Pt(IV) chemotherapeutic prodrugs and their controlled release for tumor treatment

Abstract

There is a need to develop platinum-based drugs and / or platinum-based regimens that have low toxicity and high therapeutic efficacy. [Solution] The present disclosure provides a Pt(IV) complex for use as a prodrug that is activated by radiation to release a Pt(II) complex for treating tumors. The present disclosure also provides a pharmaceutical composition containing the Pt(IV) complex and the use of the Pt(IV) complex in the manufacture of a medicament that is activated by radiation to treat tumors. The present disclosure also provides a kit containing the Pt(IV) complex and instructions for administering the Pt(IV) complex followed by radiation therapy to treat tumors.

Description

[Technical Field]

[0001] The present invention is in the field of medicinal chemistry. Specifically, the present invention relates to Pt(IV) chemotherapeutic prodrugs and their controlled release for tumor treatment. [Background technology]

[0002] Cancer is one of the diseases that poses the most serious threat to human life and health. Surgery, radiotherapy and chemotherapy are called the three treatment modalities for tumors.

[0003] Radiation therapy is a localized treatment method that uses radiation to treat tumors. The therapeutic effect of radiation therapy depends on radiation sensitivity, and different tissues, organs, and tumor tissues react differently to radiation. For example, fibrosarcoma, osteosarcoma, and melanoma are tumors that are insensitive (resistant) to radiation. It is difficult for radiation therapy to kill all cancer cells in a tumor, and the killing effect on hypoxic cancer cells is undesirable.

[0004] Chemotherapy uses chemical agents to kill cancer cells and achieve its therapeutic goal. Divalent platinum-based drugs have effective and broad-spectrum anticancer activity and have become clinically important first-line chemotherapy drugs, widely used to treat common malignancies such as lung cancer, bladder cancer, ovarian cancer, cervical cancer, esophageal cancer, gastric cancer, colorectal cancer, and head and neck tumors. Cisplatin is a representative first-generation platinum-based anticancer drug; carboplatin and nedaplatin are representative second-generation platinum-based anticancer drugs; and oxaliplatin and lobaplatin are representative third-generation platinum-based anticancer drugs. The application of divalent platinum-based drugs is limited by side effects such as nephrotoxicity, gastrointestinal toxicity, hematotoxicity, neurotoxicity, and ototoxicity, and their therapeutic efficacy is also limited by tumor drug resistance. Research into tetravalent platinum-based drugs is also underway to expand the platinum-based drug market. Tetravalent platinum compounds themselves have low killing ability against cancer cells, and can exert anticancer activity by being reduced under physiological conditions to release divalent platinum. This retains the advantage of conventional divalent platinum-based drugs in that they have broad-spectrum anticancer efficacy, while also providing other unique advantages due to the different coordination structures between tetravalent platinum and divalent platinum. Tetravalent platinum is a 2 sp 3 It has a hexacoordinated structure and is more stable than divalent platinum, resulting in high blood stability. The tetravalent platinum complex has two additional ligands in the axial direction, providing more options for platinum-based drug design. However, although some tetravalent platinum complexes, such as iproplatin or satraplatin, have entered clinical research in the last century, no tetravalent platinum-based drug has been approved for sale to date. Summary of the Invention [Problem to be solved by the invention]

[0005] Therefore, there remains a need to develop platinum-based drugs and / or platinum-based drug regimens that have low toxicity and high therapeutic efficacy. [Means for solving the problem]

[0006] Through intensive research and creative efforts, the present inventors have discovered that Pt(IV) complexes can be used as prodrugs, and that irradiation of the prodrugs releases divalent platinum-based drugs, thereby enabling tumor treatment. Effectively combining radiation therapy with Pt(IV) complexes, i.e., activating the Pt(IV) complexes through irradiation for controlled release, can effectively improve the therapeutic effect.

[0007] In one aspect, the present disclosure provides a Pt(IV) complex of formula (I) that is activated by radiation and used as a prodrug for treating tumors, [ka] (wherein L1 to L6 are platinum ligands.) The complex provides a Pt(IV) complex that can release L5 and L6 after irradiation to give a Pt(II) complex of formula (II).

[0008] [ka] Preferably, the Pt(II) complex of formula (II) is a cis-Pt(II) complex, such as cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin, heptaplatin, cycloplatin, myoplatin, enloplatin, sebriplatin, spiroplatin, zeniplatin, TRK-710, aroplatin, bis(isopropylamine)platinum(II), or bis(cyclopentylamine)platinum(II). In a preferred embodiment, the Pt(II) complex of formula (II) is cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin, or heptaplatin.

[0009] Preferably, L5 and L6 are each independently - OC(O)-R, where R is an optionally substituted C 1-20 Alkyl groups, optionally substituted C 1-20 alkyloxy group or an optionally substituted amino group, the substituents being C 1-18 Alkyl group, carboxyl group, hydroxyl group, halogen, mercapto group, amino group, C 1-3 Dialkylamino group, carbonyl group, phenyl group, halogenated phenyl group, C 1-6

[0033] For example, each R is independently selected from a phenyl group substituted with an alkyl group, a maleimide group, and a triphenylphosphonium group. For example, R is independently selected from a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, an icosyl group, a carboxymethylene group, a 2-carboxyethylene group, a 3-carboxypropylene group, a 4-carboxybutylene group, a 5-carboxypentylene group, a 6-carboxyhexylene group, a (dimethylamino)methylene group, a 2-(dimethylamino)ethylene group, a 3-(dimethylamino)propylene group, a 4-(dimethylamino)butylene group, a 5-(dimethylamino)pentylene group, a 6-(dimethylamino)hexylene group, a 5-maleimidepentylene group, and a 6-maleimide group. The alkyl group is selected from a hexylidene group, a 7-maleimidoheptylene group, an 8-maleimidooctylene group, a 3-(4-iodophenyl)propylene group, a 3-(3-iodophenyl)propylene group, a 3-(3,5-diiodophenyl)propylene group, a 3-(4-bromophenyl)propylene group, a 3-(3-bromophenyl)propylene group, a 3-(3,5-dibromophenyl)propylene group, a methylamine group, an ethylamine group, a propylamine group, a butylamino group, a pentylamino group, a hexylamino group, a heptylamino group, an octylamino group, a nonylamino group, a decylamino group, an undecylamino group, a dodecylamino group, a tridecylamino group, a tetradecanoylamino group, a pentadecanoylamino group, a hexadecanoylamino group, a heptadecylamino group, and an octadecanoylamino group.

[0010] Preferably, the tumor is leukemia, lung cancer, malignant lymphoma, breast cancer, ovarian cancer, soft tissue sarcoma, osteogenic sarcoma, rhabdomyosarcoma, Ewing's sarcoma, blastoma, neuroblastoma, bladder cancer, thyroid cancer, prostate cancer, head and neck tumor, nasopharyngeal cancer, esophageal cancer, testicular cancer, gastric cancer, liver cancer, pancreatic cancer, cervical cancer, endometrial cancer, melanoma, or colorectal cancer.

[0011] In another aspect, the present disclosure provides a pharmaceutical composition comprising the Pt(IV) complex.

[0012] In another aspect, the present disclosure further provides the use of said Pt(IV) complex in the manufacture of a medicament for treating tumors that is activated by radiation, preferably said radiation resulting from radiotherapy.

[0013] In another aspect, the present disclosure further provides a method of treating a tumor, comprising administering to a subject the Pt(IV) complex and irradiating the subject.

[0014] Preferably, said radiation is from radiotherapy.

[0015] Preferably, the radiotherapy is carried out 0.5 to 6 hours after administration of the Pt(IV) complex.

[0016] In one embodiment, the radiation dose is less than 60 Gy.

[0017] Preferably, the tumor is leukemia, lung cancer, malignant lymphoma, breast cancer, ovarian cancer, soft tissue sarcoma, osteogenic sarcoma, rhabdomyosarcoma, Ewing's sarcoma, blastoma, neuroblastoma, bladder cancer, thyroid cancer, prostate cancer, head and neck tumor, nasopharyngeal cancer, esophageal cancer, testicular cancer, gastric cancer, liver cancer, pancreatic cancer, cervical cancer, endometrial cancer, melanoma, or colorectal cancer.

[0018] In another aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: the Pt(IV) complex or a pharmaceutical composition comprising the Pt(IV) complex; and instructions for administering radiation therapy to treat the tumor after administration.

[0019] In order to more clearly describe the technical solutions of the embodiments of the present disclosure, the drawings related to the embodiments will be briefly described below. Obviously, the drawings described below are only related to some embodiments of the present disclosure and are not intended to limit the present invention. [Brief explanation of the drawings]

[0020] [Figure 1] It exhibits a wide range of properties for reducing metal ions by radiation. [Figure 2] It exhibits a wide range of radiation-induced reduction properties for metal complexes. [Figure 3] We demonstrate that radiation-induced Pt(IV) complexes effectively release FDA-approved Pt(II) drugs over a broad range. [Figure 4] We demonstrate that radiation induces effective controlled release of oxaliplatin in living cells. [Figure 5] We demonstrate that radiation-driven reduction of the oxaliPt(IV)-(OAc)2 prodrug to release oxaliplatin can be used to treat the oxaliplatin-sensitive HCT116 tumor cell line, achieving combined radiotherapy and chemotherapy. DETAILED DESCRIPTION OF THE INVENTION

[0021] In order to clarify the objectives, technical means and advantages of the embodiments of the present disclosure, the technical means of the embodiments of the present disclosure will be described clearly and completely below with reference to the drawings according to the embodiments of the present disclosure. Obviously, the described embodiments are only a part of the embodiments of the present disclosure, but not all of the embodiments. All other embodiments that can be obtained by those skilled in the art based on the described embodiments of the present disclosure without any creative work are also within the scope of protection of the present invention.

