Oxaliplatin prodrugs, their preparation and use

Abstract

The application belongs to the field of pharmaceutical chemistry, and particularly relates to an oxaliplatin prodrug and a preparation and application thereof. The structure of the oxaliplatin prodrug is specifically shown as formula (I). The oxaliplatin prodrug can be dissolved in physiological saline to form a nano preparation, which not only solves the instability problem of oxaliplatin in physiological saline, but also reduces the systemic toxicity of oxaliplatin, and achieves the effect of reducing toxicity and increasing efficiency. The oxaliplatin prodrug can be reduced in a reducing environment in tumor cells to release oxaliplatin to kill tumor cells, and achieve an antitumor effect superior to that of oxaliplatin. The synthesis method of the oxaliplatin prodrug and the preparation method of the nano preparation are simple and easy to implement, which are conducive to solving the poor stability problem of oxaliplatin in physiological saline, and are expected to realize clinical transformation.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to an oxaliplatin prodrug and its preparation and application. Background Technology

[0002] Oxaliplatin causes DNA damage and induces immunogenic cell death (ICD) in tumor cells, and can be used in combination with PD-1 antibodies to achieve chemotherapy combined with immunotherapy. Furthermore, when administered intraperitoneally, oxaliplatin can directly act on metastatic lesions, increasing local concentration and thus enhancing efficacy. Therefore, oxaliplatin has been widely used in the treatment of peritoneal metastases. However, the following issues limit its use in the treatment of peritoneal metastases: 1. Oxaliplatin is unstable in 0.9% sodium chloride solution; its oxalate ligand is easily replaced by chloride ions to form dichlorodiaminocyclohexaneplatin, which has no antitumor activity and significantly increases systemic toxicity; 2. During chemotherapy, oxaliplatin is often used in 5% glucose solution as a solvent, which can lead to electrolyte imbalance, tissue edema, intraperitoneal hemorrhage, and hyperglycemia; 3. Rapid absorption of oxaliplatin into the bloodstream can cause systemic toxicity, such as numbness in the hands and feet and hematopoietic dysfunction.

[0003] The emergence of oxaliplatin prodrugs offers a new option for overcoming the aforementioned shortcomings of oxaliplatin. Traditional platinum-based drugs exist as divalent platinum (Pt(II)), which can be converted to tetravalent platinum (Pt(IV)) through a simple oxidation step. Due to the structural inertness of the six-coordinate octahedral configuration of tetravalent platinum, it needs to be reduced to the active divalent platinum to exert its antitumor effect. This process ensures its safety to normal tissues and allows for the release of Pt(II) under the influence of high concentrations of reducing agents within tumor cells, thereby damaging tumor cell DNA and alleviating drug resistance to some extent. Furthermore, the two hydroxyl groups of Pt(IV) can be further modified to develop functional Pt(IV) prodrugs. Current research focuses primarily on encapsulating oxaliplatin prodrugs using liposomes or responsive polymers and developing them into injectable or oral formulations for cancer treatment. However, regarding the critical issue of oxaliplatin's poor stability in saline, there are no reports on how to directly use saline as a solvent in the treatment of peritoneal metastases. Therefore, this invention is of great significance in solving the problem of poor stability of oxaliplatin in physiological saline solution and promoting its application in clinical tumor treatment.

[0004] Based on the existing technology and current status, this invention aims to provide an oxaliplatin prodrug that is stable in physiological saline, in order to solve the problem of poor stability of oxaliplatin in physiological saline, and to realize the replacement of 5% glucose with physiological saline in the treatment of peritoneal metastatic cancer, thereby achieving its clinical translation. Summary of the Invention

[0005] To address the poor stability of oxaliplatin in physiological saline, this invention provides a stable oxaliplatin prodrug in physiological saline, its preparation method, and its applications. This invention designs and synthesizes a novel oxaliplatin prodrug that can self-assemble into micelles in both water and physiological saline, and is stable in physiological saline. Furthermore, under the abnormally high reducing environment within tumor cells, it is reduced to divalent platinum (Pt(II)) to exert anticancer activity, demonstrating good potential for clinical translation.

[0006] To achieve the above objectives, one aspect of the present invention provides a compound of formula (I): Formula (I) in, R1 is selected from hydrogen or -CONH(CH2)n1CH3, where n1 is an integer selected from 5 to 30; R2 is selected from -OH or -NHCH2(CH2)n2(CH3)2NO, and n2 is selected from integers from 1 to 10.

[0007] In some implementations, n1 is selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30.

[0008] In some implementations, n1 is selected from integers between 5 and 17.

[0009] In some implementations, n1 is selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17.

[0010] In some implementations, n1 is selected from integers between 10 and 17.

[0011] In some implementations, n1 is selected from 10, 11, 12, 13, 14, 15, 16 or 17.

[0012] In some implementations, n2 is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0013] In some implementations, n2 is selected from integers from 1 to 5.

[0014] In some implementations, n2 is selected from integers from 1 to 4.

[0015] In some implementations, n2 is selected from integers from 1 to 3.

[0016] In some implementations, n2 is selected from 2 or 3.

[0017] In some embodiments, the compound of formula (I) is selected from the following: Q1: Q2: Q3: Q4: Q5: Q6: Q7: Q8: Q9: Q 10 : Q 11 : Q 12 : Q 13 : Q 14 : Q 15 : Q 16 : Q 17 : Q 18 : Q 19 : Q 20 : .

[0018] Another aspect of the present invention provides the following compounds: .

[0019] Another aspect of the present invention provides the following compounds: .

[0020] In another aspect, the present invention provides a method for preparing the aforementioned compound of formula (I), the method comprising the following steps: S1: Oxaliplatin is oxidized to obtain a Pt(IV) oxidized oxaliplatin intermediate containing axial hydroxyl groups; S2: The Pt(IV) oxaliplatin oxide intermediate is modified by carboxylation to introduce carboxyl groups at its axial position to obtain a carboxyl-containing oxaliplatin oxide intermediate; S3: The carboxyl-containing oxaliplatin oxide intermediate is reacted with an isocyanate alkylating agent to obtain a lipophilic oxaliplatin prodrug intermediate; S4: Oxidize amine compounds to obtain oxidized amine intermediates; S5: Under the action of a condensing agent, the lipophilic oxaliplatin prodrug intermediate is reacted with the oxidized amine intermediate to obtain compound (I).

