Force-triggered hydrophobic block depolymerization type amphiphilic block polymer as well as preparation method and application thereof

Abstract

The invention discloses a force-triggered hydrophobic block depolymerization type amphiphilic block polymer as well as a preparation method and application thereof. The force-triggered hydrophobic block depolymerization type amphiphilic block polymer is composed of three parts: a) a mechanochromic group located at the center of two blocks as a trigger depolymerization end, b) a self-degradable hydrophobic block capable of triggering depolymerization, and c) a hydrophilic polymer block. The polymer is obtained by blocking a self-degradation hydrophobic block with a DA chromophore and initiating a hydrophilic monomer to polymerize through an alpha-bromo-ester active end group at the tail end of the chromophore. The centers of the two blocks of the polymer are DA force chromophores, and a force-triggered self-degradable polymer assembly can be constructed through self-assembly in water. Under the action of ultrasonic waves, the DA chromophore end group of the assembly is broken, an r-DA reaction is induced, a furan carbonate end-capped self-degradable polymer is generated, the end group is quickly decomposed, a continuous elimination reaction is immediately triggered to depolymerize a hydrophobic block, the assembly is promoted to be degraded, and the assembly is used as a carrier material for controllably releasing drugs.

Description

Technical Field

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

[0002] In recent years, the mechano-degradation behaviors of polymers with various topological structures (including linear, branched, comb-shaped, cross-linked, etc.) have been well studied, and a series of functional materials with self-diagnosis, self-repair or degradable regeneration properties have been developed (Chem. Commun. 2019, 55(48): 6831-6834, Macromolecules, 2019, 52, 9561-9568, Macromol. Chem. Phys. 2016, 217(3): 354-364). However, the mechano-degradation behaviors of complex amphiphilic block polymers and their assemblies have been rarely studied. In particular, due to the limitation of polymer structure and molecular weight threshold of force-induced degradation (Chem. Soc. Rev. 2013, 42 (18), 7497), the force-induced degradation of polymers in amphiphilic block polymers and their assemblies reported so far is only force-induced chain scission, and most degradation sites are uncontrollable. After degradation, only two shorter polymer chains are often generated. If they continue to participate in assembly, irregular aggregates may be formed (Macromol. Chem. Phys. 2011, 212 (5), 498-506). At the same time, it is difficult to force-induced degradation. Therefore, the degradation process of amphiphilic block polymers and their assemblies is uncontrollable and the degree of force-induced degradation is generally low (ACS Macro Letters, 2016, 5 (9): 995-998). The above disadvantages seriously restrict the in-depth research and wide application of force-induced degradation of amphiphilic block polymers and their assemblies.

[0003] In recent years, a class of polymers with triggered self-degradation ability (self-immolative polymers) has attracted widespread attention. Under the action of appropriate stimuli, the end groups can be removed, and then the polymer chain undergoes cascade 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 (Macro molecules,2013,46(21):8416-8425). Self-degradable polymers have many advantages: 1) by changing the end groups, the polymers 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 it is easy to construct self-degradable amphiphilic block polymers and their assemblies.

[0004] In recent years, significant progress has been made in constructing stimulus-responsive self-degradable amphiphilic polymers and their assemblies using functional motif-terminated self-degradable polymers (J. Am. Chem. Soc. 2014, 136 (20): 7492-7497, Macromolecules, 2013, 46 (21): 8416-8425, Acta Polymerica Sinica, 2017, 6, 937-945), but force (stimulus)-triggered self-degradable amphiphilic block polymers and their assemblies have not been reported so far. To achieve their successful construction, it is crucial to facilitate mechanical force as a stimulus source. Using force-responsive functional motifs to terminate self-degradable polymers is a feasible approach, but it is necessary to find or design suitable force-responsive functional motifs. Diels-Alder (DA) mechanochromophore is a classic force-responsive functional unit. In 2019, Professor Robb et al. constructed a polymer system with mechanical force-triggered cascade reactions based on DA mechanochromophore (J.Am.Chem.Soc.2019,141(38):15018-15023). In theory, it is possible to construct the target system by using DA mechanochromophore to terminate self-degradable polymers and then synthesize amphiphilic block polymers. Based on the target polymer, applying stress can induce r-DA reaction to generate furan carbonate-terminated self-degradable polymers. The end groups decompose rapidly, and then trigger continuous elimination reactions to cause depolymerization, which promotes the degradation of polymers and their assemblies, and has the application potential of controlled release drugs.

