Cabazitaxel derivatives and liposome preparations thereof

Abstract

Cabazitaxel derivatives and liposome preparations thereof belong to the field of pharmaceutical technology. The present invention relates to cabazitaxel derivatives represented by general formula (I) or (II) and liposome preparations thereof, and specifically to the synthesis of cabazitaxel derivatives and liposome preparations containing such derivatives. These cabazitaxel derivatives exhibit enhanced tumor cell toxicity. When prepared as liposomes, they can effectively reduce the amount of impurities generated during the preparation process, thereby avoiding the need for extensive safety studies during formulation development and reducing development costs. Furthermore, the liposome preparations of the present invention exhibit enhanced efficacy. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to cabazitaxel derivatives and preparations thereof, and particularly to the synthesis of cabazitaxel derivatives and liposome preparations containing the derivatives and applications thereof in drug delivery systems. Background Art

[0002] Cabazitaxel (CTX) is a second-generation taxane drug with broad-spectrum anti-tumor activity. Its mechanism of action is similar to that of paclitaxel and docetaxel, which acts on the M phase of cells by binding to tubulin to inhibit cell proliferation. Due to the methylation of the 7- and 10-hydroxyl groups in the structure, cabazitaxel has a low affinity for P-glycoprotein, which can overcome the multidrug resistance problem of other taxane drugs and treat docetaxel-resistant tumors. Sanofi-Aventis has developed cabazitaxel injection. It was approved for marketing by the U.S. Food and Drug Administration (FDA) in June 2010 for use in combination with prednisone to treat advanced metastatic castration-resistant prostate cancer after docetaxel treatment.

[0003] Cabazitaxel is poorly water-soluble and commercially available preparations Using Tween 80 and 13% (w / w) ethanol as co-solvents, studies have shown that the use of Tween 80 can cause severe hemolytic reactions, allergic reactions, and peripheral neuropathy. In addition, the injection has serious side effects such as decreased white blood cell levels, severe gastrointestinal problems (gastric or intestinal leakage, intestinal obstruction, infection, and gastric or intestinal bleeding), and renal failure. Clinical trial results show that the maximum tolerated dose of cabazitaxel is 25 mg / m 2 , which is much lower than the other two types of taxane anti-tumor drugs. In addition, Because it needs to be dissolved and diluted with 13% (w / w) ethanol before administration, and then diluted twice with sterile saline or 5% glucose solution, the final infusion solution is prone to precipitation, has poor stability, and cannot be stored for long-term use.

[0004] To address the shortcomings of commercially available cabazitaxel formulations, new formulations that enhance the anti-tumor efficacy of cabazitaxel while minimizing side effects are needed. Liposomes are bilayer vesicles composed of lipids. Liposomes are ideal drug delivery systems, offering numerous advantages: their morphology is similar to that of cell membranes, resulting in excellent biocompatibility and biodegradability; they can encapsulate water-soluble drugs, poorly soluble drugs, and biomacromolecules; they are easily chemically modified to enhance drug delivery; and they protect drugs from in vivo effects such as enzymatic degradation, immune responses, and chemical inactivation. Researchers have also found that surface-modified liposomes with polyethylene glycol significantly improve stability and blood circulation time after intravenous administration, reducing macrophage recognition and adsorption, thereby enhancing the therapeutic efficacy of liposome-delivered drugs. Liposomes can be loaded with drugs through both passive and active loading methods. Currently, most research on cabazitaxel liposomes focuses on passive loading. However, liposomes prepared using passive loading methods suffer from low drug loading, are prone to leakage, exhibit poor stability, and exhibit rapid drug release. The active drug loading method uses the principle that the neutral form of weak acid and weak base drugs can cross the lipid bilayer, enter the inner aqueous phase, and then be protonated to form a stable complex with the counterion, but does not have the ability to cross the membrane to encapsulate the drug.

