Force and GSH dual stimulation triggered hydrophobic block self-degradation type amphiphilic block polymer as well as preparation method and application thereof

Abstract

The invention discloses a force and GSH dual stimulation triggered hydrophobic block self-degradation type amphiphilic block polymer as well as a preparation method and application thereof. The amphiphilic block polymer capable of triggering self-degradation of the hydrophobic segment is composed of three parts: a) a functional element positioned in the center of the amphiphilic block, which can be used as a chromophore and a GSH response element and is used as a self-degradation triggering depolymerization end of the hydrophobic segment, b) a self-degradation hydrophobic block capable of being stimulated to trigger depolymerization, and c) a hydrophilic polymer block. According to the dual-stimulation-triggered hydrophobic block self-degradation type amphiphilic block polymer disclosed by the invention, a self-degradation hydrophobic block is terminated based on a disulfide bond force chromophore or a GSH response element; terminal alkynyl of a disulfide bond functional element on a hydrophobic segment and an azide functionalized chain transfer agent participate in polymerization to obtain a hydrophilic polymer, and the terminal azide group is subjected to a click reaction to obtain the amphiphilic polymer. The centers of the two blocks of the polymer are disulfide bond functional elements, and a force and GSH dual stimulation trigger type self-degradable polymer assembly can be constructed through self-assembly in water.

Description

Technical Field

[0001] The invention relates to the technical field of degradable polymer materials and applications, and in particular to a hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation of force and GSH, and a preparation method and application thereof. Background Art

[0002] In recent years, stimulus-responsive amphiphilic block polymers and their assemblies have shown great potential and application prospects in the field of controlled drug release (European Polymer Journal 172 (2022) 111224, Critical Reviews in Oncology / Hematology 185 (2023) 103961). This type of polymer is usually composed of hydrophilic and hydrophobic blocks, and can self-assemble to form a nanoassembly with a core / shell structure. The hydrophilic block constitutes the outer shell to ensure stability in aqueous solution, and the hydrophobic block constitutes the inner core, which is loaded with hydrophobic drugs. Responsive groups or segments are introduced to enable the assembly to respond to external stimuli (such as pH, temperature, redox, etc.), thereby controlling the release of drugs. It is suitable for responding to the action of the stimulus source to cause the hydrophobicity of the inner core to change to hydrophilicity, thereby achieving stimulus-responsive controlled release of drugs loaded in the hydrophobic core. This intelligence enables the release of drugs at specific times, places and conditions, greatly improving the efficacy and safety of drugs (Chem. Commun., 2012, 48, 7542-7552, Chem. Eur. J. 2015, 21, 13164-13174, Biomater. Sci., 2021, 9, 38-50). However, the current drug controlled release process of stimulus-responsive amphiphilic block polymers mainly relies on the stimulus source to stimulate the hydrophobic segment to undergo chemical changes and transform from hydrophobic to hydrophilic, but the transformation is often incomplete, resulting in the presence of hydrophobic structures, resulting in a relatively low drug release rate; at the same time, the hydrophobic to hydrophilic transformation process is affected by the chemical reaction kinetics, one stimulus signal can only make one element respond, the transformation process is relatively slow, and the transformation process is uncontrollable, resulting in the drug release efficiency and release rate controllability is still slightly poor (Chem. Mater. 2024, 36, 4054-4077, Biomacromolecules 2023, 24, 4958-4969, Polym. Chem., 2022, 13, 3294-3303).

[0003] In recent years, a class of self-degradable polymers has attracted widespread attention. Under the action of appropriate stimuli, the end groups can be removed, and then the polymer chain undergoes tandem dissociation from head to tail (J.Am.Chem.Soc.2008,130(16):5434-5435). In 2014, Professor Liu Shiyong of the University of Science and Technology of China and others successfully constructed self-degradable polymer vesicles triggered by light and reducing environment, and applied them to drug controlled release (J.Am.Chem.Soc.2014,136(20):7492-7497). In 2016, Professor Li Zichen of Peking University and others successfully prepared H2O2-triggered self-degradable poly(ester-amide) system, and used it to construct nanoassemblies, realizing the controlled release of model drugs (Macromol ecules,2013,46(21):8416-8425). Self-degradable polymers have many advantages: 1) By changing the end-capping group, the polymer can respond to different stimuli and induce self-degradation; 2) Self-degradation is actually sequential depolymerization, and the degree of degradation is extremely high; 3) There are rich varieties, some systems are highly stable and easy to construct self-degradable amphiphilic block polymers and their assemblies. This type of self-degradable polymer assembly can be sequentially depolymerized under the action of external stimuli, achieving efficient degradation of the hydrophobic block, and finally all converted into a single hydrophilic block, with a high degree of degradation and efficient chemical transformation; at the same time, one stimulus signal can achieve the depolymerization of a self-degradable hydrophobic segment, the stimulus source has a high degree of response, the transformation process is relatively fast, and the transformation process is highly controllable, and the drug release efficiency and release rate are high and controllable. Based on the functional element (stimulus source) end-capped self-degradable polymer acting as a hydrophobic block to obtain an amphiphilic block polymer and its assembly, it has important application value in achieving controlled drug release, especially highly controllable release rate and efficiency.

[0004] In recent years, the construction of GSH-responsive amphiphilic block polymers based on disulfide bond primitives and the realization of controlled release of drugs from their assemblies have been widely studied. The introduction of disulfide bonds is the key because it can be broken under the action of GSH in tumor cells, thereby triggering the release of drugs. This responsive mechanism enables precise delivery and controlled release of drugs in a specific time and space, allowing drugs to be efficiently released at the lesion site, reducing damage to normal tissues (Colloids and Surfaces B: Biointerfaces 247 (2025) 114421, Chem. Eur. J. 2015, 21, 13164-13174, Chem. Eur. J. 2023, 29, e202300594, RSC Adv., 2019, 9, 37232-37240). In addition, in recent years, more and more researchers have constructed ultrasound-responsive amphiphilic block polymers based on disulfide bonds as force chromophores, and prepared amphiphilic assembly systems that are chemically bonded or embedded with drug molecules, and achieved controllable and efficient drug release through ultrasonic action. Among them, the introduction of disulfide bonds is still the key, allowing the polymer to break under the action of ultrasound, thereby achieving precise drug release. It is particularly noteworthy that ultrasound, as a non-invasive external stimulation method, has the advantages of strong controllability and great penetration depth, which makes it possible for remote controlled release of drugs. For example, Professor Herrmann and others used disulfide bonds (-SS-) force chromophores to successfully construct a polymer system that triggers a cascade reaction by mechanical force and achieves controlled release of drugs or model molecules (J.Am.Chem.Soc.2020,142,14725-14732). In addition, they also successfully realized the construction of an ultrasound-induced luminescence response system based on disulfide bond chromophores and similar polymer systems (CCS Chem. 2021, 3, 2333-2344). Furthermore, they also constructed an application system for ultrasound-induced drug molecule release and simultaneous luminescence to achieve drug release tracking (Chem. Sci., 2021, 12, 1668-1674). Although many drug controlled release systems have been constructed based on disulfide bonds, the reported systems mostly rely on disulfide bonds to covalently bond drug molecules. Under the action of GSH or ultrasound, the disulfide bonds break and the drug molecules are released. One stimulation signal can only stimulate the release of one drug molecule, the drug release efficiency is low, and the drug release rate is not ideal.

