Prodrug compound capable of being activated by radiation, metal organic monolayer material loaded by prodrug compound and application of metal organic monolayer material

Abstract

The invention discloses a prodrug compound capable of being activated through radiation, a metal organic single-layer material loaded by the prodrug compound and application of the metal organic single-layer material, and belongs to the field of biological medicine. The invention specifically comprises a prodrug shielding group capable of efficiently responding to hydroxyl free radicals, a hafnium-element-based two-dimensional metal organic single-layer material with radiotherapy sensitization capability and a preparation method of the hafnium-element-based two-dimensional metal organic single-layer material.

Description

Technical Field

[0001] This application belongs to the field of biomedicine, specifically relating to a radiation-activated prodrug compound and its supported metal-organic monolayer material and its uses. Background Technology

[0002] Radiation therapy (RT) is a local treatment method that uses radiation to treat tumors. It utilizes alpha, beta, and gamma rays produced by radioactive isotopes, or X-rays, electron beams, proton beams, and other high-energy particle beams generated by accelerators to irradiate tumor tissue and achieve therapeutic effects against cancer. Ionizing radiation can induce DNA damage, including base damage, single-strand breaks, double-strand breaks, and interstrand cross-links. Unrepaired or improperly repaired double-strand breaks are a major cause of cancer cell death. Approximately 50% of cancer patients require radiation therapy during cancer treatment. The role and importance of radiation therapy in tumor treatment are increasingly prominent, and it has become one of the main methods for treating malignant tumors.

[0003] Due to differences in tissue density and limitations in treatment planning capabilities, traditional radiotherapy treats large areas with uneven radiation doses. While ionizing radiation kills cancer cells, it inevitably damages surrounding normal tissues as well. The effectiveness of radiotherapy is significantly reduced when dealing with large tumors with poor blood supply, low oxygen levels, and low radiation sensitivity. How to improve treatment efficacy within limited radiation doses, or how to reduce radiation doses and minimize toxic side effects while maintaining therapeutic efficacy, are pressing issues that need to be addressed in the development of novel radiotherapy techniques. Summary of the Invention

[0004] The purpose of this application is to provide a radiation-activated prodrug compound and its loaded metal-organic monolayer material, along with its uses. This compound or material is beneficial for improving therapeutic efficacy within a limited radiation dose.

[0005] A first aspect of this application is to provide a radiation-activated prodrug compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, said compound having the structure of Formula I:

[0006]

[0007] A is any therapeutic agent or chromogenic agent capable of being linked to the ester moiety of a compound of formula I, wherein A is capable of separating from the ester moiety under radiation and releasing a therapeutically active or chromogenic component.

[0008] In some embodiments, the compound can be specifically activated by hydroxyl radicals;

[0009] Preferably, the compound can serve as a prodrug molecule that responds to hydroxyl radicals;

[0010] and / or;

[0011] When the compound is present with water and under radiation, the ester group in the compound of formula I is removed, and A is released.

[0012] Preferably, the release rate of the compound under radiation is less than or equal to 100%.

[0013] In these embodiments, this application discloses that the release rate of the compound under radiation is any one of 100%, 99%, 95%, etc., or any one of the ranges of both of the above.

[0014] In some embodiments, A is a fluorescent group or a pharmaceutical group;

[0015] Preferably, A is a drug group for treating cancer;

[0016] Preferably, A is a drug group for chemotherapy or radiotherapy;

[0017] Preferably, A is a radiotherapy or chemotherapy drug containing an amino group or a colorimetric component containing an amino group, and the amino group is linked to the ester group of the compound of formula I.

[0018] and / or;

[0019] R1 represents substituted or unsubstituted C6-C. 10 Aryl, substituted or unsubstituted C6-C 10 Any of the heteroaryl groups; each of the substituents is independently selected from one or more of the following: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH-(C1-C6 alkylene)-NH2.

[0020] In some embodiments, R1 is a substituted or unsubstituted phenyl group, and each substituent is independently selected from any one or more of the following: C1-C6 alkyl, C1-C6 alkoxy, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH-(C1-C6 alkylene)-NH2;

[0021] and / or;

[0022] A is selected from 7-amino-4-methylcoumarin or MeRho as a fluorescent group;

[0023] and / or;

[0024] A is selected from eczema as a pharmaceutical group.

[0025] In some embodiments, R1 is selected from any of the following groups:

[0026]

[0027] Preferably, the compound of formula I has any one of the following structures:

[0028]

[0029] A second aspect of this application is to provide an intermediate compound comprising:

[0030] Alkyne functional group: used to replace hydrogen atoms in the prodrug compound described in the first aspect and covalently linked with the prodrug compound to form the intermediate compound.

[0031] In some embodiments, the intermediate compound comprises a ring-strained alkyne functional group;

[0032] Preferably, the ring-strained alkyne functional group includes any one of the following groups:

[0033]

[0034] In some embodiments, the intermediate compound has any of the following structural formulas:

[0035]

[0036] A third aspect of this application is to provide a metal-organic material loaded with a hydroxyl radical-responsive prodrug, comprising:

[0037] At least one of the intermediate compounds described in the second aspect;

[0038] Nano-hafnium-based metal-organic monolayer material: used for loading the intermediate compound;

[0039] The intermediate compound and the nano-hafnium-based metal-organic monolayer material have covalent bonds.

[0040] In some embodiments, the intermediate compound forms the covalent bond with the nano-hafnium-based metal-organic monolayer material through an addition reaction.

[0041] In some embodiments, the nano-hafnium-based metal-organic monolayer material is obtained by modifying hafnium atom clusters with carboxyl groups of terphenyl dicarboxylic acid ligands through coordination bonds.

[0042] In some embodiments, the terphenyl ligand includes an azide group or contains a functional group that can be converted into an azide group;

[0043] Preferably, the terphenyl phthalic acid ligand has any one of the following structures:

[0044]

[0045] In Formula II-3, X is selected from any one of Cl, Br, I, and -OSO2CF3.

[0046] In some embodiments, the intermediate compound forms the covalent bond with the nano-hafnium-based organometallic monolayer material via an azide-alkyne addition reaction;

[0047] and / or;

[0048] The distance between the surface of the nano-hafnium-based metal-organic monolayer material and the prodrug compound in the intermediate compound is less than 10 nm;

[0049] Preferably, it is less than 8nm;

[0050] Preferably, it is less than 5nm.

[0051] In these embodiments, this application discloses that the distance between the surface of the nano-hafnium-based metal-organic monolayer material and the prodrug compound in the intermediate compound is any one of 9.5 nm, 9 nm, 8.5 nm, 8 nm, 7.5 nm, 7 nm, 6.5 nm, 6 nm, 5.5 nm, 5 nm, 4.5 nm, 4 nm, or any one of the above ranges.

[0052] The fourth aspect of this application is to provide a method for treating or diagnosing a disease, the method comprising administering to an individual the prodrug compound described in the first aspect, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof;

[0053] or;

[0054] The organometallic material described in the second aspect is applied to an individual;

[0055] The individual was then irradiated with a therapeutically effective dose.

[0056] In some implementations, the method is used to treat or suppress cancer, reduce its severity, decrease its risk, or inhibit its metastasis in an individual.

[0057] In some embodiments, the cancer is selected from one or more of breast cancer, colorectal cancer, lung cancer, and stomach cancer.

[0058] In some embodiments, the radiation is high-energy radiation, preferably X-rays or gamma rays;

[0059] Preferably, the intensity of the X-rays or gamma rays is less than or equal to 60 Gy;

[0060] Preferably, the intensity of the X-rays or gamma rays is less than or equal to 20 Gy;

[0061] Preferably, the intensity of the X-rays or gamma rays is less than or equal to 10 Gy;

[0062] Preferably, the intensity of the X-rays or gamma rays is less than or equal to 4 Gy.

[0063] In these embodiments, this application discloses X-rays or gamma rays with intensities of 60 Gy, 50 Gy, 40 Gy, 30 Gy, 20 Gy, 10 Gy, 5 Gy, 4 Gy, 3 Gy, or any combination thereof.

[0064] The beneficial effects of this application are:

[0065] 1. This application develops a prodrug platform technology that can be efficiently activated by radiotherapy rays in vivo, including a prodrug shielding group that can efficiently respond to hydroxyl radicals and a two-dimensional metal-organic monolayer material based on hafnium element with radiosensitizing ability.

