficiencies of metal bilayer hydroxide hybrids including radioisotope lutetium-177 in one embodiment of the present disclosure.
FIG. 20 shows lutetium-177 label stability over time in various media of metal bilayer hydroxide hybrids including radioisotope lutetium-177 in one embodiment of the present disclosure.
FIG. 21 shows the results of cell penetration experiments (PANC-2 cells) on metal bilayer hydroxide hybrids containing radioisotope lutetium-177 in one embodiment of the present disclosure.
FIG. 22 is an X-ray diffraction pattern of metal bilayer hydroxides in which an carbonate ion and an iodine anion are located in a layer, in an embodiment of the present disclosure.
FIG. 23 is an X-ray diffraction pattern of a metal bilayer hydroxide comprising non-radioactive yttrium in one embodiment of the present disclosure. FIG.
24 is a diagram illustrating changes in unit lattice parameters according to an amount of non-radioactive isotope yttrium of a metal double layer hydroxide according to an exemplary embodiment of the present disclosure.
25 shows cytotoxicity results (L929 cells) of metal bilayer hydroxide hybrids in which non-radioactive isotope yttrium is included in proportions in one embodiment of the present disclosure.
FIG. 26 shows cytotoxicity results (Hepa-1c1c7 cells) of metal bilayer hydroxide hybrids in which non-radioactive isotope yttrium is included in proportion in one embodiment of the present application.
FIG. 27 is an X-ray diffraction pattern of metal bilayer hydroxides including non-radioactive isotope gallium in one embodiment of the present disclosure.
FIG. 28 is an SEM image of metal bilayer hydroxides containing non-radioactive isotope gallium in one embodiment of the present disclosure. FIG.
FIG. 29 shows the labeling efficiency of gallium-68 of a metal bilayer hydroxide comprising gallium-68 in the lattice, in one embodiment of the present disclosure.
30 shows TLC evaluation of a metal bilayer hydroxide comprising gallium-68 in one embodiment of the present disclosure.
FIG. 31 shows a cell penetration result (MDA-MB-231) of a metal bilayer hydroxide including gallium-68 in one embodiment of the present application.
FIG. 32 is an X-ray diffraction pattern of metal double layer hydroxides obtained as a result of ion exchange with a solution containing phosphate ions according to a pH change according to an embodiment of the present disclosure.
FIG. 33 is an X-ray diffraction pattern of metal double layer hydroxides obtained as a result of ion exchange with a solution containing phosphate ions according to a concentration condition in an example of the present disclosure.
FIG. 34 shows infrared spectroscopic analysis of metal bilayer hydroxides obtained as a result of ion exchange with a solution containing phosphate ions according to a pH change according to an embodiment of the present disclosure.
FIG. 35 shows infrared spectroscopic analysis of metal double layer hydroxides obtained as a result of ion exchange with a solution containing phosphate ions according to concentration conditions in an embodiment of the present disclosure.
36 is an X-ray diffraction pattern of a metal double layer hydroxide obtained as a result of ion exchange between a metal double layer hydroxide containing non-radioactive isotope yttrium and a solution containing phosphate ions according to one embodiment of the present invention.
FIG. 37 shows infrared spectroscopic analysis of metal bilayer hydroxides obtained as a result of ion exchange between a metal bilayer hydroxide containing non-radioactive isotope yttrium and a solution containing phosphate ions according to an embodiment of the present disclosure.

DETAILED DESCRIPTION Hereinafter, exemplary embodiments of the present disclosure will be described in detail with reference to the accompanying drawings so that those skilled in the art may easily implement the present disclosure. As those skilled in the art would realize, the described embodiments may be modified in various different ways, all without departing from the spirit or scope of the present invention. In the drawings, parts irrelevant to the description are omitted for simplicity of explanation, and like reference numerals designate like parts throughout the specification.

Throughout this specification, when a part is said to be "connected" with another part, this includes not only the "directly connected" but also the "electrically connected" between other elements in between. do.

Throughout this specification, when a member is located “on” another member, this includes not only when one member is in contact with another member but also when another member exists between the two members.

Throughout this specification, when a part is said to "include" a certain component, it means that it can further include other components, without excluding the other components unless otherwise stated. As used throughout this specification, the terms “about”, “substantially”, and the like, are used at, or in close proximity to, numerical values when manufacturing and material tolerances inherent in the meanings indicated are provided, and an understanding of the present application may occur. Accurate or absolute figures are used to assist in the prevention of unfair use by unscrupulous infringers. As used throughout this specification, the term “step of” or “step of” does not mean “step for”.

Throughout this specification, the term "combination (s) thereof" included in the expression of a makushi form refers to one or more mixtures or combinations selected from the group consisting of components described in the expression of makushi form, It means to include one or more selected from the group consisting of the above components.

Throughout this specification, the description of “A and / or B” means “A or B, or A and B”.

Hereinafter, with reference to the accompanying drawings will be described embodiments and embodiments of the present application; However, the present disclosure may not be limited to these embodiments, examples, and drawings.

A first aspect of the present disclosure provides a radioisotope-containing metal bilayer hydroxide hybrid comprising radioisotopes located within and / or between layers of a lattice of metal bilayer hydroxides.

In one embodiment of the present application, the radioisotope being used for cancer diagnosis, cancer treatment, or cancer diagnosis and cancer treatment is stably included in the lattice and / or interlayer of the metal double layer hydroxide, or the metal double layer hydroxide By including chelates or polyatomic ions containing radioisotopes between layers, the labeling efficiency of radioisotopes can be enhanced, and targeted to cancer cells selectively to enhance concentration on cancer cells, and cell membranes against cancer cells. Highly permeable and biocompatible radioisotope-containing metal bilayer hydroxide hybrids can be provided.

In one embodiment of the present application, the radioisotope may be included in the lattice of the metal double layer hydroxide, but may not be limited thereto.

In one embodiment of the present application, the radioisotope located between the layers of the metal bilayer hydroxide may include ions of the radioisotope and / or chelates or polyatomic ions comprising the radioisotope, This may not be limited.

In one embodiment of the present application, the radioactive isotope is included in the lattice of the metal bilayer hydroxide, and the chelate or the ion of the radioisotope located between the layers of the metal bilayer hydroxide and / or the radioisotope. It may include polyatomic ions, but may not be limited thereto. For example, the radioisotope may be included in the form of ions between the layers of the metal bilayer hydroxide, or in the form of a chelate or polyatomic ion containing the radioisotope.

The polyatomic ion forms including radioactive isotopes include phosphate ions, hydrogen phosphate ions, dihydrogen phosphate ions, phosphite ions, sulfate ions, hydrogen sulfate ions, sulfite ions, hydrogen sulfite ions, nitrate ions, nitrite ions, carbonate ions, Hydrogen ions, hydroxide ions, chlorate ions, perchlorate ions, chlorite ions, chromium ions, dichromate ions, permanganese ions, iodinate ions, acetate ions, oxalate ions, hydrogen oxalate ions, hydrogen sulfide ions Ammonium ions, or cyanate ions, cyanide ions and the like may be included, but are not limited thereto.

Referring to FIG. 1C, the radioactive isotope may be located within and / or between the lattice of the metal bilayer hydroxide, and the chelate comprising the radioisotope may be located between the layers of the metal bilayer hydroxide. Can be.

In one embodiment of the present application, the radioisotope may include one or more, but may not be limited thereto.

In one embodiment of the present application, the radioisotope located in the lattice of the metal double layer hydroxide and the radioisotope located between the layers of the metal double layer hydroxide may be the same or different from each other, but may not be limited thereto. For example, when the radioisotope-containing metal bilayer hydroxide hybrid is used for cancer diagnosis, the radioisotope and the radioisotope when used for cancer treatment may be different, and the radioisotope-containing Depending on the purpose of using the metal double layer hydroxide hybrid, it may be to use one or more radioisotopes which are the same or different from each other.

In one embodiment of the present application, the radioisotope positioned in the lattice of the metal double layer hydroxide and the radioisotope positioned between the layers of the metal double layer hydroxide may be the same as or different from each other, but may not be limited thereto. For example, when the radioisotope-containing metal bilayer hydroxide hybrid is used for cancer diagnosis, the radioisotope and the radioisotope when used for cancer treatment may be different, and the radioisotope-containing Depending on the purpose of using the metal double layer hydroxide hybrid, it may be to use one or more radioisotopes which are the same or different from each other.

For example, a radioisotope located within the lattice of the metal bilayer hydroxide, an ion of the radioisotope located between the layers of the metal bilayer hydroxide, and the radioisotope located between the layers of the metal bilayer hydroxide. Chelates or polyatomic ions may include, but are not limited to, radioisotopes identical or different from one another.

1 is a schematic diagram showing the structure of a radioisotope-containing metal double layer hydroxide hybrid.

Referring to FIG. 1, in one embodiment of the present disclosure, the radioisotope may be included in the lattice of the metal double layer hydroxide, and a schematic diagram of the hybrid is shown in FIG. 1A.

In one embodiment of the present application, the radioisotope or the chelate containing the radioisotope may be included between the layers of the metal double layer hydroxide, a schematic diagram of the hybrid is shown in Figure 1 (b) It was.

In one embodiment of the present application, the metal layered double hydroxide may be represented by the following Formula 1, but is not limited thereto:

[Formula 1]

[M ²⁺ _(1-x) M ³⁺ _x (OH ⁻ ) ₂ ] ^{x +} [(A ⁿ⁻ ) _{x / n} yH ₂ O] ^x- ;

In the above formula,

M ²⁺ is a divalent metal cation + ^{2, Ni 2 +, Mg 2 +} , Ca 2 +, Zn 2 +, Mn 2 +, Co 2 +, Fe 2 +, Cu 2 +, Cd 2 +, and their A metal cation selected from the group consisting of combinations,

M ³⁺ is a +3 valent metal cation, Fe ^{+ 3,} Al ^{+ 3,} Cr ^{+ 3,} Mn ^{+ 3,} Ga ^{+ 3,} Co ^{+ 3,} Ni ^{+ 3,} Sc ^{+ 3,} La ^{+ 3,} V ³⁺ , Sb ^{+ 3,} Y ^3+, in ^{+ 3,} Ti ^{+ 3,} Y ^3+, Gd ^{+ 3,} Lu ^{+ 3,} and is to include a metal cation selected from the group consisting of the combinations thereof,

A ^n- is an anion selected from the group consisting of Cl ⁻ , Br ⁻ , nitrate ions (NO ₃ ⁻ ), carbonate ions (CO ₃ ^2- ), sulfate ions (SO ^2- ), and combinations thereof,

0≤x <1,

n is an integer from 1 to 3,

y is a number from 0.1 to 20.

In one embodiment of the invention, the radioisotope located in the lattice of the metal bilayer hydroxide is oxygen-15 (Oxygen-15, ¹⁵ O), calcium-47 (Calcium-47, ⁴⁷ Ca), scandium-46 ( Scabduyn-46, ⁴⁶ Sc), Chromium-51, 57 (Chromium-51, 57, ⁵¹ Cr, ⁵⁷ Cr), Cobalt-57, 60 (Cobalt-57, 60, ⁵⁷ Co, ⁶⁰ Co), Manganese-54 (Manganese-54, ⁵⁴ Mn), Iron-55, 59 (Iron-55, 59, ⁵⁵ Fe , ⁵⁹ Fe), Nickel-63 (Nikel-63, ⁶³ Ni), Copper-61, 64, 67 (copper-61, 64, 67, ⁶¹ Cu, ⁶⁴ Cu, ⁶⁷ Cu), Zinc-65 (Zinc-65, ⁶⁰ Zn), Gallium-67, 68 (Gallium-67, 68, ⁶⁷ Ga, ⁶⁸ Ga), Germanium-68 (Germanium-68, ⁶⁸ Ge) Selenium-75 (Selenium-75, ⁷⁵ Se), Rubidium-82 (Rubidium-82, ⁸² Ru), Strontium-82, 85, 89, 90 (Strontium-82, 85, 89, 90, ⁸² Sr, ⁸⁵ Sr, ⁸⁹ Sr, ⁹⁰ Sr), Yttrium-90 (Yttrium-90, ⁹⁰ Y), Ruthenium-97, 103 (Ruthenium-97, 103, ⁹⁷ Ru, ¹⁰³ Ru), Molybdenum-99 (Molybdenum-99, ⁹⁹ Mo), Technetium -99m (Technetium-99m, ^99m Tc), Palladium-103 (Palladium-103, ¹⁰³ Pd), Indium-111 (Indium-111, ¹¹¹ In), Silver-110m (Silver-110m, ^110m Ag), Cadmium-109 , 115 (Cadmium-109, 115, ¹⁰⁹ Cd, ¹¹⁵ Cd), tin-117, 113 (Tin-117, 113, ¹¹⁷ Sn, ¹¹³ Sn), antimony-119 (Antimony-119, ¹¹⁹ Sb), tellurium- 118, 123 (Tellurium-118, 123, ¹¹⁸ Te, ¹²³ Te), Barium-131, 140 (Barium-131, 140, ¹³¹ Ba, ¹⁴⁰ Ba), Lanthanum-140 (Lanthanum-140, ¹⁴⁰ La), Cesium -137 (Cesium-137, ¹³⁷ Ce), Gadolinium-149, 151 (Gadolinium-149, 151, ¹⁴⁹ Gd, ¹⁵¹ Gd), Samarium-153 (Samarium-153, ¹⁵³ Sm) Dysprosium-159, 165 (Dysprosium-159 , 165, ¹⁵⁹ Dy, ¹⁶⁵ Dy), Terbium-160 (Terbium-160, ¹⁶⁰ Tb), Holmium-166 (Holmiun-166, ¹⁶⁶ Ho), Erbium-169 (Erbium-169, ¹⁶⁹ Er), Ytterbium-169 , 177 (Ytterbium-169, 177, ¹⁶⁹ Yb, ¹⁶⁹ Yb), Lutetium-177 ( ¹⁷⁷ Lu), Rhenium-186, 188 (Rhenium-186, 188, ¹⁸⁶ Re, ¹⁸⁸ Re), Iridium-192 (Iridium-192, ¹⁹² Ir), Gold-198 , 199 (Gold-198, 199, ¹⁹⁸ Au, ¹⁹⁹ Au), thallium-201, 204 (Thallium-201, 204, ²⁰¹ Tl, ²⁰⁴ Tl), lead-210 (Lead-210, ²¹⁰ Pb), bismuth-213 (Bismuth-213, ²¹³ Bi), Astatine-211 (Astatine-211, ²¹¹ At), Radium-223, 224, 226 (Radium-223, 224, 226, ²²³ Ra, ²²⁴ Ra, ²²⁶ Ra), Actinium-225 (Actinium-225, ²²⁵ Ac), and combinations thereof may be selected from the group consisting of, but may not be limited thereto.

