KR20240035781A - Pharmaceutical composition including nanozyme and method for preventing or treating proliferative diseases using the same - Google Patents

Abstract

The present application relates to a pharmaceutical composition containing nanozyme and a method for preventing or treating proliferative diseases using the same.

Description

Pharmaceutical composition containing nanozyme and method for preventing or treating proliferative diseases using the same {PHARMACEUTICAL COMPOSITION INCLUDING NANOZYME AND METHOD FOR PREVENTING OR TREATING PROLIFERATIVE DISEASES USING THE SAME}

The present application relates to a pharmaceutical composition containing nanozyme and a method for preventing or treating proliferative diseases using the same.

A single-atom catalyst (SAC) is used as a single metal atom center for catalysis, and impregnation of the metal is generally accomplished through coordination chemistry. In the monoatomic catalyst, N-ligand, O-ligand, P-ligand and S-ligand are most commonly used. Zero-dimensional monoatomic catalysts currently have efficiencies that surpass heterogeneous catalysts and have the advantage of being less active but more stable than homogeneous catalysts. Monatomic catalysts can be used in fuel cells, water splitting, N ₂ or CO ₂ reduction, and/or biomedical applications.

Specifically, monoatomic catalysts can maximize atom utilization to possess high selectivity and reactivity; Insoluble and/or inexpensive supports (eg, carbon, ceria, Al ₂ O ₃ ) may be utilized; Has high recyclability; The orbital structure can be easily tuned by switching the ligand and embedded metal; and may cause different chemical reactions depending on the coordination/metal. Exemplarily, the monoatomic catalyst includes enzymes, MN/C (e.g., Fe-N/C), M@Metal Oxide (e.g., Au@Ceria), and zeolite/MOF (metal organic framework) (e.g. For example, it can be classified as Ir@Zeolite Y).

Nanozymes with enzyme-like activity based on catalytic nanomaterials are used for catalytic activities such as hydrogen peroxide decomposition and glucose oxidase enzymes, and have various biomedical applications such as anticancer treatment, antibacterial film, antioxidant, imaging, biosensing, and tissue regeneration. It is being used in the field.

International Publication No. WO 2018/186725.

The present application seeks to provide a pharmaceutical composition containing nanozyme and a method for preventing or treating proliferative diseases using the same.

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

The first aspect of the present application includes a first pharmaceutical composition in which gold nanoparticles are supported on a metal-organic framework, and a second pharmaceutical composition in which an iron atom is supported in a metal-organic framework, and is used to prevent cancer or Provided is a pharmaceutical composition for therapeutic use, wherein the central metal of the metal-organic framework is zirconium.

A second aspect of the present application is a method for preventing or treating cancer, comprising a first pharmaceutical composition in which gold nanoparticles are supported on a metal-organic framework and a second pharmaceutical composition in which an iron atom is supported in a metal-organic framework. Provided is a method for preventing or treating cancer, which includes injecting a pharmaceutical composition into the body, wherein the method is applied except for humans.

The manufacturing method of each of the first pharmaceutical composition and the second pharmaceutical composition according to the embodiments of the present application, unlike the conventional method of manufacturing MOF-based nanozyme, does not require high temperature heat treatment and is a simple chelating method. It is easy to synthesize.

According to embodiments of the present application, a pharmaceutical composition comprising the first pharmaceutical composition and the second pharmaceutical composition may have high selectivity and activity.

According to embodiments of the present application, the first pharmaceutical composition may act on mitochondria, and the second pharmaceutical composition may act on the cytoplasm.

A pharmaceutical composition comprising the first pharmaceutical composition and the second pharmaceutical composition according to embodiments of the present application can be used in the prevention or treatment of proliferative diseases.

According to embodiments of the present application, the gold nanoparticles included in the first pharmaceutical composition reduce nutrients in the malignant cells by using glucose in the malignant cells that cause proliferative disease during a glucose oxidase mimicking reaction. , it may be possible to prevent or treat proliferative diseases through starvation therapy.