[0066] 2. The compounds or materials provided in this application are beneficial to improving the therapeutic effect within a limited irradiation dose. Attached Figure Description

[0067] Figure 1 A schematic diagram of the construction of a clickable metal-organic monolayer and a schematic diagram of the mechanism by which it releases functional molecules under X-ray irradiation;

[0068] Figure 2 : Figure 2 a represents a bioactive species that undergoes water radiolysis; Figure 2 b represents the screening of protecting groups in response to hydroxyl radicals; Figure 2 c represents the reactivity assessment of different protecting groups; Figure 2 d represents the stability assessment of different protecting groups;

[0069] Figure 3 Hf 12 -NH2(ac), Hf 12 -N3(df), and Hf 12 The structural characterizations of -AMC(gi) are as follows:

[0070] Figure 3 a is Hf 12 Transmission electron microscopy (TEM) of -NH2; Figure 3 b is Hf 12 High-resolution transmission electron microscopy (HRTEM) of -NH2; Figure 3 c is Hf 12 Atomic force microscopy (AFM) of -NH2;

[0071] Figure 3 d is Hf 12 Transmission electron microscopy (TEM) of -N3; Figure 3 e is Hf 12 -N3 high-resolution transmission electron microscope (HRTEM); Figure 3 f is Hf 12 Atomic force microscopy (AFM) of -N3;

[0072] Figure 3 g is Hf 12 - Transmission electron microscopy (TEM) of AMC; Figure 3 h is Hf 12 -AMC's high-resolution transmission electron microscope (HRTEM); Figure 3 i is Hf 12 -AMC's atomic force microscope (AFM);

[0073] Figure 4 Hf 12 -NH2、Hf 12 -N3、Hf 12 -AMC, Hf 12 -Rho、Hf 12 -Fourier transform infrared spectrum of Exa;

[0074] Figure 5 Hf 12 -NH2、Hf 12 -N3、Hf 12 -AMC, Hf 12 -Rho、Hf 12 -UV-Vis absorption spectrum of Exa;

[0075] Figure 6 Hf 12 -NH2、Hf 12 -N3、Hf 12 -AMC, Hf 12 -Rho、Hf 12 -Powder X-ray diffraction pattern of Exa;

[0076] Figure 7 Hf 12 -NH2、Hf 12 -N3 and Hf 12 -AMC's ability to generate hydroxyl radicals under X-ray irradiation in aqueous solution;

[0077] Figure 8 AEAP-AMC, BCN-AMC and Hf 12- The efficiency of AMC release under X-ray irradiation;

[0078] Figure 9 Hf 12 -AMC-Rho-Exa simultaneously and quantitatively modifies multi-component functional molecules, which are then released synchronously under X-ray irradiation. Hf 12 -AMC-Rho-Exa simulation structure ( Figure 9 a) Transmission electron microscope images ( Figure 9 b) High-resolution transmission electron microscope images ( Figure 9 c) and the release of functional molecules under X-ray irradiation ( Figure 9 d);

[0079] Figure 10 AEAP-AMC and Hf 12 - The efficiency of AMC release under X-ray irradiation in different hydroxyl radical quenchers;

[0080] Figure 11 Hf 12 -N3( Figure 11 a) and Hf 12 -Rho( Figure 11 b) Cytotoxicity assessment;

[0081] Figure 12 AEAP-Rho and Hf 12 -Rho in 4T1( Figure 12 a) and MC38 Figure 12 b) The efficiency of MeRho release under X-ray irradiation in the two cell types;

[0082] Figure 13 Hf 12 -N3 and Hf 12 -Exa in 4T1( Figure 13 a) and MC38 Figure 13 b) Cell-killing capacity under X-ray irradiation in two cell types;

[0083] Figure 14 Hf 12 -N3 and Hf 12 -Exa’s ability to damage DNA double strands under X-ray irradiation in 4T1 cells;

[0084] Figure 15 The inhibitory effects of different treatment groups on tumor growth in 4T1 tumor-bearing mice. Groups were: PBS control group, Hf... 12 -Exa group, PBS+X-ray group, Hf 12 -N3+ X-ray group, Hf 12 -Exa+ X-ray group.

[0085] The following is an explanation and description of the terms and concepts used in this application:

[0086] Application A is a radiotherapy or chemotherapy drug containing an amino group or a chromogenic molecule containing an amino group, wherein the amino group is connected to the ester group of the compound of formula I.

[0087] This application uses anticancer drugs containing primary or secondary amines as the molecules corresponding to Part A. These anticancer drugs containing primary or secondary amines include, for example, ibrutinib, acalatinib, zanubrutinib, doxorubicin, mitomycin-C, mitomycin-A, daunorubicin, aminopterin, actinomycin, bleomycin, 9-aminocamptothecin, N8-acetylspermine, 1-(2-chloroethyl)-1,2-dimethylsulfonylhydrazide, yunnanmycin, gemcitabine, cytarabine, dolalastatin, dacarbazine, 5-fluorouracil, and their derivatives. Drugs containing primary or secondary amines also include amino derivatives of drugs that do not naturally contain an amino group. In other words, drugs that do not normally contain an amino group can be chemically modified to have an amino group, and then coupled or linked to a radiation-responsive group using the primary or secondary amine coupling method described in this application.

[0088] The term "pharmaceutically acceptable" in this application means that the compound or composition is chemically and / or toxicologically compatible with other components constituting the formulation and / or with humans or mammals for the prevention or treatment of diseases or conditions.

[0089] The term "chemotherapeutic agent" or "chemotherapeutic drug" refers to chemotherapeutic drugs that can kill tumor cells. These drugs can act on different stages of tumor cell growth and reproduction, thereby inhibiting or killing tumor cells.

[0090] The term "individual" includes humans or non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. "Non-human animals" in this application includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0091] The term "rhodamine" refers to a dye molecule having one of two backbone structures, wherein the ring atoms are optionally substituted.

[0092] The term "coumarin" refers to a dye molecule having the following backbone structure, wherein the ring atoms are optionally substituted.

[0093] The term "pharmaceuticalally acceptable salt" refers to a relatively non-toxic addition salt of the compound of this application. See, for example, SMBerge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19.

[0094] Suitable pharmaceutically acceptable salts of the compounds of this application may be, for example, acid addition salts of the compounds of this application that carry a nitrogen atom in the chain or ring and are sufficiently basic, such as acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, or nitric acid, or acid addition salts formed with organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, etc. 3-Hydroxy-2-naphtholic acid, nicotinic acid, pyruvic acid, pectinic acid, persulfate, 3-phenylpropionic acid, picric acid, pentanoic acid, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecyl sulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucohepanoic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, or thiocyanate.

[0095] Alternatively, another suitable pharmaceutically acceptable salt of the compound of this application having sufficient acidity is an alkali metal salt such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt, a triethylamine salt, or a salt formed with an organic base that provides a physiologically acceptable cation, such as a salt formed with N-methylglucosamine, dimethylglucosamine, ethylglucosamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, sarcosine, serine, trihydroxymethylaminomethane, aminopropylene glycol, 1-amino-2,3,4-butanetriol. In addition, basic nitrogen-containing groups can be quaternized using the following reagents: lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate; long-chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides, etc.

[0096] Those skilled in the art will also recognize that the acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable inorganic or organic acid using any of a variety of known methods. Alternatively, the alkali metal and alkaline earth metal salts of the acidic compounds of this application can be prepared by reacting them with a suitable base using various known methods.

[0097] This application includes all possible salts of the compounds of this application, which may be a single salt or any mixture of said salts in any proportion.

[0098] The term "solvent" refers to a substance formed by combining, physically binding, and / or solvating the compounds of this application with solvent molecules, such as a disolvent, monosolvent, or hemisolvent, wherein the ratio of solvent molecules to the compounds of this application is about 2:1, about 1:1, or about 1:2, respectively. This physical binding involves, to varying degrees, ionization and covalent bonding (including hydrogen bonding). In some cases (e.g., when one or more solvent molecules are bound to the lattice of a crystalline solid), the solvate can be separated. Therefore, a solvate includes a solution phase and a separable solvate. The compounds of this application can be in a solvated form with pharmaceutically acceptable solvents (e.g., water, methanol, and ethanol), and this application is intended to cover both solvated and non-solvated forms of the compounds of this application. One type of solvate is a hydrate.

[0099] The term "effective amount" refers to the amount of an active ingredient that, when administered, will alleviate one or more symptoms of the disease being treated to a certain extent.

[0100] In the context of this application, "radiation" refers to radiation that is not visible or ultraviolet, preferably high-energy radiation, such as X-rays or gamma rays, for example, any radiation used in radiotherapy.

[0101] "Stereoisomers" are compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and hindered isomers, etc.

[0102] The term "group" refers to the portion of a molecule formed by removing one, two, or more hydrogen free radicals. That is, "fluorescent group" or "drug group" refers to the group formed by removing one, two, or more hydrogen free radicals from fluorescent molecules or drug molecules commonly used in the art.