In one embodiment of the invention, the radioisotope located between the layers of the metal double layer hydroxide is carbon-11, 14 (Carbon-11, 14, ¹¹ C, ¹⁴ C), nitrogen-13 (Nitrogen-13, ¹³ N), Oxygen-15, ¹⁵ O, Fluorine-18, ¹⁸ F, Chlorine-36, Sodium-22, 24, ²² Na , ²⁴ Na), phosphorus-32, 33 (Phosphorus-32, 33, ³² P, ³³ P), sulfur-35 (Sulphur-35, ³⁵ S), potassium-42, 43 (Potassium-42, 43, ⁴² K , ⁴³ K), calcium-47 (Calcium-47, ⁴⁷ Ca), scandium-46 (Scabduyn-46, ⁴⁶ Sc), chromium-51, 57 (Chromium-51, 57, ⁵¹ Cr, ⁵⁷ Cr), cobalt- 57, 60 (Cobalt-57, 60, ⁵⁷ Co, ⁶⁰ Co), Manganese-54 (Manganese-54, ⁵⁴ Mn), Iron-55, 59 (Iron-55, 59, ⁵⁵ Fe, ⁵⁹ Fe), Nickel-63 (Nikel-63, ⁶³ Ni), Copper-61, 64, 67 (copper-61, 64, 67, ⁶¹ Cu, ⁶⁴ Cu, ⁶⁷ Cu), Zinc-65 (Zinc -65, ⁶⁰ Zn), Gallium-67, 68 (Gallium-67, 68, ⁶⁷ Ga, ⁶⁸ Ga), Germanium-68 (Germanium-68, ⁶⁸ Ge) Selenium-75 (Selenium-75, ⁷⁵ Se), Rubidium-82 ( ⁸² Ru), Strontium-82, 85, 89, 90 (Strontium-82, 85, 89, 90, ⁸² Sr, ⁸⁵ Sr, ⁸⁹ Sr, ⁹⁰ Sr), yttrium-90 (Yttrium-90, ⁹⁰ Y), ruthenium-97, 103 (Ruthenium-97, 103, ⁹⁷ Ru, ¹⁰³ Ru), molybdenum-99 (Molybdenum-99 , ⁹⁹ Mo), Technetium-99m ( ^99m Tc), Palladium-103 (Palladium-103, ¹⁰³ Pd), Indium-111 (Indium-111, ¹¹¹ In), Silver-110m (Silver-110m, ^110m Ag), cadmium-109, 115 (Cadmium-109, 115, ¹⁰⁹ Cd, ¹¹⁵ Cd), Tin-117, 113 (Tin-117, 113, ¹¹⁷ Sn, ¹¹³ Sn), Antimony-119 (Antimony-119, ¹¹⁹ Sb), Tellurium-118, 123 (Tellurium-118, 123 , ¹¹⁸ Te, ¹²³ Te), Iodine-123, 124, 125, 129, 131 (Iodine-123, 124, 125, 129, 131, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I, ¹³¹ I), Barium- 131, 140 (Barium-131, 140, ¹³¹ Ba, ¹⁴⁰ Ba), Lanthanum-140 (Lanthanum-140, ¹⁴⁰ La), Cesium-137 (Cesium-137, ¹³⁷ Ce), Gadolinium-149, 151 (Gadolinium- 149, 151, ¹⁴⁹ Gd, ¹⁵¹ Gd), Samarium-153 (Samarium-153, ¹⁵³ Sm) Dysprosium-159, 165 (Dysprosium-159, 165, ¹⁵⁹ Dy, ¹⁶⁵ Dy), Terbium-160 (Terbium-160, ¹⁶⁰ Tb), Holmun-166 ( ¹⁶⁶ Ho), Erbium-169 (Erbium-169, ¹⁶⁹ Er), Ytterbium-169, 177 (Ytterbium-169, 177, ¹⁶⁹ Yb, ¹⁶⁹ Yb), Lutetium-177 ( ¹⁷⁷ Lu), Rhenium-186, 188 (Rhenium-186, 188, ¹⁸⁶ Re, ¹⁸⁸ Re), Iridium-192 (Iridium-192, ¹⁹² Ir), Gold-198 , 199 (Gold-198, 199, ¹⁹⁸ Au, ¹⁹⁹ Au), thallium-201, 204 (Thallium-201, 204, ²⁰¹ Tl, ²⁰⁴ Tl), lead-210 (Lead-210, ²¹⁰ Pb), bismuth-213 (Bismuth-213, ²¹³ Bi), Astatine-211 (Astatine-211, ²¹¹ At), Radium-223, 224, 226 (Radium-223, 224, 226, ²²³ Ra, ²²⁴ Ra, ²²⁶ Ra), Actinium-225 (Actinium-225, ²²⁵ Ac), and combinations thereof may be selected from the group consisting of, but may not be limited thereto.

In one embodiment of the present application, the chelate material comprising the radioisotope is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DTPA (diethylenetriamine pentaacetate), NOTA ( 1,4,7-triazacyclononane-triacetic acid), chelates including carboxylate functional groups, and combinations thereof, but may be selected from the group consisting of, but may not be limited thereto. For example, there may be a high probability that a chelating material comprising the carboxylate functional group can be intercalated between the metal bilayer hydroxide layers.

In one embodiment of the present application, the radioisotope-containing metal bilayer hydroxide hybrid may have a nanometer size, but may not be limited thereto. For example, when the radioisotope-containing metal double layer hydroxide hybrid is used for the body, the radioisotope-containing metal double layer hydroxide hybrid may have a nanometer size to be injected into the body, but may not be limited thereto. In addition, for example, when the radioisotope-containing metal double layer hydroxide hybrid is used in vitro, the radioisotope-containing metal double layer hydroxide hybrid may have a size of micrometer or more, but may not be limited thereto. For example, the use for extracorporeal use may include the case where it is injected into the body by oral.

In one embodiment of the present application, the radioisotope-containing metal bilayer hydroxide hybrid may include an anticancer material between the layers of the metal bilayer hydroxide, but may not be limited thereto. For example, two or more anticancer substances may be included in the same section as other materials' properties or not interfering with each other when included in layers, and may be crossed or different from each other (eg, , Anticancer substances and radioisotopes, or chelates of the radioisotopes) may be inserted into the layers as one substance by interaction, but may not be limited thereto. The anticancer substance may be included as long as it is a known anticancer substance, for example, selected from the group consisting of pemetrexate (PMX), methotrexate (MTX), cyclophosphamide (CPA), artesunate (AS), and combinations thereof. It may be to include, but may not be limited to this.

In one embodiment of the present application, the radioisotope-containing metal bilayer hydroxide hybrid may have a size of about 5 nm to about 10 μm, but may not be limited thereto. For example, the radioisotope-containing metal bilayer hydroxide hybrid can have about 5 nm to about 10 μm, about 5 nm to 1 μm, about 5 nm to about 500 nm, about 5 nm to about 100 nm, about 5 nm to about 50 nm, about 5 nm to about 10 nm, about 10 nm to about 10 μm, about 50 nm to about 10 μm, about 100 nm to about 10 μm, about 500 nm to about 10 μm, or about 1 μm To about 10 μm in size, but may not be limited thereto.

In one embodiment of the present application, the radioisotope-containing metal bilayer hydroxide hybrid may be one capable of cancer treatment and / or cancer diagnosis, but may not be limited thereto.

In one embodiment of the present disclosure, the labeling efficiency of the radioisotope of the radioisotope-containing metal bilayer hydroxide hybrid may be about 50% to about 100%. For example, the labeling efficiency may be about 50% to about 100%, about 50% to about 90%, about 50% to about 80%, about 50% to about 70%, about 50% to about 60%, about 60 % To about 100%, about 70% to about 100%, about 75% to about 100%, about 80% to about 100%, or about 90% to about 100%, but may not be limited thereto.

In one embodiment of the present application, the radioisotope-containing metal double layer hydroxide hybrid is a radioisotope is stably composed of a lattice layer like the metal ions of the metal double layer hydroxide, it is included in the metal double layer hydroxide It is possible to improve the labeling efficiency of the radioisotope, and the radioisotope can be very stable in vivo because it is stably present in the metal bilayer hydroxide lattice layer.

In one embodiment of the present application, the radioisotope-containing metal bilayer hydroxide hybrid has low intracellular toxicity and is biocompatible, and can provide a hybrid that can stably deliver radioisotopes against cancer at local sites. In addition, since it exhibits high selectivity for cancer cells, it can be applied to radiation therapy and diagnosis of tumors. For example, the cancer diagnosis may be positron emission tomography (PET) imaging or single photon emission computed tomography imaging, but may not be limited thereto.

According to a second aspect of the present invention, after mixing an aqueous solution including metal salts including metal-based elements forming a metal double layer hydroxide and an aqueous solution including at least one radioisotope, the reacted mixed solution is reacted with a base solution. Making a step; And hydrothermally synthesizing the mixed solution to form a metal bilayer hydroxide comprising the radioisotope in the lattice and / or between the layers, providing a method for producing a radioisotope-containing metal bilayer hydroxide hybrid.

According to a third aspect of the present disclosure, after mixing an aqueous solution including metal salts including metal-based elements forming a metal double layer hydroxide and an aqueous solution including at least one radioisotope, reacting the mixed solution by a base solution ; Hydrothermally synthesizing the reacted mixed solution to form a metal bilayer hydroxide comprising the radioisotope in a lattice and / or between layers; And ion of radioisotopes, chelates containing radioisotopes, or polyatomic ions comprising radioisotopes in an ion exchange method between the layers of metal bilayer hydroxides containing the radioisotopes formed in the lattice and / or between layers. Provided is a method of making a radioisotope-containing metal bilayer hydroxide hybrid, comprising the step of intercalating by insertion.

Hereinafter, the manufacturing methods of the second aspect and the third aspect of the present application will be described in more detail, and the contents described with respect to the first aspect of the present application apply to the second and third aspects of the present application.

In one embodiment of the present application, the radioisotope-containing metal double layer hydroxide hybrid includes an aqueous solution including metal salts including divalent metals and / or trivalent metal elements forming the metal double layer hydroxide, and the first species. The radioisotope is divalent and / or 3 by titrating a mixed solution of the above-described radioactive isotope solution using a base solution, followed by stirring at least for several minutes at room temperature or constant temperature, and then hydrothermally synthesizing the radioisotope. It is possible to produce metal bilayer hydroxides that are stably located in the lattice and / or between layers, such as a valent metal element.

In one embodiment of the present application, the radioisotope-containing metal double layer hydroxide hybrid is an aqueous solution comprising a metal salt comprising a divalent metal and / or a trivalent metal element forming the metal double layer hydroxide and the first species. The radioisotope is divalent and / or 3 by titrating a mixed solution of the above-described radioactive isotope solution using a base solution, followed by stirring at least for several minutes at room temperature or constant temperature, and then hydrothermally synthesizing the radioisotope. After preparing a metal bilayer hydroxide which is stably configured in a lattice and / or between layers, such as a valent metal element, a chelate or polyatomic ion containing radioactive isotopes or radioactive isotopes by ion exchange method within a controlled pH range Can be prepared by intercalating the metal bilayer hydroxide.

In one embodiment of the present application, the radioisotope may be included in the lattice of the metal double layer hydroxide, but may not be limited thereto.

In one embodiment of the present application, the radioisotope located between the layers of the metal bilayer hydroxide may include ions of the radioisotope and / or chelates or polyatomic ions comprising the radioisotope, This may not be limited.

In one embodiment of the present application, the radioactive isotope is included in the lattice of the metal bilayer hydroxide, and the chelate or the ion of the radioisotope located between the layers of the metal bilayer hydroxide and / or the radioisotope. It may include polyatomic ions, but may not be limited thereto. For example, the radioisotope may be present in the form of a cation or an anion or in the form of a chelate or polyatomic ion containing the radioisotope between the layers of the metal bilayer hydroxide.

The polyatomic ion form comprising the radioisotope is phosphate ion, hydrogen phosphate ion, dihydrogen phosphate ion, phosphite ion, sulfate ion, hydrogen sulfate ion, sulfite ion, hydrogen sulfite ion, nitrate ion, nitrite ion, carbonate ion , Hydrogen carbonate ion, hydroxide ion, chlorate ion, perchlorate ion, chlorite ion, chromium ion, dichromate ion, permanganese ion, iodinate ion, acetate ion, oxalate ion, hydrogen oxalate ion, hydrogen sulfide ion, It may include, but is not limited to, ammonium ions, cyanate ions, or cyanide ions.

In one embodiment of the present application, the step of reacting the mixed solution with a base solution may be performed for about 5 minutes or more, but may not be limited thereto. For example, reacting the mixed solution with a base solution may comprise about 5 minutes to about 24 hours, about 5 minutes to about 12 hours, about 5 minutes to about 6 hours, about 5 minutes to about 1 hour, about 5 Minutes to about 30 minutes, about 5 minutes to about 10 minutes, about 10 minutes to about 24 hours, about 30 minutes to about 24 hours, about 1 hour to about 24 hours, about 6 hours to about 24 hours, or about 12 hours To about 24 hours, but may not be limited thereto. By fully reacting the reaction for at least about 5 minutes, since all of the radioisotopes constitute the metal double layer hydroxide, the radioisotope removed due to unreaction may be reduced, thereby improving the labeling efficiency of the radioisotope. You can.

In one embodiment of the present application, the radioisotope may include one or more, but may not be limited thereto.

In one embodiment of the present application, the radioisotope located in the lattice of the metal double layer hydroxide and the radioisotope located between the layers of the metal double layer hydroxide may be the same or different from each other, but may not be limited thereto. For example, when the radioisotope-containing metal bilayer hydroxide hybrid is used for cancer diagnosis, the radioisotope and the radioisotope when used for cancer treatment may be different, and the radioisotope-containing Depending on the purpose of using the metal double layer hydroxide hybrid, it may be to use one or more radioisotopes which are the same or different from each other.

In one embodiment of the present application, the radioisotope positioned in the lattice of the metal double layer hydroxide and the radioisotope positioned between the layers of the metal double layer hydroxide may be the same as or different from each other, but may not be limited thereto. For example, when the radioisotope-containing metal bilayer hydroxide hybrid is used for cancer diagnosis, the radioisotope and the radioisotope when used for cancer treatment may be different, and the radioisotope-containing Depending on the purpose of using the metal double layer hydroxide hybrid, it may be to use one or more radioisotopes which are the same or different from each other.

