A kind of tetravalent platinum complex, nanoparticle and its preparation method and application

Abstract

The present application relates to a kind of tetravalent platinum complex, nanoparticle and its preparation method and application, the structural formula of the tetravalent platinum complex is as shown in formula I, wherein, cisplatin, carboplatin or oxaliplatin;N is the integer selected from 1-8. The tetravalent platinum complex or the nanoparticle comprising it can be reduced to divalent platinum counterpart under tumor cell environment, and play tumor cell killing effect, can reduce tumor cell drug resistance, enhance the effect of tumor cell killing, have obvious enhanced anti-tumor immune effect.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, in particular to a tetravalent platinum complex, a nanoparticle and a preparation method and application thereof. BACKGROUND

[0002] Worldwide, cancer has become an important cause of death threatening human health, nearly 100 million cases (or nearly one sixth of the total number of deaths from disease) were caused by cancer in 2020. The most common cancers are breast cancer, lung cancer, colon cancer, rectal cancer and prostate cancer. There are currently three conventional treatment methods for tumors, surgery, radiotherapy and chemotherapy, of which only chemotherapy is a systemic means that can kill cancer cells that have spread (metastasized) to sites far from the primary tumor. However, chemotherapy is often accompanied by serious side effects.

[0003] Platinum (II) anticancer drugs (such as cisplatin) are one of the most successful chemotherapy drugs for treating malignant tumors, but their efficacy is limited by severe toxic side effects and drug resistance. Platinum drugs mainly form Pt-DNA crosslinks, thereby inhibiting DNA replication, transcription and inducing apoptosis. In the search for the next generation of platinum drugs, platinum (IV) complexes show great promise. By adjusting the axial ligands of platinum (IV) complexes, the oral availability, anticancer activity and toxic side effects of the drugs can be adjusted. At the same time, as a prodrug, platinum (IV) complexes are reduced to platinum (II) complexes after entering cells, thereby exerting Pt-DNA crosslinking effect. For example, the platinum (IV) carboxylate compound Satraplatin (a kind of oral anti-prostate cancer prodrug) has passed phase III clinical trials. However, there is still a lack of platinum (IV) complexes with good antitumor effect and small toxic side effects. SUMMARY

[0004] The purpose of the present application is to provide a tetravalent platinum complex, a nanoparticle and a preparation method and application thereof, which can be reduced to the bivalent platinum counterpart under the tumor cell environment and exert tumor cell killing effect, can reduce tumor cell drug resistance, enhance tumor cell killing effect and have obvious enhanced antitumor immune effect.

[0005] To this end, the first aspect of the present application provides a tetravalent platinum complex, the structural formula of which is shown as formula I,

[0006]

[0007] wherein, cisplatin, carboplatin or oxaliplatin; n is an integer selected from 1-8.

[0008] The four-valent platinum complex provided by the application achieves excellent technical effects of enhancing killing effect and enhancing anti-tumor immune effect by adopting IMTs (inhibitors of mitochondrial transcription) and alkyl carbon chain to modify the axial ligand of four-valent cisplatin.

[0009] In some embodiments, the structural formula of the four-valent platinum complex is selected from the group consisting of:

[0010]

[0011]

[0012] wherein n is an integer selected from 1-8.

[0013] In some embodiments, n can be selected from 1, 2, 3, 4, 5, 6, 7 or 8.

[0014] In a second aspect of the application, a preparation method of the four-valent platinum complex is provided, comprising: oxidizing a divalent platinum compound into a four-valent platinum intermediate with double axial hydroxyl groups; and reacting the four-valent platinum intermediate with a compound of formula II and a compound of formula III, to obtain the four-valent platinum complex.

[0015] The divalent platinum compound is cisplatin, carboplatin or oxaliplatin.

[0016] The compound of formula II and the compound of formula III are respectively:

[0017]

[0018] wherein n is an integer selected from 1-8.

[0019] In some embodiments, the molar ratio of the four-valent platinum intermediate to the compound of formula III is 1:1.

[0020] In some embodiments, hydrogen peroxide is used to oxidize the divalent platinum compound. In some examples, the hydrogen peroxide is hydrogen peroxide with a concentration of 25-35%.

