Cabazitaxel prodrug anticancer drug

Abstract

The cabazitaxel prodrug anticancer drug of the present invention belongs to the field of novel excipients and novel dosage forms for pharmaceutical formulations. In this invention, cabazitaxel-fatty alcohol small molecule prodrugs having the general formulas (I), (II), and (III) with different fatty alcohol side chains and different linkers were synthesized and self-assembled nanoparticles were prepared. Results showed that the cabazitaxel-fatty alcohol small molecule prodrug self-assembled nanoparticles can effectively improve the efficacy of cabazitaxel and reduce toxic side effects. The length of the branched fatty alcohol side chain, the structure of the fatty alcohol side chain, the elemental composition of the linker, and the length of the linker significantly affect the pharmaceutical properties, biofate, and antitumor activity of the cabazitaxel prodrug self-assembled nanoparticles. The prodrug self-assembled nanoparticles have higher antitumor activity and lower toxicity than cabazitaxel linear fatty alcohol small molecule prodrug self-assembled nanoparticles. JPEG2025528763000026.jpg200106

Description

[Technical Field]

[0001] The present invention relates to the field of new excipients and new formulations for drug formulations, and to antitumor formulations of cabazitaxel prodrugs, specifically to the construction of cabazitaxel-branched alcohol prodrugs and self-assembled nanoparticles, and the application of cabazitaxel prodrugs in drug delivery systems (DDS).

[0002] In recent years, the incidence of malignant tumors has increased, posing a serious threat to human health. Chemotherapy is one of the most effective strategies for cancer treatment. Cabazitaxel (CTX) belongs to the taxane class of antitumor drugs and has strong cytotoxicity and antitumor effects. However, cabazitaxel is associated with serious side effects, including gastrointestinal disturbances, allergic reactions, renal dysfunction, and a decrease in neutral granulocytes. Cabazitaxel has very poor solubility in water, and the commercially available cabazitaxel solution (Jevtana®) requires the addition of Tween 80 and ethanol for solubilization. Despite the use of solvents, the stability of cabazitaxel solutions is poor, prone to precipitation after dilution, and exhibits poor pharmacokinetic properties. These drawbacks limit the clinical application of cabazitaxel.

[0003] The prodrug strategy is an effective method for increasing the delivery efficiency of chemotherapy drugs. Using the prodrug strategy to modify the cabazitaxel structure effectively alleviates the problems of cabazitaxel's low solubility and toxic side effects. Nanodrug delivery systems effectively extend the drug's circulation time in the body and increase antitumor efficacy. Therefore, self-assembling nanodrug delivery systems based on the prodrug strategy, which combine the advantages of nanotechnology and prodrug strategies, have attracted considerable research attention in recent years due to their advantages such as high drug loading capacity and the elimination of solvent addition.

[0004] A prodrug typically consists of three parts: a parent drug, a linker, and a side chain, with the parent drug and side chain connected via the linker. To construct a self-assembling prodrug, current cabazitaxel prodrugs often use linear fatty acids or fatty alcohols as side chains. The aliphatic side chain increases the structural flexibility of the prodrug molecule, balances intermolecular forces, and promotes prodrug self-assembly. Branched fatty alcohols are expected to effectively disrupt prodrug molecules, thereby eliminating dense accumulation and enhancing the self-assembly ability of the prodrug. Furthermore, the carbon chain length of the branched fatty alcohol may affect the pharmaceutical properties, biofate, and antitumor efficacy of prodrug self-assembled nanoparticles. Currently, there are no comparative studies on the effect of branched fatty alcohol carbon chain length on prodrug self-assembled nanoparticles, and no studies have been reported on the effects of branched and linear fatty alcohols as side chains on prodrug self-assembled nanoparticles.

[0005] The tumor microenvironment differs significantly from that of normal tissue cells. Large amounts of reactive oxygen species and glutathione are produced in tumor cells, leading to an imbalanced redox state in the tumor microenvironment. Monosulfide bonds, disulfide bonds, and monoselenium bonds all possess redox dual-sensing properties, intelligently responding to the high redox state in tumor cells and releasing drugs. Because the elemental composition of different linkers results in different redox dual-sensing properties, cabazitaxel prodrugs modified with different linkers also have pharmaceutical properties, biofate, and antitumor activity. Furthermore, the chain length of the linker also affects the redox dual-sensing properties of prodrug self-assembled nanoparticles, which in turn affects the antitumor activity of the prodrug self-assembled nanoparticles. Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention aims to overcome the above technical shortcomings by providing a cabazitaxel prodrug anticancer drug. Specifically, it provides a cabazitaxel-branched fatty alcohol small molecule prodrug and nanoparticles, as well as their preparation and use. The nanoparticles are self-assembled nanoparticles with the advantages of small particle size, uniform distribution, high drug loading, good stability, strong antitumor effect, and good safety.

[0007] Another objective of the present invention is to design and synthesize cabazitaxel prodrugs with branched fatty alcohol side chains of different lengths, cabazitaxel prodrugs with linear fatty alcohol side chains, and cabazitaxel prodrugs with different linkers to prepare self-assembled nanoparticles. Experimental results show that the length of the branched fatty alcohol side chain, the structure of the fatty alcohol side chain (branched or linear), the elemental composition of the linker, and the length of the linker all affect the antitumor efficacy and safety of the prodrug self-assembled nanoparticles. The present invention provides a new option for a novel prodrug self-assembled nanodrug delivery system, addressing the urgent need for highly efficient and low-toxicity chemical formulations in clinical practice. [Means for solving the problem]

[0008] In order to achieve the above object, the present invention employs the following technical means.

[0009] The branched fatty alcohol small molecule prodrug of cabazitaxel or a pharmaceutically acceptable salt thereof has a structure represented by general formula (I), (II), or (III).

[0010] JPEG2025528763000002.jpg65112

[0011] JPEG2025528763000003.jpg65116

[0012] JPEG2025528763000004.jpg62120

[0013] Here, n=1 to 3.

[0014] R is saturated or unsaturated C3-C 30 R is a hydrocarbon group containing a branched structure, and the branch is C1 to C 18 Alkyl groups, C2-C 18 Alkenyl group or C2-C 18 It is one or more of the alkynyl groups.

[0015] Furthermore, R is saturated or unsaturated C3-C 24 The R is a hydrocarbon group containing a branched structure, and the branch is a linear C6-C 10 Alkyl groups, C6-C 10 Alkenyl group or C6-C 10 It is one or more of the alkynyl groups.

[0016] Furthermore, R can be saturated or unsaturated C 10 ~C 24 R is a hydrocarbon group containing a branched structure, and the branch is a linear C6-C 10 Alkyl groups, C6-C 10 Alkenyl group or C6-C 10 It is one or more of the alkynyl groups.

[0017] Furthermore, R is C 10 ~C 24 The R is an alkyl group having a branched structure, and the branch is a linear C6 to C10 alkyl group.

[0018] Furthermore, R can be saturated or unsaturated C 16~ C 24 R is a hydrocarbon group containing a branched structure, and the branch is a linear C6-C 10 It is an alkyl group.

[0019] Furthermore, R is C 16 ~C 24 wherein R is an alkyl group having a branched structure, and the branch is a linear C6 to C10 It is an alkyl group.

[0020] When R is an unsaturated hydrocarbon group, the unsaturated hydrocarbon group contains 1 to 5 alkenyl groups, alkynyl groups, or a sum of alkenyl groups and alkynyl groups.

[0021] The branched fatty alcohol is one of 2-hexyl-octanol, 1-heptyl-octanol, 2-hexyl-decanol, 1-butyl-dodecanol, 1-heptyl-nonanol, 1-octyl-nonanol, 2-octyl-decanol, 2-heptyl-undecanol, 1-nonyl-decanol, 2-octyl-dodecanol, 2-decyltetradecanol, or 2-dodecyltetradecanol.

[0022] Preferentially, said branched fatty alcohol is chosen to be 2-hexyl-decanol, 2-heptylun-decanol, 2-octyldo-decanol or 2-decyltetra-decanol.

[0023] In the cabazitaxel branched fatty alcohol small molecule prodrug, cabazitaxel and the branched fatty alcohol are connected via a dibasic acid linker, and the dibasic acid is a monothiodibasic acid, a monoselenodibasic acid, or a dithiodibasic acid, wherein the monothiodibasic acid is monothiodiacetic acid, monothiodipropionic acid, or monothiodipropionic acid, the monoselenodibasic acid is monoselenodiacetic acid, selenodipropionic acid, or selenodibutyric acid, and the dithiodibasic acid is 2,2'-dithiodiacetic acid, 3,3'-dithiodipropionic acid, or 4,4'-dithiodibutyric acid.

[0024] Specifically, the present invention provides 2-hexyldecanol prodrug of cabazitaxel, 2-heptylundecanol prodrug of cabazitaxel, 2-octyldodecanol prodrug of cabazitaxel, and 2-decyltetradecanol prodrug of cabazitaxel, in which 2,2-dithiodiacetic acid is selected as the linker, and the corresponding prodrugs are named CTX-SS-HD, CTX-SS-HU, CTX-SS-OD, and CTX-SS-DT, respectively, and their general formulas are as follows:

[0025] JPEG2025528763000005.jpg52144

[0026] JPEG2025528763000006.jpg55150

[0027] JPEG2025528763000007.jpg60153

[0028] JPEG2025528763000008.jpg64156

[0029] The present invention provides a linear fatty alcohol small molecule prodrug - cabataxel-arachidil alcohol prodrug, and 2,2'-dithiodiacetic acid is selected as the linker. The corresponding prodrug is named CTX-SS-AA, and its general formula is as follows:

[0030] JPEG2025528763000009.jpg45136

[0031] The above is a cabazitaxel arachidiolic alcohol prodrug (CTX-SS-AA) using 2,2'-dithiodiacetic acid as a linker.

