CN108066770B - Amphiphilic polymer prodrug capable of releasing original drug in reduction response manner and preparation method thereof - Google Patents

Abstract

The invention relates to an amphiphilic polymer prodrug capable of releasing original drugs in a reduction response manner and a preparation method thereof. The hydrophilic polymer and the hydrophobic drug in the amphiphilic polymer prodrug are linked through the connecting arm containing the self-destruction disulfide bond, the disulfide bond is broken in a tumor cell reduction environment to generate molecular rearrangement, original drug molecules are released, the activity of the drug is ensured, and the amphiphilic polymer prodrug can be self-assembled into nano-micelles in an aqueous medium, so that long-acting circulation in vivo is expected to be realized, accumulation in tumor tissues is improved, and the aims of improving the curative effect of the drug and reducing toxic and side effects are fulfilled.

Description

Amphiphilic polymer prodrug capable of releasing original drug in reduction response manner and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to an amphiphilic prodrug capable of releasing original medicine in a reduction response manner and formed by a hydrophilic polymer and a hydrophobic medicine, and a preparation method thereof.

Background

Chemotherapy is a basic method for treating tumors, and mainly aims to kill tumor cells by using anticancer drugs to treat tumors. Clinically common anticancer drugs mainly comprise camptothecins, taxanes, vinblastine, anthraquinones and the like, and the anticancer drugs have poor physicochemical properties (such as poor solubility in water, poor selectivity and the like), have serious toxic and side effects on normal cells and tissues, and cause poor tumor chemotherapy effect, so the clinical application is limited.

Hydrophilic groups are introduced through chemical modification to prepare the water-soluble prodrug, so that the water-solubility problem of the drug can be effectively solved. Among water-soluble high molecular polymers, polyethylene glycol has attracted much attention. Polyethylene glycol is a polymer material with excellent biocompatibility, and has been approved by the FDA in the united states as one of pharmaceutical polymers that can be injected in vivo. After the medicine is modified by polyethylene glycol, the water solubility and the in vivo stability are improved, the renal clearance rate can be obviously reduced, the blood circulation time is greatly prolonged, the accumulation of a tumor part can be enhanced through the EPR effect, and the effects of improving the tumor treatment effect and reducing the toxic and side effects are all very important.

In recent years, the nano drug delivery system has attracted wide attention with its excellent characteristics, and the nano drug delivery system has the characteristics of greatly improving the water solubility of the drug, realizing passive targeting on tumors by improving the permeability and retention Effect (EPR), prolonging the circulation time in vivo, improving the utilization rate of the drug, reducing toxic and side effects and the like. However, the common nanometer preparation can not identify the tumor part and the normal part, and can not distinguish the environment inside and outside the cell, so that how to make the nanometer preparation selectively release the original medicine in vivo is still a great problem.

It was found that the intracellular glutathione concentration (0.5 to 10 mM/L) is 200 times or more the extracellular glutathione concentration (2 to 20. Mu.M/L), and that disulfide bonds are reduced to thiol groups in the presence of a reducing agent such as Glutathione (GSH) or Dithiothreitol (DTT) in a certain amount, but are very stable under the conditions of normal body temperature, p H, oxidation and the like of the human body, that is, the extracellular glutathione concentration is insufficient to reduce disulfide bonds, and that tumor tissue cells are anoxic compared with normal tissue cells and have a reducing environment. Therefore, the hydrophilic polymer and the hydrophobic drug can be linked through disulfide bonds and self-assembled into nano-micelles in a solvent, and the nano-micelles enter target cells through endocytosis and are reduced by GSH (glutathione) to generate sulfydryl, so that the drug is quickly and effectively released and diffused to structures such as cell nucleuses, and cancer cells are killed. The most commonly used disulfide linker arm at present is mainly 3,3 '-dithiodipropionic acid, and 3, 3' -dithiodipropionic acid is used as a prodrug of the linker arm, and under the reducing conditions of GSH, DTT and the like, the disulfide bond is rapidly broken, but the released drug usually carries a "tail" rather than an original drug molecule.

