Thermosensitive block polymer as well as preparation method and application thereof

Abstract

The invention provides a thermo-sensitive block polymer as well as a preparation method and application thereof. The temperature-sensitive block polymer comprises a temperature-sensitive unit, a hydrophilic unit and a pH response unit, the number-average molecular weight of the thermo-sensitive block polymer is 1 * 10 < 3 > g / mol to 2.5 * 10 < 5 > g / mol, preferably 8 * 10 < 3 > g / mol to 2.0 * 10 < 4 > g / mol; molecular weight distribution lt; 1.50, preferably < 1.30. The preparation method comprises the following steps: mixing an RAFT reagent, an initiator, a hydrophilic polymer or a hydrophilic monomer, a temperature-sensitive monomer, a pH response monomer and a solvent, carrying out an active free radical polymerization reaction in a protective gas atmosphere, and carrying out post-treatment on a product to obtain the temperature-sensitive block polymer. The obtained thermo-sensitive block polymer is narrow in molecular weight distribution, the drug release rate is more controllable, and the drug effect is improved.

Description

Technical Field

[0001] The present invention relates to the field of polymer materials. Further, it relates to a temperature-sensitive block polymer, a preparation method thereof, and an application thereof. Background Art

[0002] Temperature-sensitive block copolymers are polymer materials that can respond to temperature changes and have a lower critical solution temperature in aqueous solutions. When the temperature rises or falls, the hydrophobic interaction or hydrogen bond interaction between some groups in the temperature-sensitive block copolymer chain and water is destroyed, resulting in a change in their solubility in water. As the temperature changes, the dissolution state of the temperature-sensitive block copolymer changes near the critical point. The transition between the hydrophilic structure and the hydrophobic structure of the temperature-sensitive block copolymer is reversible and can undergo multiple "precipitation-dissolution" processes with temperature.

[0003] There are mainly three types of temperature-sensitive block copolymers: low-temperature dissolution block copolymers with LCST, high-temperature dissolution block copolymers with upper critical solution temperature (UCST), and block copolymers with both LCST and UCST. When the temperature is lower than its LCST, the low-temperature dissolution block copolymer can dissolve in water, and when the temperature rises, it changes from soluble to insoluble. Contrary to the low-temperature dissolution block copolymer, the high-temperature dissolution block copolymer can dissolve in water when the temperature is higher than its UCST.

[0004] It is necessary to prepare a temperature-sensitive block copolymer with a narrow molecular weight distribution, a more uniform molecular chain size, and a more uniform drug amount during drug slow release. Summary of the Invention

[0005] In order to solve the technical problems existing in the prior art, the present invention provides a temperature-sensitive block polymer, a preparation method thereof, and an application thereof.

[0006] The present invention provides a temperature-sensitive block polymer applicable to drug controlled release, with a narrow molecular weight distribution, a molecular weight distribution < 1.50, a uniform polymer molecular chain, a more controllable drug release rate, and better effects of the pH-responsive groups of the temperature-sensitive block polymer on transporting hydrophobic drugs, improving the drug efficacy.

[0007] One of the purposes of the present invention is to provide a temperature-sensitive block polymer, including a temperature-sensitive unit, a hydrophilic unit, and a pH-responsive unit;

[0008] The weight-average molecular weight of the temperature-sensitive block polymer is 1×10 3 g / mol to 2.5×10 5 g / mol, preferably 8×10 3 g / mol to 2.0×10 4g / mol; The molecular weight distribution is <1.50, preferably <1.30.

[0009] In a preferred embodiment of the present invention,

[0010] The thermosensitive unit includes a thermosensitive group, and the thermosensitive group is at least one of an amide bond and an ether bond;

[0011] The hydrophilic unit includes a hydrophilic group, and the hydrophilic group is at least one of a hydroxyl group, a sulfate group, and an amino group;

[0012] The pH-responsive unit includes a pH-sensitive group, and the pH-sensitive group is at least one of a carboxyl group, a pyridyl group, and an imidazolyl group.

[0013] In a preferred embodiment of the present invention,

[0014] The thermosensitive unit is polymerized from a thermosensitive monomer, and the thermosensitive monomer can synthesize a thermosensitive polymer. The thermosensitive monomer is at least one of N-isopropylacrylamide, N-vinylcaprolactam, N-propylacrylamide, N-ethyl-N-methylacrylamide, dimethylaminoethyl methacrylate, N-ethyl-N-ethylacrylamide, 1-(allyl)pyrrolidin-2-one, and 1-(piperidin-1-yl)prop-2-en-1-one;

[0015] The hydrophilic unit is polymerized from a hydrophilic polymer or a hydrophilic monomer; the hydrophilic polymer is at least one of polyvinyl alcohol, polysaccharide, and polypeptide, and the polysaccharide is preferably at least one of cellulose, starch, carboxymethyl cellulose, hydroxymethyl cellulose, and carboxymethyl starch; the hydrophilic monomer is at least one of ethylene oxide, vinyl alcohol, 2-hydroxyethyl methacrylate, and oligoethylene glycol methacrylate (OEGMA);

[0016] The pH-responsive unit is polymerized from a pH-responsive monomer, and the pH-responsive monomer can synthesize a pH-responsive polymer. The pH-responsive monomer is at least one of acrylic acid, methacrylic acid, L-glutamic acid, 4-vinylpyridine, and 2-(dimethylamino)ethyl methacrylate.