[0005] Cabazitaxel is poorly water-soluble and a hydrophobic, uncharged compound, making it difficult to encapsulate in liposomes using active drug loading. Therefore, an esterification reaction can be used to attach a nitrogen-containing group to the 2'-hydroxyl group of cabazitaxel, rendering the derivative weakly alkaline. This allows for high drug loading and high encapsulation efficiency using active drug loading.

[0006] During the preparation of liposome formulations, factors such as the pH of the internal and external aqueous phases, the drug loading temperature, and other factors in the liposome formulation and process can lead to the degradation of derivatives, thereby introducing new impurities. The limit for degradation products in new drug formulations stipulates that when the maximum daily dose is 10-100 mg, if the degradation product exceeds 0.5%, a series of safety studies will be required, which will significantly increase R&D costs and may increase the toxic side effects of the formulation due to the increase in degradation products. Therefore, controlling the amount of impurities is of great significance to the development of cabazitaxel formulations. Summary of the Invention

[0007] Regarding the currently used cabazitaxel injection in clinical practice The invention has the problems of large toxic and side effects. Two weakly alkaline cabazitaxel derivatives are synthesized and prepared into liposome preparations with high drug loading, high encapsulation efficiency and good stability by using an active drug loading method.

[0008] Comparative studies have shown that compared to the previously disclosed cabazitaxel derivative CN1 (CN111004195A), the cabazitaxel derivative designed and synthesized by the present invention, when prepared as liposomes, significantly reduces unknown impurities, improves the safety of the formulation, and effectively reduces development costs. The structural formula of CN1 is:

[0009]

[0010] The purpose of the present invention is to modify cabazitaxel to a weak base and prepare it into a liposome nano drug delivery system, thereby giving it a long circulation property in the blood for anti-tumor research.

[0011] The present invention achieves the above-mentioned purpose through the following technical solutions:

[0012] The cabazitaxel derivative or a pharmaceutically acceptable salt thereof of the present invention has a structure represented by the general formula (I) or (II):

[0013]

[0014] Wherein, n=1 to 5;

[0015] Furthermore, the cabazitaxel derivative or a pharmaceutically acceptable salt thereof is selected from the following compounds:

[0016]

[0017] The pharmaceutically acceptable salt is a salt formed by the cabazitaxel derivative and a pharmaceutically acceptable inorganic acid or organic acid.

[0018] The method for synthesizing a cabazitaxel derivative provided by the present invention comprises the following steps:

[0019] Under the catalysis of DMAP and EDCI, 4-diethylaminobutyric acid or 4-(4-methyl-1-piperazinyl)butyric acid undergoes an esterification reaction with cabazitaxel, which is then separated and purified. The entire reaction is carried out under N2 protection.

[0020] Furthermore, the present invention provides a liposome containing a cabazitaxel derivative, wherein the liposome comprises a weakly basic cabazitaxel derivative, a phospholipid, cholesterol, and a PEGylated phospholipid. The weight ratio of the cabazitaxel derivative to total lipids is 0.10 to 0.50, preferably 0.15 to 0.45. The total lipids are the sum of phospholipids, cholesterol, and / or PEGylated phospholipids. The amounts of phospholipids, cholesterol, and PEGylated phospholipids are all conventionally used in the art.

[0021] The present invention also provides a method for preparing the liposome containing the cabazitaxel derivative, comprising the following steps:

[0022] (1) Weighing the membrane materials required for preparing liposomes, preparing liposomes by thin film dispersion method, ethanol injection method or cross-flow mixing method, and sequentially extruding through polycarbonate membranes of different pore sizes to form nanosized unilamellar liposomes;

[0023] (2) replacing the external aqueous phase of the small unilamellar liposomes obtained in step (1) to obtain blank liposomes having a gradient of internal and external aqueous phases;

[0024] (3) adding an organic solution of a cabazitaxel derivative to the gradient blank liposomes obtained in step (2), and incubating the mixture to obtain a cabazitaxel derivative liposome preparation.