Disclosure of Invention

One of the purposes of the invention is to provide an amphiphilic polymer prodrug which can release original medicine in a reduction response manner, thereby achieving the effects of increasing water solubility, targeting tumor and reducing toxicity.

The second purpose of the invention is to provide a preparation method of the amphiphilic polymer prodrug capable of releasing the original drug in a reduction response manner.

The invention also aims to provide a nano micelle preparation of the amphiphilic polymer prodrug capable of releasing the original drug in a reduction response manner.

The fourth purpose of the invention is to provide the application of the amphiphilic polymer prodrug capable of releasing the original drug in a reduction response manner in the preparation of antitumor drugs.

The technical solution of the invention is as follows:

the invention provides an amphiphilic polymer prodrug for releasing original drugs through reduction response, which is characterized in that polyethylene glycol and hydrophobic drugs are combined through a connecting arm containing a self-destruction disulfide bond, and the precursor has the following general formula:

wherein n is 5 to 400; m is 1 or 2; r is hydrophobic antitumor drug.

R is an antitumor drug containing a hydroxyl structural group, and comprises camptothecin (camptothecin, irinotecan, topotecan, 10-hydroxycamptothecin, 7-ethyl-10-hydroxycamptothecin and the like), taxane (paclitaxel, docetaxel, cabazitaxel and the like) or vinblastine (vinblastine, vincristine, vinorelbine and the like) and the like.

The invention provides an amphiphilic polymer prodrug capable of releasing original drug in a reduction response mode, wherein m is 1, and the amphiphilic polymer prodrug has the following general formula:

wherein the average molecular weight of the polyethylene glycol is 500-20,000 daltons; the connecting bond is a small molecule connecting arm containing a disulfide bond.

The preparation method of the amphiphilic polymer prodrug capable of releasing the original drug in a reduction response manner comprises the following steps:

(1) 4-bromobutyric acid reacts with thiourea to obtain 4-mercaptobutyric acid;

(2) Reacting dithiodipyridine with the 4-mercaptobutyric acid obtained in the step (1) to obtain disulfide bond-containing 4- (2-pyridyldithio) butyric acid;

(3) Condensing the disulfide bond-containing 4- (2-pyridyl disulfide group) butyric acid obtained in the step (2) and a hydrophobic anti-tumor drug under the action of a catalyst to obtain a 4- (2-pyridyl disulfide group) butyric acid drug conjugate;

(4) And (4) carrying out sulfydryl-disulfide bond exchange reaction on the 4- (2-pyridyl-disulfide group) butyric acid drug conjugate obtained in the step (3) and sulfhydrylation polyethylene glycol to obtain a disulfide bond-containing polyethylene glycol anticancer prodrug, namely an amphiphilic polymer prodrug capable of releasing original drugs in a reduction response manner.

Specifically, the step (1) comprises the following reaction steps: adding 4-bromobutyric acid and thiourea into ethanol according to the mol ratio of 1-1 to 1, refluxing for 2-8 hours, then adding NaOH ethanol solution, continuously refluxing for 6-20 hours, cooling, filtering, dissolving, washing with ether, separating, adjusting pH, extracting and drying to obtain 4-mercaptobutyric acid;

the step (2) comprises the following reaction steps: dissolving 4-mercaptobutyric acid and dipyridyl disulfide in methanol according to a molar ratio of 1-1;

the step (3) comprises the following reaction steps: dissolving a hydrophobic anti-tumor drug and 4- (2-pyridyl disulfide group) butyric acid in DMF according to the molar ratio of 1 to 1;

the step (4) comprises the following reaction steps: under the protection of nitrogen, dropwise adding thiolated polyethylene glycol into a DMF (dimethyl formamide) solution of the 4- (2-pyridyl disulfide group) butyric acid drug conjugate under the stirring condition, reacting at room temperature for 12-36 hours, concentrating, purifying by a silica gel column, concentrating, dissolving, filtering and freeze-drying to obtain the polyethylene glycol anticancer drug precursor containing disulfide bonds, wherein the molar ratio of the thiolated polyethylene glycol to the 4- (2-pyridyl disulfide group) butyric acid drug conjugate is 1.