[0017] The second object of the present invention is to provide a method for preparing a thermosensitive block polymer, including:

[0018] Mixing a RAFT reagent, an initiator, a thermosensitive monomer, a hydrophilic polymer or a hydrophilic monomer, a pH-responsive monomer, and a solvent, and performing a living radical polymerization reaction under a protective gas atmosphere. After post-treatment of the product, the thermosensitive block polymer is obtained; preferably,

[0019] The reaction temperature is 0°C to 100°C, more preferably 40 to 80°C; and / or,

[0020] The reaction time is 1 to 24 h, more preferably 4 to 18 h.

[0021] In a preferred embodiment of the present invention,

[0022] the preparation method is Method 1 or Method 2;

[0023] Method 1 includes:

[0024] Adding a RAFT reagent, an initiator, a hydrophilic polymer, and a thermosensitive monomer into a solvent, and carrying out the first living radical polymerization reaction under a protective gas atmosphere. Then, a pH-responsive monomer is added to carry out the second living radical polymerization reaction. After the product is post-treated and dried, the thermosensitive block polymer is obtained; wherein, the addition order of the thermosensitive monomer and the pH-responsive monomer can be arbitrarily interchanged;

[0025] Method 2 includes:

[0026] Adding a RAFT reagent, an initiator, and a pH-responsive monomer into a solvent, and carrying out the third living radical polymerization reaction under a protective gas atmosphere. Then, a thermosensitive monomer is added to carry out the fourth living radical polymerization reaction. After that, a hydrophilic monomer is added to carry out the fifth living radical polymerization reaction. After the product is post-treated and dried, the thermosensitive block polymer is obtained; wherein, the addition order of the pH-responsive monomer, the thermosensitive monomer, and the hydrophilic monomer can be arbitrarily interchanged.

[0027] In a preferred embodiment of the present invention,

[0028] The RAFT reagent is at least one of dithiocarbonates, trithiocarbonates, xanthates, dithiocarbamates, aryl dithiol esters, cyano disulfates, cyano dithioesters, and disulfiram-like compounds, preferably at least one of bis(dodecylsulfanylthiocarbonyl) disulfide, benzonitrile disulfuric acid, cyanopropyl isopropyl dithiobenzoate, 2-phenylethylbenzene dithiol ester, benzyl dithiobenzoate, 2-cyano-2-propyl dodecyl trithiocarbonate, 2-cyano-2-butyl benzene dithioester, N-hydroxysuccinimide ester of 2-dodecylthiocarbonylthio-2-methylpropionic acid, tetramethylthiuram disulfide, and tetraethylthiuram disulfide;

[0029] The initiator is at least one of azo initiators and organic peroxide initiators, preferably at least one of azodiisobutyronitrile, azodiisoheptonitrile, azodiisovaleronitrile, azodiisobutamidine hydrochloride, azodiisobimidazoline hydrochloride, dimethyl azodiisobutyrate, azoisobutyronitrile carboxamide, azodicyanovaleric acid, azodicyclohexylcarbonitrile, benzoyl peroxide, tert-butyl hydroperoxide, di-tert-butyl peroxide, tert-butyl peroxybenzoate, lauroyl peroxide, 2,5-di-tert-butylperoxy-2,5-dimethylhexane, diisopropyl peroxydicarbonate;

[0030] The solvent is at least one of hydroxyl group-containing solvents, ester solvents, ketone solvents, ether solvents, aromatic solvents, and cyclic solvents with polar groups, preferably at least one of methanol, ethanol, isopropanol, methyl formate, ethyl acetate, methyl acetate, n-propyl acetate, acetone, methyl ethyl ketone, cyclohexanone, tetrahydrofuran, toluene, N,N-dimethylformamide;

[0031] The protective gas is at least one of nitrogen and inert gases; the inert gas is preferably argon.