For example, a chelate comprising a radioisotope located within the lattice of the metal bilayer hydroxide, an ion of the radioisotope located between the layers of the metal bilayer hydroxide and the radioisotope located between the layers of the metal bilayer hydroxide. Alternatively, the multiatomic ions may include the same or different radioisotopes, but are not limited thereto.

In one embodiment of the present application, the metal layered double hydroxide may be represented by the following Formula 1, but is not limited thereto:

[Formula 1]

[M ²⁺ _(1-x) M ³⁺ _x (OH ⁻ ) ₂ ] ^{x +} [(A ⁿ⁻ ) _{x / n} yH ₂ O] ^x- ;

In the above formula,

M ²⁺ is a divalent metal cation + ^{2, Ni 2 +, Mg 2 +} , Ca 2 +, Zn 2 +, Mn 2 +, Co 2 +, Fe 2 +, Cu 2 +, Cd 2 +, and their A metal cation selected from the group consisting of combinations,

M ³⁺ is a +3 valent metal cation, Fe ^{+ 3,} Al ^{+ 3,} Cr ^{+ 3,} Mn ^{+ 3,} Ga ^{+ 3,} Co ^{+ 3,} Ni ^{+ 3,} Sc ^3+, La ^{3 +,} V ³⁺ , Sb ^{+ 3,} Y ^3+, in ^{+ 3,} Ti ^{+ 3,} Y ^3+, Gd ^{+ 3,} Lu ^{+ 3,} and is to include a metal cation selected from the group consisting of the combinations thereof,

A ^n- is an anion selected from the group consisting of Cl ⁻ , Br ⁻ , nitrate ions (NO ^3- ), carbonate ions (CO ₃ ^2- ), sulfate ions (SO ^2- ), and combinations thereof,

0≤x <1,

n is an integer from 1 to 3,

y is a number from 0.1 to 20.

In one embodiment of the invention, the radioisotope located within the lattice of the metal bilayer hydroxide is calcium-47 (Calcium-47, 47Ca), scandium-46 (Scabduyn-46, ⁴⁶ Sc), chromium-51, 57 (Chromium-51, 57, ⁵¹ Cr, ⁵⁷ Cr), Cobalt-57, 60 (Cobalt-57, 60, ⁵⁷ Co, ⁶⁰ Co), Manganese-54 (Manganese-54, ⁵⁴ Mn), Iron-55, 59 (Iron-55, 59, ⁵⁵ Fe , ⁵⁹ Fe), Nickel-63 (Nikel-63, ⁶³ Ni), Copper-61, 64, 67 (copper-61, 64, 67, ⁶¹ Cu, ⁶⁴ Cu, ⁶⁷ Cu), Zinc-65 (Zinc-65, ⁶⁰ Zn), Gallium-67, 68 (Gallium-67, 68, ⁶⁷ Ga, ⁶⁸ Ga), Germanium-68 (Germanium-68, ⁶⁸ Ge) Selenium-75 (Selenium-75, ⁷⁵ Se), Rubidium-82 (Rubidium-82, ⁸² Ru), Strontium-82, 85, 89, 90 (Strontium-82, 85, 89, 90, ⁸² Sr, ⁸⁵ Sr, ⁸⁹ Sr, ⁹⁰ Sr), Yttrium-90 (Yttrium-90, ⁹⁰ Y), Ruthenium-97, 103 (Ruthenium-97, 103, ⁹⁷ Ru, ¹⁰³ Ru), Molybdenum-99 (Molybdenum-99, ⁹⁹ Mo), Technetium -99m (Technetium-99m, ^99m Tc), Palladium-103 (Palladium-103, ¹⁰³ Pd), Indium-111 (Indium-111, ¹¹¹ In), Silver-110m (Silver-110m, ^110m Ag), Cadmium-109 , 115 (Cadmium-109, 115, ¹⁰⁹ Cd, ¹¹⁵ Cd), tin-117, 113 (Tin-117, 113, ¹¹⁷ Sn, ¹¹³ Sn), antimony-119 (Antimony-119, ¹¹⁹ Sb), tellurium- 118, 123 (Tellurium-118, 123, ¹¹⁸ Te, ¹²³ Te), Barium-131, 140 (Barium-131, 140, ¹³¹ Ba, ¹⁴⁰ Ba), Lanthanum-140 (Lanthanum-140, ¹⁴⁰ La), Cesium -137 (Cesium-137, ¹³⁷ Ce), Gadolinium-149, 151 (Gadolinium-149, 151, ¹⁴⁹ Gd, ¹⁵¹ Gd), Samarium-153 (Samarium-153, ¹⁵³ Sm) Dysprosium-159, 165 (Dysprosium-159 , 165, ¹⁵⁹ Dy, ¹⁶⁵ Dy), Terbium-160 (Terbium-160, ¹⁶⁰ Tb), Holmium-166 (Holmiun-166, ¹⁶⁶ Ho), Erbium-169 (Erbium-169, ¹⁶⁹ Er), Ytterbium-169 , 177 (Ytterbium-169, 177, ¹⁶⁹ Yb, ¹⁶⁹ Yb), Lutetium-177 ( ¹⁷⁷ Lu), Rhenium-186, 188 (Rhenium-186, 188, ¹⁸⁶ Re, ¹⁸⁸ Re), Iridium-192 (Iridium-192, ¹⁹² Ir), Gold-198 , 199 (Gold-198, 199, ¹⁹⁸ Au, ¹⁹⁹ Au), thallium-201, 204 (Thallium-201, 204, ²⁰¹ Tl, ²⁰⁴ Tl), lead-210 (Lead-210, ²¹⁰ Pb), bismuth-213 (Bismuth-213, ²¹³ Bi), Astatine-211 (Astatine-211, ²¹¹ At), Radium-223, 224, 226 (Radium-223, 224, 226, ²²³ Ra, ²²⁴ Ra, ²²⁶ Ra), Actinium-225 (Actinium-225, ²²⁵ Ac), and combinations thereof may be selected from the group consisting of, but may not be limited thereto.

In one embodiment of the invention, the radioisotope located between the layers of the metal double layer hydroxide is carbon-11, 14 (Carbon-11, 14, ¹¹ C, ¹⁴ C), nitrogen-13 (Nitrogen-13, ¹³ N), Oxygen-15, 15O, Fluorine-18, ¹⁸ F, Chlorine-36, Sodium-22, 24, ²² Na, ²⁴ Na), phosphorus-32, 33 (Phosphorus-32, 33, ³² P, ³³ P), sulfur-35 (Sulphur-35, ³⁵ S), potassium-42, 43 (Potassium-42, 43, ⁴² K, ⁴³ K), Calcium-47 (Calcium-47, ⁴⁷ Ca), Scandium-46 (Scabduyn-46, ⁴⁶ Sc), Chromium-51, 57 (Chromium-51, 57, ⁵¹ Cr, ⁵⁷ Cr), Cobalt-57 , 60 (Cobalt-57, 60, ⁵⁷ Co, ⁶⁰ Co), Manganese-54 (Manganese-54, ⁵⁴ Mn), Iron-55, 59 (Iron-55, 59, ⁵⁵ Fe, ⁵⁹ Fe), Nickel-63 (Nikel-63, ⁶³ Ni), Copper-61, 64, 67 (copper-61, 64, 67, ⁶¹ Cu, ⁶⁴ Cu, ⁶⁷ Cu), Zinc-65 (Zinc -65, ⁶⁰ Zn), Gallium-67, 68 (Gallium-67, 68, ⁶⁷ Ga, ⁶⁸ Ga), Germanium-68 (Germanium-68, ⁶⁸ Ge) Selenium-75 (Selenium-75, ⁷⁵ Se), Rubidium-82 ( ⁸² Ru), Strontium-82, 85, 89, 90 (Strontium-82, 85, 89, 90, ⁸² Sr, ⁸⁵ Sr, ⁸⁹ Sr, ⁹⁰ Sr), yttrium-90 (Yttrium-90, ⁹⁰ Y), ruthenium-97, 103 (Ruthenium-97, 103, ⁹⁷ Ru, ¹⁰³ Ru), molybdenum-99 (Molybdenum-99 , ⁹⁹ Mo), Technetium-99m ( ^99m Tc), Palladium-103 (Palladium-103, ¹⁰³ Pd), Indium-111 (Indium-111, ¹¹¹ In), Silver-110m (Silver-110m, ^110m Ag), cadmium-109, 115 (Cadmium-109, 115, ¹⁰⁹ Cd, ¹¹⁵ Cd), Tin-117, 113 (Tin-117, 113, ¹¹⁷ Sn, ¹¹³ Sn), Antimony-119 (Antimony-119, ¹¹⁹ Sb), Tellurium-118, 123 (Tellurium-118, 123 , ¹¹⁸ Te, ¹²³ Te), Iodine-123, 124, 125, 129, 131 (Iodine-123, 124, 125, 129, 131, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I, ¹³¹ I), Barium- 131, 140 (Barium-131, 140, ¹³¹ Ba, ¹⁴⁰ Ba), Lanthanum-140 (Lanthanum-140, ¹⁴⁰ La), Cesium-137 (Cesium-137, ¹³⁷ Ce), Gadolinium-149, 151 (Gadolinium- 149, 151, ¹⁴⁹ Gd, ¹⁵¹ Gd), Samarium-153 (Samarium-153, ¹⁵³ Sm) Dysprosium-159, 165 (Dysprosium-159, 165, ¹⁵⁹ Dy, ¹⁶⁵ Dy), Terbium-160 (Terbium-160, ¹⁶⁰ Tb), Holmun-166 ( ¹⁶⁶ Ho), Erbium-169 (Erbium-169, ¹⁶⁹ Er), Ytterbium-169, 177 (Ytterbium-169, 177, ¹⁶⁹ Yb, ¹⁶⁹ Yb), Lutetium-177 ( ¹⁷⁷ Lu), Rhenium-186, 188 (Rhenium-186, 188, ¹⁸⁶ Re, ¹⁸⁸ Re), Iridium-192 (Iridium-192, ¹⁹² Ir), Gold-198 , 199 (Gold-198, 199, ¹⁹⁸ Au, ¹⁹⁹ Au), thallium-201, 204 (Thallium-201, 204, ²⁰¹ Tl, ²⁰⁴ Tl), lead-210 (Lead-210, ²¹⁰ Pb), bismuth-213 (Bismuth-213, ²¹³ Bi), Astatine-211 (Astatine-211, ²¹¹ At), Radium-223, 224, 226 (Radium-223, 224, 226, ²²³ Ra, ²²⁴ Ra, ²²⁶ Ra), Actinium-225 (Actinium-225, ²²⁵ Ac), and combinations thereof may be selected from the group consisting of, but may not be limited thereto.

In one embodiment of the present application, the chelate material comprising the radioisotope is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DTPA (diethylenetriamine pentaacetate), NOTA ( 1,4,7-triazacyclononane-triacetic acid), chelates including carboxylate functional groups, and combinations thereof, but may be selected from the group consisting of, but may not be limited thereto. For example, there may be a high probability that a chelating material comprising the carboxylate functional group can be intercalated between the metal bilayer hydroxide layers.

In one embodiment of the present application, the ion exchange method may be performed at about pH 5 to about pH 10, but may not be limited thereto. For example, the ion exchange method may comprise about pH 5 to about pH 10, about pH 5 to about pH 9, about pH 5 to about pH 8, about pH 5 to about pH 7, about pH 5 to about pH 6, about pH 6 to about pH 10, about pH 7 to about pH 10, about pH 8 to about pH 10, or about pH 9 to about pH 10, but may not be limited thereto.

In one embodiment of the present application, the radioisotope-containing metal bilayer hydroxide hybrid may have a nanometer size, but may not be limited thereto. For example, when the radioisotope-containing metal double layer hydroxide hybrid is used for the body, the radioisotope-containing metal double layer hydroxide hybrid may have a nanometer size to be injected into the body, but may not be limited thereto. In addition, for example, when the radioisotope-containing metal double layer hydroxide hybrid is used in vitro, the radioisotope-containing metal double layer hydroxide hybrid may have a size of micrometer or more, but may not be limited thereto. For example, the extracorporeal use may include the case injected into the body by oral.

In one embodiment of the present application, the radioisotope-containing metal bilayer hydroxide hybrid may include an anticancer material between the layers of the metal bilayer hydroxide, but may not be limited thereto. For example, two or more anticancer substances may be included in the same section as other materials' properties or not interfering with each other when included in layers, and may be crossed or different from each other (eg, , Anticancer substances and radioisotopes, or chelates of the radioisotopes) may be inserted into the layers as one substance by interaction, but may not be limited thereto. The anticancer substance may be included as long as it is a known anticancer substance, for example, selected from the group consisting of pemetrexate (PMX), methotrexate (MTX), cyclophosphamide (CPA), artesunate (AS), and combinations thereof. It may be to include, but may not be limited to this.

In one embodiment of the present application, the base solution is a group consisting of sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium carbonate (Na ₂ CO ₃ ), sodium hydrogen carbonate (Na ₂ CO ₃ ), and combinations thereof It may be to include a selected from, but may not be limited thereto.

In one embodiment of the present application, the hydrothermal synthesis may be performed in a temperature range of about 40 ℃ to about 200 ℃, but may not be limited thereto. For example, the hydrothermal synthesis may be about 40 ° C. to about 200 ° C., about 40 ° C. to about 150 ° C., about 40 ° C. to about 120 ° C., about 40 ° C. to about 100 ° C., about 40 ° C. to about 80 ° C., about 40 In a temperature range of about 60 ° C., about 60 ° C. to about 200 ° C., about 80 ° C. to about 200 ° C., about 100 ° C. to about 200 ° C., about 120 ° C. to about 200 ° C., or about 150 ° C. to about 200 ° C. It may be performed, but may not be limited thereto.

In one embodiment of the present disclosure, the labeling efficiency of the radioisotope of the radioisotope-containing metal bilayer hydroxide hybrid may be about 50% to about 100%. For example, the labeling efficiency may be about 50% to about 100%, about 50% to about 90%, about 50% to about 80%, about 50% to about 70%, about 50% to about 60%, about 60 % To about 100%, about 70% to about 100%, about 80% to about 100%, or about 90% to about 100%, but may not be limited thereto.

In one embodiment of the present application, the radioisotope-containing metal double layer hydroxide hybrid is a radioisotope is stably composed of a lattice layer like the metal ions of the metal double layer hydroxide, it is included in the metal double layer hydroxide It is possible to improve the labeling efficiency of the radioisotope, and the radioisotope can be very stable in vivo because it is stably present in the metal bilayer hydroxide lattice layer.