The preparation method of the polymer prodrug in the form of the nano micelle comprises the following steps:

the polymer nano micelle is prepared by a solvent volatilization film hydration method. Specifically, adding the polymer prodrug into ethanol for dissolving, performing reduced pressure rotary evaporation to dryness under the condition of 40-50 ℃ water bath, adding water for hydration under the condition of 50-60 ℃ water bath after the ethanol is volatilized, filtering a membrane after the hydration is completed, and adding mannitol for freeze drying to obtain the reduction response type polymer nano micelle.

The invention also provides the application of the amphiphilic polymer prodrug capable of releasing original drug in a reduction response manner in the preparation of antitumor drugs. The tumor is colorectal cancer or breast cancer. Taking 7-ethyl-10-hydroxycamptothecin as an example, the mechanism of releasing original drug molecules in reductive response is shown as follows:

the specific drug release mechanism of the amphiphilic polymer prodrug capable of releasing the original drug in a reduction response manner is as follows: under the action of a reducing agent, a disulfide bond is broken to generate a free sulfhydryl group, and under the influence of structural stability factors, the sulfhydryl group attacks an adjacent ester bond through nucleophilic attack to generate a stable five-membered ring or six-membered ring structure and release a raw drug molecule at the same time.

Compared with the prior art, the invention has the advantages that:

1. the invention adopts the thinking of tumor microenvironment targeted drug delivery, and by introducing the self-destruction disulfide bond connecting arm sensitive to the reducing environment, the disulfide bond is broken in the specific reducing environment (GSH) of the tumor tissue, the molecular rearrangement occurs, and simultaneously the anti-cancer drugs are quickly released in the form of original drug molecules, thereby exerting the specific anti-tumor effect; not only retains the advantages of the nano drug-carrying system, but also exerts the characteristic of specific degradation of disulfide bonds at tumor sites. As compared with the conventional linker arm of 3, 3' -dithiodipropionic acid or the like, an anticancer drug in the form of a bulk drug molecule can be obtained without further hydrolysis.

2. The amphiphilic polymer prodrug obtained by the invention can be spontaneously assembled into a nano micelle in a solvent.

3. The preparation method of the amphiphilic polymer prodrug capable of releasing the original drug in a reduction response manner, which is provided by the invention, has the advantages of easily available raw materials, mild reaction conditions, high yield, high product purity and the like, and is beneficial to batch production.

Drawings

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of 4-mercaptobutanoic acid prepared in example 1;

FIG. 2 is a NMR hydrogen spectrum (FIG. 2A) and a mass spectrum (FIG. 2B) of 4- (2-pyridyldithio) butanoic acid prepared in example 1;

FIG. 3 is a NMR hydrogen spectrum (FIG. 3A) and mass spectrum (FIG. 3B) of 4- (2-pyridyldithio) butanoic acid conjugate with SN-38 prepared in example 1;

FIG. 4 is a NMR spectrum of the PEG-disulfide-SN 38 prodrug prepared in example 1;

FIG. 5 is an HPLC chromatogram demonstrating release of prodrug in polyethylene glycol-disulfide-SN 38 prodrug reduction response;

FIG. 6 is a mechanism of release of SN-38 prodrug by PEG-disulfide-SN 38 prodrug reduction response;

FIG. 7 is a graph showing a distribution of particle sizes of the polyethylene glycol-disulfide bond-SN 38 micelles prepared in example 7;

FIG. 8 is a transmission electron microscope image of the polyethylene glycol-disulfide bond-SN 38 micelle prepared in example 7;

FIG. 9 shows the proliferation inhibitory activity of the PEG-disulfide-SN 38 micelle prepared in example 7 with SN-38 on colorectal cancer cells HCT116 (FIG. 9A), HT29 (FIG. 9B);

FIG. 10 is a graph showing the proliferation inhibitory activity of the polyethylene glycol-disulfide-SN 38 micelle and SN-38 prepared in example 7 on breast cancer MCF-7.