[0032] The present invention provides a cabataxel-2-octyldodecanol prodrug using 4,4'-dithiodibutyric acid as a linker, and the corresponding prodrug is named γ-CTX-SS-OD, whose general formula is as follows:

[0033] JPEG2025528763000010.jpg5194

[0034] The above is a cabazitaxel-2-octyldodecanol prodrug (γ-CTX-SS-OD) using 4,4′-dithiodibutyric acid as a linker.

[0035] The present invention provides the use of cabazitaxel 2-octyldodecanol prodrugs using monosulfurized diethanesulfonic acid and monoselenized diethanesulfonic acid as linkers, and the corresponding prodrugs are named CTX-S-OD and CTX-Se-OD, and their general formulas are as follows:

[0036] JPEG2025528763000011.jpg63152

[0037] JPEG2025528763000012.jpg58148

[0038] The synthesis of the branched fatty alcohol small molecule prodrug of cabazitaxel is as follows.

[0039] Step 1: A dibasic acid is dissolved to form a dibasic acid anhydride, which is then esterified with a branched fatty alcohol to obtain a branched fatty alcohol-dibasic acid monoester intermediate product. The molar ratio of the branched fatty alcohol to the dibasic acid anhydride is (1-10):(5-15), and the dibasic acid is a monothiodibasic acid, a monoselenodibasic acid, or a dithiodibasic acid.

[0040] Step 2: The branched fatty alcohol-dibasic acid monoester and cabazitaxel undergo an esterification reaction to obtain the final product, a branched fatty alcohol small molecule prodrug of cabazitaxel, at a molar ratio of branched fatty alcohol-dibasic acid monoester to cabazitaxel of 1:(0.5-10). The reaction scheme is as follows:

[0041] JPEG2025528763000013.jpg72137

[0042] JPEG2025528763000014.jpg74138

[0043] JPEG2025528763000015.jpg73135

[0044] Here, n=1 to 3.

[0045] R is saturated or unsaturated C3-C 30 a hydrocarbon group, wherein R is an alkyl hydrocarbon group containing a branched structure, and the branch is a C1-C 18 Alkyl groups, C2-C 18 Alkenyl group or C2-C 18 There may be more than one type of alkynyl group.

[0046] The synthesis method of the cabazitaxel branched fatty alcohol small molecule prodrug specifically includes the following steps:

[0047] 1. Dissolve the dibasic acid in acetic anhydride and stir at room temperature for 2 to 4 hours to convert the dibasic acid to the dibasic acid anhydride. After the reaction is complete, add toluene and remove the toluene and acetic anhydride by rotary evaporation under reduced pressure.

[0048] 2. Take the branched fatty alcohol and 4-dimethylaminopyridine (DMAP) and dissolve them in dichloromethane along with the dibasic acid anhydride obtained in step (1). Stir at room temperature for 12 to 18 hours, then separate using column chromatography to obtain the intermediate product, the branched fatty alcohol-dibasic acid monoester.

[0049] 3. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), and 4-dimethylaminopyridine (DMAP) are dissolved in anhydrous dichloromethane along with the intermediate product, a branched fatty alcohol dibasic acid monoester. The mixture is then stirred in an ice bath for 2-4 hours, followed by addition of cabazitaxel. The mixture is then stirred at room temperature for 24-48 hours, and the final product, a branched fatty alcohol prodrug, is obtained by separation and purification using preparative liquid chromatography.

[0050] The reactions in the synthesis of the branched fatty alcohol small molecule prodrug of cabazitaxel were mainly carried out by protecting nitrogen.

[0051] In Step 1, the dibasic acid includes monothiodiacetic acid, monothiodipropionic acid, monothiodibutyric acid, selenodiacetic acid, selenodipropionic acid, selenodibutyric acid, 2,2'-dithiodiacetic acid, 3,3'-dithiodipropionic acid, or 4,4'-dithiodibutyric acid.

[0052] In step 1, the ratio of dibasic acid to acetic anhydride is 1:(1-10), preferably 1:(1-2), and the unit is mmol:mL. In step 2, the branched fatty alcohol is C3-C 30 A saturated or unsaturated fatty alcohol, the branched chain consisting of C1 to C 18 Alkyl groups, C2-C 18 Alkenyl group or C2-C 18 It may be one or more of the alkynyl groups.

[0053] In the step 2, the molar ratio of DMAP: branched fatty alcohol: dibasic acid anhydride is 1: (1-10): (5-15), and the ratio of 1: (2-5): (10-15) is preferentially selected.

[0054] In Step 3, the molar ratio of the intermediate product, branched fatty alcohol-diabasic acid monoester:HOBt:EDCI:DMAP:cabazitaxel is 1:(1-10):(2-6):(0.2-5):(0.5-10), with a preferred ratio of 1:(1-2):(2-4):(0.5-2):(0.8=2).

[0055] In the step 3, the purity of the prepared cabazitaxel branched fatty alcohol small molecule prodrug is 99% or more.

[0056] The present invention also provides a method for synthesizing selenodiacetic acid, the steps of which are as follows:

[0057] Place selenium powder and a small amount of water in a pear-shaped flask, place the flask in an ice-water bath, and slowly add aqueous sodium borohydride, stirring until the solution becomes clear and transparent. Allow the temperature to rise to 100-110°C, stir for 30-45 minutes, then return to room temperature. Add aqueous bromoacetic acid and react for 10-20 hours. After the reaction, filter the liquid and add ethyl acetate for extraction, repeating this process until the aqueous layer becomes colorless. The ethyl acetate layer is then dried and removed by rotary evaporation under reduced pressure to obtain the product. The entire reaction process is carried out under nitrogen gas protection.

[0058] The present invention also provides self-assembled nanoparticles of cabazitaxel fatty alcohol small molecule prodrugs, which are non-PEGylated prodrug self-assembled nanoparticles, PEG-modified / active targeting-modified prodrug self-assembled nanoparticles, or prodrug self-assembled nanoparticles encapsulating a hydrophobic fluorescent substance or a drug.

[0059] The preparation method of the cabazitaxel branched fatty alcohol small molecule prodrug self-assembled nanoparticles includes the following steps:

[0060] For non-PEGylated cabazitaxel fatty alcohol small molecule prodrug self-assembled nanoparticles, the preparation method is as follows.

[0061] A certain amount of prodrug is dissolved in an appropriate amount of organic solvent, and the solution is slowly added dropwise to water while stirring. The prodrug spontaneously forms uniform nanoparticles. The organic solvent in the formulation is removed using vacuum rotary evaporation, resulting in a nanocolloidal solution free of any organic solvent. This is the non-PEGylated cabazitaxel fatty alcohol small molecule prodrug.

[0062] The following describes a method for preparing self-assembled nanoparticles of cabazitaxel fatty alcohol small molecule prodrugs modified with PEG and active targeting groups. A certain amount of PEG modifier and active targeting modifier are dissolved in an appropriate amount of organic solvent along with the prodrug. The solution is slowly added dropwise to water with stirring, and the prodrug spontaneously forms uniform nanoparticles. The organic solvent in the formulation is removed using vacuum rotary evaporation, yielding a nanocolloidal solution free of organic solvent. This results in self-assembled nanoparticles of cabazitaxel fatty alcohol small molecule prodrugs modified with PEG and active targeting groups. The mass ratio of the cabazitaxel branched fatty alcohol small molecule prodrug to the PEG modifier / active targeting modifier is set at 1:1 (0.1-1). The PEG modifier is an amphiphilic polymer and targeting group, such as DSPE-PEG, TPGS, PLGA-PEG, PE-PEG, or DSPE-PEG-FA. On the other hand, active targeting modifiers are selected from substances that have the ability to target specific tissues, such as antibodies, carbohydrate residues, hormones, receptors, or ligands.

[0063] The following describes a method for preparing self-assembled nanoparticles of cabazitaxel fatty alcohol small molecule prodrugs with embedded hydrophobic fluorescent substances and drugs. A certain amount of PEG modifier, hydrophobic fluorescent substance / drug, and prodrug are dissolved in an appropriate amount of organic solvent. The solution is slowly added dropwise to water with stirring, and the prodrug spontaneously forms uniform nanoparticles. The organic solvent in the formulation is removed using reduced-pressure rotary evaporation, yielding an organic-solvent-free nanocolloidal solution. This results in self-assembled nanoparticles of cabazitaxel fatty alcohol small molecule prodrugs with embedded hydrophobic fluorescent substances / drugs, in which the mass ratio of cabazitaxel branched fatty alcohol small molecule prodrugs, PEG modifier, and hydrophobic fluorescent substance / drug is set to 1:(0.1-1):(0.1-1).

[0064] The cabazitaxel branched fatty alcohol small molecule prodrug or the self-assembled nanoparticles are applied in the preparation of anti-tumor drugs.

[0065] The application of the branched fatty alcohol small molecule prodrug of cabazitaxel or the self-assembled nanoparticles in the preparation of an injectable, oral or topical administration system.

[0066] The application of the branched fatty alcohol small molecule prodrug of cabazitaxel or the self-assembled nanoparticles is in the manufacture of a drug delivery system that improves therapeutic efficacy and reduces toxicity.