Figure 1 is a schematic diagram of the synthesis of a metal organic framework (MOF) according to Example 1 of the present application.
Figure 2(a) is ¹ H-NMR data of the MOF according to Example 1 of the present application, and Figure 2(b) is a transmission electron microscope (TEM) image of the MOF.
Figure 3(a) is a schematic diagram showing the synthesis process of Au nanoparticle-MOF according to Example 2 of the present application, and Figure 3(b) is an image showing the structure of Au nanoparticle-MOF.
Figure 4(a) is the TEM images (scale bar: 50 nm, 10 nm and 5 nm) of the Au nanoparticle-MOF according to Example 2 of the present application, and Figure 4(b) is the TEM image of the Au nanoparticle-MOF. This is the UV-vis absorption spectrum.
Figure 5 shows analysis data according to X-ray photoelectron spectroscopy (XPS) of the Au nanoparticle-MOF according to Example 2 of the present application.
Figure 6(a) is a schematic diagram showing the synthesis process of Fe single atom-MOF according to Example 3 of the present application, and Figure 6(b) is an image showing the structure of Fe single atom-MOF.
Figure 7(a) is a scanning transmission electron microscopy (STEM) image of the Fe single atom-MOF according to Example 3 of the present application, and Figure 7(b) is an energy dispersive image of the Fe single atom-MOF. It shows analysis data according to X-ray spectroscopy (EDS or EDX; energy dispersive x-ray spectroscopy).
Figures 8(a) and 8(b) show the Fe 2p and N 1s of the Fe single atom-MOF according to Example 3 of the present application, respectively, according to x-ray photoelectron spectroscopy (XPS). This shows the analysis data.
Figure 9 is a schematic diagram of cancer treatment of a MOF-based nanostructure into which Au nanoparticle-MOF and Fe monatom-MOF were introduced according to Example 4 of the present application.
Figure 10 shows glucose oxidase mimicking nano samples in the control group (ctrl) where glucose was not added to the Au nanoparticle-MOF and the case where glucose was added to the Au nanoparticle-MOF (Au NP-MOF + glucose). This is a graph showing the activity of the enzyme.
Figure 11 is a graph showing the pH change in the control group where glucose was not added to the Au nanoparticle-MOF (ctrl) and when glucose was added to the Au nanoparticle-MOF (Au NP-MOF + glucose).
Figure 12 is a graph showing thiol group absorption when Au NP-MOF and glutathione are present together (Au NP-MOF + GSH) and when glutathione is not present (ctrl).
Figure 13 is an absorbance graph showing peroxidase mimicking activity in the case of reacting Fe-MOF with hydrogen peroxide (Fe-MOF + H ₂ O ₂ ) and the control group (H ₂ O ₂ ).
Figure 14 is a graph showing the formation of hydroxy radicals when Fe-MOF and hydrogen peroxide are reacted (Fe-MOF + H ₂ O ₂ ) and when hydrogen peroxide is not reacted (Fe-MOF).
Figure 15 shows control (TA + DI-water), Au NP-MOF + glucose, Fe-MOF + glucose, Au NP-MOF + Fe-MOF + glucose, Au NP-MOF, Fe-MOF and Au NP-MOF. + This is a graph showing the cascade enzymatic activity of each Fe-MOF.

Hereinafter, with reference to the attached drawings, implementation examples and embodiments of the present invention will be described in detail so that those skilled in the art can easily implement the present invention. However, the present application may be implemented in various different forms and is not limited to the implementation examples and examples described herein. In order to clearly explain the present invention in the drawings, parts that are not related to the description are omitted, and similar parts are given similar reference numerals throughout the specification.

Throughout this specification, when a part is said to be “connected” to another part, this includes not only the case where it is “directly connected,” but also the case where it is “electrically connected” with another element in between. do.