[0021] In some embodiments, in step S1, oxaliplatin is dissolved in a solvent and then oxidized with an oxidant to obtain a Pt(IV) oxaliplatin oxidized intermediate containing axial hydroxyl groups.

[0022] In some embodiments, in step S1, the Pt(IV) oxaliplatin oxidase intermediate containing axial hydroxyl groups is HO-OxPt. IV -OH.

[0023] In some implementations, in step S1, the solvent is selected from deionized water, alcohol, or a water / alcohol mixture.

[0024] In some implementations, in step S1, the solvent is deionized water.

[0025] In some implementations, in step S1, oxaliplatin is dissolved in deionized water to form an aqueous suspension of oxaliplatin.

[0026] In some embodiments, in step S1, the oxidant is selected from hydrogen peroxide, persulfate, m-CPBA, or organic peroxide.

[0027] In some implementations, in step S1, the oxidant is a hydrogen peroxide solution.

[0028] In some embodiments, the oxidation reaction in step S1 is carried out under light-protected conditions.

[0029] In some implementations, in step S2, the oxaliplatin oxide intermediate HO-OxPt obtained in step S1 is subjected to... IV The -OH group was modified by carboxylation to introduce a carboxyl group at the axial position, resulting in a monocarboxylated oxaliplatin oxide intermediate.

[0030] In some implementations, in step S2, the oxaliplatin oxide intermediate HO-OxPt obtained in step S1 is subjected to... IV -OH groups are dissolved in a solvent and then modified by carboxylation with a carboxylating agent to introduce carboxyl groups at the axial position, thus obtaining a monocarboxylated oxaliplatin oxide intermediate.

[0031] In some embodiments, the monocarboxylated oxaliplatin oxide intermediate is HO-OxPt. IV -COOH.

[0032] In some embodiments, in step S2, the carboxylating agent is selected from succinic anhydride, maleic anhydride, or maleic anhydride.

[0033] In some implementations, in step S2, the solvent is selected from DMSO, DMF, NMP, or acetonitrile.

[0034] In some implementations, the carboxylation modification in step S2 is performed under light-protected conditions.

[0035] In some implementations, in step S3, the monocarboxylated oxaliplatin oxidase intermediate HO-OxPt obtained in step S2 is... IV -COOH and isocyanate alkylating agents are dissolved in solvents and reacted to obtain a lipophilic oxaliplatin prodrug intermediate.

[0036] In some embodiments, the lipophilic oxaliplatin prodrug intermediate is R1-OxPt. IV -COOH, R1 is defined as before.

[0037] In some implementations, the isocyanate alkylating agent is CH3(CH2)n1CNO, where n1 is defined as above.

[0038] In some embodiments, in step S3, the solvent is selected from DMF, NMP, THF, or acetonitrile.

[0039] In some implementations, the solvent in step S3 is DMF.

[0040] In some implementations, the reaction in step S3 is carried out under light-protected conditions.

[0041] In some embodiments, in step S4, the amine compound is dissolved in a solvent and then reacted with an oxidant to obtain an oxidized amine intermediate.

[0042] In some embodiments, in step S4, the amine compound is NH2CH2(CH2)n2(CH3)2N, where n2 is defined as before.

[0043] In some implementations, in step S4, the oxidized amine intermediate is NH2CH2(CH2)n2(CH3)2NO, where n2 is defined as before.

[0044] In some embodiments, in step S4, the oxidant is selected from hydrogen peroxide, m-CPBA, or sodium hypochlorite.

[0045] In some implementations, in step S4, the oxidant is a hydrogen peroxide solution.

[0046] In some implementations, in step S4, the solvent is selected from methanol, ethanol, isopropanol, or a water / alcohol mixture.

[0047] In some implementations, the solvent in step S4 is methanol.

[0048] In some implementations, the reaction in step S4 is carried out under light-protected conditions.

[0049] S5: Under the action of a condensing agent, the condensing agent, the lipophilic oxaliplatin prodrug intermediate, and the oxidized amine intermediate are dissolved in a solvent and reacted to obtain compound (I).

[0050] In some implementations, in step S5, the condensing agent is selected from EDCI, HOBT, DCC, HATU, or PyBOP.

[0051] In some implementations, in step S5, the solvent is selected from DMF, NMP, DMSO, or dichloromethane.

[0052] In some implementations, the solvent in step S5 is DMF.

[0053] In some implementations, step S5 is carried out under light-protected conditions.

[0054] In some embodiments, the preparation method includes the following steps: S1: An aqueous suspension of oxaliplatin and a hydrogen peroxide solution were reacted under light-protected conditions with stirring to obtain the oxaliplatin oxide intermediate HO-OxPt. IV -OH; S2: Oxaliplatin oxide intermediate HO-OxPt IV -OH is dissolved in DMSO, succinic anhydride is added, and the reaction is carried out under light-protected conditions with stirring to obtain monocarboxylated oxaliplatin oxide HO-OxPt. IV -COOH; S3: Monocarboxylated oxaliplatin HO-OxPt IV -COOH and CH3(CH2)n1CNO were dissolved in DMF to obtain monocarboxylated oxaliplatin oxy HO-OxPt IV A DMF solution containing -COOH and a DMF solution containing CH3(CH2)n1CNO were reacted under light-protected conditions to yield the lipophilic oxaliplatin prodrug R1-OxPt. IV -COOH; where R1 and n1 are defined as before; S4: A methanol solution of NH2CH2(CH2)n2(CH3)2N and a hydrogen peroxide solution are stirred and reacted in the dark to obtain NH2CH2(CH2)n2(CH3)2NO, where n2 is defined as before; S5: Transfer R1-OxPt IV -COOH, NH2CH2(CH2)n2(CH3)2NO, EDCI and HOBT were reacted with stirring in the dark to obtain compound (I).

[0055] In some embodiments, in step S1, the volume ratio of the oxaliplatin suspension aqueous solution to the hydrogen peroxide solution is 1:2 to 1:5.

[0056] In some embodiments, in step S1, the mass-to-volume ratio of oxaliplatin to deionized water in the oxaliplatin suspension is 200 mg: 5-10 mL.

[0057] In some implementations, in step S1, the hydrogen peroxide solution has a mass fraction of 20-40%.

[0058] In some implementations, in step S2, the oxaliplatin oxide intermediate HO-OxPt IV A suspension of -OH in DMSO solution and a DMSO solution of succinic anhydride were reacted under light-protected conditions with stirring to yield monocarboxylated oxaliplatin oxide HO-OxPt. IV -COOH.