[0005] It is expected that the constructed force-triggered hydrophobic block depolymerization type amphiphilic block polymer can achieve DA mechanochromophore cleavage with the help of ultrasound, and then trigger the depolymerization of the hydrophobic segment sequence to achieve high degradation. At the same time, the degradation process can be controlled by regulating whether ultrasound is applied. The assembly constructed by amphiphilic polymers can be used as a drug controlled release carrier. The controllable force-induced degradation of the polymer carrier can be achieved through ultrasound, thereby achieving controlled release of the drug. The development of the above system brings important opportunities for the research and development of new ultrasound-responsive drug controlled release systems. Although the target system has a strong novelty and high application and 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 force-triggered hydrophobic block depolymerization type amphiphilic block polymer and a preparation method 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 with the help of ultrasonic wave 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 solution adopted by the present invention is: the force-triggered hydrophobic block depolymerization type amphiphilic block polymer is obtained by Diels-Alder (DA) force chromophore-terminated polyaromatic carbonate and other self-degradable hydrophobic blocks, and the hydrophilic monomer polymerization is initiated by ATRP through the α-bromoester active end group at the end of the force chromophore. The two-block center of the polymer is the DA force chromophore, and self-assembly in water can construct a force-triggered self-degradable polymer assembly. Under the action of ultrasound, the DA force chromophore end group of the assembly breaks, inducing r-DA reaction, generating a furan carbonate-terminated self-degradable polymer, the end group rapidly decomposes, and then triggers a continuous elimination reaction to cause the hydrophobic block to depolymerize, promoting the degradation of the assembly, and is suitable for use as a carrier material for controlled release of drugs.

[0008] The present invention provides a force-triggered hydrophobic block depolymerization type amphiphilic block polymer, the general structure of which is as follows: the polymer consists of three parts: a) a DA force chromophore located at the center of the two blocks as a triggering depolymerization end, b) a self-degradable hydrophobic block that can trigger depolymerization, and c) a hydrophilic polymer block.

[0009]

[0010] Wherein: m and n represent the degree of polymerization, m is 100-400, n is 30-200;

[0011] Furthermore, the present invention also provides a method for preparing the above-mentioned force-triggered hydrophobic block depolymerization type amphiphilic block polymer, the method comprising: using end-capped polyaromatic carbonate or polyanisole as the hydrophobic block, using a DA force chromophore modified with an initiating end group α-bromoester to end-cap the hydrophobic block, and polymerizing the hydrophilic monomer through active free radical polymerization to prepare the amphiphilic block polymer.

[0012] Furthermore, in the above technical solution, the self-degradable hydrophobic block Diels-Alder (DA) chromophore as a triggering element is selected from one of the structural compounds shown below:

[0013]

[0014] The structural differences among the above three are the number and presence of substituents on the six-membered ring structure. The structural differences will affect the force response sensitivity of the chromophore.

[0015] Furthermore, in the above technical solution, the synthesis path of the triggering element-terminated self-degradable hydrophobic block Diels-Alder (DA) chromophore is as follows:

[0016]

[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 structural formula is as follows:

[0019] Polybenzyl carbamate, Polyaromatic carbonate, Polythiocarbonate, Polyanisole, Polyphthalaldehyde; wherein: End-cap is a DA chromophore, and R can be 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 used under an inert gas atmosphere. After a certain period of polymerization, phosgene functionalized with DA is used as an end-capping agent, 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 functionalization of the hydrophobic block polymer chromophore is achieved.

[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 1:100-400, 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 DA chromophore to initiator methanol to be 2 / 1-5 / 1.