[0005] In view of the above, if the disulfide-terminated self-degradable polymer can act as a hydrophobic block and introduce a hydrophilic block through subsequent chemical modification, or an amphiphilic block polymer and its assembly can be constructed, the application of the dual stimulus responsive amphiphilic block polymer assembly to drug controlled release can be realized, and the drug controlled release rate and efficiency can be highly controlled. The development of the above system brings an important opportunity for the research and development of a new multi-responsive drug controlled release system. Although the target system has a strong novelty and high application promotion value, due to the great challenges in its synthesis, the current research is almost blank. Summary of the invention

[0006] In view of this, the technical problem to be solved by the present invention is to provide a self-degradable amphiphilic block polymer with hydrophobic blocks triggered by dual stimulation of force and GSH, and a preparation method and application thereof, and to obtain the corresponding assembly by self-assembly in a solvent, and to regulate and control the depolymerization of the hydrophobic segment of the polymer in the assembly by means of GSH stimulation or ultrasonic action, so as to achieve controllable degradation of the assembly, which can be used to develop new drug transport carrier materials.

[0007] To achieve the above purpose, the technical scheme adopted by the present invention is: GSH and force-triggered hydrophobic block self-degradable amphiphilic block polymers are modified with disulfide-based force chromophores or GSH response units end-capped polyaromatic carbonates and other self-degradable hydrophobic blocks, and the end-alkyne groups of the hydrophilic polymers obtained by polymerization with azide functionalized chain transfer agents participate in the click reaction to prepare the amphiphilic block polymers. The two-block center of the polymer is a disulfide bond, and self-assembly in water can construct a GSH and force dual stimulus-triggered self-degradable polymer assembly. Under the action of GSH and ultrasound, the assembly induces the breakage of the disulfide bond end group to generate a thiol-terminated self-degradable polymer, and the end group rapidly undergoes an intramolecular cyclization reaction, which then triggers a continuous elimination reaction to cause depolymerization, promotes the degradation of the assembly, and is suitable for use as a carrier material for controlled release of drugs under dual stimulus response. The present invention realizes the construction and application of ultrasound and GSH dual stimulus-responsive self-degradable drug carriers, and has important application value in the field of controlled release of new drugs.

[0008] The present invention provides a hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation of force and GSH, and the general structural formula thereof is as follows:

[0009]

[0010] Wherein: m is selected from 100-400, n is selected from 1-3, and k is selected from 30-200;

[0011] The polymer consists of three parts: a) a functional unit located in the center of the amphiphilic block can act as both a chromophore and a GSH response unit and serve as a triggering depolymerization end for the self-degradation of the hydrophobic segment, b) a self-degradable hydrophobic block that can be depolymerized by stimuli, and c) a hydrophilic polymer block.

[0012] Furthermore, the present invention also provides a method for preparing a self-degradable amphiphilic block polymer with a hydrophobic block triggered by dual stimulation of force and GSH, the method comprising: using a capped polyaromatic carbonate or polyanisole that is stable to heat, light, acid and alkali, etc. as a self-degradable hydrophobic block, capping the hydrophobic block with a disulfide-based force chromophore modified with an alkynyl group or a GSH response unit, and preparing an amphiphilic block polymer by a click reaction between the terminal alkynyl group of the hydrophobic segment and the terminal azide group of the hydrophilic polymer obtained by polymerization with an azide-functionalized chain transfer agent.

[0013] Furthermore, in the above technical solution, the disulfide bond-based chromophore or GSH response motif used as a trigger motif to cap the self-degradable hydrophobic block is selected from one of the structural compounds shown below:

[0014]

[0015] According to the difference in the main structure of the functional motifs, they can be divided into two categories. The two types of disulfide motifs have slightly different cyclization elimination reactions after cleavage induced by force or GSH stimulation, and the subsequent depolymerization rates of the hydrophobic blocks may be different;

[0016] Furthermore, in the above technical solution, the synthesis route of the disulfide bond system of the triggering element-terminated self-degradable hydrophobic block is as follows:

[0017]

[0018] Furthermore, in the above technical solution, the self-degradable hydrophobic block that can trigger depolymerization is selected from end-capped polyaromatic carbonate or polyanisole, and the structure is as follows:

[0019] Polybenzyl carbamate, Polyaromatic carbonate, Polythiocarbonate, Polyanisole, Polyphthalaldehyde, in the above structure, End-cap is the aforementioned disulfide bond-based chromophore or GSH response unit, and R is selected from H, CH3 or OCH3.

[0020] Furthermore, in the above technical scheme, aromatic carbonate or anisole is used as a monomer to prepare the end-capped polyaromatic carbonate or polyanisole hydrophobic block by low-temperature anionic polymerization. In the polymerization process, a trace amount of methanol is used as an initiator, P2-t-Bu phosphazene base is used as a catalyst, benzyl carbamate, aromatic carbonate, thiocarbonate, anisole or o-phthalaldehyde is used as a monomer, and a low-temperature polymerization method (-20°C) is adopted under an inert gas atmosphere. A one-step method or a two-step method is adopted. After a certain period of polymerization, phosgene functionalized disulfide bond functional units are used as end-capping agents, and the end-capped stable polymer is achieved by means of the efficient reaction between phosgene and the terminal hydroxyl group of the self-degradable hydrophobic block polymer, and the hydrophobic block polymer is given a force-responsive or GSH-responsive functionalization.