[0021] In some embodiments, the reaction temperature of the oxidation is 20-50°C; for example, it can be room temperature.

[0022] In some embodiments, the reaction conditions of the four-valent platinum intermediate with the compound of formula II and the compound of formula III include: reacting at 20-50°C for 3-24 hours; for example, reacting at room temperature for 3-24 hours.

[0023] In some embodiments, after the reaction of the tetravalent platinum intermediate with the compound of formula II, the compound of formula III, the process further comprises a purification step, which comprises in sequence: removing solvent, precipitating, centrifuging or chromatographing, and drying.

[0024] In some embodiments, the purification step specifically comprises: removing solvent by distillation under reduced pressure; adding methanol and dissolving, dropping into a large amount of anhydrous ether solution, precipitating, collecting the precipitate in the organic phase by centrifugation and drying; or,

[0025] removing solvent by distillation under reduced pressure, adding methanol and dissolving, column chromatography to separate the solid product and drying.

[0026] In some embodiments, the method for preparing the tetravalent platinum complex comprises:

[0027] S1, mixing the divalent platinum compound with hydrogen peroxide, stirring at room temperature for 20-26 hours, filtering under normal pressure, collecting the filtrate; the filtrate is left to stand at 4°C overnight, then the supernatant is discarded, the precipitate is collected and dried, and a yellow solid product, i.e. the tetravalent platinum intermediate, is prepared;

[0028] S2, taking the tetravalent platinum intermediate prepared in step S1, adding super-dry DMF and stirring until uniform, then adding the alkyl anhydride shown in formula II, and reacting at room temperature for 6-48 hours; after the reaction solution is substantially clear, removing the insoluble matter by filtration, removing the solvent by distillation under reduced pressure, dissolving in a small amount of anhydrous methanol, then dropping into a large amount of anhydrous ether solution, precipitating, collecting the precipitate in the organic phase by centrifugation and drying; or, removing the solvent by distillation under reduced pressure, adding methanol and dissolving, column chromatography to separate the solid product and drying, i.e. preparing the tetravalent platinum complex intermediate shown in formula IV;

[0029] S3, taking the tetravalent platinum complex intermediate prepared in step S3, adding super-dry DMF and stirring until uniform, adding the compound of formula III, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and triethylamine, and reacting at 20-50°C for 3-24 hours; monitoring the reaction progress by TLC until the starting material is completely consumed, then removing the solvent by distillation under reduced pressure, dissolving in methanol, dropping into a large amount of anhydrous ether solution, precipitating, collecting the precipitate in the organic phase by centrifugation and drying; or, removing the solvent by distillation under reduced pressure, dissolving in methanol, column chromatography to separate the solid product and drying, i.e. preparing the tetravalent platinum complex shown in formula I;

[0030] The divalent platinum compound is cisplatin, carboplatin or oxaliplatin;

[0031] The compound of formula II, the compound of formula III, and the compound of formula IV are respectively:

[0032]

[0033] wherein, is cisplatin, carboplatin or oxaliplatin; n is an integer selected from 1-8.

[0034] In a third aspect of the present application, a nanoparticle is provided, which is assembled from a nanocarrier and the tetravalent platinum complex.

[0035] The present application can achieve enrichment effect at the tumor site and improve the targeting property in the platinum drug delivery process by assembling the tetravalent platinum complex with the nanocarrier into a nanoparticle due to its EPR effect (Enhanced Permeability and Retention Effect of solid tumors), thereby further reducing the toxic side effects on healthy tissue cells. In addition, the present application also finds that the nanoparticle has significantly better technical effect in apoptosis than the tetravalent platinum complex before assembly, and can achieve stronger tumor killing effect.

[0036] In some embodiments, the nanocarrier is selected from albumin, mPEG-PLGA (methoxy-terminated polyoxyethylene-poly(lactic-co-glycolic acid) copolymer), liposome molecules (such as mPEG-DSPE, methoxy-polyethylene glycol-phosphatidylethanolamine), etc.

[0037] In some embodiments, the albumin is human serum albumin.