[0059] In some embodiments, the oxaliplatin oxide intermediate HO-OxPt IVOxidation of oxaliplatin intermediate HO-OxPt in a suspension of DMSO solution containing -OH IV The mass-to-volume ratio of -OH to DMSO is 300 mg: 10-30 mL.

[0060] In some embodiments, the mass-to-volume ratio of succinic anhydride to DMSO in the succinic anhydride DMSO solution is 70 mg: 5-10 mL.

[0061] In some embodiments, the monocarboxylated oxaliplatin HO-OxPt IV The molar ratio of -COOH to CH3(CH2)n1CNO is 1:1-1:6, where n1 is defined as before.

[0062] In some embodiments, the molar ratio of NH2CH2(CH2)n2(CH3)2N to hydrogen peroxide is 1:1 to 1:10, where n2 is defined as before.

[0063] In some implementations, in step S4, the mass fraction of the hydrogen peroxide solution is 20-40%.

[0064] In some implementations, in step S5, R1-OxPt IV -COOH, NH2CH2(CH2)n2(CH3)2NO, EDCI and HOBT were reacted in DMF protected from light to obtain compound (I), wherein R1 and n2 are defined as before.

[0065] In some implementations, the R1-OxPt IV The molar ratio of -COOH to NH2CH2(CH2)n2(CH3)2NO is 1:1-1:6, where R1 and n2 are defined as before.

[0066] In some implementations, the R1-OxPt IV The molar ratio of -COOH to EDCI is 1:1 to 1:6, where R1 is defined as before.

[0067] In some implementations, the R1-OxPt IV The molar ratio of -COOH to HOBT is 1:1 to 1:6, where R1 is defined as before.

[0068] In some embodiments, the preparation method includes the following steps: S1: Under stirring at 100-200 rpm and 40-60 ℃, the aqueous suspension of oxaliplatin and hydrogen peroxide solution were reacted in the dark for 6 hours. The mixture was then cooled to 25 ℃ and reacted for another 12-48 hours. After removing water using a rotary evaporator, the Pt(IV) oxide oxaliplatin intermediate HO-OxPt containing axial hydroxyl groups was obtained. IV -OH; S2: Stirring at 30-50℃ and 100-200 rpm; HO-OxPt IV A suspension of -OH in DMSO and a DMSO solution of succinic anhydride were reacted under light-protected conditions with stirring for 12-48 hours. After removing DMSO with an oil pump, the mixture was washed three times with ice-cold diethyl ether and then vacuum dried to obtain the monocarboxylated oxaliplatin oxide intermediate HO-OxPt. IV -COOH; S3: Oxaliplatin monocarboxylation intermediate HO-OxPt was prepared under stirring at 25-45℃ and 100-200 rpm. IV A DMF solution containing -COOH and a DMF solution containing the isocyanate alkylating agent CH3(CH2)n1CNO were stirred and reacted in the dark for 12-48 hours. After removing DMF with an oil pump, the mixture was washed three times with ice-cold ether, dried under vacuum, and purified by liquid chromatography to obtain the lipophilic oxaliplatin prodrug intermediate R1-OxPt. IV -COOH; where R1 and n1 are defined as before; S4: NH2CH2(CH2)n2(CH3)2N in methanol and hydrogen peroxide solution are reacted in the dark at 20-40℃ and 100-200 rpm for 12-48 h. After removing hydrogen peroxide and methanol by rotary evaporation, the mixture is washed three times with cold diethyl ether and dried under vacuum to obtain NH2CH2(CH2)n2(CH3)2NO; where n1 is defined as before. S5: R1-OxPt under stirring at 25-45℃ and 100-200 rpm IV -COOH, NH2CH2(CH2)n2(CH3)2NO, EDCI and HOBT were stirred in DMF in the dark for 12-48 h. After removing DMF with an oil pump, the mixture was washed three times with ice-cold ether, dried under vacuum, and purified by liquid phase to obtain compound (I).

[0069] When the compound of formula (I) of the present invention is activated by a reducing agent, it releases oxaliplatin.

[0070] The compound of formula (I) of the present invention can self-assemble into micelles in an aqueous medium.

[0071] In some embodiments, the aqueous medium is selected from water, NaCl aqueous solution, glucose solution, and ion aqueous solution.

[0072] In some embodiments, the NaCl aqueous solution has a mass fraction of 0.3%, 0.6%, 0.9%, 1.2%, or 1.5%.

[0073] In some implementations, the NaCl aqueous solution has a mass fraction of 0.9%, i.e., physiological saline.

[0074] In some embodiments, the temperature of the NaCl aqueous solution is 0-45°C.

[0075] In some embodiments, the temperature of the NaCl aqueous solution is 25-40°C.

[0076] In some embodiments, the temperature of the NaCl aqueous solution is 25-37°C.

[0077] In some embodiments, the glucose solution has a mass fraction of 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, or 17%.

[0078] In another aspect, the present invention provides a micelle formed by the self-assembly of a compound of the aforementioned formula (I) in an aqueous medium.

[0079] In some embodiments, the aqueous medium is selected from water, NaCl aqueous solution, glucose solution, and ion aqueous solution.

[0080] In some embodiments, the NaCl aqueous solution has a mass fraction of 0.3%, 0.6%, 0.9%, 1.2%, or 1.5%.

[0081] In some implementations, the NaCl aqueous solution has a mass fraction of 0.9%, i.e., physiological saline.

[0082] In some embodiments, the temperature of the NaCl aqueous solution is 0-45°C.

[0083] In some embodiments, the temperature of the NaCl aqueous solution is 25-40°C.

[0084] In some embodiments, the temperature of the NaCl aqueous solution is 25-37°C.

[0085] In some embodiments, the glucose solution has a mass fraction of 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, or 17%.

[0086] In some embodiments, the micelles have an average particle size of about 5-120 nm in physiological saline.

[0087] In some embodiments, the micelles have an average particle size of about 5-110 nm in physiological saline.

[0088] In some embodiments, the micelles have an average particle size of about 5-100 nm in physiological saline.

[0089] In some embodiments, the micelles have an average particle size of about 5-70 nm in physiological saline.

[0090] In some embodiments, the micelles have an average particle size of about 40-65 nm in physiological saline.