[0067] The lyophilized powder injection of cabazitaxel branched fatty alcohol small molecule prodrug self-assembled nanoparticles contains a cabazitaxel branched fatty alcohol small molecule prodrug self-assembled nanoparticle solution and a lyoprotectant, the self-assembled nanoparticle solution having a concentration of 0.1 mg / mL to 20 mg / mL, and the lyoprotectant being one or more of monosaccharides such as glucose and galactose, disaccharides such as trehalose and sucrose, polyhydric alcohols such as mannitol, sorbitol, and xylitol, and polymers such as polyethylene glycol, hydroxyethyl starch, and dextran, and the dosage of the lyoprotectant is 1% to 20% (W / V) (i.e., the mass concentration of the lyoprotectant is 10 g / L to 200 g / L), preferably 5% to 10% (W / V).

[0068] The preparation method of the cabazitaxel branched fatty alcohol small molecule prodrug self-assembled nanoparticles lyophilized powder injection comprises the following steps:

[0069] The solution of cabazitaxel branched fatty alcohol small molecule prodrug self-assembled nanoparticles is placed in a flask, and a lyoprotectant is added. After the lyoprotectant is completely dissolved, the solution is frozen at -80°C for 8-12 hours. The solution is then placed in a freeze dryer and freeze-dried for 24-72 hours. The resulting white mass is the lyophilized powder injection of cabazitaxel branched fatty alcohol small molecule prodrug self-assembled nanoparticles.

[0070] The beneficial effects of the present invention are as follows:

[0071] 1. The present invention designs and synthesizes cabazitaxel fatty alcohol small molecule prodrugs containing different fatty alcohol side chains and different linkers, which have the advantages of a simple and practical synthesis method, smaller particle size, uniform particle size distribution of cabazitaxel fatty alcohol small molecule prodrug self-assembled nanoparticles, and a simple preparation method that is easy to implement.

[0072] 2. The effects of four different lengths of branched fatty alcohol side chains, the structure of the fatty alcohol side chain (branched or linear), and four different linkers on the formulation properties, biofate, and antitumor activity of prodrug self-assembled nanoparticles were discussed.

[0073] The results showed that cabazitaxel fatty alcohol small molecule prodrug self-assembled nanoparticles effectively enhanced the efficacy of cabazitaxel and reduced toxic side effects. Different side chains and linkers significantly affected the pharmaceutical properties, biofate, and antitumor activity of cabazitaxel prodrug self-assembled nanoparticles. When 2-octyldodecanol was used as the side chain, the safety of the prodrug self-assembled nanoparticles was superior. Compared with linear cabazitaxel fatty alcohol small molecule prodrug self-assembled nanoparticles, cabazitaxel branched fatty alcohol small molecule prodrug self-assembled nanoparticles had superior antitumor efficacy and safety. Furthermore, cabazitaxel fatty alcohol small molecule prodrug self-assembled nanoparticles using a disulfide bond as a linker exhibited even better antitumor efficacy. When the linker was 4,4'-dithiodibutyric acid and the side chain was 2-octyldodecanol, the compound exhibited the strongest antitumor activity, the best safety, and the highest tolerated dose. The present invention provides novel strategies and options for developing highly efficient and less toxic chemotherapy formulations. [Brief explanation of the drawings]

[0074] [Figure 1] This is a graph showing changes in tumor volume in an in vivo antitumor experiment using PEG-modified self-assembled nanoparticles of small molecule prodrugs in Example 13 of the present invention. nS: P≧0.05 *: P<0.05 **: P<0.01 ***: P<0.001 ****: P<0.0001 (all two-tailed t-test). [Figure 2] This is a graph showing changes in mouse body weight during an in vivo antitumor experiment using PEG-modified self-assembled nanoparticles of small molecule prodrugs in Example 13 of the present invention. nS: P≧0.05 *: P<0.05 **: P<0.01 ***: P<0.001 ****: P<0.0001 (all two-tailed t-test). [Figure 3] FIG. 10 shows blood routine indexes in an in vivo antitumor experiment of PEG-modified small molecule prodrug self-assembled nanoparticles in Example 13 of the present invention. [Figure 4] This is a graph showing changes in tumor volume in an in vivo antitumor experiment using PEG-modified self-assembled nanoparticles of small molecule prodrugs in Example 14 of the present invention. nS: P≧0.05 *: P<0.05 **: P<0.01 ***: P<0.001 ****: P<0.0001 (all two-tailed t-test). [Figure 5] This is a graph showing changes in mouse body weight during an in vivo antitumor experiment using PEG-modified self-assembled nanoparticles of small molecule prodrugs in Example 14 of the present invention. nS: P≧0.05 *: P<0.05 **: P<0.01 ***: P<0.001 ****: P<0.0001 (all two-tailed t-test). [Figure 6] This figure shows the tumor burden in an in vivo antitumor experiment of PEG-modified small molecule prodrug self-assembled nanoparticles in Example 14 of the present invention. nS: P≧0.05 *: P<0.05 **: P<0.01 ***: P<0.001 ****: P<0.0001 (all two-tailed t-test). [Figure 7] FIG. 10 is a blood test index diagram for the in vivo antitumor experiment of PEG-modified low molecular weight prodrug self-assembled nanoparticles in Example 14 of the present invention. [Figure 8] 10 is a chart showing general routine biochemical indicators in in vivo antitumor experiments of PEG-modified small molecule prodrug self-assembled nanoparticles in Example 14 of the present invention. [Figure 9] This is a graph showing changes in tumor volume in an in vivo antitumor experiment using PEG-modified self-assembled nanoparticles of small molecule prodrugs in Example 15 of the present invention. nS: P≧0.05 *: P<0.05 **: P<0.01 ***: P<0.001 ****: P<0.0001 (all two-tailed t-test). [Figure 10]This is a graph showing changes in mouse body weight during an in vivo antitumor experiment using PEG-modified self-assembled nanoparticles of small molecule prodrugs in Example 15 of the present invention. nS: P≧0.05 *: P<0.05 **: P<0.01 ***: P<0.001 ****: P<0.0001 (all two-tailed t-test). [Figure 11] This figure shows the tumor burden in an in vivo antitumor experiment of PEG-modified small molecule prodrug self-assembled nanoparticles in Example 15 of the present invention. nS: P≧0.05 *: P<0.05 **: P<0.01 ***: P<0.001 ****: P<0.0001 (all two-tailed t-test). [Figure 12] This is a graph showing changes in tumor volume in an in vivo antitumor experiment using PEG-modified self-assembled nanoparticles of small molecule prodrugs in Example 16 of the present invention. nS: P≧0.05 *: P<0.05 **: P<0.01 ***: P<0.001 ****: P<0.0001 (all two-tailed t-test). [Figure 13] This is a graph showing changes in mouse body weight during an in vivo antitumor experiment using PEG-modified self-assembled nanoparticles of small molecule prodrugs in Example 16 of the present invention. nS: P≧0.05 *: P<0.05 **: P<0.01 ***: P<0.001 ****: P<0.0001 (all two-tailed t-test). [Figure 14] This figure shows the tumor burden in an in vivo antitumor experiment of PEG-modified small molecule prodrug self-assembled nanoparticles in Example 16 of the present invention. nS: P≧0.05 *: P<0.05 **: P<0.01 ***: P<0.001 ****: P<0.0001 (all two-tailed t-test). [Figure 15] This is a graph showing changes in tumor volume in an in vivo antitumor experiment using PEG-modified self-assembled nanoparticles of small molecule prodrugs in Example 17 of the present invention. nS: P≧0.05 *: P<0.05 **: P<0.01 ***: P<0.001 ****: P<0.0001 (all two-tailed t-test). [Figure 16]This is a graph showing changes in mouse body weight during an in vivo antitumor experiment using PEG-modified self-assembled nanoparticles of small molecule prodrugs in Example 17 of the present invention. nS: P≧0.05 *: P<0.05 **: P<0.01 ***: P<0.001 ****: P<0.0001 (all results are based on a two-tailed t-test). DETAILED DESCRIPTION OF THE INVENTION

[0075] The present invention will be described in more detail below with reference to examples.

[0076] Example 1: Synthesis of cabazitaxel 2-hexyldecanol prodrug using 2,2'-dithiodiacetic acid as a linker An appropriate amount of 2,2'-dithiodiacetic acid was dissolved in acetic anhydride in a 25 mL flask. After complete dissolution, the mixture was stirred magnetically at 25 °C for 2 hours. The mixture was then transferred to a 100 mL flask, three volumes of toluene were added, and the toluene and acetic anhydride were removed by rotary evaporation under reduced pressure. An appropriate amount of dichloromethane was then added to dissolve the resulting dithiodiacetic anhydride. A solution of 2-hexyldecanol in dichloromethane was then added, followed by a solution of 4-dimethylaminopyridine (DMAP) dissolved in dichloromethane, and the mixture was stirred magnetically at 25 °C for 12 hours. The resulting intermediate product, 2-hexyldecanol dithiodiacetic acid monoester, was then isolated and purified by column chromatography using a cyclohexane-acetone elution system. The product purified in the previous step was added to a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), and 4-dimethylaminopyridine (DMAP) in dichloromethane, and the mixture was activated in an ice bath at 0 °C for 2 hours. A dichloromethane solution of cabazitaxel was then added and the mixture was stirred at 25°C for 48 hours. After the reaction was complete, the resulting liquid phase was used to separate the product, yielding the cabazitaxel 2-hexyldecanol prodrug with 2,2'-dithiodiacetic acid as a linker. The molar ratios used in the reaction were as follows: 2,2'-dithiodiacetic acid:acetic anhydride = 1:1 (unit: mmol:mL); DMAP:2-hexyldecanol:dithiodiacetic anhydride = 0.4:2:1; 2-hexyldecanol dithiodiacetic acid monoester:HOBt:EDCI:DMAP:cabataxel = 1:1:2:0.4:0.8.