[0022] The present invention may be embodied in other specific forms without departing from the essential attributes of the present invention. It should be understood that, unless inconsistent, any and all embodiments of the present invention may be combined with technical features of any one or more other embodiments to obtain another embodiment. The present invention includes the other embodiment obtained from such a combination.

[0023] All publications and patents mentioned in this disclosure are incorporated herein by reference in their entirety. If the terms or usage used in any publication or patent incorporated by reference conflict with the terms or usage used in this disclosure, the terms and usage in this disclosure shall control.

[0024] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter discussed above.

[0025] Unless otherwise defined, all technical and scientific terms used herein have their common meaning within the field to which the subject matter sought to be protected belongs. In the event that a term has a plurality of definitions, those in this specification are to be used.

[0026] All numerical values ​​expressed in the present specification and claims, such as amounts of materials, reaction conditions, durations, quantitative properties of materials, etc., should be understood to be modified in all cases by the term "about" unless otherwise specified in the examples or otherwise. Any numerical range recited in this application is intended to include all subranges within that range and any combination of the endpoints of that range or subrange, for example, an alkyl group having 1 to 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, with subranges including alkyl groups having 1-4, 1-6, 1-10, 2-4, or 2-10 carbon atoms, etc.

[0027] The specifications of the present disclosure are to be construed in accordance with the laws and principles of chemical bonding. In some instances, hydrogen atoms may be removed to accommodate substituents at a given position.

[0028] As used in this disclosure, words such as "comprise," "contain," or "comprise" or similar words are intended to mean that the elements appearing before the word cover the elements listed after the word and their equivalents, and do not exclude elements not listed. As used herein, the terms "comprise" or "comprise" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of." As used in this disclosure, the singular forms "a," "an," and "the" can also include the plural form unless otherwise specified.

[0029] Unless otherwise specified, the present disclosure uses standard names and standard laboratory steps and techniques in analytical chemistry, organic synthetic chemistry, and coordination chemistry. Unless otherwise specified, the present disclosure uses conventional methods such as mass spectrometry and elemental analysis, and the steps and conditions can refer to the general operating steps and conditions in this field.

[0030] The reagents and raw materials used in this disclosure are either commercially available or prepared by common chemical synthesis methods.

[0031] When the term "optionally" is used herein to describe a certain situation, it means that this situation may or may not occur. For example, "optionally fused to a ring" means either fused to a ring or not fused to a ring. For example, the term "optionally substituted" used herein means unsubstituted or having at least one non-hydrogen substituent that does not impair the purpose or performance of an unsubstituted analog.

[0032] In the present disclosure, unless otherwise specified, the number of the "substitutions" may be one or more, and when there are more than one, they may be two, three, or four. When there are more than one "substitutions," the "substitutions" may be the same or different.

[0033] In the present disclosure, the position of "substitution" is arbitrary unless otherwise specified.

[0034] As used herein, the term "axial ligand" refers to the d 2 sp 3 This refers to the two axial ligands in a hexacoordinated structure, which are eliminated from the complex after it is reduced by irradiation.

[0035] As used herein, the term "lateral ligand" refers to the d 2 sp 3 It refers to the four lateral ligands in the hexacoordinated structure that are still able to coordinate with the divalent platinum ion after the complex has been reduced by irradiation.

[0036] As used herein, the term "neutral ligand" or "anionic ligand" refers to a ligand capable of coordinating to platinum, which is generally uncharged or negatively charged, but which may contain a portion of a cation, such as a triphenylphosphine or ammonium group.

[0037] In the context of the present application, unless specifically stated to the contrary, the term "treatment" may also include prophylaxis.

[0038] The term "subject" or "patient" as used herein includes humans and mammals.

[0039] As used herein, the term "C1-C 20The term "alkyl group" refers to a straight or branched alkane chain containing 1 to 20 carbon atoms. For example, 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), t-butyl (C4), s-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentane (C5), neopentyl (C5), 3-methyl-2-butane (C5), t-pentyl (C5), n-hexyl (C6), and the like. The term "lower alkyl group" refers to a straight or branched alkyl group having 1 to 4 carbon atoms. The term "substituted alkyl group" refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available attachment point. The term "haloalkyl group" means an alkyl group having one or more halogen substituents, including, but not limited to, groups such as -CHBr, -CHI, -CHCl, -CHF, -CHF, and -CF.

[0040] As used herein, the term "alkylene group" refers to a divalent hydrocarbon group having two points of attachment, as described above for "alkyl group." For example, a methylene group is a -CH- group, and an ethylene group is a -CH-CH- group.

[0041] As used herein, the terms "alkoxy" and "alkylthio" refer to alkyl groups as defined above bonded through an oxygen (-O-) or sulfide (-S-) bond, respectively. The terms "substituted alkoxy" and "substituted alkylthio" refer to substituted alkyl groups bonded through an oxygen or sulfide bond, respectively. A "lower alkoxy" is an OR group where R is a lower alkyl group (an alkyl group containing 1 to 4 carbon atoms).

[0042] As used herein, the term "halogen" means fluorine, chlorine, iodine or bromine.

[0043] The radiation source of the present disclosure may be α, β, or γ rays generated by the decay of radionuclides. X-rays, γ rays, high-energy electrons, protons, heavy ions generated by external radiation sources, α particles generated by boron neutron capture therapy (BNCT), and other possible external or internal radiation may also be applied to the present disclosure.

[0044] The high-energy radiation used in radiotherapy has high spatial and temporal resolution, high tissue penetration ability, and is highly clinically relevant. The activation of prodrug molecules in vivo by the high-energy radiation used in radiotherapy for chemical reactions has value in basic research and clinical application.

[0045] Chemical reactions activated by high-energy radiation involve the radiolysis of water to produce large amounts of reactive species, which then react with target substrates. Among the products of water radiolysis, the compounds with the highest yields are hydroxyl radicals and hydrated electrons.

[0046] The body is generally in a reducing environment, and large amounts of substances such as glutathione and vitamin C quench hydroxyl radicals and increase the yield of hydrated electrons. Thus, using hydrated electrons to perform chemical reactions is a major breakthrough in biochemistry.

[0047] High-energy radiation (e.g., X-rays and gamma rays) can be used as an external stimulus to reduce tetravalent platinum complexes to yield divalent platinum complexes. Due to the high penetration ability and high spatiotemporal resolution of radiation, prodrugs can be converted to divalent platinum complexes very effectively using radiation therapy equipment. For example, X-ray irradiation can be used as an external trigger to activate prodrugs. The radiation-induced chemical reaction can be controlled spatially and temporally, allowing for precise control of the area, time, and dose required to convert the prodrug to its active form.

[0048] The present disclosure demonstrates that radiation can rapidly and effectively reduce the properties of metal complexes, allowing Pt(IV) prodrugs to release Pt(II) drugs, thereby achieving the goal of controlled release of chemotherapy drugs. Therefore, radiation can be used to reduce relatively less toxic Pt(IV) prodrugs and release Pt(II) drugs, such as oxaliplatin, effectively inhibiting various cell lines that are highly sensitive to oxaliplatin. In HCT116 tumor-bearing mice, this strategy resulted in almost complete tumor regression. This reduction is achieved by using hydrated electrons (e) generated by the radiolysis of water. aq - ) and is applied to the hypoxic, reducing tumor microenvironment. Therefore, a strategy of activating a prodrug to release a chemotherapy drug by radiation therapy has potential clinical value.

[0049] In tumor treatment, more than 50% of cases require radiation therapy. Modern radiation therapy techniques allow precise irradiation of tumors and the delivery of high localized doses of radiation.

[0050] Cancer response to radiation can be explained by radiosensitivity. Highly radiosensitive cancer cells (leukemia, many lymphomas, and germ cell tumors) are rapidly killed by moderate doses of radiation. Moderately radiosensitive cancer cells (many epithelial cancers) require higher doses of radiation (60–70 Gy) to completely kill them. Some cancers (renal cell carcinoma and melanoma) have significant radiation resistance and require doses much higher than clinically safe for cure. Many common moderately radioresponsive tumors typically undergo radiation therapy in their early stages. Metastatic cancers are generally not cured by radiation therapy because it is not possible to treat the entire body.

[0051] Radiation therapy itself is painless. Many low-dose palliative treatments (e.g., radiation therapy for bone metastases) have minimal or no side effects. Higher doses result in different 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 the radiation, the type of radiation, the dose, number of times, synchronous chemotherapy, and the patient. Side effects are dose-dependent; for example, relatively high doses of radiation to the head and neck can cause cardiovascular complications, thyroid dysfunction, and pituitary dysfunction. Modern radiation therapy aims to minimize side effects and help patients understand and cope with unavoidable side effects.

[0052] Radiation therapy destroys the DNA of cancer cells using photons or charged particles. The atoms that make up the DNA chain are ionized directly or indirectly. Indirect ionization involves the ionization of water to form radicals, which then destroy the DNA. Cells have mechanisms to repair DNA damage, but double-stranded DNA breaks are more difficult to repair and can cause significant chromosomal abnormalities and gene deletions. Targeted double-strand breaks increase the likelihood of cell death. Experiments conducted by Gray et al. in the 1950s demonstrated that hypoxic cells require three times the radiation dose to kill compared with normoxic cells. Because normal tissues have limited tolerance to radiation, it is generally not possible to compensate for tumor hypoxia by increasing the radiation dose. After radiation therapy, hypoxic tumor cells persist and divide, potentially leading to persistent tumor persistence and the development of a more aggressive tumor phenotype.