Throughout this specification, when a member is said to be located “on” another member, this includes not only the case where the member is in contact with the other member, but also the case where another member exists between the two members.

Throughout the specification of the present application, when a part “includes” a certain element, this means that it may further include other elements rather than excluding other elements, unless specifically stated to the contrary.

As used herein, the terms “about,” “substantially,” and the like are used to mean at or close to a numerical value when manufacturing and material tolerances inherent in the stated meaning are presented, and to aid understanding of the present application. It is used to prevent unscrupulous infringers from unfairly exploiting disclosures in which precise or absolute figures are mentioned.

The terms “step of” or “step of” as used throughout the specification herein do not mean “step for.”

Throughout this specification, the term "combination(s) thereof" included in the Markushi format expression means a mixture or combination of one or more selected from the group consisting of the components described in the Markushi format expression, It means containing one or more selected from the group consisting of the above components.

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

Hereinafter, embodiments of the present application have been described in detail, but the present application may not be limited thereto.

The first aspect of the present application includes a first pharmaceutical composition in which gold nanoparticles are supported on a metal-organic framework, and a second pharmaceutical composition in which an iron atom is supported in a metal-organic framework, and is used to prevent cancer or Provided is a pharmaceutical composition for therapeutic use, wherein the central metal of the metal-organic framework is zirconium.

Metal-organic framework (MOF) is a material included in microporous materials and consists of clusters of cationic metal ions connected by valent anions (linkers) that form multivalent coordination bonds. The metal-organic framework is artificially manufactured and can perform various functions such as separation of chemical species, gas storage, catalyst, drug delivery, and chemical sensor by forming a three-dimensional structure.

In one embodiment of the present application, the metal-organic framework may be UiO-67.

In one embodiment of the present application, the gold nanoparticles may exist in a metal state in the metal-organic framework, and the iron single atom may exist in a single atomic state in the metal-organic framework. It is not limited to this. Specifically, the gold nanoparticle may have an oxidation state of 0, and the iron atom may have an oxidation state of +2 or +3.

In one embodiment of the present application, a pharmaceutical composition comprising the first pharmaceutical composition and the second pharmaceutical composition may have high selectivity and activity.

In one embodiment of the present application, the iron atom may be chelated on the metal-organic framework, and the gold nanoparticle may be supported on the metal-organic framework, but is not limited thereto.

In one embodiment of the present application, the second pharmaceutical composition may have folic acid introduced as a targeting moiety.

In one embodiment of the present application, the pharmaceutical composition may have the activities of glucose oxidation enzyme and hydrogen peroxide decomposition enzyme, but is not limited thereto. Specifically, the first pharmaceutical composition may have the activity of a glucose oxidation enzyme, and the second pharmaceutical composition may have the activity of a hydrogen peroxide decomposition enzyme.

In one embodiment of the present application, the gold nanoparticles can induce the production of hydrogen peroxide to promote the Fenton reaction and induce glucose oxidase mimicking to supply an acidic environment, but are not limited thereto. Specifically, when the gold nanoparticles mimic the glucose oxidase reaction, they use glucose in the malignant cells that cause the proliferative disease, thereby reducing the nutrients of the malignant cells and reducing the proliferative disease through starvation therapy. Makes prevention or treatment possible.

In one embodiment of the present application, the iron atom may induce the Fenton reaction for generating reactive oxygen species (ROS) and induce peroxidase mimicking, but is not limited thereto.

In one embodiment of the present application, the iron atom can induce the generation of reactive oxygen species through the Fenton reaction under spontaneous replenishment of hydrogen peroxide, but is not limited thereto.

A second aspect of the present application is a method for preventing or treating cancer, comprising a first pharmaceutical composition in which gold nanoparticles are supported on a metal-organic framework and a second pharmaceutical composition in which an iron atom is supported in a metal-organic framework. Provided is a method for preventing or treating cancer, which includes injecting a pharmaceutical composition into the body, wherein the method is applied except for humans.