[0038] In some embodiments, the mass ratio of the nanocarrier to the tetravalent platinum complex is 10:(0.5-5), such as 10:0.5, 10:1, 10:2, 10:3, 10:4, 10:5, etc.

[0039] In some embodiments, the particle size of the nanoparticle is 80-200 nm; for example, it can be about 80 nm, 90 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, etc.

[0040] In a fourth aspect of the present application, a preparation method of the nanoparticle is provided, which comprises: self-assembling the nanocarrier and the tetravalent platinum complex under stirring to form the nanoparticle.

[0041] In a fifth aspect of the present application, the tetravalent platinum complex or the nanoparticle is used in the preparation of a cancer treatment drug.

[0042] In some embodiments, the cancer includes ovarian cancer, colon cancer, lung cancer, breast cancer, etc.

[0043] Compared with the prior art, the technical scheme of the present application has at least the following progress:

[0044] (1) The present application provides a new tetravalent platinum complex by adopting alkyl carbon chain and IMTs to modify the axial ligand of tetravalent cisplatin. The tetravalent platinum complex can be reduced to the divalent platinum counterpart in the tumor cell environment and exert tumor cell killing effect.

[0045] (2) The present application further provides nanoparticles assembled by the tetravalent platinum complex and albumin. Compared with the un-assembled tetravalent platinum complex, the nanoparticles further reduce systemic toxicity and have significantly stronger tumor cell killing effect.

[0046] (3) The tetravalent platinum ligand and nanoparticles thereof provided by the present application both have the effects of reducing tumor cell drug resistance, enhancing tumor cell killing, and more importantly, significantly enhancing anti-tumor immune effect, and have good clinical application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0047] Various other advantages and benefits will become apparent to those of ordinary skill in the art upon reading the following detailed description of the preferred embodiments. The accompanying drawings are included to provide a description of preferred embodiments, and are not meant to limit the present application. In the drawings:

[0048] Figure 1 : H-NMR spectrum (DMSO-d6, 400MHz) of the compound IMT-Pt-C8 prepared in Example 1 of the present application. 1 H-NMR spectrum (DMSO-d6, 400MHz) of the compound IMT-Pt-C8 prepared in Example 1 of the present application.

[0049] Figure 2 : C-NMR spectrum (DMSO-d6, 400MHz) of the compound IMT-Pt-C8 prepared in Example 1 of the present application. 13 C-NMR spectrum (DMSO-d6, 400MHz) of the compound IMT-Pt-C8 prepared in Example 1 of the present application.

[0050] Figure 3 : Pt-NMR spectrum (DMSO-d6, 400MHz) of the compound IMT-Pt-C8 prepared in Example 1 of the present application. 195 Pt-NMR spectrum (DMSO-d6, 400MHz) of the compound IMT-Pt-C8 prepared in Example 1 of the present application.

[0051] Figure 4 : High resolution mass spectrum of the compound IMT-Pt-C8 prepared in Example 1 of the present application.

[0052] Figure 5 : H-NMR spectrum (DMSO-d6, 400MHz) of the compound IMT-Pt-C12 prepared in Example 2 of the present application. 1 H-NMR spectrum (DMSO-d6, 400MHz) of the compound IMT-Pt-C12 prepared in Example 2 of the present application.

[0053] Figure 6 : High resolution mass spectrum of compound IMT-Pt-C12 prepared in Example 2 of the present application; 13 H-NMR spectrum (DMSO-d6, 400 MHz);

[0054] Figure 7 : High resolution mass spectrum of compound IMT-Pt-C16 prepared in Example 3 of the present application;

[0055] Figure 8 : High resolution mass spectrum of compound IMT-Pt-C16 prepared in Example 3 of the present application; 1 H-NMR spectrum (DMSO-d6, 400 MHz);

[0056] Figure 9 : High resolution mass spectrum of compound IMT-Pt-C16 prepared in Example 3 of the present application;

[0057] Figure 10 : Results of cytotoxicity experiment of the tetravalent platinum complex on A2780, OVCAR cells according to some embodiments of the present application;