[0053] Radiotherapy has a limited radiation dose tolerance in clinical settings (generally less than 60 Gy), while hypoxic tumors are resistant to radiotherapy and are adversely affected by DNA damage caused by oxygen-induced radiation. Therefore, to improve tumor cure rates, radiotherapy often needs to be combined with chemotherapy drugs. However, many clinically approved anticancer drugs have a narrow therapeutic window and significant systemic toxicity. Therefore, prodrug strategies must often be implemented to further improve dosage and reduce toxicity. Prodrug doses exceed 50 times the normal dose and can overcome tumor resistance to chemotherapy drugs to some extent. However, due to limited activation efficiency and poor tumor selectivity of prodrugs, prodrug strategies are difficult to implement clinically. Using radiotherapy as a precise exogenous stimulus can enable highly selective activation of active pharmaceutical ingredients at tumor sites, solving these challenges. However, in vivo radiation-induced degradation chemistry has not yet been established, and only a limited number of studies have implemented this strategy at the test tube or cellular level over the past 30 years. However, without establishing the chemistry of radiation activation in vivo, radiotherapy-induced activation of chemotherapy drugs is unlikely to have clinical impact.

[0054] The radiochemical changes of molecules are the material basis for studying all radiochemical effects. Radiochemical effects are mainly divided into two types: direct effects, in which ionizing radiation causes direct chemical changes in target molecules, and indirect effects, in which radiation deposits on environmental molecules and then causes indirect chemical reactions on target molecules. Direct and indirect effects exist simultaneously, but indirect effects dominate in living organisms. Since 70-80% of tissues are water, various active substances are mainly generated by the radiolysis of water (Scheme 1a), with the highest yields being hydroxyl radicals (·OH) and hydrated electrons (e aq - ) The radiolysis of water is 10 -4Because radiation-induced reactions are often instantaneous, they are highly controllable. While ·OH-induced decomposition reactions and related fluorescent probes have been successfully applied to bioimaging, the rapid quenching of ·OH by the reducing tumor microenvironment inhibits the evolution of ·OH in vivo. Radiation-generated e aq - The yield of , another major product of water radiolysis, increases in a reducing environment. Therefore, we aim to precisely deliver radiotherapy to the local area and aq - We investigated the feasibility of generating to mediate chemical shear reactions ( Scheme 1b ) and using radiation as a chemical tool to release target molecules in a highly tumor-selective manner ( Scheme 1c ).

[0055] [ka] Scheme 1a [ka] Scheme 1b (M is Fe, Co, Ni, Cu, Ru, Rh, Pd, Ag, etc.) [ka] Scheme 1c Scheme 1. Radiation-induced controlled release of metal complexes in tumors. a) Radiolysis of water by ionizing radiation. The G value of hydrated electrons is 2.63 (G value is the number of molecules formed by absorbing 100 eV of energy in a system). b) Hydrated electrons generated by radiation can reduce metal ions and metal complexes. c) Pt(IV) complexes can be reduced by radiation to release Pt(II) anticancer drugs.

[0056] Through research, the inventors developed a novel bioshear chemistry to realize radiation-induced metal reduction in vivo. This strategy was applied to the activation of Pt(IV) prodrugs, using radiation therapy as an exogenous stimulus to trigger drug release, achieving the release of chemotherapy drugs at the tumor site under precise radiation therapy guidance. Furthermore, this strategy also contributes to solving the problem of radiation therapy resistance in hypoxic tumors, and can even improve the drug release efficiency under hypoxic conditions. Radiation-induced e aq - Inducing direct metal reduction of β-glucan can be extended to other metal or biological complexes (e.g., metalloproteins), providing an effective tool for mechanistic analysis of complex biological processes.

[0057] The Pt(IV) complexes of formula (I) according to one embodiment of the present disclosure are used as prodrugs for the treatment of tumors upon activation by irradiation, [ka] In the formula, L1 to L6 are platinum ligands, and the complex can release L5 and L6 after irradiation to obtain a Pt(II) complex of formula (II).

[0058] [ka] The Pt(IV) complex of formula (I) of the present disclosure can be reduced to release axial ligands L5 and L6 to obtain a Pt(II) complex of formula (II). The Pt(IV) complex of formula (I) was developed based on the Pt(II) complex and can be considered a prodrug of the Pt(II) complex of formula (II). From the correspondence between formulas I and II, the lateral 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).

[0059] The lateral ligands of the Pt(IV) complex of formula (I) may be in the cis or trans configuration. In one embodiment, the lateral ligands of the Pt(IV) complex of formula (I) are in the cis configuration.

[0060] In one embodiment, the Pt(II) complex of formula (II) is a cis Pt(II) complex.

[0061] The Pt(II) complex of formula (II) may be a divalent platinum ligand known for its anticancer activity. In one embodiment, the Pt(II) complex of formula (II) is a commercially available or clinically available divalent platinum complex, such as cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin, heptaplatin, cycloplatin, myoplatin, enloplatin, sebriplatin, spiroplatin, zeniplatin, TRK-710, aroplatin, bis(isopropylamine)platinum(II), or bis(cyclopentylamine)platinum(II).

[0062] In a preferred embodiment, the Pt(II) complex of formula (II) is cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin, or heptaplatin.

[0063] L5 and L6 are each a monovalent negative ligand of Pt(IV) that can be released from the Pt(IV) complex of formula (I) under irradiation. L5 and L6 may be the same or different.

[0064] In one embodiment, L5 and L6 are each - OC(O)-R, where R is an optionally substituted C 1-20 Alkyl groups, optionally substituted C 1-20 alkyloxy group or an optionally substituted amino group, the substituents being C 1-18 Alkyl group, carboxyl group, hydroxyl group, halogen, mercapto group, amino group, C 1-3 Dialkylamino group, carbonyl group, phenyl group, halogenated phenyl group, C 1-6 The term "optionally substituted" means a phenyl group substituted with an alkyl group, a maleimide group, or a triphenylphosphonium group. 1-20 This means that the alkyl group or amino group may or may not be substituted with a substituent. 1-20The alkyl group includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and icosyl groups. Those skilled in the art will rationally select the substituents according to the stability of the chemical structure.

[0065] In one embodiment, L5 and L6 are each independently - OC(O)-R, each R independently represents a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, an icosyl group, a carboxymethylene group, a 2-carboxyethylene group, a 3-carboxypropylene group, a 4-carboxybutylene group, a 5-carboxypentylene group, a 6-carboxyhexylene group, a (dimethylamino)methylene group, a 2-(dimethylamino)ethylene group, a 3-(dimethylamino)propylene group, a 4-(dimethylamino)butylene group, a 5-(dimethylamino)pentylene group, a 6-(dimethylamino)hexylene group, a 5-maleimidopentylene group, a 6 ... The alkyl group is selected from an imidohexylidene group, a 7-maleimidoheptylene group, an 8-maleimidooctylene group, a 3-(4-iodophenyl)propylene group, a 3-(3-iodophenyl)propylene group, a 3-(3,5-diiodophenyl)propylene group, a 3-(4-bromophenyl)propylene group, a 3-(3-bromophenyl)propylene group, a 3-(3,5-dibromophenyl)propylene group, a methylamine group, an ethylamine group, a propylamine group, a butylamino group, a pentylamino group, a hexylamine group, a heptylamino group, an octylamino group, a nonylamino group, a decylamino group, an undecylamino group, a dodecylamino group, a tridecylamino group, a tetradecanoylamino group, a pentadecanoylamino group, a hexadecanoylamino group, a heptadecylamino group, and an octadecanoylamino group.

[0066] For example, platinum(IV) complexes are compounds 1 to 22, which are cisplatin-based prodrugs.

[0067] [ka] where: [Table 1-1] [Table 1-2] For example, platinum(IV) complexes are compounds 23 to 44, which are carboplatin-based prodrugs.

[0068] [ka] where: [Table 2-1] [Table 2-2] For example, platinum(IV) complexes are compounds 45-66, which are prodrugs of oxaliplatin.

[0069] [ka] where: [Table 3-1] [Table 3-2] For platinum(IV) complexes, the divalent platinum complex of formula (II) can be hydroxylated with an oxidizing agent, such as hydrogen peroxide, to give a platinum(IV) dihydroxy complex, in which the two dihydroxy groups can be replaced with carboxylate groups by the action of an acylating agent, such as an anhydride.

[0070] For example, a platinum(IV) complex can be produced by the following scheme:

[0071] [ka] The corresponding Pt(II) drug A (12.6 mmol, 1.0 equiv.) was mixed with 12 mL of HO, diluted with 15 mL of HO, and stirred at 50 °C for 5 h. After complete consumption of the Pt(II) drug, the product was collected in a centrifuge tube at room temperature and washed with water, ethanol, and ethyl ether, respectively. The precipitate was freeze-dried to obtain a white powder of compound B.

[0072] Compound II (1.0 equivalent) and the corresponding acid anhydride (e.g., succinic anhydride, acetic anhydride, N,N-dimethylglycine anhydride) (1.0 equivalent) were mixed and dissolved in 4 mL of anhydrous DMF, followed by stirring for 1 hour to give crude compound C.