Detailed description of parts overlapping with the first aspect of the present application has been omitted, but the description of the first aspect of the present application can be applied equally even if the description is omitted in the second aspect of the present application.

In one embodiment of the present application, the central metal of the metal-organic framework may be zirconium.

In one embodiment of the present application, the metal-organic framework may be UiO-67.

In one embodiment of the present application, the pharmaceutical composition may be injected directly into cells, but is not limited thereto.

In one embodiment of the present application, the method of injecting the pharmaceutical composition into the body can be applied without limitation to the method of injecting the pharmaceutical composition into the body, as long as it does not specifically conflict with the present invention.

In one embodiment of the present application, the pharmaceutical composition comprising the first pharmaceutical composition and the second pharmaceutical composition may have high selectivity and activity.

In one embodiment of the present application, the iron atom included in the second pharmaceutical composition can be used to prevent or treat proliferative diseases caused by the generation of reactive oxygen species through the Fenton reaction under spontaneous supplementation of hydrogen peroxide, but is limited thereto. That is not the case.

In one embodiment of the present application, the first pharmaceutical composition may act on mitochondria, but is not limited thereto.

In one embodiment of the present application, the first pharmaceutical composition may be treated with a triphenylphosphonium solution, but is not limited thereto. Specifically, the triphenylphosphonium solution enables targeting the first pharmaceutical composition to mitochondria.

In one embodiment of the present application, the first pharmaceutical composition can amplify the depletion efficiency of glutathione (GSH) present in mitochondria by treating it with a triphenylphosphonium solution, thereby amplifying the depletion efficiency of glutathione (GSH) within the cell. By increasing oxidative stress, the treatment effect of proliferative diseases can be maximized.

In one embodiment of the present application, the second pharmaceutical composition may act on the cytoplasm, but is not limited thereto.

In one embodiment of the present application, the second pharmaceutical composition may contain folic acid as a targeting moiety, but is not limited thereto. Specifically, folic acid enables targeting the second pharmaceutical composition into cells.

In one embodiment of the present application, the first pharmaceutical composition may act on mitochondria, and the second pharmaceutical composition may act on cytoplasm.

In one embodiment of the present application, the first pharmaceutical composition may include oxidizing glucose to produce hydrogen peroxide and gluconic acid, and the second pharmaceutical composition may include decomposing the hydrogen peroxide to form hydroxy radicals. However, it is not limited to this.

In one embodiment of the present application, the hydroxy radical may function for one or more of sterilization, cancer cell killing, inflammatory response regulation, and aging inhibition, but is not limited thereto.

In one embodiment of the present application, as glucose is oxidized by the gold nanoparticles, the concentration of glucose, which is a growth factor for the proliferative disease, is lowered by hydroxy radicals, thereby obtaining a starvation therapy effect. .

In one embodiment of the present application, the cancer is solid tumor, blood cancer, colorectal cancer, uterine cancer, uterine fibroids, meningioma, lung cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, colon cancer, intestinal cancer, breast cancer, and ovarian cancer. , prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma, but is not limited thereto. The pharmaceutical composition according to one embodiment of the present application is an object of prevention or treatment and may be applicable to diseases not limited to carcinoma.

Hereinafter, the present application will be described in more detail using examples. However, the following examples are merely illustrative to aid understanding of the present application, and the content of the present application is not limited to the following examples.

[Example]

Example 1: Synthesis of metal organic framework (MOF)

1) Synthesis of metal-organic frameworks

2,2'-bipyridine-5,5'-dicarboxylic acid (98.0%, TCI), biphenyl-4,4'-dicarboxylic acid biphenyl-4,4'-dicarboxylic acid (97%, Aldrich), zirconium (IV) chloride (≥ 99.5% based on trace metals, Aldrich), gold(III) chloride trihydrate (gold(III) chloride trihydrate) (HAuCl _4· 3H ₂ O; ≥ 99.9% based on trace metals), trisodium citrate dihydrate, sodium borohydride (NaBH ₄ , 99% ), Iron(II) chloride (FeCl ₂ , 98%), and N,N-dimethylformamide anhydrous (DMF, 99.8%) were purchased from Aldrich. did.