[0103] The expression "optionally substituted" means that one, two, three, or more than three hydrogen atoms in a group can be substituted by various substituents independently of each other. The substituents can be selected from alkyl, alkenyl, alkoxy, halogen, cyano, amino, nitro, hydroxyl, etc.

[0104] The term "alkyl" refers to a saturated straight-chain or branched carbon chain. Preferably, the chain contains 1 to 10 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms. The alkyl group is, for example, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, pentyl, or octyl. The alkyl group may optionally be substituted.

[0105] The term "alkoxy group" includes -O-alkyl groups and alkyl groups in which the O atom is within an alkyl chain, such as -CH2-O-CH3, which contain 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms. The alkoxy group may optionally be substituted.

[0106] The term "alkenyl" includes both straight-chain alkyl groups and branched-chain alkyl groups containing at least two carbon atoms and at least one carbon-carbon double bond, comprising 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, and most preferably 2 to 3 carbon atoms. The alkenyl group may optionally be substituted.

[0107] The term "alkynyl" indicates that it contains at least one unsaturated site, i.e., one carbon-carbon sp triple bond, comprising 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, and most preferably 2 to 3 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc. The alkynyl group may optionally be substituted.

[0108] The term "aryl" preferably refers to an aromatic monocyclic system containing 6 carbon atoms, an aromatic bicyclic system containing 10 carbon atoms, or an aromatic tricyclic system containing 14 carbon atoms. Examples are phenyl, naphthyl, or anthracene. The aryl group may optionally be substituted.

[0109] The term "heteroaryl" preferably refers to a five- or six-membered aromatic monocyclic ring in which at least one carbon atom is substituted by one, two, three, or four (for five-membered rings) or one, two, three, four, or five (for six-membered rings) identical or different heteroatoms, the heteroatoms preferably selected from O, N, and S; or an aromatic bicyclic system in which one, two, three, four, five, or six of eight, nine, ten, eleven, or twelve carbon atoms are substituted by identical or different heteroatoms, the heteroatoms preferably selected from O, N, and S; or an aromatic tricyclic system in which one, two, three, four, five, or six of thirteen, fourteen, fifteen, or sixteen carbon atoms are substituted by identical or different heteroatoms, the heteroatoms preferably selected from O, N, and S. The nitrogen atom present in a heteroaryl group can exist in the form of an onium group, for example, by attaching an alkyl group or oxygen atom to a trivalent aromatic nitrogen atom to form an onium group. Therefore, in the context of this application, "heteroaryl" includes heteroaryl groups in their free form (where the nitrogen atom is not salted) and heteroaryl groups existing in the form of onium salts. Examples include pyridinyl, N-oxypyridinyl, N-alkylpyridinyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrroleyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, and 1-benzene. 2-Benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, 1H-indazoleyl, benzimidazolyl, benzoxazolyl, indolazinyl, 2,1-benzoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1,2,3-benzotriazinyl or 1,2,4-benzotriazinyl.

[0110] The term "halogen" refers to fluorine, chlorine, bromine, iodine, and astatine.

[0111] The term "optional" means that the situation may or may not occur.

[0112] When “about” is followed by a value or ratio, it means such a value or ratio is ±10%, preferably ±5%, and more preferably ±1%.

[0113] Unless otherwise stated, when disclosing or claiming protection for any type of scope, the intent to separately disclose or claim protection for each possible value that scope may reasonably cover, including any sub-scopes included therein. For example, the number of groups 1 to 6 indicates integers within the scope, where 1-6 should be understood to include 1, 2, 3, 4, 5, 6, as well as sub-scopes of 1-5, 1-4, and 1-3.

[0114] This application should be interpreted as consistent with the laws and principles of chemical bonding. In some cases, it may be necessary to remove a hydrogen atom to accommodate a substituent at a given position.

[0115] As used herein, the terms “comprising,” “containing,” or “including” mean that the element preceding the word encompasses the elements listed following the word and their equivalents, without excluding elements not described herein. The terms “containing” or “comprising (including)” as used herein can be open-ended, semi-closed, or closed-ended. In other words, the terms also include “consistently composed of” or “composed of”.

[0116] Obviously, based on the above content of this application, and in accordance with the common technical knowledge and practices in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of this application. Detailed Implementation

[0117] In the treatment of malignant tumors, the effectiveness of radiotherapy is significantly reduced when dealing with tumors that are large, poorly vascularized, low in oxygen content, and have low radiation sensitivity. How to improve treatment efficacy within a limited radiation dose, or how to reduce the radiation dose and minimize toxic side effects while maintaining therapeutic efficacy, are urgent problems to be solved in the development of new radiotherapy techniques.

[0118] Radiosensitization refers to enhancing the sensitivity of tumors to radiation through specific materials or drugs, thereby improving the effectiveness of radiotherapy. For example, high atomic number materials (such as hafnium- or gold-containing nanoparticles) can absorb radiation energy more efficiently, generating more reactive oxygen species that damage DNA, thus enhancing radiation energy deposition. Clinically approved hafnium oxide nanoparticles (trade name NBTXR3), when injected locally into tumors, can increase radiotherapy energy deposition by approximately 30%, but their function is singular and cannot simultaneously achieve precise drug release.

[0119] Metal-organic frameworks (MOFs) are a class of porous crystalline materials formed by chemical bonds between metal ions and organic ligands, possessing high specific surface areas and customizable pore structures. Their porous structures exhibit strong adsorption properties, such as adsorbing functional molecules like drugs or fluorescent molecules. By replacing the metal or ligands or altering the synthesis method, the structural properties of the materials can be adjusted, achieving morphological diversity and designability. In recent years, nano-metal-organic monolayers (nMOLs) have been developed as two-dimensional versions of MOFs, with a single-layer thickness (approximately 1-2 nanometers). Their specific surface area is far greater than that of three-dimensional MOFs; they have more surface active sites, faster mass transfer rates, and are more suitable for chemical modification. However, their synthesis and functionalization techniques are still immature, and existing methods often suffer from low efficiency, operational complexity, or insufficient physiological stability. These problems limit the potential of nMOLs in clinical applications.

[0120] Radiotherapy-activated prodrugs (RAPs) are a class of prodrugs with low toxicity that can be activated and restored to high activity upon irradiation with medical radiotherapy rays (ionizing radiation). The design philosophy of RAPs is to rationally utilize the tumor targeting, tissue penetration (up to 15 cm or more), and high clinical relevance of radiotherapy rays (more than 50% of cancer patients receive radiotherapy). After administration, they remain low in toxicity before exposure to ionizing radiation. Upon irradiation, a chemical reaction occurs, transforming the molecular structure into a highly active form, which then produces a therapeutic effect on the lesion within the irradiated area. Radiotherapy rays primarily mediate the breaking of covalent bonds by radiolyzing water within tumor tissue to generate active substances (such as hydroxyl free radicals or hydrated electrons), releasing the drug to enhance the therapeutic effect of concurrent chemoradiotherapy / immunotherapy while minimizing the systemic toxicity associated with traditional chemotherapy / immunotherapy. However, due to the high reactivity and low selectivity of hydroxyl radicals, as well as the quenching effect of antioxidants widely present in vivo, the development of prodrug strategies for hydroxyl radical responses has encountered numerous difficulties. Therefore, existing radiotherapy-responsive drug technologies mainly focus on the development of hydrated electrons, and the potential of hydroxyl radicals as activators remains to be explored.

[0121] The following examples further illustrate this application, but are not intended to limit the scope of this application.

[0122] Example 1: A method for synthesizing a radiation-activated prodrug compound is provided, specifically including the synthesis of compounds I-1 to I-10:

[0123] 1. Synthesis of compounds a, b, c and d

[0124]

[0125] p-Aminophenol (0.72 mmol, 1.0 equivalent), N-Boc-2-aminoacetaldehyde (0.86 mmol, 1.2 equivalent), and acetic acid (41 μL, 1.0 equivalent) were dissolved in dichloromethane (5 mL) and stirred in an ice-water bath for 1 hour. Then, sodium triacetoxyborohydride (1.1 mmol, 1.5 equivalent) was added, and the reaction was continued for another hour. After the reaction was complete, 20 mL of distilled water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by rapid column chromatography with petroleum ether / ethyl acetate (8:1 to 4:1) to give a yellow oily compound a. Compound a: 1HNMR (400MHz, DMSO-d6) δ6.83(t,J=5.8Hz,1H),6.57-6.50(m,2H),6.45-6.39(m,2H),3.06(t,J=6.3Hz,2H),2.95(t,J=6.8Hz,2H),1.38(s,9H). 13 C NMR(101MHz,DMSO-d6)δ163.01,155.72,148.36,141.41,115.71,113.32,77.63,43.98,28.24.HRMS(ESI + ): m / z calculated value C 13 H 21 N2O3 + ([M+H)) + ):253.1547, Measured value:253.1543.