[0022] Furthermore, in the above technical scheme, a method for preparing a force-triggered hydrophobic block depolymerization type amphiphilic block polymer is also provided, the method comprising: the hydrophilic polymer block is prepared by atom transfer radical polymerization, a terminal α-bromoester functionalized DA force chromophore-terminated self-degradable hydrophobic block polymer is used as an initiator, and cuprous bromide or cuprous chloride and pentamethyldiethylenetriamine are used as a catalyst system to initiate solution polymerization or bulk polymerization of the hydrophilic monomer.

[0023] Furthermore, in the above technical solution, the hydrophilic monomer is selected from N-isopropylacrylamide, 2-(2-methoxyethoxy)ethyl methacrylate, oligo(ethylene glycol) methyl ether methacrylate or polyethylene glycol methyl ether acrylate.

[0024] Furthermore, in the above technical scheme, a method for preparing a hydrophilic polymer block is also provided, the method comprising: the molar ratio of cuprous bromide or cuprous chloride to pentamethyldiethylenetriamine is 1:1, the molar ratio of the terminal α-bromoester functionalized hydrophobic block polymer initiator to pentamethyldiethylenetriamine is 1:1-4, and the molar ratio of the initiator to the monomer is 1:200-600.

[0025] In addition, the present invention also describes the application of force-triggered hydrophobic block depolymerization type amphiphilic block polymers as drug carriers to achieve ultrasound-responsive controlled drug release.

[0026] Furthermore, in the above technical scheme, a method for applying force-triggered hydrophobic block depolymerization type 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%), thereby achieving controllable degradation of the assembly and controlled release of the drug molecules.

[0027] The present invention aims to provide a force-triggered hydrophobic block depolymerization type amphiphilic block polymer and its preparation method, and apply it to construct an assembly loaded with drugs, and further realize the controllable force-induced degradation of the polymer through ultrasonic action, thereby realizing the controlled release of the loaded drugs. This brings an important opportunity for the research and development of new ultrasound-responsive drug controlled release systems.

[0028] Advantageous Effects of the Invention

[0029] 1. The force-triggered hydrophobic block depolymerization amphiphilic block polymer of the present invention has a novel structure, a unique force response mechanism, and an ingenious synthesis idea, which is of great significance for filling the research and development gap of force-triggered self-degradable polymers and their assembly systems and applications;

[0030] 2. The synthesis method of the force-triggered hydrophobic block depolymerization amphiphilic block polymer of the present invention is relatively simple. By adjusting the DA mechanochromophore 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 force response sensitivity, and different ultrasonic degradation and drug controlled release properties can be obtained;

[0031] 3. 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 degrade them by force. 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 force-induced degradation of the force-triggered hydrophobic block depolymerization-type amphiphilic block polymer and its assembly described in the present invention is controllable and can achieve the depolymerization of the hydrophobic segment and the 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.

[0032] 4. The present invention not only provides a method for preparing a force-triggered hydrophobic block depolymerization type amphiphilic block polymer, but also realizes ultrasonic controlled release of drug model molecules, providing a basis for the development of force-responsive drug controlled release systems. At the same time, a unique controllable degradation mode of self-degradation of the assembly triggered by external force stimulation is formed, and a new type of controllable degradable functional polymer assembly is obtained, which will theoretically promote people's understanding of the law of force on nanoscale ordered assemblies. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 The force-triggered primitive DA mechanochromophore obtained in Example 1 1 H NMR;

[0034] Figure 2 The anisole self-degradable monomer obtained in Example 2 1 H NMR;

[0035] Figure 3 The GPC spectra of the self-degradable hydrophobic block (terminated polyanisole) with triggerable depolymerization obtained in Example 3 and the force-triggered hydrophobic block depolymerization-type amphiphilic block polymer obtained in Example 4;

[0036] Figure 4 The force-triggered hydrophobic block depolymerization type amphiphilic block polymer obtained in Example 4 1 H NMR;

[0037] Figure 5 The dynamic light scattering data diagram (DLS spectrum) of the block polymer assembly obtained in Assembly Example 1;

[0038] Figure 6 This is the TEM electron microscope image of the amphiphilic block polymer assembly obtained in Assembly Example 1.