[0073] For compound D (urethane bond, i.e., R2 represents an amino compound), To the reaction mixture, 2 mL of anhydrous DMF solution of the corresponding isocyanate was added. The reaction was allowed to proceed overnight, and the solvent was removed under reduced pressure at 65°C. 2 mL of ethyl ether was added to the oily residue, and the mixture was sonicated for 1 minute and centrifuged. The solid was further washed with 4 mL of DCM and 2 mL of ethyl ether. The washed solid was left under vacuum overnight to give compound D.

[0074] For compound D (ester bond, i.e., R2 represents an alkyl compound): Compound C was precipitated with ethyl ether and lyophilized to obtain a white powder. Compound C (1.0 equivalent) and the corresponding carboxylic acid (2.0 equivalents) were dissolved in 5 mL of DMF, and the condensing agent TBTU (2.0 equivalents) was added. The mixture was heated to 50 °C and reacted overnight in the dark. The solvent was evaporated under reduced pressure, washed with water, and then lyophilized to obtain compound D.

[0075] The tetravalent platinum complexes of the present disclosure are believed to treat tumors primarily by being reduced to divalent platinum in vivo. When the tetravalent platinum complexes are administered (orally, intravenously, intracavitary, etc.), the drug is circulated throughout the body and reaches most organs and tissues, but the level of reduction to divalent platinum by the cells themselves varies in each organ and tissue. However, subsequent radiation therapy can precisely irradiate tumors, providing a locally high dose of radiation, thereby locally increasing the level of reduction of tetravalent platinum to divalent platinum.

[0076] Prodrugs of the tetravalent platinum complexes of the present disclosure can be used to treat leukemia, lung cancer, malignant lymphoma, breast cancer, ovarian cancer, soft tissue sarcoma, osteogenic sarcoma, rhabdomyosarcoma, Ewing's sarcoma, blastoma, neuroblastoma, bladder cancer, thyroid cancer, prostate cancer, head and neck tumors, nasopharyngeal cancer, esophageal cancer, testicular cancer, gastric cancer, liver cancer, pancreatic cancer, cervical cancer, endometrial cancer, melanoma, or colon cancer.

[0077] Another aspect of the present disclosure provides a pharmaceutical composition comprising the above-described Pt(IV) complex and pharmaceutically acceptable auxiliary materials.

[0078] The term "pharmaceutically acceptable" or "pharmaceutically acceptable" as used herein means that the compound or composition is chemically and / or toxicologically compatible with the other ingredients that make up the formulation and / or with the human or mammal in which it is used to prevent or treat a disease or condition.

[0079] The term "auxiliary material" as used herein refers to an excipient or vehicle for administering a compound, including, but not limited to, diluents, disintegrants, precipitation retardants, surfactants, flow aids, adhesives, lubricants, coating materials, etc. auxiliary materials are generally described in E.W. Martin's "Remington's Pharmaceutical Sciences." Examples of auxiliary materials include, but are not limited to, vegetable oil, cyclodextrin, aluminum monostearate, aluminum stearate, carboxymethylcellulose, sodium carboxymethylcellulose, crospovidone, glyceryl isostearate, glyceryl monostearate, hydroxyethylcellulose, hydroxymethylcellulose, hydroxydioctadecyl hydroxystearate, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, etc.

[0080] At least one embodiment of the present disclosure provides a method for producing a pharmaceutical composition, the method comprising mixing at least one Pt(IV) complex of the present disclosure with pharmaceutically acceptable auxiliary materials.

[0081] The Pt(IV) complexes of the present disclosure can be prepared as injections and powder injections, which are diluted with saline or a 5% glucose solution and administered intravenously.

[0082] Divalent platinum-based drugs are generally administered parenterally and are not suitable for oral administration, however, the Pt(IV) complexes of the present disclosure can also be prepared as pharmaceutical compositions for oral administration.

[0083] For example, a pharmaceutical composition for oral administration comprises a suspension of a Pt(IV) complex in at least one pharmaceutically acceptable vegetable, animal, mineral, synthetic, or semi-synthetic oil. In one embodiment, the pharmaceutical composition may be encapsulated in a hard gelatin capsule, a hydroxypropyl methylcellulose capsule, or a soft gelatin capsule, wherein the capsule contains 50 to 350 mg of the Pt(IV) complex.

[0084] For example, the pharmaceutical composition for oral administration may contain a form of an inclusion complex of a Pt(IV) complex with a cyclodextrin, which can be obtained by dissolving the Pt(IV) complex in an organic solvent such as acetone, then reacting it with a cyclodextrin, such as a β- or γ-cyclodextrin substituted with a C1-4 hydroxyalkyl group, and then removing the solvent by sublimation and drying under reduced pressure.

[0085] The present disclosure further provides the use of the Pt(IV) complexes in the manufacture of radiation-activated drugs for treating tumors.

[0086] In another aspect, the present disclosure further provides a method of treating a tumor, comprising administering to a subject the Pt(IV) complex described above and irradiating the subject with radiation.

[0087] In one embodiment, the radiation is from radiation therapy.

[0088] Radiation therapy includes external beam radiotherapy (including general external beam radiotherapy, stereotactic radiotherapy, 3D conformal radiotherapy, and intensity-modulated radiotherapy), particle beam therapy, Auger therapy, contact X-ray brachytherapy (particle interventional therapy), and radioisotope therapy.

[0089] Available equipment includes deep x-ray machines, cobalt-60 machines, medical electron linear accelerators, medical proton accelerators, medical heavy ion accelerators, gamma knives, etc.

[0090] The radiation therapy of the present disclosure differs from synchronous radiation therapy. While synchronous radiation therapy uses low-dose chemotherapy to improve tissue sensitivity to radiation, the radiation therapy of the present disclosure simultaneously promotes the reduction of a prodrug to a divalent platinum-based drug and its function through radiation exposure during chemotherapy. The radiation therapy of the present disclosure differs from sequential chemoradiotherapy. While sequential chemoradiotherapy involves administering one set of chemotherapy followed by one set of radiation therapy, or one set of radiation therapy followed by one set of chemotherapy, the radiation therapy of the present disclosure involves administering radiation therapy shortly after chemotherapy, for example, 0.5 to 6 hours later.

[0091] In one embodiment, the radiotherapy is administered 0.5 to 6 hours after administration of the Pt(IV) complex.

[0092] For example, the radiation therapy is performed 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, or 3 hours after administration of the Pt(IV) complex, and irradiation is performed for 1 to 10 minutes (for example, 1, 2, 3, 4, or 5 minutes).

[0093] For example, the radiation therapy device is a linear accelerator (e.g., Varian Medical Systems' Clinac iX) that generates 6 MeV X-rays, with a total local tumor irradiation dose of 4 Gy and a dose rate of 2 Gy / min. The regimen involves two weekly treatments (one treatment consisting of drug and radiation therapy), with radiation therapy administered 2 hours after the Pt(IV) complex is administered, with the radiation therapy duration approximately 2 minutes and an interval of 2 days, for a total of 4 weeks.

[0094] [ka] Combination radiotherapy with the Pt(IV) complexes of the present disclosure can treat hypoxic tumors that are resistant to conventional radiotherapy, such as pancreatic and prostate cancers.

[0095] The radiation therapy scheme of the present disclosure may be performed using conventional radiation therapy methods, or may be performed at a lower dose than conventional radiation therapy methods, and when performed at a lower dose, can reduce the side effects of radiation therapy.

[0096] In one embodiment, the radiation dose is less than 60 Gy.

[0097] The Pt(IV) complexes of the present disclosure can be used in combination with radiation therapy to treat cancer, such as leukemia, lung cancer, malignant lymphoma, breast cancer, ovarian cancer, soft tissue sarcoma, osteogenic sarcoma, rhabdomyosarcoma, Ewing's sarcoma, blastoma, neuroblastoma, bladder cancer, thyroid cancer, prostate cancer, head and neck tumors, nasopharyngeal cancer, esophageal cancer, testicular cancer, gastric cancer, liver cancer, pancreatic cancer, cervical cancer, endometrial cancer, melanoma, or colon cancer.

[0098] In yet another aspect, the present disclosure further provides a kit comprising the Pt(IV) complex or a pharmaceutical composition comprising the Pt(IV) complex, and instructions for administering the complex followed by radiation therapy to treat a tumor.

[0099] Example The starting materials of the examples are commercially available and / or can be prepared by 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 solvents, reaction atmospheres, reaction temperatures, experiment durations and post-treatments) from the synthesis methods described below. Those skilled in the art of organic synthesis will understand that the functional groups present on each part of the molecule must be compatible with the proposed reagents and reactions.

[0100] Reagents and equipment All chemical reagents were purchased from Energy Chemical Industry (China), Bailingwei (China), Yinuokai (China), and China National Pharmaceutical Group (China). They were used as received and required no further purification. Solvents were dehydrated with Na or CaH2 and then distilled before use. Cell Counting Kit-8 (CCK-8) was purchased from Biyuntian Biotechnology Institute. Ultrapure water (18.2 MΩ / cm) used throughout the process was from a Milli-Q reference system (Millipore). Nuclear magnetic resonance (NMR) spectra were recorded using a Brook AVANCE 400 MHz spectrometer. Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) was performed using 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 is generated by an X-ray generator (RS2000 Pro 225, 225kV, 17.7mA, Rad Source Technologies, Inc.). The total dose for single-tube experiments is 0-60Gy, with a dose rate of 5Gy / min. The total dose for cell experiments is 0-16Gy, with a dose rate of 1.6Gy / min. Local irradiation is performed on implanted tumors using a customized mouse mold. The local tumor irradiation dose is 4Gy, with a dose rate of 1Gy / min, and other parts of the body are shielded with 5mm thick lead. γ-ray irradiation is performed using a 60 Provided by a Co source.