[0077] Mass spectrometry and 1 The structure of the product was confirmed by H-NMR, and the spectral analysis results are as follows:

[0078] 1H-NMR(600MHz, DMSO-D6) δ7.966(2H, D), 7.840(1H, m,), 7.650-7.677(2H, m,), 7.348(2H, m), 7.174(3H, m), 5.812(1H, S,13-H), 5.070-5.131(2H, D, 2-H, 3'-H), 4.954(1H, D, 2'-H), 4.931(3H, m, 3-H, -CH=CH-), 4.686(1H, D, 4-H), 4.459(1H, m, 5-H), 4.013(1H, D, 20α-H), 3.996(4H, m, -OCH2CH2O-), 3.857(1H, D, 7-H), 3.590(1H, D, 8-H), 3.291(4H, m, -CH2-SS-CH2-), 3.207(4H, m, 6α-H, S, 4-COCHCH2), 2.650(1H, m, 14α-H), 2.236-2.495(2H, m, 14β-H, 15α-H), 1.791(7H, t, 6β-H, -CH2CH=CHCH2-), 1.504(5H,S,19-H,10-COCH3), 1.376(6H,m,-CH2CH2CH2CO-), 1.245(31H, t, 17-H), 0.978(7H, S, 16-H), 0.852(6H, t, -CH3).

[0079] MS(ESI)m / zforC 65 H 93 NO 17 S2NA [M+NA] + :1246.

[0080] Example 2: Synthesis of cabazitaxel 2-heptylundecanol prodrug using 2,2'-dithiodiacetic acid as a linker An appropriate amount of 2,2'-dithiodiacetic acid was dissolved in acetic anhydride in a 25 mL flask. After complete dissolution, the mixture was stirred magnetically at 25 °C for 2 hours. The mixture was then transferred to a 100 mL flask, three volumes of toluene were added, and the toluene and acetic anhydride were removed by rotary evaporation under reduced pressure. An appropriate amount of dichloromethane was then added to dissolve the resulting dithiodiacetic anhydride. A solution of 2-heptylundecanol in dichloromethane was then added, followed by a solution of 4-dimethylaminopyridine (DMAP) dissolved in dichloromethane, and the mixture was stirred magnetically at 25 °C for 12 hours. The resulting intermediate product, 2-heptylundecanol dithiodiacetic acid monoester, was then isolated and purified by column chromatography using a cyclohexane-acetone elution system. The product purified in the previous step was added to a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), and 4-dimethylaminopyridine (DMAP) in dichloromethane, and the mixture was activated in an ice bath at 0 °C for 2 hours. A dichloromethane solution of cabazitaxel was then added and the mixture was stirred at 25°C for 48 hours. After the reaction was complete, the resulting liquid phase was used to separate the product, yielding the cabazitaxel 2-heptylundecanol prodrug, which uses 2,2'-dithiodiacetic acid as a linker. The reaction mixture was mixed in the following ratios: 2,2'-dithiodiacetic acid:acetic anhydride = 1:1 (unit: mmol:mL); DMAP:2-heptylundecanol:dithiodiacetic anhydride = 0.4:2:1; and 2-heptylundecanol-dithiodiacetic acid monoester:HOBt:EDCI:DMAP:cabataxel = 1:1:2:0.4:0.8 (molar ratio).

[0081] Mass spectrometry and 1 The structure of the product was confirmed by H-NMR and the results of spectrum analysis are as follows:

[0082] 1H-NMR(600MHz, DMSO-D6) δ7.967(2H, D), 7.817(1H, m), 7.737(2H, m), 7.658(2H, m), 7.175(3H, m),5.814(1H, S, 13-H), 5.131-5.358(2H, D, 2-H, 3'-H), 5.071(1H, D, 2'-H), 4.932(3H, m, 3-H, -CH=CH-), 4.687(1H, D, 4-H), 4.460(1H, m, 5-H), 4.015(1H, D, 20α-H), 3.976(4H, m, -OCH2CH2O-), 3.857(1H, D, 7-H), 3.574(1H, D, 8-H), 3.293(4H, m, -CH2-SS-CH2-), 3.207(4H, m, 6α-H, S, 4-COCHCH2), 2.651(1H, D, 18-H), 2.237-2.500(2H, m, 14β-H, 15α-H), 1.792(7H, t, 6β-H, -CH2CH=CHCH2-), 1.505(5H, S, 19-H, 10-COCH3), 1.377(6H, m, -CH2CH2CH2CO-), 1.243(35H, t, 17-H), 0.979(7H, S, 16-H), 0.853(6H, t, -CH3).

[0083] MS(ESI)m / zfor C 67 H 97 NO 17 S2NA [M+NA] + :1276.

[0084] Example 3: Synthesis of cabazitaxel 2-octyldodecanol prodrug using 2,2'-dithiodiacetic acid as a linker An appropriate amount of 2,2'-dithiodiacetic acid was dissolved in acetic anhydride in a 25 mL flask. After complete dissolution, the mixture was stirred magnetically at 25 °C for 2 hours. The mixture was then transferred to a 100 mL flask, three volumes of toluene were added, and the toluene and acetic anhydride were removed by rotary evaporation under reduced pressure. An appropriate amount of dichloromethane was then added to dissolve the resulting dithiodiacetic anhydride. A solution of 2-octyldodecanol in dichloromethane was then added, followed by a solution of 4-dimethylaminopyridine (DMAP) dissolved in dichloromethane, and the mixture was stirred magnetically at 25 °C for 12 hours. The resulting intermediate product, 2-octyldodecanol dithiodiacetic acid monoester, was then isolated and purified by column chromatography using a cyclohexane-acetone elution system. The product purified in the previous step was then added to a dichloromethane solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), and 4-dimethylaminopyridine (DMAP) and activated in an ice bath at 0 °C for 2 hours. A dichloromethane solution of cabazitaxel was then added and stirred at 25°C for 48 hours. After the reaction was completed, the resulting liquid phase was used to separate the product, yielding a cabazitaxel 2-octyldodecanol prodrug using 2,2'-dithiodiacetic acid as a linker. The reaction mixture was in the following ratios: 2,2'-dithiodiacetic acid:acetic anhydride = 1:1 (unit: mmol:mL); the molar ratios of DMAP:2-octyldodecanol:dithiodiacetic anhydride = 0.4:2:1; and the molar ratios of 2-octyldodecanol-dithiodiacetic acid monoester:HOBt:EDCI:DMAP:cabataxel = 1:1:2:0.4:0.8.

[0085] Mass spectrometry and 1 The structure of the product was confirmed using H-NMR, and the spectral analysis results are as follows:

[0086] 1H-NMR(600MHz, DMSO-D6) δ7.967(2H, t), 7.662(3H, D), 7.378-7.423(3H, m), 7.153-7.189(2H, m),5.807(1H, D, -NH), 5.355(1H, D, 3'-H), 5.124(1H, D, 2-H), 5.065(4H, m, 2'-H, -CH=CH-, 5-H), 4.924-4.954(1H, t, 7-H), 4.685(1H, D, 20α-H), 4.477(1H, D, 20β-H), 3.993-4.012(2H, D, 15α-H, 15β-H), 3.861(3H, D, 3-H),3.736(4H, m, 6α-H, 4-COCH3), 2.647(1H, m, 13-H), 2.501(3H, t, 14α-H, -CH2CO-), 1.790(6H, S, -CH2CH=CHCH2-), 1.618(4H, S, 18-H), 1.503(t, 5H, 6β-H), 1.377(10H, S, 16-H, 19-H, -CH2CH2CO-), 1.240(24H, t, 17-H), 0.975(3H, t, -CH3),0.850(5H, t, -CH2CH3).

[0087] MS(ESI)m / zforC 69 H 101 NO 17 S2NA [M+NA] + :1303.

[0088] Example 4: Synthesis of cabazitaxel 2-decyltetradecanol prodrug using 2,2'-dithiodiacetic acid as a linker An appropriate amount of 2,2'-dithiodiacetic acid was dissolved in acetic anhydride in a 25 mL flask. After complete dissolution, the mixture was stirred magnetically at 25 °C for 2 hours. The mixture was then transferred to a 100 mL flask, three volumes of toluene were added, and the toluene and acetic anhydride were removed by rotary evaporation under reduced pressure. An appropriate amount of dichloromethane was then added to dissolve the resulting dithiodiacetic anhydride. A solution of 2-decyltetradecanol in dichloromethane was then added, followed by a solution of 4-dimethylaminopyridine (DMAP) dissolved in dichloromethane, and the mixture was stirred magnetically at 25 °C for 12 hours. The resulting intermediate product, 2-decyltetradecanol dithiodiacetic acid monoester, was then isolated and purified by column chromatography using a cyclohexane-acetone elution system. The product purified in the previous step was then added to a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), and 4-dimethylaminopyridine (DMAP) in dichloromethane, and the mixture was activated in an ice bath at 0 °C for 2 hours. A dichloromethane solution of cabazitaxel was then added and the mixture was stirred at 25°C for 48 hours. After the reaction was complete, the resulting liquid phase was used to separate the product, yielding the cabazitaxel 2-decyltetradecanol prodrug, which uses 2,2'-dithiodiacetic acid as a linker. The reaction mixture was as follows: 2,2'-dithiodiacetic acid:acetic anhydride = 1:1 molar ratio, units are mmol:mL. Based on the molar ratio, the molar ratio of DMAP:2-decyltetradecanol:dithiodiacetic anhydride was 0.4:2:1. Furthermore, the molar ratio of 2-decyltetradecanol-dithiodiacetic anhydride monoester:HOBt:EDCI:DMAP:cabataxel was 1:1:2:0.4:0.8.

