Adriamycin chiral polyurethane delivery micelle as well as preparation and application thereof

Abstract

The invention discloses a doxorubicin chiral polyurethane delivery micelle as well as preparation and application thereof. The doxorubicin chiral polyurethane delivery micelle comprises a micelle carrier and doxorubicin, wherein the micelle carrier is formed by self-assembly of an amphiphilic polymer, and the doxorubicin is entrapped in the micelle carrier; the amphiphilic polymer comprises a hydrophobic chain segment and a hydrophilic chain segment which are covalently connected through a dynamic borate bond; the hydrophilic chain segment contains methoxy polyethylene glycol gallate; the hydrophobic chain segment comprises a hydrophobic chiral polyurethane main chain and a coumarin-phenylboronic acid conjugate covalently grafted to the hydrophobic chiral polyurethane main chain, and the hydrophobic chiral polyurethane main chain is formed by alternately connecting chiral binaphthol units and isophorone diisocyanate units; according to the doxorubicin chiral polyurethane delivery micelle, the water solubility of doxorubicin is improved, targeted release of doxorubicin can be achieved through pH and ROS response, side effects are reduced, and the affinity of cells to the doxorubicin chiral polyurethane delivery micelle is increased by using chiral binaphthol as a skeleton component.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical pharmaceutical preparations, and particularly relates to an adriamycin chiral polyurethane delivery micelle and its preparation and application. Background Art

[0002] DOX, an anthracycline antibiotic, is isolated from the pigment of Streptomyces ( Streptomyces peucetius var. Caesius ). It has broad-spectrum antitumor activity. However, in clinical applications, adriamycin (DOX) faces many challenges. The first problem is related to the concentration-dependent toxicity of adriamycin and its side effects on other organs and tissues of the body, especially the heart. Another problem is the lack of specific delivery of adriamycin to tumor tissues, which greatly reduces its potential in cancer suppression, prompting researchers to find solutions. Using different polymeric carriers (such as micelles) for delivery is one of the solution strategies. For example: Literature reports that Zhang et al. synthesized LMWH-ATRA polymer (LHR) by formic acid modification of low molecular weight heparin (LMWH), and the prepared DOX / LHR micelles have good physicochemical properties and in vitro antitumor characteristics. Its successful preparation will help improve the antitumor effect of DOX. Chen et al. We used three different polymeric polymers, polyethylene glycol (PEG), polycaprolactone (PCL), and Pluronic P105, to prepare and synthesize adriamycin-loaded micelles to deliver celastrol.

[0003] For the delivery of antitumor drugs by nano-micelles, due to various factors such as poor nano-stability, low drug loading rate, insufficient cell uptake, etc., even if the toxic and side effects of some drugs are improved, their therapeutic effects are greatly reduced, falling short of expectations, and it is easy to produce toxic and side effects.

[0004] Therefore, there is a need to provide a solution to increase the cell uptake of adriamycin nano-drugs while minimizing its toxicity. Summary of the Invention

[0005] In view of this, the present application provides an adriamycin chiral polyurethane delivery micelle and its preparation and application, which are used to solve the problem of how to improve the chemotherapy effect and safety of traditional adriamycin nano-drugs.

[0006] To achieve the above technical objectives, the present application adopts the following technical solutions: In the first aspect, the present application provides an adriamycin chiral polyurethane delivery micelle, including: A micelle carrier formed by self-assembly of an amphiphilic polymer and doxorubicin encapsulated in the micelle carrier; the amphiphilic polymer comprises a hydrophobic segment and a hydrophilic segment covalently linked by a dynamic borate ester bond; the hydrophilic segment comprises methoxypolyethylene glycol gallate; the hydrophobic segment comprises a hydrophobic chiral polyurethane backbone and a coumarin-phenylboronic acid conjugate covalently grafted to the hydrophobic chiral polyurethane backbone, and the hydrophobic chiral polyurethane backbone is formed by alternating connection of chiral binaphthol units and isophorone diisocyanate units.

[0007] Preferably, the chiral binaphthol unit is selected from R-BINOL, Racemic-BINOL or S-BINOL, and the hydrophobic chiral polyurethane backbone formed by the chiral binaphthol unit is correspondingly selected from one of R-CPCA, Racemic-CPCA or S-CPCA.

[0008] Preferably, the drug loading rate of doxorubicin is 30-45%.

[0009] In a second aspect, the present application provides a method for preparing a doxorubicin chiral polyurethane delivery micelle, comprising the following steps: Dissolve 7-hydroxy-3-carboxycoumarin and 3-aminophenylboronic acid in a first solvent, and carry out a coupling reaction to obtain a coumarin-phenylboronic acid conjugate; Under an inert atmosphere, dissolve chiral binaphthol and isophorone diisocyanate in a second solvent, and carry out a polymerization reaction to obtain an NCO-terminated hydrophobic chiral polyurethane backbone; Under an inert atmosphere, dissolve the hydrophobic chiral polyurethane backbone and the coumarin-phenylboronic acid conjugate in a third solvent, and carry out a grafting reaction to obtain a hydrophobic segment; Under anhydrous vacuum and the action of a catalyst, dissolve methoxypolyethylene glycol and gallic acid in a fourth solvent, and carry out an esterification reaction to obtain methoxypolyethylene glycol gallate, that is, a hydrophilic segment; Dissolve methoxypolyethylene glycol gallate and the hydrophobic segment in an organic solvent, add triethylamine, and carry out a condensation reaction and self-assembly to obtain a micelle carrier; Mix doxorubicin with the micelle carrier, and after stirring and reacting, obtain a doxorubicin chiral polyurethane delivery micelle. According to the different chiral binaphthol units and the hydrophobic chiral polyurethane backbones formed by the chiral binaphthol units, doxorubicin chiral polyurethane delivery micelles of R-CPM, Racemic-CPM or S-CPM are correspondingly obtained.

[0010] Preferably, the first solvent includes one or more of ethanol, methanol, acetonitrile, dimethyl sulfoxide, and dichloromethane; the molar mass ratio of 7-hydroxy-3-carboxycoumarin to 3-aminophenylboronic acid is 1:(1-2); the temperature of the coupling reaction is -5~30°C, the reaction time is 4-8h, and the pH value of the reaction is 6-7.

[0011] Preferably, the second solvent includes one or more of methanol, DMF, ethanol, and DMSO; the temperature of the polymerization reaction is 25-40 °C, and the reaction time is 12-36 h; the molar mass ratio of isophorone diisocyanate to chiral binaphthol is (1-1.5):1.

[0012] Preferably, the third solvent includes one or more of PBS, water, ethanol, and DMF; the molar mass ratio of isophorone diisocyanate, chiral binaphthol to coumarin-phenylboronic acid conjugate is (1-1.5):1:1; the temperature of the grafting reaction is 30-70 °C, and the reaction time is 24-48 h.

