KR20210047171A - PET-MRI contrast agent and preparation method thereof - Google Patents

Abstract

The present invention relates to a dual-modality positron emission tomography (PET)-magnetic resonance imaging (MRI) contrast agent and a method for manufacturing the same, wherein the PET-MRI contrast agent of the present invention contains a nanocomposite particle including a magnetic metal element and a radionuclide, and a hydrophilic coating layer on the surface of at least a portion of the nanocomposite particle. The present invention can provide stable, high-sensitivity, and high-precision PET-MRI dual-mode imaging information with high accuracy.

Description

PET-MRI contrast agent and preparation method thereof TECHNICAL FIELD

The present invention relates to a dual-modality positron emission tomography (PET)-magnetic resonance imaging (MRI) contrast medium and a method of manufacturing the same.

The PET-MRI nuclear medicine diagnostic technology, which began to be developed in the late 2000s, started with hardware research and development, and led to the development of a new contrast agent related thereto from the 2010s, and studies on the application of nuclear medical evaluation of various cancer cells using the same have been conducted.

Recently, research in the field of PET-MRI contrast agents is mainly on the synthesis of combinations of magnetic materials for MRI imaging, radioactive materials for PET imaging, and carrier materials that direct the contrast agent to the target cell tissue.

The study of the MRI image-compatible material uses nanoparticles with a size of about 10 nm, which synthesizes nanomagnetic materials based on Fe and Gd elements, and is a complex function for reducing material stability and toxicity of nanomaterials through surface modification of magnetic materials. Compound development is the main focus, and research on PET image-compatible materials is mainly focused on the development of radiolabeled compounds in the form of chelate compounds using radioactive isotopes that emit β+. And by pre-synthesizing these chelate compounds based on heterocyclic compounds or acetate compounds with nanoparticles for MRI imaging, a cold (non-radioactive) type kit is prepared, and radiolabeling (RI) before use of the contrast agent. Research and development is in progress in a way to use it (Fig. 1).

The focus of current research and development is in the form of a combination of conventional MRI and PET contrast agent compounds, and these complex molecular contrast agents have a large molecular shape of the product, and the ligand-coordinated compound causes structural changes due to the influence of the surrounding environment. The molecular bonding stability is relatively weak. In particular, various ion concentrations and pH environments in a living body environment may frequently stimulate the binding structure of such a ligand compound, thereby causing a structural change. Accordingly, various problems such as separation of the RI-labeled compound and the MRI-labeled compound, separation of the migration tracer, and decomposition of magnetic substances have been discovered in the clinical trial stage. Eventually, RI images are observed in normal cells other than target cancer cells, resulting in accurate lesions. There have even been reports of problems that cause the state of being unable to discriminate. Accordingly, it is time for a new solution to overcome these difficulties.

The present invention is to provide a new type of PET-MRI contrast medium that can overcome the limitations of the prior art.

An object of the present invention is to solve the problem that magnetic materials for MRI images and radioactive materials for PET images are physically spaced apart from each other by mixing a magnetic material and a radioactive material in one core part, so that they are separated according to an external environment.

Accordingly, it is intended to provide an accurate image as it is stable against changes in the external environment, and radioactivity and magnetism can be confirmed at the same location.

In addition, a magnetic material and a radioactive material are not linked by a ligand binding, that is, to provide a contrast medium whose size is reduced because it does not contain a ligand. In addition, it is intended to provide a contrast agent that facilitates introduction of other substitution materials by reducing the particle size of the contrast agent itself.

In order to achieve the above object, an aspect of the present invention provides a PET-MRI contrast medium comprising a nanocomposite particle including a magnetic metal element and a radionuclide, and a hydrophilic coating layer on the surface of at least a portion of the nanocomposite particle.

One aspect of the present invention is a step of forming a nanocomposite particle by hydrothermal reaction using a mixture of a material containing a magnetic metal element and a material containing a radionuclide, and coating at least a portion of the surface of the nanocomposite particle with a hydrophilic coating material. It provides a method for preparing a PET-MRI contrast medium comprising a.