Detailed Description

The invention is further illustrated and explained by the following examples, which are not to be construed as limiting the invention.

Example 1 Synthesis of polyethylene glycol-disulfide-SN 38

(1) Preparation of 4-mercaptobutyric acid:

4-Bromobutyric acid (10 g,59.9 mmol) and thiourea (6.37 g,83.8 mmol) were added to 250 mL of ethanol and refluxed for 4 hours. NaOH (24 g,600 mmol) was dissolved in 250 mL of ethanol, added to the reaction system, and refluxed for 16 hours. Cooled to room temperature, filtered to give a white solid, which was dissolved in water. The aqueous phase was washed with ether, separated, adjusted to pH 1 with 2M HCl, extracted with ether, dried over anhydrous sodium sulfate and dried in vacuo to give 4.9 g of a pale yellow oil in 68% yield. Of the product detected ¹ H NMR showed that 4-mercaptobutyric acid of the structure shown in formula a is obtained, as shown in FIG. 1.

(2) Preparation of 4- (2-pyridyldithio) butanoic acid:

4-Mercaptobutyric acid (4.9 g,40.8 mmol) and dithiodipyridine (Py-SS-Py, 18 g,81.7 mmol) were dissolved in 60 mL of methanol and reacted at room temperature for 3 hours. The methanol was evaporated under reduced pressure, separated on a neutral alumina column, concentrated and dried in vacuo to give 5.4 g of a pale yellow oil in 58% yield. Of the product detected ¹ H NMR showed 4- (2-pyridyldithio) butanoic acid of the structure shown in formula B to be obtained as shown in FIGS. 2A and 2B.

(3) Preparation of 4- (2-pyridyldithio) butanoic acid conjugate with SN-38:

SN-38 (2.0 g,5.1 mmol), 4- (2-pyridyldithio) butanoic acid (1.3 g,5.6 mmol), 4-dimethylaminopyridine (DMAP, 0.80 g,6.5 mmol), N, N-Diisopropylethylamine (DIEA, 1.1 mL,6.5 mmol) was dissolved in 160 mL of DMF, and 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 1.25 g,6.5 mmol) was added under ice-bath and reacted at room temperature for 48 hours. Dichloromethane (DCM) was added to the reaction solution, and the organic phase was washed with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine in this order, separated, dried, and then the solvent was evaporated under reduced pressure. Purification by silica gel column, concentration and vacuum drying gave 2.3 g of yellow solid with a yield of 75%. Of the product detected ¹ H NMR indicated that a conjugate of 4- (2-pyridyldithio) butanoic acid and SN-38 (Py-SS-SN 38) having the structure shown in formula c was obtained, as shown in FIGS. 3A and 3B.

(4) Preparation of polyethylene glycol-disulfide-SN 38:

mixing mPEG ₂₀₀₀ -SH (4.9 g,2.4 mmol) is dissolved in 100 mL DMF and a solution of Py-SS-SN38 (1.8 g,2.9 mmol) in DMF (100 mL) is added dropwise with stirring under nitrogen and allowed to react at room temperature for 24 hours. The DMF was evaporated under reduced pressure, purified by silica gel column, concentrated, dissolved in water, filtered and the filtrate was lyophilized to give 3.2 g of a pale yellow solid with a yield of 53%. Of the product detected ¹ H NMR, which showed that the polyethylene glycol-disulfide-SN 38 of formula d was obtained, as shown in FIG. 4.

The synthetic route is as follows:

the disulfide bond of the polyethylene glycol-disulfide bond-SN 38 is broken under the condition of reducing the glutathione in the tumor tissue, the molecular rearrangement occurs, and meanwhile, the medicine is released in the form of original medicine molecules. The reduction response of the polyethylene glycol-disulfide bond-SN 38 prodrug to release the original drug molecule is verified by adopting high performance liquid chromatography, as shown in figure 5.