[0013] Preferably, the fourth solvent includes one or more of ethanol, methanol, acetonitrile, dimethyl sulfoxide, dichloromethane, and methoxypolyethylene glycol; the temperature of the esterification reaction is 80-120 °C, and the reaction time of the esterification reaction is 8-15 h; the catalyst includes one or more of potassium bisulfate and sodium bisulfate; the molecular weight of methoxypolyethylene glycol is 1000-5000; the molar mass ratio of methoxypolyethylene glycol, gallic acid, and the catalyst is 1:(1-2):(0.2-0.4).

[0014] Preferably, the mass ratio of the hydrophobic segment to methoxypolyethylene glycol gallate is 1:(1-2); the temperature of the condensation reaction is 20-30 °C, and the reaction time is 2-8 h; the temperature of the stirring reaction is 10-30 °C, and the reaction time is 10-24 h.

[0015] Fourthly, the present application provides an application of doxorubicin chiral polyurethane delivery micelles in the preparation of anticancer drugs.

[0016] The beneficial effects of the present application are as follows: the doxorubicin chiral polyurethane delivery micelles of the present application improve the water solubility of doxorubicin, and can achieve targeted release of doxorubicin through pH and ROS responses, reducing side effects. At the same time, chiral binaphthol is used as a backbone component, increasing the affinity of cells for doxorubicin chiral polyurethane delivery micelles, and enhancing the nano-chemotherapy effect of the drug on doxorubicin; the doxorubicin chiral polyurethane delivery micelles of the present application improve the uptake of doxorubicin nano-drugs by tumors, enhance the chemotherapy effect of doxorubicin nano-drugs, and reduce the toxicity brought by traditional doxorubicin nano-drugs. Description of the Drawings

[0017] Figure 1 It is a synthetic route diagram of doxorubicin delivery polyurethane micelles; Figure 2 It is a chemical structure characterization diagram of doxorubicin delivery chiral micelles; among them, Figure 2 a is the infrared spectrum of R-CPCA, R-CPM, and mPEG-GA; Figure 2b is the infrared spectrum of Racemic-CPCA, Racemic-CPM, and mPEG-GA; Figure 2 c is the infrared spectrum of S-CPCA, S-CPM, and mPEG-GA; Figure 2 d is the infrared spectrum of Coumarin-APBA, R-CPCA, Racemic-CPCA, and S-CPCA; Figure 2 e is the 1H NMR spectrum of mPEG-GA (DMSO-d6, 400 Hz); Figure 2 f is the 1H NMR spectrum of Coumarin-APBA (DMSO-d6, 400 Hz); Figure 2 g is the 1H NMR spectrum of R-CPCA, Racemic-CPCA, and S-CPCA (DMSO-d6, 400 Hz); Figure 2 h is the 1H NMR spectrum of R-CPM, Racemic-CPM, and S-CPM (DMSO-d6, 400 Hz); Figure 3 is the characterization diagram of doxorubicin-loaded chiral polyurethane micelles (R-CPM-DOX, Racemic-CPM-DOX, S-CPM-DOX); among them, Figure 3 a is the transmission electron microscopy image of R-CPM-DOX; Figure 3 b is the transmission electron microscopy image of Racemic-CPM-DOX; Figure 3 c is the transmission electron microscopy image of S-CPM-DOX; Figure 3 d is the particle size distribution diagram of R-CPM; Figure 3 e is the particle size distribution diagram of Racemic-CPM; Figure 3 f is the particle size distribution diagram of S-CPM; Figure 3 g is the zeta potential diagram of R-CPM, Racemic-CPM, and S-CPM; Figure 3 h is the zeta potential diagram of R-CPM-DOX, Racemic-CPM-DOX, and S-CPM-DOX; Figure 4 is the in vitro release diagram of three configurations of CPM-DOX under the conditions of pH 7.4, 6.5, and 0.1 mM H2O2; among them: Figure 4 a is the change of the fluorescence spectrum of R-CPM-DOX with time under these conditions; Figure 4 b is the change of the fluorescence spectrum of Racemic-CPM-DOX with time under these conditions; Figure 4 c is the change of the fluorescence spectrum of S-CPM-DOX with time under these conditions; Figure 4 d is the change of the fluorescence spectrum of DOX in R-CPM-DOX with time; Figure 4e is the change of the fluorescence spectrum of DOX in Racemic-CPM-DOX over time; Figure 4 f is the change of the fluorescence spectrum of DOX in S-CPM-DOX over time; Figure 4 g is the release profile of R-CPM-DOX, Racemic-CPM-DOX, and S-CPM-DOX under the conditions of pH 7.4 and pH 6.5; Figure 4 h is the release profile of R-CPM-DOX, Racemic-CPM-DOX, and S-CPM-DOX under the conditions of pH 7.4 + 0.1 mM H2O2 and pH 6.5 + 0.1 mM H2O2; Figure 5 is the stability structure of the micelles of the three configurations of CPM-DOX; among them, Figure 5 a, Figure 5 b, Figure 5 c, Figure 5 d, Figure 5 e, Figure 5 f respectively correspond to the particle size change trends of R-CPM, Racemic-CPM, S-CPM, R-CPM-DOX, Racemic-CPM-DOX, and S-CPM-DOX over 20 days; Figure 6 is the confocal laser scanning microscopy image of MCF-7 cells cultured with doxorubicin-loaded micelles for 12 h; from top to bottom are the coumarin staining (blue), doxorubicin (red), and the superimposed image of the two colors; Figure 7 is the result of the effect of blank micelles at different concentrations on the proliferation of 4T1, 3T3, MCF-7, and HaCat cells; 7a is the effect of blank micelles on the proliferation of 4T1 (murine breast cancer cell line); 7b is the effect of blank micelles on the proliferation of 3T3 (mouse embryonic fibroblast cell line); 7c is the effect of blank micelles on the proliferation of MCF-7 (human breast cancer cell line); 7d is the effect of blank micelles on the proliferation of HaCat (human keratinocyte cell line).

[0018] Figure 8 is the comparison chart of the viability of doxorubicin-loaded micelles at different concentrations after culturing with 4T1, MCF-7, HeLa, and HepG2 cells for 48 h; 8a is the effect of the drug-loaded micelles on the proliferation of 4T1 (murine breast cancer cell line); 8b is the effect of the drug-loaded micelles on the proliferation of MCF-7 (human breast cancer cell line) (mouse embryonic fibroblast cell line) proliferation; 8c is the effect of the drug-loaded micelles on the proliferation of Hela (human cervical cancer cell line); 8d is the effect of the drug-loaded micelles on the proliferation of HepG2 (human liver cancer cell line).