[0021] Furthermore, in the above technical scheme, a method for preparing the triggerable depolymerization self-degradable hydrophobic block polymer is also provided, the method comprising: controlling the molar ratio of initiator methanol to monomer to be 1:100-1:400, the molar ratio of initiator methanol to P2-t-Bu phosphazene base catalyst to be 2:1-1:4, and the molar ratio of end-capping agent disulfide bond functional unit to initiator methanol to be 2:1-5:1.

[0022] Furthermore, in the above technical scheme, a method for preparing a hydrophilic polymer block in a hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation of force and GSH is also provided, the method comprising: initiating the polymerization of hydrophilic monomers with azobisisobutyronitrile (AIBN) in the presence of a terminal azide group functionalized trithioester chain transfer reagent, the molar ratio of the azide group functionalized trithioester chain transfer reagent and the initiator AIBN is 3:1-8:1, the molar ratio of the azide group functionalized trithioester chain transfer reagent to the monomer is 1:200-1:600, the solvent is selected from dioxane, tetrahydrofuran, anisole, DMF, DMSO or acetonitrile, and the reaction temperature is 70-90°C.

[0023] Furthermore, in the above technical solution, the hydrophilic monomer is selected from at least one of N-isopropylacrylamide, 2-(2-methoxyethoxy)ethyl methacrylate, oligo(ethylene glycol) methyl ether methacrylate, polyethylene glycol methyl ether acrylate, N,N-dimethylacrylamide, acrylamide, vinyl pyrrolidone and vinyl imidazole.

[0024] Furthermore, in the above technical scheme, a method for preparing a hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation of force and GSH is also provided, the method comprising: preparing an amphiphilic block polymer by a click chemical reaction between the terminal alkyne group of the hydrophobic self-degradable polymer and the azide at the terminal of the hydrophilic polymer block.

[0025] In addition, the present invention also describes the application of the hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation of force and GSH as a drug carrier to achieve the controlled release of drugs responsive to dual stimulation of ultrasound and GSH.

[0026] Further, in the above technical scheme, the application of the stimulus-triggered hydrophobic block self-degradable amphiphilic block polymer in GSH stimulus-responsive controlled release drugs is also provided, the application comprising: obtaining the corresponding assembly (concentration 0.1 mg / mL-1 mg / mL, as a preferred concentration of 0.2 mg / mL) by self-assembly in pure water, and loading the drug molecule (model drug molecule Nile Red) by physical embedding method. Take 1 mL of the assembly with a concentration of 0.2 mg / mL in a 10 mL sample bottle, add 1 mL of phosphate buffer solution (pH=6.0, 200 mM), and then add 0.2 mL of glutathione (GSH) aqueous solution with a concentration of 100 mM, and then incubate the mixed system at 37°C, take samples and monitor at fixed time points, test the depolymerization of the molecular chain level after triggering by gel permeation chromatography, observe the changes in the physical properties of the polymer particles after the triggered depolymerization by nanoparticle tracking analyzer and transmission electron microscope, and track the polymer degradation and the fluorescence emission before and after the drug release by fluorescence spectroscopy.

[0027] Furthermore, in the above technical scheme, a method for applying a stimulus-triggered hydrophobic block self-degradable amphiphilic block polymer in ultrasonic controlled drug release is also provided, the method comprising: obtaining a corresponding assembly (concentration 0.1 mg / mL-1 mg / mL) by self-assembly in a solvent (pure water or a mixed solvent), and loading drug molecules (model drug molecule Nile red) by physical encapsulation, and then regulating and controlling the depolymerization of the hydrophobic segment of the polymer in the assembly with the help of ultrasonic action and power (1%-30%) to achieve controllable degradation of the assembly and controllable release of the drug molecules, specifically: sampling and monitoring at fixed time points, and tracking the degradation process using a fluorescence spectrometer (Nile red is originally embedded in the hydrophobic segment and has strong fluorescence; after ultrasonic degradation, Nile red will be released and the fluorescence will weaken) (Note: the entire ultrasonic process is carried out under low temperature conditions of 3-5°C).

[0028] The present invention aims to provide a self-degradable amphiphilic block polymer with hydrophobic blocks triggered by dual stimulation of force and GSH and a preparation method thereof, and to apply the same to construct an assembly loaded with drugs, and further to achieve controlled high degradation of the polymer (complete depolymerization of the hydrophobic blocks) through the action of GSH and ultrasound, thereby achieving efficient and controlled release of the loaded drugs. This provides an important opportunity for the research and development of new GSH and ultrasound-responsive drug controlled release systems.

[0029] Advantageous Effects of the Invention

[0030] 1. The hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation of force and GSH described in the present invention has a novel structure, a unique dual response mechanism of force and GSH, and an ingenious synthesis idea, which is of great significance for enriching the research on multi-stimulus triggered self-degradable polymers and their assembly systems and applications;

[0031] 2. The synthesis method of the hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation of force and GSH of the present invention is relatively simple. By adjusting the disulfide force chromophore or reduction response unit structure type, the type of hydrophobic self-degradable polymer and the type of hydrophilic polymer block, as well as the molecular weight of the hydrophilic and hydrophobic blocks and the ratio of the two, a structurally rich amphiphilic block polymer system with different structures, adjustable response sensitivity, and different GSH and ultrasound-induced degradation and drug controlled release characteristics can be obtained;

[0032] 3. The stimulus-responsive amphiphilic block polymers reported so far include systems containing disulfide bonds, and their drug controlled release process mainly depends on the stimulus source stimulus response primitive, or causes the hydrophilic and hydrophobic transitions, or a single stimulus disulfide bond cleavage releases a drug molecule, which often results in incomplete transitions or low release rates, resulting in a relatively slow release process, and slightly poor controllability of drug release efficiency and release rate; while the amphiphilic block polymer assembly based on disulfide bond building power and GSH dual stimulus responsiveness can achieve deep degradation of the assembly through a single stimulus-induced hydrophobic segment depolymerization, and complete structural transformation, thereby assisting in achieving efficient and controllable drug controlled release;