[0101] 1. Synthesis and characterization of Pt(IV) complexes As previously described, Pt(IV) complexes were prepared with the corresponding Pt(II) reagents and oxidized with hydrogen peroxide to give dihydroxy platinum(IV) complexes. The two dihydroxy groups of the dihydroxy platinum(IV) complexes were then reacted with the corresponding acid anhydrides to produce Compounds 1 to 66. The products were characterized by mass spectrometry.

[0102] [Table 4-1] [Table 4-2] [Table 4-3] 2.Analysis method 2.1 Detection of iron ions and complexes Fe 2+ / Fe 3+ For the stock solution, 2.78 mg of FeSO4·7H2O and 2.70 mg of FeCl3·6H2O were each dissolved in 1 mL of deionized water to obtain a 10 mM stock solution, and 100 μL of the stock solution was diluted to 100 μM in 10 mL.

[0103] Fe 2+ / Fe 3+ For the probe, 54.06 mg of phenanthroline was dissolved in 1 mL of DMSO to obtain a 300 μM stock solution, which could be used for detection without further dilution. 3+ The probe was dissolved in 1 mL of DMSO to give a 10 mM stock solution, and 100 μL was diluted to 100 μM with 10 mL of MeOH / H 2 O (v / v, 1:1).

[0104] [Fe(phen))3] 2+ For the solution, add 15 μL of phenol stock solution to 15 mL of 100 μM Fe 2+ Add to the solution [Fe(phen)3] 2+ A complex was obtained.

[0105] Fe by phen 2+ / Fe 3+ For the detection of 100 μM Fe 2+ / Fe 3+ The solution was further diluted to 80 μM, 60 μM, 40 μM, 20 μM, and 0 μM. 2+ / Fe 3+ The final concentration of phenol was 300 μM because 3 μL of a phenol stock solution was added to the solution, leaving the concentration of Fe largely unaffected. UV-Vis absorption was detected at 510 nm.

[0106] Fe 2+ / Fe 3+ Fe 3+ Detected with a probe. 100 μM Fe 2+ / Fe 3+ The solution was further diluted to 80 μM, 60 μM, 40 μM, 20 μM, and 0 μM. 600 μL of Fe 2+ / Fe 3+ solution and 2400 μL of Fe 3+ Since the probe was mixed with Fe 2+ / Fe 3+ The final concentrations of Fe were 20 μM, 16 μM, 10 μM, 8 μM, 4 μM, and 0 μM. 3+ The probe concentration was 80 μM. The reaction was incubated at 37° C. for 20 minutes and detected at 450 nm with a UV-visible spectrophotometer.

[0107] [ka] 2.2 Detection of copper ions and complexes Cu 2+ For the stock solutions, 2.50 mg of CuSO4·5H2O was dissolved in 1 mL of deionized water to obtain 10 mM stock solutions, respectively.

[0108] Cu 2+ For the probe, 34.25 mg of sodium diethyldithiacarbamate was dissolved in 1 mL of DMSO to give a 200 mM stock solution.

[0109] Cu with sodium diethyldithiacarbamate 2+ For the detection of Cu, 100 μL of 10 mM Cu 2+ The stock solution was diluted to 100 μM in 10 mL and further diluted to 80 μM, 60 μM, 40 μM, 20 μM, and 0 μM. 2+ 3 μL of sodium diethyldithiocarbamate stock solution was added to the solution, so the final concentration of phen was 200 μM, and Cu 2+ The concentration of is hardly affected. UV-visible absorption was detected at 450 nm.

[0110] 2.3 Detection of nickel ions and complexes Ni 2+ For the stock solution, 2.38 mg of NiCl2·6H2O was dissolved in 1 mL of deionized water to obtain a 10 mM stock solution, and 100 μL was diluted to 125 μM in 8 mL.

[0111] For the dimethylacetaldehyde oxime (DMG) solution, 89 mg of DMG was dissolved in 1.5 mL of 10 M NaOH(aq) to give a 0.51 M solution.

[0112] For the K2S2O8 solution, 57 mg of K2S2O8 was dissolved in 1.5 mL of deionized water to give a 0.14 mmol solution.

[0113] Ni 2+ For the detection of 125 μM Ni 2+ The solution was further diluted to 100 μM, 75 μM, 50 μM, 25 μM, and 0 μM. 50 μL of KSO solution, 100 μL of 1 M NaOH(aq), and 50 μL of DMG solution were added in sequence to 800 μL of Ni 2+ Ni 2+ The final concentrations of were 100 μM, 80 μM, 60 μM, 40 μM, 20 μM, and 0 μM. The reaction was incubated at 25°C for 20 minutes and detected at 530 nm in a UV-visible spectrophotometer.

[0114] 2.4 Probe-free detection of ions / complexes A 10 mM stock solution of the metal ion or complex and the corresponding compound was prepared and diluted to 100 μM, 80 μM, 60 μM, 40 μM, 20 μM, and 0 μM in sequence. The ion or complex was detected by the following method.

[0115] 1. ICP-AES [Table 5] 2. UV-Visible Spectrum Detection [Table 6] 3.UPLC-MS [Table 7] 2.5 Detection of the ligand release status of Pt(IV) complex 1 in different solutions A 10 mM stock solution of Pt(IV) complex 1 was prepared and diluted to 100 μM with a solution of HO, PBS, 5 mM Tyr, Trp, DMEM, CM (complete medium), and FBS. After X-ray irradiation, 200 μL of ACN was added to each solution, and the solution was centrifuged to obtain the supernatant. This was repeated two more times to obtain a final concentration of 1 / 8 of the original concentration. Ligand release was detected by UPLC-MS and quantified using a coumarin calibration curve.

[0116] 2.6 Detection of the release status of the corresponding platinum-based drug from Pt(IV)-(Suc)2 195 Pt NMR measurements (Fig. 3d, e, f) Pt(IV)-(Suc) was dissolved in 1 mL of deuterated water (80 mmol) and adjusted to pH 7 with NaOH. After deoxygenation, the solution was exposed to 40 kGy of gamma irradiation ( 60 Co source, 200 Gy / min, 200 min). After the reaction, DMSO was added to redissolve the precipitate (oxaliPt(IV)-(Suc)2), or the clear solution after the reaction was used as it was (cisPt(IV)-(Suc)2, carboPt(IV)-(Suc)2). 195 Pt NMR measurements were carried out.

[0117] Product determination by UPLC-MS (Figure 3b and c). OxaliPt(IV)-(Suc) was dissolved in 1 mL of deionized water (1 mM) and adjusted to pH 7 with NaHCO. After deoxygenation, the solution was exposed to 1 kGy of gamma irradiation ( 60 Co source, 100 Gy / min, 10 min). The crude reaction product was analyzed by UPLC-MS, and the released product was determined to be oxaliplatin by UPLC-MS.

[0118] 2.7 Measurement of release efficiency by UPLC-MS 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 purified water. After deoxygenation, the solution was irradiated with 60 Gy of X-rays (4 Gy / min, 15 min). The crude reaction product was analyzed by UPLC-MS. The released product was determined to be the corresponding divalent platinum drug. The concentration of the divalent platinum drug was determined using an external standard curve for the platinum drug, and the release efficiency was calculated.

[0119] 3. Biological methods 3.1 Cell culture The BGC823 cell line was from the National Cell Line Resource Infrastructure (Beijing, China). HCT116, Ls513, HT29, and LoVo were purchased from the American Type Culture Collection (ATCC). HCT116, Ls513, HT29, and BGC823 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 maintained at 37°C and 5% carbon dioxide. 3.2 Measurement of cell viability Cellular activity was assessed by CCK-8 detection. Each test was repeated three times.

[0120] To detect the cytotoxicity of oxaliPt(IV)-(OAc)2, HCT116, Ls513, LoVo, HT29, and BGC823 were cultured at a concentration of 5 × 10 4Cells were seeded into 96-well plates at 200 μL of RPMI-1640 or F-12K medium containing 10% FBS and 1% penicillin / streptomycin at 37°C and 5% CO2 for 24 hours in an incubator. Cells and 10 μM oxaliPt(IV)-(OAc)2 were incubated under hypoxic conditions for 24 hours. The cells were then irradiated with 8 Gy of X-rays and incubated for an additional 3 days. After incubation, blank medium containing 0.5 mg / mL CCK-8 was added to the cells. The 96-well plates were incubated for 2 hours at 37°C and 5% CO2, and the absorbance was measured at 450 nm. The absorbance of the treated cells was compared with that of the control group, and the viability of the untreated control group was set at 100%.

[0121] 3.3 Tumor model All animal experiments were performed in accordance with standards approved by the Peking University Ethics Committee.

[0122] Six-week-old female Nu / Nu mice were purchased from Weitong Lihua Laboratory (Beijing, China) and grown under specific conditions with no pathogens and sufficient water and food. 6 HCT116 cells in 100 μL of PBS were subcutaneously injected into the right shoulder of each mouse to establish a tumor xenograft model. The tumor volume was calculated as 1 / 2 length x width. 2 is.

[0123] Tumor volume 50mm 3 Treatment was initiated when the tumor size reached 1500 mm (approximately 6 days), and the regimen is shown in Figure 5. Based on the pharmacokinetics of oxaliPt(IV)-(OAc)2, after 1 hour of prodrug injection, the mice underwent radiotherapy, i.e., 4 Gy of X-rays were irradiated to the tumor area. The weight and tumor size of the mice were recorded every 2 days, and when the tumor size of the mice reached 1500 mm 3 If the mean age exceeded 10 years, the mice were euthanized in accordance with the guidelines of the ethical committee. Records were kept up to 40 days after the start of treatment.