[0091] In some embodiments, the micelles have an average particle size of 42.27 ± 0.26 nm, 59.53 ± 0.15 nm, or 62.00 ± 0.68 nm in physiological saline.

[0092] In some embodiments, the polymer dispersity index (PDI) of the micelles in physiological saline is approximately 0.1–0.6.

[0093] In some embodiments, the polymer dispersity index (PDI) of the micelles in physiological saline is approximately 0.1–0.4.

[0094] In some embodiments, the polymer dispersity index (PDI) of the micelles in physiological saline is approximately 0.1–0.3.

[0095] In some embodiments, the polymer dispersity index (PDI) of the micelles in physiological saline is approximately 0.180–0.285.

[0096] In some embodiments, the polymerization dispersion index of the micelles in physiological saline is approximately 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.32, 0.34, 0.36, 0.38, 0.40, 0.42, 0.44, 0.46, 0.48, 0.50, 0.52, 0.54, 0.56, 0.58, or 0.60.

[0097] In some embodiments, the polymerization dispersion index of the micelles in physiological saline is 0.28±0.03, 0.26±0.01, or 0.22±0.01.

[0098] In another aspect of the present invention, a method for preparing self-assembled nanoparticles of the aforementioned compound (I) is provided, comprising the following steps: dissolving the compound (I) in an organic solvent, slowly adding the mixed solution dropwise to water, stirring, self-assembling into nanoparticles, and removing the organic solvent by dialysis to obtain the nanoparticles.

[0099] In some embodiments, the organic solvent is methanol, DMF, or DMSO.

[0100] In some embodiments, the stirring conditions are stirring at 200-600 rpm for 10-20 min.

[0101] In some implementations, the dialysis time is 24-72 hours.

[0102] The compound of formula (I) described in this invention can remain stable in physiological saline at different temperatures (25, 37°C).

[0103] The compound of formula (I) described in this invention can be reduced in a reducing environment within tumor cells to release OxPt; compared with OxPt, it exerts a more efficient anti-tumor effect.

[0104] In another aspect, the present invention provides a pharmaceutical composition comprising the aforementioned compound of formula (I), or the compound of formula (I) obtained by the aforementioned preparation method, or the aforementioned micelles and pharmaceutical excipients.

[0105] In some embodiments, the pharmaceutical composition is in the form of an injection.

[0106] In some embodiments, the pharmaceutical composition is in the form of a powder for injection.

[0107] In some embodiments, the injection solution is the aforementioned compound of formula (I), or the compound of formula (I) obtained by the aforementioned preparation method, or the aforementioned micelles dissolved in physiological saline to form a colloidal injection solution.

[0108] In some implementations, the injectable is used for peritoneal metastatic cancer.

[0109] In another aspect, the present invention provides a pharmaceutical formulation comprising a compound of formula (I) and an aqueous medium, wherein the compound of formula (I) is stably present in the aqueous medium by self-assembly forming micelles.

[0110] In some embodiments, the aqueous medium in the pharmaceutical preparation is an aqueous NaCl solution, preferably, the mass fraction of the aqueous NaCl solution is 0.3%, 0.6%, 0.9%, 1.2% or 1.5%; preferably, the aqueous medium is physiological saline.

[0111] Another aspect of the present invention provides the use of the aforementioned compound of formula (I), or the compound of formula (I) obtained by the aforementioned preparation method, or the aforementioned micelles, the aforementioned pharmaceutical composition, or pharmaceutical formulation in the preparation of a drug delivery system.

[0112] Another aspect of the present invention provides the use of the aforementioned compound of formula (I), or the compound of formula (I) obtained by the aforementioned preparation method, or the aforementioned micelles, or the self-assembled nanoparticles of the aforementioned compound of formula (I) in the preparation of drug delivery systems.

[0113] Another aspect of the present invention provides the use of the aforementioned compound of formula (I), or the compound of formula (I) obtained by the aforementioned preparation method, or the aforementioned micelles, the aforementioned pharmaceutical composition, or pharmaceutical formulation in the preparation of a medicament for treating cancer.

[0114] In some embodiments, the aforementioned compound of formula (I), or the compound of formula (I) obtained by the aforementioned preparation method, or the aforementioned micelles, the aforementioned pharmaceutical composition, or pharmaceutical formulation is administered by intraperitoneal or intravenous injection.

[0115] In some implementations, the cancer is a solid tumor or a hematologic malignancy.

[0116] In some implementations, the solid tumor is selected from colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, hepatobiliary tumors, ovarian cancer, testicular cancer, or bladder cancer.

[0117] In some implementations, the colorectal cancer is colon cancer or rectal cancer.

[0118] In some implementations, the hepatobiliary tumor is selected from bile duct cancer or gallbladder cancer.

[0119] In some implementations, the hematologic malignancy is selected from non-Hodgkin's lymphoma or chronic lymphocytic leukemia.

[0120] In some implementations, the cancer can be constructed in animal models as peritoneal metastatic tumor models or subcutaneous xenograft tumor models.

[0121] In some implementations, the peritoneal metastasis model is a colorectal cancer peritoneal metastasis model.

[0122] In some implementations, the subcutaneous xenograft model is a subcutaneous tumor model derived from colorectal cancer.

[0123] In some embodiments, the antitumor activity of the compound is evaluated using the peritoneal metastatic tumor model or the subcutaneous xenograft model.

[0124] In some implementations, when the concentration of the aforementioned compound (I) is ≤10 μM, the survival rate of tumor cells is 50%.

[0125] In some implementations, when the concentration of the aforementioned compound (I) is ≤6 μM, the survival rate of tumor cells is 50%.

[0126] In some implementations, when the concentration of the aforementioned compound (I) is ≤5 μM, the survival rate of tumor cells is 50%.

[0127] In some implementations, when the concentration of the aforementioned compound (I) is ≤4 μM, the survival rate of tumor cells is 50%.

[0128] In some implementations, when the concentration of the aforementioned compound (I) is ≤3 μM, the survival rate of tumor cells is 50%.

[0129] In some implementations, when the concentration of the aforementioned compound (I) is ≤2 μM, the survival rate of tumor cells is 50%.

[0130] In some implementations, when the concentration of the aforementioned compound (I) is ≤1 μM, the survival rate of tumor cells is 50%.

[0131] In some implementations, the tumor cells are colon cancer cells.

[0132] In some implementations, the tumor cells are colon cancer cells.

[0133] In some implementations, the tumor cells are colon cancer cells.