[0025] Preferably, in step (2), the inner aqueous phase solution is citric acid solution, ammonium sulfate solution, sulfobutyl ether-β-cyclodextrin triethylammonium salt solution or sucrose octasulfate triethylammonium salt solution.

[0026] Further preferably, the inner aqueous phase solution is a sucrose octasulfate triethylammonium salt solution.

[0027] Preferably, in step (2), the external aqueous phase solution is a sucrose solution and a histidine solution, a HEPES buffer, a phosphate buffer or an acetate buffer.

[0028] Further preferably, the external aqueous phase solution is a sucrose solution and a histidine solution.

[0029] Preferably, in step (3), the solvent of the organic solution is methanol, ethanol, acetone, tetrahydrofuran, acetonitrile or DMSO; the organic solvent is removed by tangential ultrafiltration, dialysis or the like.

[0030] More preferably, the solvent of the organic solution is DMSO.

[0031] The present invention prepares cabazitaxel into a weakly alkaline derivative, which is then used to prepare liposomes, thereby solving the problem of side effects caused by Tween 80 in cabazitaxel injection and also increasing its anti-tumor effect, thus having great clinical application potential.

[0032] The present invention also provides use of the cabazitaxel derivative or a pharmaceutically acceptable salt thereof or the liposome containing the cabazitaxel derivative in preparing a drug delivery system.

[0033] The present invention also provides use of the cabazitaxel derivative or a pharmaceutically acceptable salt thereof or the liposome containing the cabazitaxel derivative in the preparation of anti-tumor drugs.

[0034] The advantages of the liposome nano drug delivery system of the present invention are: (1) small and uniform particle size (~100nm), which is conducive to enrichment at the tumor site through the EPR effect; (2) high drug loading, high encapsulation efficiency, and good stability, which are conducive to reducing adverse reactions caused by excipients and biomaterials and easy to industrialize; (3) effectively avoiding uptake by the reticuloendothelial system, achieving a long circulation effect in the blood, and increasing the chance of reaching the tumor site; (4) compared with commercially available preparations Compared with other methods, it can improve the anti-tumor effect and reduce toxic side effects; (5) the content of new impurities after the preparation of liposomes is small, which can effectively ensure the safety of the preparation and reduce the development cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is a structural diagram of the cabazitaxel derivative (CTX-DA) whose base moiety is 2'-O-(4-diethylaminobutyryl) according to Example 1 of the present invention.

[0036] Figure 2 The base portion of the cabazitaxel derivative (CTX-DA) of Example 1 of the present invention is 2'-O-(4-diethylaminobutyryl) 1 H-NMR spectrum.

[0037] Figure 3 This is a structural diagram of the cabazitaxel derivative (CTX-PA) whose base moiety is 2'-O-(N-methyl-piperazinylbutyryl) according to Example 2 of the present invention.

[0038] Figure 4 The base portion of the cabazitaxel derivative (CTX-PA) of Example 2 of the present invention is 2'-O-(N-methyl-piperazinylbutyryl) 1 H-NMR spectrum. DETAILED DESCRIPTION

[0039] The following examples are intended to further illustrate the present invention, but are not intended to limit the present invention in any way.

[0040] Example 1

[0041] Synthesis of Cabazitaxel Derivatives (CTX-DA) with 2'-O-(4-diethylaminobutyryl) as the Base