[0039] Figure 7 The GPC spectrum of the dynamic changes of the block polymer assembly during ultrasonic degradation in Application Example 2;

[0040] Figure 8 The dynamic changes of the polymer assembly during ultrasonic degradation in Application Example 2 1 H NMR group images;

[0041] Fig. 9 The DLS spectrum of the dynamic changes of the block polymer assembly during ultrasonic degradation in Application Example 2;

[0042] Fig.10 This is the dynamic fluorescence change spectrum of the ultrasound-controlled release of Nile red loaded on the assembly in Application Example 4;

[0043] Fig.11 Schematic diagram of the retrosynthetic analysis of the force-triggered hydrophobic block depolymerization type amphiphilic block polymer in the present invention. DETAILED DESCRIPTION

[0044] The present invention will be further described below in conjunction with specific implementation. The structure of the force-triggered hydrophobic block depolymerization type amphiphilic block polymer obtained in the following examples of the present invention is characterized by nuclear magnetic hydrogen spectrum (1H NMR), and the relative molecular weight and molecular weight distribution of the polymer are measured by gel permeation chromatography (Viscotek270 high performance liquid chromatography pump, Viscotek gel chromatography column (G2000H HR, G3000H HR, and G4000H HR), Viscotek differential refractive index detector, containing chromatographic grade tetrahydrofuran (THF) column temperature 35 ° C, flow rate 1.0mL / min); Brookhaven 173Plus dynamic light scattering instrument and Japanese electronic JEOL JEM-ACE 200F transmission electron microscope are used to detect the assembly behavior of the amphiphilic polymer to confirm the formation of the amphiphilic structure; F-7000 Japan Hitachi fluorescence spectrometer is used to detect the fluorescence characteristics of the model drug molecule before and after ultrasonic release.

[0045] 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.

[0046] Example 1: Synthesis of the force-triggered DA mechanochromophore

[0047] The force-triggered primitive DA mechanochromophore used in the present invention is obtained by the following method:

[0048]

[0049] 1) Add 5-methylfuran-2-carboxaldehyde (7.7784 g, 54.9 mmol) and ether (300 mL) to a 1L round-bottom flask equipped with a stirring magnet, cool the solution to -30°C, and then slowly add 42 mL of 3M methylmagnesium bromide (130 mmol, ether solution). Then heat the mixture to a constant temperature and stir to react for 12 hours, then cool the reaction mixture to 0°C and quench with 200 mL of 10% NH4Cl solution. The reaction mixture is extracted with ethyl acetate (3*100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation to obtain a yellow viscous oily intermediate 5-methylfuranol;

[0050] 2) The above intermediate 5-methyl furanol (2.16 g, 17.16 mmol) and N-hydroxyethyl maleimide (2.015 g, 14.3 mmol) were dissolved in 10 mL chloroform and placed in a 20 mL Schlenk bottle. The reaction solution was nitrogen purged and sealed. The reaction system was then stirred at 55 ° C for 14 hours. After being spin-dried, it was dissolved in 20 mL ethyl acetate to obtain a precipitate, which was a crude product. The pure intermediate was separated by column chromatography (2-4% methanol / dichloromethane);

[0051] 3) The intermediate obtained above (0.6678 g, 2.50 mmol), triethylamine (0.39 mL, 2.8 mmol) and 50 mL of dry anhydrous dichloromethane were added to a three-necked round-bottom flask with a stirring magnetic rod. The solution was cooled to 0°C in an ice bath, and then α-bromoisobutyryl bromide (0.33 mL, 2.7 mmol) was added dropwise to the solution. The reaction system was allowed to react overnight, and then the reaction solution was washed with NH4Cl (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered and dried. The crude product was purified by column chromatography (35-55% EtOAc / hexane) to obtain a colorless viscous oily intermediate;