[0134] In some implementations, the tumor cells are colon cancer cells.

[0135] Beneficial effects The oxaliplatin prodrug of this invention, namely compound (I), is soluble in physiological saline and self-assembles to form a nano-formulation, which solves the technical problem of poor stability and easy degradation of the active pharmaceutical ingredient oxaliplatin in physiological saline and broadens the range of clinical drug delivery carriers.

[0136] The prodrug can be specifically reduced in the highly reducing microenvironment of tumor cells, precisely releasing the active site of oxaliplatin. While ensuring the anti-tumor efficacy, it significantly reduces the systemic toxicity of the drug and improves the safety of medication.

[0137] The oxaliplatin prodrug synthesis method and nano-formulation preparation process provided by this invention have simple steps, mild reaction conditions, strong controllability, no need for complex equipment, and have the potential for large-scale production. Attached Figure Description

[0138] Figure 1 C 12 -OxPt IV -C3-TMAO(Q1) 1 H NMR spectrum.

[0139] Figure 2 C 12 -OxPt IV Mass spectrum of -C3-TMAO(Q1).

[0140] Figure 3 C 16 -OxPt IV -C3-TMAO(Q2) 1 H NMR spectrum.

[0141] Figure 4 C 16 -OxPt IV Mass spectrum of -C3-TMAO(Q2).

[0142] Figure 5 C 16 -OxPt IV -C4-TMAO(Q3) 1 H NMR spectrum.

[0143] Figure 6 C 16 -OxPt IV Mass spectrum of -C4-TMAO(Q3).

[0144] Figure 7 The figure shows the stability of OxPt (oxaliplatin) and its Q1, Q2, and Q3 in physiological saline at 25°C.

[0145] Figure 8 The figure shows the stability of OxPt and its Q1, Q2, and Q3 in physiological saline at 37°C.

[0146] Figure 9 This is the restored response diagram for Q2.

[0147] Figure 10 For NPtIV The in vitro characterization diagram of T2, in which, Figure 10 A in the context is NPt IV Particle size distribution of T2; Figure 10 B in the equation is NPt IV Transmission electron microscope image of T2; Figure 10 C in the context is NPt IV Zeta potential diagram of T2; Figure 10 D in the diagram represents the CMC chart for Q2.

[0148] Figure 11 For NPt IV Stability investigation diagram of T2 in NaCl solutions of different temperatures (25℃, 37℃) and concentrations; among which... Figure 11 A in the context is NPt IV Particle size distribution of T2 in NaCl solutions of different temperatures (25, 37℃) and concentrations; Figure 11 B in the equation is NPt IV T2 PDI values ​​of NaCl solutions at different temperatures (25, 37℃) and different concentrations; Figure 11 C in the context is NPt IV Particle size distribution of T2 in physiological saline.

[0149] Figure 12 The graph shows the antitumor efficacy of oxaliplatin and Q1, Q2, and Q3 in colon cancer cells.

[0150] Figure 13 Evaluation of NPt in a CT26 mouse model of peritoneal metastatic cancer IV The anti-tumor efficacy graph of T2, in which, Figure 13 A in the context is NPt IV A schematic diagram of the treatment plan for T2 in the CT26 mouse model of peritoneal metastatic cancer; Figure 13 In the figure, B represents the changes in body weight of mice after treatment in the control group, oxaliplatin group, and prodrug group. Figure 13 In the figure, C represents the tumor weight at the end of treatment for the control group, oxaliplatin group, and prodrug group.

[0151] Figure 14 Evaluation of NPt in MC38 subcutaneous tumor mouse model IV The anti-tumor efficacy of T2, among which, Figure 14 A in the context is NPt IV A schematic diagram of the treatment plan for T2 in the MC38 subcutaneous tumor mouse model; Figure 14 In the figure, B represents the changes in body weight of mice after treatment in the control group, oxaliplatin group, and prodrug group. Figure 14 In the figure, C represents the tumor growth inhibition curves after treatment in the control group, oxaliplatin group, and prodrug group. Figure 14 In the figure, D represents the tumor weight at the end of treatment for the control group, oxaliplatin group, and prodrug group. Detailed Implementation

[0152] I. Definition To facilitate understanding of the technical solution of this invention, unless otherwise specified, the following terms in this specification have the following meanings: The term "oxaliplatin prodrug" refers to the tetravalent platinum (Pt) represented by formula (I) of this invention. IV The compound can be reduced to divalent platinum (Pt) in the reducing microenvironment of tumor cells. II It releases the active form of oxaliplatin to exert its anti-tumor effect.

[0153] The term "aqueous medium" refers to a solvent system containing water, including but not limited to water, physiological saline, glucose solution with a mass fraction of 5%-17%, and ionized water solution.

[0154] The term "physiological saline" refers to a 0.9% sodium chloride aqueous solution, which is a commonly used injection solvent in clinical practice.

[0155] The term "micelle" refers to the nanoscale aggregates formed by the self-assembly of the compound of formula (I) in an aqueous medium through intermolecular forces, which is the nano-formulation of the prodrug.

[0156] The term "average particle size" refers to the hydrodynamic diameter of micelle nanoparticles, measured in nanometers (nm), using a conventional nanoparticle size analyzer in this field.

[0157] The term "Polymer Dispersity Index (PDI)" is used to characterize the uniformity of particle size distribution of micelle nanoparticles. The smaller the value, the more uniform the particle size distribution.

[0158] The term "condensing agent" refers to a reagent that can promote the amidation condensation reaction between carboxyl and amino groups, including but not limited to EDCI, HOBT, DCC, HATU, and PyBOP.

[0159] The term "light-protected conditions" refers to avoiding direct exposure to natural light and ultraviolet light during the reaction process, and using light-protected containers or light-protected environments to carry out the reaction.

[0160] The term "reducing environment / high-reducing microenvironment" refers to the intracellular environment of tumor cells with a high concentration of reducing substances (such as glutathione), which can reduce the tetravalent platinum prodrug of the present invention to the divalent platinum active form.

[0161] The term "peritoneal metastasis / subcutaneous xenograft" refers to the constructed animal models of tumors, namely, metastatic tumor models formed by intraperitoneal inoculation of tumor cells and solid tumor models formed by subcutaneous inoculation, which are used to evaluate the antitumor activity of the compounds of this invention.