[0019] Figure 9This is the mechanism diagram of chiral micelle self-assembly, tumor cell delivery, and drug release for this application. Detailed implementation manners

[0020] In order to make the objectives, technical solutions, and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below in conjunction with embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0021] Polymeric micelles are composed of a unique core-shell structure. Amphiphilic polymers are high-molecular polymers composed of hydrophilic and lipophilic parts. The hydrophobic core can encapsulate poorly soluble drugs, and the hydrophilic shell separates the drugs from the water-soluble environment, which can stabilize the micelles and prevent the micelles from being excreted from the body by the reticuloendothelial system in the body. Polymeric micelles can not only improve the solubility of anticancer drugs in water, but also have the potential for precise targeted release through design and synthesis, thereby improving the drug efficacy. Chirality is an important property of natural molecules. Chiral isomers have specific and selective effects on biological systems and have extraordinary significance for various biological events such as cell metabolism, cell fate, and even organism evolution. For example, in eukaryotes, small molecules such as amino acids, nucleic acids, and carbohydrates also have chirality. Most amino acids are L, while sugars and the well-known DNA double helix structure are mostly D. Chiral polymeric micelles have increased interactions with the living system due to their unique chiral characteristics. For example, the interaction between chiral proteins and chiral polymeric micelles increases the therapeutic effect of chiral polymeric micelles.

[0022] Based on this, this application was created.

[0023] This application provides a doxorubicin chiral polyurethane delivery micelle, including: A micelle carrier formed by self-assembly of an amphiphilic polymer and doxorubicin encapsulated in the micelle carrier; the amphiphilic polymer includes a hydrophobic segment and a hydrophilic segment covalently connected by a dynamic borate ester bond; the hydrophilic segment includes methoxypolyethylene glycol gallate; the hydrophobic segment includes a hydrophobic chiral polyurethane main chain and a coumarin-phenylboronic acid conjugate covalently grafted to the hydrophobic chiral polyurethane main chain, and the hydrophobic chiral polyurethane main chain is formed by alternating connection of chiral binaphthol units and isophorone diisocyanate units.

[0024] In some embodiments, the chiral binaphthol (BINOL) unit is selected from R-BINOL, Racemic-BINOL, or S-BINOL, and the hydrophobic chiral polyurethane main chain formed by the chiral binaphthol unit is correspondingly selected from one of R-CPCA, Racemic-CPCA, or S-CPCA. Different configurations of binaphthol (BINOL) make the hydrophobic chiral polyurethane main chain (CPCA) correspondingly have three different chiralities.

[0025] In some embodiments, the chiral binaphthol (BINOL) unit is R-BINOL, and the hydrophobic chiral polyurethane main chain formed by the chiral binaphthol unit is R-CPCA. The chiral polyurethane micelle formed by the combination of hydrophobic and hydrophilic self-assembly is R-CPM.

[0026] In short, in this application, the doxorubicin chiral polyurethane delivery micelle includes: (a) A micelle carrier formed by self-assembly of an amphiphilic polymer, the amphiphilic polymer comprising a hydrophobic segment and a hydrophilic segment covalently linked by a pH- and ROS-responsive dynamic borate ester bond; (b) Doxorubicin drug encapsulated in the inner core of the micelle carrier; Wherein, The hydrophobic segment is composed of the following components: (i) A chiral binaphthol unit selected from one of R-BINOL, Racemic-BINOL or S-BINOL; (ii) An isophorone diisocyanate unit, which is alternately connected to the chiral binaphthol unit through a urethane bond to form a polyurethane main chain; (iii) A coumarin-phenylboronic acid conjugate covalently grafted to the polyurethane main chain, the coumarin group providing a fluorescence labeling function, and the phenylboronic acid group serving as a switch for the responsive release of the chiral polyurethane micelle; The hydrophilic segment is methoxypolyethylene glycol gallate (mPEG-GA), which is formed by an esterification reaction between the phenolic hydroxyl group of gallic acid (GA) and the terminal hydroxyl group of methoxypolyethylene glycol (mPEG); The dynamic borate ester bond is formed by a condensation reaction between the phenolic hydroxyl group of gallic acid and the carboxyl group of phenylboronic acid. Since the dynamic borate ester bond has pH and ROS responsiveness, it can be cleaved at the target site to target the release of doxorubicin. In this application, by introducing binaphthol (BINOL) with different chiral configurations, the hydrophobic chiral polyurethane main chain (CPCA) has chiral characteristics, and a chiral micelle carrier (CPM) is obtained. The chiral micelle carrier reduces the toxicity of doxorubicin, improves the water solubility of doxorubicin, can target the release of doxorubicin. At the same time, the chiral micelle carrier with chiral characteristics increases the interaction between the micelle and cells and improves the chemotherapy effect. The chiral configuration of the micelle is determined by the steric configuration of the chiral binaphthol unit, and the R-type micelle (R-CPM) corresponding to R-BINOL is significantly superior to the S (S-CPM) type and Racemic (Racemic-CPM) type micelles in terms of tumor suppression effect.

[0027] In some embodiments, the drug loading rate of doxorubicin is 30-45%.

[0028] This application provides a method for preparing a doxorubicin chiral polyurethane delivery micelle, which includes the following steps: S1. Under the activation of EDS / NHS, dissolve 7-hydroxy-3-carboxycoumarin and 3-aminophenylboronic acid in the first solvent and carry out a coupling reaction to obtain a coumarin-phenylboronic acid conjugate (Coumarin-APBA); S2. Under an inert atmosphere, dissolve chiral binaphthol and isophorone diisocyanate (IPDI) in the second solvent and carry out a polymerization reaction to obtain an NCO-terminated hydrophobic chiral polyurethane main chain (PU-BINOL-NCO); S3. Under an inert atmosphere, dissolve the hydrophobic chiral polyurethane main chain and the coumarin-phenylboronic acid conjugate in the third solvent and carry out a grafting reaction to obtain a hydrophobic segment (CPCA); S4. Under anhydrous vacuum and the action of a catalyst, dissolve methoxypolyethylene glycol and gallic acid in the fourth solvent and carry out an esterification reaction to obtain methoxypolyethylene glycol gallate (mPEG-Ga); S5. Dissolve methoxypolyethylene glycol gallate (mPEG-Ga) and the hydrophobic segment (CPCA) in an organic solvent, add triethylamine, and carry out a condensation reaction to obtain a micelle carrier. According to the different chirality of the hydrophobic chiral polyurethane main chain, the corresponding R-CPM, Racemic-CPM or S-CPM type micelle carriers are obtained; S6. Mix doxorubicin with the micelle carrier, and after stirring and reacting, doxorubicin chiral polyurethane delivery micelles are obtained. According to the different chirality of the hydrophobic chiral polyurethane main chain, the corresponding R-CPM-DOX, Racemic-CPM-DOX or S-CPM-DOX type doxorubicin chiral polyurethane delivery micelles are obtained.