[0042] Diethylamine (12.5 mL, 6.1 g, 84 mmol) and ethyl 4-bromobutyrate (3.16 mL, 4.1 g, 21 mmol) were dissolved in ethyl acetate and stirred at room temperature overnight. The reaction progress was monitored by thin-layer chromatography until the bromide was completely consumed. After the reaction was completed, the organic phase was washed with water, saturated sodium bicarbonate aqueous solution, and sodium chloride aqueous solution, then dried over sodium sulfate and concentrated to obtain a slightly yellow oil, which was separated and purified by column chromatography to obtain ethyl 4-diethylaminobutyrate. Water (10 mL) and hydrochloric acid (HCl, 12 mL) were added to the ethyl 4-diethylaminobutyrate obtained above and heated to reflux at 110°C for 8 h. The reaction mixture was then cooled to room temperature and concentrated until an oily liquid remained. It was then dissolved in distilled water and the concentration process was repeated twice to remove excess HCl to obtain a white solid. The white solid was dissolved in 4 mL of hot glacial acetic acid, allowed to stand at room temperature for 3 h, and then transferred to a 4°C refrigerator for 16 h. The obtained solid was ground and washed three times with 20 mL of ether, and the supernatant ether was discarded. The precipitate was placed in a vacuum drying oven and dried at 37° C. for 2 h to obtain white solid 4-diethylaminobutyric acid (yield 44.9%) which was used for further reaction.

[0043] 4-Diethylaminobutyric acid (47.7 mg, 0.3 mmol), EDCI (57.5 mg, 0.3 mmol), and DMAP (3.7 mg, 0.03 mmol) were weighed and dissolved in dichloromethane. The mixture was stirred on an ice bath for 30 min, and then cabazitaxel (125.4 mg, 0.15 mmol) was added. The reaction system was warmed to room temperature and stirred overnight. The reaction progress was monitored by thin-layer chromatography. After completion of the reaction, the cabazitaxel derivative CTX-DA was separated and purified by column chromatography to obtain a white powder (yield 68.3%, purity 99.3%). The entire reaction was carried out under N2 protection. The structure of the compound in Example 1 was confirmed by proton nuclear magnetic resonance spectroscopy, as shown in FIG. Figure 1-2 , the spectrum analysis results are as follows:

[0044] 1H NMR (400MHz, DMSO-d6) δ8.02–7.95(m,2H),7.88(d,J=8.1Hz,1H),7.74(t,J=7.3Hz,1H),7.66(t,J=7.5Hz,2 H),7.49–7.32(m,4H),7.19(t,J=7.3Hz,1H),5.83(t,J=9.2Hz,1H),5.37(d,J=7.1Hz,1H),5.09(d,J=8.0Hz, 2H),4.99–4.92(m,1H),4.69(s,1H),3.75(dd,J=10.6,6.6Hz,1H),3.59(d,J=7.1Hz,1H),3.28(s,3H),3.21( s,3H),3.09(s,4H),2.67–2.51(m,5H),2.25(s,3H),1.81(s,6H),1.58–1.12(m,21H),0.98(d,J=6.1Hz,6H).

[0045] Example 2

[0046] Synthesis of a Cabazitaxel Derivative (CTX-PA) with a 2'-O-(N-methyl-piperazinylbutyryl) Base: 4-(4-Methyl-1-piperazinyl)butyric acid (56 mg, 0.3 mmol), EDCI (57.5 mg, 0.3 mmol), and DMAP (3.7 mg, 0.03 mmol) were weighed and dissolved in dichloromethane. The mixture was stirred for 30 min under ice bath conditions. Cabazitaxel (125.4 mg, 0.15 mmol) was then added. The reaction system was warmed to room temperature and stirred overnight. The reaction progress was monitored by thin layer chromatography. After completion of the reaction, the cabazitaxel derivative CTX-PA was separated and purified by column chromatography to obtain a white powder (yield 64.44%, purity 98.9%). The entire reaction was carried out under N2 protection. The structure of the compound in Example 1 was confirmed by hydrogen nuclear magnetic resonance spectroscopy, as shown in FIG. Figure 3-4 , the spectrum analysis results are as follows:

[0047] 1H NMR(400MHz, DMSO-d6)δ8.01–7.94(m,2H),7.90–7.80(m,1H),7.78–7.70(m,1H),7.70–7.59(m,2H),7. 48–7.27(m,4H),7.18(t,J=7.3Hz,1H),5.81(t,J=9.0Hz,1H),5.37(d,J=7.1Hz,1H),5.06(q,J=3.0,2.0 Hz,2H),4.95(dd,J=9.6,2.1Hz,1H),4.69(s,1H),3.75(dd,J=10.6,6.5Hz,1H),3.61–3.55(m,1H),3.28 (s,3H),3.21(s,3H),2.72–2.59(m,1H),2.49–2.02(m,18H),1.93–1.21(m,21H),0.97(d,J=7.7Hz,6H).