[0124] Effect of radiation therapy dose on metal reduction efficiency In industry, radiation doses of 10 to 500 kGy are commonly used to treat wastewater and precipitate toxic heavy metal ions in contaminated water. Therefore, in this study, we first attempted to irradiate FeCl3 (100 μM, aq) solution with X-rays at doses of 10 to 60 Gy (clinical radiotherapy dose) (Figure 1a). 1,10-phenanthroline is a compound that reacts with Fe 3+ / Fe 2+ A classic probe for detecting redox reactions, Fe(phen)3 3+ The aqueous solution of Fe(phen)3 is colorless. 2+ Immediately after irradiation, 1,10-phenanthroline (30 mM, DMSO) was added to the FeCl3 solution (final concentration of 1,10-phenanthroline is 300 μM). The solution immediately turned orange (Fig. 1b). 2+ Explain that Fe(phen)3 2+ The calibration curve of Fe 2+ It is determined that the yield of Fe has a linear relationship with the absorbed radiation dose (Fig. 1c). 3+ Quantitative detection of Fe 3+ The consumption of Fe 2+ (Fig. 1c), and therefore, the amount of Fe 2+ is Fe 3+ It is the main product of the reduction of

[0125] The hydrated electron is one of the strongest reducing agents in water (standard electrode potential, -2.77 V) and is also one of the major products of water radiolysis (~280 nM / Gy). We have demonstrated that radiation-driven metal reduction is mediated by the e produced by water radiolysis. aq - The Fe concentration in a 10 mM methanol, t-butyl alcohol, and sodium formate solution is assumed to be mediated by 3+ By irradiating the Fe 2+ The formation of OH proves that a reducing environment (·OH quencher) is favorable for the reaction to occur. aq - Quencher: Fe 2+The amount of β-glucan released is significantly reduced (Fig. 1d). aq - Since reduction mediated by X-rays is generally applicable to most transition metals, a series of representative metal ions (100 μM, aq) were tested under the same conditions (60 Gy X-rays), and the reduction yields were determined by the absorbance of the corresponding complexes or other methods. As shown in Figure 1e, radiation-driven reduction reactions are feasible in most cases. The reduction yields of metals induced by radiation reached 240 nM / Gy, e aq - This is close to the theoretical yield.

[0126] Figure 1 illustrates the broad range of radiation-induced reduction of metal ions. Fe 3+ / Fe 2+ The redox reaction was detected by 1,10-phenanthroline (phen). 3+ Immediately after irradiating the solution with X-rays (0-60 Gy), phen was added, and the orange complex with Fe(II) was quantitatively formed (λ max = 510 nm), radiation causes Fe 3+ (100 μM, aq) Fe 2+ The diagram (a) and photograph (b) show the titration staining method for radiation-driven reduction. In c, Fe 3+ The consumption of [Fe(phen)3] 2+ It is approximately equal to the amount of radiation produced and is linearly related to the absorbed radiation dose. Its G value is 200 nM / Gy, and e aq - In d, treatment with a hydroxyl radical quencher leads to radiation-driven Fe 3+ / Fe 2+ The reduction yield of e aq - Treatment with a quencher reduces it. In e, radiation-driven metal ion reduction is generally applied to transition metals.

[0127] This study then further explores the feasibility of reducing metal complexes with radiation. A change in the reduction potential of a metal complex can decrease the reactivity of radiation-induced reduction. Therefore, we prepared 100 μM metal complexes, deoxidized them, and irradiated them with X-rays from 0 to 60 Gy. We are pleased to report that the metal complexes also showed good results. The calibration curves for each metal complex showed that the radiation-driven metal reduction yield exceeded 200 nM / Gy, potentially reaching 350 nM / Gy for some metals (Figure 2a). aq - This is because metal atoms with higher atomic numbers deposit more X-ray energy, increasing the ionizing radiation dose. Therefore, the reduction of metals by radiation is expected to be a broad, effective, and highly selective tool for in vivo shear chemistry.

[0128] Furthermore, UPLC-MS analysis of Pt(IV) complex 1 after radiation reduction detected the release of the axial ligand. Because Pt(IV) derivatives have great potential for clinical application, the next step is to test the effect of radiation reduction in a biological environment, i.e., radiation-driven activation of the Pt(IV) drug substance in tumors. To test biocompatibility, the Pt(IV) complex was dissolved in PBS, 5 mM Tyr, 5 mM Trp, Dulbecco's modified medium (DMEM), and complete medium (CM), and then subjected to UPLC-MS analysis after irradiation. As shown in Figure 2b, the release of the axial ligand from Pt(IV) complex 1 was observed in all of these solutions. Because the reaction yield in complete fetal bovine serum (FBS) was not significantly different from that in water, the strategy of reducing Pt(IV) complex 1 with radiation to release the axial ligand is likely feasible even under complex conditions in vivo.

[0129] Figure 2 illustrates the broad range of radiation-induced reduction of metal complexes. In a, transition metal complexes may be reduced by medical doses of radiation, with reduction yields of e aq -This is higher than the theoretical yield. Furthermore, the Pt(IV) complex (left panel, 100 μM, 1% DMSO aqueous solution) can be reduced by radiation and release the axial ligand. In Figure 2, Pt(IV) complex (100 μM) was reduced by radiation under various biological conditions (Tyr is tyrosine, Trp is tryptophan, 5 mM, DMEM medium, CM complete medium, FBS, fetal bovine serum), and the release of the corresponding axial ligand was detected by UPLC.

[0130] There are two possibilities for this radiation-driven release mechanism. The release of the axial ligand of the Pt(IV) complex can be achieved by hydrolysis or reduction. Hydrolysis cleaves the ester bond to give Pt(IV)-(OH)2 and the axial ligand, and reduction changes the valence of the platinum element to produce the corresponding divalent platinum-based drug. According to the ligand field theory, 5d 6 The most common coordination number for Pt(IV) with a valence electron configuration is 6, with 5d 8 Pt(II) with its valence electron configuration tends to form square complexes. As is evident from existing studies of Pt(IV) prodrugs, reduction of Pt(IV) to Pt(II) leads to a decrease in the coordination number and release of the ligand.

[0131] To investigate the reaction process, first, a solution of oxaliPt(IV)-(Suc)2 (80 mM, DO) was deoxidized and then irradiated with 40 kGy of gamma radiation ( 60 The solution was irradiated with a Co source at 200 Gy / min for 200 min (Figure 3a). The post-irradiation solution was analyzed by UPLC-MS. Only one new peak was observed, the retention time (Figure 3b) and mass spectrometry signal (Figure 3c) of which matched those of an oxaliplatin standard sample. The product was analyzed by nuclear magnetic resonance (NMR). 195As shown by Pt-NMR, the peak at 1615 ppm of the Pt(IV) complex almost disappeared after irradiation (top of Figure 3d), and a new single peak appeared at -1988 ppm (middle of Figure 3d), which is within the chemical shift range of the Pt(II) complex and matches the chemical shift of oxaliplatin (bottom of Figure 3d). Both of these experiments demonstrate that the release of the axial ligand is due to the radiation-induced reduction of Pt(IV), not due to hydrolysis.

[0132] To explore the generality of this strategy, we performed similar studies on two other platinum-based drugs commonly used worldwide: carboplatin and cisplatin. Nuclear magnetic resonance characterization revealed that cisPt(IV)-(Suc)2 and carboPt(IV)-(Suc)2 released the corresponding Pt(II) drug after γ-irradiation in DO (Figure 3e, f). Given the wide application of platinum-based drugs in chemotherapy, the strategy proposed in this work, which involves radiation-induced reduction of the Pt(IV) prodrug followed by controlled release of Pt(II), is highly desirable for the realization of radiation-driven precision chemotherapy.

[0133] Figure 3 illustrates the effective broad-spectrum radiation-driven release of FDA-approved Pt(II) drugs from Pt(IV) complexes. (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 main product released by 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 release of oxaliPt(IV)-(Suc)2 reveals that the released product is oxaliplatin. In d–f, the Pt(II) drug released from the Pt(IV) complex was studied by nuclear magnetic resonance (NMR). d shows the Pt(II) drug released from the Pt(IV) complex (1615 ppm, top), the irradiation product (−1988 ppm, middle), and the external standard (bottom). 195 Pt-NMR spectra of cisPt(IV)-(Suc)2 (1082 ppm, top), the irradiation product (-2150 ppm, middle), and the external standard (bottom). 195 Pt-NMR spectra. f shows the Pt-NMR spectra of carboPt(IV)-(Suc)2 (1883 ppm, top), the irradiation product (1707 ppm, middle), and the external standard (bottom). 195 Pt-NMR spectrum. 195 Pt-NMR spectra demonstrate that the FDA-approved radiation-driven release of Pt(II) drugs is effective and widely applied to Pt(IV) complexes.