2) Synthesis of UiO-67 metal organic framework

Figure 1 shows a schematic diagram of the synthesis of a metal-organic framework, in which ZrCl ₄ (9.3 mg, 0.04 mmol) was mixed with acetic acid (0.5 mL) in a 20 mL glass vial with N, N'-dimethylformamide (DMF; N, N'-dimethylformamide, 5 mL). Ligands biphenyl-4,4'-dicarboxylic acid, 2,2'-bipyridine-5,5'-dicarboxylic acid (2,2'-bipyridine) The ligand was prepared using a solution of -5,5'-dicarboxylic acid) and DMF (5 mL).

After preparing the ligand, a well-dispersed ligand solution was added to the metal solution, and the sealed vial was kept in an oven at 85° C. for 12 hours without light. Afterwards, it was cooled to room temperature and the solid was separated by centrifugation (8,000 rpm, 10 minutes). Afterwards, it was washed once with DMF and three times with methanol. After washing, the product was dried in a vacuum oven to obtain MOF. The MOF synthesized here was Zr-based, and the size of the obtained MOF was about 50 mm. Figure 2(a) shows ¹ H-NMR data of MOF. According to Figure 2(a), the ligands biphenyl-4,4'-dicarboxylic acid and 2,2'-bipyridine- It can be confirmed that the ratio of 5,5'-dicarboxylic acid is 1:1. Due to the N-group in the 2,2'-bipyridine-5,5'-dicarboxylic acid, chelating of Fe metal may be possible. It can be seen from the transmission electron microscope (TEM) image in Figure 2(b) that the MOF was well synthesized.

Example 2: Au nanoparticle-MOF

1) Synthesis of Au nanoparticle-MOF

Figure 3(a) shows the synthesis process of Au nanoparticle-MOF. First, the MOF (1 mg/mL) synthesized in Example 1 was dispersed in DMF, and then HAuCl ₄ (1 mg/mL) was added and mixed. After incubation for one day, the remaining HAuCl ₄ was removed by centrifugation, and NaBH ₄ (0.6 M), a reducing agent, was added and stirred for one day to synthesize Au nanoparticles. Afterwards, it was centrifuged again and washed to obtain Au nanoparticle-MOF, a glucose oxidase mimicking nanozyme. Figure 3(b) is an image showing the structure of the obtained Au nanoparticle-MOF.

Figure 4(a) shows TEM images (scale bar: 50 nm, 10 nm, and 5 nm) of the Au nanoparticle-MOF. The TEM image in Figure 4(a) shows that the Au nanoparticles are present in the MOF. It can be confirmed that it was well synthesized. In addition, Figure 4(b) is a UV-vis absorption spectrum of the Au nanoparticle-MOF. Considering that the absorption peak was observed at about 540 nm, which is the absorption peak of the Au nanoparticle, it was confirmed that the Au nanoparticle was well synthesized in the MOF. You can see that it has been done.

2) Characteristics of Au nanoparticle-MOF

Figure 5 shows analysis data according to x-ray photoelectron spectroscopy (XPS) of Au nanoparticle-MOF. In Figure 5, when the peaks of 84 eV and 87.3 eV, which are the respective peaks of Au 4f _7/2¸ Au 4f _5/2 , appear, it can be seen that the oxidation state of Au is 0, which means that Au It can be seen that it exists in metal form.

