Pt(iv) chemotherapy prodrugs and their controlled release for the treatment of tumors

Abstract

A Pt(Ⅳ) complex is provided, which, as a prodrug, is activated by irradiation to release a Pt(II) complex for treating tumors. A pharmaceutical composition comprising said Pt(Ⅳ) complex is also provided, as well as the use of said Pt(Ⅳ) complex in the preparation of a medicament for irradiation-activated treatment of tumors. A kit comprising said Pt(Ⅳ) complex and instructions for use, the instructions indicating that radiotherapy should be administered after administration to treat tumors, is also provided.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry. Specifically, this invention relates to a Pt(Ⅳ) chemotherapeutic prodrug and its controlled release for the treatment of tumors. Background Technology

[0002] Cancer is one of the most serious diseases threatening human life and health in modern times. Surgery, radiotherapy, and chemotherapy are collectively known as the three major treatment methods for cancer.

[0003] Radiation therapy is a local treatment method that uses radiation to treat tumors. The effectiveness of radiation therapy depends on radiosensitivity; different tissues and organs, as well as various tumor tissues, react differently after being irradiated. For example, fibrosarcoma, osteosarcoma, and melanoma are radiation-resistant tumors. Radiation therapy cannot kill all cancer cells in a tumor, and its effectiveness in killing hypoxic cancer cells is very limited.

[0004] Chemotherapy aims to kill cancer cells using chemical drugs. Divalent platinum-based drugs possess highly effective and broad-spectrum anticancer activity and have become important first-line chemotherapy drugs in clinical practice, widely used to treat common malignant tumors such as lung cancer, bladder cancer, ovarian cancer, cervical cancer, esophageal cancer, gastric cancer, colorectal cancer, and head and neck tumors. First-generation platinum-based anticancer drugs are represented by cisplatin; second-generation by carboplatin and nedaplatin; and third-generation by oxaliplatin and levoplatin. Side effects of divalent platinum-based drugs, such as nephrotoxicity, gastrointestinal toxicity, hematologic toxicity, neurotoxicity, and ototoxicity, limit their application, and tumor resistance also limits their therapeutic efficacy. To expand the range of platinum-based drugs, research has also been conducted on tetravalent platinum-based drugs. Tetravalent platinum compounds themselves have relatively low cancer-killing ability; however, they can exert anticancer activity by being reduced under physiological conditions and releasing divalent platinum. This retains the broad-spectrum and highly effective anticancer advantages of traditional divalent platinum-based drugs, while also offering unique advantages due to the different coordination structure of tetravalent platinum compared to divalent platinum. Tetravalent platinum has a d2sp3 six-coordinate structure, which is more stable than divalent platinum, thus resulting in higher blood stability. The axial presence of two additional ligands in tetravalent platinum complexes provides more options for the design of platinum-based drugs. However, although some tetravalent platinum complexes, such as isopropylplatin or ceterplatin, entered clinical trials in the last century, no tetravalent platinum drugs have been approved for marketing to date.

[0005] Therefore, there is still a need to develop platinum-based drugs and / or platinum-based treatment regimens with lower toxicity and higher efficacy. Summary of the Invention

[0006] Through in-depth research and creative work, the inventors have discovered that Pt(Ⅳ) complexes can be used as prodrugs. These prodrugs, upon irradiation, release divalent platinum drugs to treat tumors. Furthermore, by efficiently combining radiotherapy with Pt(Ⅳ) complexes—that is, by utilizing radiation activation for the controlled release of Pt(Ⅳ) complexes—the therapeutic effect can be effectively improved.

[0007] On the one hand, this disclosure provides a Pt(Ⅳ) complex of formula (I) for use as a prodrug activated by irradiation in the treatment of tumors.

[0008]

[0009] L1 to L6 are platinum ligands; after irradiation, this complex can release L5 and L6 to obtain the Pt(II) complex of formula (II).

[0010]

[0011] Optionally, the Pt(II) complex of formula (II) is a cis-configuration Pt(II) complex. For example, the Pt(II) complex of formula (II) is cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin, heptaplatin, cycloplatin, miboplatin, enloplatin, sebriplatin, spiroplatin, Zeniplatin, TRK-710, aroplatin, bis(isopropylamine)platin(II), or bis(cyclopentanamine)platin(II). In a preferred embodiment, the Pt(II) complex of formula (II) is cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin, or heptaplatin.

[0012] Optionally, L5 and L6 can be independently configured. - OC(O)-R, where R is selected from optionally substituted C 1-20 Alkyl, optionally substituted C 1-20 Alkyloxy or optionally substituted amino groups, wherein the substituents are selected from C 1-18 Alkyl, carboxyl, hydroxyl, halogen, mercapto, amino, dicarbon 1-3 Alkylamine, carbonyl, phenyl, halophenyl, C 1-6Alkyl-substituted phenyl, maleimide, or triphenylphosphonium. For example, R is independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, nonadecanyl, eicosyl, carboxymethyl, 2-carboxyethylidene, 3-carboxypropylidene, 4-carboxybutylidene, 5-carboxypentylidene, 6-carboxyhexylidene, (dimethylamino)methylene, 2-(dimethylamino)ethylidene, 3-(dimethylamino)propylidene, 4-(dimethylamino)butylidene, 5-(dimethylamino)pentylidene, 6-(dimethylamino)hexylidene, 5- Maleimide-pentylene, 6-maleimide-hexylene, 7-maleimide-heptylene, 8-maleimide-octylene, 3-(4-iodophenyl)propylene, 3-(3-iodophenyl)propylene, 3-(3,5-diiodophenyl)propylene, 3-(4-bromophenyl)propylene, 3-(3-bromophenyl)propylene, 3-(3,5-dibromophenyl)propylene, methylamino, ethylamino, propylamino, butylamino, pentamino, hexamino, heptanamino, octamino, nonamino, decamino, undecylalkylamino, dodecylalkylamino, tridecylalkylamino, tetradecylalkylamino, pentadecylalkylamino, hexadecylalkylamino, heptadecanylalkylamino, octadecylalkylamino.

[0013] Optionally, the tumor may be leukemia, lung cancer, malignant lymphoma, breast cancer, ovarian cancer, soft tissue sarcoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, blastoma, neuroblastoma, bladder cancer, thyroid cancer, prostate cancer, head and neck tumors, nasopharyngeal carcinoma, esophageal cancer, testicular cancer, gastric cancer, liver cancer, pancreatic cancer, cervical cancer, endometrial cancer, melanoma, or colorectal cancer.

[0014] In another aspect, this disclosure provides a pharmaceutical composition comprising the above-mentioned Pt(Ⅳ) complex.

[0015] On the other hand, this disclosure also provides the use of the above-mentioned Pt(Ⅳ) complex in the preparation of a medicament for the irradiation-activated treatment of tumors. Optionally, the irradiation is derived from radiotherapy.

[0016] In another aspect, this disclosure also provides a method for treating tumors, comprising: administering the above-mentioned Pt(Ⅳ) complex to a subject, and irradiating the subject.

[0017] Optionally, the irradiation is derived from radiotherapy.

[0018] Optionally, the radiotherapy is performed 0.5-6 hours after administration of the Pt(Ⅳ) complex.

[0019] In one implementation, the radiation dose is less than 60 Gy.

[0020] Optionally, the tumor may be leukemia, lung cancer, malignant lymphoma, breast cancer, ovarian cancer, soft tissue sarcoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, blastoma, neuroblastoma, bladder cancer, thyroid cancer, prostate cancer, head and neck tumors, nasopharyngeal carcinoma, esophageal cancer, testicular cancer, gastric cancer, liver cancer, pancreatic cancer, cervical cancer, endometrial cancer, melanoma, or colorectal cancer.

[0021] In another aspect, this disclosure provides a kit comprising:

[0022] The above-mentioned Pt(Ⅳ) complex or the above-mentioned pharmaceutical composition containing Pt(Ⅳ) complex, and

[0023] The instructions state that radiation therapy should be administered after drug administration to treat tumors. Attached Figure Description

[0024] To more clearly illustrate the technical solutions of the embodiments of this disclosure, the accompanying drawings of the embodiments will be briefly described below. Obviously, the drawings described below only relate to some embodiments of this disclosure and are not intended to limit the invention.

[0025] Figure 1 The broad spectrum of radiation-reduced metal ions is described.

[0026] Figure 2 The broad spectrum of radiation-reduced metal complexes is described.

[0027] Figure 3 This paper describes radiation-driven Pt(Ⅳ) complexes for the broad-spectrum and efficient release of FDA-approved Pt(Ⅱ) drugs.

[0028] Figure 4 The study describes how radiation-induced release of oxaliplatin can be effectively controlled in living cells.

[0029] Figure 5 This study describes a radiotherapy-driven reduction and release of oxaliplatin from the prodrug oxaliplatin (Ⅳ)-(OAc)2 for use in oxaliplatin-sensitive HCT116 cell line tumors, enabling combined radiotherapy and chemotherapy. Detailed Implementation

[0030] To make the objectives, technical solutions, and advantages of the embodiments of this disclosure clearer, the technical solutions of the embodiments of this disclosure will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this disclosure. All other embodiments obtained by those skilled in the art based on the described embodiments of this disclosure without creative effort are within the scope of protection of this invention.

[0031] This invention may be implemented in other specific forms without departing from its essential attributes. It should be understood that, without conflict, any and all embodiments of this invention can be combined with technical features of any or more other embodiments to obtain further embodiments. This invention includes such combinations to obtain further embodiments.

[0032] All publications and patents mentioned in this disclosure are incorporated herein by reference in their entirety. In the event of any conflict between the use or terminology used in any publications and patents incorporated by reference and the use or terminology used in this disclosure, the use and terminology of this disclosure shall prevail.

[0033] The chapter titles used in this article are for organizational purposes only and should not be construed as limiting the subject matter.