[0089] Mass spectrometry and 1 The structure of the product was confirmed using H-NMR, and the spectral analysis results are as follows:

[0090] 1H-NMR(600MHz, DMSO-D6) δ7.967(2H, D), 7.817(1H, m), 7.737(2H, m), 7.658(2H, m), 7.175(3H, m),5.814(1H, S, 13-H), 5.131-5.358(2H, D, 2-H, 3'-H), 5.071(1H, D, 2'-H), 4.932(3H, m, 3-H, -CH=CH-), 4.687(1H, D, 4-H), 4.460(1H, m, 5-H), 4.015(1H, D, 20α-H), 3.976(4H, m, -OCH2CH2O-), 3.857(1H, D, 7-H), 3.574(1H, D, 8-H), 3.293(4H, m, -CH2-SS-CH2-), 3.207(4H, m, 6α-H, S, 4-COCHCH2), 2.651(1H, D, 18-H), 2.237-2.500(2H, m, 14β-H, 15α-H), 1.792(7H, t, 6β-H, -CH2CH=CHCH2-), 1.505(5H, S, 19-H, 10-COCH3), 1.377(6H, m, -CH2CH2CH2CO-), 1.243(35H, t, 17-H), 0.979(7H, S, 16-H), 0.853(6H, t, -CH3).

[0091] MS(ESI)m / zforC 73 H 109 NO 17 S2NA [M+NA] + :1359.

[0092] Example 5: Synthesis of cabazitaxel arachidyl alcohol prodrug using 2,2'-dithiodiacetic acid as a linker An appropriate amount of 2,2'-dithiodiacetic acid was dissolved in acetic anhydride in a 25 mL flask. After complete dissolution, the mixture was stirred magnetically at 25 °C for 2 hours. The mixture was then transferred to a 100 mL flask, three volumes of toluene were added, and the toluene and acetic anhydride were removed by rotary evaporation under reduced pressure. An appropriate amount of dichloromethane was then added to dissolve the resulting dithiodiacetic anhydride. A solution of arachidyl alcohol in dichloromethane was then added, followed by a solution of 4-dimethylaminopyridine (DMAP) dissolved in dichloromethane, and the mixture was stirred magnetically at 25 °C for 12 hours. The resulting intermediate product, arachidyl alcohol dithiodiacetic acid monoester, was then isolated and purified by column chromatography using a cyclohexane-acetone elution system. The purified product from the previous step was then added to a dichloromethane solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), and 4-dimethylaminopyridine (DMAP), and the mixture was activated in an ice bath at 0 °C for 2 hours. A dichloromethane solution of cabazitaxel was then added and the mixture was stirred at 25°C for 48 hours. After the reaction was complete, the resulting liquid phase was used to separate the product, synthesizing the cabazitaxel arachidyl alcohol prodrug using 2,2'-dithiodiacetic acid as a linker. The reaction ratios were as follows: 2,2'-dithiodiacetic acid:acetic anhydride = 1:1 (units: mmol:mL). The molar ratio of DMAP:arachidyl alcohol:dithiodiacetic anhydride = 0.4:2:1, and the molar ratio of arachidyl alcohol-dithiodiacetic anhydride monoester:HOBt:EDCI:DMAP:cabataxel was 1:1:2:0.4:0.8.

[0093] Mass spectrometry and 1 The structure of the product was confirmed by H-NMR, and the spectral analysis results are as follows:

[0094] 1H-NMR(600MHz, DMSO-D6) δ7.967(2H, t), 7.662(3H, D), 7.378-7.423(3H, m), 7.153-7.189(2H, m),5.807(1H, D, -NH), 5.355(1H, D, 3'-H), 5.124(1H, D, 2-H), 5.065(4H, m, 2'-H, -CH=CH-, 5-H), 4.924-4.954(1H, t, 7-H), 4.685(1H, D, 20α-H), 4.477(1H, D, 20β-H), 3.993-4.012(2H, D, 15α-H, 15β-H), 3.861(3H, D, 3-H),3.736(4H, m, 6α-H, 4-COCH3), 2.647(1H, m, 13-H), 2.501(3H, t, 14α-H, -CH2CO-), 1.790(6H, S, -CH2CH=CHCH2-), 1.618(4H, S, 18-H), 1.503(t, 5H, 6β-H), 1.377(10H, S, 16-H, 19-H, -CH2CH2CO-), 1.240(24H, t, 17-H), 0.975(3H, t, -CH3),0.850(5H, t, -CH2CH3).

[0095] MS(ESI)m / zforC 69 H 101 NO 17 S2NA [M+NA] + :1280.

[0096] Example 6: Synthesis of cabazitaxel 2-octyldodecanol prodrug using 4,4'-dithiobutyric acid as a linker An appropriate amount of 4,4'-dithiobutyric acid was dissolved in acetic anhydride and placed in a 25 mL flask. After complete dissolution, the mixture was stirred magnetically at 25°C for 2 hours. The mixture was then transferred to a 100 mL flask, three volumes of toluene were added, and the toluene and acetic anhydride were removed by rotary evaporation under reduced pressure. An appropriate amount of dichloromethane was then added to dissolve the resulting dithiobutyric anhydride. A solution of 2-octyldodecanol in dichloromethane was then added, followed by the dropwise addition of 4-dimethylaminopyridine (DMAP) in dichloromethane. The mixture was then stirred magnetically at 25°C for 12 hours. The resulting intermediate product, 2-octyldodecanol-dithiobutyric acid monoester, was then isolated and purified by column chromatography using a cyclohexane-acetone elution system. The product purified in the previous step was added to a dichloromethane solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), and 4-dimethylaminopyridine (DMAP) and activated in an ice bath at 0 °C for 2 hours. A dichloromethane solution of cabazitaxel was then added and stirred at 25 °C for 48 hours. After the reaction was complete, the resulting liquid phase was used to separate the product, yielding the cabazitaxel 2-octyldodecanol prodrug using 4,4'-dithiodiacetic acid as a linker. The ratio of 4,4'-dithiodiacetic acid to acetic anhydride was 1:1 (unit: mmol:mL), and the molar ratio was DMAP:2-octyldodecanol:4,4'-dithiodiacetic acid = 0.4:2:1. Furthermore, the molar ratio of 2-octyldodecanol-dithiobutyric acid monoester:HOBt:EDCI:DMAP:cabataxel is 1:1:2:0.4:0.8.

[0097] Mass spectrometry and 1 The structure of the product was confirmed using H-NMR, and the spectral analysis results are as follows:

[0098] 1H-NMR(600MHz, DMSO-D6) δ7.965(2H, t), 7.691(3H, D), 7.349-7.425(3H, m), 7.152-7.189(2H, m),5.753(1H, D, -NH), 5.352(1H, D, 3'-H), 5.120(1H, D, 2-H), 5.026-5.069(4H, m, 2'-H, -CH=CH-, 5-H), 4.927-4.951(1H, t, 7-H), 4.682(1H, D, 20α-H), 4.474(1H, D, 20β-H), 3.986-4.011(2H, D, 15α-H, 15β-H), 3.583(3H, D, 3-H),3.495(4H, m, 6α-H, 4-COCH3), 2.670(1H, m, 13-H), 2.501(3H, t, 14α-H, -CH2CO-), 1.780(6H, S, -CH2CH=CHCH2-), 1.609(4H, S, 18-H), 1.501(t, 5H, 6β-H), 1.370(10H, S, 16-H, 19-H, -CH2CH2CO-), 1.210(24H, t, 17-H), 0.957(3H, t, -CH3),0.831(5H, t, -CH2CH3).

[0099] MS(ESI)m / zforC 73 H 101 NO 17 S2NA [M+NA] + :1351.

[0100] Example 7: Synthesis of cabazitaxel 2-octyldodecanol prodrug using a single sulfur bond as the linker Dissolve an appropriate amount of monothiodiacetic acid in acetic anhydride in a 25 mL flask. After complete dissolution, magnetically stir at 25 °C for 2 hours. Then, transfer to a 100 mL flask, add three volumes of toluene, and remove the toluene and acetic anhydride by rotary evaporation under reduced pressure. Add an appropriate amount of dichloromethane to dissolve the resulting monothiodiacetic anhydride. Next, add a solution of 2-octyldodecanol in dichloromethane, and gradually add a solution of 4-dimethylaminopyridine (DMAP) in dichloromethane. Stir magnetically at 25 °C for 12 hours. The resulting intermediate product, 2-octyldodecanol-monothiodiacetic acid monoester, is isolated and purified by column chromatography using a cyclohexane-acetone elution system. Add a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), and 4-dimethylaminopyridine (DMAP) in dichloromethane to the purified product and activate it in an ice bath at 0 °C for 2 hours. A dichloromethane solution of cabazitaxel was then added and stirred at 25°C for 48 hours. After the reaction was complete, the resulting liquid phase was used to separate the product, yielding the cabazitaxel 2-octyldodecanol prodrug, which uses a monosulfur bond as a linker. The reaction mixture was in the following ratios: monothiodiacetic acid:acetic anhydride = 1:1 (unit: mmol:mL), and the molar ratios were DMAP:2-octyldodecanol:monothiodiacetic acid = 0.4:2:1. Furthermore, the ratios of 2-octyldodecanol-monothiodiacetic acid monoester:HOBt:EDCI:DMAP:cabataxel were 1:1:2:0.4:0.8.