In one embodiment of the present application, the radioisotope-containing metal bilayer hydroxide hybrid has low intracellular toxicity and is biocompatible, and can provide a hybrid that can stably deliver radioisotopes against cancer at local sites. In addition, since it exhibits high selectivity for cancer cells, it can be applied to radiation therapy and diagnosis of tumors. For example, the cancer diagnosis may be positron emission tomography (PET) imaging or single photon emission computed tomography imaging, but may not be limited thereto.

Hereinafter, the embodiments of the present application will be described in detail. However, the present application may not be limited thereto.

EXAMPLE

< Comparative example  One: Non-radioactive  Isotopes, copper in the lattice Supported  metal Double layer  Synthesis of Hydroxide Hybrids>

A metal double layer hydroxide hybrid stably containing non-radioactive copper in the lattice was synthesized as follows.

Magnesium and aluminum nitrates, and the ratio of copper nitrates with non-radioactive isotope species were based on 2: 1-x: x, and x was mixed in distilled water with a mixture adjusted to a ratio of 0.01, 0.2 M sodium carbonate and 0.5 M Titrated with a mixed solution of sodium hydroxide. After titration until the pH became 10.0, the mixture was stirred at room temperature for 10 minutes, and the mixed solution was subjected to hydrothermal synthesis at 100 ° C for 3 hours. In order to improve the in vivo dispersion of the magnesium aluminum copper metal bilayer hydroxide obtained as a result of the reaction, it was reacted with a solution containing Bovine serum albumin (BSA) to obtain a metal bilayer hydroxide having BSA adsorbed on the surface. As a control, a mixture of magnesium and aluminum nitrates of 2: 0.99 was dissolved in distilled water and titrated with a 0.2 M sodium carbonate and 0.5 M sodium hydroxide mixed solution. After titration until pH became 10.0, it stirred for 20 minutes at room temperature, and the mixed solution was subjected to hydrothermal synthesis reaction at 100 degreeC for 12 hours. The obtained magnesium aluminum metal double layer hydroxide was mixed with a sodium acetate buffer solution containing a non-radioactive isotope of copper at a ratio of 0.01 to aluminum, and the mixed solution was added at 37 ° C. The reaction was stirred for a time. As another control, a mixture of magnesium and aluminum nitrates of 2: 0.99 was dissolved in distilled water and titrated with a 0.2 M sodium carbonate and 0.5 M sodium hydroxide mixed solution. After titration until pH is 10.0, the mixture was stirred at room temperature for 30 minutes, and the mixed solution was boil serum albumin (BSA) in a solution containing magnesium aluminum metal double layer hydroxide obtained by hydrothermal synthesis at 100 ° C. for 12 hours. Reaction with the solution included to obtain a metal double layer hydroxide adsorbed on the surface BSA. The BSA-adsorbed metal bilayer hydroxide and the non-radioactive isotope copper were mixed with a sodium acetate buffer solution containing 0.01% of aluminum, and the mixed solution was mixed at 37 ° C. Prepared by stirring for hours.

< Example  One: Cancer diagnosis possible  Radioisotope, copper-64 in the lattice Supported  Synthesis of Metal Double Layer Hydroxide Hybrids>

FIG. 2 shows a process for the preparation of a metal double layer hydroxide hybrid that stably contains radioisotope copper-64 in a lattice.

Referring to Figure 2, the ratio of the solution having magnesium and aluminum nitrate, and radioisotope copper-64 species was based on 2: 1: x, the ratio of x can not be specified due to the radioisotope characteristics can not be set arbitrarily However, the amount of radiation was controlled in units of mCi, in units of the amount of radiation, in proportion to the amount of copper-64 radiation required for the experiment. A mixture of magnesium and aluminum nitrates was dissolved in distilled water, mixed with a 0.1 M hydrochloric acid solution containing copper-64, and then titrated with a 0.2 M sodium carbonate and 0.5 M sodium hydroxide mixed solution. The solution was titrated until the pH became 10.0 and stirred at room temperature for 10 minutes, and the mixed solution was subjected to hydrothermal synthesis at 100 ° C for 3 hours. In order to improve the biodispersity of the magnesium aluminum copper-64 metal double layer hydroxide obtained as a result of the reaction, it was reacted with a solution containing bovin serum albumin (BSA) to obtain a metal double layer hydroxide having BSA adsorbed on the surface. As a control, a mixture of magnesium and aluminum nitrates of 2: 1 was dissolved in distilled water and titrated with a 0.2 M sodium carbonate and 0.5 M sodium hydroxide mixed solution. After titration until pH became 10.0, it stirred at room temperature for 30 minutes, and the mixed solution was hydrothermally synthesized at 100 degreeC for 12 hours. The obtained magnesium aluminum metal bilayer hydroxide was mixed with a sodium acetate buffer solution containing copper-64 which is a radioisotope as much as the amount of radiation required for the experiment. The reaction was stirred at a temperature of 3 hours. As another control, a mixture of magnesium and aluminum nitrates of 2: 1 was dissolved in distilled water and titrated with a 0.2 M sodium carbonate and 0.5 M sodium hydroxide solution. After titration until pH is 10.0, the mixture was stirred at room temperature for 30 minutes, and the mixed solution contained bovin serum albumin (BSA) in a solution containing magnesium aluminum metal bilayer hydroxide obtained by hydrothermal synthesis at 100 ° C. for 12 hours. It reacted with the solution, and the metal double layer hydroxide which BSA adsorbed on the surface was obtained. The BSA-adsorbed metal bilayer hydroxide solution and the radioisotope copper acetate-containing sodium acetate buffer solution were mixed, and the mixed solution was stirred at 37 ° C. for 3 hours. Reacted.

Experimental Example 1-1 X-ray Diffraction Analysis

X-ray diffraction analysis (Rigaku D / MAX RINT 2200-Ultima, Japan) of the magnesium aluminum copper metal double layer hydroxides obtained in Comparative Example 1 was performed, and the results are shown in FIG. 3. In the metal double layer hydroxide containing copper, it was confirmed that the copper element was well formed in the metal double layer hydroxide without a separate impurity peak. Even when BSA was coated on the surface, it was confirmed that the structure of the metal double layer hydroxide was maintained without deformation.

Experimental Example 1-2: Scanning Electron Microscope (SEM) Analysis

The particle size and shape of the magnesium aluminum copper metal double layer hydroxides obtained in Comparative Example 1 were analyzed using a scanning electron microscope (SEM, JEOL JSM-6700F), and the image is shown in FIG. 4. It was confirmed that the metal double layer hydroxide containing copper had a plate-like structure of 10 nm to 20 nm in thickness and 70 nm to 80 nm in size. In addition, it was confirmed that even when BSA is coated, the structure of the metal double layer hydroxide is maintained without deformation.

Experimental Example 1-3 Cytotoxicity Test

The cytotoxicity test results for the metal double layer hydroxide containing copper which is a non-radioactive isotope obtained in Comparative Example 1 are shown in FIG. 5. Cytotoxicity was treated by incubating MDA-MB-231 (human breast cancer cell line) cells for 12 hours and then varying the concentration of copper-containing metal bilayer hydroxide and BSA-coated metal bilayer hydroxide. Cytotoxicity after time was confirmed. As a result, both the metal bilayer hydroxide containing copper and the metal bilayer hydroxide coated with hydroxide and BSA showed cell viability of 90% or more at a concentration of 50 μg / mL or lower, and 62.5 μg at a concentration of 50 μg / mL or higher. Although the cell viability dropped slightly to 80% at the / mL concentration, the cell survival rate of 90% or more was observed when the BSA-coated metal bilayer hydroxide was treated for 24 hours. As a result, it could be seen that the metal bilayer hydroxide prepared in Example showed low cytotoxicity, and it was confirmed that the cell survival rate could be improved by BSA coating.

Experimental Example 1-4: Labeling Efficiency Analysis of Radioisotopes

Labeling efficiencies of copper-64 of magnesium aluminum metal bilayer hydroxides containing the radioisotope copper-64 obtained in Example 1 are shown in FIGS. 6 and 7. At this time, the labeling efficiency was centrifuged at 13,000 rpm for 20 minutes using Amicon® Ultra Centrifugal Filters (filter pore = 10K) to disperse the precipitate and supernatant. , The radioactivity of each was measured and calculated by using the equation of radioactivity of sediment / (radioactivity of sediment + radioactivity of supernatant) × 100. As a result of confirming the labeling amount of the radioisotope copper-64 on the metal bilayer hydroxide in FIG. 6, it was confirmed that the labeling had a high labeling efficiency of 99% or more even if the amount of copper-64 was increased. The labeling efficiencies of the metal double layer hydroxides including copper-64 obtained in Example 2 and the metal double layer hydroxides coated with BSA were shown in FIG. 7. As a result, it was confirmed that the labeling efficiency of the metal bilayer hydroxide including copper-64 and the BSA-coated metal bilayer hydroxide prepared by the method of the present invention has a very high labeling efficiency of 99% or more. The material prepared by the method of firstly preparing the hydroxide followed by the inclusion of copper-64 was 64.4%, showing an efficiency of at least 30% lower than the material prepared according to the present invention.

In addition, the results of evaluating the labeling efficiency of each metal double layer hydroxide using a chromatographic technique using thin layer chromatography (TLC) are shown in FIG. 8. 1 μL of the metal bilayer hydroxide suspension obtained in Example 2 was dropped on a 1.5 cm (width) × 12 cm (length) size ITLC plate at a point of 1 cm of vertical height, and the ITLC plate was moved to the mobile phase. Into the prepared 20 mM sodium citrate / 50 mM EDTA (pH 5) solution soaked only 0.5 cm of vertical height. The mobile phase was taken out as it rose 11 cm or more along the ITLC plate, and the free copper-64 dropped out of the metal bilayer hydroxide was measured. In the case of free copper-64 dissolved in the solution, as shown in FIG. 8 (e), a radioactivity peak is seen at a point 10 cm (11 cm in height of the ITLC plate). TLC results of a metal bilayer hydroxide comprising radioisotope copper-64 and a metal bilayer hydroxide coated with BSA thereof showed that copper-64 was desorbed by the mobile phase, as shown in FIGS. 8A and 8B. It was found that the radioactive peak appeared at 0 cm without any phenomenon, indicating that the radioisotope 64-copper was very stably located in the metal bilayer hydroxide lattice layer. On the other hand, in the case of a material prepared by synthesizing a metal double layer hydroxide first and then including copper-64, as shown in Figs. The phenomenon which detached | desorbed by was confirmed. This is an indirect confirmation of the possibility that copper-64 is attached to the surface layer, rather than being present in the metal bilayer hydroxide gap layer.

Experimental Example 1-5: Label Stability Analysis of Radioisotopes

The labeling stability in various media of metal bilayer hydroxides comprising radioisotope copper-64 obtained in Example 1 was determined using saline, PBS, mouse serum and human serum. Centrifuged in the same manner as above after incubating for a certain period of time in the above), and obtained by calculating the amount of copper-64 present in the metal double layer hydroxide layer without desorption using the same labeling efficiency equation after incubation. 9 and FIG. 10. In the case of particles synthesized first with a metal double layer hydroxide, coated with BSA, and labeled with 64-copper, the labeling stability in the saline solution, which is most used as water for injection, was found to be very low, at a level of 58%. This was in good agreement with the result of the most desorption of copper-64 by TLC in Experimental Example 2-1. In addition, the particles were found to be fairly stable in all media without copper-64 desorption.

Experimental Example 1-6 Intracellular Infiltration Experiment

Experimental results of the penetration of the metal bilayer hydroxide containing the radioisotope copper-64 obtained in Example 1 into cells (MBA-MD-231) are shown in FIG. 11. As a result, it was confirmed that the intracellular penetration effect of the metal double layer hydroxide containing copper-64 in the lattice was 43% based on 24 hours. The second highest cell penetration effect was obtained by BSA-coated metal bilayer hydroxide containing copper-64 in the lattice, showing 31% intracellular penetration effect on a 24-hour basis. The somewhat less penetrating effect of intracellular penetration by coating BSA is that the surface charge of a metal bilayer hydroxide containing copper without BSA is 22 mV, while the negative charge becomes -6 mV by coating BSA. It is a phenomenon that the interaction with the cells showing the relatively poor. Nevertheless, it was confirmed that the same negative charge resulted in a weak but highly invasive cell interaction. On the other hand, metal bilayer hydroxides were prepared first and then copper-64 labeled materials showed 8% intracellular penetration at 24 hours, and BSA coated 3% intracellular penetration. Indicated. It has a high surface charge of 41 mV and 18 mV, respectively, which is relatively high in copper-64 desorption, as shown in Experimental Examples 1-4 and 1-5, can relatively reduce the amount of infiltration into cells. An example can be described.

Experimental Example 1-7: Cytotoxicity Test

Cell (MBA-MD-231) toxicity test was performed on the metal bilayer hydroxide including the radioisotope copper-64 obtained in Example 1 in the lattice layer and the material coated with BSA. The cytotoxicity test results were calculated as 'cell viability (%) = 100 × (number of living cells) / (number of living cells + number of dead cells)' and are shown in FIG. 12. As a result, it was confirmed that the cytotoxicity for both particles is very low.

< Experimental Example  1-8: Positron Emission Tomography tomography , PET) imaging and in vivo distribution experiments>

PET imaging experiments of the metal bilayer hydroxide containing the radioisotope copper-64 obtained in Example 1 in the lattice layer and the material coated with BSA were confirmed in the animal model in which tumors were grown with MBA-MD-231 cell species. It was. Metal bilayer hydroxides containing copper-64 with a radiation dose of 300 μCi were added to the tumor model in I.V. After intravenous injection, PET images of 2 hours, 6 hours, 24 hours, and 48 hours later were confirmed and the results are shown in FIG. 13. As time increased, the amount of tumor infiltrate increased, and in the case of BSA-coated material, the amount of infiltrated tumor increased as the biocirculation increased.