The contrast agent of the present invention may simultaneously contain a magnetic element for an MRI image and a radioactive element for a PET image, thereby providing stable, high-sensitivity, high-precision PET-MRI dual-mode imaging information with high accuracy.

In addition, due to its high stability in aqueous solution, it can be very useful for non-invasive high-sensitivity real-time imaging of various biological events such as cell migration, diagnosis of various diseases (eg, cancer diagnosis), and drug delivery.

In addition, the contrast agent of the present invention includes both magnetic elements and radioactive elements, has nano-sized particles, and has an effect of improving biocompatibility through a coating layer on the surface of the particles.

In addition, the contrast agent of the present invention does not contain a separate chelator for combining the magnetic element and the radioactive element, so in the prior art to contain the magnetic element and the radioactive element in one molecule by the chelator, the magnetic element and the It can solve the problem of separating radioactive elements.

The following drawings attached to the present specification illustrate preferred embodiments of the present invention, and serve to further understand the technical idea of the present invention together with the contents of the present invention. It is limited and should not be interpreted.
1 is a schematic diagram of the basic structure of a conventional PET-MRI contrast medium. Specifically, 1. Magnetic nanoparticles for MRI images, 2. Molecular skeleton organic compounds, 3. Selective target-oriented functional groups, 4. Radioactive isotope-labeled compounds for PET images.
Figure 2 shows a schematic diagram of the synthesis route of the nanocomposite particles containing radioactive Cu and magnetic Fe. Here, RMNP stands for Radioactive Magnetic Nano Particles.
3 shows an SEM image of Cu and Fe-containing nanocomposite particles. In order to compare the particle distribution size on the SEM image, a red line was used along with the dimensions.
4 shows a graph of the particle size analysis results of the nanocomposite particles.
5 shows a TEM image of the prepared PET-MRI contrast medium.

Hereinafter, the present invention will be described in detail.

The PET-MRI contrast agent of the present invention includes a nanocomposite particle containing a magnetic metal element and a radionuclide, and a hydrophilic coating layer on the surface of at least a portion of the nanocomposite particle.

The PET-MRI contrast agent may have a core/shell structure including a core portion made of the nanocomposite particles and a shell portion made of a hydrophilic coating layer covering the surface of the core portion.

The nanocomposite particle includes a magnetic metal element and a radionuclide, wherein the atomic ratio of the magnetic metal element and the radionuclide may be 1:1 to 10:1, specifically 1:1 to 9:1, 2:1 To 8:1, 3:1 to 7:1, 4:1 to 6:1, such as 5:1. When the core portion is formed, particles may be formed around the magnetic metal element, and thus the concentration gradient of the magnetic metal element increases toward the center of the core portion. The principle of forming the PET-MRI contrast agent of the present invention is not limited thereto.

The magnetic metal element may be selected from transition metal elements, but is not limited thereto, for example, scandium (Sc), titanium (Ti), vanadium (V), chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), yttrium (Y), zirconium (Zr), niobium (Nb), molybdenum (Mo), technetium (Tc), ruthenium (Ru) , Rhodium (Rh), palladium (Pd), silver (Ag), hafnium (Hf), tantalum (Ta), tungsten (W), rhenium (Re), osmium (Os), iridium (Ir), platinum (Pt) ) And gold (Au). Specifically, the magnetic metal element may be Fe.

The radionuclide may be selected from the group consisting of metallic radioactive isotopes and non-metallic radioactive isotopes, and specifically, those selected from metallic radioactive isotopes may be used, but the present invention is not limited thereto.