Example 3: Fe monatomic-MOF

1) Synthesis of Fe monatomic-MOF

Figure 6(a) is a schematic diagram of the synthesis process of Fe monoatomic-MOF, and the MOF (1 mg/mL) synthesized in Example 1 was dispersed in DMF and then added with FeCl ₂ (1 mg/mL). and mixed. The ratio of MOF and FeCl ₂ is 5.5 wt% based on 100 parts by weight of MOF. After incubation for one day, centrifugation and washing were performed to obtain Fe monoatomic-MOF, a peroxidase mimicking nanozyme. Figure 6(b) shows the structure of Fe monoatom-MOF.

Figure 7(a) is a scanning transmission electron microscopy (STEM) image of the Fe single atom-MOF, and Figure 7(b) is an energy dispersive X-ray spectroscopy (EDS) image of the Fe single atom-MOF. Alternatively, it shows analysis data according to EDX (energy dispersive x-ray spectroscopy). According to FIGS. 7(a) and 7(b), it can be confirmed that the Fe single atom was well introduced into the MOF. Specifically, as a bright spot is observed within the red circle in Figure 7(a), it can be seen that Fe single atoms exist in the pores of the MOF, and in the EDX analysis in Figure 7(b), It was confirmed that Zr and Fe forming each structure were observed, indicating that Fe single atoms were well introduced into the pores of the MOF.

2) Characteristics of Fe monatomic-MOF

Figures 8(a) and 8(b) are graphs showing analysis data according to X-ray photoelectron spectroscopy (XPS) according to Fe 2p and N 1s of Fe single atom-MOF, respectively. , in Figure 8(a), the respective peaks of Fe 2p _3/2 and Fe 2p _1/2 are 709 eV and 722.6 eV, and in the XPS of Figure 8(b), pyridinic N and Fe-N can confirm.

Example 4: Cancer treatment using a pharmaceutical composition containing Au nanoparticle-MOF and Fe monatomic-MOF

(1) Cancer treatment method using a pharmaceutical composition containing Au nanoparticle-MOF and Fe monatomic-MOF

Figure 9 is a schematic diagram of cancer treatment of a MOF-based nanostructure into which Au nanoparticle-MOF and Fe monatom-MOF are introduced. After the nanostructure is delivered, excess glucose in cancer cells is oxidized due to the glucose oxidase mimicking properties of the Au nanoparticle-MOF, and the oxidized glucose is decomposed into hydrogen peroxide and gluconic acid. At this time, the hydrogen peroxide formed and the hydrogen peroxide present in excess in cancer cells are decomposed by Fe monatom-MOF, a monoatomic nanozyme, to form hydroxy radicals. Cancer is killed by the formed hydroxy radicals (reactive oxygen species, ROS), and the concentration of glucose, a growth factor for cancer cells, is lowered, thereby providing a starvation therapy effect.

(2) Activity of Au nanoparticle-MOF nanozyme

By additionally treating the Au nanoparticle-MOF with triphenylphosphonium (TPP), which can target mitochondria, the depletion efficiency of glutathione (GSH) present in the mitochondria can be amplified. In addition, due to the characteristics of the Au nanoparticle-MOF, the glutathione present in the mitochondria is depleted by forming Au-S groups, thereby increasing oxidative stress within the cell, thereby maximizing the cancer treatment effect by the reactive oxygen species. You can. The Au nanoparticle-MOF can be subjected to surface treatment for cell and animal experiments.

Amplex red is a reagent that can detect hydrogen peroxide, and when it reacts with hydrogen peroxide, a fluorescence peak is observed at about 570 nm. Using the amplex red, it was confirmed whether the Au nanoparticle-MOF nanozyme formed hydrogen peroxide, and the results are shown in Figure 10. Figure 10 shows the activity of the glucose oxidase mimicking nanozyme of the Au nanoparticle-MOF. As can be seen in Figure 10, when glucose was added to the Au nanoparticle-MOF (Au NP-MOF + glucose) compared to the control sample (ctrl) to which no glucose was added, a strong fluorescence peak was observed at about 570 nm. From this, it can be seen that the Au nanoparticle-MOF effectively oxidizes glucose to form hydrogen peroxide.