[0126] Following the same procedure described above, replacing p-aminophenol with an equimolar amount of 4-amino-3-methoxyphenol yields compound c; Compound c: 1 H NMR (400MHz, DMSO-d6) δ8.16 (s, 1H), 6.90 (t, J = 5.7Hz, 1H), 6.39-6.28 (m, 2H), 6.19 (dd, J = 8.4, 2.5Hz,1H),3.70(s,3H),3.10(q,J=6.2Hz,2H),3.00(d,J=6.1Hz,2H),2.07(s,1H),1.38(s,9H). 13 C NMR (101MHz, DMSO-d6) δ163.27,155.92,148.52,147.28,130.70,109.92,106.22,99.54,77.65,55.17,43.81,28.24,1.15.HRMS (ESI + ): m / z calculated value C 14 H 23 N2O4 + ([M+H)) + ):283.1652, Measured value:283.1653.

[0127] Compound a (0.4 mmol, 1.0 equivalent) was dissolved in 2 mL of tetrahydrofuran, and di-tert-butyl dicarbonate (Boc₂O, 0.4 mmol, 1.0 equivalent) was added. The mixture was stirred overnight at room temperature. The solvent was removed by rotary evaporation, and compound b was obtained without further purification. Compound d was prepared by replacing compound a with an equimolar amount of compound c following the same procedure.

[0128] 2. Synthesis of compounds 3, 7, and 8

[0129]

[0130] 7-Amino-4-methylcoumarin (0.28 mmol, 1.0 equivalent) and triethylamine (0.86 mmol, 3.0 equivalent) were dissolved in 3 mL of dichloromethane and cooled to 0 °C with stirring in an ice bath. Triphosgene (0.11 mmol, 0.4 equivalent) was then added, and the resulting solution was stirred at room temperature for 20 minutes. The corresponding phenolic compound (0.28 mmol, 1.0 equivalent) was then added, and the reaction was continued for 4 hours, with the reaction progress monitored by thin-layer chromatography. After the reaction was complete, the solvent was removed by rotary evaporation, and the resulting solid was redissolved in 2 mL of DMF and finally purified by high-performance liquid chromatography (HPLC).

[0131] Compound 3:

[0132] 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),7.72(d,J=8.7Hz,1H),7.56(d,J=2.1Hz,1H),7.45(dd,J=8.7,2.1 Hz,1H),7.09-7.01(m,2H),6.77-6.69(m,2H),6.25(d,J=1.4Hz,1H),2.89(s,6H),2.39(d,J=1.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ159.98,153.81,153.15,152.26,148.49,142.46,140.84, 126.11,122.11,114.62,114.39,112.84,112.08,104.66,40.51,17.99.HRMS(ESI + ): m / z calculated value C 19 H 19 N2O4 + ([M+H)) + ):339.1339, Measured value:339.1341.

[0133] Compound 7:

[0134] 1H NMR (400MHz, DMSO-d6) δ10.60(s,1H),9.47(s,1H),7.71(d,J=8.7Hz,1H),7.55(d,J=2.1Hz,1H),7.44(d d,J=8.7,2.1Hz,1H),7.07-7.00(m,2H),6.82-6.75(m,2H),6.24(d,J=1.5Hz,1H),2.39(d,J=1.3Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ159.99,155.04,153.80,153.14,152.11,142.41,126.10,122.69,115.58,114.67,114.42,112.12,104.72,18.00.HRMS(ESI + ): m / z calculated value C 17 H 14 NO5 + ([M+H)) + ):312.0866, Measured value:312.0869.

[0135] Compound 8:

[0136] 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),7.72(d,J=8.7Hz,1H),7.56(d,J=2.1Hz,1H),7.45(dd,J=8.7,2.1 Hz,1H),7.23-7.14(m,2H),7.02-6.93(m,2H),6.25(d,J=1.3Hz,1H),3.77(s,3H),2.39(d,J=1.3Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ159.96,156.85,153.79,153.12,151.94,143.64,142 .31,126.11,122.80,114.71,114.41,112.15,104.75,55.43,17.98.HRMS(ESI + ): m / z calculated value C 18 H 16 NO5 + ([M+H)) + ):326.1023, Measured value:326.1020.

[0137] 3. Synthesis of compounds I-1, I-2, I-4, I-5, I-6, I-9, and I-10

[0138]

[0139] 7-Amino-4-methylcoumarin (0.28 mmol, 1.0 equivalent) and triethylamine (0.86 mmol, 3.0 equivalent) were dissolved in 3 mL of dichloromethane. After cooling to 0 °C with stirring in an ice bath, triphosgene (0.11 mmol, 0.4 equivalent) was added. The resulting solution was stirred at room temperature for 20 minutes. The corresponding phenolic compound (0.28 mmol, 1.0 equivalent) was added, and the reaction mixture was allowed to react for 4 hours (monitored by thin-layer chromatography). After the reaction was complete, the solvent was removed by rotary evaporation, and the solid was redissolved in 3 mL of dichloromethane. 1 mL of trifluoroacetic acid was added to remove the Boc protecting group. After stirring the mixture for 1 hour, it was purified by HPLC.

[0140] Compound 1 (I-1):

[0141] 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),7.72(d,J=8.7Hz,1H),7.56(d,J=2.0Hz,1H ),7.46(dd,J=8.7,2.1Hz,1H),7.40-7.27(m,4H),6.27-6.20(m,1H),2.39(s,3H). 13 C NMR(101MHz,DMSO-d6)δ159.94,153.75,153.12,151.47,148.38,142.09,131.56,126.14,123.13,114.85,114.52,112.24,104.88,17.99.HRMS(ESI + ): m / z calculated value C 17 H 15 N2O4 + ([M+H)) + ):311.1026, Measured value:311.1026.

[0142] Compound 2 (I-2):

[0143] 1H NMR (400MHz, DMSO-d6) δ10.59(s,1H),7.73(d,J=8.7Hz,1H),7.56(d,J=2.0Hz,1H),7.45(dd,J=8.7,2.1 Hz,1H),7.09-6.92(m,2H),6.73-6.59(m,2H),6.25(d,J=1.5Hz,1H),2.71(s,3H),2.40(d,J=1.3Hz,3H). 13 C NMR (101MHz, DMSO-d6) δ160.00,153.82,153.19,152.28,142.47,126.15,122.35,114.65,114.42,113.04,112.10,104.68,30.75,18.00.HRMS (ESI + ): m / z calculated value C 18 H 17 N2O4 + ([M+H)) + ):325.1183, Measured value:325.1181.

[0144] Compound 4 (I-4):

[0145] 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),7.70(d,J=8.7Hz,1H),7.54(d,J=2.0Hz,1H),7.44(dd ,J=8.7,2.1Hz,1H),6.71(s,2H),6.24(d,J=1.3Hz,1H),2.39(d,J=1.2Hz,3H),2.11(s,6H). 13 C NMR(101MHz,DMSO-d6)δ160.00,153.82,153.15,152.44,142.56,141.51,140.29,126 .08,121.70,120.74,114.56,114.35,112.03,104.59,40.43,17.99,17.79.HRMS(ESI + ): m / z calculated value C 19 H 19 N2O4 + ([M+H)) + ):339.1339, measured value:339.1340.

[0146] Compound 5 (I-5):

[0147] 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),7.72(d,J=8.7Hz,1H),7.53(s,1H),7.44(d,J=8.7Hz,1H),7.35(d, J=2.7Hz,1H),7.24(dd,J=9.0,2.8Hz,1H),6.83(d,J=9.0Hz,1H),6.25(s,1H),6.06(s,2H),2.39(s,3H). 13 C NMR(101MHz,DMSO-d6)δ159.95,153.77,153.12,151.90,149.86,142.19,139.44,128.77, 126.12,124.81,117.34,116.06,114.77,114.45,112.19,104.79,92.98,17.98.HRMS(ESI + ): m / z calculated value C 18 H 14 N3O4 + ([M+H)) + ):336.0979, measured value:336.0981.

[0148] Compound 6 (I-6):

[0149] 1 H NMR (400MHz, DMSO-d6) δ10.56(s,1H),7.73(d,J=8.7Hz,1H),7.56(d,J=2.0Hz,1H),7.46(dd,J=8.7,2.1Hz,1H),6.73(d,J =2.4Hz,1H),6.62(d,J=8.4Hz,1H),6.55(dd,J=8.4,2.4Hz,1H),6.25(d,J=1.4Hz,1H),3.76(s,3H),2.40(d,J=1.2Hz,3H). 13 CNMR(101MHz,DMSO-d6)δ160.00,153.82,153.18,152.36,146.33,142.52,140.62,135.41 ,126.13,114.61,114.40,113.54,112.91,112.08,105.37,104.66,55.55,18.00.HRMS(ESI + ): m / z calculated value C 18 H 17 N2O5+ ([M+H)) + ):341.1132, Measured value:341.1137.