[0101] Mass spectrometry and 1 The structure of the product was confirmed using H-NMR, and the spectral analysis results are as follows:

[0102] 1H-NMR(600MHz, DMSO-D6) δ7.965(2H, t), 7.691(3H, D), 7.349-7.425(3H, m), 7.152-7.189(2H, m),5.753(1H, D, -NH), 5.352(1H, D, 3'-H), 5.120(1H, D, 2-H), 5.026-5.069(4H, m, 2'-H, -CH=CH-, 5-H), 4.927-4.951(1H, t, 7-H), 4.682(1H, D, 20α-H), 4.474(1H, D, 20β-H), 3.986-4.011(2H, D, 15α-H, 15β-H), 3.583(3H, D, 3-H),3.495(4H, m, 6α-H, 4-COCH3), 2.670(1H, m, 13-H), 2.501(3H, t, 14α-H, -CH2CO-), 1.780(6H, S, -CH2CH=CHCH2-), 1.609(4H, S, 18-H), 1.501(t, 5H, 6β-H), 1.370(10H, S, 16-H, 19-H, -CH2CH2CO-), 1.210(24H, t, 17-H), 0.957(3H, t, -CH3),0.831(5H, t, -CH2CH3).

[0103] MS(ESI)m / zforC 69 H 101 NO 17 SNA [M+NA] + :1271.

[0104] Example 8: Synthesis of cabazitaxel 2-octyldodecanol prodrug using a single selenium bond as a linker

[0105] Dissolve an appropriate amount of selenodiacetic acid in acetic anhydride in a 25 mL flask. After complete dissolution, magnetically stir at 25°C for 2 hours. Transfer to a 100 mL flask, add three volumes of toluene, and remove the toluene and acetic anhydride by rotary evaporation under reduced pressure. Add an appropriate amount of dichloromethane to dissolve the resulting monoselenodiacetic anhydride. Next, add a solution of 2-octyldodecanol in dichloromethane, and slowly add a solution of 4-dimethylaminopyridine (DMAP) in dichloromethane dropwise. Stir magnetically at 25°C for 12 hours. The resulting intermediate product, 2-octyldodecanol-monoselenodiacetic acid monoester, is isolated and purified by column chromatography using a cyclohexane-acetone elution system. The product purified in the previous step was added to a dichloromethane solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), and 4-dimethylaminopyridine (DMAP) and activated in an ice bath at 0 °C for 2 hours. A dichloromethane solution of cabazitaxel was then added and stirred at 25 °C for 48 hours. After the reaction was complete, the resulting liquid phase was used to separate the product, yielding the cabazitaxel 2-octyldodecanol prodrug using a single selenium bond as a linker. The ratio of selenodiacetic acid to acetic anhydride was 1:1 (unit: mmol:mL), and the molar ratio of DMAP to 2-octyldodecanol to selenodiacetic acid was 0.4:2:1. Furthermore, the ratio of 2-octyldodecanol-monoselenodiacetic acid monoester:HOBt:EDCI:DMAP:cabataxel was 1:1:2:0.4:0.8.

[0106] Mass spectrometry and 1 The structure of the product was confirmed using H-NMR, and the spectral analysis results are as follows:

[0107] 1H-NMR(600MHz, DMSO-D6) δ7.969(2H, t), 7.661(3H, D), 7.385-7.428(3H, m), 7.175(2H, m),5.807(1H, D, -NH), 5.355(1H, D, 3'-H), 5.117(1H, D, 2-H), 4.932-4.958(4H, m, 2'-H, -CH=CH-, 5-H), 4.685(1H, D, 20α-H), 4.474(1H, D, 20β-H), 3.986-4.011(2H, D, 15α-H, 15β-H), 3.571-3.829(3H, D, 3-H)3.197(4H, m, 6α-H, 4-COCH3), 2.670(1H, m, 13-H), 2.492(3H, t, 14α-H, -CH2CO-), 1.795(6H, S, -CH2CH=CHCH2-), 1.501(4H, S, 18-H), 1.379(10H, S, 16-H, 19-H, -CH2CH2CO-), 1.239(24H, t, 17-H), 0.958(3H, t, -CH3),0.850(5H, t, -CH2CH3).

[0108] MS(ESI) m / z for Or C 69 H 101 NO 17 SeNA [M+NA] + :1319.

[0109] Example 9: Preparation of PEG-modified small molecule prodrug self-assembled nanoparticles 0.4 mg DSPE-PEG 2k Accurately weighing 2 mg of prodrug and dissolving it in 200 μL of acetone, the resulting ethanol solution was slowly added dropwise to 1.8 mL of deionized water, resulting in the spontaneous formation of uniformly sized PEG-modified nanoparticles. The acetone was removed using rotary evaporation under reduced pressure, yielding a nanocolloidal solution free of organic reagents. As shown in Table 1, with the exception of the CTX-SS-AA nanoparticles, all nanoparticles were approximately 100 nm in diameter, had a particle size distribution of less than 0.2, and a surface charge of approximately -20 mV.

[0110] JPEG2025528763000016.jpg158138

[0111] The results showed that cabazitaxel prodrugs with different linkers and different fatty alcohol side chains could all form self-assembled nanoparticles, and the self-assembled nanoparticles of cabazitaxel branched fatty alcohol small molecule prodrugs had smaller particle sizes and particle size distributions than the self-assembled nanoparticles of cabazitaxel linear fatty alcohol small molecule prodrugs. The particle sizes of the self-assembled nanoparticles of cabazitaxel branched fatty alcohol small molecule prodrugs were all approximately 100 nm, with a very uniform particle size distribution of approximately 0.1 nm, which helped the nanoparticles achieve tumor targeting by utilizing their high permeability and retention in the tumor. The surface charge of the nanoparticles was approximately -20 mV, which advantageously utilized charge repulsion to prevent nanoparticle accumulation.

[0112] Example 10: Preparation of freeze-dried powder of small molecule prodrug self-assembled nanoparticles One mL of the PEGylated, monosulfide-linked cabazitaxel 2-octyldodecanol prodrug self-assembled nanoparticles prepared in Example 9 was placed in a syringe. The nanoparticles were freeze-dried for 24 hours in a lyophilizer using 5% sucrose, 10% sucrose, 5% lactose, 10% lactose, 5% trehalose, 10% trehalose, 5% mannitol, 10% mannitol, 5% glucose, and 10% glucose as lyoprotectants. The resulting lyophilized powder was reconstituted in deionized water, and the particle size and surface charge were measured. The results, shown in Table 2, demonstrate that the particle size and particle size distribution of the lyophilized prodrug self-assembled nanoparticles prepared with a single lyoprotectant were larger after reconstitution.

[0113] JPEG2025528763000017.jpg208159

[0114] Example 11: Preparation of self-assembled nanoparticle lyophilized powder of small molecule prodrug One mL of the PEGylated, monosulfide-linked cabazitaxel-2-octyldodecanol prodrug self-assembled nanoparticles prepared in Example 9 was placed in a syringe. The lyoprotectants were 5% lactose and 5% mannitol, 5% lactose and 5% maltose, 5% lactose and 5% sucrose, and 5% lactose and 5% trehalose. After the lyoprotectants were completely dissolved, they were pre-frozen at -80°C for 12 hours and then freeze-dried in a lyophilizer for 24 hours to obtain a white mass. The resulting lyophilized powder was redissolved in deionized water, and the particle size and surface charge were measured. The results are shown in Table 3. As shown, the lyophilized powder prepared with the combined lyophilizer resulted in smaller particle sizes after reconstitution compared to the lyophilized powder prepared with a single lyophilizer.

[0115] JPEG2025528763000018.jpg122150

[0116] Example 12: Pharmacokinetic study of small molecule prodrug self-assembled nanoparticles Twenty-four healthy male rats (weight 180-220 g) were randomly divided into four groups and fasted for 12 hours before administration with free access to water. Cabazitaxel solution and the PEG-modified prodrug self-assembled nanoparticles prepared in Example 9 were each injected via the tail vein at 4 mg / kg (equivalent to cabazitaxel). Blood samples were collected at the specified time points. Blood drug concentrations were measured using liquid chromatography-mass spectrometry (LC-MS). The results are shown in Table 4. The cabazitaxel solution had a short circulation time and was rapidly metabolized and eliminated in the body after administration. In contrast, the PEG-modified small molecule prodrug self-assembled nanoparticles exhibited significantly longer circulation times, significantly improved bioavailability, and significantly improved pharmacokinetic parameters. Overall AUC values ​​for CTX-SS-OD nanoparticles, CTX-Se-OD nanoparticles, and CTX-S-OD nanoparticles were 0.01 mg / kg. 0~24H (the sum of the prodrug and parent drug) were 395.47, 277.37, and 260.19 times that of the cabazitaxel solution, respectively, and t 1 / 2were 19.72, 10.16, and 11.51 times that of the cabazitaxel solution, respectively, and C mAX The pharmacokinetic parameters of CTX-SS-OD nanoparticles were 76.35-fold, 51.80-fold, and 51.18-fold higher than those of the cabazitaxel solution, respectively. The most significant improvement in the pharmacokinetic parameters of CTX-SS-OD nanoparticles was demonstrated, demonstrating the superiority of the disulfide bond as a linker.