[0048] Example 3

[0049] Preparation of Cabazitaxel Derivative Liposomes

[0050] The preparation method 1 of the cabazitaxel derivative liposome of this embodiment comprises the following steps:

[0051] (1) Preparation of blank liposomes: HSPC (hydrogenated soybean lecithin), Chol (cholesterol) and DSPE-mPEG were weighed in a ratio of 3:1:0.05 (w / w). 2000 Distearoylphosphatidylethanolamine-polyethylene glycol 2000 was dissolved in a small amount of chloroform in an eggplant-shaped bottle. The chloroform was evaporated under reduced pressure at 37°C to form a uniform film on the bottle wall. A 650 mM ammonium ion concentration of sucrose octasulfate triethylammonium salt solution (internal aqueous phase) was added and hydrated at 65°C for 30 minutes.

[0052] Or weigh HSPC, Chol and DSPE-mPEG in a ratio of 3:1:0.05 (w / w) 2000 Dissolve in anhydrous ethanol, draw up with a syringe, and inject into a 650 mM sucrose octasulfate triethylammonium salt solution (inner aqueous phase) stirred at 65°C. Stir for approximately 30 minutes to evaporate the ethanol. If the alcohol content is high, further remove the alcohol by rotary evaporation. Pass the solution through polycarbonate membranes with pore sizes of 400 nm, 200 nm, and 100 nm ten times each at 65°C under nitrogen flow to obtain blank liposomes.

[0053] (2) Preparation of gradient blank liposomes: The liposomes were passed through an agarose gel column pre-equilibrated with a 300 mM sucrose + 25 mM histidine solution (external aqueous phase) at pH 6.5, and the eluate containing the light blue opalescent portion was collected to obtain blank liposomes with a sucrose octasulfate triethylammonium gradient.

[0054] (3) Drug loading process: CTX-DA or CTX-PA DMSO stock solution (20 mg / mL) was slowly added dropwise to the blank liposome preparation, and the drug loading was incubated in a 60°C water bath for 20 min. After the incubation, the drug loading was terminated by ice bath to obtain CTX-DA-LPs and CTX-PA-LPs. The encapsulation efficiencies were determined by HPLC and were 99.66±1.07% and 99.86±2.35%, respectively.

[0055] The preparation method 2 of the cabazitaxel derivative liposome of this embodiment comprises the following steps:

[0056] (1) Preparation of blank liposomes: HSPC, Chol and DSPE-mPEG were weighed in a ratio of 3:1:0.05 (w / w). 2000 Dissolve the solution in a small amount of chloroform in an eggplant-shaped bottle and evaporate the chloroform under reduced pressure at 37°C to form a uniform film on the bottle wall. Add 350mM ammonium sulfate solution (inner aqueous phase) and hydrate at 65°C for 30 minutes.

[0057] Or weigh HSPC, Chol and DSPE-mPEG in a ratio of 3:1:0.05 (w / w) 2000 Dissolve in anhydrous ethanol, draw up with a syringe, and inject into a 350 mM ammonium sulfate solution (inner aqueous phase) stirred at 65°C. Stir for approximately 30 minutes to evaporate the ethanol. If the alcohol content is high, further remove the alcohol by rotary evaporation. Pass the solution through polycarbonate membranes with pore sizes of 400 nm, 200 nm, and 100 nm ten times each at 65°C under nitrogen flow to obtain blank liposomes.