[0150] Compound 9 (I-9): It is named AEAP-AMC.

[0151] 1 H NMR (400MHz, DMSO-d6) δ10.67(s,1H),8.21(d,J=6.4Hz,2H),7.73(d,J=8.7Hz,1H),7.57(d,J=2.0Hz,1H),7.46(dd,J=8.7,2.1Hz ,1H),7.11-7.04(m,2H),6.84(d,J=8.4Hz,2H),6.25(d,J=1.4Hz,1H),3.36(s,2H),3.02(h,J=5.9Hz,2H),2.39(d,J=1.2Hz,3H). 13 C NMR (101MHz, DMSO-d6) δ160.01,153.81,153.20,152.15,142.42,126.14,122.62,114.69,114.47,112.13,104.74,42.04,37.44,18.02.HRMS(ESI + ): m / z calculated value C 19 H 20 N3O4 + ([M+H)) + ):354.1448, Measured value:354.1455.

[0152] Compound 10 (I-10):

[0153] 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),7.98(s,2H),7.72(d,J=8.7Hz,1H),7.58(d,J=2.0Hz,1H),7.45(dd,J=8.7,2.1Hz,1H),6.79(d,J=2.5Hz,1H) ,6.67(dd,J=8.5,2.5Hz,1H),6.59(d,J=8.6Hz,1H),6.24(d,J=1.4Hz,1H ),3.79(s,3H),3.35(t,J=6.3Hz,2H),3.01(q,J=5.6Hz,2H),2.39(s,3H). 13C NMR(101MHz,DMSO-d6)δ163.02,160.00,153.81,153.18,152.33,146.79,142.50,140.82,135.29,126.10,1 14.62,114.45,113.52,112.07,108.47,105.11,104.69,55.64,40.55,38.16,37.86,24.01,17.99.HRMS(ESI + ): m / z calculated value C 20 H 22 N3O + ([M+H)) + ):384.1554, Measured value:384.1555.

[0154] In Example 1 of this application, based on the chemical mechanism of oxidative dearylation of para-aminophenol derivatives, a series of radioactive prodrug compounds were designed as hydroxyl radical responsive groups. Specifically, the structure can be specifically activated by hydroxyl radicals, efficiently releasing the amino group of the masked molecule. Through amino modification, functional molecules such as chemotherapeutic drugs or fluorescent probes can be flexibly linked, supporting modular construction.

[0155] Example 2: A method for synthesizing a radiation-activated prodrug compound is provided, specifically including Examples 2-1 to 2-3.

[0156] Example 2-1 provides a method for preparing an intermediate compound, specifically the synthesis of compound 11 (named BCN-AMC):

[0157]

[0158] BCN-NHS (10 mM) and N,N-diisopropylethylamine (10 mM) were added to a DMF solution (10 mM) of compound 9. The reaction mixture was stirred overnight at room temperature and purified by HPLC to give a white solid compound 11 (named BCN-AMC). 1H NMR (400MHz, DMSO-d6) δ10.72(s,1H),7.73(d,J=8.7Hz,1H),7.57(d,J=2.1Hz,1H),7.46(dd,J= 8.7,2.2Hz,1H),7.36-7.25(m,1H),7.20(d,J=8.4Hz,2H),7.17-7.08(m,2H),6.26(d,J=1.4Hz, 1H),3.88(d,J=6.4Hz,2H),3.24(s,2H),2.59(s,4H),2.39(d,J=1.3Hz,3H),2.30(dd,J=13.3,2 .9Hz,2H),2.20(d,J=13.9Hz,2H),2.11-2.02(m,2H),1.31(d,J=11.4Hz,1H),0.69-0.60(m,2H). 13 C NMR(101MHz,DMSO-d6)δ172.77,169.97,159.98,156.54,153.80,153.17,151.82,142.28,126.16,122.88,114.78,11 4.49,112.19,104.81,98.94,68.06,38.05,32.82,32.57,25.24,23.31,22.66,22.24,20.83,20.68,18.01.HRMS (ESI + ): m / z calculated value C 30 H 32 N3O6 + ([M+H)) + ):530.2286, Measured value:530.2291.

[0159] Example 2-2 provides a method for preparing an intermediate compound, specifically the synthesis of compound 13 (named BCN-Rho):

[0160] 1. Synthesis of compounds 12 (AEAP-Rho) and 13 (BCN-Rho)

[0161]

[0162] MeRho (0.28 mmol, 1.0 equivalent) and triethylamine (0.86 mmol, 3.0 equivalent) were dissolved in 3 mL of dichloromethane. The mixture was cooled to 0 °C with stirring in an ice bath, and then triphosgene (0.11 mmol, 0.4 equivalent) was added. The resulting solution was stirred at room temperature for 20 minutes, followed by the addition of compound b (0.28 mmol, 1.0 equivalent). The reaction mixture was stirred continuously for 4 hours (monitored by thin-layer chromatography). After the reaction was complete, the solvent was removed by rotary evaporation, and the solid was redissolved in 3 mL of dichloromethane and 1 mL of trifluoroacetic acid to remove the Boc protecting group. After stirring the mixture for 1 hour, it was purified by HPLC to finally obtain a yellow solid compound 12. 1 H NMR(600MHz,DMSO-d6)δ10.43(s,1H),8.02(dt,J=7.7,1.0Hz,1H),7.91(s,2H),7.80(td ,J=7.5,1.2Hz,1H),7.73(td,J=7.5,1.0Hz,1H),7.60(d,J=2.1Hz,1H),7.28(dt,J=7.6,0 .9Hz,1H),7.21(dd,J=8.7,2.2Hz,1H),7.00-6.97(m,3H),6.79-6.70(m,2H),6.67(d,J= 8.8Hz,1H),6.66-6.60(m,2H),3.81(s,3H),3.28(t,J=6.3Hz,2H),2.97(h,J=6.1Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ168.67,161.12,152.52,152.40,151.76,151.00,145.91,141.23,141.02,135.77,130.27,128.98,128.72 ,125.80,124.80,123.98,122.45,114.61,112.81,112.56,112.14,110.78,105.23,100.88,82.13,55.71,40.80,38.01.HRMS(ESI + ): m / z calculated value C 30 H 26 N3O6 + ([M+H)) + ):524.1816, measured value:524.1820.

[0163] BCN-NHS (10 mM) and N,N-diisopropylethylamine (10 mM) were added to a DMF solution (10 mM) of compound 12. The reaction mixture was stirred overnight at room temperature and purified by HPLC to give compound 13 as a white solid.1 H NMR (600MHz, DMSO-d6) δ10.41(s,1H),8.02(d,J=7.6Hz,1H),7.79(td,J=7.5,1.2Hz,1H),7.76-7.70(m,1H),7.60(d,J=2.2H z,1H),7.28(d,J=7.6Hz,1H),7.22-7.17(m,2H),7.00(d,J=2.5Hz,1H),6.96-6.92(m,2H),6.77-6.69(m,2H),6.67(d,J=8.8 Hz,1H),6.60-6.55(m,2H),3.87(d,J=6.8Hz,2H),3.81(s,3H),3.14(q,J=6.4Hz,2H),3.07(t,J=6.8Hz,2H),2.50(p,J=1.9H z,3H),2.30(dq,J=13.3,2.9Hz,2H),2.26-2.17(m,2H),2.07(dt,J=16.0,3.5Hz,2H),1.35-1.26(m,2H),0.71-0.61(m,3H). 13 C NMR(151MHz,DMSO-d6)δ168.68,161.12,156.61,152.54,152.45,151.78,151.01,146 .43,141.28,140.47,135.76,135.00,130.25,128.95,128.71,127.95,125.80,124.7 9,123.98,122.34,114.60,112.76,112.16,112.04,110.78,105.20,100.87,98.95,8 2.15,67.89,55.71,43.01,40.06,32.90,32.83,26.59,23.36,22.22,20.84.HRMS(ESI + ): m / z calculated value C 41 H 38 N3O8 + ([M+H)) + ):700.2653, Measured value:700.2663.