[0033] 4. The force-induced degradation of polymers in the currently reported assemblies is mostly force-induced chain scission, and most of the degradation sites are uncontrollable. After degradation, only two shorter polymer chains are often generated. If they continue to participate in the assembly, irregular aggregates may be formed, and it is difficult to force-induced degradation. Therefore, the degradation process of the assembly is uncontrollable and the degree of force-induced degradation is generally low. The above disadvantages seriously restrict the application of assemblies in controlled drug release. In contrast, the self-degradable amphiphilic block polymers triggered by hydrophobic blocks and their assemblies described in the present invention have better force response characteristics, controllable force-induced degradation, and can achieve the depolymerization of the hydrophobic segment and achieve deep degradation of the polymer assembly, which is of great significance for enriching the research on the force-induced degradation behavior of the assembly and improving its application in the field of controlled drug release. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The disulfide bond-based force chromophore or GSH response motif obtained in Example 1 1 H NMR;

[0035] Figure 2 The anisole self-degradable monomer obtained in Example 3 1 H NMR;

[0036] Figure 3The GPC spectra of the self-degradable hydrophobic block (terminated polyanisole) that can trigger depolymerization in response to stimulus obtained in Example 4 and the self-degradable amphiphilic block polymer of hydrophobic block triggered by dual stimulus of force and GSH obtained in Example 7;

[0037] Figure 4 The self-degradable hydrophobic block that can trigger depolymerization in response to stimulation obtained in Example 4 1 H NMR;

[0038] Figure 5 The hydrophobic block self-degradable amphiphilic block polymer obtained in Example 7 is triggered by dual stimulation of force and GSH. 1 H NMR;

[0039] Figure 6 The dynamic light scattering data diagram (DLS spectrum) of the block polymer assembly obtained in Assembly Example 1;

[0040] Figure 7 This is the TEM electron microscope image of the amphiphilic block polymer assembly obtained in Assembly Example 1.

[0041] Figure 8 The GPC spectrum of the dynamic changes of the block polymer assembly during ultrasonic degradation in Application Example 4;

[0042] Fig. 9 The dynamic changes of the polymer assembly during ultrasonic degradation in Application Example 4 1 H NMR group images;

[0043] Fig.10 The DLS spectrum of the dynamic changes of the block polymer assembly during ultrasonic degradation in Application Example 4;

[0044] Fig.11 This is the dynamic fluorescence change spectrum of the GSH stimulation-responsive controlled release of Nile red loaded in the assembly in Application Example 6;

[0045] Fig.12 Schematic diagram of the retrosynthetic analysis of the hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation of force and GSH of the present invention. DETAILED DESCRIPTION

[0046] The present invention will be further described below in conjunction with specific implementations. The structures of the hydrophobic block self-degradable amphiphilic block polymers obtained in the following examples of the present invention were determined by nuclear magnetic resonance (H NMR) spectroscopy. 1H NMR) was used to characterize the polymers. The relative molecular weight and molecular weight distribution of the polymers were determined by gel permeation chromatography (Viscote k270 HPLC pump, Viscotek gel chromatography columns (G2000H HR, G3000H HR, and G4000H HR), Viscotek differential refractive index detector, containing chromatographic grade tetrahydrofuran (THF) at a column temperature of 35°C and a flow rate of 1.0 mL / min). Brookhaven 173 Plus dynamic light scattering instrument and JEOL JEM-ACE200F transmission electron microscope were used to detect the assembly behavior of the amphiphilic polymers to confirm the formation of the amphiphilic structure. Hitachi F-7000 fluorescence spectrometer was used to detect the fluorescence characteristics of the model drug molecules before and after ultrasonic release.

[0047] In order to further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the present invention.

[0048] Example 1: Synthesis of disulfide bond-based mechanochromophore or GSH-responsive motif (based on disulfide diol as raw material)

[0049] The disulfide bond-based force chromophore or GSH response motif (based on disulfide glycol as raw material) used in the present invention is obtained by the following method:

[0050]

[0051] 1) Under nitrogen atmosphere, 4-pentynoic acid (7.08 mmol, 0.6945 g) was dissolved in 20 mL of dry dichloromethane at 0°C, and then N, N'-dicyclohexylcarbodiimide (1.753 g, 1.2 eq.) was added and stirred at 0°C for 10 minutes, followed by addition of 2,2-dithiodiethanol (2.184 g, 2 eqv.) and DMAP (50 mg), and stirred at room temperature overnight. Dichloromethane was removed under reduced pressure, 50 mL of ethyl acetate was added, and the solution was filtered. The filtrate was evaporated to remove the solvent to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain an intermediate product;

[0052] 2) Under nitrogen atmosphere, triphosgene (0.50 g, 1.7 mmol) and anhydrous tetrahydrofuran (20 mL) were added to a round-bottom flask dried by a high-temperature flame drying gun equipped with a stirring magnet. The solution system was cooled to 0°C in an ice bath, and then the intermediate (1.175 g, 5 mmol) obtained by the one-step synthesis and anhydrous pyridine (0.40 mL, 5.0 mmol) were added dropwise and dissolved in anhydrous tetrahydrofuran solution (35 mL). A white precipitate was formed soon after the addition. In a dry nitrogen atmosphere glove box, the slurry was filtered with a silica gel column to remove insoluble by-products, and the solvent was vacuum-evaporated to obtain a dry crude mixture, which was added to dry dichloromethane (20 mL), further filtered twice in the glove box, and continued to concentrate by rotary evaporation to obtain a white powdery final product, which was stored in a glove box under a nitrogen atmosphere. Its structure was characterized by nuclear magnetic hydrogen spectrum, and the results were shown in Figure 1 .