Example 2 Synthesis of different molecular weight polyethylene glycol-disulfide-SN 38

The synthesis is as in example 1, with mPEG ₁₀₀₀ -SH or mPEG ₅₀₀₀ -SH substitution mPEG ₂₀₀₀ -SH, resulting in polyethylene glycol-disulfide-SN 38 conjugates of different molecular weights.

Example 3 Synthesis of polyethylene glycol-disulfide bond-cabazitaxel

(1) Preparation of 5- (2-pyridyldithio) pentanoic acid:

5-Bromopentanoic acid (2 g,11 mmol) and thiourea (1.18 g,15.5 mmol) were added to 60 mL of ethanol and refluxed for 4 hours. NaOH (4.4 g,110 mmol) was dissolved in 60 mL of ethanol, added to the reaction and refluxed for an additional 16 hours. Cooled to room temperature, filtered to give a white solid, which was dissolved in water. The aqueous phase was washed with ether, separated, adjusted to pH 1 with 2M HCl, extracted with ether, dried over anhydrous sodium sulfate and dried in vacuo to give 0.88 g of a pale yellow oil.

(2) The pale yellow oil and dithiodipyridine (Py-SS-Py, 2.9 g,13.1 mmol) were dissolved in 30 mL of methanol and reacted at room temperature for 3 hours. The methanol was evaporated under reduced pressure, separated on a neutral alumina column, concentrated and dried in vacuo to give 1.04 g of a pale yellow oil. The yield of the two-step reaction was 39%. Of the product detected ¹ H NMR showed that 5- (2-pyridyldithio) pentanoic acid of formula e was obtained.

(3) Preparation of 5- (2-pyridyldithio) pentanoic acid conjugate with cabazitaxel:

cabazitaxel (1.0 g,1.2 mmol), 5- (2-pyridyldithio) pentanoic acid (0.3 g,1.3 mmol), 4-dimethylaminopyridine (DMAP, 0.18 g,1.5 mmol), N, N-diisopropylethylamine (DIEA, 0.25 mL,1.5 mmol) were dissolved in 50 mL of DMF, and 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 0.3 g,1.5 mmol) was added under ice-cooling and reacted at room temperature for 48 hours. Dichloromethane (DCM) was added to the reaction solution, and the organic phase was washed with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine in this order, subjected to liquid separation, dried, and evaporated under reduced pressure to remove the solvent. Purification by silica gel column, concentration and vacuum drying gave 0.95 g of yellow solid with a yield of 75%. Of the product detected ¹ H NMR indicated that a conjugate of 5- (2-pyridyldithio) pentanoic acid and cabazitaxel (Py-SS-cabazitaxel) with the structure shown as the formula f was obtained.

(4) Preparation of polyethylene glycol-disulfide-cabazitaxel:

mixing mPEG ₂₀₀₀ -SH (1.0 g,0.5 mmol) is dissolved in 30 mL DMF, and a solution of Py-SS-cabazitaxel (0.64 g,0.6 mmol) in DMF (30 mL) is added dropwise with stirring under nitrogen protection, and the reaction is carried out at room temperature for 24 hours. The DMF was evaporated under reduced pressure, purified by silica gel column, concentrated, dissolved in water, filtered and the filtrate was lyophilized to give 0.88 g of a pale yellow solid with a yield of 60%. Of the product detected ¹ H NMR shows that the polyethylene glycol-disulfide bond-cabazitaxel with the structure shown in the formula g is obtained.

The synthetic route is shown as follows:

example 4 Synthesis of different molecular weight polyethylene glycol-disulfide bond-cabazitaxel

The synthesis is as in example 3, in which mPEG is used ₁₀₀₀ -SH or mPEG ₅₀₀₀ -SH substitution mPEG ₂₀₀₀ and-SH to obtain polyethylene glycol-disulfide bond-cabazitaxel conjugates with different molecular weights.