[0117] JPEG2025528763000019.jpg124120

[0118] Example 13: In vivo antitumor experiments of PEGylated small molecule prodrug self-assembled nanoparticles Mouse breast cancer cell suspension (4T1, 5x10 6 CeLLS / 100 μL) was inoculated under the dorsal skin of female BALB / C mice. 3 Once tumors reached the tumor size, the mice were randomly divided into six groups of eight mice each: saline group, cabazitaxel solution group, CTX-SS-HU nanoparticle group, CTX-SS-HD nanoparticle group, CTX-SS-OD nanoparticle group, and CTX-SS-DT nanoparticle group. The nanoparticles used for administration were the PEG-modified self-assembling nanoparticles of small molecular prodrugs prepared in Example 9, administered at a dose of 10 mg / kg (equivalent to cabazitaxel). The administration was performed every other day for five consecutive doses. After administration, the mice were examined daily for survival and weight changes, and tumor volume was measured. Finally, the mice were sacrificed the day after drug administration, and organs and tumors were collected for further analysis. The results are shown in Figures 1 to 3. As shown in Figure 1, in the saline group, tumor volume grew rapidly, reaching approximately 1,000 mm by day 10. 3 In contrast, the nanoparticles and cabazitaxel solution all showed a significant improvement in tumor growth (<200 mm 3) was suppressed. As shown in Figure 2, the body weight of the cabazitaxel solution group decreased significantly, while that of the prodrug self-assembled nanoparticle group showed no significant change. As shown in Figure 3, all formulations in each group caused a decrease in the white blood cell count in the mice's blood. The CTX-SS-OD nanoparticle group and the CTX-SS-HU nanoparticle group showed the least decrease. The results demonstrated that the cabazitaxel-branched fatty alcohol small molecule prodrug self-assembled nanoparticles chemically linked by disulfide bonds possessed potent antitumor effects without causing significant systemic toxicity, making them a safe and effective chemotherapy drug delivery system.

[0119] Example 14: In vivo antitumor experiments of PEGylated small molecule prodrug self-assembled nanoparticles Mouse breast cancer cell suspension (4T1, 5x10 6 The cells (100 μL each) were inoculated subcutaneously into the dorsal skin of female BALB / C mice. The tumor volume was 100–120 mm. 3 Once tumors reached a certain size, the mice bearing the tumors were randomly divided into seven groups of eight mice each: saline group, CTX-SS-OD nanoparticles (2 mg / kg, 10 mg / kg, 20 mg / kg), and CTX-SS-AA nanoparticles (2 mg / kg, 10 mg / kg, 20 mg / kg). The nanoparticles used for administration were PEG-modified small molecule prodrug self-assembling nanoparticles prepared in Example 9, and the dose was calculated based on the cabazitaxel concentration. The administration was performed every other day for five consecutive doses. The mice were monitored daily for survival and weight changes, and tumor volumes were measured. The mice were then sacrificed the day after administration, and organs and tumors were collected for further analysis. The results are shown in Figures 4-8. As shown in Figure 4, tumor volume rapidly increased in the saline group, reaching approximately 1,000 mm by day 10. 3Although tumor growth was completely suppressed in the prodrug self-assembled nanoparticle group, tumor volume was smaller in the CTX-SS-OD nanoparticle group than in the CTX-SS-AA nanoparticle group at the same dose. Figure 5 shows that, at the same dose, the CTX-SS-AA nanoparticle group had a higher body weight than the CTX-SS-OD nanoparticle group. Figure 6 also shows that the prodrug self-assembled nanoparticle group had a lower tumor burden than the saline group. At the same dose, the CTX-SS-OD nanoparticles had a lower tumor burden than the CTX-SS-AA nanoparticles. Figure 7 shows that, at the same dose, the CTX-SS-OD nanoparticle group had a smaller decrease in white blood cell count. Figure 8 shows that, at a dose of 20 mg / kg, the CTX-SS-OD nanoparticle group had a smaller increase in urea nitrogen. The results indicate that cabazitaxel branched fatty alcohol small molecule prodrug self-assembled nanoparticles have a stronger antitumor effect and a better safety profile than cabazitaxel linear fatty alcohol small molecule prodrug self-assembled nanoparticles.

[0120] Example 15: In vivo antitumor experiments of PEGylated small molecule prodrug self-assembled nanoparticles Mouse breast cancer cell suspension (4T1, 5 × 10 6 Female BALB / C mice were inoculated subcutaneously into the back with 100-120 mm2 of 100 cells / 100 μL of 100 cells per ... 3 Once tumors had grown to a certain size, the mice bearing the tumors were randomly divided into five groups of eight mice each: saline group, cabazitaxel solution group, CTX-S-OD nanoparticle group, CTX-SS-OD nanoparticle group, and CTX-Se-OD nanoparticle group. The nanoparticles used for administration were the PEG-modified self-assembling nanoparticles of small molecule prodrugs prepared in Example 9, administered at a dose of 4 mg / kg (calculated cabazitaxel concentration). Administration was performed every other day for five consecutive days. The survival status and weight changes of the mice were checked daily, and tumor volume was measured. Finally, the mice were sacrificed the day after administration, and organs and tumors were collected for further analysis. The results are shown in Figures 9-11. As shown in Figure 9, tumor volume in the saline group grew rapidly, reaching approximately 700 mm by day 10. 3The tumor volume (<400 mm) of the CTX-S-OD nanoparticle group and the CTX-Se-OD nanoparticle group was 3 ), and the tumor volumes (<200 mm) of the CTX-SS-OD nanoparticle group and the cabazitaxel solution group were 3 ) was relatively small. Furthermore, as shown in Figure 10, no significant changes were observed in the body weight of the three nanoparticle groups, except for a significant decrease in the body weight of the cabazitaxel solution group. As shown in Figure 11, no statistically significant difference was observed between the tumor burden in the CTX-SS-OD nanoparticle group and the cabazitaxel solution group. The results showed that CTX-SS-OD nanoparticles had excellent antitumor effects and superior safety compared to the cabazitaxel solution. The use of disulfide bonds as a linker is more advantageous than monosulfide or monoselenium bonds.

[0121] Example 16: In vivo antitumor experiments of PEGylated small molecule prodrug self-assembled nanoparticles Mouse breast cancer cell suspension (4T1, 5 × 10 6 Female BALB / C mice were inoculated subcutaneously into the back with 100-120 mm2 of 100 cells / 100 μL ... 3 Once tumors reached the tumor size, the mice bearing the tumors were randomly divided into eight groups of eight mice each: saline group, cabazitaxel solution 2 mg / kg group, cabazitaxel solution 10 mg / kg group, cabazitaxel solution 15 mg / kg group, CTX-SS-OD nanoparticles 2 mg / kg group, CTX-SS-OD nanoparticles 10 mg / kg group, CTX-SS-OD nanoparticles 15 mg / kg group, and CTX-SS-OD nanoparticles 20 mg / kg group. The nanoparticles used for administration were PEG-modified small molecule prodrug self-assembling nanoparticles prepared in Example 9, and the dose was calculated based on the cabazitaxel concentration. The administration was performed every other day for five consecutive doses. The mice were examined daily for survival and weight changes, and tumor volumes were measured. Finally, the mice were sacrificed the day after drug administration, and organs and tumors were collected for further analysis. The results are shown in Figures 12-14. As shown in Figures 12 and 14, the tumor volume in the blank control group rapidly increased, reaching approximately 800 mm on day 10. 3At a dose of 2 mg / kg, the tumor volume and tumor burden in the CTX-SS-OD nanoparticle group were lower than those in the cabazitaxel solution group. At doses of 10 mg / kg and 15 mg / kg, the tumor volume and tumor burden in the CTX-SS-OD nanoparticle group were not statistically significantly different from those in the cabazitaxel solution group. As shown in Figure 13, at a dose of 2 mg / kg, there was no significant change in body weight between the CTX-SS-OD nanoparticle group and the cabazitaxel solution group. At a dose of 10 mg / kg, there was no change in body weight in the CTX-SS-OD nanoparticle group, and a decrease in body weight in the cabazitaxel solution group. At a dose of 15 mg / kg, all mice in the cabazitaxel solution group died, but none in the CTX-SS-OD nanoparticle group died. These results demonstrated that CTX-SS-OD nanoparticles have the same antitumor effect as cabazitaxel solution, but are less toxic than cabazitaxel solution.