[0053] Example 2: Synthesis of disulfide-based force chromophore or GSH-responsive motif (based on pyridine disulfide as raw material)

[0054] The disulfide bond-based force chromophore or GSH response motif (based on pyridine disulfide as a raw material) used in the present invention is obtained by the following method:

[0055] 1) Pyridine dithiomonocarboxylic acid (6.8 g, 31.6 mmol) and dry triethylamine (4.6 mL, 38.00 mmol) were dissolved in 20 mL dry dichloromethane, and triisopropylsilane (TIPSCl, 6.09 g, 31.6 mmol) was added dropwise at 0°C. After the addition was completed, the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the dichloromethane was removed from the reaction mixture by rotary evaporation, and the mixture was diluted with ethyl acetate (100 mL). The organic layer was separated by extraction, washed with saturated sodium bicarbonate solution and brine, and finally dried with anhydrous magnesium sulfate. The ethyl acetate was removed by rotary evaporation, and the crude product was purified by column using petroleum ether / ethyl acetate (10 / 1) as eluent to obtain an intermediate product;

[0056]

[0057] 2) The intermediate (5 g, 13.461 mmol) synthesized in the previous step was dissolved in 15 mL of dry tetrahydrofuran, and then 2-mercaptoethanol (1.26 g, 16.15 mmol) was added dropwise to the obtained solution, and then the mixed solution was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was spin-dried to obtain a crude product, which was further purified by silica gel column with petroleum ether / ethyl acetate (4 / 1) as eluent to obtain an intermediate product;

[0058] 3) Under nitrogen atmosphere, 4-pentynoic acid (7.08 mmol, 0.6945 g) was dissolved in 20 mL of dry dichloromethane at 0°C, and then N,N'-dicyclohexylcarbodiimide (1.753 g, 1.2 eqv.) was added and stirred at 0°C for 10 minutes. Then, the intermediate (5.38 g, 2 eqv.) and DMAP (50 mg) obtained in the previous step were added and stirred at room temperature overnight. Dichloromethane was removed under reduced pressure, 50 mL of ethyl acetate was added, and the solution was filtered. The filtrate was evaporated to remove the solvent to obtain a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain an intermediate;

[0059] 4) The intermediate (1g) synthesized in the previous step was dissolved in 3mL of dry anhydrous pyridine and 3mL of anhydrous acetonitrile, and 5mL of pyridine hydrofluoride was added to the solution. The solution was stirred for 30 minutes, and then 50mL of ethyl acetate was added to quench the reaction. The organic layer was then extracted and separated, washed with water, saturated copper sulfate solution and brine, and the organic solution was dried over anhydrous magnesium sulfate, and finally concentrated by rotary evaporation to obtain a crude product. Purification by silica gel column (eluent: hexane / ethyl acetate = 1 / 1) gave an intermediate product;

[0060] 5) The intermediate (6 g) synthesized in the previous step was dissolved in 50 mL of dry anhydrous dichloromethane, and then thionyl chloride (5.47 mL, 75.0 mmol) and N,N'-dimethylformamide (194 μL, 0.05 mmol) were added thereto, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed by rotary evaporation to obtain the final product, which was directly used for the end-capping reaction without further treatment.

[0061] Example 3: Synthesis of anisole self-degradable monomer

[0062] The anisole self-degradable monomer used in the present invention is obtained by the following method: concentrated hydrochloric acid (36% w / v, 15 mL) is added dropwise to a mixed solution of 2,6-dimethylphenol (10.7 g, 87.6 mmol) in petroleum ether (44 mL, 2.0 M) and formaldehyde aqueous solution (37% w / v, 16 mL, 198 mmol), and the mixture is added dropwise at room temperature for 10 minutes. The reaction mixture is then stirred at room temperature for 2 hours. After the time is up, the reaction mixture is poured into 400 mL of deionized water. A white suspension is found to appear, and stirring is continued at room temperature for 20 minutes. The white solid is then collected by filtration, washed with a large amount of water (300 mL), and finally dried overnight in vacuo at 70°C to obtain the starting material;

[0063]

[0064] 1) Add iodomethane (890 μL, 14.3 mmol) dropwise to a DMF (40 mL, 0.35 M) solution of the starting material (3.66 g, 14.3 mmol) and potassium carbonate (2.17 g, 15.7 mmol). The reaction mixture was stirred at room temperature for 24 hours. It was then extracted with ethyl acetate (4×75 mL). The combined organic phases were washed with brine (100 mL) and dried over anhydrous magnesium sulfate. The solids were then filtered off and the solution was concentrated by rotary evaporation. A yellow crude product was obtained, which was purified by silica gel column chromatography (10-40% ethyl acetate / petroleum ether gradient elution) to obtain an intermediate;

[0065] 2) Silver oxide (3.64 g, 15.7 mmol) was added to a solution of the intermediate (2.12 g, 7.85 mmol) obtained in the previous step in ether (79 mL, 0.1 M), and the reaction mixture was stirred at room temperature for 16 hours. The solvent was then evaporated to obtain a yellow solid, which was recrystallized from boiling cyclohexane to obtain a bright yellow final product. Its structure was characterized by H NMR, and the results were shown in Figure 2 , proving that the synthesized anisole self-degradable monomer was successfully synthesized.

[0066] Example 4: Synthesis of self-degradable hydrophobic block (capped polyanisole) that can trigger depolymerization in response to stimulus (based on the disulfide responsive motif synthesized in Example 1 as the capping agent)

[0067] The stimulus-responsive self-degradable hydrophobic block (terminated polyanisole) used in the present invention that can trigger depolymerization is obtained by the following method:

[0068] One-step synthesis: A 10 mL Schlenk bottle equipped with a stirring magnet was flame-dried under vacuum and purged with N2. Afterwards, the system was transferred to a glove box, and the anisole self-degradable monomer synthesized by the method of Example 3 (0.230609 g, 0.86 mmol, 1 eq) was added to the Schlenk bottle, and then 1 mL of dry THF was injected with a syringe. Afterwards, an initiator solution was prepared, 34.5 μL of dry methanol was taken with a micro syringe and dissolved in 2 mL of dry THF, 6 μL of the initiator solution was taken with a micro syringe and added to the monomer solution in the Schlenk bottle, and then 2.1 μL of P2-t-Bu phosphazene base solution (2M THF solution; 0.00427 mmol) was immediately added. The reaction mixture was stirred at -20°C for 4.5 hours, and then the disulfide response unit synthesized in Example 1 (1.2 eq, 310 mg) and imidazole (70.3 mg, 1.2 eq) were added to the solution. After that, the solution was stirred and reacted for 16 hours at 5°C, and then cold MeOH (60 mL) was added at -20°C for precipitation three times. A white self-degradable hydrophobic block (capped polyanisole) terminated with a disulfide-responsive motif was obtained. The molecular weight and distribution of the self-degradable hydrophobic block (capped polyanisole) are shown in Figure 3 (above), its structure was characterized by H NMR spectroscopy, and the results showed Figure 4 .