The copper-64 detection curve and the degree of tumor penetration in the organs (liver, muscle, blood, tumor) over time of the copper double layer containing copper-64 obtained through the PET results are shown in FIGS. 14 and 15, respectively. . As a result of detecting copper-64 in the liver over time, the metal double layer hydroxide containing copper-64 in the lattice layer was found to have a weak emission from the liver at a level of 23% ID / g to 24% ID / g. On the other hand, in the case of BSA-coated metal double cathodic hydroxide, the penetration rate was slightly higher at 46% ID / g at 2 hours, but it was confirmed that it was continuously discharged at 22% ID / g at 48 hours. In the tumor infiltration results shown in FIG. 15, the metal bilayer hydroxide containing copper-64 in the lattice layer was 2.4% ID / g at 48 hours, whereas the metal double layer hydroxide coated with BSA was about 4.9% ID / g. Two times more tumor invasive effect was confirmed. When confirming the results of copper-64 detection in blood over time, the metal bilayer hydroxide containing copper-64 in the lattice layer maintained the level of 0.5% ID / g, while 0.6% ID for the BSA-coated material. It can be assumed that a relatively high amount of metal bilayer hydroxide circulating in the blood at a level of / g to 1% ID / g increases the probability of penetrating the tumor.

The degree of in vivo distribution of the metal bilayer hydroxide including the radioisotope copper-64 obtained in Example 1 in the lattice layer and the material coated with the BSA is shown in FIG. 16. The results were in good agreement with the PET imaging results shown in FIGS. 13 to 15.

< Comparative example  2: Non-radioactive  Isotopes, lutetium in the lattice Supported  metal Double layer  Synthesis of Hydroxide Hybrids>

Metal bilayer hydroxides containing copper as a non-radioactive isotope were synthesized as follows. The ratio of lutetium chloride with nitrates of magnesium and aluminum and non-radioactive isotope species was based on 2: 1-x: x, and the mixture of x adjusted to 0.01 was dissolved in distilled water, 0.2M sodium carbonate and 0.5M Titrated with a mixed solution of sodium hydroxide. After titration until pH was 10.0, the mixture was stirred at room temperature for 20 minutes, and the mixed solution was subjected to hydrothermal synthesis at 100 ° C for 3 hours. In order to attach the functional material to the magnesium aluminum ruthenium metal double layer hydroxide obtained as a result of the reaction, surface modification through silane treatment was attempted. The mixed solution of metal bilayer hydroxide obtained by hydrothermal synthesis for 3 hours and 3-aminopropyl-triethoxysilane (APS) were stirred for 1 hour. A polymer-coated metal bilayer hydroxide was prepared by mixing with a solution in which a polymer (polyethylene glycol, PEG) was dissolved in order to improve the in vivo circulation in a solution in which the surface-modified metal bilayer hydroxide was dispersed for 1 hour. In addition, in order to improve the degree of targeting of the metal bilayer hydroxide to the tumor, the mixture of the solution containing the surface-modified metal bilayer hydroxide and the solution containing folic acid (FA) is agitated. A supported metal double layer hydroxide was prepared. To improve the in vivo circulation and tumor targeting simultaneously, a solution containing a polymer glycol (polyethylene glycol, PEG) and folic acid (FA) are contained in a solution in which a surface-modified metal bilayer hydroxide is dispersed. A mixed solution of the solution was added and folate and polymer-coated metal bilayer hydroxide were prepared by stirring.

< Example  2: Synthesis of Metal Double-Layer Hydroxide Supported in the Lattice of Radioteotope, Lutetium-177, for Cancer Treatment and Diagnosis>

A metal bilayer hydroxide stably containing radioisotope lutetium-177 in the lattice was synthesized as follows.

The ratio of the solution of lutetium containing magnesium and aluminum nitrates and the radioisotope lutetium-177 species was based on 2: 1: x, and the ratio of x was arbitrarily set because the concentration cannot be specified due to the radioisotope characteristics. In the mean unit, mCi units were adjusted to the ratio of the amount of radiation of lutetium-177 required for the experiment. The mixture of magnesium and aluminum nitrates was dissolved in distilled water, mixed with a 0.01 M hydrochloric acid solution containing lutetium-177, and then titrated with a 0.2 M sodium carbonate and 0.5 M sodium hydroxide mixed solution. The solution was titrated until the pH became 10.0 and stirred at room temperature for 20 minutes, and the mixed solution was subjected to hydrothermal synthesis at 100 ° C for 3 hours.

In order to attach the functional material to the magnesium aluminum lutetium-177 metal bilayer hydroxide thus obtained, surface modification through silane treatment was attempted. The mixed solution of 3-aminopropyl-triethoxysilane (APS) and the solution containing the metal double layer hydroxide obtained by hydrothermal synthesis for 3 hours were stirred for 1 hour. In order to improve in vivo circulation in the solution in which the surface-modified metal double layer hydroxide is dispersed, a polymer coated metal double layer hydroxide was prepared by mixing with a solution in which polymer (polyethylene glycol, PEG) was dissolved. In addition, in order to improve the degree of targeting of the metal bilayer hydroxide to the tumor, the mixture of the solution containing the surface-modified metal bilayer hydroxide and the solution containing folic acid (FA) is agitated. A supported metal double layer hydroxide was prepared. To improve the in vivo circulation and tumor targeting, the solution containing the polymer (polyethylene glycol, PEG) and folic acid (FA) are contained in the solution of the surface-modified metal bilayer hydroxide. A mixed solution of the solution was added and folate and polymer-coated metal bilayer hydroxide were prepared by stirring.

Experimental Example 2-1 X-ray Diffraction Analysis

X-ray diffraction analysis results of the metal bilayer hydroxide including the radioisotope lutetium obtained in Comparative Example 2 in the lattice layer and the materials coated with folic acid and the polymer are shown in FIG. 17. For all metal bilayer hydroxides, it was confirmed by x-ray diffraction analysis that ruthetium, folic acid, and other impurities due to the polymer were not formed and the typical metal double layer hydroxide structure was maintained. However, in the case of a metal double layer hydroxide coated with hydrochloric acid and a polymer at the same time, it was difficult to carry out x-ray diffraction analysis because the amount obtained was very small, but it is expected that the metal double layer hydroxide structure is well maintained without forming other impurities.

Experimental Example 2-2: Infrared Spectroscopy Analysis

Infrared spectroscopic analysis results of the metal bilayer hydroxide including the radioisotope lutetium obtained in Comparative Example 2 and the materials coated with folic acid and the polymer are shown in FIG. 18. Of Figure 18 (a) in the basic physical properties of the metal hydroxide having double layer, that is - a peak was confirmed at 1,605 cm ^-1 indicates the inter-layer water of 3,500 cm ^-1 OH vibration and double-layer metal hydroxides, 1,365 cm ^-1 position, Peaks generated by the vibration of carbonate, an interlayer ion, were identified. In the case of a metal double layer hydroxide encoded by a general polymer with infrared spectroscopic peaks, a polymer having a CH ₂ chain as a basic skeleton and a polymer having -CH ₃ on the other side which is not connected to the metal double layer hydroxide is 2,864 cm ^-1. CH ₂ symmetry stretching and asymmetry stretching peaks at 2,932 cm ^-1 were observed, and CH ₃ asymmetry stretching peaks were observed at the 2,975 cm ^-1 position (FIGS. 18 (b) and (d)). In addition, when folic acid was coated, a peak was observed due to the aromatic phenylene ring of folic acid at ~ 1,460 cm ^-1 , and the other side of folic acid not connected with the metal double layer hydroxide was NH ₂ at 1,570 cm ^-1 . The peak by NH ₂ scissoring was confirmed (Fig. 18 (c) and (d)). Through this, it was confirmed through infrared spectroscopic analysis that the coating of folic acid and polymer on the metal double layer hydroxide was well performed.

Experimental Example 2-3: Analysis of Labeling Efficiency of Radioisotopes

The labeling efficiency of lutetium-177 of magnesium aluminum metal bilayer hydroxides stably including lutetium-177 obtained in Example 2 in the lattice is shown in FIG. 19. The labeling efficiency was determined by centrifuging the solution containing the metal bilayer hydroxide at 13,000 rpm for 20 minutes using Amicon® Ultra Centrifugal Filters (filter pore = 10K) to separate the precipitate and the supernatant, respectively. The radioactivity of the was measured and calculated using the equation of radioactivity of precipitate / radioactivity of supernatant + supernatant × 100. The labeling efficiency of 99-100% was confirmed for all the particles, and it was indirectly confirmed that lutetium-177 was very stable in the metal bilayer hydroxide lattice layer.

Experimental Example 2-4: Label Stability Analysis of Radioisotopes

The labeling stability in various media of the magnesium aluminum metal bilayer hydroxides containing lutetium-177 obtained in Example 2 was consistent with the metal bilayer hydroxide in saline, mouse serum and human serum. Centrifugation was carried out in the same manner as above after incubating for a period of time, and was obtained by calculating the amount of lutetium-177 present in the metal bilayer hydroxide layer without desorption using the same labeling efficiency equation after incubation, which is shown in FIG. 20. Indicated. For 7 days corresponding to the half-life (6.7 days) of lutetium-177, a very high label stability was confirmed, with more than 99%. In addition, the result of confirming the stability of 14 days after the two half-life periods of lutetium-177 showed that the metal bilayer hydroxide containing lutetium-177, the polymer coated material, the folic acid coated material, and the polymer and folic acid were simultaneously coated. 87-89%, 93-99%, 96-97%, and 96-98% for each material was somewhat less stable than day 7, but still very high label stability.

Experimental Example 2-5 Intracellular Infiltration Experiment

Experimental results of the penetration of the metal bilayer hydroxide containing the radioisotope lutetium-177 obtained in Example 2 into cells (MBA-MD-231) are shown in FIG. 21. As a result, all particles showed a tendency to fall out after intracellular penetration quickly within 30 minutes. The metal bilayer hydroxide containing lutetium-177 in the lattice exhibited intracellular penetration of 3.3% ID within 30 minutes, and the intracellular penetration effect increased to 5.1% ID when the polymer was coated. In addition, when coated with folic acid, which serves as an active targeting role, it was confirmed that the cells were absorbed by 7.6% ID for 30 minutes, and showed the greatest cell penetration effect.

< Example  3: Cancer diagnosis possible  Radioisotope, technetium-99m in the lattice Supported  Synthesis of Metal Double Layer Hydroxide Hybrids>

A metal double layer hydroxide containing radioisotope technetium-99m stably in the lattice was synthesized as follows.

The ratio of the technetium solution containing magnesium and aluminum nitrates and the radioisotope technetium-99m species was based on 2: 1: x, and the ratio of x was arbitrarily set because the concentration cannot be specified due to the radioisotope characteristics. In the mean unit of mCi unit was adjusted to the ratio of the amount of technetium-99m radiation required for the experiment. The mixture of magnesium and aluminum nitrates was dissolved in distilled water and mixed with a 0.01 M hydrochloric acid solution containing Technetium-99m, followed by titration with a 0.2 M sodium carbonate and 0.5 M sodium hydroxide mixed solution. The solution was titrated until the pH became 10.0 and stirred at room temperature for 20 minutes, and the mixed solution was subjected to hydrothermal synthesis at 100 ° C for 3 hours.

The labeling efficiency of technetium-99m of magnesium aluminum metal double layer hydroxides stably including the technetium-99m obtained as a result of the reaction was confirmed. The labeling efficiency was determined by centrifuging the solution containing the metal bilayer hydroxide at 13,000 rpm for 20 minutes using Amicon® Ultra Centrifugal Filters (filter pore = 10K) to separate the precipitate and the supernatant, respectively. The radioactivity of the was measured and calculated using the equation of radioactivity of precipitate / radioactivity of supernatant + supernatant × 100. The labeling stability of various media of magnesium aluminum metal bilayer hydroxides containing Technetium-99m was determined by incubating the metal bilayer hydroxide in saline, mouse serum and human serum for a period of time before centrifugation in the same manner as described above. The formula was used to calculate the amount of 99m-technetium present in the metal bilayer hydroxide layer without desorption.

Experiments were carried out for the intracellular penetration effect of the metal double layer hydroxide containing radioisotope technetium-99m, and the results of cytotoxicity test showed that 'cell viability (%) = 100 × (number of living cells) / ( The number of living cells + number of dead cells). In addition, SPECT images of metal bilayer hydroxides containing technetium-99m in tumor-grown animal models were examined, and the organs (liver, muscle, blood, etc.) of the metal bilayer hydroxides containing technetium-99m derived from the tumors were obtained. , Tumor) in the technetium-99m detection curve and the degree of tumor penetration was confirmed. At the same time, the degree of in vivo distribution of metal bilayer hydroxide containing radioisotope technetium-99m was also confirmed.

< Comparative example  3: Non-radioactive  Isotopes, gallium in the lattice Supported  metal Double layer  Synthesis of Hydroxide Hybrids>

Metal bilayer hydroxides stably containing gallium, a non-radioactive isotope, in a lattice were synthesized as follows. The ratio of magnesium and aluminum nitrates and gallium nitrates with non-radioactive isotope species is based on 2: 1-x: x, and x is mixed with distilled water in a mixture adjusted to a ratio of 0.01, 0.2 M sodium carbonate and 0.5 M Titrated with a mixed solution of sodium hydroxide. The solution was titrated until the pH became 10.0 and stirred at room temperature for 30 minutes, and the mixed solution was subjected to hydrothermal synthesis at 100 ° C for 3 hours. In order to improve the dispersibility of the magnesium aluminum gallium metal bilayer hydroxide obtained as a result of the reaction, it was reacted with a solution containing bovine serum albumin (BSA) to obtain a metal bilayer hydroxide having BSA adsorbed on the surface. X-ray diffraction patterns of the magnesium aluminum gallium metal bilayer hydroxides obtained as a result of the reaction were analyzed and confirmed by SEM images showing the particle size and shape.

< Example  4: Cancer diagnosis possible  Radioisotope, Gallium-67 in the lattice Supported  Synthesis of Metal Double Layer Hydroxide Hybrids>

A metal double layered hydroxide stably containing radioisotope gallium-67 in the lattice was synthesized as follows.

The ratio of the gallium solution containing magnesium and aluminum nitrates and the radioisotope gallium-67 species was based on 2: 1: x, and the ratio of x was arbitrarily set because the concentration could not be specified due to the radioisotope characteristics. In the mean units, mCi units were adjusted in proportion to the amount of radiation of gallium-67 required for the experiment. The mixture of magnesium and aluminum nitrates was dissolved in distilled water, mixed with a 0.01 M hydrochloric acid solution containing gallium-67, and then titrated with a 0.2 M sodium carbonate and 0.5 M sodium hydroxide mixed solution. The solution was titrated until the pH became 10.0 and stirred at room temperature for 20 minutes, and the mixed solution was subjected to hydrothermal synthesis at 100 ° C for 3 hours.