[0052] 4) Under a nitrogen atmosphere, triphosgene (0.50 g, 1.7 mmol) and 20 mL of anhydrous dry THF were added to a round-bottom flask dried with a stirring magnetic high-temperature flame drying gun. The solution was cooled to 0°C in an ice bath, and then the above intermediate (2.0753 g, 5.0 mmol) and anhydrous dry pyridine (0.40 mL, 5.0 mmol) dissolved in 35 mL of anhydrous THF were added dropwise. A white precipitate was formed soon after the addition. Under an inert nitrogen atmosphere, the slurry was filtered with silica gel to remove insoluble by-products. Then, in a glove box (nitrogen atmosphere), the crude mixture was poured into dry dichloromethane (20 mL) and filtered twice to remove insoluble solids. The filtrate was concentrated by rotary evaporation to obtain a white powdery final product. Its structure was characterized by nuclear magnetic hydrogen spectrum, and the results were shown in Figure 1 , proving the synthesized force-triggered primitive DA force chromophore.

[0053] Example 2: Synthesis of anisole self-degradable monomer

[0054] The anisole self-degradable monomer used in the present invention is obtained by the following method:

[0055]

[0056] 1) Add concentrated hydrochloric acid (36% w / v, 15 mL) 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) at room temperature for 10 minutes. Then the reaction mixture was stirred at room temperature for 2 hours. After the time was up, the reaction mixture was poured into 400 mL of deionized water. A white suspension was found to appear, and stirring was continued at room temperature for 20 minutes. Then the white solid was collected by filtration, washed with a large amount of water (300 mL), and finally dried overnight in vacuo at 70 ° C to obtain the raw material;

[0057] 2) Add iodomethane (890 μL, 14.3 mmol) dropwise to a DMF (40 mL, 0.35 M) solution of the above raw materials (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 (eluted with a 10-40% ethyl acetate / petroleum ether gradient) to obtain an intermediate;

[0058] 3) Silver oxide (3.64 g, 15.7 mmol) was added to a solution of the intermediate (2.12 g, 7.85 mmol) 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.

[0059] Example 3: Synthesis of self-degradable hydrophobic block (capped polyanisole) capable of triggering depolymerization

[0060] The self-degradable hydrophobic block (terminated polyanisole) capable of triggering depolymerization used in the present invention is obtained by the following method:

[0061]

[0062] One-step synthesis: A 10 mL Schlenk bottle equipped with a stirring magnet was flame-dried under vacuum and purged with N2. Then, the system was transferred to a glove box, and the anisole self-degradable monomer (0.230609 g, 0.86 mmol, 1 equivalent) synthesized by the method of Example 2 was added to the Schlenk bottle, and then 1 mL of dry THF was injected with a syringe. Then, the 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 force-triggered primitive DA force chromophore (1.2 eq, 538 mg) and imidazole (70.3 mg, 1.2 eq) synthesized in Example 1 were added to the solution. The solution was then stirred and reacted for 16 hours at 5°C, and then cold MeOH (60 mL) was added at -20°C for precipitation three times. The self-degradable hydrophobic block (capped polyanisole) capped with a white DA chromophore was obtained. The molecular weight and distribution of the self-degradable hydrophobic block (capped polyanisole) are shown in Figure 3 (superior).

[0063] 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 2 are added to one of the flasks. Then, at -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 2 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 force-triggering motif DA force chromophore (1.2 eq, 538 mg) and imidazole (70.3 mg, 1.2 eq) were added to quench the reaction mixture, and the solution was stirred for 16 hours at 5°C. Finally, cold MeOH (60 mL) was added at -20°C for precipitation 3 times to obtain a white DA force chromophore-terminated self-degradable hydrophobic block (terminated polyanisole).

[0064] Example 4: Synthesis of force-triggered hydrophobic block depolymerization amphiphilic block polymer

[0065] The force-triggered hydrophobic block depolymerization type amphiphilic block polymer used in the present invention is obtained by the following method:

[0066]