[0069]

[0070] Two-step synthesis: In order to further increase the degree of polymerization of the hydrophobic block, the polymerization reaction is carried out step by step by a separate initiation. Two Schlenk flasks (10 mL) equipped with stirring magnets are prepared in advance and flame-dried under vacuum. The system is transferred to a glove box, and then anisole self-degradable monomer (100 mg, 0.33 mmol) and ultra-dry THF (0.30 mL) synthesized by the method of Example 3 are added to one of the flasks. Then, at a temperature of -20°C, ultra-dry MeOH (6.9 μL, 0.171 mmol) and P2-t-Bu phosphazene base solution (80 μL, 0.171 mmol) are added to the flask in sequence. The solution is stirred and polymerized for 45 minutes. During this period, anisole self-degradable monomer (0.25 g, 0.86 mmol) and 1 mL ultra-dry THF synthesized by the method of Example 3 are added to another reaction flask, precooled to -20°C, and 20 μL of initiator solution is taken by a micro syringe and added to the reaction solution for polymerization for 1 hour. Then, the reaction mixture was quenched with disulfide responsive motif (1.2 eq, 310 mg) and imidazole (70.3 mg, 1.2 eq), and the solution was stirred and reacted for 16 hours at 5°C. Finally, cold MeOH (60 mL) was added at -20°C for precipitation 3 times to obtain a white disulfide responsive motif-terminated self-degradable hydrophobic block (terminated polyanisole).

[0071] Example 5: Synthesis of self-degradable hydrophobic block (capped polyanisole) that can trigger depolymerization in response to stimulus (based on the disulfide responsive motif synthesized in Example 2 as the capping agent)

[0072] The stimulus-responsive self-degradable hydrophobic block (terminated polyanisole) used in the present invention that can trigger depolymerization is obtained by the following method:

[0073] One-step synthesis: A 10 mL Schlenk bottle equipped with a stirring magnet was flame-dried under vacuum and purged with N2. Afterwards, the system was transferred to a glove box, and the anisole self-degradable monomer (0.230609 g, 0.86 mmol, 1 eq) synthesized by the method of Example 3 was added to the Schlenk bottle, and then 1 mL of dry THF was injected with a syringe. Afterwards, an initiator solution was prepared, 34.5 μL of dry methanol was taken with a microsyringe and dissolved in 2 mL of dry THF, 6 μL of the initiator solution was taken with a microsyringe and added to the monomer solution in the Schlenk bottle, and then 2.1 μL of P2-t-Bu phosphazene base solution (2M THF solution; 0.00427 mmol) was immediately added. The reaction mixture was stirred at -20°C for 4.5 hours, and then the disulfide response unit synthesized in Example 2 (more than 1.2 eq, 400 mg) and imidazole (70.3 mg, 1.2 eq) were added to the solution. After that, the solution was stirred and reacted for 16 hours at 5° C., and then cold MeOH (60 mL) was added for precipitation three times at −20° C. Thus, a white self-degradable hydrophobic block (terminated polyanisole) capped with a disulfide-responsive motif was obtained.

[0074]

[0075] Two-step synthesis: In order to further increase the degree of polymerization of the hydrophobic block, the polymerization reaction is carried out step by step using a separate initiation method. Two Schlenk flasks (10 mL) equipped with stirring magnets are prepared in advance and flame-dried under vacuum. The system is transferred to a glove box, and then anisole self-degradable monomer (100 mg, 0.33 mmol) and ultra-dry THF (0.30 mL) synthesized by the method of Example 3 are added to one of the flasks. Then, at a temperature of -20°C, ultra-dry MeOH (6.9 μL, 0.171 mmol) and P2-t-Bu phosphazene base solution (80 μL, 0.171 mmol) are added to the flask in sequence. The solution is stirred and polymerized for 45 minutes. During this period, anisole self-degradable monomer (0.25 g, 0.86 mmol) and 1 mL ultra-dry THF synthesized by the method of Example 3 are added to another reaction flask, precooled to -20°C, and 20 μL of initiator solution is taken by a micro syringe and added to the reaction solution for polymerization for 1 hour. Then, the reaction mixture was quenched with disulfide responsive motif (more than 1.2 eq, 400 mg) and imidazole (70.3 mg, 1.2 eq), and the solution was stirred at 5° C. for 16 hours. Finally, cold MeOH (60 mL) was added at -20° C. for precipitation 3 times to obtain a white disulfide responsive motif-terminated self-degradable hydrophobic block (terminated polyanisole).

[0076] Example 6: Preparation of hydrophilic polymer blocks by chain transfer free radical polymerization using a chain transfer reagent with an azide group at the end

[0077] The chain transfer reagent with an azide group at the end used in the present invention participates in chain transfer free radical polymerization to prepare the hydrophilic polymer block by the following method:

[0078]

[0079] NIPAM (5.70 g, 55.6 mmol, 400 eq.), a chain transfer reagent with an azide group at the end (48 mg, 0.111 mmol, 1 eq.), azobisisobutyronitrile purified by ethanol recrystallization (3.7 mg, 0.0222 mmol, 0.2 eq.) and dry DMF (3 mL) were transferred to a 20 mL dry Schlenk flask. The solution was freeze-thawed and vacuum-filled with nitrogen 3-5 times. After fully removing the dissolved oxygen, nitrogen was passed. Finally, the flask was sealed with a rubber stopper and stirred in a 70°C oil bath. After the required time, the rubber stopper was opened to ventilate, and 5 mL of THF was added to fully dissolve. The polymer solution was added dropwise to n-hexane for precipitation. The collected hydrophilic polymer block was vacuum dried at 50°C.

[0080] Example 7: Synthesis of hydrophobic block self-degradable amphiphilic block polymers triggered by dual stimulation of force and GSH

[0081] The hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation of force and GSH used in the present invention is obtained by the following method:

[0082]

[0083] The target amphiphilic block polymer is prepared by a click chemistry reaction between a hydrophobic self-degradable polymer with an alkyne group at the terminal and a hydrophilic polymer block with an azide group at the terminal.

[0084] Weigh 3 mg of copper sulfate pentahydrate and sodium L-ascorbate, respectively, and dissolve them in 1 mL of deoxygenated water. Take a sample bottle, add high-purity water (1 mL), and add a DMF mixture (100 mL) of a hydrophilic polymer block with an azide group at the end and a self-degradable hydrophobic block that can trigger depolymerization in response to stimulus response. Then, add it dropwise to the sample bottle containing the catalyst (copper sulfate pentahydrate and sodium L-ascorbate) under ultrasonic conditions. After the addition is completed, continue ultrasonication for 10 minutes and react in a 40°C water bath overnight. After the reaction is completed, transfer them to dialysis bags (Mw 14000) respectively, first dialyze in a saturated aqueous solution of EDTA-2Na, and then dialyze in high-purity water to remove other impurities, and obtain a self-degradable amphiphilic block polymer with hydrophobic blocks triggered by dual stimulation of force and GSH. The molecular weight and distribution of amphiphilic block polymers can be found in Figure 3 (below), its structure was characterized by H NMR spectroscopy, and the results are shown in Figure 5 .