The metallic radioactive isotopes are gallium (Ga), copper (Cu), gold (Au), lead (Pb), nickel (Ni), dysprosium (Dy), radium (Ra), lanthanum (La), and rhenium (Re ), rubidium Ru), lutetium (Lu), manganese (Mn), molybdenum (Mo), bismuth (Bi), samarium (Sm), cesium (Ce), sodium (Na), scandium (Sc), strontium (Sr), americium (Am), zinc (Zn), erbium (Er), uranium (U), silver (Ag), iridium (Ir), ytterbium (Yt), indium (In), germanium (Ge) , Xenon (Xe), iron (Fe), cadmium (Cd), californium (Cf), calcium (Ca), cobalt (Co), curium (Cm), chromium (Cr), krypton (Kr), thallium (Tl) ), technetium (Tc), tungsten (W), thorium (Th), palladium (Pa), potassium (K), polonium (Po), promethium (Pm), plutonium (Pu) and holmium (Ho) It may be an element of choice. The metallic radioactive isotopes are, for example, Ga-67, Ga-68, Cu-64, Cu-67, Au-198, Pb-210, Ni-63, Dy-165, Ra-226, La-140, Re -186, Re-188, Ru-82, Lu-177, Mn-54, Mo-99, Bi-213, Sm-153, Ce-137, Na-24, Sc-46, Sr-82, Sr-85 , Sr-89, Sr-90, Am-241, Zn-65, Er-169, U-234, U-235, U-238, Ag-110m, Ir -192, Ir -169, Ir -177, Yt -169, Yt-177, In-111, Ge-68, Fe-55, Cd-109, Ca-47, Cf-252, Co-57, Co-60, Cm-244, Cr-51, Cr-57 , Kr-81, Kr-85, Tl-201, Tl-204, Tc-99m, Th-229, Th-230, Pd-103, K-42, Po-210, Pm-147, Pu-238, Hp -166, Ac-225, Ra-223, and the like. Specifically, the metallic radioactive isotope may be Cu-64, Cu-67, Ge-68, or a mixture thereof, and more specifically, Cu-64, Cu-67, or a mixture thereof.

The non-metallic radioactive isotopes are fluorine (F), oxygen (O), chlorine (Cl), iodine (I), nitrogen (N), selenium (Se), carbon (C), phosphorus (P), and sulfur. It may be an element selected from the group consisting of (S) and tritium (T). The non-metallic radioactive isotopes are, for example, F-18, O-15, Se-75, Cl-36, I-123, I-124, I-125, I-129, I-131, N-13, It may be C-11, C-14, P-32, P-33, S-35, or mixtures thereof.

In the present invention, it is preferable to use a combination of elements different from each other as the magnetic metal element and the radionuclide. For example, the magnetic metal element may be Fe, the radionuclide may be Cu, Mn, or a mixture thereof, more preferably the magnetic metal element may be Fe, and the radionuclide may be Cu.

The nanocomposite particle including the magnetic metal element and a radionuclide may be spherical, elliptical, or needle-shaped, and specifically, may be spherical.

The average particle size (D50) of the spherical nanocomposite particles may be 0.1 to 150 nm, and specifically, it may be preferably 1 to 10 nm.

The nanocomposite particles may have a hydrophobic surface due to the hydrophobic surfactant used when forming the nanocomposite particles. Since the PET-MRI contrast agent according to the present invention can be finally administered and used in a living body, it must be stably dispersed in an aqueous solution, and thus may include a hydrophilic coating layer to impart hydrophilicity to the surface of the nanocomposite particles. .

Specifically, the PET-MRI contrast agent includes a hydrophilic coating layer on at least a portion of the surface of the core portion. Preferably, a hydrophilic coating layer may be coated on the entire surface of the core part.

By including the hydrophilic coating layer, it is possible to improve the hydrophilicity of the contrast agent, and when the contrast agent is administered to a living body, it is possible to prevent the nanocomposite particles of the core part from directly contacting the living body.

Accordingly, in consideration of biocompatibility, the hydrophilic coating layer may preferably be a coating layer containing _{silicon dioxide (SiO 2} ), and specifically, may be a coating layer made _{of silicon dioxide (SiO 2 ).} The hydrophilic coating layer may be formed of a silane-based compound. This will be described in more detail in the following method for producing a contrast agent.

The average particle size (D50) of the PET-MRI contrast agent may be 1 to 500 nm, specifically 1 to 200 nm, 1 to 150 nm, 1 to 100 nm, or 1 to 50 nm.