[0067] NIPAM (0.570 g, 5.56 mmol, 400 eq.), the initiator (94.35 mg, 0.0111 mmol, 1 eq.) synthesized in Example 3, which can trigger depolymerization and self-degradation of hydrophobic blocks (capped polyanisole), Me6TREN (10 μL, 0.0252 mmol, 1.7 eq.) and dry tert-butyl alcohol (0.5 mL) were transferred to a 10 mL dry Schlenk flask. The solution was frozen-thawed and vacuumed and filled with nitrogen 3 to 5 times. After fully removing dissolved oxygen, CuCl (4.00 mg, 0.0303 mmol, 2.0 eq.) was added under nitrogen. Finally, the flask was sealed with a rubber stopper and stirred in an oil bath at 45°C. After the required time, the rubber stopper was opened to ventilate, and 150 mL of THF was added. The copper and the complex were filtered through a short silica gel column. The solution was evaporated to remove the solvent, and the THF concentrated solution of the polymer was added dropwise to n-hexane for precipitation. The amphiphilic block polymer was collected and dried under vacuum at 50°C. The molecular weight and distribution of the force-triggered hydrophobic block depolymerization amphiphilic block polymer are shown in Figure 3 (below), its structure was characterized by H NMR spectroscopy, and the results are shown in Figure 4 , proving that the synthesized force-triggered hydrophobic block depolymerization type amphiphilic block polymer.

[0068] Assembly Example 1: Preparation of force-triggered hydrophobic block depolymerization amphiphilic block polymer assembly (assembly in pure water)

[0069] Take 50 mg of the amphiphilic polymer in Example 4 and dissolve it in 0.5 mL of THF. After dissolution, slowly drip it into 10 mL of deionized water while stirring. Then put the assembly solution into a dialysis bag and dialyze it in water for two days, changing the water 4 times in the middle to remove THF. Dilute the assembly solution to a concentration of 0.1-1.0 mg / mL, and use a dynamic light scattering instrument and a transmission electron microscope to measure its particle size and particle size distribution or observe its morphology, see the attached Figure 5 and 6 .

[0070] Assembly Example 2: Preparation of force-triggered hydrophobic block depolymerization amphiphilic block polymer assembly (assembly in mixed solvent)

[0071] 50 mg of the amphiphilic polymer prepared in Example 4 was dissolved in 25 mL of THF, and then slowly added to 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.

[0072] Application Example 1: Force-triggered hydrophobic block depolymerization and single-chain ultrasonic degradation of amphiphilic block polymers

[0073] 30 mg of the amphiphilic polymer prepared in Example 4 was weighed and dissolved in 10 mL of THF. The system was filtered through a 220 nm organic filter membrane. The ultrasonic probe was inserted into the polymer THF solution using a probe ultrasonic device. Ultrasonic degradation experiments were performed using 1%, 5%, 10% and 30% ultrasonic powers. The degradation process was monitored by gel permeation chromatography (GPC) and nuclear magnetic hydrogen spectrum 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). (Note: In order to avoid the influence of heating on the cleavage of the DA group, the entire ultrasonic process was carried out at a low temperature of 3-5 ° C.)

[0074] Application Example 2: Ultrasonic degradation of force-triggered hydrophobic block depolymerization amphiphilic block polymer assembly (pure water)

[0075] The assembly solution obtained in Assembly Example 1 was used for ultrasonic degradation experiments. The ultrasonic probe was inserted into the above assembly solution using a probe-type ultrasonic device. The ultrasonic degradation experiment was carried out 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 Figure 2. Figure 7 , 8 and 9. (Note: In order to avoid the influence of heating on the cleavage of DA groups, the entire ultrasonic process was carried out at a low temperature of 3-5°C)

[0076] Application Example 3: Ultrasonic degradation of force-triggered hydrophobic block depolymerization amphiphilic block polymer assembly (mixed solvent assembly)

[0077] 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 ultrasonic degradation experiments were performed at intervals of 1h, 2h, 4h and 6h (ultrasonic mode: 1s on and 1s off, ultrasonic 1s pause 1s). After taking out appropriate solutions and drying them, the samples were monitored for degradation process using gel permeation chromatography (GPC) and nuclear magnetic hydrogen spectrum, and the dynamic changes of particle size and particle size distribution were also monitored using dynamic light scattering. (Note: In order to avoid the influence of heating on the cleavage of DA groups, the entire ultrasonic process was carried out at a low temperature of 3-5°C)