[0164] Examples 2-3 provide a method for preparing an intermediate compound, specifically the synthesis of compound 15 (named BCN-Exa):

[0165] 1. Synthesis of Compound 14 (AEAP-Exa) and Compound 15 (BCN-Exa)

[0166]

[0167] Ecinotecan (0.19 mmol, 1.0 equivalent) and triethylamine (0.57 mmol, 3.0 equivalent) were dissolved in 40 mL of dichloromethane and cooled to 0 °C with stirring in an ice bath. Triphosgene (0.08 mmol, 0.4 equivalent) was then added. The resulting solution was stirred at room temperature for 20 minutes, followed by the addition of compound b (0.19 mmol, 1.0 equivalent), and stirred overnight. After the reaction was complete, the solvent was removed by rotary evaporation, and the solid was redissolved in a mixture of 3 mL dichloromethane and 1 mL trifluoroacetic acid to remove the Boc protecting group. After stirring the mixture for 1 hour, it was purified by HPLC to obtain a yellow solid, compound 14. 1 H NMR (600MHz, DMSO-d6) δ8.40(d,J=9.0Hz,1H),7.76-7.69(m,1H),7.31(d,J=1.7Hz,1H),7.05(d,J=8. 6Hz,2H),6.66-6.59(m,2H),5.44(d,J=2.4Hz,2H),5.40-5.34(m,1H),5.29(td,J=8.9,4.5Hz,1H),5. 17-5.09(m,1H),3.27(t,J=6.7Hz,2H),3.17-3.08(m,1H),2.96(t,J=6.3Hz,2H),2.36(d,J=3.6Hz,3H ),2.34-2.27(m,1H),2.15(d,J=10.2Hz,1H),1.88(dhept,J=21.4,7.3Hz,2H),0.88(t,J=7.3Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ172.47,162.42,160.77,156.74,155.31,152.57,152.54,150.02,145.87,145.05,141.63,141.40,136.29,124.95,1 22.65,121.49,119.12,112.48,109.94,109.79,96.73,72.39,65.30,4 9.74,47.93,41.33,38.20,30.35,28.53,24.44,10.96,7.78.HRMS(ESI + ): m / z calculated value C 33 H 33 FN5O6 + ([M+H)) + ):614.2409, Measured value:614.2418.

[0168] BCN-NHS (10 mM) and N,N-diisopropylethylamine (10 mM) were added to a DMF solution (10 mM) of compound 14. The reaction mixture was stirred overnight at room temperature and purified by HPLC to give compound 15 as a white solid.

[0169] The intermediate compound provided in Example 2 of this application contains an alkynyl functional group, which facilitates loading onto nano-hafnium-based metal-organic monolayer materials.

[0170] [Preparation of Hafnium Nanoparticle-Based Metal-Organic Monolayer Materials]

[0171] Synthesis of 1,2'-azido-[1,1':4',1”-terphenyl]-4,4”-dicarboxylic acid

[0172]

[0173] In a 20 mL solution of 2'-amino-[1,1':4',1”-terphenyl]-4,4”-dicarboxylic acid (1 mmol, 1.0 equivalent) in tetrahydrofuran, t-BuONO (2 mmol, 2.0 equivalent) was added at 0 °C in the dark. After stirring the mixture for 30 min, TMS-N (1.5 mmol, 1.5 equivalent) was slowly added dropwise. Stirring was continued for 1 h, followed by reaction at room temperature for 10 h. The mixture was filtered to obtain a yellow solid, which was washed successively with DMF and acetone to finally give 2'-azido-[1,1':4',1”-terphenyl]-4,4”-dicarboxylic acid. 11H NMR (600 MHz, DMSO-d6) δ 8.37 (d, J = 9.0 Hz, 1H), 7.71 (d, J = 10.8 Hz, 1H), 7.31 (s, 1H), 7.20 (t, J = 5.7 Hz, 1H), 7.01 (d, J = 8.3 Hz, 2H), 6.58 (d, J = 8.8 Hz, 2H), 6.54 (s, 1H), 5.62 (t, J = 5.8 Hz, 1H), 5.49 - 5.40 (m, 2H), 5.37 (d, J = 18.6 Hz, 1H), 5.30 (qd, J = 7.9, 4.8 Hz, 1H), 5.12 (d, J = 18.5 Hz, 1H), 3.88 (d, J = 6.7 Hz, 2H), 3.16 - 3.08 (m, 4H), 2.50 (p, J = 1.8 Hz, 2H), 2.35 (d, J = 1.8 Hz, 3H), 2.33 - 2.26 (m, 3H), 2.21 (td, J = 13.3, 7.2 Hz, 2H), 2.14 (dd, J = 9.1, 4.7 Hz, 1H), 2.06 (dt, J = 16.3, 3.7 Hz, 2H), 1.87 (dhept, J = 21.5, 7.3 Hz, 2H), 1.36 - 1.26 (m, 2H), 1.23 (dd, J = 5.4, 2.3 Hz, 1H), 0.88 (t, J = 7.3 Hz, 3H), 0.72 - 0.60 (m, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 172.50, 162.42, 160.77, 156.75, 156.63, 155.37, 152.56, 150.00, 147.93, 147.83, 146.32, 145.04, 141.44, 141.16, 136.32, 136.28, 124.90, 123.78, 123.66, 122.59, 121.48, 119.15, 112.01, 109.94, 109.79, 98.95, 96.73, 72.40, 68.00, 67.91, 65.33, 49.74, 47.94, 43.04, 32.84, 30.35, 29.05, 29.01, 28.55, 26.57, 24.47, 23.52, 23.37, 22.23, 20.84, 11.01, 10.97, 7.80. HRMS (ESI + ): calculated for C 44 H 45 FN5O8 + ([M + H] + ): 790.3247, found: 790.3244.

[0174] 2. Hf12 Synthesis of -NH2

[0175] 40 mL of DMF was added to a 200 mL reaction vessel, followed by the slow addition of 2'-amino-1,1':4,1”-terphenyl-4,4”-dicarboxylic acid (126 mg, 0.38 mmol, dissolved in 40 mL DMF) and hafnium tetrachloride (HfCl4, 240 mg, 0.75 mmol, dissolved in 40 mL DMF). Then, 2.4 mL of propionic acid and 600 μL of distilled water were added, and the mixture was stirred thoroughly. The reaction vessel was placed in an oven at 80 °C for 24 hours. The precipitate was collected by centrifugation and washed with DMF and ethanol. The product was finally dispersed in ethanol to obtain a white HfCl4 solution. 12 The structural characterization of the -NH2 dispersion using transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), and atomic force microscopy (AFM) is shown in [reference needed]. Figure 3 The Fourier transform infrared spectrum is shown below. Figure 4 The UV-Vis absorption spectrum is shown below. Figure 5 The powder X-ray diffraction pattern is shown in [reference needed]. Figure 6 ;Hf 12 The ability of -NH2 to generate hydroxyl radicals under X-ray irradiation in aqueous solution is shown in the figure. Figure 7 .

[0176] 3. Nanoscale hafnium-based metal-organic monolayer materials (Hf 12 Synthesis of -N3)

[0177] Post-modification method: 20mg Hf 12 -NH2 was washed with anhydrous acetonitrile and dispersed in 4 mL of anhydrous acetonitrile. 63 μL of tert-butyl nitrite and 58 μL of trimethylsilyl azide were added, and the mixture was stirred at 0 °C in the dark for 3 hours. The precipitate was collected by centrifugation and washed with DMF and ethanol. The product was finally dispersed in ethanol to give pale yellow Hf. 12 -N3 dispersion.

[0178] Direct synthesis: 2'-azido-[1,1':4',1”-terphenyl]-4,4”-dicarboxylic acid (11.3 mg, 0.03 mmol, dissolved in 5 mL DMF) and hafnium tetrachloride (HfCl4, 20 mg, 0.06 mmol, dissolved in 5 mL DMF) were added to a 20 mL glass bottle. Then, 200 μL of propionic acid and 60 μL of distilled water were added, and the mixture was stirred thoroughly. The reaction vessel was placed in an oven at 80 °C for 24 hours. The precipitate was collected by centrifugation, washed with DMF and ethanol, and finally dispersed in ethanol to obtain a pale yellow HfCl4. 12 -N3 dispersion.

[0179] Structural characterization by transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), and atomic force microscopy (AFM) is shown in [reference needed]. Figure 3 The Fourier transform infrared spectrum is shown below. Figure 4 After N3 modification, Hf 12 -N3 at 2110cm -1 A distinct -N3 characteristic peak appears at [location missing]. After the Click reaction, depending on the modification rate, the -N3 characteristic peak weakens or even almost disappears completely; see the UV-Vis absorption spectrum [image missing]. Figure 5 The powder X-ray diffraction pattern is shown in [reference needed]. Figure 6 Hf 12 The ability of -N3 to generate hydroxyl radicals under X-ray irradiation in aqueous solution is shown in the figure. Figure 7 .

[0180] The hafnium-based metal-organic monolayer (nMOLs, diameter ~150 nm, thickness ~1.7 nm) provided in this application is synthesized from a cluster of 12 hafnium atoms and an aromatic amination ligand. It allows for the efficient conversion of amino groups to azide groups through azidation modification. This hafnium-based metal-organic monolayer can be covalently loaded with the intermediate compound provided in Example 2 via an azido-alkyne cycloaddition reaction, achieving a loading rate greater than 95%. It enables rapid and efficient functionalization of modifiers with small spatial volumes, while maintaining stable morphology after modification. Under quantitative reaction conditions, this platform supports the simultaneous loading of multiple functional molecules, enabling flexible, on-demand functionalization modification of the platform.