[0162] The term "injectable preparation" refers to a sterile formulation made from a raw material drug and suitable excipients, intended for injection into the body. Routes of administration may include intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, spinal injection, and intraperitoneal instillation. Based on their form and method of administration, injectable preparations can be classified as injection solutions, concentrated solutions for injection, and sterile powders for injection.

[0163] The term "powder for injection" refers to sterile powder for injection, which is a sterile powder or sterile block made from raw materials or with suitable excipients. It must be dissolved or suspended in a sterile solution before it can be injected.

[0164] II. Examples Unless otherwise specified, the experimental methods described in the following examples are conventional methods; the reagents and materials described are commercially available unless otherwise specified.

[0165] Example 1: Oxaliplatin prodrug Q2 (C 16 -OxPt IV Preparation of -C3-TMAO) S1: Oxaliplatin (0.5 mmol, 200 mg) was suspended in 5 mL of ultrapure water under stirring at 160 rpm and 50 °C. Then, 10 mL of hydrogen peroxide (30 wt%) was added to the ultrapure water. The reaction mixture was stirred in the dark for 6 hours, and then stirred for another 24 hours at room temperature. The reaction solution was evaporated to dryness to obtain a white powder, which was then washed three times with ice-cold ether and dried under vacuum to obtain 208.4 mg HO-OxPt. IV -OH, which is a white powder with a yield of 96.0%.

[0166] S2: Stirring at 30℃ and 160 rpm, mix HO-OxPt IV -OH (193.2 mg, 0.448 mmol) and succinic anhydride (44.8 mg, 0.448 mmol) were reacted in 15 mL DMSO for 24 h. After the reaction was complete, the mixture was concentrated by rotary evaporation, washed three times with ice-cold ether, and dried under vacuum to obtain 211.2 mg HO-OxPt. IV -COOH, which is a white powder, with a yield of 88.8%.

[0167] S3: Cetyl isocyanate (220.2 mg, 0.414 mmol) and HOOC-OxPt were stirred at 30 °C and 160 rpm. IV-OH (110.8 mg, 0.414 mmol) was stirred in 15 mL of DMF in the dark for 24 hours to obtain a pale yellow solution. The reaction solution was dried under vacuum, dissolved in methanol, washed three times with ice-cold ether, dried under vacuum, purified by liquid chromatography, and freeze-dried for 48 hours to obtain 268.8 mg C. 16 -OxPt IV -COOH, which is a white powder, with a yield of 81.2%.

[0168] S4: At 25℃ and 160 rpm, 1 g of 3-(dimethylamino)propylamine was added to 10 mL of methanol, and then 1.5 equivalents of hydrogen peroxide (30 wt%, 1.3 mL) solution was slowly added. The reaction was continued for 24 h. After rotary evaporation and concentration, the mixture was washed three times with ice-cold ether and dried under vacuum to obtain 882.5 mg of H2N-C3-TMAO, which is a colorless viscous oil with a yield of 76.3%.

[0169] S5: Under stirring at 30°C and 160 rpm, add 1.5 equal volumes of EDCI (31.2 mg, 0.163 mmol), HOBT (22.0 mg, 0.163 mmol), and H2N-C3-TMAO (19.3 mg, 0.163 mmol) to a volume containing C. 16 -OxPt IV The solution of -COOH (86.8 mg, 0.109 mmol) was stirred in 15 mL of DMF in the dark for 24 h. The solution was dissolved in methanol and washed three times with ice-cold ether, dried under vacuum, purified by liquid chromatography, and freeze-dried for 48 h to obtain 72.4 mg C. 16 -OxPt IV -C3-TMAO, which is a white powder; yield: 73.9%.

[0170] Based on the above preparation method, Q1, Q3, and Q4-Q can be prepared. 20 .

[0171] Example 2: Q1-Q 20 Self-assembled micelles (NPt) IV T1-NPt IV T 20 Preparation of ) Q1-Q 20(100.0 mg) was stirred thoroughly in 5 mL of DMSO and then slowly added dropwise to 30 mL of ultrapure water. The above solution was dialyzed in a dialysis bag (MWCO: 1000 Da) for 48 h, and then freeze-dried to obtain NPt. IV T1-NPt IV T 20 .

[0172] Example 3: NPt IV T1-NPt IV T 20 Particle size and PDI value determination in physiological saline Accurately weigh 1 mg of NPt IV T1-NPt IV T 20 Dissolve it in 1 mL of physiological saline and vortex for 2 min to obtain NPt. IV T1-NPt IV T 20 The micelle solution was then analyzed, and its particle size and PDI value were determined using a Malvern particle size analyzer. The results are shown in Table 1; as can be seen from Table 1, Q1-Q 20 In physiological saline, it can self-assemble to form nanomicelles with uniform particle size, in which NPt IV T1-NPt IV T3 has an average particle size of approximately 5-120 nm and a polymerization dispersion index (PDI) of approximately 0.1–0.6. The micelle system exhibits homogeneity and good stability, making it suitable for physiological saline drug delivery systems. NPt IV T4-NPt IV T 20 The average particle size and PDI also fall within the above range.

[0173] Table 1: Characterization results of micelle size and PDI Example 4: Stability determination of oxaliplatin and Q1, Q2, and Q3 in physiological saline at different temperatures (25°C, 37°C) 1 mg of oxaliplatin and Q1, Q2, and Q3 were accurately weighed and dissolved in 10 mL of physiological saline, respectively. Each sample was divided into three portions and incubated at different temperatures (25℃, 37℃). Finally, HPLC analysis was performed at different time points (0 h, 24 h, 48 h). The results are as follows: Figure 7 and Figure 8 As shown, oxaliplatin is unstable in physiological saline, and heating accelerates its hydrolysis. However, Q1, Q2, and Q3 are relatively stable in physiological saline at different temperatures because they can spontaneously form micelles in physiological saline and form a salt-resistant hydration layer on their surface to block the interference of chloride ions.

[0174] Example 5: Determination of the reduction response performance of Q2 in Vc test tubes Vitamin C (Vc, 10 mM) was dissolved in deionized water at pH 7.4 and transferred to a 2 mL test tube. Then, 100 μM of Q2 was added to conduct a reduction reaction test. The test tube was sealed and incubated at 37°C. HPLC analysis was performed at 0 h, 12 h, 24 h, 48 h, and 72 h of incubation. The mobile phase for reversed-phase high-performance liquid chromatography was 10% phosphate buffer (0.26% sodium dihydrogen phosphate solution adjusted to pH 3.0 with phosphoric acid) and 90% methanol. The results are as follows: Figure 9 As shown, Q2 undergoes a reduction reaction under the action of Vc; after 72 hours, the amount of Q2 decreased by 55%; it can be seen that Q2 has good reduction response performance in the presence of Vc.