Figure 11 is a graph showing the pH change in the control group where glucose was not added to the Au nanoparticle-MOF (ctrl) and when glucose was added to the Au nanoparticle-MOF (Au NP-MOF + glucose). During the process of glucose oxidation by Au nanoparticle-MOF, not only hydrogen peroxide but also gluconic acid is formed. According to Figure 11, it can be seen that when glucose was added to the Au nanoparticle-MOF (Au NP-MOF + glucose), the pH gradually decreased over time compared to the control sample (ctrl) to which no glucose was added. This shows that glucose oxidized by the Au nanoparticle-MOF is changed into gluconic acid. Acidic pH can help improve the peroxidase mimicking nanozyme activity of Fe-MOF.

Ellman's reagent [Ellman's test, DTNB; [5,5-dithio-bis-(2-nitrobenzoic acid)] is a reagent that detects (-SH) of a thiol group, and when the thiol group is present, it exhibits an absorption peak at about 420 nm. Depletion of the thiol group was confirmed in FIG. 12 through the Au nanoparticle-MOF using the Ellman reagent, and FIG. 12 shows that when Au NP-MOF and glutathione are present together (Au NP-MOF + Thiol group absorption was confirmed in the absence of glutathione (GSH) and glutathione (ctrl). As can be seen in Figure 12, when Au nanoparticle-MOF and glutathione are present together (Au NP-MOF + GSH), no absorption peak was observed at about 420 nm (no absorption peak of the thiol group), This shows that glutathione is depleted. Through the depletion of glutathione, oxidative stress within cells can be increased, thereby further increasing the cancer treatment effect.

(3) Activity of Fe-MOF nanozyme

The Fe monoatom-MOF can be introduced with folic acid as a targeting moiety for cell and mouse experiments.

3,3', 5,5'-tetramethylbenzidine (TMB) is a substrate that changes to oxidized TMB (oxTMB) when reacted with hydrogen peroxide, and exhibits an absorption peak at about 650 nm. Through Figure 13, peroxidase mimicking activity was shown in the case of reacting Fe-MOF with hydrogen peroxide (Fe-MOF + H ₂ O ₂ ) and the control group (H ₂ O ₂ ). Looking at Figure 13, it can be seen that when Fe-MOF and hydrogen peroxide are reacted (Fe-MOF + H ₂ O ₂ ), TMB changes to oxTMB and shows a strong absorption peak at about 650 nm, and the control (H ₂ O ₂ ) shows a weaker peak at about 650 nm than Fe-MOF + H ₂ O ₂ . This shows that the MOF chelated with monoatomic Fe effectively decomposes hydrogen peroxide.

Terephthalic acid (TA) is a reagent that detects hydroxy radicals, and reacts with hydroxy radicals to produce a strong fluorescence peak at about 450 nm. Through Figure 14, the formation of hydroxy radicals is shown when Fe-MOF and hydrogen peroxide are reacted (Fe-MOF + H ₂ O ₂ ) and when hydrogen peroxide is not reacted (Fe-MOF). As can be seen in Figure 14, when Fe-MOF and hydrogen peroxide are reacted (Fe-MOF + H ₂ O ₂ ), a strong fluorescence peak can be observed at about 450 nm, which allows Fe-MOF to effectively react with hydrogen peroxide. It can be confirmed that it decomposes to form hydroxy radicals. When Fe-MOF and hydrogen peroxide are not reacted (Fe-MOF), it shows a weaker peak than Fe-MOF + H ₂ O ₂ at about 450 nm.