[0029] As Figure 1 shown, the route for preparing doxorubicin chiral polyurethane delivery micelles in this application is as follows: The carboxyl group provided by 7-hydroxy-3-carboxycoumarin covalently binds to the amino group provided by 3-aminophenylboronic acid through an amide bond to prepare a Coumarin-APBA conjugate; The hydroxyl group of binaphthol first connects to the isocyanate group of IPDI to form a polyurethane polymer, that is, an NCO-terminated hydrophobic chiral polyurethane main chain (PU-BINOL-NCO). The polyurethane polymer covalently binds to the Coumarin-APBA conjugate to form a hydrophobic segment (CPCA); At the same time, gallic acid (GA) and methoxypolyethylene glycol (mPEG) are prepared into methoxypolyethylene glycol gallate (mPEG-GA) as the hydrophilic segment of the micelle carrier through an esterification reaction; The hydrophobic segment and the hydrophilic segment form a stable borate ester bond through the phenolic hydroxyl group on gallic acid and the carboxyl group of phenylboronic acid, thereby forming an amphiphilic polymer with a hydrophobic segment and a hydrophilic segment, and then self-assembling to form chiral polyurethane micelles (CPM). The tumor cell delivery and drug release mechanism of the chiral micelles in this application are as Figure 9 shown.

[0030] In this application, by introducing binaphthol (BINOL) with different chiral configurations, the hydrophobic chiral polyurethane main chain (CPCA) is endowed with chiral properties, and a chiral micelle carrier (CPM) is successfully prepared. This chiral micelle carrier has the following advantages: 1. Significantly reduce the toxicity of doxorubicin and improve its water solubility; 2. Achieve targeted release of doxorubicin and improve drug utilization rate; 3. Enhance the interaction between micelles and cells and improve the chemotherapy effect; 4. Remain stable without pH and ROS response and no drug release; 5. Have a selective killing effect on tumor cells, while having low toxicity to normal cells and high safety; 6. There is chiral recognition between polyurethane micelles with different chiral configurations and tumor cells.

[0031] In this application, a polyurethane chiral polymer (micelle carrier) is used as a doxorubicin carrier, and the targeted release of the drug is achieved through reversible covalent bonds. The obtained chiral polyurethane micelles for doxorubicin delivery have the following advantages: low toxicity, effectively reducing the damage of the drug to normal tissues by introducing a chiral structure; chiral selectivity for tumor cells, where the R-type micelles show excellent tumor suppression effects; intelligent responsiveness, achieving precise release of the drug in the tumor microenvironment; good biocompatibility, improving the water solubility and stability of the drug.

[0032] In step S1, under the activation of EDS / NHS, the carboxyl group of 7-hydroxy-3-carboxycoumarin couples with the amino group of 3-aminophenylboronic acid to obtain a coumarin-phenylboronic acid conjugate (Coumarin-APBA); the first solvent includes one or more of ethanol, methanol, acetonitrile, dimethyl sulfoxide, and dichloromethane. Preferably, the first solvent is methanol and dichloromethane with a volume ratio of 1:(1 - 2), which is beneficial to improving the solubility of the raw materials and subsequent purification; the molar mass ratio of 7-hydroxy-3-carboxycoumarin to 3-aminophenylboronic acid is 1:(1 - 2). In the coupling reaction, the coupling agent is EDC hydrochloride and NHS with a molar mass ratio of 1:1. Specifically, the molar mass ratio of 7-hydroxy-3-carboxycoumarin, 3-aminophenylboronic acid, EDC hydrochloride, and NHS is 1:(1 - 2):1:1. Preferably, the molar mass ratio of 7-hydroxy-3-carboxycoumarin, 3-aminophenylboronic acid, EDC hydrochloride, and NHS is 1:1.5:1:1; the temperature of the coupling reaction is -5~30°C, the reaction time is 4 - 8 h, and the pH value of the reaction is 6 - 7; preferably, the temperature of the coupling reaction is 0 - 30°C, the reaction time is 6 h, and the pH value is adjusted to 6.5 with HCl. If the pH is too high, the reaction is slow, and if the pH is too low, the product is easily decomposed.

[0033] In step S2, the chiral binaphthol is 1,1-binaphthol (R-BINOL, Racemic-BINOL, S-BINOL), and the second solvent includes one or more of methanol, DMF, ethanol, and DMSO; the temperature of the polymerization reaction is 25-40 °C, and the reaction time is 12-36 h; preferably, the temperature of the polymerization reaction is 25 °C. If the temperature is too high, the molecular weight is low and it is not conducive to the formation of micelles. If the temperature is too low, the reaction is incomplete. The reaction time is 24 h; the molar mass ratio of chiral binaphthol to isophorone diisocyanate is 1:(1-2); preferably, the molar mass ratio of chiral binaphthol to isophorone diisocyanate is 1:1.5.

[0034] In step S3, the third solvent includes one or more of PBS, water, ethanol, and DMF; preferably, the third solvent is 0.001-0.01 M PBS buffer solution or DMF; the molar mass ratio of isophorone diisocyanate, chiral binaphthol, and coumarin-phenylboronic acid conjugate is (1-1.5):1:1. Preferably, the molar mass ratio of isophorone diisocyanate, chiral binaphthol, and coumarin-phenylboronic acid conjugate is 1.5:1:1; the temperature of the grafting reaction is 30-70 °C, and the reaction time is 24-48 h; preferably, the temperature of the grafting reaction is 60 °C, and the reaction time is 30 h; after the grafting reaction is completed, the product is rotary-evaporated to remove the third solvent and then dissolved in DMSO, and the solution is transferred to a MWCO 2000 dialysis bag for dialysis for 1-4 days. The dialysis solution is a 20% DMSO solution, and the dialysis solution is freeze-dried to obtain a yellow fluffy solid.

[0035] In step S4, the fourth solvent includes one or more of ethanol, methanol, acetonitrile, dimethyl sulfoxide, dichloromethane, and methoxypolyethylene glycol. Preferably, the fourth solvent is methoxypolyethylene glycol. Using the raw material itself as the solvent is beneficial to reducing costs and improving solubility; the temperature of the esterification reaction is 80-120 °C, and the time of the esterification reaction is 8-15 h; preferably, the temperature of the esterification reaction is 110 °C, and the time of the esterification reaction is 12 h; the catalyst includes one or more of potassium bisulfate and sodium bisulfate. The catalyst is a weak acid and has no oxidizing property. In this application, conventional esterification catalysts such as strong acids (sulfuric acid) are not used to avoid the oxidation of the phenolic hydroxyl group of gallic acid; the molecular weight of methoxypolyethylene glycol is 1000-5000; the molar ratio of methoxypolyethylene glycol, gallic acid, and the catalyst is 1:(1-2):(0.2-0.4); after the esterification reaction is completed, the product is collected by adding a solvent to precipitate the solid. Before the product undergoes the next reaction, it is washed to remove the solvent and unreacted raw materials. At this ratio, the esterification reaction is complete and there are no excess monomers.