[0058] Figure 11 : Results of liquid chromatography analysis of IMT-Pt-C8 co-incubated with sodium ascorbate according to some embodiments of the present application;

[0059] Figure 12 : Results of cytotoxicity experiment of the tetravalent platinum complex on ES2, OVCAR, MC38, A549 and 4T1 cell lines according to some embodiments of the present application;

[0060] Figure 13 : Results of particle size and zeta potential characterization of nanoparticles comprising the tetravalent platinum complex according to some embodiments of the present application;

[0061] Figure 14 : Results of flow cytometry apoptosis detection of A2780 cells co-cultured with nanoparticles comprising the tetravalent platinum complex according to some embodiments of the present application;

[0062] Figure 15 : Results of in vivo tumor inhibition experiment of nanoparticles comprising the tetravalent platinum complex according to some embodiments of the present application; (A) Results of tumor weight measurement after 10 days of first administration; (B) Results of photograph of tumor of mice after treatment with different drugs (PBS, cisplatin, NP1, NP2 and NP3); (C) Results of statistics of body weight change of mice with first administration as day 0; (D) Results of statistics of tumor volume change of mice with first administration as day 0. DETAILED DESCRIPTION

[0063] Exemplary embodiments of the present disclosure will be described in greater detail below. It should be understood that the present disclosure can be implemented in various forms and should not be limited by the embodiments set forth herein. Rather, these embodiments are provided so that the present disclosure will be thoroughly and completely understood, and will fully convey the scope of the present disclosure to those skilled in the art.

[0064] Example 1 compound IMT-Pt-C8

[0065]

[0066] 1. Weigh 1 g of cisplatin into a 50 mL round bottom flask, add 10 mL of 30% H2O2, stir at room temperature for 24 hours, filter at normal pressure, collect the precipitate and dry in a drying oven, and obtain a light yellow solid product HO-Pt(IV)-OH.

[0067] 2. Weigh HO-Pt(IV)-OH (1.0 eq) into a dry round bottom flask, add 500 mL of DMF (ultra-dry) and stir at room temperature, and weigh caprylic anhydride (1.0 eq) into the reaction bottle, react at room temperature for 48 hours, and monitor the reaction progress by TLC. When the solution is clear, remove the solvent by distillation under reduced pressure, add anhydrous methanol and drop into 100 mL of anhydrous ether, and a precipitate appears in the organic phase, centrifuge to collect the precipitate and dry to obtain the product Pt(IV)-C8.

[0068] 3. Weigh Pt(IV)-C8 (1.0 eq), add 20 mL of DMF (ultra-dry) to dissolve, and add TBTU (1.0 eq), triethylamine (TEA, 1.0 eq), and IMT (1.0 eq), stir at room temperature for 24 hours, and monitor the reaction progress by TLC. When the reaction is complete, remove the solvent by distillation under reduced pressure, and separate the product IMT-Pt-C8 by column chromatography. The product is detected by 400 MHz nuclear magnetic resonance spectrometer (NMR spectrometer) and high resolution mass spectrometry (HR-ESI-MS), and the detection results are shown in Table 1. Figures 1-4

[0069] Example 2 compound IMT-Pt-C12

[0070]

[0071] 1. Weigh 1 g of cisplatin into a 50 mL round bottom flask, add 10 mL of 30% H2O2, stir at room temperature for 24 hours, filter at normal pressure, collect the precipitate and dry in a drying oven, and obtain a light yellow solid product HO-Pt(IV)-OH.

[0072] ​2. Weigh HO-Pt(IV)-OH (1.0 eq) in a dry round bottom flask, add 500 mL DMF (ultra dry) and stir at room temperature. Weigh dodecanoic anhydride (1.0 eq) and add to the reaction flask. Stir at room temperature for 48 hours. Monitor the progress of the reaction by TLC. When the solution is clear, remove the solvent by distillation under reduced pressure. Add anhydrous methanol and drop into 100 mL of anhydrous ether. A precipitate appears in the organic phase. Collect the precipitate by centrifugation and dry to obtain the product Pt(IV)-C12.