[0085] Assembly Example 1: Preparation of hydrophobic block self-degradable amphiphilic block polymer assembly triggered by dual stimulation of force and GSH (assembly in pure water)

[0086] 50 mg of the amphiphilic polymer prepared in Example 7 was dissolved in 0.5 mL of DMF, and then slowly dripped into 10 mL of deionized water while stirring. The assembly solution was then placed in a dialysis bag and dialyzed in water for two days, with the water changed 4 times in between to remove DMF. The assembly solution was diluted to a concentration of 0.1-1.0 mg / mL, and its particle size and particle size distribution or morphology was measured using a dynamic light scattering instrument and a transmission electron microscope, as shown in the attached figure. Figure 6 and 7 .

[0087] Assembly Example 2: Preparation of hydrophobic block self-degradable amphiphilic block polymer assembly triggered by dual stimulation of force and GSH (assembly in mixed solvent)

[0088] 50 mg of the amphiphilic polymer prepared in Example 7 was dissolved in 25 mL of DMF, and then slowly dripped into 25 mL of deionized water while stirring to obtain a mixed solvent assembly. The assembly solution was diluted to a concentration of 0.1-1.0 mg / mL, and its particle size and particle size distribution or morphology was measured using a dynamic light scattering instrument and a transmission electron microscope.

[0089] Application Example 1: GSH-induced reduction degradation of hydrophobic block self-degradable amphiphilic block polymers at the single chain level triggered by dual stimulation of force and GSH

[0090] 10 mg of the amphiphilic polymer prepared in Example 7 was dissolved in 50 mL of DMF (concentration 0.2 mg / mL). 1 mL of the 0.2 mg / mL polymer solution was taken, and 0.2 mL of a 100 mM glutathione (GSH) aqueous solution was added, and then the mixed system was incubated at 37° C. Samples were taken at fixed time points for monitoring, and the degradation process was monitored by gel permeation chromatography and nuclear magnetic resonance hydrogen spectroscopy.

[0091] Application Example 2: Dual stimulation of force and GSH triggers the single-chain ultrasonic degradation of hydrophobic block self-degradable amphiphilic block polymers

[0092] Take 30 mg of the amphiphilic polymer prepared in Example 7 and dissolve it in 10 mL of DMF (concentration 3 mg / mL). Pass the system through a 220 nm organic filter membrane, insert the ultrasonic probe into the DMF solution of the above polymer using a probe-type ultrasonic device, and conduct ultrasonic degradation experiments using 1%, 5%, 10% and 30% ultrasonic powers, at intervals of 1 h, 2 h, 4 h and 6 h (ultrasonic mode: 1 s on and 1 s off, ultrasound 1 s pause 1 s) using gel permeation chromatography (GPC) and nuclear magnetic hydrogen spectrum to monitor the degradation process. (Note: The entire ultrasonic process is carried out at a low temperature of 3-5 ° C)

[0093] Application Example 3: GSH-induced reductive degradation of hydrophobic block self-degradable amphiphilic block polymer assembly (pure water) triggered by dual stimulation of force and GSH

[0094] The assembly solution (concentration 0.2 mg / mL) was obtained by using assembly example 1, 1 mL of the assembly with a concentration of 0.2 mg / mL was taken into a 10 mL sample bottle, 1 mL of phosphate buffer solution (pH = 6.0, 200 mM) was added, and then 0.2 mL of a 100 mM glutathione (GSH) aqueous solution was added, and then the mixed system was incubated at 37°C, and samples were taken for monitoring at fixed time points. The depolymerization at the molecular chain level after triggering was tested by gel permeation chromatography, and the changes in the physical properties of the polymer particles after the triggered depolymerization were observed by nanoparticle tracking analyzer and transmission electron microscopy.

[0095] Application Example 4: Ultrasonic degradation of hydrophobic block self-degradable amphiphilic block polymer assembly (pure water) triggered by dual stimulation of force and GSH

[0096] The assembly solution (concentration 0.2 mg / mL) was obtained by using the assembly example 1. The ultrasonic probe was inserted into the above assembly solution using a probe ultrasonic device. Ultrasonic degradation experiments were performed using 1%, 5%, 10% and 30% ultrasonic powers. The appropriate solution was taken out at intervals of 1h, 2h, 4h and 6h (ultrasonic mode: 1s on and 1s off, ultrasound 1s pause 1s). The samples were freeze-dried and the degradation process was monitored by gel permeation chromatography (GPC) and nuclear magnetic hydrogen spectrum. At the same time, the dynamic changes of particle size and particle size distribution were monitored by dynamic light scattering. The relevant results are shown in the table below. Figure 8 , 9 and 10. (Note: The entire ultrasonic process is carried out at a low temperature of 3-5°C)

[0097] Application Example 5: Ultrasonic degradation of hydrophobic block self-degradable amphiphilic block polymer assembly (mixed solvent assembly) triggered by dual stimulation of force and GSH

[0098] The assembly solution obtained in Assembly Example 2 was used for ultrasonic degradation experiments. The ultrasonic probe was inserted into the above assembly solution using a probe-type ultrasonic device, and ultrasonic degradation experiments were performed using 1%, 5%, 10% and 30% ultrasonic powers. The appropriate solution was taken out and dried, and the samples were monitored for degradation using gel permeation chromatography (GPC) and nuclear magnetic hydrogen spectrum. At the same time, the dynamic changes of particle size and particle size distribution were monitored using dynamic light scattering. (Note: The entire ultrasonic process was carried out under low temperature conditions of 3-5°C)

[0099] Application Example 6: Force and GSH dual stimulation triggers the self-degradation of hydrophobic block amphiphilic block polymer assembly after drug loading and GSH-induced reduction degradation to control drug release

[0100] Prepare 1mM Nile Red THF mother solution, take 100 microliters and add 10mL of 3mg / mL solution of the amphiphilic block polymer prepared in Example 7 in THF solution, add 10mL of water slowly at 1mL / h at 25°C, and then dialyze to remove THF. Take 1mL of the assembly with a concentration of 0.2mg / mL in a 10mL sample bottle, add 1mL of phosphate buffer solution (pH=6.0, 200mM), and then add 0.2mL of 100mM glutathione (GSH) aqueous solution, and then incubate the mixed system at 37°C, take samples for monitoring at fixed time points, and use a fluorescence spectrometer to track the degradation and release process (Nile Red is originally embedded in the hydrophobic segment, and the fluorescence is strong; after ultrasonic degradation, Nile Red will be released and the fluorescence will become weak). The results of fluorescence spectrometer monitoring are as follows Fig.11 shown.