[0036] In step S5, the mass ratio of the hydrophobic chain segment to methoxypolyethylene glycol gallate is 1:(1 - 2), the temperature of the condensation reaction is 20 - 30 °C, the reaction time is 2 - 8 h, triethylamine is added to adjust the pH to 7 - 8.5. Preferably, the temperature of the condensation reaction is 25 °C, the reaction time is 3 h; the pH is 8.0. After the condensation reaction is completed, the product is slowly added dropwise to deionized water and stirred vigorously for 2 hours, and dialyzed with MWCO 7000 for 1 - 4 days, and the dialysate is deionized water.

[0037] In step S6, the solvent for dissolving doxorubicin includes one or more of dimethyl sulfoxide and N,N-dimethylformamide; the temperature of the stirring reaction is 10 - 30 °C, and the reaction time is 10 - 24 h; preferably, the temperature of the stirring reaction is 25 °C, and the reaction time is 12 h; after the stirring reaction is completed, the reaction solution is transferred to a MWCO 2000 dialysis bag and dialyzed for 0.5 - 3 days. The dialysis bag is preferred, the dialysate is ionic water, the dialysis temperature is 0 - 15 °C, and the dialysate is freeze-dried to obtain a white fluffy solid.

[0038] The following further illustrates this solution through specific examples.

[0039] Term description: Gallic acid: gallic acid; mPEG: methoxypolyethylene glycol; mPEG-Ga: methoxypolyethylene glycol gallate; 3-Carboxy-7-hydroxycoumarin: 7-hydroxy-3-carboxycoumarin; APBA: 3-aminophenylboronic acid; IPDI: isophorone diisocyanate; BINOL: binaphthol; Chiral prepolymer: chiral prepolymer; Coumarin-APBA: coumarin-phenylboronic acid conjugate; Chiral polymer-Coumarin-APBA (CPCA): chiral polymer; Chiral polymer micelle (CPM): chiral polymer micelle.

[0040] Example 1 A preparation method of doxorubicin chiral polyurethane delivery micelles includes the following steps: Dissolve 0.2061 g of 7-hydroxy-3-carboxycoumarin and 0.3834 g of EDC·HCl in 10 mL of methanol, and perform carboxyl activation at 0 °C for 6 hours. When a slight yellow solid precipitates in the solution, add dichloromethane to adjust the polarity of the reaction system until the precipitated solid completely dissolves. Then add 0.2054 g of 3-aminophenylboronic acid and 0.0575 g of NHS, and continue to stir and react at room temperature for 36 hours to couple the carboxyl group of 7-hydroxy-3-carboxycoumarin with the amino group of 3-aminophenylboronic acid to form a conjugate. After the reaction, use silica gel (200 - 300 mesh) column chromatography to purify the product. The mobile phase is ethyl acetate:petroleum ether = 1:5 for elution. Collect the eluate and evaporate the solvent to obtain a pale yellow solid, which is the coumarin-phenylboronic acid conjugate (Coumarin-APBA); Under an inert atmosphere, add 0.2863 g of R-type 1,1-binaphthol (R-BINOL) and 0.3334 g of isophorone diisocyanate (IPDI) to 2 mL of dry DMF respectively. After stirring and dissolving, react at 25 °C for 24 hours to obtain an NCO-terminated hydrophobic chiral polyurethane backbone (PU-BINOL-NCO, R-CPM). Add 0.3250 g of Coumarin-APBA conjugate to the obtained PU-BINOL-NCO polymer solution, and react at 60 °C for 30 hours. After the reaction, spin-dry DMF and then add 20 mL of DMSO. Transfer the solution to a 2 kDa dialysis bag and dialyze in an aqueous solution of 20% DMSO for four days. Filter by suction to obtain a pale yellow solid, which is the chiral polymer (CPCA), namely the hydrophobic segment; Dehydrate 10 g of methoxypolyethylene glycol under vacuum at 110 °C for 1 hour. Add 0.3762 g of gallic acid and 0.1089 g of potassium bisulfate catalyst, maintain a vacuum and anhydrous environment, and react at 110 °C for 12 hours. After the reaction, naturally cool to room temperature, add 50 mL of dichloromethane, stir, and the unreacted gallic acid and catalyst precipitate. The product dissolves in dichloromethane. Filter by suction to discard the solid cake, concentrate the filtrate to 10 mL, add 200 mL of n-hexane, stir rapidly, and the product gradually precipitates as a white solid powder. Filter by suction and place in an oven at 40 °C for 2 hours to volatilize the residual n-hexane to obtain the solid white powder product methoxypolyethylene glycol gallate (mPEG-Ga), namely the hydrophilic segment, and store it in vacuum for later use; Dissolve 60 mg of methoxypolyethylene glycol gallate (mPEG-Ga) in 500 μL of DMSO, add 10 μL of triethylamine, and then add 10 mg of coumarin-aminophenylboronic acid-coupled chiral binaphthol polymer (CPCA). After stirring at room temperature for 3 hours, slowly drop the reaction solution into 10 mL of deionized water and stir vigorously for 2 hours. Transfer the solution to a dialysis bag (7000 DA) and dialyze in deionized water for three days. After freeze-drying the dialysis solution, the corresponding chiral polymer micelles (CPM) are obtained, namely micelle carriers of R, Racemic, and S configurations; Dissolve 10 mg of chiral polymer micelles (CPM) in 500 μL of DMSO and stir to dissolve at room temperature. Add 10 mg of doxorubicin and stir at room temperature for 1 hour. Then drop the solution into 20 mL of deionized water. Transfer the reaction solution to a dialysis bag (MWCO 2000) and dialyze in deionized water for three days. After freeze-drying the dialysis solution, doxorubicin chiral polymer micelles (drug-loaded chiral polymer micelles CPM-DOX) are obtained, which are dried and stored for later use.

[0041] Example 2 A preparation method of doxorubicin chiral polyurethane delivery micelles, with other contents being the same as in Example 1, except that 1,1-binaphthol with different chirality is used. Replace R-BINOL in Example 1 with Racemic-BINOL to obtain a hydrophobic chiral polyurethane main chain (Racemic-CPCA), the corresponding chiral polymer micelles (Racemic-CPM), and the obtained doxorubicin chiral polyurethane delivery micelles are drug-loaded polymer micelles Racemic-CPM-DOX.