[0175] Example 6: NPt IV Determination of particle size and zeta potential of T2 in ultrapure water Accurately weigh 1 mg of NPt IV T2 was dissolved in 1 mL of ultrapure water and vortexed for 2 min to obtain NPt. IV The micelle solution of T2 was then analyzed, and its particle size was determined using transmission electron microscopy (TEM) and its zeta value was determined using a Malvern particle size analyzer. The results are as follows: Figure 10 As shown in B and C, the Zeta value is -10.64 ± 2.27.

[0176] Example 7: Determination of the Critical Micelle Concentration (CMC) of Q2 in physiological saline A DMF solution (1 mL) of Q2 (1.5, 1.2, 1.0, 0.8, 0.6, 0.4, 0.2, 0.1, 0.05 mg) and Nile Red (0.02 mg) was added dropwise to 3 mL of physiological saline. The solution was dialyzed for 48 hours in a dialysis bag (MWCO: 1000 Da). Fluorescence monitoring of the mixture was then performed. The critical micelle concentration was calculated based on the peak changes. (Excitation wavelength: 532 nm; Emission wavelength: 630 nm); results are shown below. Figure 10 As shown in D, the CMC value of Q2 in physiological saline is 0.37 mg / mL.

[0177] Example 8: NPt IV Stability of T2 in NaCl solutions at different temperatures (25, 37°C) and concentrations Investigating NPt at different temperatures (25, 37℃) IV The particle size and PDI changes of T2 in NaCl solutions of different concentrations; 12 1 mg portions of NPt were accurately weighed. IVT2 was dissolved in 1 mL of different concentrations of NaCl solution (0.3%, 0.6%, 0.9%, 1.2%, 1.5%) and ultrapure water, respectively, and vortexed for 2 min to obtain NPt. IV The micelle solution of T2 was then analyzed, and its particle size and PDI changes in NaCl solutions of different concentrations were determined using a Malvern particle size analyzer. The results are as follows: Figure 11 As shown in A and B, NPt IV The particle size of T2 at room temperature (25℃) is approximately 60 nm; under heating, the particle size increases slightly, remaining at approximately 70 nm; the NPt of the micelles IV T2 showed little difference across different temperatures and NaCl solutions of varying concentrations, remaining between 0.2 and 0.3, indicating that the micelle size uniformity met experimental requirements. Further consideration was given to NPt... IV The long-term stability of T2 in NaCl solution remains a concern, and further investigation into NPt is needed. IV The stability of T2 in 0.9% NaCl solution was investigated.

[0178] Example 9: NPt IV Long-term stability of T2 in 0.9% NaCl solution Accurately weigh 3 portions of 1mg NPt IV T2 was dissolved separately in 1 mL of 0.9% NaCl solution, and vortexed for 2 min to obtain NPt. IV T2 micelle solution; samples were taken at different time points (0, 1, 2, 3, 4, 5, 6, 7 days) and particle size and PDI were determined using a particle size analyzer (n=3). Results are as follows: Figure 11 As shown in C, after 7 days of testing at room temperature (25℃), NPt was found to be... IV The average particle size of T2 is around 60 nm, which shows that the NPt prepared in this application... IV T2 exhibits good stability in 0.9% NaCl solution, which can be used as a NPt. IV The experimental reagents for T2.

[0179] Example 10: Investigation of the cytotoxicity of oxaliplatin and Q1, Q2, and Q3 in colon cancer cells using the CCK8 assay The cytotoxicity of oxaliplatin and its Q1, Q2, and Q3 derivatives in colorectal cancer was evaluated using the CCK8 assay. Cell culture: Human colon cancer cells (HT29 and HCT116) and mouse colon cancer cells (CT26 and MC38) were cultured in a complete medium supplemented with 10% (v / v) fetal bovine serum (FBS), 100 μg / mL penicillin, and 100 μg / mL streptomycin. The culture conditions were 37°C, 5% CO2, and incubation for 48 hours.

[0180] Experimental steps The anticancer activity of Pt-containing cells was determined using cell viability assay. Cancer cells (HCT116, CT26, HT29, MC38) were first seeded in 96-well plates (5 × 10⁶ cells / well). 3 Cells were incubated at 37°C for 24 h after adding complete culture medium, followed by treatment with DMEM, oxaliplatin, and Q1, Q2, and Q3. After 48 h of drug exposure, cell viability was determined using the CCK8 assay: 100 μL of CCK8 reagent was added to each well, and incubation was continued for 1 h. Absorbance was then measured at 450 nm using a microplate reader. IC50 50 The specific values ​​are shown in Table 2.

[0181] Table 2 shows that Q1, Q2, and Q3 all exhibited better inhibitory effects on the four cancer cell lines mentioned above compared to oxaliplatin. Specifically, Q2 showed the highest IC50 value against the CT26 colon cancer cell line. 50 The value is the lowest. This indicates that Q2 has a better inhibitory effect on CT26. In conclusion, compared with oxaliplatin, Q2 has greater potential for application in anti-tumor therapy.

[0182] Table 2: The IC50 of compounds on the inhibition of colon cancer cells 50 value Example 11: Evaluation of NPt in the CT26 peritoneal metastatic cancer model IV T2's anti-tumor effects Establishment of the CT26 peritoneal metastatic cancer model: Female BALB / c mice were selected, and each mouse was injected intraperitoneally with 2×10⁻⁶ mg / L. 5 CT26 cells were used to construct a CT26 peritoneal metastatic cancer model after being housed in an animal facility for 7 days.

[0183] Experimental plan: Mice that successfully developed the model were randomly divided into 3 groups (n=5). The drugs were administered via intraperitoneal injection every 2 days for a total of 3 times. The dosing regimens for each group are as follows: Control group: physiological saline (100 μL); Oxaliplatin group: oxaliplatin solution (100 μL, 1.23 mg Pt / kg); Prodrug group: NPt IV T2 (100 μL, 1.23 mg Pt / kg).