[0134] The key to successful prodrug development is balancing the demands for stability and reactivity under physiological conditions. A critical drawback of metal complexes in chemotherapy drugs is their limited biological stability. Indeed, most Pt(IV) prodrugs reported to date can release active Pt(II) anticancer drugs under bioreductive conditions within cells. Therefore, the biological stability of Pt(IV) prodrugs is a key premise for realizing this strategy. Based on existing research, tetracarboxy Pt(IV) has a clear stability advantage. Therefore, we further designed oxaliPt(IV)-(OAc)2 (Figure 4a). OxaliPt(IV)-(Suc)2 has two carboxyl groups as axial ligands, which result in two negative charges under physiological conditions in vivo, preventing effective tumor concentration. Accordingly, oxaliPt(IV)-(OAc)2 possesses high stability and reactivity. After 24 h of incubation with 20 equivalents of Vc, over 95% of oxaliPt(IV)-(OAc)2 remains fully stable (Figure 4b). After irradiating oxaliPt(IV)-(OAc)2 (10 μM in deoxygenated PBS) with 0–60 Gy of X-rays, we found that the released oxaliplatin exhibited a positive correlation with the radiation dose (Figure 4c). The toxicity of oxaliPt(IV)-(OAc)2 to oxaliplatin-sensitive cell lines, such as HCT116, HT29, LoVo, and Ls513 (human colon cancer cell lines), is two to three orders of magnitude lower than that of oxaliplatin, with an IC50 of approximately submicromolar.

[0135] To verify whether radiation-driven oxaliplatin release into the cellular environment exerts its anticancer function, we performed cell viability assays of oxaliPt(IV)-(OAc)2 + X-rays using several cell lines. In this experiment, cells were treated with complete medium as a control and with 8 Gy of X-rays, 10 μM oxaliPt(IV)-(OAc)2, and 10 μM oxaliPt(IV)-(OAc)2 + 8 Gy of X-rays, respectively. After 96 h of culture, CCK-8 assays showed that the cell viability of the group treated with 10 μM oxaliPt(IV)-(OAc)2 + 8 Gy of X-rays was significantly lower than that of the groups treated with 10 μM oxaliPt(IV)-(OAc)2 or 8 Gy of X-rays alone (Figure 4(d)). This demonstrates the feasibility of the strategy of releasing oxaliplatin from oxaliPt(IV)-(OAc)2 in cells.

[0136] Figure 4 demonstrates that radiation-induced controlled oxaliplatin release is effective in living cells. (a) Schematic diagram of radiation-induced oxaliplatin release from the prodrug oxaliPt(IV)-(OAc)2. Oxaliplatin is a widely used chemotherapy drug. (b) Stability of the oxaliPt(IV)-(OAc)2 prodrug is shown. 10 μM oxaliPt(IV)-(OAc)2 was incubated with 20 equivalents of Vc (200 μM). After 24 h, over 95% of oxaliPt(IV)-(OAc)2 remained stable. (c) 10 μM oxaliPt(IV)-(OAc)2 released oxaliplatin at clinically relevant doses (0–60 Gy, X-rays), with an efficiency of up to 70%. d shows cell viability assay of in vitro controlled release of oxaliplatin (prodrug oxaliPt(IV)-(OAc) = 10 μM (h), X-ray, 8 Gy, n = 6). HCT116, LoVo, Ls513, and HT69 are human colon cancer cells that are highly sensitive to oxaliplatin.

[0137] To find the optimal dosage, we evaluated the effects of different doses of oxaliplatin and prodrugs on the health of healthy mice. Similar to the therapeutic administration regimen, mice were administered once every two days, and weight curves were recorded. Injection of 3 μmol / kg oxaliplatin or 30 μmol / kg oxaliPt(IV)-(OAc)2 did not result in weight loss in mice. However, injection of oxaliplatin at doses above 10 μmol / kg and 100 μmol / kg oxaliPt(IV)-(OAc)2 showed significant side effects, resulting in weight loss in mice (Figure 5a). When the oxaliplatin dose reached 30 μmol / kg, mice experienced severe weight loss, died on day 8, and all died on day 16 (Figure 5b). The long-term survival and weight curves of the mice indicated that 3 μmol / kg oxaliplatin and 30 μmol / kg oxaliPt(IV)-(OAc)2 could be administered at appropriate doses without any obvious side effects. To achieve optimal radiotherapy efficacy, we investigated the pharmacokinetics of oxaliPt(IV)-(OAc)2 in HCT116 tumor-bearing mice using ICP-MS to determine the optimal radiotherapy time. HCT116 tumor-bearing mice were injected with 30 μmol / kg oxaliPt(IV)-(OAc)2 via tail vein injection and then sacrificed at the scheduled time. Subsequently, ICP-MS was used to detect the concentrations of platinum-based drugs in the blood, tumor, liver, and kidney, respectively. ICP-MS data from multiple time points showed that the prodrug was primarily metabolized by the liver and kidney, with tumor uptake reaching a peak (approximately 15 μM) 1 hour after administration, then gradually decreasing and being completely eliminated 48 hours after injection (Figure 5c). One hour after administration, the prodrug concentrations in the muscle and brain of mice were relatively low, demonstrating that the drug did not cause side effects in these organs.

[0138] The radiation-mediated release of oxaliplatin in mice and the corresponding therapeutic effects were then further evaluated. 3HCT116 cells were implanted into the right flank of Nu / Nu mice until tumor size reached 1000 μg. The mice were randomly divided into seven groups: control group (PBS only), 3 μmol / kg oxaliplatin group, 30 μmol / kg oxaliPt(IV)-(OAc)2 group, X-ray group, 3 μmol / kg oxaliplatin + X-ray group, 30 μmol / kg oxaliPt(IV)-(OAc)2 + X-ray group, and 3 μmol / kg transPt(IV)-(OAc)2 + X-ray group. Drugs were injected on day 0 (Figure 5d). Treatment groups were irradiated with 4 Gy of X-rays 1 hour after injection, and the treatment cycle was repeated on days 10–12. On day 18 after the start of treatment, 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. The 30 μmol / kg oxaliPt(IV)-(OAc)2 + X-ray group showed significant tumor suppression (Figure 5e, f) and prolonged mouse survival (Figure 5g), demonstrating that the therapeutic effect was due to radiation-mediated oxaliplatin release. Furthermore, mice treated with oxaliPt(IV)-(OAc)2 + X-rays showed no weight loss (Figure 5h), demonstrating the high biological safety of our strategy. Therefore, the therapeutic results in HCT116 tumor-bearing mice demonstrate the feasibility of this radiation-driven Pt(II) drug release in vivo.

[0139] Figure 5 illustrates the combined use of radiation-driven reduction of the oxaliPt(IV)-(OAc)2 prodrug to release oxaliplatin for chemotherapy of the oxaliplatin-sensitive HCT116 tumor cell line. (a) Weight change curves and (b) survival curves of mice intravenously injected with different doses of oxaliPt(IV)-(OAc)2 and oxaliplatin are shown. Drug tolerance studies in nude mice revealed that the maximum tolerated doses of oxaliplatin and oxaliPt(IV)-(OAc)2 were approximately 3 μmol / kg and 30 μmol / kg, respectively. (c) Pharmacokinetics of the oxaliPt(IV)-(OAc)2 prodrug was used to determine the optimal timing of radiation therapy. Tumor uptake of the oxaliPt(IV)-(OAc)2 prodrug peaked 1–2 hours after injection and then gradually declined. Other prodrugs were rapidly cleared from the blood and excreted from the body via the kidneys, liver, and biliary system. d shows the regimen. e-h show the use of radiation-driven oxaliplatin release for tumor treatment (n=6 mice in each group). e shows the tumor volume of a single mouse. f shows the average tumor volume. The prodrug was injected intravenously a total of four times at a dose of 30 μmol / kg. One hour after intravenous injection, the tumor site in the irradiation group was irradiated with 4 Gy of X-rays. The tumor volume of each group was measured every two days for 40 days. g shows the survival curve of the mice. In accordance with the guidelines of the Peking University Animal Ethics Committee, mice were treated with oxaliplatin until the tumor volume reached 1500 mm 3 The mice were sacrificed when the body weight reached 100 mg / kg / day. h is the weight curve of the mice. No obvious side effects were observed, highlighting the biological safety of this novel therapeutic strategy.

[0140] This study developed a novel bioshear chemistry to achieve radiation-induced metal reduction in vivo. This strategy was applied to the activation of Pt(IV) prodrugs, using radiation as an exogenous stimulus to trigger drug release, achieving precise radiation-guided release of chemotherapy drugs at tumor sites. Furthermore, this strategy also contributes to solving the problem of hypoxic tumor resistance to radiation therapy and can even improve drug release efficiency under hypoxic conditions. Radiation-induced e aq - Inducing direct metal reduction of β-glucan can be extended to other metal or biological complexes (e.g., metalloproteins), providing an effective tool for mechanistic analysis of complex biological processes.

[0141] From the above description, those skilled in the art can easily ascertain the essential features of the present invention, and can make various changes and modifications to the present invention to adapt it to various uses and conditions without departing from the spirit and scope of the present invention. Accordingly, other embodiments are within the scope of the appended claims.

[0142] This application claims priority from Chinese Patent Application No. 202011337782.X filed on November 25, 2020, the contents of which are incorporated herein by reference.