The labeling efficiency of gallium-67 of magnesium aluminum metal bilayer hydroxides stably including gallium-67 obtained as a result of the reaction was confirmed. The labeling efficiency was determined by centrifuging the solution containing the metal bilayer hydroxide at 13,000 rpm for 20 minutes using Amicon® Ultra Centrifugal Filters (filter pore = 10K) to separate the precipitate and the supernatant, respectively. The radioactivity of was measured by calculating the radioactivity of the precipitate / radioactivity of the precipitate + radioactivity of the supernatant × 100. The labeling stability of various media of magnesium aluminum metal bilayer hydroxides containing gallium-67 was determined by incubating the metal bilayer hydroxide in saline, mouse serum and human serum for a period of time, followed by centrifugation in the same manner as described above. The formula was used to calculate the amount of gallium-67 present in the metal bilayer hydroxide layer without desorption.

< Comparative example  4: Non-radioactive  Isotopes, metals with iodine interlayered Double layer  Synthesis of Hydroxide Hybrids>

Metal bilayer hydroxides containing iodine anions which are non-radioactive isotopes stably in the hydroxide interlayer were synthesized as follows. The nitrate ratio of magnesium to aluminum was 2: 1, and was prepared by mixing with a 0.2 M potassium iodide solution having a non-radioactive isotopic species and titrating with a 0.5 M sodium hydroxide solution. After titration until the pH is 10.0 and stirred at room temperature for 3 hours. For comparison, nitrates of magnesium and aluminum, the ratio is 2: 1 in a mixed solution of 0.2 M sodium carbonate and 0.5 M sodium hydroxide solution is titrated until the pH is 10.0, and then stirred at room temperature for 3 hours to carbonate Magnesium aluminum metal bilayer hydroxide containing ions was synthesized.

Experimental Example 4-1 X-ray Diffraction Analysis

X-ray diffraction pattern of magnesium aluminum metal bilayer hydroxide containing carbonate ions prepared by stirring for 3 hours at room temperature obtained as a result of reaction in Comparative Example 4 and magnesium aluminum metal bilayer hydroxide containing iodine which is a non-radioactive isotope Is shown in FIG. 22. All of them maintained the metal double layer hydroxide structure, and the d-spacing of magnesium aluminum metal double layer hydroxide containing carbonate ion was 7.6 kW, while the d-spacing of magnesium aluminum metal double layer hydroxide containing iodine was 8.3 kW. X-ray diffraction analysis showed that iodine is located within the metal bilayer hydroxide layer.

< Example  5: Synthesis of Metal Double-Layer Hydroxide Hybrid with Iodine-131 Interposed Between Radioactive Isotopes and Cancer Treatment>

A metal double layer hydroxide containing iodine-131, a radioisotope, stably contained in the hydroxide interlayer was synthesized as follows. The nitrate ratio of magnesium and aluminum was 2: 1, and titrated with a solution containing 0.2 M of sodium iodide and radioisotope iodine-131 with a non-radioactive isotopic species and a solution of 0.5 M sodium hydroxide. . The solution was titrated until the pH became 10.0 and stirred at room temperature for 30 minutes, and the mixed solution was subjected to hydrothermal synthesis at 100 ° C for 3 hours. The iodine-131 labeling efficiency of the magnesium aluminum metal bilayer hydroxide including iodine-131 obtained as a result of the reaction was confirmed. The labeling efficiency was determined by centrifuging the solution containing the metal bilayer hydroxide at 13,000 rpm for 20 minutes using Amicon® Ultra Centrifugal Filters (filter pore = 10K) to separate the precipitate and the supernatant, respectively. The radioactivity of was measured by calculating the radioactivity of the precipitate / radioactivity of the precipitate + radioactivity of the supernatant × 100. Labeling stability in various media of magnesium aluminum metal bilayer hydroxides containing iodine-131 was determined by incubating the metal bilayer hydroxide in saline, mouse serum and human serum for a period of time, followed by centrifugation in the same manner as described above. The formula was used to calculate the amount of iodine-131 present in the metal bilayer hydroxide layer without desorption.

Experiments were conducted on the intracellular penetration of metal bilayer hydroxides containing radioactive isotope iodine-131, and the results of cytotoxicity test showed that 'cell viability (%) = 100 × (number of living cells) / ( The number of living cells + number of dead cells). In addition, SPECT images of metal bilayer hydroxides containing iodine-131 in tumor-grown animal models were confirmed, and the degree of in vivo distribution of metal bilayer hydroxides containing radioisotope iodine-131 was also confirmed. In addition, the tumor size change and survival rate of the experimental mouse group according to the injection of metal bilayer hydroxide containing iodine-131 in the tumor-grown animal model were confirmed by comparison with the control group.

< Comparative example  5: Non-radioactive  Isotopes, cobalt in the lattice Supported  metal Double layer  Synthesis of Hydroxide Hybrids>

Metal bilayer hydroxides containing stably cobalt, a non-radioactive isotope, in a lattice were synthesized as follows. The ratio of magnesium and aluminum nitrates and cobalt nitrates with non-radioactive isotope species was determined on a 2: 1-x: x basis, where x was mixed in distilled water with a mixed agent adjusted to a ratio of 0.01, 0.2 M sodium carbonate and 0.5 M Titrated with a mixed solution of sodium hydroxide. The mixture was titrated until the pH became 10.0 and stirred at room temperature for 30 minutes, and the mixed solution was subjected to hydrothermal synthesis at 100 ° C for 3 hours. In order to improve the in vivo dispersion of magnesium aluminum cobalt metal bilayer hydroxide obtained as a result of the reaction, it was reacted with a solution containing bovine serum albumin (BSA) to obtain a metal double layer hydroxide adsorbed on the surface. The X-ray diffraction patterns of the magnesium aluminum gallium metal bilayer hydroxides obtained as a result of the reaction were analyzed and confirmed by SEM images showing the particle size and shape.

< Comparative example  6: Non-radioactive  Isotopes, yttrium in the lattice Supported Double layer  Synthesis of Hydroxide Hybrids>

Metal double layer hydroxides were synthesized as follows. The nitrates of magnesium and aluminum and the yttrium nitrates with non-radioactive isotope species were based on 2: 1-x: x, where x is 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.8, and 1 The mixture adjusted to the ratio of was dissolved in distilled water, sodium carbonate was added to the solution to the same molar ratio as magnesium, and then titrated with 0.5 M sodium hydroxide solution. The mixture was titrated until the pH became 10.0 and stirred at room temperature for 3 hours, and the mixed solution was subjected to hydrothermal synthesis at 100 ° C for 24 hours.

Experimental Example 6-1 X-ray Diffraction Analysis

The X-ray diffraction pattern of the magnesium aluminum yttrium metal double layer hydroxide obtained as a result of the reaction in Comparative Example 6 is shown in FIG. 23. As the yttrium content increases, the width of the peak intensity decreases. In addition, when the ratio of aluminum to yttrium is included in the range of 1-x: x by 0.6, it was found that the metal double layer hydroxide was not maintained in the amorphous form. This result shows that the yttrium ion radius is 0.9 Å, which is larger than the aluminum ion radius of 0.56 Å, which shows that there is a limit to the amount that can be placed in the lattice. Accordingly, the variation of cell parameters in the x, y, and z axis directions of the metal double layer hydroxide according to the composition ratio of yttrium was derived through Rietveld refinment profiling, and the result is illustrated in FIG. 24. Shown in As can be seen from the change in the lattice constant of the unit cell, the lattice constant a means the direction of the x-axis and the lattice constant c means the direction of the y-axis, and the ratio of aluminum and yttrium is 1-x: x at x. Increased until 0.4, and then moved out of the trend line when x was 0.5. This is a result indicating that the ratio of yttrium that can stably enter the lattice is x = 0.4.

Experimental Example 6-2 Cytotoxicity Test

The cytotoxicity test results of the magnesium aluminum yttrium metal bilayer hydroxide obtained as a result of the reaction in Comparative Example 6 are shown in FIGS. 25 and 26. Cytotoxicity was incubated with L929 cells (mouse fibroblast cell line) and Hepa-1c1c7 (mouse liver cancer cell line) cells for 12 hours, and then the ratio of aluminum and yttrium was 1-x: x to x from 0 to 0.4 Different concentrations of metal bilayer hydroxides were treated, and cytotoxicity was confirmed after 24 hours and 48 hours. As a result, when yttrium content is increased as a whole, cell viability tends to be lowered, which is considered to be caused by yttrium toxicity. The cell viability after 48 hours in L929 cells was found to be low in cytotoxicity with an average of more than 90%. In addition, even when Hepa-1c1c7 cells were treated with a metal bilayer hydroxide concentration of 63 μg / mL or more, the cell viability of 80% was slightly decreased, but it was confirmed that the cytotoxicity was low overall.

< Comparative example  7: Non-radioactive  Isotopes, gallium in the lattice Supported Double layer  Synthesis of Hydroxide Hybrids>

Metal bilayer hydroxides stably containing gallium, a non-radioactive isotope, in a lattice were synthesized as follows. The ratio of magnesium nitrate and gallium nitrate having non-radioactive isotope species was dissolved in distilled water on a 2: 1 basis and titrated with a 0.2 M sodium carbonate and 0.5 M sodium hydroxide solution. After titration until the pH is 10.0, the reaction was stirred at room temperature for 6 hours. In addition, a mixed solution (2: 1) of magnesium and gallium nitrate was titrated with a mixed solution of sodium carbonate and sodium hydroxide, and stirred at room temperature for 30 minutes to hydrothermally synthesize the mixed solution at 100 ° C for 6 hours. The X-ray diffraction patterns of the magnesium gallium metal bilayer hydroxides obtained as a result of reactions at different temperatures (at room temperature and 100 ° C.) were analyzed and confirmed by SEM images showing their particle size and shape.

< Example  7: Cancer diagnosis possible  Radioisotope, Gallium-67 in the lattice Supported  Synthesis of Metal Double Layer Hydroxide Hybrids>

A metal bilayer hydroxide containing stably radioisotope gallium-68 in the lattice was synthesized as follows.

The ratio of gallium solution containing magnesium and gallium nitrate and the radioisotope gallium-68 species was 2: 1: x, and the ratio of x was set arbitrarily because the concentration could not be specified due to the radioisotope characteristics. In the mean units, mCi units were adjusted in proportion to the amount of radiation of gallium-68 required for the experiment. The mixture of magnesium and gallium nitrate was dissolved in distilled water, mixed with a 0.01 M hydrochloric acid solution containing gallium-68, and then titrated with a 0.2 M sodium carbonate and 0.5 M sodium hydroxide mixed solution. The solution was titrated until the pH became 10.0 and stirred at room temperature for 5 minutes, and the mixed solution was subjected to hydrothermal reaction for 1 hour at 100 ° C.

< Experimental Example  7-1: X-ray diffraction analysis: Non-radioactive  Isotopes, gallium in the lattice Supported Double layer  Synthesis of Hydroxide Hybrids>

An X-ray diffraction pattern of the magnesium gallium metal bilayer hydroxide including gallium, which is a non-radioactive isotope obtained as a result of the reaction in Comparative Example 7, is shown in FIG. 27. It was confirmed by X-ray diffraction analysis that all the metal double layer hydroxides produced at room temperature and 100 ° C. were formed of a typical metal double layer hydroxide structure without forming other impurities by magnesium or gallium. In addition, it was confirmed that the strength of the (hkl) peaks of the magnesium gallium metal double layer hydroxide formed under high temperature conditions was higher than that of the magnesium gallium metal double layer hydroxide synthesized at room temperature.

Experimental Example 7-2 Scanning Electron Microscope (SEM) Analysis

The particle size and shape of the magnesium gallium metal bilayer hydroxide (synthesized at 100 ° C.) including gallium, the non-radioactive isotope obtained in Comparative Example 7, were analyzed using a scanning electron microscope (SEM, JEOL JSM-6700F). And the image is shown in FIG. Metal bilayer hydroxide containing gallium was confirmed to have a plate-like structure of 100 nm to 400 nm size.

Experimental Example 7-3 Analysis of Labeling Efficiency of Radioisotopes

The labeling efficiency of gallium-68 of magnesium gallium metal bilayer hydroxides including the radioisotope gallium-68 obtained in Example 6 is shown in FIG. 29. At this time, the labeling efficiency was centrifuged for 30 minutes at 13000 rpm using Eppendorf Tubes® (1.5 mL) to disperse the metal bilayer hydroxide, to separate the precipitate (precipitation) and the supernatant (supernatant), respectively, The activity (radioactivity) was measured and calculated using the equation 'Radiation activity of precipitates / (Radiation activity of precipitates + radioactivity of supernatant) × 100'. As a result, it was confirmed that it has a high labeling efficiency of more than 97%, it was indirectly confirmed that gallium-68 is located very stably in the metal double layer hydroxide lattice layer. In addition, the results of evaluating the labeling efficiency of each metal double layer hydroxide using the chromatographic technique using thin layer chromatography (TLC) are shown in FIG. 30. Into a 1.5 cm (width) x 12 cm (length) size ITLC plate, 1 μL of the metal bilayer hydroxide suspension obtained in Example 7 was dropped to a 1 cm point of vertical height, and the ITLC plate was prepared as a mobile phase. In a solution of mM sodium citrate / 50 mM EDTA (pH 5), only 0.5 cm of height was submerged. The mobile phase was removed when it was raised more than 11 cm in height along the ITLC plate, and the free gallium-68 was removed from the metal bilayer hydroxide. In the case of pregallium-68 dissolved in solution, a radioactivity peak is seen at a point of 10 cm (11 cm in height of the ITLC plate). The metal double layer hydroxide containing radioisotope gallium-68 As shown in FIG. 30, it was confirmed that the radioactive peak appeared at the 0 cm position without the phenomenon that gallium-68 was desorbed by the mobile phase. This shows that the radioisotope gallium-68 is very stable in the metal bilayer hydroxide lattice layer.

Experimental Example 7-4: Infiltration into Cells

The experimental results of the penetration of the metal bilayer hydroxide containing the radioisotope gallium-68 obtained in Example 7 into cells (MBA-MD-231) are shown in FIG. 31. As a result, the intracellular penetration of metal bilayer hydroxide containing gallium-68 into the lattice tended to increase for 60 minutes and then to decrease at 120 minutes.

< Comparative example  8: Non-radioactive  Isotopes, metals with phosphorus interlayered Double layer  Synthesis of Hydroxide Hybrids>

A metal double layer hydroxide in which phosphorus, which is a non-radioactive isotope, is stably positioned between the hydroxide layers was prepared by ion exchange. Magnesium and aluminum nitrate was prepared by mixing so that the ratio is 2: 1, titrated with 0.2 M sodium carbonate and 0.5 M sodium hydroxide solution until the pH is 10.0 and stirred at room temperature for 24 hours. The obtained magnesium aluminum metal bilayer hydroxide was prepared by re-dispersing in distilled water for 1 hour, and mixed with this tribasic sodium phosphate solution to adjust the pH to 6.5, 10, and 12.5, respectively, and stirred for 24 hours.