[0181] Example 3: A method for preparing organometallic materials loaded with hydroxyl radical-responsive prodrugs is provided, specifically including Examples 3-1 to 3-4.

[0182] Example 3-1 provides a metal-organic material (Hf) loaded with a hydroxyl radical-responsive prodrug. 12 Preparation method of -AMC:

[0183] Hf 12 -N3 (dispersed in 100 μL ethanol, N3 concentration 10 mM) and compound 11 from Example 2-1 (100 μL, 10 mM DMF solution) were added to a 1.5 mL centrifuge tube and incubated overnight at room temperature with shaking. The precipitate was collected by centrifugation, washed with DMF and ethanol, to obtain Hf 12 -AMC. By adjusting the amount of compound 11 added (25, 50, 75, 100 μL, 10 mM DMF solution), Hf with different modification rates can be obtained. 12 - See attached diagram for a schematic diagram of the AMC product and its construction process. Figure 1 The Fourier transform infrared spectrum is shown below. Figure 4 The UV-Vis absorption spectrum is shown below. Figure 5 The powder X-ray diffraction pattern is shown in [reference needed]. Figure 6 The ability of Hf12-AMC to generate hydroxyl radicals under X-ray irradiation in aqueous solution is shown in [reference needed]. Figure 7 Comparison of AMC release efficiencies of AEAP-AMC, BCN-AMC, and Hf12-AMC under X-ray irradiation. Figure 8 The efficiency of AMC release from AEAP-AMC and Hf12-AMC under X-ray irradiation in different hydroxyl radical quenchers is shown in [reference needed]. Figure 10 .

[0184] Example 3-2 provides organometallic materials (Hf) loaded with hydroxyl radical-responsive prodrugs. 12 Preparation method of -Rho):

[0185] Hf 12 -N3 (dispersed in 100 μL ethanol, N3 concentration 10 mM) and compound 13 from Example 2-2 (100 μL, 10 mM DMF solution) were added to a 1.5 mL centrifuge tube and incubated overnight at room temperature with shaking. The precipitate was collected by centrifugation, washed with DMF and ethanol, to obtain Hf 12 -Rho, Fourier transform infrared spectrum (see...) Figure 4 The UV-Vis absorption spectrum is shown below. Figure 5 The powder X-ray diffraction pattern is shown in [reference needed]. Figure 6 .

[0186] Examples 3-3 provide organometallic materials (Hf) loaded with hydroxyl radical-responsive prodrugs. 12 Preparation method of -Exa):

[0187] Hf 12 -N3 (dispersed in 100 μL ethanol, N3 concentration 10 mM) and compound 15 from Examples 2-3 (100 μL, 10 mM DMF solution) were added to a 1.5 mL centrifuge tube and incubated overnight at room temperature with shaking. The precipitate was collected by centrifugation, washed with DMF and ethanol, to obtain Hf 12 -Exa, Fourier transform infrared spectrum (see Exa) Figure 4 The UV-Vis absorption spectrum is shown below. Figure 5 The powder X-ray diffraction pattern is shown in [reference needed]. Figure 6 .

[0188] Examples 3-4 provide organometallic materials (Hf) loaded with hydroxyl radical-responsive prodrugs. 12 Preparation method of -AMC-Rho-Exa):

[0189] Hf 12-N3 (dispersed in 100 μL ethanol, N3 concentration 10 mM), compound 11 (25 μL, 10 mM DMF solution), compound 13 (25 μL, 10 mM DMF solution), and compound 15 (25 μL, 10 mM DMF solution) were added to a 1.5 mL centrifuge tube and incubated overnight at room temperature with shaking. The precipitate was collected by centrifugation and washed with DMF and ethanol to obtain Hf. 12 -AMC-Rho-Exa,Hf 12 Simultaneous quantitative modification of multi-component functional molecules with AMC-Rho-Exa is described in [link to documentation]. Figure 9 Simulated structure of Hf12-AMC-Rho-Exa (a), transmission electron microscopy image (b), high-resolution transmission electron microscopy image (c), and release of functional molecules under X-ray irradiation (d).

[0190] The organometallic material provided in Example 3 of this application utilizes the high atomic number effect of hafnium to enhance radiation energy deposition, achieving a 100% increase in release efficiency compared to bulk aqueous solutions. The covalently bonded AEAP-prodrug structure is less than 5 nm from the surface of nMOLs, and the spatial proximity effect causes the activation reaction to occur with high priority. For example, the radiation activation efficiency of AEAP is 2.5 times higher than that of similar structures previously reported, making it one of the most efficient responding groups reported to date.

[0191] Example 1: Quantitative Analysis of Radiation-Activated Drug Release

[0192] For small molecules (using compound 1 as an example): A DMF solution (10 mM) of compound 1 was diluted to 10 μM with PBS (0.01 M, pH 7.4). The solution was then irradiated with X-rays at different absorbed doses. The reaction mixture was analyzed by UPLC-MS, and the release of the target molecule was quantified using a standard curve. Figure 2 ).

[0193] For Hf 12 -MOLs (with Hf) 12 (Taking AMC as an example): Hf 12 A DMF solution of AMC (10 mM) was diluted to 100 μM with PBS (0.01 M, pH 7.4). After irradiation with different absorbed doses of X-rays, an equal volume of DMF solution containing 5% H3PO4 was added for digestion. The reaction mixture was analyzed by UPLC-MS, and the release of the target molecule was quantified using a standard curve.

[0194] Example 2: Effects of OH quencher on AEAP-AMC and Hf under X-ray irradiation 12 -The effect of AMC releasing AMC

[0195] Add AEAP-AMC to PBS solution (200mM) or Hf 12 - PBS dispersion (200 mM) of AMC was mixed with equal volumes of vitamin C solution (20 mM), HCOONa solution (20 mM), GSH solution (20 mM), IPA solution (20 mM), or RPMI-1640 medium containing 10% fetal bovine serum (FBS). After irradiation with 20 Gy X-rays, the reaction mixture was analyzed by UPLC-MS, and the released AMC was quantified using a standard curve. AEAP-AMC and Hf 12 The efficiency of AMC release under X-ray irradiation in different hydroxyl radical quenchers is shown in the figure. Figure 10 .

[0196] Example 3Hf 12 -N3 and Hf 12 -Rho's cytotoxicity studies

[0197] 4T1 cells and MC38 cells were seeded in 96-well plates (1 × 10⁶ cells per well). 4 Cells were cultured for 12 hours. Then, they were treated with different concentrations of Hf. 12 -N3 or Hf 12 Cells were treated with Rho medium (Hf concentrations of 0, 12.5, 25, 50, 100, 200, and 400 μM). After incubation for 48 hours, the cells were washed three times with PBS, and cell viability was analyzed using a standard CCK-8 assay. The specific steps were as follows: cells were treated with 0.5 mg / mL Rho medium. -1 After incubating the CCK-8 culture medium at 37°C for 40 minutes, the absorbance was measured at 450 nm using a microplate reader. The absorbance of the treatment group was compared with that of the control group (cell viability set to 100%) to calculate cell viability. 12 -N3(a) and Hf 12 Cytotoxicity assessment of -Rho(b) can be found in [link to relevant documentation]. Figure 11 .

[0198] Example 4: AEAP-Rho and Hf 12 Research on intracellular release of MeRho by -Rho

[0199] 4T1 cells were seeded in 35 mm confocal culture dishes (2 × 10⁻⁶ cells / mL). 5 Cultured in 10 μM cells for 12 hours. Then treated with AEAP-Rho (10 μM) or Hf. 12Cells were treated with AEAP-Rho (MeRho concentration 10 μM) medium. After incubation for 24 hours, the cells were washed three times with PBS and then irradiated with 0, 8, and 16 Gy X-rays, respectively. Confocal fluorescence images were captured using a Nikon A1R-si laser scanning confocal microscope with an excitation wavelength of 488 nm and a fluorescence emission window of 500-530 nm. All cells in the images were selected as regions of interest (ROIs), and fluorescence intensity, AEAP-Rho, and Hf were quantitatively analyzed using ImageJ software. 12 The efficiency of MeRho release under X-ray irradiation in 4T1(a) and MC38(b) cells is shown in [reference needed]. Figure 12 .