[0073] 3. Weigh Pt(IV)-C12 (1.0 eq), add 20 mL DMF (ultra dry) to dissolve, and add TBTU (1.0 eq), triethylamine (TEA, 1.0 eq), IMT (1.0 eq). Stir at room temperature for 24 hours. Monitor the progress of the reaction by TLC. When the reaction is complete, remove the solvent by distillation under reduced pressure. Isolate the product IMT-Pt-C12 by column chromatography. Test the product by 400 MHz nuclear magnetic resonance spectrometer (NMR spectrometer) and high resolution mass spectrometry (HR-ESI-MS). The test results are shown in Table 1. Figures 5-7

[0074] Example 3 Compound IMT-Pt-C16

[0075]

[0076] 1. Weigh 1 g of cisplatin into a 50 mL round bottom flask. Add 10 mL of 30% H2O2. Stir at room temperature for 24 hours. Filter under normal pressure. Collect the precipitate and dry in a drying oven. Obtain the product HO-Pt(IV)-OH as a light yellow solid.

[0077] 2. Weigh HO-Pt(IV)-OH (1.0 eq) in a dry round bottom flask, add 500 mL DMF (ultra dry) and stir at room temperature. Weigh hexadecanoic anhydride (1.0 eq) and add to the reaction flask. Stir at room temperature for 48 hours. Monitor the progress of the reaction by TLC. When the solution is clear, remove the solvent by distillation under reduced pressure. Add anhydrous methanol and drop into 100 mL of anhydrous ether. A precipitate appears in the organic phase. Collect the precipitate by centrifugation and dry to obtain the product Pt(IV)-C16.

[0078] ​3. Pt(IV)-C16 (1.0 eq) was weighed, dissolved in 20 mL DMF (ultra dry), and TBTU (1.0 eq), triethylamine (TEA, 1.0 eq), IMT (1.0 eq) were added, stirred at room temperature for 24 h, and the reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and the product IMT-Pt-C16 was separated by column chromatography. The product was detected by 400 MHz nuclear magnetic resonance spectrometer (NMR spectrometer) and high resolution mass spectrometry (HR-ESI-MS), and the detection results are shown in Figures 8-9 .

[0079] Example 4 Cell cytotoxicity screening

[0080] The half-inhibitory concentration of the tetravalent platinum complex provided by the application on cell growth was determined by MTT method to measure the anti-tumor activity. The selected cell strains were A2780 (human ovarian cancer cells) and OVCAR (ovarian cancer cell) lines. The cancer cells were cultured in DMEM medium containing 10% serum. The cells were cultured in a 37°C, 5% incubator.

[0081] The uniform cell suspension cultured in vitro was added to a 96-well plate, and the cells were fully adhered after overnight culture; the compounds IMT-Pt-C8, IMT-Pt-C12 and IMT-Pt-C16 synthesized in Examples 1-3 were added to the 96-well plate in a certain concentration gradient (0-40 μM), 3 parallel holes for each concentration; MTT was added after 48 h of incubation, SDS was added after 4 h of standing, and after 12 h, the absorption values of each well at 570 nm and 650 nm were detected by automatic enzyme marker. The negative control group was set at the same time, and an equal volume of normal saline was used instead of the drug, which was recorded as 100% cell viability, and the results are shown in Figure 10 .

[0082] Example 5 In vitro reduction of tetravalent platinum

[0083] Tetravalent platinum can be reduced to its divalent platinum counterpart to exert anticancer effect. In order to verify whether the tetravalent platinum complex provided by the application can be reduced to its divalent platinum counterpart and the speed of its reduction rate, IMT-Pt-C8 prepared in Example 1 was used to explore its reduction kinetics by high performance liquid chromatography. IMT-Pt-C8 was co-incubated with sodium ascorbate (ASA) at room temperature. Figure 11 The results show that as the mixing time increases, the peaks of ASA (1.72 min) and IMT-Pt-C8 (4.74 min) gradually decrease, and a new peak appears at 2.64 min, which belongs to IMT, indicating that the tetravalent platinum complex IMT-Pt-C8 provided by the application can be reduced by ASA to generate cisplatin and IMT.