[0101] Application Example 7: Ultrasonic controlled release of drug-loaded hydrophobic block self-degradable amphiphilic block polymer assemblies triggered by dual stimulation of force and GSH

[0102] Prepare 1mM Nile Red THF mother solution, take 100 microliters and add to 10mL of 3mg / mL solution of the amphiphilic block polymer prepared in Example 7 in THF solution, slowly add 10mL of water at 1mL / h at 25°C, and then dialyze to remove THF. Use a probe-type ultrasonic device to insert the ultrasonic probe into the assembly solution coated with Nile Red, and use 1%, 5%, 10% and 30% ultrasonic power to perform ultrasonic degradation experiments. Take samples every 10 minutes and use a fluorescence spectrometer to track the degradation and release process (Nile Red is originally embedded in the hydrophobic segment and has strong fluorescence; after ultrasonic degradation, Nile Red will be released and the fluorescence will weaken). (Note: The entire ultrasonic process is carried out at a low temperature of 3-5°C)

[0103] The reverse synthesis analysis of the hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation of force and GSH of the present invention is shown in the schematic diagram Fig.12 .

[0104] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation of force and GSH, the general structural formula of which is as follows: in, m is selected from 100-400, n is selected from 1-3, and k is selected from 30-200; the polymer consists of three parts: a) a functional unit located at the center of the amphiphilic block can act as both a chromophore and a GSH response unit, and serves as a triggering depolymerization end for self-degradation of the hydrophobic segment, b) a self-degradable hydrophobic block that can be stimulated to trigger depolymerization, and c) a hydrophilic polymer block.

2. The method for preparing the hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation of force and GSH as claimed in claim 1, characterized in that: End-capped polyaromatic carbonate or polyanisole is used as a self-degradable hydrophobic block, and the hydrophobic block is capped by a disulfide-based chromophore modified with an alkynyl group or a GSH response unit. The terminal alkynyl group of the hydrophobic segment and the azide functionalized chain transfer agent participate in the polymerization to obtain a hydrophilic polymer terminal azide group, which undergoes a click reaction to prepare an amphiphilic block polymer.

3. The hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation of force and GSH according to claim 2, characterized in that: The disulfide bond-based chromophore or GSH response motif is selected from one of the following structural compounds:

4. The hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation of force and GSH according to claim 3, characterized in that: The synthesis pathway of the disulfide bond-based chromophore or GSH response motif is as follows:

5. The method for preparing the hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation with GSH according to claim 2, characterized in that: The end-capped polyaromatic carbonate or polyanisole, etc., has the following structure: Polybenzyl carbamate, Polyaromatic carbonate, Polythiocarbonate, Polyanisole, Polyphthalaldehyde, wherein: End-cap is the disulfide bond-based chromophore or GSH response motif described in claim 2, and R is selected from H, CH3 or OCH3.

6. The method for preparing the hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation with GSH according to claim 5, characterized in that: The end-capped polyaromatic carbonate or polyanisole hydrophobic block is prepared by low-temperature anionic polymerization using aromatic carbonate or anisole as a monomer. During the polymerization process, a trace amount of methanol is used as an initiator, P2-t-Bu phosphazene base is used as a catalyst, benzyl carbamate, aromatic carbonate, thiocarbonate, anisole or o-phthalaldehyde is used as a monomer, and a low-temperature polymerization method is used in an inert gas atmosphere. A one-step method or a two-step method is used. After a certain polymerization time, phosgene functionalized disulfide bond functional units are used as end-capping agents. The end-capped and stabilized polymer is achieved by means of an efficient reaction between phosgene and the terminal hydroxyl group of the self-degradable hydrophobic block polymer, and the hydrophobic block polymer is given a mechano-responsive or GSH-responsive functionalization.

7. The method for preparing the hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation with GSH according to claim 6, characterized in that: The molar ratio of initiator methanol to monomer is controlled to be 1:100-1:400, the molar ratio of initiator methanol to P2-t-Bu phosphazene base catalyst is controlled to be 2:1-1:4, and the molar ratio of end-capping agent disulfide bond functional unit to initiator methanol is controlled to be 2:1-5:

1.

8. The method for preparing the hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation of force and GSH according to claim 2, characterized in that: The hydrophilic polymer block is prepared by a chain transfer free radical polymerization method, wherein a terminal azide group functionalized trithioester chain transfer reagent participates in AIBN to initiate the polymerization of hydrophilic monomers, the molar ratio of the azide group functionalized trithioester chain transfer reagent to the initiator AIBN is 3:1-8:1, the molar ratio of the azide group functionalized trithioester chain transfer reagent to the monomer is 1:200-1:600, the solvent is selected from dioxane, tetrahydrofuran, anisole, DM, DMSO or acetonitrile, and the reaction temperature is 70-90°C; the hydrophilic monomer is selected from at least one of N-isopropylacrylamide, 2-(2-methoxyethoxy)ethyl methacrylate, oligo(ethylene glycol) methyl ether methacrylate, polyethylene glycol methyl ether acrylate, N,N-dimethylacrylamide, acrylamide, vinyl pyrrolidone and vinyl imidazole.

9. The method for preparing the hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation of force and GSH according to claim 1, characterized in that: The amphiphilic block polymers were prepared by a click chemistry reaction between the terminal alkyne group of the hydrophobic self-degradable polymer and the azide at the terminal of the hydrophilic polymer block.

10. Use of the hydrophobic block self-degradable amphiphilic block polymer triggered by dual stimulation of force and GSH as claimed in claim 1 in drug carriers to achieve ultrasound and GSH dual stimulation responsive controlled drug release.

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