[0184] During treatment, mouse body weight was measured every one day to assess systemic toxicity. At the end of day 10, mice were euthanized, and abdominal tumor tissue was dissected and weighed to evaluate the antitumor effect. Figure 13As shown, compared to the control group, the prodrug group showed a significant therapeutic effect on tumors, and secondly, the therapeutic effect was slightly better than that of the oxaliplatin group. Specifically, on day 4 after administration on day 3, the weight loss in the oxaliplatin group was more significant compared to day 2; indicating that the systemic toxicity of the oxaliplatin group was greater than that of the prodrug group. Therefore, NPt... IV T2 has shown good anti-tumor effects in mice and has good potential for clinical translation.

[0185] Example 12: Evaluation of NPt in MC38 subcutaneous tumor mouse model IV T2's anti-tumor effects Establishment of the MC38 subcutaneous tumor mouse model: A mouse model of MC38 subcutaneous tumor was established using female C57 mice. Each mouse received a subcutaneous injection of 1×10⁻⁶ oz. in the left axilla. 6 MC38 cells were used to successfully construct a mouse model of MC38 subcutaneous tumor after 7 days of feeding in an animal facility.

[0186] Experimental grouping and dosing regimen Mice that successfully developed the model were randomly divided into 3 groups (n=5 in each group) and administered the drug via tail vein injection for a total of 4 times. The administration regimens for each group are as follows: Control group: physiological saline (100 μL); Oxaliplatin group: oxaliplatin solution (100 μL, 3.5 mg Pt / kg); Prodrug group: NPt IV T2 (100 μL, 3.5 mg Pt / kg).

[0187] The mice were weighed every other day during treatment. After the 9th day of treatment, the mice were euthanized, the tumors were dissected and weighed to evaluate the treatment effect.

[0188] like Figure 14 As shown, compared to the control group, the prodrug group showed a significant therapeutic effect on tumors, and secondly, the therapeutic effect was slightly better than that of the oxaliplatin group. Furthermore, with subsequent treatment, the body weight of mice in the oxaliplatin group decreased significantly, while the body weight of mice in the prodrug group remained essentially unchanged. This indicates that the systemic toxicity of the oxaliplatin group was greater than that of the prodrug group. Therefore, NPt IV T2 has shown good anti-tumor effects in mice and has good potential for clinical translation.

Claims

1. The compound shown in formula (I): Equation (I) in, R1 is selected from hydrogen or -CONH(CH2)n1CH3, where n1 is an integer selected from 5 to 30; R2 is selected from -OH or -NHCH2(CH2)n2(CH3)2NO, and n2 is selected from integers from 1 to 10.

2. The compound of formula (I) according to claim 1, characterized in that, n1 is an integer selected from 10 to 17.

3. The compound of formula (I) according to claim 1, characterized in that, n2 is an integer selected from 1 to 4.

4. The compound of formula (I) according to claim 1, characterized in that, The compounds of formula (I) are selected from the following: Q1： Q2： Q3： Q4: Q5: Q6： Q7: Q8： Q9： Q 10 ： Q 11 ： Q 12 ： Q 13 : Q 14 : Q 15 : Q 16 : Q 17 : Q 18 : Q 19 : Q 20 : 。 5. A method for preparing the compound of formula (I) according to any one of claims 1-4, characterized in that, The preparation method includes the following steps: S1: Oxaliplatin is oxidized to obtain a Pt(IV) oxidized oxaliplatin intermediate containing axial hydroxyl groups; S2: The Pt(IV) oxaliplatin oxide intermediate is modified by carboxylation to introduce carboxyl groups at its axial position to obtain a carboxyl-containing oxaliplatin oxide intermediate; S3: The carboxyl-containing oxaliplatin oxide intermediate is reacted with an isocyanate alkylating agent to obtain a lipophilic oxaliplatin prodrug intermediate; S4: Oxidize amine compounds to obtain oxidized amine intermediates; S5: Under the action of a condensing agent, the lipophilic oxaliplatin prodrug intermediate is reacted with the oxidized amine intermediate to obtain compound (I).

6. The compound of formula (I) according to any one of claims 1-4, or the compound of formula (I) obtained by the preparation method according to claim 5, characterized in that, The compound of formula (I) can self-assemble into micelles in an aqueous medium.

7. The compound according to claim 6, characterized in that, The aqueous medium is physiological saline.

8. A micelle, characterized in that, The micelles are formed by self-assembly in an aqueous medium of the compound of formula (I) as described in any one of claims 1-4 or 6-7, or the compound of formula (I) obtained by the preparation method according to claim 5.

9. The micelles according to claim 8, characterized in that, The aqueous medium is physiological saline.

10. The micelles according to claim 8 or 9, characterized in that, The average particle size of the micelles is 5-120 nm; the polymerization dispersion index of the micelles is 0.1-0.

6.

11. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-4 or 6-7, or a compound of formula (I) obtained by the preparation method according to claim 5, or micelles and pharmaceutical excipients according to any one of claims 8-10.

12. The pharmaceutical composition according to claim 11, characterized in that, The pharmaceutical composition is used to treat peritoneal metastatic cancer.

13. A pharmaceutical formulation comprising a compound of formula (I) according to any one of claims 1-4 or 6-7 and an aqueous medium, wherein the compound of formula (I) is stably present in the aqueous medium by self-assembly forming micelles.

14. The pharmaceutical preparation according to claim 13, characterized in that, The aqueous medium is physiological saline.

15. The use of the compound of formula (I) according to any one of claims 1-4 or 6-7, or the compound of formula (I) obtained by the preparation method according to claim 5, or the micelles according to any one of claims 8-10, the pharmaceutical composition according to claim 11 or 12, or the pharmaceutical formulation according to claim 13 or 14 in the preparation of a drug delivery system.

16. The use of the compound of formula (I) according to any one of claims 1-4 or 6-7, or the compound of formula (I) obtained by the preparation method according to claim 5, or the micelles according to any one of claims 8-10, the pharmaceutical composition according to claim 11 or 12, or the pharmaceutical formulation according to claim 13 or 14 in the preparation of a medicament for treating cancer.

17. The application according to claim 16, characterized in that, The cancer in question is a peritoneal metastatic cancer.

18. The application according to claim 16 or 17, characterized in that, The cancer is a solid tumor or a hematologic malignancy.

19. The application according to claim 18, characterized in that, The solid tumor is selected from colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, hepatobiliary tumors, ovarian cancer, testicular cancer, or bladder cancer.

20. The application according to claim 18, characterized in that, The hematologic malignancies are selected from non-Hodgkin's lymphoma or chronic lymphocytic leukemia.

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