[0078] Application Example 4: Ultrasonic controlled release of drug-loaded amphiphilic block polymer assemblies triggered by force-triggered hydrophobic block depolymerization

[0079] Prepare 1mM Nile Red THF mother solution, take 100 microliters and add to 10mL of 3mg / mL solution of amphiphilic block polymer prepared in Example 4 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 become weak). The results monitored by the fluorescence spectrometer are as follows Fig.10 (Note: In order to avoid the influence of heating on the cleavage of DA groups, the entire ultrasonic process was carried out at a low temperature of 3-5°C)

[0080] The retrosynthetic analysis of the force-triggered hydrophobic block depolymerization type amphiphilic block polymer in the present invention is shown in the schematic diagram Fig.11 .

[0081] 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 force-triggered hydrophobic block depolymerization amphiphilic block polymer, the general structure of which is as follows: in: m is 100-400, n is 30-200; the polymer consists of three parts: a) a DA chromophore located in the center of the two blocks as a triggering depolymerization end, b) a self-degradable hydrophobic block that can trigger depolymerization, and c) a hydrophilic polymer block.

2. The method for preparing the force-triggered hydrophobic block depolymerization type amphiphilic block polymer according to claim 1, characterized in that: The end-capped polyaromatic carbonate or polyanisole is used as the hydrophobic block, the hydrophobic block is capped by using a DA chromophore modified with an initiating terminal α-bromoester, and the hydrophilic monomer is polymerized by living free radical polymerization to prepare an amphiphilic block polymer.

3. The method for preparing the force-triggered hydrophobic block depolymerization type amphiphilic block polymer according to claim 2, characterized in that: The DA chromophore is selected from one of the following structural compounds:

4. The method for preparing the force-triggered hydrophobic block depolymerization type amphiphilic block polymer according to claim 3, characterized in that: The synthetic route of the DA power chromophore is as follows:

5. The method for preparing the force-triggered hydrophobic block depolymerization type amphiphilic block polymer 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 selected from the DA power chromophore described in claim 2, and R is selected from H, CH3 or OCH3.

6. The method for preparing the force-triggered hydrophobic block depolymerization type amphiphilic block polymer 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. 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 is used under an inert gas atmosphere. After a certain period of polymerization, phosgene functionalized with DA is used as an end-capping agent, and an end-capped stable 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 functionalization of the hydrophobic block polymer chromophore is achieved.

7. The method for preparing the force-triggered hydrophobic block depolymerization type amphiphilic block polymer according to claim 6, characterized in that: The molar ratio of initiator methanol to monomer is 1:100-400, the molar ratio of initiator methanol to P2-t-Bu phosphazene base catalyst is 2 / 1-1 / 4, and the molar ratio of end-capping agent DA chromophore to initiator methanol is 2 / 1-5 / 1.

8. The method for preparing the force-triggered hydrophobic block depolymerization type amphiphilic block polymer according to claim 2, characterized in that: The hydrophilic polymer block is prepared by atom transfer radical polymerization, using a terminal α-bromoester functionalized DA chromophore-terminated self-degradable hydrophobic block polymer as an initiator, and using cuprous bromide or cuprous chloride and pentamethyldiethylenetriamine as a catalyst system to initiate solution polymerization or bulk polymerization of the hydrophilic monomer.

9. The method for preparing the force-triggered hydrophobic block depolymerization type amphiphilic block polymer according to claim 8, characterized in that: The hydrophilic monomer is selected from N-isopropyl acrylamide, 2-(2-methoxyethoxy)ethyl methacrylate, oligo(ethylene glycol) methyl ether methacrylate or polyethylene glycol methyl ether acrylate; the molar ratio of cuprous bromide or cuprous chloride to pentamethyldiethylenetriamine is 1:1, the molar ratio of the terminal α-bromoester functionalized hydrophobic block polymer initiator to pentamethyldiethylenetriamine is 1:1-4, and the molar ratio of the initiator to the monomer is 1:200-600.

10. Use of the force-triggered hydrophobic block depolymerization type amphiphilic block polymer as claimed in claim 1 in drug carriers to achieve ultrasound-responsive controlled drug release.

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