[0122] Example 17: In vivo antitumor experiments of PEGylated small molecule prodrug self-assembled nanoparticles Mouse breast cancer cell suspension (4T1, 5 × 10 6 Female BALB / C mice were inoculated subcutaneously with 100-120 mm2 of 100 cells / 100 μL of the IgG1-positive cells into the dorsal skin. 3When tumors reached a normal size, the tumor-bearing mice were randomly divided into seven groups of eight mice each: saline group, CTX-SS-OD nanoparticles 20 mg / kg group, CTX-SS-OD nanoparticles 30 mg / kg group, CTX-SS-DT nanoparticles 20 mg / kg group, CTX-SS-DT nanoparticles 30 mg / kg group, γ-CTX-SS-OD nanoparticles 20 mg / kg group, and γ-CTX-SS-OD nanoparticles 30 mg / kg group. The nanoparticles used for administration were PEG-modified small molecule prodrug self-assembling nanoparticles prepared in Example 9, and the dose was calculated based on the cabazitaxel concentration. The drug was administered every other day for five consecutive doses. The mice were monitored daily for survival and weight changes, and tumor volumes were measured. Finally, after drug administration, the mice were sacrificed, and organs and tumors were collected for further analysis. The results are shown in Figures 15 and 16. As shown in Figure 15, all three nanoparticles demonstrated excellent antitumor effects, significantly inhibiting tumor growth. As shown in Figure 16, when the doses were the same, the γ-CTX-SS-OD group showed the least weight loss, and γ-CTX-SS-OD nanoparticles have a higher safety profile than CTX-SS-OD nanoparticles and CTX-SS-DT nanoparticles.

[0123] Example 18: Tolerance test of PEGylated small molecule prodrug self-assembled nanoparticles Female BALB / C mice were divided into 11 groups, each with three mice. Four groups received cabazitaxel solution at concentrations of 30 mg / kg, 40 mg / kg, 50 mg / kg, and 60 mg / kg via tail vein injections. The remaining seven groups received CTX-SS-HD nanoparticles, CTX-SS-HU nanoparticles, CTX-SS-OD nanoparticles, CTX-SS-DT nanoparticles, CTX-S-OD nanoparticles, CTX-SS-AA nanoparticles, and γ-CTX-SS-OD nanoparticles at a single dose of 200 mg / kg every 8 hours via tail vein injections. The dose was calculated based on the cabazitaxel concentration until all mice died. The survival status of mice after each injection is shown in Table 5. The results demonstrated that the prodrug self-assembled nanoparticles were significantly more tolerable than the cabazitaxel solution. Among the four nanoparticles containing branched fatty alcohol side chains, CTX-SS-HD nanoparticles, CTX-SS-HU nanoparticles, CTX-SS-OD nanoparticles, and CTX-SS-DT nanoparticles, CTX-SS-OD nanoparticles exhibited the highest safety profile, demonstrating the safety benefits of using 2-octyldodecanol as a side chain. Furthermore, when comparing nanoparticles with different side chain structures (branched or linear), CTX-SS-OD nanoparticles containing branched fatty alcohols exhibited superior nanoparticle safety compared to CTX-SS-AA nanoparticles containing linear fatty alcohols, demonstrating the safety benefits of branched fatty alcohols as side chains over linear fatty alcohols. When comparing linkers of different lengths, γ-CTX-SS-OD nanoparticles containing longer linkers exhibited superior safety compared to CTX-SS-OD nanoparticles, demonstrating the safety benefits of using 4,4'-dithiodibutyric acid as a linker. Among all nanoparticle formulations, γ-CTX-SS-OD nanoparticles had the highest maximum tolerated dose, 40 times higher than cabazitaxel solution.

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Claims

1. a cabazitaxel-branched fatty alcohol small molecule prodrug or a pharmaceutically acceptable salt thereof, wherein the branched fatty alcohol is any of 2-hexyl-octanol, 1-heptyl-octanol, 2-hexyl-decanol, 1-butyl-dodecanol, 1-heptyl-nonanol, 1-octyl-nonanol, 2-octyl-decanol, 2-heptyl-undecanol, 1-nonanol-decanol, 2-octyl-dodecanol, 2-decyl-tetradecanol, or 2-dodecyl-tetradecanol.

2. 2. The cabazitaxel-branched fatty alcohol small molecule prodrug or a pharmaceutically acceptable salt thereof according to claim 1, wherein the branched fatty alcohol is 2-hexyl-decanol, 2-heptyl-undecanol, 2-octyl-dodecanol, or 2-decyl-tetradecanol; the cabazitaxel and the branched fatty alcohol in the cabazitaxel-branched fatty alcohol small molecule prodrug are linked together via a dibasic acid linker, and the dibasic acid is a monothiodicarboxylic acid, a monoselenodiacid, or a dithiodicarboxylic acid, and the monothiodibasic acid is monothiodiacetic acid, monothiodipropionic acid, or monothiodibutyric acid; the monoselenodibasic acid is monoselenodiacetic acid, monoselenodipropionic acid, or monoselenodibutyric acid; or the dithiodibasic acid is 2,2'-dithiodiacetic acid, 3,3'-dithiodipropionic acid, or 4,4'-dithiodibutyric acid.

3. The cabazitaxel-branched fatty alcohol small molecule prodrug or pharmaceutically acceptable salt thereof according to claim 2, wherein the cabazitaxel-branched fatty alcohol small molecule prodrug or pharmaceutically acceptable salt thereof has the following structure:

4. The synthesis method of the cabazitaxel-branched fatty alcohol small molecule prodrug comprises the following steps: Step 1: A dibasic acid is dissolved in a dibasic acid anhydride, and then esterified with a branched fatty alcohol under the catalysis of 4-dimethylaminopyridine (DMAP) to obtain a branched fatty alcohol-diabasic acid monoester intermediate product, in which the molar ratio of DMAP:branched fatty alcohol:diabasic acid anhydride is 1:(1-10):(5-15), and the dibasic acid is a thiodibasic acid, a monoselenodibasic acid, or a dithiodibasic acid; Step 2: The cabazitaxel-branched fatty alcohol small molecule prodrug or a pharmaceutically acceptable salt thereof according to claim 3, wherein the branched fatty alcohol-diabasic acid monoester and cabazitaxel are subjected to an esterification reaction to obtain a cabazitaxel-branched fatty alcohol small molecule prodrug as a final product, in which the molar ratio of branched fatty alcohol-diabasic acid monoester to cabazitaxel is 1:(0.5-10), and the reaction scheme is as follows: Here, n and R are as defined in claim 3.

5. the self-assembled nanoparticles of cabazitaxel-branched fatty alcohol small molecule prodrug are self-assembled nanoparticles of non-PEGylated prodrugs, self-assembled nanoparticles of prodrugs modified with PEG / active targeting modifiers, or self-assembled nanoparticles of prodrugs carrying a hydrophobic fluorescent substance / drug; The method for preparing the self-assembled nanoparticles of cabazitaxel-branched fatty alcohol small molecule prodrug comprises the following steps: In the case of non-PEGylated cabazitaxel branched fatty alcohol small molecule prodrug self-assembled nanoparticles, the prodrug is dissolved in an organic solvent, and the solution is added dropwise to water under stirring. The prodrug spontaneously forms uniform nanoparticles. The organic solvent in the formulation is removed by vacuum rotary evaporation to obtain an organic solvent-free nanocolloid solution of non-PEGylated cabazitaxel branched fatty alcohol small molecule prodrug; For the PEG-modified / active targeting group-modified cabazitaxel-branched fatty alcohol small molecule prodrug self-assembled nanoparticles, the PEG modifier / active targeting modifier and prodrug are dissolved in an organic solvent, and the solution is added dropwise to water under stirring. The prodrug spontaneously forms uniform nanoparticles. The organic solvent in the formulation is removed by vacuum rotary evaporation to obtain an organic solvent-free nanocolloidal solution of PEG-modified / active targeting group-modified cabazitaxel-branched fatty alcohol small molecule prodrug self-assembled nanoparticles. The mass ratio of the cabazitaxel-branched fatty alcohol small molecule prodrug to the PEG modifier / active targeting modifier is 1:(1-0.1), the PEG modifier is DSPE-PEG, TPGS, PLGA-PEG, PE-PEG, or DSPE-PEG-FA, and the active targeting modifier is an antibody, a carbohydrate residue, a hormone, a receptor, or a ligand; For self-assembled nanoparticles of cabazitaxel-branched fatty alcohol small molecule prodrug loaded with a hydrophobic fluorescent substance / drug, the PEG modifier, the hydrophobic fluorescent substance / drug, and the prodrug are dissolved in an organic solvent, and the solution is added dropwise to water with stirring, causing the prodrug to spontaneously form uniform nanoparticles. The organic solvent in the formulation is removed by vacuum rotary evaporation to obtain an organic solvent-free nanocolloidal solution, in which the mass ratio of the cabazitaxel-branched fatty alcohol small molecule prodrug to the PEG modifier and the hydrophobic fluorescent substance / drug is 1:(0.1-1):(0.1-1); 2. The cabazitaxel-branched fatty alcohol small molecule prodrug or a pharmaceutically acceptable salt thereof according to claim 1, wherein the self-assembled nanoparticles of cabazitaxel-branched fatty alcohol small molecule prodrug can be prepared into a lyophilized powder injection, the lyophilized powder injection comprising a cabazitaxel-branched fatty alcohol small molecule prodrug self-assembled nanoparticle solution and a lyoprotectant, the self-assembled nanoparticle solution having a concentration of 0.1 mg / mL to 20 mg / mL, the lyoprotectant being one or more of glucose, galactose, trehalose, sucrose, mannitol, sorbitol, xylitol, polyethylene glycol, hydroxyethyl starch, and dextran, and the lyoprotectant having a concentration of 1% to 20% (W / V).

6. 10. The cabazitaxel-branched fatty alcohol small molecule prodrug, or a pharmaceutically acceptable salt thereof, according to claim 1, for use in the manufacture of an antitumor drug, for use in an injectable, oral or topical drug system, or for use in the manufacture of a drug delivery system with improved efficacy and reduced toxicity.

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