[0058] (2) Preparation of gradient blank liposomes: The liposomes were passed through an agarose gel column pre-equilibrated with 300 mM sucrose solution (external aqueous phase), and the eluate containing the light blue opalescent portion was collected to obtain blank liposomes with an ammonium sulfate gradient.

[0059] (3) Drug loading process: CTX-DA or CTX-PA DMSO stock solution (20 mg / mL) was slowly added dropwise to the blank liposome preparation, and the drug loading was carried out by incubating in a 60°C water bath for 20 min. After the incubation, the drug loading was terminated by ice bath to obtain CTX-DA and CTX-PA liposomes. The encapsulation efficiencies were determined by HPLC and were 93.82±1.74% and 87.36±4.77%, respectively, with a high content of impurities.

[0060] Example 4

[0061] Related substance analysis of cabazitaxel derivative liposomes CTX-DA-LPs, CTX-PA-LPs, and CN1-LPs (principal component self-comparison method)

[0062] Appropriate amounts of CTX-DA-LPs, CTX-PA-LPs, and CN1-LPs were prepared by adding methanol to break the emulsions. After nitrogen purging, the methanol was evaporated. The solvent in the initial mobile phase ratio of each sample was added to a test solution with a concentration of 0.5 mg / mL. A reference solution with a concentration of approximately 5.0 μg / mL was prepared by precisely measuring the appropriate amount of the test solution and adding the solvent in the initial mobile phase ratio. The test and reference solutions were filtered through a 0.22 μm filter, and 20 μL of each filtrate was precisely measured and injected for analysis. The results showed that CTX-DA-LPs contained no unknown impurities, while the unknown impurities in CTX-PA-LPs were 0.48±0.05%, and in CN1-LPs were 0.88±0.09%. The unknown impurities in CTX-DA-LPs and CTX-PA-LPs were less than 0.5%, meeting the requirements. However, the unknown impurities in CN1-LPs exceeded 0.5%, exceeding the limit.

[0063] Table 1 Related substance results of cabazitaxel derivative liposomes (CTX-DA-LPs, CTX-PA-LPs and CN1-LPs).

[0064]

[0065] Example 5

[0066] In vitro cytotoxicity study of cabazitaxel derivative liposomes

[0067] Cells were seeded at 2000 cells / well in a 96-well plate and incubated in an incubator for 24 hours. Cell attachment was observed under a microscope, and the old culture medium was discarded. Seven agents (CTX solution, CTX-DA solution, CN1 solution, CN1-LPs, CTX-DA-LPs, and CTX-PA-LPs) of varying molar concentrations were serially diluted with fresh culture medium. 200 μL of drug-containing culture medium was added to each well, with three replicates per concentration. Blank culture medium was added to the zeroed wells, and a control well contained blank culture medium containing cells. The 96-well plate containing drug-containing culture medium was incubated in a 37°C incubator for 48 hours. After removal, 20 μL of MTT was added to each well and incubated for 4 hours. The culture medium was discarded, and 200 μL of DMSO was added to each well, followed by shaking for 10 minutes to fully dissolve the formazan. The absorbance of each well was measured at 490 or 570 nm using a microplate reader to calculate cell viability.

[0068] The results, shown in Table 2, show that the antitumor activities of CTX-DA and CTX-PA were slightly reduced compared to CTX, with similar differences between the two. However, the cytotoxicity of CTX-DA and CTX-PA was enhanced compared to CN1. The cytotoxicity of the liposomes was reduced compared to the free cabazitaxel derivatives, and both CTX-DA-LPs and CTX-PA-LPs were more potent than CN1-LPs.

[0069] Table 2 Half-inhibitory concentration (IC) of cabazitaxel derivative liposomes (CTX-DA-LPs, CTX-PA-LPs and CN1-LPs) 50 ).