[0034] Unless otherwise specified, all technical and scientific terms used herein have their usual meaning in the field to which the claimed subject matter pertains. Where multiple definitions exist for a term, the definition herein shall prevail.

[0035] Unless otherwise indicated in the working embodiments or elsewhere, all figures set forth in the specification and claims expressing the amount of material, reaction conditions, duration, and quantitative properties of the material shall be understood to be modified by the term "about" in all cases. It should also be understood that any numerical range listed herein is intended to include all subranges within that range and any combination of the endpoints of that range or subrange, such as alkyl groups having 1-20 carbon atoms (C... 1-20 Alkyl groups include alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, and also include subranges of alkyl groups having 1-4, 1-6, 1-10, 2-4 or 2-10 carbon atoms.

[0036] This disclosure 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.

[0037] As used herein, the words “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. 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”.

[0038] It should be understood that the singular form used in this disclosure (such as "a") may include plural references unless otherwise specified.

[0039] Unless otherwise specified, this disclosure employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, organic synthetic chemistry, and coordination chemistry. Unless otherwise stated, this disclosure employs conventional methods of mass spectrometry and elemental analysis, and the steps and conditions can be referred to conventional operating procedures and conditions in the art.

[0040] The reagents and raw materials used in this disclosure are commercially available or can be prepared by conventional chemical synthesis methods.

[0041] The term "optional" is used herein to describe a situation that may or may not occur. For example, "optionally fused with a ring" means that it is fused with a ring or not fused with a ring. For example, the term "optionally substituted" as used herein means unsubstituted or having at least one non-hydrogen substituent that does not impair the desired properties possessed by the unsubstituted analogue.

[0042] In this disclosure, unless otherwise specified, the number of "substitutes" may be one or more; when there are multiples, there may be two, three, or four. Furthermore, when there are multiple "substitutes," the "substitutes" may be the same or different.

[0043] In this disclosure, the position of "replace" may be arbitrary unless otherwise specified.

[0044] The term "axial ligand" used in this article refers to the d-ligand of tetravalent platinum. 2 sp 3 The two axial ligands in the six-coordinate structure detach from the complex after irradiation reduction.

[0045] The term "lateral ligand" used in this article refers to the d-ligand of tetravalent platinum. 2 sp 3 The four transverse ligands in the six-coordinate structure can still coordinate with divalent platinum ions after the complex is irradiated and reduced.

[0046] The term “neutral ligand” or “anionic ligand” as used in this article refers to a ligand that can coordinate with platinum, which is generally uncharged or negatively charged, but may have local cations such as triphenylphosphonium or ammonium groups.

[0047] In the context of this application, unless specifically stated otherwise, the term "treatment" may also include prevention.

[0048] The terms “subject” or “patient” in this application include both humans and mammals.

[0049] The term "C1-C" used in this article 20"Alkyl" refers to a straight-chain or branched alkane chain containing 1 to 20 carbon atoms. Representative examples of C1-C6 alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "lower alkyl" refers to a straight-chain or branched alkyl group having 1 to 4 carbon atoms. "Substituted alkyl" refers to an alkyl group substituted at any available linker with one or more substituents, preferably 1 to 4 substituents. The term "halogenated alkyl" refers to an alkyl group having one or more halogen substituents, including but not limited to groups such as -CH2Br, -CH2I, -CH2Cl, -CH2F, -CHF2, and -CF3.

[0050] As used herein, the term "alkylene" refers to a divalent hydrocarbon group having two connection points, as described above for "alkyl". For example, methylene is a -CH2- group, and ethylene is a -CH2-CH2- group.

[0051] As used herein, the terms “alkoxy” and “alkylthio” refer to the alkyl group as described above, which is connected via an oxygen bond (-O-) or a sulfur bond (-S-), respectively. The terms “substituted alkoxy” and “substituted alkylthio” refer to the substituted alkyl group, which is connected via an oxygen bond or a sulfur bond, respectively. “Lower alkoxy” is the group OR, where R is a lower alkyl group (an alkyl group containing 1 to 4 carbon atoms).

[0052] The term "halogen" as used in this article refers to fluorine, chlorine, iodine, or bromine.

[0053] The radiation source disclosed herein may be alpha, beta, or gamma rays produced by the decay of radioactive nuclides. X-rays, gamma rays, high-energy electrons, protons, heavy ions, and alpha particles produced by boron neutron capture therapy (BNCT), as well as other possible exogenous or endogenous radiation, produced by external radiation sources may also be applicable to this disclosure.

[0054] High-energy rays used in radiotherapy possess high spatiotemporal resolution and high tissue penetration capability, while also exhibiting high clinical relevance. Utilizing high-energy rays in radiotherapy to activate prodrug molecules and initiate chemical reactions in vivo has both basic research value and clinical application value.

[0055] High-energy ray-activated chemical reactions involve the radiation of water to produce a large number of reactive substances, which then react with the target substrate. Among the products of water radiation, the compounds with the highest yields are hydroxyl radicals and hydrated electrons.

[0056] Living organisms generally exist in a reducing environment, where substances such as glutathione and vitamin C quench hydroxyl radicals and increase the production of hydrated electrons. Therefore, utilizing hydrated electrons in chemical reactions would be a major breakthrough in living chemistry.

[0057] High-energy rays (such as X-rays and gamma rays) can be used as external stimuli to reduce tetravalent platinum complexes to divalent platinum complexes. Due to the high penetrating power and high spatiotemporal resolution of these rays, prodrugs can be converted into divalent platinum complexes very efficiently using radiotherapy equipment. For example, X-ray irradiation, as an external trigger for activating prodrugs, allows for precise control over the area, time, and dose at which the prodrug is converted to its active form, as the radiation-induced chemical reaction can be controlled both spatially and temporally.

[0058] This disclosure utilizes the instantaneous and efficient reduction of metal complexes by radiation to achieve the release of Pt(II) drugs from Pt(IV) prodrugs, thus enabling the controlled release of chemotherapeutic drugs. Therefore, by using radiation to reduce Pt(IV) prodrugs with low toxicity to release Pt(II) drugs such as oxaliplatin, various oxaliplatin-sensitive cell lines can be effectively inhibited. In HCT116 tumor-bearing mice, this strategy resulted in near-complete tumor regression. This reduction is achieved through the generation of hydrated electrons (e) via water irradiation. aq - This is mediated by radiotherapy and is suitable for the hypoxic, reducing tumor microenvironment. Therefore, the strategy of using radiotherapy to activate prodrug release of chemotherapeutic drugs has certain potential clinical value.

[0059] More than 50% of cancer cases require radiotherapy. Modern radiotherapy techniques can precisely irradiate tumors and deliver high doses of radiation locally.

[0060] Cancer's response to radiation can be described by its radiation sensitivity. Highly radiation-sensitive cancer cells (leukemia, most lymphomas, and germ cell tumors) are rapidly killed by moderate doses of radiation. Moderately radiation-sensitive cancer cells (most epithelial cancers) require higher doses (60-70 Gy) to be completely killed. Some cancers (renal cell carcinoma and melanoma) are remarkably radiation-resistant, requiring doses much higher than clinically safe for a cure. Many common, moderately radiation-responsive tumors are typically treated with radiation therapy if they are in their early stages. Metastatic cancers are usually not curable with radiation therapy because it is impossible to treat the entire body.

[0061] Radiation therapy itself is painless. Many low-dose palliative treatments (e.g., radiation therapy for bone metastases) cause few or no side effects. Higher doses can lead to a variety of side effects, including acute side effects during treatment, side effects months or years after treatment (long-term side effects), or side effects after retreatment (cumulative side effects). The nature, severity, and duration of side effects depend on the organ receiving radiation, the type of radiation, the dose, the fractionation, concurrent chemotherapy, and the patient. Side effects are dose-dependent; for example, higher doses of head and neck radiation can cause cardiovascular complications, thyroid dysfunction, and pituitary axis dysfunction. Modern radiation therapy aims to minimize side effects and help patients understand and manage the unavoidable side effects.

[0062] Radiation therapy destroys the DNA of cancer cells through photons or charged particles. This involves the direct or indirect ionization of atoms that make up the DNA strand. Indirect ionization occurs through the ionization of water to form free radicals that then damage DNA. Cells have mechanisms to repair DNA damage; however, double-stranded DNA breaks are more difficult to repair and can lead to significant chromosomal abnormalities and gene deletions. Targeting double-strand breaks increases the likelihood of cell death. In the 1950s, experiments by Gray et al. showed that killing hypoxic cells required three times the radiation dose compared to normoxic cells. Since normal tissues have limited tolerance to radiation, it is generally impossible to increase the radiation dose to compensate for tumor hypoxia. After radiation therapy, hypoxic tumor cells may persist and divide, leading to tumor persistence and the development of a more aggressive tumor phenotype.

[0063] Radiotherapy faces challenges due to two main issues: firstly, the clinically permissible radiation dose is limited (generally less than 60 Gy); secondly, hypoxic tumors often develop resistance to radiotherapy, hindering oxygen fixation and preventing DNA damage caused by radiation. Therefore, radiotherapy often needs to be combined with chemotherapy to improve tumor cure rates. However, most clinically approved anticancer drugs have narrow therapeutic windows and high systemic toxicity, often necessitating prodrug strategies to further increase dosage and reduce toxicity. Prodrug dosages can exceed normal doses by 50 times and can overcome tumor resistance to chemotherapy to some extent. However, due to limited prodrug activation efficiency and lack of tumor selectivity, prodrug strategies are difficult to implement clinically. Utilizing radiotherapy as a precise exogenous stimulus to highly selectively activate the original drug at the tumor site could solve these problems. However, no in vivo radiation-induced cleavage chemistry has yet been established in vivo; only some work in the past thirty years has achieved this strategy at the in vitro or cellular level. Without establishing radiation-activated chemistry in vivo, radiotherapy-induced chemotherapy drug activation is unlikely to have a significant clinical impact.