The PET-MRI contrast agent is a biologically active substance, such as an antibody, protein, antigen, peptide, nucleic acid, enzyme, cell, etc., or chemical activity to further impart a function other than contrast (eg, cancer diagnosis/treatment). A substance, for example, a single molecule, a polymer, an inorganic support, a phosphor, or a drug may be combined. For example, the functional imparting material may be chemically bonded to the hydrophilic coating layer, for example, through a covalent bond or an ionic bond.

The PET-MRI contrast agent according to the present invention has the effect of obtaining both PET and MRI images, and the PET-MRI contrast agent contains radionuclides in the core part, so that the radioactive material was labeled immediately before use. It can exhibit more useful properties. In addition, there is an effect of showing excellent dispersibility and uniformity in aqueous solution, including the hydrophilic coating layer on the surface.

Hereinafter, a method of manufacturing the PET-MRI contrast medium of the present invention will be described.

The manufacturing method of the PET-MRI contrast agent of the present invention comprises the steps of forming nanocomposite particles by hydrothermal reaction using a mixture of a material containing a magnetic metal element and a material containing a radionuclide, and at least a part of the nanocomposite particles as a hydrophilic coating material. And covering the surface of the.

In the material containing the magnetic metal element, the magnetic metal element is the same as described above in the PET-MRI contrast medium, and thus a description thereof will be omitted.

In the radionuclide-containing material, the radionuclide is the same as described above in the PET-MRI contrast medium, and thus a description thereof will be omitted.

As in the PET-MRI contrast medium, the magnetic metal element and the radionuclide are preferably elements different from each other.

The magnetic metal element-containing material and the radionuclide-containing material are not limited thereto, but, for example, metal acetylacetonate may be used independently of each other.

For example, when an iron (Fe) element is used as the magnetic metal element, the magnetic metal element-containing material may be iron acetylacetonate.

The hydrothermal reaction is not limited thereto, and may be performed at, for example, 100 to 500°C, for example, performed at a temperature of 100 to 400°C, 150 to 300°C, 150 to 250°C, such as 200°C. Can be.

The hydrothermal reaction is not limited thereto, and may be performed at the temperature for 30 minutes to 24 hours, for example, 30 minutes to 12 hours, 30 minutes to 6 hours, 30 minutes to 4 hours, 1 hour It may be performed for 3 hours, for example, 2 hours.

As the hydrophilic coating material for forming the hydrophilic coating layer, it may be preferable to use a silane-based compound in consideration of biocompatibility, and the silane-based compound may be a compound represented by Formula 1 below.

[Formula 1]

In Formula 1,

R ₁ to R ₄ are each independently selected from hydrogen, a C ₁ to C ₂₀ alkyl group, a C ₂ to C ₂₀ alkenyl group, and a C ₁ to C ₂₀ alkoxy group.

Specifically, R ₁ to R ₄ may each independently be a C ₁ to C ₂₀ alkoxy group, and more specifically, R ₁ to R ₄ may be an ethoxy group.

Hereinafter, examples, etc. will be described in detail to aid understanding of the present invention.

Example. Synthesis of PET-MRI contrast agent

[Formation of nanocomposite particles containing radioactive Cu and magnetic Fe]

0.261 g (1 mmol) of Cu(acac) ₂ , 0.352 g (1 mmol) of Fe(acac) ₃ , 1.292 g (5 mmol) of 1,2-hexadikendiol, 0.7 mL (3 mmol) of La Uric acid and dodecylamine (3 mmol) were dissolved in 10 mL diphenyl ether solvent under argon gas, and then refluxed at 200° C. for 2 hours to perform a hydrothermal reaction.

Here, Cu was used in the form of Cu-64, Cu-67, or a mixture thereof.

After the synthesis was completed, it was cooled to room temperature, and 20 mL isopropyl alcohol was added to induce a precipitation reaction to form nanocomposite particles, and then centrifuged at 15,000 rpm for 10 minutes using a centrifuge to recover the nanoparticle precipitate. The recovered precipitate was dispersed by adding 10 mL of hexane again, and then 35 mL of isopropyl alcohol was added to wash the organic solvent and residual organic substances used in the synthesis.