[0084] Example 6 Cytotoxicity experiment

[0085] The half maximal inhibitory concentration of the tetravalent platinum complex provided by the application on cell growth was determined by MTT method to measure its anti-tumor activity. The selected cell strains were ES2 (human ovarian cancer cells), OVCAR (ovarian cancer cells), MC38 (mouse colon cancer cells), A549 (human lung adenocarcinoma cells) and 4T1 (mouse breast cancer cells) cell lines. The cancer cells were cultured with DMEM medium containing 10% serum. The cells were incubated in a 37°C, 5% incubator.

[0086] The uniform cell suspension cultured in vitro was added to the 96-well plate and incubated overnight to allow the cells to adhere fully; the compound IMT-Pt-C8 synthesized in Example 1 was added to the 96-well plate in a certain concentration gradient (0-40 μM), with 3 parallel holes for each concentration; MTT was added after 48 h of incubation, SDS was added after 4 h of standing, and after 12 h, the absorption values of each well at 570 nm and 650 nm were detected by automatic enzyme marker. The negative control group was set up at the same time, with an equal volume of normal saline instead of the drug, which was recorded as 100% cell viability, and cisplatin was added as a control compound, and the results are shown in Figure 12 .

[0087] Example 7 Preparation of nanoparticles

[0088] 1. HSA@IMT-Pt-C8 (NP1)

[0089] 50 mg of human serum albumin (HSA) as a nanocarrier was dissolved in 10 mL of distilled water and continuously stirred; then, 5 mg of IMT-Pt-C8 was dissolved in 1 mL of DMSO, slowly dropped into the above HSA-melted water and continuously stirred.

[0090] 2. PLGA@IMT-Pt-C8 (NP2)

[0091] 50 mg of mPEG-PLGA was weighed and dissolved in 1 mL of DMSO, and 5 mg of IMT-Pt-C8 was weighed and added to dissolve, slowly dropped into 10 mL of distilled water and continuously stirred; after 10 minutes, dialysis was performed to remove the organic solvent, and the nanoparticle PLGA@IMT-Pt-C8 (abbreviated as NP2) was prepared.

[0092] 3. DSPE@IMT-Pt-C16 (NP3)

[0093] Weigh 50 mg of mPEG-DSPE and dissolve it in 1 mL of DMSO. Separately weigh 5 mg of IMT-Pt-C8 and add it to the solution to dissolve. Slowly add the solution dropwise to 10 mL of distilled water while stirring continuously. After 10 minutes, dialyze to remove the organic solvent, thus preparing the nanoparticles DSPE@IMT-Pt-C8 (abbreviated as NP3).

[0094] The size of the nanoparticles was characterized using a Malvern Zetasizer Nano ZS90 laser particle size analyzer (NanoZS, UK).

[0095] The results of particle size and potential characterization of the three types of nanoparticles are as follows: Figure 13 As shown, the average particle sizes were 148 nm, 163.8 nm and 126.3 nm, respectively; the PDI values ​​were 0.197, 0.056 and 0.107, respectively; and the potentials were -5.02 mV, -24.3 mV and -21.6 mV, respectively. The properties of the obtained nanoparticles showed little difference.

[0096] Example 8 Apoptosis Experiment

[0097] This embodiment uses the Annexin V-FITC / PI apoptosis kit and flow cytometry to detect cell apoptosis 24 hours after drug treatment. Cisplatin (…) Figure 14 Cisplatin (as used in Example 7), NP1, PN2, and NP3 prepared in Example 7 were co-cultured with ovarian cells for apoptosis experiments. A control group treated with PBS was also included. The experimental results are as follows: Figure 14 As shown, according to Figure 14 The upper left region (Q1-UL) showed a positive PI result and a negative Annexin V result, indicating cell necrosis; the upper right region (Q1-UR) showed a positive PI result and a positive Annexin V result, indicating late-stage apoptosis; the lower right region (Q1-LR) showed a negative PI result and a positive Annexin V result, indicating early-stage apoptosis; and the lower left region (Q1-LL) showed a negative PI result and a negative Annexin V result, indicating normal cells.