[0064] Radiochemical alterations of molecules form the material basis for studying all radiochemical effects. There are two main types of radiochemical effects: direct effects, where ionizing radiation causes direct chemical changes in target molecules, and indirect effects, where radiation deposits on environmental molecules and causes indirect chemical reactions in target molecules. Both direct and indirect effects exist simultaneously, but indirect effects are dominant in living organisms. Because tissues are 70–80% water, various reactive substances are mainly produced through the radiolysis of water (Scheme 1a), with the highest yields being hydroxyl radicals (·OH) and hydrated electrons (e). aq - Water radiolysis at 10 -4 The process is completed within seconds, therefore radiation-induced reactions often occur instantaneously, thus possessing strong controllability. The cleavage chemical reaction induced by ·OH and related fluorescent probes have been successfully used in bioimaging; however, the rapid quenching of ·OH by the reducing tumor microenvironment hinders its development within living systems. Meanwhile, radiation-generated e- aq - The yield of [e], another major product of water radiolysis, increases in a reducing environment. Therefore, we explore here the production of [e] through precise local radiotherapy. aq - Feasibility of mediating chemical shearing reactions (Scheme 1b), using radiation as a chemical tool to release target molecules in a highly tumor-selective manner (Scheme 1c).

[0065]

[0066] Option 1a

[0067]

[0068] Option 1b (M can be Fe, Co, Ni, Cu, Ru, Rh, Pd, Ag, etc.)

[0069]

[0070] Option 1c

[0071] Option 1. Controlled release of radiation-induced metal complexes in tumors. a) Radiolysis of water by ionizing radiation. The G value of hydrated electrons is 2.63 (G value refers to the number of molecules formed by absorbing 100 eV of energy in the system). b) Radiation-generated hydrated electrons can reduce metal ions and metal complexes. c) Pt(Ⅳ) complexes can be reduced by radiation, releasing Pt(Ⅱ) anticancer drugs.

[0072] The inventors achieved radiation-induced metal reduction in vivo, thus constructing a novel in vivo shear chemistry. This strategy was applied to the activation of Pt(IV) prodrugs, making radiotherapy an exogenous stimulus that triggers drug release, thereby enabling the release of chemotherapeutic drugs at the tumor site under the guidance of precise radiotherapy. Furthermore, this strategy also helps address the radiotherapy resistance problem in hypoxic tumors, actually improving drug release efficiency under hypoxic conditions. Through radiation-induced e aq - Direct metal reduction can also be extended to other metals or biological complexes (such as metalloproteins), providing an efficient tool for elucidating the mechanisms of complex biological processes.

[0073] This disclosure provides a Pt(Ⅳ) complex of formula (I) as a prodrug for irradiation-activated treatment of tumors.

[0074]

[0075] L1 to L6 are platinum ligands; after irradiation, this complex can release L5 and L6 to obtain the Pt(II) complex of formula (II).

[0076]

[0077] The Pt(Ⅳ) complex of formula (I) disclosed herein releases axial ligands L5 and L6 through reduction to obtain the Pt(II) complex of formula (II). The Pt(Ⅳ) complex of formula (I) is developed based on the Pt(II) complex and can be regarded as a prodrug of the Pt(II) complex of formula (II). Based on the above correspondence between formula I and formula II, the transverse ligands L1 to L4 of the Pt(Ⅳ) complex of formula (I) can be determined from the ligands L1 to L4 of the Pt(II) complex of formula (II).

[0078] The transverse ligand of the Pt(Ⅳ) complex of formula (I) can be either cis or trans configuration. In one embodiment, the transverse ligand of the Pt(Ⅳ) complex of formula (I) is cis configuration.

[0079] In one embodiment, the Pt(II) complex of formula (II) is a cis configuration Pt(II) complex.

[0080] The Pt(II) complex of formula (II) can be a divalent platinum ligand known to have anticancer activity. In one embodiment, the Pt(II) complex of formula (II) is a marketed or clinically available divalent platinum complex, such as cisplatin, carboplatin, nedaplatin, oxaliplatin, levoplatin, or epplatin, cycloplatin, miplatin, enloplatin, sepplatin, spiroplatin, zeniplatin, TRK-710, Aroplatin, bis(isopropylamine)platin(II), or bis(cyclopentamine)platin(II).

[0081] In a preferred embodiment, the Pt(II) complex of formula (II) is cisplatin, carboplatin, nedaplatin, oxaliplatin, levoplatin, or epazolidinium.

[0082] L5 and L6 are monovalent negative ligands of Pt(Ⅳ), which can be released from the Pt(Ⅳ) complex of formula (I) under irradiation. L5 and L6 can be the same or different.

[0083] In one implementation, L5 and L6 are respectively - OC(O)-R, where R is selected from optionally substituted C 1-20 Alkyl, optionally substituted C 1-20 Alkyloxy or optionally substituted amino groups, wherein the substituents are selected from C 1-18 Alkyl, carboxyl, hydroxyl, halogen, mercapto, amino, dicarbon 1-3 Alkylamine, carbonyl, phenyl, halophenyl, C 1-6 Alkyl-substituted phenyl, maleimide, or triphenylphosphonium. The optional substitution here refers to C... 1-20 The alkyl or amino group can be substituted or unsubstituted. Unsubstituted C 1-20 Alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptyl, octadecyl, nonadecyl, and eicosyl. Those skilled in the art will rationally select substituents based on the stability of the chemical structure.

[0084] In one implementation, L5 and L6 are respectively -OC(O)-R, wherein each of R is independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, nonadecanyl, eicosyl, carboxymethyl, 2-carboxyethylidene, 3-carboxypropylidene, 4-carboxybutylidene, 5-carboxypentylidene, 6-carboxyhexylidene, (dimethylamino)methylene, 2-(dimethylamino)ethylidene, 3-(dimethylamino)propylidene, 4-(dimethylamino)butylidene, 5-(dimethylamino)pentylidene, 6-(dimethylamino)hexylidene 5-Maleimide pentylene, 6-Maleimide hexylene, 7-Maleimide heptylene, 8-Maleimide octylene, 3-(4-iodophenyl)propylene, 3-(3-iodophenyl)propylene, 3-(3,5-diiodophenyl)propylene, 3-(4-bromophenyl)propylene, 3-(3-bromophenyl)propylene, 3-(3,5-dibromophenyl)propylene, methylamino, ethylamino, propylamino, butylamino, pentamamino, hexamino, heptamamino, octamino, nonamino, decamino, undecylalkylamino, dodecylalkylamino, tridecylalkylamino, tetradecylalkylamino, pentadecylalkylamino, hexadecylalkylamino, heptadecanylalkylamino, octadecylalkylamino.

[0085] For example, platinum(IV) complexes are prodrugs based on cisplatin: Compound 1-Compound 22

[0086]

[0087] in:

[0088]

[0089]

[0090] For example, platinum(IV) complexes are prodrugs based on carboplatin: compounds 23-44

[0091]

[0092] in:

[0093]

[0094]

[0095] For example, platinum(IV) complexes are prodrugs based on oxaliplatin: compounds 45-66

[0096]

[0097] in:

[0098]

[0099]

[0100] Platinum(IV) complexes can be oxidized by an oxidizing agent such as hydrogen peroxide to obtain platinum(IV) dihydroxy complexes. The two hydroxyl groups on the platinum(IV) dihydroxy complexes can be replaced by carboxyl groups by an acylating agent such as anhydride.

[0101] For example, platinum(IV) complexes can be prepared by the following scheme:

[0102]

[0103] The corresponding Pt(II) drug A (12.6 mmol, 1.0 equivalent) was mixed with 12 mL H2O2, diluted with 15 mL H2O, and stirred at 50 °C for 5 hours. After the Pt(II) drug was completely consumed, the product was collected in a centrifuge tube at room temperature, washed with water, ethanol, and ether, respectively, and the precipitate was lyophilized to obtain a white powder, which was compound B.

[0104] Compound II (1.0 equivalent) was mixed with the corresponding acid anhydride (e.g., succinic anhydride, acetic anhydride, N,N-dimethylglycine anhydride) (1.0 equivalent), dissolved in 4 mL of anhydrous DMF, and stirred for 1 hour to obtain unpurified compound C.

[0105] Compound D (carbamate bond, i.e., R2 represents an amino compound):

[0106] Add 2 mL of anhydrous DMF solution of the corresponding isocyanate to the above reaction solution. React overnight, and remove the solvent under reduced pressure at 65 °C. Add 2 mL of diethyl ether to the oily residue, sonicate the mixture for 1 minute, and centrifuge. Wash the solid further with 4 mL of DCM and 2 mL of diethyl ether. Place the washed solid under vacuum overnight to obtain compound D.

[0107] Compound D (ester bond, i.e., R2 represents an alkyl compound):

[0108] Compound C was precipitated with diethyl ether and lyophilized to obtain a white powder. Compound C (1.0 equivalent) and the corresponding carboxylic acid (2.0 equivalent) were dissolved in 5 mL of DMF, and the condensing agent TBTU (2.0 equivalent) was added. The mixture was heated to 50 °C and reacted overnight in the dark. After evaporating the solvent under reduced pressure, the precipitate was washed with water and then lyophilized to obtain compound D.

[0109] It is believed that the tetravalent platinum complexes disclosed herein primarily treat tumors by reducing them to divalent platinum in the body. Although administration of tetravalent platinum complexes (oral, intravenous, and intracavitary administration, etc.) allows the drug to circulate throughout most organs and tissues of the body via the bloodstream, the level at which they are reduced to divalent platinum by the cells themselves varies in different organs and tissues. However, subsequent radiotherapy can precisely irradiate the tumor, delivering a high dose of radiation locally, thereby locally increasing the level at which tetravalent platinum is reduced to divalent platinum.