[0200] Example 5: Cell Viability Detection

[0201] Exatecan, AEAP-Exa and Hf 12 -Exa cytotoxicity assay: 4T1 and MC38 cells were seeded in 96-well plates (1 × 10⁶ cells per well). 4 Cells were cultured for 12 hours. They were then treated with different concentrations of Exatecan, AEAP-Exa, or Hf. 12 Cells were treated with Exa medium. After incubation for 48 hours, cells were washed with PBS, and cell viability was analyzed using a standard CCK-8 assay.

[0202] Hf under X-ray irradiation 12 -N3 and Hf 12 -Exa cytotoxicity assay: 4T1 and MC38 cells were seeded in 96-well plates (1 × 10⁶ cells per well). 4 Cells were cultured for 12 hours. They were then incubated with PBS and Hf... 12 -N3 or Hf 12 Cells were treated with Exa (3 μM Hf, 1 μM Exatecan) medium for 12 hours, followed by X-ray irradiation (0, 4, 8 Gy). After irradiation, cells were cultured for another 48 hours, washed with PBS, and cell viability was analyzed using a standard CCK-8 assay. 12 -N3 and Hf 12 -Exa showed cytotoxicity under X-ray irradiation in both 4T1(a) and MC38(b) cell lines as follows: Figure 13 ;Hf 12 -N3 and Hf 12 -Exa's ability to cause DNA double-strand damage under X-ray irradiation in 4T1 cells, see Figure 14 .

[0203] Example 6: γ-H2AX Immunofluorescence Analysis

[0204] 4T1 cells were seeded in 35 mm confocal culture dishes (2 × 10⁻⁶ cells / mL). 5 Cultured in 1 cell for 12 hours. Then, cultured with PBS and Hf... 12 -N3 and Hf 12 Cells were treated with Exa (3 μM Hf, 1 μM Exatecan) medium. After incubation for 12 hours, the cells were washed three times with PBS, followed by X-ray irradiation at 0 or 8 Gy and cultured for another 24 hours. Cells were washed three times with PBS, fixed with 4% paraformaldehyde at room temperature for 15 minutes, washed three times with PBS, permeabilized with PBS containing 0.1% Triton at room temperature for 10 minutes, and blocked with PBS containing 1% BSA at 4°C for 1 hour. The supernatant was discarded, and Anti-γ-H2AX primary antibody (diluted 200-fold in PBS containing 1% BSA) was added, followed by incubation at 4°C for 12 hours. After washing three times with PBS, Cy5-conjugated sheep anti-mouse secondary antibody (diluted 500-fold in PBS containing 1% BSA) was added, and incubation was performed at 4°C for 1 hour, followed by washing three times with PBS. Cell nuclei were stained with DAPI, mounted with an anti-fluorescence quencher, and photographed using a confocal fluorescence microscope. All cell nuclei in the image were selected as regions of interest (ROIs), and the fluorescence intensity was quantitatively analyzed using ImageJ software.

[0205] Example 7H 12 -In vivo antitumor efficacy study of Exa

[0206] Establishment of tumor model: Female BALB / c mice were subcutaneously injected with 4T1 cells (1×10⁻⁶) in the right shoulder. 6 (100 cells, dispersed in 50 μL PBS). The length (L) and width (W) of the tumor were measured using digital calipers and calculated according to the formula V = 1 / 2 × L × W. 2 Calculate the tumor volume.

[0207] When the tumor volume in 4T1 tumor-bearing mice reaches 80–100 mm... 3 At the same time, intratumoral injections were performed: PBS (20 μL) and Hf. 12 -N3 (200 μg dispersed in 20 μL PBS) or Hf 12 -Exa (200 μg dispersed in 20 μL PBS). Tumor sites were irradiated with 4 Gy X-rays at 12 and 36 hours post-injection. Tumor size and mouse weight were recorded every two days. Mice were sacrificed on day 20, tumor tissue was isolated, weighed, photographed, and analyzed using H&E staining of major organs in each group.

[0208] The inhibitory effects of different treatment groups on tumor growth in 4T1 tumor-bearing mice are shown in the figure. Figure 15 .

[0209] Therefore, the design method provided in this application has good application prospects in the treatment of malignant tumors.

[0210] The above description is merely a preferred embodiment of this application, but the scope of protection of this application is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in this application should be included within the scope of protection of this application. Therefore, the scope of protection of this application should be determined by the scope of the claims.

Claims

1. A radiation-activated prodrug compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, characterized in that: The compound has the structure of Formula I: A is any therapeutic agent or chromogenic agent capable of being linked to the ester moiety of a compound of formula I, wherein A is capable of separating from the ester moiety under radiation and releasing a therapeutically active or chromogenic component.

2. The prodrug compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, characterized in that: The compound can be specifically activated by hydroxyl radicals; Preferably, the compound can serve as a prodrug molecule that responds to hydroxyl radicals; and / or; When the compound is present with water and under radiation, the ester group in the compound of formula I is removed, and A is released. Preferably, the release rate of the compound under radiation is less than or equal to 100%.

3. The prodrug compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, characterized in that: A is a fluorescent group or a pharmaceutical group; Preferably, A is a drug group for treating cancer; Preferably, A is a drug group for chemotherapy or radiotherapy; Preferably, A is a radiotherapy or chemotherapy drug containing an amino group or a colorimetric component containing an amino group, and the amino group is linked to the ester group of the compound of formula I. and / or; R1 represents substituted or unsubstituted C6-C. 10 Aryl, substituted or unsubstituted C6-C 10 Any of the heteroaryl groups; each of the substituents is independently selected from one or more of the following: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH-(C1-C6 alkylene)-NH2.

4. The prodrug compound according to claim 3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, characterized in that: R1 is a substituted or unsubstituted phenyl group, and each substituent is independently selected from any one or more of the following: C1-C6 alkyl, C1-C6 alkoxy, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH-(C1-C6 alkylene)-NH2; and / or; A is selected from 7-amino-4-methylcoumarin or MeRho as a fluorescent group; and / or; A is selected from eczema as a pharmaceutical group.

5. The prodrug compound according to claim 3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, characterized in that: R1 is selected from any of the following groups: Preferably, the compound of formula I has any one of the following structures:

6. An intermediate compound, characterized in that: include: Alkyne functional group: used to replace the hydrogen atom in the prodrug compound according to any one of claims 1 to 5, and covalently linked with the prodrug compound to form the intermediate compound; The intermediate compound contains a ring-strained alkyne functional group.

7. The intermediate compound according to claim 6, characterized in that: The ring-strained alkyne functional group includes any one of the following groups: Preferably, the intermediate compound has any one of the following structural formulas:

8. A metal-organic monolayer material loaded with a hydroxyl radical-responsive prodrug, characterized in that, include: At least one of the intermediate compounds according to any one of claims 6 to 7; Nano-hafnium-based metal-organic monolayer material: used for loading the intermediate compound; The intermediate compound and the nano-hafnium-based metal-organic monolayer material have covalent bonds; Preferably, the intermediate compound forms the covalent bond with the nano-hafnium-based metal-organic monolayer material through an addition reaction.

9. The metal-organic monolayer material according to claim 8, characterized in that, The nano-hafnium-based metal-organic monolayer material is obtained by modifying hafnium atom clusters with carboxyl groups of terphenyl dicarboxylic acid ligands through coordinate bonds; Preferably, the terphenyl ligand comprises an azide group or contains a functional group that can be converted into an azide group; Preferably, the terphenyl phthalic acid ligand has any one of the following structures: In Formula II-3, X is selected from any one of Cl, Br, I, and -OSO2CF3.

10. The metal-organic monolayer material according to claim 9, characterized in that, The intermediate compound forms the covalent bond with the nano-hafnium-based organometallic monolayer material through an azide-alkyne addition reaction; and / or; The distance between the surface of the nano-hafnium-based metal-organic monolayer material and the prodrug compound in the intermediate compound is less than 10 nm; Preferably, less than 8nm; Preferably, it is less than 5nm.

11. A method for treating or diagnosing a disease, characterized in that: The method includes administering to an individual the prodrug compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof; or; Applying the metal-organic monolayer material according to any one of claims 8 to 10 to an individual; The individual was then irradiated with a therapeutically effective dose.

12. The method according to claim 11, characterized in that: The method is used to treat or suppress cancer, reduce its severity, reduce its risk, or inhibit its metastasis in an individual. Preferably, the cancer is selected from one or more of breast cancer, colorectal cancer, lung cancer, and stomach cancer; And / or; the radiation is high-energy radiation, preferably X-rays or gamma rays; Preferably, the intensity of the X-rays or gamma rays is less than or equal to 60 Gy; Preferably, the intensity of the X-rays or gamma rays is less than or equal to 20 Gy; Preferably, the intensity of the X-rays or gamma rays is less than or equal to 10 Gy; Preferably, the intensity of the X-rays or gamma rays is less than or equal to 4 Gy.

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