After the washing process was completed, the nanoparticles were dispersed again and centrifuged for 10 minutes at 15,000 rpm in a centrifuge to separate the solution and the precipitate again.

After repeating the solvent washing operation 3 times, the final precipitate was collected, 3 mL hexane was added, transferred to a cap vial, dispersed again, and dried in vacuum to remove the solvent, thereby containing Cu and Fe nanocomposite having a _{size of 8 nm (D 50 ).} The particles were synthesized.

2 shows a schematic for the synthesis of Cu and Fe-containing nanocomposite particles.

As a result of ICP-MS analysis of the atomic ratio in the nanocomposite particles, it was confirmed that the Fe:Cu was contained in a ratio of 5:1.

[Formation of hydrophilic coating layer on the surface of nanocomposite particles]

In the case of the nanocomposite particles synthesized above, the functional groups of lauric acid (surfactant) are adsorbed on the surface, and thus have a hydrophobic surface characteristic. Therefore, when applied in vivo, since non-polar surface molecules have a problem of dispersibility in aqueous solution, in order to modify the surface polarity from hydrophilic to polarity, a hydrophilic coating material (TEOS, Tetraethylorthosilicate) is used to form a hydrophilic coating layer and the nanocomposite particles are cored. A contrast agent having a core/shell structure was prepared with a negative and a hydrophilic coating layer as a shell portion.

Specifically, the Cu and Fe-containing nanocomposite particles prepared above were dispersed in cyclohexane at a concentration of 0.8 g/mL. 0.56 mmol polyethylene nonylphenyl ether (Igepal CO-520) was added to 25 mL of cyclohexane and dispersed using ultrasonic waves. To the solution in which nonylphenol ethoxylate (Igepal ^® CO-520) was dispersed, 300 μL of Cu and Fe-containing composite nanoparticles were added, followed by stirring. Thereafter, 35 μL of aqueous ammonia (29.4%) and 20 μL of TEOS were sequentially added to the solution, followed by reaction for 16 hours at room temperature under argon gas, and then 3 mL of methanol was added to move the nanocomposite particles containing Cu and Fe to the methanol layer. To terminate the reaction.

After centrifugation at 15,000 rpm for 10 minutes, the washing process of dispersing the precipitate in 25 mL of ethanol was repeated three times, and then the precipitate obtained in the last process was dispersed in anhydrous ethanol, and the nanocomposite particles containing Cu and Fe (core)/SiO ₂ coating layer ( Shell) was prepared.

Experimental Example 1-1. Evaluation of physical properties of Cu and Fe-containing nanocomposite particles

[Particle distribution analysis-TEM image]

The TEM image of the Cu and Fe-containing nanocomposite particles prepared above is shown in FIG. 3.

As can be seen in FIG. 3, it was confirmed that the shape of the nanocomposite particles was distributed as small particles in the range of 5 to 7 nm.

In addition, as in the result of analyzing the TEM image in the particle size analyzer analysis of the nanocomposite particles in FIG. 4, it was confirmed that Cu and Fe-containing nanocomposite particles were prepared in the form of distribution of small particles having a size of about 4 to 10 nm.

[Elemental analysis in nanocomposite particles]

The composition of the prepared Cu and Fe-containing nanocomposite particles was confirmed through EDX analysis, and the results are shown in FIG. 5 and Table 1.

As can be seen in FIG. 5 and Table 1, it was confirmed that the Cu element and the Fe element were simultaneously present in the prepared nanocomposite particles. Specifically, it was confirmed that the present equivalent ratio of Fe:Cu has a molar ratio of 5:1.