[0110] The tetravalent platinum complex prodrug disclosed herein may be used to treat leukemia, lung cancer, malignant lymphoma, breast cancer, ovarian cancer, soft tissue sarcoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, blastoma, neuroblastoma, bladder cancer, thyroid cancer, prostate cancer, head and neck tumors, nasopharyngeal carcinoma, esophageal cancer, testicular cancer, gastric cancer, liver cancer, pancreatic cancer, cervical cancer, endometrial cancer, melanoma, or colorectal cancer.

[0111] Another aspect of this disclosure provides a pharmaceutical composition comprising the above-described Pt(Ⅳ) complex and pharmaceutically acceptable excipients.

[0112] The terms “pharmaceutical acceptable” or “medicinal” in this application mean 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.

[0113] The term "excipient" in this application refers to an excipient or medium used to administer a compound, including but not limited to diluents, disintegrants, precipitation inhibitors, surfactants, flow aids, binders, lubricants, coating materials, etc. Excipients are generally described in EWMartin's "Remington's Pharmaceutical Sciences". Examples of excipients include, but are not limited to, vegetable oils, cyclodextrins, aluminum monostearate, aluminum stearate, carboxymethyl cellulose, sodium carboxymethyl cellulose, cropovidone, glyceryl isostearate, glyceryl monostearate, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxyoctadecyl hydroxystearate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, lactose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, etc.

[0114] At least one embodiment of this disclosure provides a method for preparing a pharmaceutical composition, the method comprising mixing at least one Pt(Ⅳ) complex of this disclosure with a pharmaceutically acceptable excipient.

[0115] The Pt(Ⅳ) complexes disclosed herein can be formulated into injections and powder injections, and can be administered intravenously after dilution with physiological saline or 5% glucose solution.

[0116] Divalent platinum drugs are typically administered parenterally and are not suitable for oral administration. However, the Pt(Ⅳ) complexes disclosed herein can also be formulated into pharmaceutical compositions for oral administration.

[0117] For example, an orally administered pharmaceutical composition comprises a suspension of a Pt(Ⅳ) complex in at least one pharmaceutically acceptable vegetable oil, animal oil, mineral oil, synthetic oil, or semi-synthetic oil. In one embodiment, the pharmaceutical composition may be encapsulated in a hard gelatin or hydroxypropyl methylcellulose capsule or in a soft gelatin capsule containing 50 to 350 mg of the Pt(Ⅳ) complex.

[0118] For example, an oral pharmaceutical composition may comprise an inclusion complex of a cyclodextrin and a Pt(Ⅳ) complex, which is obtained by dissolving the Pt(Ⅳ) complex in an organic solvent such as acetone, then reacting it with a cyclodextrin such as a C1-4 hydroxyalkyl-substituted β or γ cyclodextrin and subsequently removing the solvent by low-pressure sublimation drying.

[0119] This disclosure also provides the use of the above-mentioned Pt(Ⅳ) complex in the preparation of medicaments for the treatment of tumors by irradiation activation.

[0120] In another aspect, this disclosure also provides a method for treating tumors, comprising: administering the above-mentioned Pt(Ⅳ) complex to a subject, and irradiating the subject.

[0121] In one implementation, the irradiation is derived from radiotherapy.

[0122] Radiation therapy includes: external beam radiation therapy (including conventional external beam radiation therapy; stereotactic radiation; 3D conformal radiation therapy; intensity-modulated radiation therapy), particle therapy, Auger therapy, contact X-ray, brachytherapy (particle-assisted therapy), and radionuclide therapy.

[0123] The equipment that can be used includes: deep X-ray therapy machine, cobalt-60 therapy machine, medical linear accelerator, medical proton accelerator, medical heavy ion accelerator, gamma knife, etc.

[0124] Please note that the radiotherapy disclosed herein differs from concurrent chemoradiotherapy: concurrent chemoradiotherapy uses low-dose chemotherapy to increase tissue sensitivity to radiation; while the radiotherapy disclosed herein involves irradiation simultaneously with chemotherapy to promote the reduction of the prodrug into a divalent platinum drug to exert its effect. Please also note that the radiotherapy disclosed herein differs from sequential chemoradiotherapy: sequential chemoradiotherapy involves either a chemotherapy session followed by a radiotherapy session or vice versa; while the radiotherapy disclosed herein is administered shortly after chemotherapy, for example, 0.5-6 hours later.

[0125] In one embodiment, the radiotherapy is performed 0.5-6 hours after administration of the Pt(Ⅳ) complex.

[0126] For example, the radiotherapy is performed 0.5, 1 h, 1.5 h, 2 h, 2.5 h, and 3 h after administration of the Pt(Ⅳ) complex, and the radiotherapy is performed for 1-10 minutes (e.g., 1, 2, 3, 4, 5 minutes).

[0127] For example, the radiotherapy equipment is a linear accelerator (such as the Varian Medical Systems Clinac iX), producing X-rays with an energy of 6 MeV. The total local irradiation dose to the tumor is 4 Gy, with a dose rate of 2 Gy / min. The treatment regimen involves two treatments per week (medication + radiotherapy constitutes one treatment). Radiotherapy is administered 2 hours after the Pt(IV) complex is given, with a duration of approximately 2 minutes. The interval between treatments is 2 days, and the treatment is repeated for a total of four weeks.

[0128]

[0129] The Pt(IV) complex combined with radiotherapy disclosed herein can treat hypoxic tumors, such as pancreatic cancer and prostate cancer, that are untreatable by conventional radiotherapy.

[0130] The radiotherapy protocol disclosed herein can be performed using conventional radiotherapy methods or with a lower dose than conventional radiotherapy methods. When a lower dose is used, the side effects of radiotherapy can be reduced.

[0131] In one implementation, the radiation dose is less than 60 Gy.

[0132] The Pt(Ⅳ) complex disclosed herein can be used in combination with radiotherapy to treat cancers such as leukemia, lung cancer, malignant lymphoma, breast cancer, ovarian cancer, soft tissue sarcoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, blastoma, neuroblastoma, bladder cancer, thyroid cancer, prostate cancer, head and neck tumors, nasopharyngeal carcinoma, esophageal cancer, testicular cancer, gastric cancer, liver cancer, pancreatic cancer, cervical cancer, endometrial cancer, melanoma, or colorectal cancer.

[0133] In another aspect, this disclosure also provides a kit comprising the above-described Pt(Ⅳ) complex or the above-described pharmaceutical composition comprising the Pt(Ⅳ) complex, and further comprising instructions for administration of the kit to indicate that radiotherapy is to be administered after administration to treat a tumor.

[0134] Example

[0135] The starting materials used in the examples are commercially available and / or can be prepared using various methods well known to those skilled in the art of organic synthesis. Those skilled in the art of organic synthesis will appropriately select the reaction conditions (including solvent, reaction atmosphere, reaction temperature, duration of the experiment, and post-treatment) from the synthetic methods described below. Those skilled in the art of organic synthesis will understand that the functional groups present on the various parts of the molecule should be compatible with the proposed reagents and reactions.

[0136] Reagents and Instruments

[0137] All chemical reagents were purchased from Energy Chemical (China), Bailingwei (China), Innovent (China), and Sinopharm (China), and were used as is without further purification. Solvents were distilled after dehydration with Na or CaH2 before use. Cell counting kit-8 (CCK-8) was purchased from Beyotime Biotechnology Research Institute. Ultrapure water (18.2 MΩ / cm) used throughout the process was obtained from the Milli-Q reference system (Millipore). Nuclear magnetic resonance (NMR) spectra were recorded using a Bruker AVANCE 400MHz spectrometer. Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was performed on an ACQUITY UPLC H-Class PLUS instrument equipped with a Waters PDA eλ detector and a Waters Acquity QDA mass spectrometer. Absorption spectra were measured using a UV-1100 spectrophotometer. X-ray irradiation was generated by an X-ray generator (RS2000Pro 225, 225kV, 17.7mA; Rad Source Technologies, Inc.). The total dose for a single test tube experiment was 0–60 Gy at a dose rate of 5 Gy / min. The total dose for cell experiments was 0–16 Gy at a dose rate of 1.6 Gy / min. A custom-made mouse model was used to locally irradiate the implanted tumor. The local irradiation dose to the tumor was 4 Gy at a dose rate of 1 Gy / min, and the rest of the body was shielded with 5 mm thick lead. Gamma-ray irradiation was... 60 Co source provided.

[0138] 1. Synthesis and characterization of Pt(Ⅳ) complexes

[0139] The Pt(Ⅳ) complex was prepared as described above using the corresponding Pt(II) drug. After oxidation with hydrogen peroxide, the platinum(Ⅳ) dihydroxy complex was obtained. The two hydroxyl groups on the platinum(Ⅳ) dihydroxy complex were reacted with the corresponding acid anhydrides to prepare compounds 1 to 66.

[0140] The product was characterized by mass spectrometry.

[0141]

[0142]

[0143] 2. Analytical Methods

[0144] 2.1 Detection of iron ions and complexes

[0145] Fe 2+ / Fe 3+Stock solution: Dissolve 2.78 mg FeSO4·7H2O and 2.70 mg FeCl3·6H2O in 1 mL of deionized water to obtain a 10 mM stock solution. Dilute 100 μL of the stock solution to 100 μM in 10 mL.

[0146] Fe 2+ / Fe 3+ Probe: Dissolve 54.06 mg of phenanthroline in 1 mL of DMSO to obtain a 300 μM stock solution, which can be used for detection without further dilution. Add 2.48 mg of Fe... 3+ The probe was dissolved in 1 mL of DMSO to obtain a 10 mM stock solution, and 100 μL was diluted to 100 μM in 10 mL of MeOH / H2O (v / v, 1:1).