In another ion exchange method, a metal double layer hydroxide was prepared in which the non-radioactive isotope phosphorus was stably positioned between the metal double layer hydroxide layers. Magnesium and aluminum nitrate was prepared by mixing so that the ratio is 2: 1, titrated with 0.2 M sodium carbonate and 0.5 M sodium hydroxide solution until the pH is 10.0 and stirred at room temperature for 24 hours. The obtained magnesium aluminum metal bilayer hydroxide was prepared by redispersing in distilled water for 1 hour, mixed with a sodium phosphate monophosphate solution prepared at 10 times and 25 times the aluminum concentration of the metal double layer hydroxide and stirred for 24 hours.

Experimental Example 8-1 X-ray Diffraction Analysis

X-ray diffraction pattern of the magnesium aluminum metal bilayer hydroxide containing non-radioactive isotope phosphorus prepared according to the pH change in Comparative Example 8 is shown in FIG. The X-ray diffraction pattern of the magnesium aluminum metal bilayer hydroxide containing carbonate did not change under alkaline conditions pH = 10 and 12.5, but only in the case of metal bilayer hydroxide prepared by ion exchange at weak acidity pH = 6.5. It was confirmed that the phosphate ions were located by ion exchange through a d-spacing change from 7.6 kPa to 10.6 kPa.

As another experimental example, X-ray diffraction patterns of the obtained products obtained as a result of the ion exchange reaction between the monophosphate and the magnesium aluminum metal double layer hydroxide prepared at different concentrations in Comparative Example 8 are shown in FIG. 33. It was confirmed that all of the ion exchange proceeded with phosphate ions, but when ion exchanged with a 10-fold sodium phosphate solution, it was ion exchanged in the form of three kinds of phosphate ions, not a metal bilayer hydroxide containing a single phase phosphorus It can be seen that it is located within the metal bilayer hydroxide interlayer. However, it was confirmed by X-ray diffraction pattern that the metal bilayer hydroxide containing single phase phosphorus was well formed when ion exchanged with 25 times sodium monophosphate solution.

Experimental Example 8-1: Infrared Spectroscopy Analysis

Infrared spectroscopic analysis results of magnesium aluminum metal bilayer hydroxide containing non-radioactive isotopic phosphorus prepared according to the pH change of the solution to be ion-exchanged in Comparative Example 8 and the concentration of the first sodium phosphate solution are shown in FIGS. 34 and 35. Shown in The 1356 cm ^-1 peak representing the carbonate ion in the metal bilayer hydroxide containing carbonate in the interlayer is 1095 PO vibration peaks that can confirm the presence of phosphorus only in the infrared spectroscopy of magnesium aluminum metal bilayer hydroxides stably located in the interlayer. It was confirmed that all appeared in cm ^-1 .

< Comparative example  9: Non-radioactive  Isotopes, yttrium in the lattice Supported  There is, Non-radioactive  Synthesis of Metal Double-Layer Hydroxide Hybrids with Isotopes and Phosphorus in Interlayers>

A metal bilayer hydroxide stably containing yttrium, which is a non-radioactive isotope, in the lattice was synthesized as follows. The ratio of magnesium nitrate and yttrium nitrate having non-radioactive isotope species was dissolved in distilled water on a basis of 2: 0.666: 0.334 and titrated with 0.5 M sodium hydroxide solution. After titration until the pH is 10.0, the reaction was stirred at room temperature for 24 hours. The obtained magnesium aluminum yttrium metal bilayer hydroxide was prepared by redispersing in distilled water for 1 hour, mixed with sodium diphosphate solution prepared at 25 times the concentration of aluminum in the metal bilayer hydroxide and stirred for 24 hours.

Experimental Example 9-1 X-ray Diffraction Analysis

The X-ray diffraction pattern of the non-radioactive yttrium and phosphorus-containing magnesium aluminum metal bilayer hydroxides obtained in Comparative Example 9 is shown in FIG. 36. Magnesium aluminum yttrium metal bilayer hydroxide prepared by placing magnesium phosphate ions in the interlayer by ion exchange method containing magnesium nitrate ions showed that the d-spacing changed from 7.9 8.1 to 8.1 Å. It was confirmed that the metal bilayer hydroxide including elemental yttrium in the lattice and phosphorus in the interlayer was well synthesized.

< Experimental Example  9-1: Infrared Spectroscopy>

37 shows the results of infrared spectroscopy of the magnesium aluminum metal double layer hydroxide containing the non-radioactive isotope yttrium and phosphorus obtained in Comparative Example 9. The 1383 cm ⁻¹ peak representing nitrate ions in the magnesium aluminum yttrium metal bilayer hydroxide containing nitrate ions in the interlayer indicates that the PO vibration peaks appear at 1095 cm ⁻¹ in the magnesium aluminum yttrium metal bilayer hydroxides stably located in the interlayer. It could be confirmed by infrared spectroscopic analysis.

The above description of the present application is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms without changing the technical spirit or essential features of the present application. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined form.

The scope of the present application is indicated by the following claims rather than the above description, and it should be construed that all changes or modifications derived from the meaning and scope of the claims and their equivalents are included in the scope of the present application.

Claims (18)