Example 5 Synthesis of polyethylene glycol-disulfide bond-vinorelbine

(1) Preparation of 4- (2-pyridyldithio) butanoic acid conjugate with vinorelbine:

4- (2-Pyridyldiphenyl) butanoic acid was prepared in the same manner as in example 1. Vinorelbine (2.0 g,2.6 mmol), 4- (2-pyridyldithio) butanoic acid (0.66 g,2.9 mmol), 4-dimethylaminopyridine (DMAP, 0.40 g,3.3 mmol), N, N-diisopropylethylamine (DIEA, 0.55 mL,3.3 mmol) were dissolved in 160 mL of DMF and 1-ethyl-3- (dimethylaminopropyl) carbonyldiimine hydrochloride (EDCI, 0.62 g,3.3 mmol) was added under ice bath and reacted at room temperature for 48 hours. Dichloromethane (DCM) was added to the reaction solution, and the organic phase was washed with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine in this order, separated, dried, and then the solvent was evaporated under reduced pressure. Purification by silica gel column, concentration and vacuum drying gave 1.5 g of yellow solid with a yield of 58%. Of the product detected ¹ H NMR showed that the conjugate of 4- (2-pyridyldithio) butanoic acid and vinorelbine (Py-SS-long) having the structure shown in formula H was obtainedShoyuabine).

(4) Preparation of polyethylene glycol-disulfide-vinorelbine:

mixing mPEG ₂₀₀₀ -SH (2.0 g,1.0 mmol) is dissolved in 50 mL DMF and a solution of Py-SS-vinorelbine (1.2 g,1.2 mmol) in DMF (50 mL) is added dropwise with stirring under nitrogen and reacted at room temperature for 24 hours. The DMF was evaporated under reduced pressure, purified by silica gel column, concentrated, dissolved in water, filtered, and the filtrate was lyophilized to give 1.2 g of an off-white solid with a yield of 42%. Of the product detected ¹ H NMR indicates that the polyethylene glycol-disulfide bond-vinorelbine with the structure shown in the formula i is obtained.

The synthetic route is shown as follows:

example 6 Synthesis of different molecular weight polyethylene glycol-disulfide-vinorelbine

The synthesis is as in example 5, in which mPEG is used ₁₀₀₀ -SH or mPEG ₅₀₀₀ -SH substitution of mPEG ₂₀₀₀ -SH, yielding polyethylene glycol-disulfide-vinorelbine conjugates of different molecular weights.

Example 7 preparation and characterization of polyethylene glycol-disulfide-SN 38 micelles

The polymer nano micelle is prepared by a solvent volatilization film hydration method. Dissolving the polymer prodrug prepared in the embodiment 1 in ethanol, performing reduced pressure rotary evaporation at 40 ℃ in a water bath, adding water to hydrate at 55 ℃ in the water bath after the ethanol is volatilized, filtering by a filter membrane after the hydration is completed, and adding mannitol for freeze drying to obtain the reduction response type polymer nano micelle. The particle size and distribution of the nano-micelle are determined by Dynamic Light Scattering (DLS), as shown in fig. 7; and the morphology of the polymer nano-micelle was observed with a Transmission Electron Microscope (TEM), as shown in fig. 8.

Example 8 inhibition of colorectal cancer cell proliferation by polyethylene glycol-disulfide-SN 38 micelles

The polyethylene glycol-disulfide bond-SN 38 micelle prepared in example 7 and SN-38 were subjected to a comparative test for the in vitro anti-tumor cell effect. Taking colorectal cancer HCT116 and HT29 as examples, cells in logarithmic growth phase were seeded in 96-well plates at an appropriate cell density, 100. Mu.l/well, and cultured at 37 ℃ in a 5% CO2 incubator. After overnight culture, the drug was administered for 48 h. A blank group and an administration group are respectively arranged, and each group is provided with 4 multiple holes. The in vitro anti-colorectal cancer effect is shown in fig. 9A and 9B. As can be seen from FIGS. 9A and 9B, PEG-disulfide-SN 38 has similar cytotoxicity to SN-38, and PEG-disulfide-SN 38 has half-lethal dose IC50 of 0.219 μ M for colorectal cancer HCT116 and half-lethal dose IC50 of 1.67 μ M for colorectal cancer HT29, and has strong antitumor activity.