[0147] [Fe(phen)3] 2+ Solution. Add 15 μL of phenol stock solution to 15 mL of 100 μM Fe solution. 2+ In the solution, [Fe(phen)3] is obtained. 2+ Complex.

[0148] Fe detection using phen 2+ / Fe 3+ : 100μM Fe 2+ / Fe 3+ The solution further decreased to 80, 60, 40, 20, and 0 μM. In 3 mL of the above Fe... 2+ / Fe 3+ 3 μL of phenol stock solution was added to the solution, resulting in a final phenol concentration of 300 μM, while the Fe concentration remained almost unaffected. UV-Vis absorption was measured at 510 nm.

[0149] Fe 3+ Probe detection of Fe 2+ / Fe 3+ 100 μM Fe 2+ / Fe 3+ The solution was further attenuated to 80, 60, 40, 20, and 0 μM. 600 μL Fe 2+ / Fe 3+ Solution and 2400 μL Fe 3+ Probe mixing, therefore Fe 2+ / Fe 3+ The final concentrations were 20, 16, 10, 8, 4, and 0 μM, for Fe. 3+ The probe concentration was 80 μM. The reaction system was incubated at 37 °C for 20 minutes and detected at 450 nm using a UV-Vis spectrophotometer.

[0150]

[0151] 2.2 Detection of copper ions and complexes

[0152] Cu 2+ Stock solutions: Dissolve 2.50 mg CuSO4·5H2O in 1 mL of deionized water to obtain 10 mM stock solutions.

[0153] Cu 2+ Probe: Dissolve 34.25 mg of sodium diethyldithiocarbamate in 1 mL of DMSO to obtain a 200 mM stock solution.

[0154] Detection of Cu using sodium diethyldithiocarbamate 2+ : Add 100 μL of 10 mM Cu 2+ The stock solution was diluted to 100 μM in 10 mL, and then further attenuated to 80, 60, 40, 20, and 0 μM. In 3 mL of the above Cu... 2+ Adding 3 μL of sodium diethyldithiocarbamate stock solution to the solution, the final concentration of phen is 200 μM. Cu 2+ The concentration is almost unaffected. UV-Vis absorption at 450 nm was measured.

[0155] 2.3 Detection of nickel ions and complexes

[0156] Ni 2+ Stock solution: Dissolve 2.38 mg NiCl2·6H2O in 1 mL of deionized water to obtain a 10 mM stock solution, and dilute 100 μL in 8 mL to 125 μM.

[0157] Dimethylacetaldehyde oxime (DMG) solution: Dissolve 89 mg DMG in 1.5 mL of 10 M NaOH (aq) to obtain a 0.51 M solution.

[0158] K2S2O8 solution. Dissolve 57 mg of K2S2O8 in 1.5 mL of deionized water to obtain a 0.14 mmol solution.

[0159] Ni 2+ Detection of Ni at 125 μM 2+ The solution was further attenuated to 100, 75, 50, 25, and 0 μM. 50 μL of K₂S₂O₈ solution, 100 μL of 1M NaOH(aq), and 50 μL of DMG solution were sequentially added to 800 μL of Ni. 2+ In solution, therefore Ni 2+ The final concentrations were 100, 80, 60, 40, 20, and 0 μM. The reaction system was incubated at 25°C for 20 minutes and detected at 530 nm using a UV-Vis spectrophotometer.

[0160] 2.4 Detection of probe-free ions / complexes

[0161] Prepare 10 mM stock solutions of metal ions or complexes with the corresponding compounds, and dilute them sequentially to 100, 80, 60, 40, 20, and 0 μM. Detect the ions or complexes using the following method.

[0162] 1. ICP-AES.

[0163] Ions / Complexes compound <![CDATA[Co 2+ ]]> <![CDATA[CoCl2·6H2O]]> <![CDATA[Pd 2+ ]]> <![CDATA[Pd(OAc)2]]> <![CDATA[Ag + ]]> <![CDATA[Ag2SO4]]>

[0164] 2. Ultraviolet-Vis spectroscopy detection:

[0165]

[0166]

[0167] 3. UPLC-MS

[0168] coordination compounds compound <![CDATA[Co(ⅡI)VB 12 ]]> <![CDATA[VB 12 ]]> Pt(Ⅳ) Pt(Ⅳ) complex 1

[0169] 2.5 Detection of ligand release from Pt(Ⅳ) complex 1 in different solutions

[0170] Prepare a 10 mM stock solution of Pt(Ⅳ) complex 1, and dilute it to 100 μM in solutions of H2O, PBS, 5 mM Tyr, Trp, DMEM, CM (complete culture medium), and FBS. After X-ray irradiation, add 200 μL of ACN to each solution, centrifuge, and collect the supernatant. Repeat twice more, with the final concentration being 1 / 8 of the original concentration. Detect ligand release using UPLC-MS and quantify using a coumarin standard curve.

[0171] 2.6 Detection of platinum drug release from Pt(Ⅳ)-(Suc)2

[0172] use 195 Pt NMR was used for determination ( Figure 3 ,def)

[0173] Pt(Ⅳ)-(Suc)₂ was dissolved in 1 mL of deuterated water (80 mmol), and the pH was adjusted to 7 with NaOH. After deoxygenation, the solution was exposed to 40 kGy γ-ray irradiation. 60 Co source, 200 Gy / min, 200 min). After the reaction, DMSO was added to redissolve the precipitate (for oxaliPt(Ⅳ)-(Suc)2), or the precipitate was directly dissolved in the clear solution after the reaction (for cisPt(Ⅳ)-(Suc)2 and for carboPt(Ⅳ)-(Suc)2). 195 Pt NMR determination.

[0174] Product identification using UPLC-MS ( Figure 3 bc)

[0175] Dissolve oxaliPt(Ⅳ)-(Suc)2 in 1 mL of deionized water (1 mM), and adjust the pH to 7 with NaHCO3. After deoxygenation, expose the solution to 1 kGy γ-ray irradiation. 60 Co source, 100 Gy / min, 10 min). The crude reaction product was analyzed by UPLC-MS, and the released product was identified as oxaliplatin.

[0176] 2.7 Release efficiency determination using UPLC-MS

[0177] The corresponding tetravalent platinum complexes (compounds 1–66) were dissolved in DMSO to obtain a tetravalent platinum stock solution (10 mM), which was then diluted to 10 μM with pure water. After deoxygenation, the solution was irradiated with 60 Gy X-rays (4 Gy / min, 15 min). The crude reaction product was analyzed by UPLC-MS, and the released product was identified as the corresponding divalent platinum drug. The concentration of the divalent platinum drug was determined by the external standard curve of the platinum drug, and the release efficiency was calculated.

[0178] 3. Biological methods

[0179] 3.1 Cell Culture

[0180] The BGC823 cell line was obtained from the National Cell Line Resource Infrastructure (Beijing, China). HCT116, Ls513, HT29, and LoVo cells were purchased from the American Type Culture Collection (ATCC). HCT116, Ls513, HT29, and BGC823 cells were grown in RPMI-1640 (Roswell Park Memorial Institute-1640) medium containing 10% FBS and 1% penicillin / streptomycin. LoVo cells were grown in Ham's F-12K (Roswell Park Memorial Institute-1640) medium containing 10% FBS and 1% penicillin / streptomycin. All cell cultures were cultured at 37°C and 5% CO2.

[0181] 3.2 Cell viability assay

[0182] Cell viability was assessed using the CCK-8 assay. Each assay was repeated three times.

[0183] To detect the cytotoxicity of oxaliPt(Ⅳ)-(OAc)2, HCT116, Ls513, LoVo, HT29, and BGC823 were used at a concentration of 5 × 10⁻⁶.4 200 μL of RPMI-1640 or F-12K medium containing 10% FBS and 1% penicillin / streptomycin was seeded in 96-well plates and incubated at 37°C in a 5% CO2 incubator for 24 hours. Cells were then cultured under hypoxic conditions with 10 μM oxaliPt(Ⅳ)-(OAc)2 for 24 hours. Cells were then irradiated with 8 Gy X-rays and incubated for another 3 days. After incubation, blank medium containing 0.5 mg / mL CCK-8 was added to the cells. The 96-well plates were incubated at 37°C in a 5% CO2 incubator for 2 hours, and absorbance was measured at 450 nm. The absorbance of the treated cells was compared with that of the control group, where the survival rate of the untreated control group was set at 100%.

[0184] 3.3 Tumor Model

[0185] All animal experiments were conducted in accordance with guidelines approved by the Peking University Ethics Committee.

[0186] Six-week-old female Nu / Nu mice were ordered from Vital River Laboratories (Beijing, China) and raised under specific pathogen-free, adequate water and food conditions. Each mouse will contain 2 × 10⁻⁶ cells. 6 One HCT116 cell was injected subcutaneously into the right shoulder of a mouse to construct a tumor xenograft model. The tumor volume was equal to 1 / 2 length * width. 2 .

[0187] When the tumor volume reaches 50mm 3 Treatment began at approximately 6 days prior, and the treatment plan was as follows: Figure 5 According to the pharmacokinetics of oxaliPt(Ⅳ)-(OAc)2, mice were given radiotherapy one hour after prodrug injection, with the tumor area receiving 4 Gy of X-rays. Mouse body weight and tumor size were recorded every two days. When the tumor size exceeded 1500 mm... 3 Following the guidance of the ethics committee, the mice were euthanized. Recordings were continued until day 40 after the start of treatment.