Element Line type Apparent Concentration k Ratio Wt% Wt% Sigma Standard Label Factory Standard C K series 0.35 0.00353 28.53 0.47 C Vit Yes O K series 1.82 0.00614 39.03 0.33 SiO2 Yes Na K series 0.13 0.00054 2.65 0.09 Albite Yes Al K series 0.04 0.00031 0.97 0.04 Al2O3 Yes Si K series 0.59 0.00466 12.36 0.12 SiO2 Yes S K series 0.01 0.00011 0.28 0.03 FeS2 Yes K K series 0.09 0.00079 1.82 0.04 KBr Yes Ti K series 0.03 0.00034 0.82 0.04 Ti Yes Fe K series 0.29 0.00286 6.94 0.13 Fe Yes Cu L series 0.06 0.00061 2.80 0.19 Cu Yes Zn L series 0.07 0.00071 3.26 0.21 Zn Yes Zr L series 0.02 0.00019 0.54 0.08 Zr Yes Total 100.00

Experimental Example 1-2. Synthesis analysis of PET-MRI contrast agent

5 shows a TEM image of the PET-MRI contrast medium including the hydrophilic coating layer prepared above.

As can be seen in FIG. 5, it was confirmed that a contrast agent in the form of spherical particles having a size of 40 nm (±5 nm) was prepared.

Claims (19)

A PET-MRI contrast agent comprising a nanocomposite particle comprising a magnetic metal element and a radionuclide, and a hydrophilic coating layer on the surface of at least a portion of the nanocomposite particle. The method according to claim 1,
A core part made of the nanocomposite particles; And PET-MRI contrast agent having a core / shell structure comprising a shell portion made of the hydrophilic coating layer covering the surface of the core portion. The method according to claim 1,
The PET-MRI contrast medium in which the concentration of the magnetic metal element increases as the nanocomposite particles go toward the center. The method according to claim 1,
The magnetic metal element is a PET-MRI contrast agent selected from transition metal elements. The method according to claim 1,
The radionuclide is a PET-MRI contrast agent selected from the group consisting of metallic radioactive isotopes and non-metallic radioactive isotopes. The method according to claim 1,
PET-MRI contrast agent that the magnetic metal element and the radionuclide are elements different from each other. The method according to claim 1,
The magnetic metal element is a PET-MRI contrast agent containing Fe element. The method according to claim 1,
The radionuclide is a PET-MRI contrast agent containing the element Cu. The method according to claim 1,
PET-MRI contrast agent that the hydrophilic coating layer contains silicon dioxide. The method according to claim 1,
The PET-MRI contrast agent in the nanocomposite particle, wherein the atomic ratio of the magnetic metal element and the radionuclide is 1:1 to 10:1. The method according to claim 1,
The PET-MRI contrast agent that the nanocomposite particles have an average particle diameter (D50) of 0.1 to 150 nm. The method according to claim 1,
PET-MRI contrast medium having an average particle diameter (D50) of 1 to 500 nm. Forming nanocomposite particles by hydrothermal reaction using a mixture of a material containing a magnetic metal element and a material containing a radionuclide; And
Coating the surface of at least a portion of the nanocomposite particles with a hydrophilic coating material; Method for producing a PET-MRI contrast medium comprising. The method of claim 13,
The method of manufacturing a PET-MRI contrast medium wherein the magnetic metal element-containing material and the radionuclide-containing material are each independently metal acetylacetonate. The method of claim 13,
The hydrothermal reaction is a method of producing a PET-MRI contrast medium to be carried out at 100 to 500 ℃ 30 minutes to 24 hours. The method of claim 13,
The method of manufacturing a PET-MRI contrast medium that the magnetic metal element and the radionuclide are different elements from each other. The method of claim 13,
The hydrophilic coating material is a method of manufacturing a PET-MRI contrast medium of a silane-based compound. The method of claim 17,
The silane-based compound is a method of manufacturing a PET-MRI contrast agent that is a compound represented by the following formula (1).
[Formula 1]

In Formula 1,
R ₁ to R ₄ are each independently selected from hydrogen, a C ₁ to C ₂₀ alkyl group, a C ₂ to C ₂₀ alkenyl group, and a C ₁ to C ₂₀ alkoxy group. The method of claim 18,
The R ₁ to R ₄ is an ethoxy group is a method for producing a PET-MRI contrast medium.

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