[0098] according to Figure 14 The experimental results showed that most cells in the control group were located in the lower left region, indicating that they were mostly normal cells. After treatment with different drugs, the number of cells undergoing necrosis, early apoptosis, and late apoptosis significantly increased. Among all treatment methods, the apoptosis effect was particularly pronounced in cells treated with the nanoparticles provided by this invention, with a much higher number of cells undergoing late apoptosis than in cells treated with cisplatin. This indicates that the antitumor effects of NP1, NP2, and NP3 are significantly superior to those of cisplatin.

[0099] Example 9 In vivo tumor inhibition experiment

[0100] A human-derived tissue xenograft (PDX) model was constructed using BALB / c-nude mice, and the tumor-bearing mice were randomly divided into groups, 5 mice in each group; the mice were administered with cisplatin or three kinds of nanoparticles prepared in Example 7 by tail vein injection; the first administration was taken as day 0, and the administration was performed on day 0, 3 and 6, respectively, a total of three times, and the administration dose was: cisplatin 2 mg / kg, and the nanoparticles were all 4 mg / kg. The tumor volume and the body weight of the mice were measured every two days, and the statistical results are shown in Table 1. Figure 15

[0101] The above is only a preferred specific embodiment of the present application, but the protection scope of the present application is not limited to this. Any person skilled in the art can easily think of changes or replacements within the technical range disclosed by the present application, which should be covered within the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.​

Claims

1. A tetravalent platinum complex characterized in that, The structural formula of the tetravalent platinum complex is shown as formula I, wherein, is cisplatin, carboplatin or oxaliplatin; n is an integer selected from 1-8.

2. The method of preparing a quadruple platinum complex according to claim 1, wherein, The method comprises the following steps: oxidizing a divalent platinum compound into a tetravalent platinum intermediate with double axial hydroxyl groups; reacting the tetravalent platinum intermediate with a compound of formula II and a compound of formula III to obtain the tetravalent platinum complex; The divalent platinum compound is cisplatin, carboplatin or oxaliplatin. The compound of formula II and the compound of formula III are respectively: wherein n is an integer selected from 1-8.

3. The production method according to claim 2, wherein The molar ratio of the tetravalent platinum intermediate to the compound of formula III is 1:

1.

4. The production method according to claim 2, wherein The divalent platinum compound is oxidized by hydrogen peroxide.

5. The production method according to claim 2, wherein The reaction conditions of the tetravalent platinum intermediate with the compound of formula II and the compound of formula III are 20-50℃ for 3-24 hours.

6. The production method according to claim 2, wherein After the reaction of the tetravalent platinum intermediate with the compound of formula II and the compound of formula III, a purification step is further included, which comprises the following steps in sequence: removing solvent, precipitating, centrifuging or chromatographing, and drying.

7. The production method according to claim 6, wherein The purification step specifically comprises the following steps: removing solvent by reduced pressure distillation; adding methanol and dissolving, dropping into a large amount of anhydrous ether solution, precipitating, centrifuging to collect the precipitate and drying; or, removing solvent by reduced pressure distillation, adding methanol and dissolving, and column chromatography to separate the solid product and dry.

8. A nanoparticle, characterized in that, The nanoparticles are formed by assembling a nano-carrier and the tetravalent platinum complex of claim 1.

9. The nanoparticle of claim 8, wherein, The nano-carrier is selected from at least one of albumin, mPEG-PLGA and mPEG-DSPE.

10. The nanoparticle of claim 8, wherein the nanoparticle has a diameter of about 1 nm to about 100 nm. The mass ratio of the nano-carrier to the tetravalent platinum complex is 10:(0.5-5).

11. The nanoparticle of any one of claims 8-10, wherein, The particle size of the nanoparticles is 80-200nm.

12. The method of claim 8-11, wherein the nanoparticles are prepared by, The method comprises the following steps: self-assembling the nano-carrier and the tetravalent platinum complex under stirring to form the nanoparticles.

13. Use of the tetravalent platinum complex of claim 1 or the nanoparticles of any one of claims 8-11 in the preparation of a medicament for treating cancer.

14. Use according to claim 13, characterized in that, The cancer includes ovarian cancer, colon cancer, lung cancer and breast cancer.

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