[0188] The effect of radiation dose on metal reduction efficiency

[0189] In industry, radiation doses of 10-500 kGy are commonly used to treat wastewater and precipitate toxic heavy metal ions from polluted water. Therefore, this study first attempted to irradiate a FeCl3 (100 μM, aq) solution with X-rays at a dose of 10-60 Gy (clinical radiotherapy dose). Figure 1 a) 1,10-Phenanthroline is a method for detecting Fe 3+ / Fe 2+ Fe(phen)3 is a classic probe for redox reactions.3+ The aqueous solution of Fe(phen)3 is colorless, while Fe(phen)3 is colorless. 2+ It is orange-red. Immediately after irradiation, adding 1,10-phenanthroline (30 mM, DMSO) to the FeCl3 solution (the final concentration of 1,10-phenanthroline is 300 μM) immediately turns the solution orange-red. Figure 1 b) indicates that Fe was generated. 2+ Through Fe(phen)3 2+ The standard curve was determined for Fe. 2+ The yield is linearly related to the absorbed radiation dose. Figure 1 c). In addition, for Fe 3 + Quantitative analysis revealed Fe 3+ The consumption is almost the same as Fe 2+ The generation is equal ( Figure 1 c), therefore, Fe 2+ It is Fe 3+ The main products of radiation reduction.

[0190] Hydrated electrons are among the strongest reducing agents in water (standard electrode potential, -2.77 V) and are also one of the major products of water radiation decomposition (~280 nM / Gy). We hypothesize that radiation-driven metal reduction is caused by hydrated electrons from water radiation decomposition. aq - Mediated by detecting Fe 3+ Fe was generated by irradiation in a 10 mM methanol, tert-butanol and sodium formate solution. 2+ The results demonstrate that a reducing environment (a quencher of ·OH) favors the occurrence of this reaction. NaNO3 and saturated oxygen solution, i.e., the known e- ions, are also favorable. aq - Quenching agents greatly reduce Fe 2+ Release amount ( Figure 1 d). e aq - The mediated reduction should be generally applicable to most transition metals; therefore, a series of representative metal ions (100 μM, aq) were tested under the same conditions (60 Gy X-rays), and the reduction yield was determined by the absorbance of the corresponding complex or other methods. Figure 1 As shown in e, radiation-driven reduction reactions are feasible in most cases. The metal reduction yield from radiation can reach as high as 240 nM / Gy, close to e. aq - Theoretical yield.

[0191] Figure 1 The example illustrates the broad spectrum of radiation-reduced metal ions. The detection of Fe using 1,10-phenanthroline (phen) 3+ / Fe2+ Redox reaction. Fe 3+ Immediately after the solution was irradiated with X-rays (0–60 Gy), phen was added, which quantitatively formed an orange-red complex (λ) with Fe(II). max =510nm), proving radiation-driven Fe 3+ (100 μM, aq) to Fe 2+ The reduction. Schematic diagram (a) and photograph (b) of radiation-driven reduction titration staining. c, Fe 3+ The disappearance of [Fe(phen)3] is almost equivalent to the disappearance of [Fe(phen)3]. 2+ The generation of [a specific substance] is linearly related to the absorbed radiation dose. Its G value is 200 nM / Gy, close to [a specific value]. aq - The theoretical G value (280 nM / Gy). d, radiation-driven Fe when treated with a hydroxyl radical quencher. 3+ / Fe 2+ Increased reduction yield, using e aq - This is reduced during quenching treatment. e. Radiation-driven reduction of metal ions is generally suitable for transition metals.

[0192] Subsequently, this study further explored the feasibility of radiation-induced reduction of metal complexes. The reduction potential of metal complexes may change, leading to a decrease in radiation reduction reactivity. Therefore, we prepared 100 μM metal complexes and irradiated them with X-rays ranging from 0 to 60 Gy after deoxidation. Encouragingly, the metal complexes all achieved good results. According to the standard curves of each metal complex, the radiation-driven metal reduction yield exceeded 200 nM / Gy, and for some metals, it could reach as high as 350 nM / Gy. Figure 2 a) exceeded e aq - The theoretical yield is high. This is because metal atoms with high atomic numbers can deposit more X-ray energy, thus amplifying the ionizing radiation dose. Therefore, the radiation reduction of metals has broad, efficient, and highly selective properties, and holds promise for development into a tool for in vivo shear chemistry.

[0193] Furthermore, UPLC-MS analysis of Pt(Ⅳ) complex 1 after radiation reduction detected the release of axial ligands. Given the high clinical application potential of Pt(Ⅳ) derivatives, the next step will be to test the role of radiation reduction in the biological environment, specifically to achieve radiotherapy-driven activation of the original Pt(Ⅳ) drug in tumors. To test biocompatibility, the Pt(Ⅳ) complex was dissolved in PBS, 5 mM Tyr, 5 mM Trp, Duchenne medulloproteinase (DMEM), and complete medium (CM), followed by UPLC-MS analysis. Figure 2As shown in b, the release of the axial ligand of Pt(Ⅳ) complex 1 was achieved in all of the above solutions. Even in complete fetal bovine serum (FBS), the reaction yield was not significantly different from that in water, thus the strategy of radiation reduction of Pt(Ⅳ) complex 1 to release the axial ligand is highly feasible under the complex conditions in vivo.

[0194] Figure 2 The example illustrates the broad spectrum of radiation-reduced metal complexes. a) Transition metal complexes can also be reduced by medical doses of radiation, with reduction yields higher than e). aq - The theoretical yield was obtained. Simultaneously, axial ligands were released upon radiation reduction of the Pt(Ⅳ) complex (left figure, 100 μM, 1% DMSO aqueous solution). b. The Pt(Ⅳ) complex (100 μM) was irradiated under various biological conditions (Tyr for tyrosine, Trp for tryptophan, 5 mM; DMEM, culture medium; CM, complete culture medium; FBS, fetal bovine serum), and the release of the corresponding ligands was detected by UPLC.

[0195] This radiation-driven release mechanism has two possibilities. Axial ligand release from the Pt(Ⅳ) complex can be achieved through hydrolysis or reduction: hydrolysis breaks the ester bond, yielding Pt(Ⅳ)-(OH)2 and the axial ligand; while reduction alters the valence state of platinum, generating the corresponding divalent platinum drug. According to ligand field theory, a 5d... 6 The most common coordination number for Pt(Ⅳ) with valence electron configuration is 6, while 5d... 8 Pt(II) with valence electron configuration tends to form tetragonal complexes. Existing studies on Pt(IV) prodrugs have shown that the reduction of Pt(IV) to Pt(II) leads to a decrease in coordination number and the release of ligands.

[0196] To investigate the reaction process, a solution of oxaliPt(Ⅳ)-(Suc)2 (80mM, D2O) was first deoxygenated and then subjected to 40kGy of γ-rays. 60 Co source, 200 Gy / min, 200 min, Figure 3 a) Irradiation, analysis of the irradiated solution using UPLC-MS, only one new peak was observed, and its retention time ( Figure 3 b) Mass spectrum signal ( Figure 3 c) All samples were consistent with the oxaliplatin standard. The products were analyzed using nuclear magnetic resonance (NMR). 195 Pt-NMR showed that the peak at 1615 ppm of the Pt(Ⅳ) complex almost disappeared after irradiation. Figure 3 (d on), while a new singlet appeared at -1988ppm (d on). Figure 3 d), located within the chemical shift range of the Pt(II) complex, and consistent with the chemical shift of oxaliplatin ( Figure 3 (d below). The above experiments all demonstrate that the release of axial ligands is caused by the radioreduction of Pt(Ⅳ) rather than hydrolysis.

[0197] To explore the generalizability of this strategy, we further conducted the same study on two other globally used platinum-based drugs—carboplatin and cisplatin. Nuclear magnetic resonance characterization revealed that cisPt(Ⅳ)-(Suc)2 and carboPt(Ⅳ)-(Suc)2 release the corresponding Pt(Ⅱ) drugs upon γ-ray irradiation in D2O. Figure 3 (e, f). Given the widespread use of platinum-based drugs in chemotherapy, the strategy proposed in this work—the controlled release of Pt(II) after radiation-driven reduction of Pt(IV) prodrug—shows great promise for achieving radiotherapy-driven precision chemotherapy.

[0198] Figure 3 This example illustrates the broad-spectrum and efficient release of FDA-approved Pt(II) drugs from Pt(IV) complexes driven by radiation. a) Schematic diagram of radiation-driven release of Pt(II) drugs from Pt(IV) complexes. b) UPLC chromatograms of oxaliPt(IV)-(Suc)2, oxaliPt(IV)-(Suc)2+radiation, oxaliplatin, and oxaliPt(IV)-(OH)2, with oxaliplatin and oxaliPt(IV)-(OH)2 as references. The major product of radiation-driven release of oxaliPt(IV)-(Suc)2 has the same retention time as oxaliplatin. The detector wavelength was set to 254 nm. c) MS analysis of the product released by radiation-driven oxaliPt(IV)-(Suc)2 confirms that the released product is oxaliplatin. df) Nuclear magnetic resonance (NMR) study of the release of Pt(II) drugs from Pt(IV) complexes. d, oxaliPt(Ⅳ)-(Suc)2 (1615ppm, top), radiation irradiation products (-1988ppm, middle) and external standard (bottom) 195 Pt-NMR spectra. e,cisPt(Ⅳ)-(Suc)2 (1082 ppm, top), radiation-irradiated products (-2150 ppm, middle), and external standard (bottom). 195 Pt-NMR spectra. f, carboPt(Ⅳ)-(Suc)2 (1883 ppm, top), radiation-irradiated products (1707 ppm, middle) and external standard (bottom). 195 Pt-NMR spectrum. 195 Pt-NMR spectroscopy indicates that radiation-driven release of FDA-approved Pt(II) drugs is effective and generally applicable to Pt(IV) complexes.