[0042] Example 3 A preparation method of doxorubicin chiral polyurethane delivery micelles, with other contents being the same as in Example 1, except that 1,1-binaphthol with different chirality is used. Replace R-BINOL in Example 1 with S-BINOL to obtain a hydrophobic chiral polyurethane main chain (S-CPCA), the corresponding chiral polymer micelles (S-CPM), and the obtained doxorubicin chiral polyurethane delivery micelles are drug-loaded polymer micelles S-CPM-DOX.

[0043] Testing and evaluation Test the product structures of Examples 1-3, as Figure 2 shown. Taking Figure 2 b as an example, from the infrared spectrum of mPEG-Ga, it can be obtained that 3469.7 cm -1 is the stretching vibration (νO-H) of the O-H of the phenolic hydroxyl group, and 1351.2 cm -1 is the in-plane bending vibration (δO-H) of the O-H of the phenolic hydroxyl group, and 1246.2 cm -1is the stretching vibration of the C-O bond of the phenolic hydroxyl group (VC-O), 2888.1 cm -1 , 2742.7 cm -1 , 2696.2 cm -1 is the vibration of the -OCH3 and -CH2 positions of methoxypolyethylene glycol, 1698.6 cm -1 , 1642 cm -1 is the skeletal stretching vibration of the benzene ring (VC=C), 842.3 cm -1 is the out-of-plane bending vibration of the C-H of the benzene ring (γC-H), 1468.4 cm -1 is the stretching vibration of C=O in the ester group (VC=O), 1112.9 cm -1 is the stretching vibration of the C-O bond of the ester group (VC-O). These infrared data illustrate the formation of the ester bond in mPEG-Ga and the presence of the phenolic hydroxyl group, indicating the successful synthesis of mPEG-Ga. For the chiral polymer Racemic-CPCA, its amide is at 3423.3 cm -1 is the stretching vibration of N-H (VN-H), 1557.2 cm -1 is the in-plane bending vibration of C-N (δC-N), 1464.3 cm-1 is the in-plane bending vibration of N-H (δN-H), 1732.9 cm -1 is the stretching vibration of C-O of the amide carbonyl (VC=O). For the IPDI structural unit, 2926.5 cm -1 , 2855.8 cm -1 is the stretching vibration of C-H (VC-H).

[0044] Coumarin phenylboronic acid conjugate structural unit: 1621.8 cm -1 , 1506.7 cm -1 is the stretching vibration of the benzene ring (Vc=c), 876.6 cm -1 , 820.1 cm -1 is the in-plane and out-of-plane bending vibrations of the benzene ring (δC=C, γC-C), 3062.7 cm -1 is the stretching vibration of the C-H of the olefin bond in the coumarin parent ring (VC-H), 1375.5 cm -1 , 1001.8 cm -1 is the in-plane bending vibration of the C-H of the olefin bond (δC-H), 1211.9 cm -1 is the stretching vibration of the C-O bond of the lactone in the coumarin parent ring (VC-O), indicating the successful reaction of the coumarin-phenylboronic acid conjugate in the polymer molecule. Chiral polymer micelles: Its 3437.4 cm -1 is the stretching vibration of N-H in the amide part (VN-H), 1724.8 cm -1It is the C=O stretching vibration (VC=O) of the amide moiety. Comparing the infrared spectrum of mPEG-Ga, its 2886.1 cm -1 is the infrared C-H vibration of the methoxy group of mPEG-Ga, and the characteristic peak of the ester group of mPEG-Ga appears at 1108.9 cm -1 , indicating that mPEG-Ga is present in the polymeric micelles, verifying the successful synthesis of the chiral polymeric micelles Racemic-CPM. Figure 2 d Comparing the infrared spectra of the three CPCAs and Coumarin-APBA, the phenolic hydroxyl stretching vibration (VO-H) of Coumarin-APBA is at 3295.5 cm -1 . The peak position of this peak disappears in R-CPCA, Racemic-CPCA, and S-CPCA, and is replaced by the N-H stretching vibration (VN-H) of the amide. At the same time, 1732.9 cm -1 , 1632.6 cm -1 corresponds to the carbonyl stretching vibration of Coumarin-APBA, and 1623.6 cm -1 such a peak of the phenylboronic acid benzene ring skeleton stretching vibration (VC=C) all prove the successful synthesis of Coumarin-APBA, the successful coupling of 3-aminophenylboronic acid, and at the same time Coumarin-APBA is also successfully attached to the polymer CPCA. In the NMR spectrum of the chiral polyurethane polymer ( Figure 2 ), the a peak at 8.82 ppm and the b peak at 9.17 ppm in the NMR spectrum are the positions of the three phenolic hydroxyl groups in mPEG-Ga, the c peak at 6.92 ppm is the two hydrogens on the benzene ring, the e and d peaks at 3.92 - 3.17 ppm are the two methylene hydrogens of the methoxypolyethylene glycol in mPEG-Ga, and the f peak at 1.24 ppm is the hydrogen of the methoxy group. These NMR data prove the successful synthesis of mPEG-Ga.