Radioactive isotopes located within and / or between lattice of metal bilayer hydroxides
A radioisotope-containing metal bilayer hydroxide hybrid comprising a.
The method of claim 1,
A radioisotope-containing metal bilayer hydroxide hybrid, comprising said radioisotope within the lattice of said metal bilayer hydroxide.
The method of claim 1,
Wherein said radioisotope located between the layers of said metal bilayer hydroxide comprises ions of said radioisotope and / or chelate or polyatomic ions comprising said radioisotope, radioisotope-containing metal bilayer hydroxide hybrid sieve.
The method of claim 1,
Comprising the radioactive isotope in the lattice of the metal bilayer hydroxide and comprising ions of the radioisotope and / or chelate or polyatomic ions comprising the radioisotope located between the layers of the metal bilayer hydroxide. , Radioisotope-containing metal bilayer hydroxide hybrids.
The method of claim 1,
Wherein said radioisotope comprises at least one species.
The method of claim 1,
Wherein the radioisotope located within the lattice of the metal bilayer hydroxide and the radioisotope located between the layers of the metal bilayer hydroxide are the same or different from each other.
The method of claim 1,
The metal layered double hydroxide is represented by the following formula 1, radioisotope-containing metal double layer hydroxide hybrid:
[Formula 1]
[M ²⁺ _(1-x) M ³⁺ _x (OH ⁻ ) ₂ ] ^{x +} [(A ⁿ⁻ ) _{x / n} yH ₂ O] ^x- ;
In the above formula,
M ²⁺ is a divalent metal cation + ^{2, Ni 2 +, Mg 2 +} , Ca 2 +, Zn 2 +, Mn 2 +, Co 2 +, Fe 2 +, Cu 2 +, Cd 2 +, and their A metal cation selected from the group consisting of combinations,
M ³⁺ is a +3 valent metal cation, Fe ^{+ 3,} Al ^{+ 3,} Cr ^{+ 3,} Mn ^{+ 3,} Ga ^{+ 3,} Co ^{+ 3,} Ni ^{+ 3,} Sc ^3+, La ^{3 +,} V ³⁺ , Sb ^{+ 3,} Y ^3+, in ^{+ 3,} Ti ^{+ 3,} Y ^3+, Gd ^{+ 3,} Lu ^{+ 3,} and is to include a metal cation selected from the group consisting of the combinations thereof,
A ^n- is Cl ^- is an anion selected from, CO ₃ ^2-, SO ^2-, and the group consisting of a combination thereof, ^-, Br ^-, NO ₃
0≤x <1,
n is an integer from 1 to 3,
y is a number from 0.1 to 20.
The method of claim 1,
The radioisotope located within the lattice of the metal bilayer hydroxide is oxygen-15 (Oxygen-15, ¹⁵ O), calcium-47 (Calcium-47, ⁴⁷ Ca), scandium-46 (Scabduyn-46, ⁴⁶ Sc), Chromium-51, 57, ⁵¹ Cr, ⁵⁷ Cr), Cobalt-57, 60 (Cobalt-57, 60, ⁵⁷ Co, ⁶⁰ Co), Manganese-54 (Manganese-54, ⁵⁴ Mn), Iron-55, 59 (Iron-55, 59, ⁵⁵ Fe , ⁵⁹ Fe), Nickel-63 (Nikel-63, ⁶³ Ni), Copper-61, 64, 67 (copper-61, 64, 67, ⁶¹ Cu, ⁶⁴ Cu, ⁶⁷ Cu), Zinc-65 (Zinc-65 , ⁶⁰ Zn), Gallium-67, 68 (Gallium-67, 68, ⁶⁷ Ga, ⁶⁸ Ga), Germanium-68 (Germanium-68, ⁶⁸ Ge) Selenium-75 (Selenium-75, ⁷⁵ Se), Rubidium- 82 (Rubidium-82, ⁸² Ru), Strontium-82, 85, 89, 90 (Strontium-82, 85, 89, 90, ⁸² Sr, ⁸⁵ Sr, ⁸⁹ Sr, ⁹⁰ Sr), Yttrium-90 (Yttrium-90, ⁹⁰ Y), Ruthenium-97, 103 (Ruthenium-97, 103, ⁹⁷ Ru, ¹⁰³ Ru), Molybdenum-99 (Molybdenum-99, ⁹⁹ Mo), Technetium -99m (Technetium-99m, ^99m Tc), Palladium-103 (Palladium-103, ¹⁰³ Pd), Indium-111 (Indium-111, ¹¹¹ In), Silver-110m (Silver-110m, ^110m Ag), Cadmium-109 , 115 (Cadmium-109, 115, ¹⁰⁹ Cd, ¹¹⁵ Cd), tin-117, 113 (Tin-117, 113, ¹¹⁷ Sn, ¹¹³ Sn), antimony-119 (Antimony-119, ¹¹⁹ Sb), tellurium- 118, 123 (Tellurium-118, 123, ¹¹⁸ Te, ¹²³ Te), Barium-131, 140 (Barium-131, 140, ¹³¹ Ba, ¹⁴⁰ Ba), Lanthanum-140 (Lanthanum-140, ¹⁴⁰ La), Cesium -137 (Cesium-137, ¹³⁷ Ce), Gadolinium-149, 151 (Gadolinium-149, 151, ¹⁴⁹ Gd, ¹⁵¹ Gd), Samarium-153 (Samarium-153, ¹⁵³ Sm) Dysprosium-159, 165 (Dysprosium-159 , 165, ¹⁵⁹ Dy, ¹⁶⁵ Dy), Terbium-160 (Terbium-160, ¹⁶⁰ Tb), Holmium-166 (Holmiun-166, ¹⁶⁶ Ho), Erbium-169 (Erbium-169, ¹⁶⁹ Er), Ytterbium-169 , 177 (Ytterbium-169, 177, ¹⁶⁹ Yb, ¹⁶⁹ Yb), Lutetium-177 (Lutetium-177, ¹⁷⁷ Lu), Rhenium-186, 188 (Rhenium-186, 18 8, ¹⁸⁶ Re, ¹⁸⁸ Re), Iridium-192, ¹⁹² Ir), Gold-198, 199 (Gold-198, 199, ¹⁹⁸ Au, ¹⁹⁹ Au), thallium-201, 204 (Thallium-201, 204, ²⁰¹ Tl, ²⁰⁴ Tl), Lead-210 (Lead-210, ²¹⁰ Pb), Bismuth-213 (Bismuth-213, ²¹³ Bi), Astatin-211 (Astatine-211, ²¹¹ At), Radium-223, 224 , 226 (Radium-223, 224, 226, ²²³ Ra, ²²⁴ Ra, ²²⁶ Ra), actinium-225 (Actinium-225, ²²⁵ Ac), and combinations thereof, Radioisotope-containing metal bilayer hydroxide hybrids.
The method of claim 1,
The radioisotope located between the layers of the metal bilayer hydroxide is carbon-11, 14 (Carbon-11, 14, ¹¹ C, ¹⁴ C), nitrogen-13 (Nitrogen-13, ¹³ N), oxygen-15 (Oxygen -15, ¹⁵ O), Fluorine-18 ( ¹⁸ F), Chlorine-36, Sodium-22, 24 (Sodium-22, 24, ²² Na, ²⁴ Na), Phosphorus-32 , 33 (Phosphorus-32, 33, ³² P, ³³ P), sulfur-35 (Sulphur-35, ³⁵ S), potassium-42, 43 (Potassium-42, 43, ⁴² K, ⁴³ K), calcium-47 (Calcium-47, ⁴⁷ Ca), Scandium-46 (Scabduyn-46, ⁴⁶ Sc), Chromium-51, 57 (Chromium-51, 57, ⁵¹ Cr, ⁵⁷ Cr), Cobalt-57, 60 (Cobalt-57, 60, ⁵⁷ Co, ⁶⁰ Co), manganese-54 (Manganese-54, ⁵⁴ Mn), iron-55, 59 (Iron-55, 59, ⁵⁵ Fe, ⁵⁹ Fe), Nickel-63 (Nikel-63, ⁶³ Ni), Copper-61, 64, 67 (copper-61, 64, 67, ⁶¹ Cu, ⁶⁴ Cu, ⁶⁷ Cu), Zinc-65 (Zinc -65, ⁶⁰ Zn), Gallium-67, 68 (Gallium-67, 68, ⁶⁷ Ga, ⁶⁸ Ga), Germanium-68 (Germanium-68, ⁶⁸ Ge) Selenium-75 (Selenium-75, ⁷⁵ Se), Rubidium-82 ( ⁸² Ru), Strontium-82, 85, 89, 90 (Strontium-82, 85, 89, 90, ⁸² Sr, ⁸⁵ Sr, ⁸⁹ Sr, ⁹⁰ Sr), yttrium-90 (Yttrium-90, ⁹⁰ Y), ruthenium-97, 103 (Ruthenium-97, 103, ⁹⁷ Ru, ¹⁰³ Ru), molybdenum-99 (Molybdenum-99 , ⁹⁹ Mo), Technetium-99m ( ^99m Tc), Palladium-103 (Palladium-103, ¹⁰³ Pd), Indium-111 (Indium-111, ¹¹¹ In), Silver-110m (Silver-110m, ^110m Ag), cadmium-109, 115 (Cadmium-109, 115, ¹⁰⁹ Cd, ¹¹⁵ Cd), Tin-117, 113 (Tin-117, 113, ¹¹⁷ Sn, ¹¹³ Sn), Antimony-119 (Antimony-119, ¹¹⁹ Sb), Tellurium-118, 123 (Tellurium-118, 123 , ¹¹⁸ Te, ¹²³ Te), Iodine-123, 124, 125, 129, 131 (Iodine-123, 124, 125, 129, 131, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I, ¹³¹ I), Barium- 131, 140 (Barium-131, 140, ¹³¹ Ba, ¹⁴⁰ Ba), Lanthanum-140 (Lanthanum-140, ¹⁴⁰ La), Cesium-137 (Cesium-137, ¹³⁷ Ce), Gadolinium-149, 151 (Gadolinium- 149, 151, ¹⁴⁹ Gd, ¹⁵¹ Gd), Samarium-153 (Samarium-153, ¹⁵³ Sm) Dysprosium-159, 165 (Dysprosium-159, 165, ¹⁵⁹ Dy, ¹⁶⁵ Dy), Terbium-160 (Terbium-160, ¹⁶⁰ Tb), Holmun-166 ( ¹⁶⁶ Ho), Erbium-169 (Erbium-169, ¹⁶⁹ Er), Ytterbium-169, 177 (Ytterbium-169, 177, ¹⁶⁹ Yb, ¹⁶⁹ Yb), Lutetium-177 ( ¹⁷⁷ Lu), Rhenium-186, 188 (Rhenium-186, 188, ¹⁸⁶ Re, ¹⁸⁸ Re), Iridium-192 (Iridium-192, ¹⁹² Ir), Gold-198 , 199 (Gold-198, 199, ¹⁹⁸ Au, ¹⁹⁹ Au), thallium-201, 204 (Thallium-201, 204, ²⁰¹ Tl, ²⁰⁴ Tl), lead-210 (Lead-210, ²¹⁰ Pb), bismuth-213 (Bismuth-213, ²¹³ Bi), Astatine-211 (Astatine-211, ²¹¹ At), Radium-223, 224, 226 (Radium-223, 224, 226, ²²³ Ra, ²²⁴ Ra, ²²⁶ Ra), Actinium-225 (Actinium-225, ²²⁵ Ac), and combinations thereof, radioisotope-containing metal bilayer hydroxide hybrid.
The method according to claim 3 or 4,
Chelating material comprising the radioisotope is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, diethylenetriamine pentaacetate, 1,4,7,10- A radioisotope-containing metal, comprising a chelate selected from the group consisting of tetraazacyclododecane-1,4,7,10-tetraacetic acid, chelates containing carboxylate functional groups, and combinations thereof Double layer hydroxide hybrids.
The method of claim 1,
Wherein said radioisotope-containing metal bilayer hydroxide hybrid has a size between 5 nm and 10 μm.
The method of claim 1,
Wherein said radioisotope-containing metal bilayer hydroxide hybrid is capable of cancer treatment and / or cancer diagnosis.
Mixing an aqueous solution containing metal salts containing metal-based elements forming a metal double layer hydroxide with an aqueous solution containing at least one radioisotope, and then reacting the mixed solution with a base solution; And
Hydrothermal synthesis of the reacted mixed solution to form a metal bilayer hydroxide comprising the radioactive isotopes in a lattice and / or between layers
A method for producing a radioisotope-containing metal bilayer hydroxide hybrid comprising a.
Mixing an aqueous solution containing metal salts containing metal-based elements forming a metal double layer hydroxide with an aqueous solution containing at least one radioisotope, and then reacting the mixed solution with a base solution;
Hydrothermally synthesizing the reacted mixed solution to form a metal bilayer hydroxide comprising the radioisotope in a lattice and / or between layers; And
Ion of radioisotopes, chelates containing radioisotopes, or polyatomic ions comprising radioisotopes in an ion exchange method between the layers of metal bilayer hydroxides containing the formed radioisotopes in a lattice and / or between layers Step by insert
A method for producing a radioisotope-containing metal bilayer hydroxide hybrid comprising a.
The method according to claim 13 or 14,
The step of reacting the mixed solution with a base solution is carried out for at least 5 minutes, the method for producing a radioisotope-containing metal double layer hydroxide hybrid.
The method according to claim 13 or 14,
Method for producing a radioisotope-containing metal double layer hydroxide hybrid, wherein the metal layered double hydroxide is represented by the following formula (1):
[Formula 1]
[M ²⁺ _(1-x) M ³⁺ _x (OH ⁻ ) ₂ ] ^{x +} [(A ⁿ⁻ ) _{x / n} yH ₂ O] ^x- ;
In the above formula,
M ²⁺ is a divalent metal cation + ^{2, Ni 2 +, Mg 2 +} , Ca 2 +, Zn 2 +, Mn 2 +, Co 2 +, Fe 2 +, Cu 2 +, Cd 2 +, and their A metal cation selected from the group consisting of combinations,
M ³⁺ is a +3 valent metal cation, Fe ^{+ 3,} Al ^{+ 3,} Cr ^{+ 3,} Mn ^{+ 3,} Ga ^{+ 3,} Co ^{+ 3,} Ni ^{+ 3,} Sc ^{+ 3,} La ^{+ 3,} V ³⁺ , Sb ^{+ 3,} Y ^3+, in ^{+ 3,} Ti ^{+ 3,} Y ^3+, Gd ^{3 +,} (Lu ^{+ 3,} and is to include a metal cation selected from the group consisting of the combinations thereof,
A ^n- is Cl ^- is an anion selected from, CO ₃ ^2-, SO ^2-, and the group consisting of a combination thereof, ^-, Br ^-, NO ₃
0≤x <1,
n is an integer from 1 to 3,
y is a number from 0.1 to 20.
The method according to claim 13 or 14,
The radioisotope located within the lattice of the metal bilayer hydroxide is oxygen-15 (Oxygen-15, ¹⁵ O), calcium-47 (Calcium-47, ⁴⁷ Ca), scandium-46 (Scabduyn-46, ⁴⁶ Sc), Chromium-51, 57, ⁵¹ Cr, ⁵⁷ Cr), Cobalt-57, 60 (Cobalt-57, 60, ⁵⁷ Co, ⁶⁰ Co), Manganese-54 (Manganese-54, ⁵⁴ Mn), Iron-55, 59 (Iron-55, 59, ⁵⁵ Fe , ⁵⁹ Fe), Nickel-63 (Nikel-63, ⁶³ Ni), Copper-61, 64, 67 (copper-61, 64, 67, ⁶¹ Cu, ⁶⁴ Cu, ⁶⁷ Cu), Zinc-65 (Zinc-65 , ⁶⁰ Zn), Gallium-67, 68 (Gallium-67, 68, ⁶⁷ Ga, ⁶⁸ Ga), Germanium-68 (Germanium-68, ⁶⁸ Ge) Selenium-75 (Selenium-75, ⁷⁵ Se), Rubidium- 82 (Rubidium-82, ⁸² Ru), Strontium-82, 85, 89, 90 (Strontium-82, 85, 89, 90, ⁸² Sr, ⁸⁵ Sr, ⁸⁹ Sr, ⁹⁰ Sr), Yttrium-90 (Yttrium-90, ⁹⁰ Y), Ruthenium-97, 103 (Ruthenium-97, 103, ⁹⁷ Ru, ¹⁰³ Ru), Molybdenum-99 (Molybdenum-99, ⁹⁹ Mo), Technetium -99m (Technetium-99m, ^99m Tc), Palladium-103 (Palladium-103, ¹⁰³ Pd), Indium-111 (Indium-111, ¹¹¹ In), Silver-110m (Silver-110m, ^110m Ag), Cadmium-109 , 115 (Cadmium-109, 115, ¹⁰⁹ Cd, ¹¹⁵ Cd), tin-117, 113 (Tin-117, 113, ¹¹⁷ Sn, ¹¹³ Sn), antimony-119 (Antimony-119, ¹¹⁹ Sb), tellurium- 118, 123 (Tellurium-118, 123, ¹¹⁸ Te, ¹²³ Te), Barium-131, 140 (Barium-131, 140, ¹³¹ Ba, ¹⁴⁰ Ba), Lanthanum-140 (Lanthanum-140, ¹⁴⁰ La), Cesium -137 (Cesium-137, ¹³⁷ Ce), Gadolinium-149, 151 (Gadolinium-149, 151, ¹⁴⁹ Gd, ¹⁵¹ Gd), Samarium-153 (Samarium-153, ¹⁵³ Sm) Dysprosium-159, 165 (Dysprosium-159 , 165, ¹⁵⁹ Dy, ¹⁶⁵ Dy), Terbium-160 (Terbium-160, ¹⁶⁰ Tb), Holmium-166 (Holmiun-166, ¹⁶⁶ Ho), Erbium-169 (Erbium-169, ¹⁶⁹ Er), Ytterbium-169 , 177 (Ytterbium-169, 177, ¹⁶⁹ Yb, ¹⁶⁹ Yb), Lutetium-177 (Lutetium-177, ¹⁷⁷ Lu), Rhenium-186, 188 (Rhenium-186, 18 8, ¹⁸⁶ Re, ¹⁸⁸ Re), Iridium-192, ¹⁹² Ir), Gold-198, 199 (Gold-198, 199, ¹⁹⁸ Au, ¹⁹⁹ Au), thallium-201, 204 (Thallium-201, 204, ²⁰¹ Tl, ²⁰⁴ Tl), Lead-210 (Lead-210, ²¹⁰ Pb), Bismuth-213 (Bismuth-213, ²¹³ Bi), Astatin-211 (Astatine-211, ²¹¹ At), Radium-223, 224 , 226 (Radium-223, 224, 226, ²²³ Ra, ²²⁴ Ra, ²²⁶ Ra), actinium-225 (Actinium-225, ²²⁵ Ac), and combinations thereof, A method of making a radioisotope-containing metal double layer hydroxide hybrid.
The method according to claim 13 or 14,
The radioisotope located between the layers of the metal bilayer hydroxide is carbon-11, 14 (Carbon-11, 14, ¹¹ C, ¹⁴ C), nitrogen-13 (Nitrogen-13, ¹³ N), oxygen-15 (Oxygen -15, ¹⁵ O), Fluorine-18 ( ¹⁸ F), Chlorine-36, Sodium-22, 24 (Sodium-22, 24, ²² Na, ²⁴ Na), Phosphorus-32 , 33 (Phosphorus-32, 33, ³² P, ³³ P), sulfur-35 (Sulphur-35, ³⁵ S), potassium-42, 43 (Potassium-42, 43, ⁴² K, ⁴³ K), calcium-47 (Calcium-47, ⁴⁷ Ca), Scandium-46 (Scabduyn-46, ⁴⁶ Sc), Chromium-51, 57 (Chromium-51, 57, ⁵¹ Cr, ⁵⁷ Cr), Cobalt-57, 60 (Cobalt-57, 60, ⁵⁷ Co, ⁶⁰ Co), manganese-54 (Manganese-54, ⁵⁴ Mn), iron-55, 59 (Iron-55, 59, ⁵⁵ Fe, ⁵⁹ Fe), Nickel-63 (Nikel-63, ⁶³ Ni), Copper-61, 64, 67 (copper-61, 64, 67, ⁶¹ Cu, ⁶⁴ Cu, ⁶⁷ Cu), Zinc-65 (Zinc -65, ⁶⁰ Zn), Gallium-67, 68 (Gallium-67, 68, ⁶⁷ Ga, ⁶⁸ Ga), Germanium-68 (Germanium-68, ⁶⁸ Ge) Selenium-75 (Selenium-75, ⁷⁵ Se), Rubidium-82 ( ⁸² Ru), Strontium-82, 85, 89, 90 (Strontium-82, 85, 89, 90, ⁸² Sr, ⁸⁵ Sr, ⁸⁹ Sr, ⁹⁰ Sr), yttrium-90 (Yttrium-90, ⁹⁰ Y), ruthenium-97, 103 (Ruthenium-97, 103, ⁹⁷ Ru, ¹⁰³ Ru), molybdenum-99 (Molybdenum-99 , ⁹⁹ Mo), Technetium-99m ( ^99m Tc), Palladium-103 (Palladium-103, ¹⁰³ Pd), Indium-111 (Indium-111, ¹¹¹ In), Silver-110m (Silver-110m, ^110m Ag), cadmium-109, 115 (Cadmium-109, 115, ¹⁰⁹ Cd, ¹¹⁵ Cd), Tin-117, 113 (Tin-117, 113, ¹¹⁷ Sn, ¹¹³ Sn), Antimony-119 (Antimony-119, ¹¹⁹ Sb), Tellurium-118, 123 (Tellurium-118, 123 , ¹¹⁸ Te, ¹²³ Te), Iodine-123, 124, 125, 129, 131 (Iodine-123, 124, 125, 129, 131, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I, ¹³¹ I), Barium- 131, 140 (Barium-131, 140, ¹³¹ Ba, ¹⁴⁰ Ba), Lanthanum-140 (Lanthanum-140, ¹⁴⁰ La), Cesium-137 (Cesium-137, ¹³⁷ Ce), Gadolinium-149, 151 (Gadolinium- 149, 151, ¹⁴⁹ Gd, ¹⁵¹ Gd), Samarium-153 (Samarium-153, ¹⁵³ Sm) Dysprosium-159, 165 (Dysprosium-159, 165, ¹⁵⁹ Dy, ¹⁶⁵ Dy), Terbium-160 (Terbium-160, ¹⁶⁰ Tb), Holmun-166 ( ¹⁶⁶ Ho), Erbium-169 (Erbium-169, ¹⁶⁹ Er), Ytterbium-169, 177 (Ytterbium-169, 177, ¹⁶⁹ Yb, ¹⁶⁹ Yb), Lutetium-177 ( ¹⁷⁷ Lu), Rhenium-186, 188 (Rhenium-186, 188, ¹⁸⁶ Re, ¹⁸⁸ Re), Iridium-192 (Iridium-192, ¹⁹² Ir), Gold-198 , 199 (Gold-198, 199, ¹⁹⁸ Au, ¹⁹⁹ Au), thallium-201, 204 (Thallium-201, 204, ²⁰¹ Tl, ²⁰⁴ Tl), lead-210 (Lead-210, ²¹⁰ Pb), bismuth-213 (Bismuth-213, ²¹³ Bi), Astatine-211 (Astatine-211, ²¹¹ At), Radium-223, 224, 226 (Radium-223, 224, 226, ²²³ Ra, ²²⁴ Ra, ²²⁶ Ra), Actinium-225 (Actinium-225, ²²⁵ Ac), and combinations thereof, the method for producing a radioisotope-containing metal double layer hydroxide hybrid.

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