[0199] The key to developing a successful prodrug lies in balancing the requirements for stability and reactivity under physiological conditions. Metal complexes in chemotherapy drugs suffer from a fatal flaw: their limited biostability. In fact, most Pt(Ⅳ) prodrugs reported to date release active Pt(Ⅱ) anticancer drugs under intracellular bioreducible conditions. Therefore, the biostability of Pt(Ⅳ) prodrugs is a crucial prerequisite for achieving this strategy. Based on existing research, tetracarboxylated Pt(Ⅳ) exhibits a significant stability advantage. Therefore, we further designed oxaliPt(Ⅳ)-(OAc)2( Figure 4 a) Because oxaliPt(Ⅳ)-(Suc)2 has two carboxyl groups as axial ligands, it carries two negative charges under physiological conditions in vivo, and therefore cannot be effectively enriched in tumors. In contrast, the corresponding oxaliPt(Ⅳ)-(OAc)2 exhibits good stability and reactivity; after co-incubation with 20 equivalents of vitamin C for 24 hours, over 95% of oxaliPt(Ⅳ)-(OAc)2 remained highly stable. Figure 4 b). After irradiation with 0-60 Gy of X-rays using OxaliPt(Ⅳ)-(OAc)2 (10 μM PBS solution, deoxygenated), studies found that the released oxaliplatin was positively correlated with a given radiation dose. Figure 4 c). OxaliPt(Ⅳ)-(OAc)2 is 2 to 3 orders of magnitude less toxic to oxaliplatin-sensitive cell lines, such as HCT116, HT29, LoVo, and Ls513 (human colorectal cancer cell lines), with an IC50 of approximately submicromolar levels.

[0200] To examine whether radiation-driven oxaliplatin is released and exerts its anticancer function in the cellular environment, we performed cell viability assays using several cell lines subjected to oxaliPt(Ⅳ)-(OAc)2+ X-rays. Complete culture medium was used as a control. Cells were treated with 8 Gy X-rays, 10 μM oxaliPt(Ⅳ)-(OAc)2, and 10 μM oxaliPt(Ⅳ)-(OAc)2+8 Gy X-rays, respectively. After 96 hours of culture, CCK-8 assays showed that the cell viability of the group treated with 10 μM oxaliPt(Ⅳ)-(OAc)2+8 Gy X-rays was significantly lower than that of the groups treated with only 10 μM oxaliPt(Ⅳ)-(OAc)2 or 8 Gy X-rays. Figure 4 d) demonstrates the feasibility of a strategy to release oxaliplatin from oxaliPt(Ⅳ)-(OAc)2 in cells.

[0201] Figure 4Examples illustrate the efficacy of radiation-induced controlled release of oxaliplatin in living cells. a, Schematic diagram of radiation-driven release of oxaliplatin from the prodrug oxaliPt(Ⅳ)-(OAc)2, a widely used chemotherapeutic agent. b, Stability of the OxaliPt(Ⅳ)-(OAc)2 prodrug. Incubation of 10 μM oxaliPt(Ⅳ)-(OAc)2 with 20 equivalents of Vc (200 μM) for 24 hours resulted in over 95% of oxaliPt(Ⅳ)-(OAc)2 remaining stable. c, Oxaliplatin release from 10 μM oxaliPt(Ⅳ)-(OAc)2 at clinically relevant doses (0–60 Gy, X-ray) with efficiencies up to 70%. d, Cell viability assay of controlled release of oxaliplatin in vitro (prodrug: [oxaliPt(Ⅳ)-(OAc)2] = 10 μM (h); X-ray, 8 Gy; n = 6). HCT116, LoVo, Ls513, and HT69 are human colorectal cancer cells that are sensitive to oxaliplatin.

[0202] To determine the optimal dosage, we evaluated the effects of different doses of oxaliplatin and the prodrug on the health of healthy mice. Following the same administration method as during treatment, mice were administered the drug every two days, and body weight curves were recorded. It was observed that injections of 3 μmol / kg oxaliplatin or 30 μmol / kg oxaliPt(Ⅳ)-(OAc)2 did not cause weight loss in mice. However, doses exceeding 10 μmol / kg oxaliplatin and 100 μmol / kg oxaliPt(Ⅳ)-(OAc)2 exhibited significant side effects, leading to weight loss in the mice. Figure 5 a). When the dose of oxaliplatin reached 30 μmol / kg, the mice experienced severe weight loss and died on day 8, with all mice dying by day 16. Figure 5 (b) From the long-term survival and weight curves of mice, it can be concluded that 3 μmol / kg oxaliplatin and 30 μmol / kg oxaliPt(Ⅳ)-(OAc)2 have no obvious side effects and can be used as appropriate dosages. To achieve the best radiotherapy and chemotherapy effect, we used ICP-MS to study the pharmacokinetics of oxaliPt(Ⅳ)-(OAc)2 in HCT116 tumor-bearing mice to explore the optimal radiotherapy time. After injecting 30 μmol / kg oxaliPt(Ⅳ)-(OAc)2 into HCT116 tumor-bearing mice via tail vein, the mice were sacrificed at selected times. Then, the concentrations of platinum drug in blood, tumor, liver, and kidney were detected by ICP-MS. ICP-MS data at multiple time points showed that the prodrug is mainly metabolized by the liver and kidneys, and the tumor uptake reaches a peak (approximately 15 μM) 1 hour after administration, then gradually decreases, and is completely cleared 48 hours after injection. Figure 5c). One hour after administration, the concentrations of the prodrug in the muscles and brain of mice were low, indicating that the drug did not have side effects on these organs.

[0203] Subsequently, the radiation-mediated release of oxaliplatin in mice and its corresponding therapeutic effects were further evaluated. HCT116 cells were implanted into the right ventral region of Nu / Nu mice until the average tumor volume reached approximately 50 mm. 3 Mice were randomly divided into 7 groups, including a control group (PBS only), groups treated with 3 μmol / kg oxaliplatin, 30 μmol / kg oxaliPt(Ⅳ)-(OAc)2, X-ray, 3 μmol / kg oxaliplatin + X-ray, 30 μmol / kg oxaliPt(Ⅳ)-(OAc)2 + X-ray, and 3 μmol / kg transPt(Ⅳ)-(OAc)2 + X-ray, and the groups were injected with the drug on day 0. Figure 5 d). For the treatment group, 4 Gy of X-ray was administered 1 hour after injection, and the treatment cycle was repeated on days 10–12. By day 18 after the start of treatment, the tumor size in the control group reached 1500 mm. 3 However, injection of 30 μmol / kg oxaliPt(Ⅳ)-(OAc)2 alone had no significant effect on tumor growth, while the 30 μmol / kg oxaliPt(Ⅳ)-(OAc)2 + X-ray group showed significant tumor inhibition. Figure 5 e,f), and improved the survival time of mice ( Figure 5 This indicates that the therapeutic effect is caused by radiation-mediated oxaliplatin release. Meanwhile, mice in the oxaliPt(Ⅳ)-(OAc)2+ X-ray treatment group did not experience weight loss. Figure 5 h) indicates that our strategy has good biosafety. Therefore, the treatment results in HCT116 tumor-bearing mice demonstrate that this radiation-driven Pt(II) drug release is highly feasible in vivo.

[0204] Figure 5This example illustrates radiotherapy-driven oxaliPt(Ⅳ)-(OAc)2 prodrug reductive release of oxaliplatin for chemoradiotherapy in oxaliplatin-sensitive HCT116 cell line tumors. Body weight change curves (a) and survival curves (b) in mice after intravenous injection of different doses of oxaliplatin (Ⅳ)-(OAc)2 and oxaliplatin. Drug adaptation studies in nude mice showed that the maximum tolerated doses of oxaliplatin and oxaliplatin (Ⅳ)-(OAc)2 were approximately 3 μmol / kg and 30 μmol / kg, respectively. (c) Pharmacokinetics of the oxaliPt(Ⅳ)-(OAc)2 prodrug were analyzed to determine the optimal timing of radiotherapy. Tumor uptake of the oxaliPt(Ⅳ)-(OAc)2 prodrug peaked 1–2 hours after injection and then gradually declined. The remaining prodrug was rapidly cleared from the blood and excreted via the kidneys and hepatobiliary system. (d) Treatment regimen. (eh) Radiotherapy-driven oxaliplatin release for tumor treatment (n=6 mice per group). e, Tumor volume of a single mouse. f, Average tumor volume. The prodrug was administered intravenously four times at a dose of 30 μmol / kg. One hour after the intravenous injection, the tumor sites in the irradiation group were irradiated with 4 Gy X-rays. Tumor volume in each group was measured every two days for 40 days. g, Survival curve of mice. Following the guidelines of the Animal Ethics Committee of Peking University, survival was achieved when the tumor volume reached 1500 mm². 3 Mice were sacrificed at the designated time. Mouse weight gain curves were observed over h. No significant side effects were observed, highlighting the biological safety of this novel treatment strategy.

[0205] This study achieved radiation-induced metal reduction in vivo, thus constructing a novel in vivo shear chemistry. Applying this strategy to the activation of Pt(IV) prodrugs allows radiotherapy to become an exogenous stimulus triggering drug release, thereby enabling the release of chemotherapeutic drugs at the tumor site under the guidance of precise radiotherapy. Furthermore, this strategy helps address radiotherapy resistance in hypoxic tumors, actually improving drug release efficiency under hypoxic conditions. Through radiation-induced e aq - Direct metal reduction can also be extended to other metals or biological complexes (such as metalloproteins), providing an efficient tool for elucidating the mechanisms of complex biological processes.

[0206] Based on the above description, those skilled in the art can readily identify the essential features of the present invention, and various changes and modifications can be made to adapt it to various uses and conditions without departing from the spirit and scope of the invention. Therefore, other embodiments are also within the scope of the appended claims.

[0207] This application claims priority to Chinese Patent Application No. 202011337782.X, filed on November 25, 2020, the disclosure of which is incorporated herein by reference in its entirety.