[0045] NMR characterization is as Figure 2As shown in e, f, g, and h, in the 1H NMR spectrum of e, peak a at 8.82 ppm and peak b at 9.17 ppm are the positions of the three phenolic hydroxyl groups in mPEG-Ga, peak c at 6.92 ppm is the two hydrogens on the benzene ring, peaks e and d in the range of 3.92 - 3.17 ppm are the two methylene hydrogens of methoxypolyethylene glycol in mPEG-Ga, and peak f at 1.24 ppm is the hydrogen of the methoxy group. These 1H NMR data prove the successful synthesis of mPEG-Ga. In the 1H NMR spectrum of f, peak a at 8.70 ppm is the phenolic hydroxyl group in Coumarin-APBA, 8.44 ppm is the hydrogen on the double bond of the coumarin parent ring, i.e., position d in the structure, 7.76 ppm corresponds to the hydrogen at position c on the benzene ring of coumarin, 7.62 ppm, 7.56 ppm, and 7.40 ppm are the hydrogens at positions h, f, and g on the benzene ring of phenylboronic acid in Coumarin-APBA, 6.85 ppm and 6.73 ppm are the hydrogens at positions b and c on the benzene ring of coumarin in Coumarin-APBA, e is the hydrogen of the amide in Coumarin-APBA, and 3.80 ppm is the two active hydrogens of phenylboronic acid. These 1H NMR data prove the successful synthesis of Coumarin-APBA. Figure g is the 1H NMR spectrum of the synthesized polymer CPCA. The 1H NMR spectra of R-CPCA, Racemic-CPCA, and S-CPCA are roughly the same. In the a region of 7.75 - 8.25 ppm is the position of binaphthyl in the polymer CPCA, which can prove the introduction of binaphthyl and the formation of a polymer containing binaphthyl. In the b region of 7.00 - 7.50 ppm and the c region of 6.00 - 7.00 ppm are some benzene ring positions of Coumarin-APBA in the polymer CPCA, which proves that the polymer CPCA contains the conjugate Coumarin-APBA. The existing phenylboronic acid structure is subsequently used to connect the hydrophilic segment. The d region of 0.50 - 1.50 ppm and 3.0 - 3.5 ppm are the characteristic peaks of IPDI in the polymer CPCA. 3.0 - 3.5 ppm are the two methyl groups on IPDI. These data prove that the reaction of the two isocyanate groups on IPDI, the two phenolic hydroxyl groups on binaphthol, and the phenolic hydroxyl group on the conjugate Coumarin-APBA has successfully prepared the polyurethane polymer CPCA with a binaphthol backbone capped with the conjugate Coumarin-APBA. The introduction of binaphthol with different chiralities endows the polymer with chiral characteristics, laying a foundation for the subsequent formation of an amphiphilic polymer by the combination of phenylboronic acid and the double bond of gallate.Figure 2h is the CPM H-NMR spectrum of the polymer micelles. Self-assembled micelles were formed by the borate bond between CPCA and methoxy gallate. Its NMR spectrum maintains some characteristic peaks of CPCA at 6.00-8.50ppm, such as structural features of binaphthol, conjugate Coumarin-APBA, phenylboronic acid, and the corresponding IPDI characteristic peaks at 0.50-1.50ppm. The main difference is that the peak of the methylene group in methoxy polyethylene glycol in methoxy polyethylene glycol gallate appears at around 3.50ppm. Figure 2 The e and d positions in the graphene correspond to each other, which indicates that the polymer CPCA is successfully combined with methoxy polyethylene glycol gallate to form amphiphilic polymer micelles with both hydrophobic and hydrophilic properties.

[0046] The chiral polymer micelles obtained in Examples 1-3 were dissolved in an appropriate amount of 0.01M (pH 7.4) PBS buffer solution to prepare a sample solution with a concentration of 1 mg / ml. 1 ml of the sample solution was added to the sample cell. The particle size and Zeta potential of the micelles were measured using a Malvern laser particle size analyzer at 25°C. The results are shown in Table 1.

[0047] Table 1. Particle size, PDI and Zeta potential of binaphthol micelles for doxorubicin delivery in aqueous and organic phases

[0048] As shown in Table 1, the particle sizes of the chiral polymer micelles with three different conformations in 0.01M PBS (pH 7.4) buffer were 128.1±0.36, 128.6±0.15, and 128.3±0.68 nm, and the PDIs were 0.10±0.01, 0.09±0.25, and 0.11±0.12, respectively. This indicates that the micelles are in a single micellar particle state and are evenly distributed in aqueous solution, and can be used as a stable drug delivery carrier.

[0049] The different chiral polymer drug-loaded micelles (CPM-DOX) obtained in Examples 1-3 were dissolved in an appropriate amount of 0.01M (pH 7.4) PBS buffer solution to prepare a sample solution with a concentration of 1 mg / ml. The sample solution was dripped onto a carbon-coated copper grid and stained with 2% (w / v) phosphotungstic acid for 2 minutes. After drying, the surface morphology of the micelles was observed by transmission electron microscopy (JEM-1230HC, Tokyo, Japan). A small amount of acid was added to the sample solution until the solution showed a light red color. The above operation was repeated to observe the surface morphology of the micelles. The results are shown in FIG. Figure 3 As shown. Through transmission electron microscopy observation, Figure 3 a shows that the micelles have a uniform spherical morphology, which is conducive to tumor cell uptake. Dissolve different chiral polymer micelles in PBS with pH 7.4 and pH 7.4 + 10% serum respectively, and monitor the particle size change of the micelles within 20 days. The results are as Figure 5 shown. The micelles are very stable in PBS with pH 7.4 and PBS containing 10% FBS. The size of the micelles does not change significantly within 20 days, indicating its extremely high stability, preventing drug leakage and reducing toxic side effects.

[0050] Seed 1×10 4 cells into a 96-well plate, and add 100 µl of RPMI-1640 medium and MEM medium mixed with 10% fetal bovine serum and 1% penicillin plus streptomycin to each well, and culture at 37 °C and 5% CO2 for 24 hours. After the culture, change the medium in each well to RPMI-1640 medium containing doxorubicin-loaded binaphthol micelles at different concentrations (0, 0.39, 0.78125, 1.5625, 3.125, 6.25, 12.5, 25, and 50 μg / mL), and culture at 37 °C and 5% CO2 for 24 hours. After the culture, remove the medium in each well and then add MTT reagent, and culture at 37 °C and 5% CO2 for 4 hours. After the culture, remove the MTT reagent in each well, and add 150 µl of dimethyl sulfoxide to dissolve the purple crystalline formazan that is insoluble in water and is reduced from MTT by succinate dehydrogenase or other reductases in the mitochondria of living cells. Measure the absorbance values of all samples at 570 nm, and calculate the cell viability according to the following formula. Cell viability (%) = As / Ac × 100%; As is the absorbance value of the cell sample, and Ac is the absorbance value of the cell control. The results are as Figure 7 , The hydrophilic and hydrophobic parts of CPM (R-CPM, Racemic-CPM, S-CPM) are connected by borate ester bonds with pH and ROS responsiveness. Tumor cells have a more acidic pH environment and higher ROS compared with normal cells, which is sufficient to open the borate ester bond of CPM. In normal cell lines: mouse cardiomyocytes 3T3 and human immortalized epidermal cells HaCat, it can be found that CPM has almost no cytotoxicity to them and has good biosafety. For c and d, which are mouse breast cancer cells 4T1 and human breast cancer cells MCF-7, it can be found that even though there is a microenvironment in cancer cells that can make CPM respond, but without encapsulating DOX, it still has no killing effect on tumor cells. CPM-DOX cytotoxicity experiment Figure 8, a, b, c, d, e, f correspond to mouse breast cancer cell line 4T1, human breast cancer cell line MCF-7, human hepatocellular carcinoma cell line HepG2, human ovarian cancer cell line Hela, mouse cardiomyocyte cell line 3T3, and human epidermal keratinocyte cell line HaCaT, respectively. It can be found that CPM-DOX loaded with DOX has obvious anti-tumor effects, and all the selected cancer cell lines are significantly killed, which lays a foundation for subsequent in vivo experiments. However, there is still no obvious cytotoxicity in the normal cell lines 3T3 and HaCaT. This is because CPM, as a drug delivery material, has good biocompatibility because the borate ester bond acts as a "safe switch" and only opens in tumor cells, which endows the CPM delivery material with stability and biological safety. CPM-DOX loaded with DOX has the ability to encapsulate and deliver DOX and has excellent anti-tumor effects. Among the three chiral polymer drug-loaded micelles, more obviously, when the concentration is relatively high, R-CPM-DOX shows the most efficient anti-tumor ability among the three configurations of CPM-DOX.