Claims

1. A compound of formula (I) which is activated by radiation and used as a prodrug for treating tumors: 【Chemistry 1】 (In the formula, L １ ~L ６ is a platinum ligand, The complex is L ５ and L ６ to release a compound of formula (II): 【Chemistry 2】 (The Pt(II) complex of A Pt(IV) complex of the formula: The Pt(II) complex of formula (II) is cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin, or heptaplatin, (i) L ５ teeth, － O—C(O)—R, each R independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and icosyl; L ６ teeth, － O—C(O)—R, and each R independently represents a (dimethylamino)methylene group, a 2-(dimethylamino)ethylene group, a 3-(dimethylamino)propylene group, a 4-(dimethylamino)butylene group, a 5-(dimethylamino)pentylene group, a 6-(dimethylamino)hexylene group, a 3-(4-iodophenyl)propylene group, a 3-(3-iodophenyl)propylene group, a 3-(3,5-diiodophenyl)propylene group, a 3-(4-bromophenyl)propylene group, a 3-(3-bromophenyl)propylene group, a a 3-(3,5-dibromophenyl)propylene group, a 3-(3,5-dibromophenyl)propylene group, a methylamino group, an ethylamino group, a propylamino group, a butylamino group, a pentylamino group, a hexylamino group, a heptylamino group, an octylamino group, a nonylamino group, a decylamino group, an undecylamino group, a dodecylamino group, a tridecylamino group, a tetradecanoylamino group, a pentadecanoylamino group, a hexadecanoylamino group, a heptadecylamino group, and an octadecanoylamino group; or (ii) L ５ teeth, － O—C(O)—R, where each R is independently selected from a carboxymethylene group, a 2-carboxyethylene group, a 3-carboxypropylene group, a 4-carboxybutylene group, a 5-carboxypentylene group, and a 6-carboxyhexylene group; L ６ teeth, － O—C(O)—R, wherein each R is independently selected from a (dimethylamino)methylene group, a 2-(dimethylamino)ethylene group, a 3-(dimethylamino)propylene group, a 4-(dimethylamino)butylene group, a 5-(dimethylamino)pentylene group, a 6-(dimethylamino)hexylene group, a 5-maleimidopentylene group, a 6-maleimidohexylidene group, a 7-maleimidoheptylene group, an 8-maleimidooctylene group, a 3-(4-iodophenyl)propylene group, a 3-(3-iodophenyl)propylene group, a 3-(3,5-diiodophenyl)propylene group, a 3-(4-bromophenyl)propylene group, a 3-(3-bromophenyl)propylene group, and a 3-(3,5-dibromophenyl)propylene group; or (iii) L ５ teeth, － O—C(O)—R, each R independently selected from a (dimethylamino)methylene group, a 2-(dimethylamino)ethylene group, a 3-(dimethylamino)propylene group, a 4-(dimethylamino)butylene group, a 5-(dimethylamino)pentylene group, and a 6-(dimethylamino)hexylene group; L ６ teeth, － O—C(O)—R, and each R independently represents a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, an icosyl group, a carboxymethylene group, a 2-carboxyethylene group, a 3-carboxypropylene group, a 4-carboxybutylene group, a 5-carboxypentylene group, a 6-carboxyhexylene group, a (dimethylamino)methylene group, a 2-(dimethylamino)ethylene group, a 3-(dimethylamino)propylene group, a 4-(dimethylamino)butylene group, a 5-(dimethylamino)pentylene group, a 6-(dimethylamino)hexylene group, a 5-maleimidopentylene group, a 6 ... selected from imidohexylene, 7-maleimidoheptylene, 8-maleimidooctylene, 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, heptylamino, octylamino, nonylamino, decylamino, undecylamino, dodecylamino, tridecylamino, tetradecanoylamino, pentadecanoylamino, hexadecanoylamino, heptadecylamino, and octadecanoylamino; or (iv) L ５ teeth, － O—C(O)—R, each R independently selected from a 5-maleimidopentylene group, a 6-maleimidohexylene group, a 7-maleimidoheptylene group, and an 8-maleimidooctylene group; L ６ teeth, － O—C(O)—R, and each R independently represents a carboxymethylene group, a 2-carboxyethylene group, a 3-carboxypropylene group, a 4-carboxybutylene group, a 5-carboxypentylene group, a 6-carboxyhexylene group, a (dimethylamino)methylene group, a 2-(dimethylamino)ethylene group, a 3-(dimethylamino)propylene group, a 4-(dimethylamino)butylene group, a 5-(dimethylamino)pentylene group, a 6-(dimethylamino)hexylene group, a 5-maleimidopentylene group, a 6-maleimidohexylene group, a 7-maleimidoheptylene group, an 8-maleimidooctylene group, a 3-(4-iodophenyl)propylene group, a 3- selected from a (3-iodophenyl)propylene group, a 3-(3,5-diiodophenyl)propylene group, a 3-(4-bromophenyl)propylene group, a 3-(3-bromophenyl)propylene group, a 3-(3,5-dibromophenyl)propylene group, a methylamino group, a propylamino group, a butylamino group, a pentylamino group, a hexylamino group, a heptylamino group, an octylamino group, a nonylamino group, a decylamino group, a undecylamino group, a dodecylamino group, a tridecylamino group, a tetradecanoylamino group, a pentadecanoylamino group, a hexadecanoylamino group, a heptadecylamino group, and an octadecanoylamino group; or (v) L ５ teeth, － O—C(O)—R, each R independently selected from a 3-(4-iodophenyl)propylene group, a 3-(3-iodophenyl)propylene group, a 3-(3,5-diiodophenyl)propylene group, a 3-(4-bromophenyl)propylene group, a 3-(3-bromophenyl)propylene group, and a 3-(3,5-dibromophenyl)propylene group; L ６ teeth, － O—C(O)—R, and each R independently represents a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, an icosyl group, a carboxymethylene group, a 2-carboxyethylene group, a 3-carboxypropylene group, a 4-carboxybutylene group, a 5-carboxypentylene group, a 6-carboxyhexylene group, a (dimethylamino)methylene group, a 2-(dimethylamino)ethylene group, a 3-(dimethylamino)propylene group, a 4-(dimethylamino)butylene group, a 5-(dimethylamino)pentylene group, a 6-(dimethylamino)hexylene group, a 5-maleimidopentylene group, a 6 ... selected from imidohexylene, 7-maleimidoheptylene, 8-maleimidooctylene, 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, heptylamino, octylamino, nonylamino, decylamino, undecylamino, dodecylamino, tridecylamino, tetradecanoylamino, pentadecanoylamino, hexadecanoylamino, heptadecylamino, and octadecanoylamino; or (vi) L ５ teeth, － O—C(O)—R, each R is independently selected from methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, heptylamino, octylamino, nonylamino, decylamino, undecylamino, dodecylamino, tridecylamino, tetradecanoylamino, pentadecanoylamino, hexadecanoylamino, heptadecylamino, and octadecanoylamino; L ６ teeth, － O—C(O)—R, and each R independently represents a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, an icosyl group, a (dimethylamino)methylene group, a 2-(dimethylamino)ethylene group, a 3-(dimethylamino)propylene group, a 4-(dimethylamino)butylene group, a 5-(dimethylamino)pentylene group, a 6-(dimethylamino)hexylene group, a 3-(4-iodophenyl)propylene group, a 3-(3-iodophenyl)propylene group, a 4-iodophenyl a 3-(3,5-diiodophenyl)propylene group, a 3-(4-bromophenyl)propylene group, a 3-(3-bromophenyl)propylene group, a 3-(3,5-dibromophenyl)propylene group, a methylamino group, an ethylamino group, a propylamino group, a butylamino group, a pentylamino group, a hexylamino group, a heptylamino group, an octylamino group, a nonylamino group, a decylamino group, an undecylamino group, a dodecylamino group, a tridecylamino group, a tetradecanoylamino group, a pentadecanoylamino group, a hexadecanoylamino group, a heptadecylamino group, and an octadecanoylamino group; Pt(IV) complexes.

2. 2. The Pt(IV) complex of claim 1, wherein the tumor is leukemia, lung cancer, malignant lymphoma, breast cancer, ovarian cancer, soft tissue sarcoma, osteogenic sarcoma, rhabdomyosarcoma, Ewing's sarcoma, blastoma, neuroblastoma, bladder cancer, thyroid cancer, prostate cancer, head and neck tumor, nasopharyngeal cancer, esophageal cancer, testicular cancer, gastric cancer, liver cancer, pancreatic cancer, cervical cancer, endometrial cancer, melanoma, or colorectal cancer.

3. A pharmaceutical composition comprising the Pt(IV) complex of claim 1.

4. 10. A pharmaceutical composition for use in a method for treating tumors, comprising the Pt(IV) complex of claim 1, The method comprises administering the pharmaceutical composition to a subject and irradiating the subject with radiation.

5. The pharmaceutical composition of claim 4 , wherein the radiation is from radiation therapy.

6. The pharmaceutical composition according to claim 5, wherein the irradiation is carried out 0.5 to 3 hours after administration.

7. The pharmaceutical composition of claim 5, wherein the radiation dose is less than 60 Gy.

8. 5. The pharmaceutical composition of claim 4, wherein the tumor is leukemia, lung cancer, malignant lymphoma, breast cancer, ovarian cancer, soft tissue sarcoma, osteogenic sarcoma, rhabdomyosarcoma, Ewing's sarcoma, blastoma, neuroblastoma, bladder cancer, thyroid cancer, prostate cancer, head and neck tumor, nasopharyngeal cancer, esophageal cancer, testicular cancer, gastric cancer, liver cancer, pancreatic cancer, cervical cancer, endometrial cancer, melanoma, or colorectal cancer.

9. A Pt(IV) complex according to claim 1; and instructions for administering radiation therapy to treat the tumor after administration.

10. The pharmaceutical composition of claim 3; and instructions for administering radiation therapy to treat the tumor after administration.

11. formula: 【Transformation 3】 (In the formula, R １ and R ２ is selected from the following table: Table 1-1 Table 1-2 2. The Pt(IV) complex of claim 1 having the structure:

12. formula: 【Chemistry 4】 (In the formula, R １ and R ２ is selected from the following table: Table 2-1 Table 2-2 2. The Pt(IV) complex of claim 1 having the structure:

13. formula: 【Transformation 5】 (In the formula, R １ and R ２ is selected from the following table: Table 3 2. The Pt(IV) complex of claim 1 having the structure:

Images