(4) Activity of double monatomic nanozyme

Figure 15 shows control (TA + DI-water), Au nanoparticle-MOF + glucose, Fe-MOF + glucose, Au nanoparticle-MOF + Fe-MOF + glucose, Au nanoparticle-MOF, Fe-MOF and Au This is a graph showing the cascade enzymatic activity of nanoparticle-MOF + Fe-MOF. In the control group (TA + DI-water), it can be confirmed that in the absence of hydroxyl radicals, the fluorescence peak due to TA does not appear. Au nanoparticle-MOF can form hydroxy radicals when Fe-MOF decomposes hydrogen peroxide generated by oxidizing glucose. In Figure 15, as a result of detecting hydroxy radicals through the TA, the strongest fluorescence peak was observed in Au nanoparticle-MOF + Fe-MOF + glucose (orange), confirming that cascade enzyme activity occurs effectively. I was able to. Through this, effective cancer treatment efficiency can be shown in cell experiments.

The description of the present application described above is for illustrative purposes, and those skilled in the art will understand that the present application can be easily modified into other specific forms without changing its technical idea or essential features. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive. For example, each component described as single may be implemented in a distributed manner, and similarly, components described as distributed may also be implemented in a combined form.

The scope of the present application is indicated by the claims described below rather than the detailed description above, and all changes or modified forms derived from the meaning and scope of the claims and their equivalent concepts should be construed as being included in the scope of the present application. .

Claims (15)

A first pharmaceutical composition comprising gold nanoparticles supported on a metal-organic framework, and
Second pharmaceutical composition comprising an iron atom supported on a metal-organic framework
Includes,
For the prevention or treatment of cancer,
As a pharmaceutical composition,
The central metal of the metal-organic framework is zirconium,
Pharmaceutical composition.
According to claim 1,
A pharmaceutical composition, wherein the metal-organic framework is UiO-67.
According to claim 1,
The gold nanoparticles exist in a metallic state in the metal-organic framework,
A pharmaceutical composition, wherein the iron monatom exists in a monatomic state in the metal-organic framework.
According to claim 1,
The iron monatom is chelated to the metal-organic framework,
A pharmaceutical composition, wherein the gold nanoparticles are supported on the metal-organic framework.
According to claim 1,
The second pharmaceutical composition is a pharmaceutical composition in which folic acid is introduced as a targeting moiety.
Injecting into the body a pharmaceutical composition for preventing or treating cancer, comprising a first pharmaceutical composition in which gold nanoparticles are supported on a metal-organic framework and a second pharmaceutical composition in which iron atoms are supported in a metal-organic framework. As a method for preventing or treating cancer, comprising:
A method of preventing or treating cancer, wherein the method is applied except for humans.
According to claim 6,
A method for preventing or treating cancer, wherein the central metal of the metal-organic framework is zirconium.
According to claim 6,
A method for preventing or treating cancer, wherein the metal-organic framework is UiO-67.
According to claim 6,
A method for preventing or treating cancer, wherein the first pharmaceutical composition acts on mitochondria.
According to claim 6,
A method of preventing or treating cancer, wherein the second pharmaceutical composition acts on the cytoplasm.
According to claim 6,
A method for preventing or treating cancer, wherein the first pharmaceutical composition acts on mitochondria, and the second pharmaceutical composition acts on cytoplasm.
According to claim 6,
The first pharmaceutical composition oxidizes glucose to produce hydrogen peroxide and gluconic acid,
The second pharmaceutical composition comprises decomposing the hydrogen peroxide to form hydroxy radicals,
Methods for preventing or treating cancer.
According to claim 6,
A method for preventing or treating cancer, wherein the first pharmaceutical composition is treated with a triphenylphosphonium solution.
According to claim 12,
A method of preventing or treating cancer, wherein the hydroxy radical acts as one or more of sterilization, killing cancer cells, regulating inflammatory response, and inhibiting aging.
According to claim 6,
The above cancers include solid tumors, blood cancers, colorectal cancers, uterine cancers, uterine fibroids, meningiomas, lung cancers, small cell lung cancers, non-small cell lung cancers, gastrointestinal cancers, colon cancers, intestinal cancers, breast cancers, ovarian cancers, prostate cancers, testicular cancers, liver cancers, A method for preventing or treating cancer, comprising one or more selected from kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.