Claims

1. Use of the Pt(Ⅳ) complex of formula (I) in the preparation of medicaments for radiation-activated tumor therapy. (I)， L1 to L6 are platinum ligands; after irradiation, this complex can release L5 and L6 to obtain the Pt(II) complex of formula (II). (II), The Pt(II) complex of formula (II) is cisplatin, carboplatin, nedaplatin, oxaliplatin, levoplatin, or epplatin. in, L5 is - OC(O)-R, wherein each of R is independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecylalkyl, dodecylalkyl, tridecylalkyl, tetradecylalkyl, pentadecylalkyl, hexadecylalkyl, heptadecanylalkyl, octadecylalkyl, nonadecanylalkyl, and eicosylalkyl. L6 is - OC(O)-R, wherein each R is independently selected from (dimethylamino)methylene, 2-(dimethylamino)ethylene, 3-(dimethylamino)propylene, 4-(dimethylamino)butylene, 5-(dimethylamino)pentene, 6-(dimethylamino)hexylene, 3-(4-iodophenyl)propylene, 3-(3-iodophenyl)propylene, 3-(3,5-diiodophenyl)propylene, 3 -(4-bromophenyl)propylidene, 3-(3-bromophenyl)propylidene, 3-(3,5-dibromophenyl)propylidene, methylamino, ethylamino, propylamino, butylamino, pentamino, hexamino, heptanamino, octamino, nonamino, decamino, undecylalkylamino, dodecylalkylamino, tridecylalkylamino, tetradecylalkylamino, pentadecylalkylamino, hexadecylalkylamino, heptadecanylalkylamino, octadecylalkylamino; The irradiation mentioned above comes from radiotherapy.

2. Use of the Pt(Ⅳ) complex of formula (I) in the preparation of medicaments for radiation-activated tumor therapy. (I)， L1 to L6 are platinum ligands; after irradiation, this complex can release L5 and L6 to obtain the Pt(II) complex of formula (II). (II), The Pt(II) complex of formula (II) is cisplatin, carboplatin, nedaplatin, oxaliplatin, levoplatin, or epplatin. in, L5 is - OC(O)-R, wherein R is selected from carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, and 6-carboxyhexyl; L6 is - OC(O)-R, where R is selected from carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, (dimethylamino)methylene, 2-(dimethylamino)ethyl, 3-(dimethylamino)propyl, 4-(dimethylamino)butyl, 5-(dimethylamino)pentyl, 6-(dimethylamino)hexyl, 3-(4-iodophenyl)propyl, 3-(3-iodophenyl) Propylene, 3-(3,5-diiodophenyl)propene, 3-(4-bromophenyl)propene, 3-(3-bromophenyl)propene, 3-(3,5-dibromophenyl)propene, methylamino, ethylamino, propylamino, butylamino, pentamino, hexamino, heptaamino, octamino, nonamino, decamino, undecylalkylamino, dodecylalkylamino, tridecylalkylamino, tetradecylalkylamino, pentadecylalkylamino, hexadecylalkylamino, heptadecanylalkylamino, octadecylalkylamino; The irradiation mentioned above comes from radiotherapy.

3. Use of the Pt(Ⅳ) complex of formula (I) in the preparation of medicaments for radiation-activated tumor therapy. (I)， L1 to L6 are platinum ligands; after irradiation, this complex can release L5 and L6 to obtain the Pt(II) complex of formula (II). (II), The Pt(II) complex of formula (II) is cisplatin, carboplatin, nedaplatin, oxaliplatin, levoplatin, or epplatin. in, L5 is - OC(O)-R, wherein R is selected from (dimethylamino)methylene, 2-(dimethylamino)ethylene, 3-(dimethylamino)propylene, 4-(dimethylamino)butylene, 5-(dimethylamino)pentene, and 6-(dimethylamino)hexylene; L6 is - OC(O)-R, where R is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, nonadecanyl, eicosyl, carboxymethyl, 2-carboxyethylidene, 3-carboxypropylidene, 4-carboxybutylidene, 5-carboxypentylidene, 6-carboxyhexylidene, (dimethylamino)methylene, 2-(dimethylamino)ethylidene, 3-(dimethylamino)propylidene, 4-(dimethylamino)butylidene, 5-( Dimethylamino)pentylene, 6-(dimethylamino)hexylene, 3-(4-iodophenyl)propylene, 3-(3-iodophenyl)propylene, 3-(3,5-diiodophenyl)propylene, 3-(4-bromophenyl)propylene, 3-(3-bromophenyl)propylene, 3-(3,5-dibromophenyl)propylene, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, heptaamino, octylamino, nonamino, decamino, undecylalkylamino, dodecylalkylamino, tridecylalkylamino, tetradecylalkylamino, pentadecylalkylamino, hexadecylalkylamino, heptadecanylalkylamino, octadecylalkylamino; The irradiation mentioned above comes from radiotherapy.

4. Use of the Pt(Ⅳ) complex of formula (I) in the preparation of medicaments for radiation-activated tumor therapy. (I)， L1 to L6 are platinum ligands; after irradiation, this complex can release L5 and L6 to obtain the Pt(II) complex of formula (II). (II), The Pt(II) complex of formula (II) is cisplatin, carboplatin, nedaplatin, oxaliplatin, levoplatin, or epplatin. in, L5 is - OC(O)-R, wherein R is selected from 3-(4-iodophenyl)propylidene, 3-(3-iodophenyl)propylidene, 3-(3,5-diiodophenyl)propylidene, 3-(4-bromophenyl)propylidene, 3-(3-bromophenyl)propylidene, and 3-(3,5-dibromophenyl)propylidene; L6 is - OC(O)-R, where R is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, nonadecanyl, eicosyl, carboxymethyl, 2-carboxyethylidene, 3-carboxypropylidene, 4-carboxybutylidene, 5-carboxypentylidene, 6-carboxyhexylidene, (dimethylamino)methylene, 2-(dimethylamino)ethylidene, 3-(dimethylamino)propylidene, 4-(dimethylamino)butylidene, 5-( Dimethylamino)pentylene, 6-(dimethylamino)hexylene, 3-(4-iodophenyl)propylene, 3-(3-iodophenyl)propylene, 3-(3,5-diiodophenyl)propylene, 3-(4-bromophenyl)propylene, 3-(3-bromophenyl)propylene, 3-(3,5-dibromophenyl)propylene, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, heptaamino, octylamino, nonamino, decamino, undecylalkylamino, dodecylalkylamino, tridecylalkylamino, tetradecylalkylamino, pentadecylalkylamino, hexadecylalkylamino, heptadecanylalkylamino, octadecylalkylamino; The irradiation mentioned above comes from radiotherapy.

5. Use of the Pt(Ⅳ) complex of formula (I) in the preparation of medicaments for radiation-activated tumor therapy. (I)， L1 to L6 are platinum ligands; after irradiation, this complex can release L5 and L6 to obtain the Pt(II) complex of formula (II). (II), The Pt(II) complex of formula (II) is cisplatin, carboplatin, nedaplatin, oxaliplatin, levoplatin, or epplatin. in, L5 is - OC(O)-R, where R is selected from methylamino, ethylamino, propylamino, butylamino, pentamino, hexamino, heptaamino, octamino, nonamino, decamino, undecylalkylamino, dodecylalkylamino, tridecylalkylamino, tetradecylalkylamino, pentadecylalkylamino, hexadecylalkylamino, heptadecanylalkylamino, and octadecylalkylamino; L6 is - OC(O)-R, where R is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, nonadecanyl, eicosyl, (dimethylamino)methylene, 2-(dimethylamino)ethylidene, 3-(dimethylamino)propylidene, 4-(dimethylamino)butylidene, 5-(dimethylamino)pentylidene, 6-(dimethylamino)methylene, 2-(dimethylamino)ethylidene, 3-(dimethylamino)propylidene, 4-(dimethylamino)butylidene, 5-(dimethylamino)pentylidene, 6-(dimethylamino)methylamino)methylamino)ethylidene, 2-(di ... (amino)hexylene, 3-(4-iodophenyl)propylene, 3-(3-iodophenyl)propylene, 3-(3,5-diiodophenyl)propylene, 3-(4-bromophenyl)propylene, 3-(3-bromophenyl)propylene, 3-(3,5-dibromophenyl)propylene, methylamino, ethylamino, propylamino, butylamino, pentamino, hexamino, heptanamino, octamino, nonamino, decamino, undecylalkylamino, dodecylalkylamino, tridecylalkylamino, tetradecylalkylamino, pentadecylalkylamino, hexadecylalkylamino; The irradiation mentioned above comes from radiotherapy.

6. Use of Pt(Ⅳ) complexes in the preparation of medicaments for radiation-activated therapy of tumors, wherein the Pt(Ⅳ) complexes are selected from: , in: ； , in: ； , in: ； The irradiation mentioned above comes from radiotherapy.

7. The use of any one of claims 1-6, wherein the irradiation is X-ray or gamma ray.

8. The use of claim 7, wherein the irradiation dose is less than 60 Gy.

9. The use according to any one of claims 1-6 and 8, wherein the tumor is selected from leukemia, lung cancer, malignant lymphoma, breast cancer, ovarian cancer, soft tissue sarcoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, blastoma, bladder cancer, thyroid cancer, prostate cancer, head and neck tumors, esophageal cancer, testicular cancer, gastric cancer, liver cancer, pancreatic cancer, cervical cancer, endometrial cancer, melanoma, or colorectal cancer.

10. The use of claim 9, wherein the tumor is selected from neuroblastoma or nasopharyngeal carcinoma.

11. The use of claim 7, wherein the tumor is selected from leukemia, lung cancer, malignant lymphoma, breast cancer, ovarian cancer, soft tissue sarcoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, blastoma, bladder cancer, thyroid cancer, prostate cancer, head and neck tumors, esophageal cancer, testicular cancer, gastric cancer, liver cancer, pancreatic cancer, cervical cancer, endometrial cancer, melanoma, or colorectal cancer.

12. The use of claim 11, wherein the tumor is selected from neuroblastoma or nasopharyngeal carcinoma.

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