[0070]

[0071] Example 6

[0072] Animal efficacy study of cabazitaxel derivative liposomes

[0073] Take 100 μL of mouse prostate cancer cells (RM-1, 1×10 8 cells / mL, PBS) suspension was subcutaneously inoculated into the right posterior lumbar region of male C57BL / 6 mice to establish the RM-1 tumor-bearing mouse model. 3 Mice were randomly divided into five groups (n=5 per group): (1) saline (control) group, (2) CTX-Sol group (6 mg / kg), (3) CN1-LPs group (6 mg CTX / kg), (4) CTX-DA-LPs group (6 mg CTX / kg), and (5) CTX-PA-LPs group (6 mg CTX / kg). The drugs were administered once every two days for a total of four times. After administration, the mice were observed, weighed, and tumor volumes were measured. On the tenth day after administration, the mice were sacrificed, and the tumors and major organs were removed for analysis and evaluation.

[0074] The results are shown in Table 3. The saline group failed to inhibit tumor growth, and the tumor grew rapidly during the administration period. CTX-Sol and CN1-LPs had weak antitumor effects. CTX-DA-LPs and CTX-PA-LPs exhibited promising antitumor effects, with CTX-PA-LPs showing the most significant in vivo antitumor effect.

[0075] Table 3 Tumor volume on the tenth day after administration of cabazitaxel derivative liposomes (CTX-DA-LPs, CTX-PA-LPs and CN1-LPs) in the in vivo antitumor experiment.

[0076]

[0077] The above description is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A cabazitaxel derivative or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds: ； The pharmaceutically acceptable salt is a salt formed by the cabazitaxel derivative and a pharmaceutically acceptable inorganic acid or organic acid; the synthesis method of the cabazitaxel derivative comprises the following steps: Under the catalysis of DMAP and EDCI, 4-diethylaminobutyric acid or 4-(4-methyl-1-piperazinyl)butyric acid and cabazitaxel undergo esterification reaction, which is then separated and purified to obtain the product. The entire reaction is carried out under N2 protection.

2. A liposome of a cabazitaxel derivative, characterized in that: The invention comprises the cabazitaxel derivative according to claim 1, phospholipids, cholesterol, and PEGylated phospholipids; the weight ratio of the cabazitaxel derivative to total lipids is 0.10-0.50, and the total lipids are the sum of phospholipids, cholesterol, and PEGylated phospholipids.

3. The method for preparing the liposome of the cabazitaxel derivative according to claim 2, characterized in that: The steps include: (1) Weighing the membrane materials required for preparing liposomes, preparing liposomes by thin film dispersion method, ethanol injection method or cross-flow mixing method, using sucrose octasulfate triethylammonium salt solution as the internal aqueous phase, and sequentially extruding through polycarbonate membranes of different pore sizes to form nanosized small unilamellar liposomes; (2) replacing the external aqueous phase of the small unilamellar liposomes obtained in step (1) with a sucrose solution and a histidine solution, a HEPES buffer, a phosphate buffer or an acetate buffer to obtain blank liposomes having a gradient of internal and external aqueous phases; (3) adding an organic solution of a cabazitaxel derivative to the gradient blank liposomes obtained in step (2), and incubating the mixture to obtain a cabazitaxel derivative liposome preparation.

4. The preparation method according to claim 3, characterized in that In the step (2), the external aqueous phase solution is a sucrose solution and a histidine solution.

5. The preparation method according to claim 3, characterized in that In the step (3), the solvent of the organic solution is methanol, ethanol, acetone, tetrahydrofuran, acetonitrile or DMSO.

6. Use of the cabazitaxel derivative or the pharmaceutically acceptable salt thereof according to claim 1 or the liposome of the cabazitaxel derivative according to claim 2 in the preparation of a drug delivery system.

7. Use of the cabazitaxel derivative or pharmaceutically acceptable salt thereof according to claim 1 or the cabazitaxel derivative liposome according to claim 2 in the preparation of an anti-tumor drug, characterized in that: Tumor cells were RM-1, 4T1 or CT26 cells.

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