Example 9 experiment on inhibition of proliferation of Breast cancer cell by polyethylene glycol-disulfide bond-SN 38 micelle

The polyethylene glycol-disulfide bond-SN 38 micelle prepared in example 7 and SN-38 were subjected to a comparative test for the effect of anti-tumor cells in vitro. Taking MCF-7 as an example of breast cancer, cells in the logarithmic growth phase were taken, and inoculated in a 96-well plate at an appropriate cell density, 100. Mu.l/well, cultured at 37 ℃ in an incubator containing 5% CO2. After overnight culture, the drug was administered for 48 h. A blank group and an administration group are respectively arranged, and each group is provided with 4 multiple holes. The effect against breast cancer cells in vitro is shown in figure 10. As can be seen from FIG. 10, PEG-disulfide-SN 38 has similar cytotoxicity to SN-38, and PEG-disulfide-SN 38 has a median lethal IC50 of 2.80. Mu.M for breast cancer MCF-7.

Claims (4)

1. An amphiphilic polymer prodrug capable of releasing original drugs in a reduction response manner is characterized by having a structural general formula as follows:

，

wherein n is 5 to 400; m is 1 or 2, when m is 1, R is SN-38 or vinorelbine, and when m is 2, R is cabazitaxel.

2. The method of preparing an amphiphilic polymeric prodrug that releases a prodrug in a reductive response as claimed in claim 1, wherein m is 1, comprising the steps of:

(1) 4-bromobutyric acid reacts with thiourea to obtain 4-mercaptobutyric acid;

(2) Reacting dithiodipyridine with the 4-mercaptobutyric acid obtained in the step (1) to obtain disulfide bond-containing 4- (2-pyridyldithio) butyric acid;

(3) Condensing the disulfide bond-containing 4- (2-pyridyl disulfide group) butyric acid obtained in the step (2) and a hydrophobic anti-tumor drug under the action of a catalyst to obtain a 4- (2-pyridyl disulfide group) butyric acid drug conjugate;

(4) And (4) carrying out sulfydryl-disulfide bond exchange reaction on the 4- (2-pyridyl-disulfide group) butyric acid drug conjugate obtained in the step (3) and sulfhydrylation polyethylene glycol to obtain a disulfide bond-containing polyethylene glycol anticancer prodrug, namely an amphiphilic polymer prodrug capable of releasing original drugs in a reduction response manner.

3. The method of preparing an amphiphilic polymer prodrug of a reductive response releasing drug according to claim 2, wherein:

the step (1) comprises the following reaction steps: adding 4-bromobutyric acid and thiourea into ethanol according to a molar ratio of 1-1;

the step (2) comprises the following reaction steps: dissolving 4-mercaptobutyric acid and dipyridyl disulfide in methanol according to a molar ratio of 1-1;

the step (3) comprises the following reaction steps: dissolving a hydrophobic anti-tumor drug and 4- (2-pyridyldithio) butyric acid in a molar ratio of 1 to 1 in DMF (dimethyl formamide) in the presence of a condensing agent and organic amine, reacting at room temperature for 36 to 72 hours, and performing acid washing, neutralization, liquid separation, drying, silica gel column purification, concentration and vacuum drying on a reaction solution to obtain a 4- (2-pyridyldithio) butyric acid drug conjugate;

the step (4) comprises the following reaction steps: under the protection of nitrogen, dropwise adding thiolated polyethylene glycol into a DMF (dimethyl formamide) solution of the 4- (2-pyridyl disulfide group) butyric acid drug conjugate under the stirring condition, reacting at room temperature for 12-36 hours, concentrating, purifying by a silica gel column, concentrating, dissolving, filtering and freeze-drying to obtain the polyethylene glycol anticancer drug precursor containing disulfide bonds, wherein the molar ratio of the thiolated polyethylene glycol to the 4- (2-pyridyl disulfide group) butyric acid drug conjugate is 1.

4. Use of the amphiphilic polymer prodrug of a reductive response releasing prodrug of claim 1 in the manufacture of an anti-colorectal cancer drug or an anti-breast cancer drug.

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