[0051] Seed 4T1 cells into a 24-well plate at a density of 1×10 5 cells per well, and add 1 ml of RPMI-1640 medium mixed with 10% fetal bovine serum and 1% penicillin-streptomycin to each well. Incubate at 37 °C and 5% CO2 for 24 hours until the cells adhere. After the incubation, change the medium in each well to an RPMI-1640 medium solution of chiral polymer drug-loaded micelles (CPM-DOX) (DOX concentration is 1 μg / mL), and incubate at 37 °C and 5% CO2 for 12 hours. After the incubation, remove the medium in each well, wash 3 times with PBS solution, add 450 μl of 4% paraformaldehyde solution to each well, and fix the cells at 37 °C for 15 minutes. Remove the paraformaldehyde solution in each well, and wash 3 times with PBS solution. Then obtain fluorescence images with a confocal microscope. The results are as Figure 6 shown. After co-culturing doxorubicin-loaded binaphthol micelles with cells for 12 hours, obvious red fluorescence appears in the cytoplasm of 4T1 cells, indicating that doxorubicin-loaded binaphthol micelles can be effectively phagocytosed by 4T1 cells. Moreover, compared with the three chiral polymer drug-loaded micelles (CPM-DOX), more R-CPM-DOX is significantly taken up. The chiral mutual recognition increases the uptake of chiral polymer micelles by tumor cells and enhances the chemotherapy effect.

[0052] The above is only the preferred specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed by the present invention should be covered by the protection scope of the present invention.

Claims

1. A doxorubicin chiral polyurethane delivery micelle, characterized in that, Comprising: A micelle carrier formed by self-assembly of an amphiphilic polymer and doxorubicin encapsulated in the micelle carrier; The amphiphilic polymer comprises a hydrophobic segment and a hydrophilic segment covalently linked by a dynamic borate ester bond; the hydrophilic segment comprises methoxypolyethylene glycol gallate; the hydrophobic segment comprises a hydrophobic chiral polyurethane backbone and a coumarin-phenylboronic acid conjugate covalently grafted to the hydrophobic chiral polyurethane backbone, and the hydrophobic chiral polyurethane backbone is formed by alternating connection of chiral binaphthol units and isophorone diisocyanate units.

2. The doxorubicin chiral polyurethane delivery micelle according to claim 1, wherein The chiral binaphthol unit is selected from R-BINOL, Racemic-BINOL or S-BINOL, and the hydrophobic chiral polyurethane backbone formed by the chiral binaphthol unit is correspondingly selected from one of R-CPCA, Racemic-CPCA or S-CPCA.

3. The doxorubicin chiral polyurethane delivery micelle according to claim 1, characterized in that, The drug loading rate of the doxorubicin is 30-45%.

4. A preparation method of the doxorubicin chiral polyurethane delivery micelle according to any one of claims 1-3, characterized in that, Including the following steps: Dissolve 7-hydroxy-3-carboxycoumarin and 3-aminophenylboronic acid in a first solvent and carry out a coupling reaction to obtain a coumarin-phenylboronic acid conjugate; Under an inert atmosphere, dissolve chiral binaphthol and isophorone diisocyanate in a second solvent and carry out a polymerization reaction to obtain an NCO-terminated hydrophobic chiral polyurethane backbone; Under an inert atmosphere, dissolve the hydrophobic chiral polyurethane backbone and the coumarin-phenylboronic acid conjugate in a third solvent and carry out a grafting reaction to obtain the hydrophobic segment; Under anhydrous vacuum and the action of a catalyst, dissolve methoxypolyethylene glycol and gallic acid in a fourth solvent and carry out an esterification reaction to obtain methoxypolyethylene glycol gallate; Dissolve the methoxypolyethylene glycol gallate and the hydrophobic segment in an organic solvent, add triethylamine, and carry out a condensation reaction and self-assembly to obtain the micelle carrier; Mix doxorubicin with the micelle carrier, and after stirring and reacting, obtain the chiral polyurethane delivery micelle of doxorubicin.

5. The preparation method of the doxorubicin chiral polyurethane delivery micelle according to claim 4, characterized in that, The first solvent includes one or more of ethanol, methanol, acetonitrile, dimethyl sulfoxide, dichloromethane; the molar mass ratio of 7-hydroxy-3-carboxycoumarin to 3-aminophenylboronic acid is 1:(1-2); the temperature of the coupling reaction is -5 to 30 °C, the reaction time is 4-8 h, and the pH value of the reaction is 6-7.

6. The preparation method of the doxorubicin chiral polyurethane delivery micelle according to claim 4, wherein, The second solvent includes one or more of methanol, DMF, ethanol, DMSO; the temperature of the polymerization reaction is 25-40 °C, and the reaction time is 12-36 h.

7. The preparation method of the doxorubicin chiral polyurethane delivery micelle according to claim 4, characterized in that, The third solvent includes one or more of PBS, water, ethanol, DMF; the molar mass ratio of isophorone diisocyanate, chiral binaphthol to the coumarin-phenylboronic acid conjugate is (1-1.5):1:1; the temperature of the grafting reaction is 30-70 °C, and the reaction time is 24-48 h.

8. The preparation method of the doxorubicin chiral polyurethane delivery micelle according to claim 4, characterized in that, The fourth solvent includes one or more of ethanol, methanol, acetonitrile, dimethyl sulfoxide, dichloromethane, and methoxypolyethylene glycol; the temperature of the esterification reaction is 80 - 120 °C, and the time of the esterification reaction is 8 - 15 h; the catalyst includes one or more of potassium bisulfate and sodium bisulfate; the molecular weight of the methoxypolyethylene glycol is 1000 - 5000; the molar mass ratio of the methoxypolyethylene glycol, gallic acid, and the catalyst is 1:(1 - 2):(0.2 - 0.4).

9. The preparation method of the doxorubicin chiral polyurethane delivery micelle according to claim 4, characterized in that, The mass ratio of the hydrophobic segment to the methoxypolyethylene glycol gallate is 1:(1 - 2); the temperature of the condensation reaction is 20 - 30 °C, and the reaction time is 2 - 8 h; the temperature of the stirring reaction is 10 - 30 °C, and the reaction time is 10 - 24 h.

10. Use of an adriamycin chiral polyurethane delivery micelle as described in claims 1 - 3 in the preparation of an anticancer drug.

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