[0032] In a preferred embodiment of the present invention,

[0033] Based on the total molar amount of the hydrophilic monomer or hydrophilic polymer, pH-responsive monomer, and temperature-responsive monomer being 100%, it includes 0.01-50% of the hydrophilic monomer or hydrophilic polymer, 0.01-50% of the pH-responsive monomer, and 0.01-50% of the temperature-responsive monomer; preferably includes 1-50% of the hydrophilic monomer or hydrophilic polymer, 1-50% of the pH-responsive monomer, and 1-50% of the temperature-responsive monomer; more preferably includes 25-40% of the hydrophilic monomer or hydrophilic polymer, 25-40% of the pH-responsive monomer, and 30-50% of the temperature-responsive monomer; for example, the molar percentage of the hydrophilic monomer, pH-responsive monomer, and temperature-responsive monomer can specifically be 30:30:40, 25:25:50, 30:35:35, etc.;

[0034] The molar ratio of the initiator to the total monomers is (0.01-10):100, preferably (0.01-5):100, more preferably (0.01-0.1):100; specifically, it can be 0.01:100, 0.02:100, 0.08:100, 0.1:100, 1:100, etc.;

[0035] The molar ratio of the RAFT reagent to the initiator is 1:(0.001-1), preferably 1:(0.01-0.2), more preferably 1:(0.01-0.05); specifically, it can be 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.08, 1:0.1, 1:0.15, 1:0.18, 1:0.2, etc.;

[0036] The mass ratio of the solvent to the total mass of the monomers is (0.1 - 50):1, preferably (0.5 - 25):1, more preferably (0.8 - 6):1; specifically, it can be 1:1, 2:1, 2.5:1, 3:1, 4:1, 6:1, 10:1, etc.

[0037] The post-treatment is carried out by drying after being treated by at least one of precipitation, dialysis, and rotary evaporation; it can be treated by one of the above methods, or multiple methods can be used in combination. Specifically, common solvents and precipitants can be used to dissolve and precipitate the system several times; the drying can adopt general methods in the prior art, such as at least one of freeze-drying, vacuum drying, and microwave drying.

[0038] In a preferred embodiment of the present invention,

[0039] The temperature of Reaction 1 is 0°C to 100°C, preferably 40 to 80°C;

[0040] The time of Reaction 1 is 1 to 12 h, preferably 2 to 6 h;

[0041] The temperature of Reaction 2 is 0°C to 100°C, preferably 40 to 80°C;

[0042] The time of Reaction 2 is 1 to 12 h, preferably 2 to 6 h;

[0043] The temperature of Reaction 3 is 0°C to 100°C, preferably 40 to 80°C;

[0044] The time of Reaction 3 is 1 to 12 h, preferably 2 to 6 h;

[0045] The temperature of Reaction 4 is 0°C to 100°C, preferably 40 to 80°C;

[0046] The time of Reaction 4 is 1 to 12 h, preferably 2 to 6 h;

[0047] The temperature of Reaction 5 is 0°C to 100°C, preferably 40 to 80°C;

[0048] The time of Reaction 5 is 1 to 12 h, preferably 2 to 6 h.

[0049] The third object of the present invention is to provide a thermosensitive block polymer obtained by the above preparation method.

[0050] The fourth object of the present invention is to provide an application of the thermosensitive block polymer in drug sustained release or controlled release.

[0051] Compared with the prior art, the present invention has the following beneficial effects:

[0052] (1) The present invention prepares a thermosensitive block polymer by using a reversible addition-fragmentation chain transfer (RAFT) controlled radical polymerization process. Compared with traditional radical polymerization, the molecular weight distribution of the block polymer is reduced. The obtained thermosensitive block polymer has a narrow molecular weight distribution, a uniform polymer molecular chain, a more controllable drug release rate, and the pH-responsive group of the thermosensitive block polymer has a better effect on delivering hydrophobic drugs, improving the drug efficacy.

[0053] (2) The reaction conditions of the RAFT polymerization reaction of the present invention are mild, the living polymerization process is more controllable, and the monomer applicability is wide. The polymerization reaction method has a wide applicability, and bulk polymerization, solution polymerization, suspension polymerization, and emulsion polymerization can be selected.

[0054] (3) By preparing a thermosensitive-pH responsive triblock polymer, the present invention can improve the drug sensitivity and targeting under the conditions of changing the environmental temperature and the pH value in the environment. Detailed implementation manners

[0055] The present invention will be specifically described below in conjunction with specific embodiments. It is necessary to point out here that the following embodiments are only used for further illustration of the present invention and cannot be understood as limiting the protection scope of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the content of the present invention still fall within the protection scope of the present invention.

[0056] For the raw materials used in the examples and comparative examples, if not specifically limited, they are all disclosed in the prior art. For example, they can be directly purchased or prepared according to the preparation methods disclosed in the prior art.

[0057] Testing methods:

[0058] Determination of molecular weight and its molecular weight distribution: The polymer was dissolved in chromatographic grade tetrahydrofuran with a sample concentration of 1.5 mg / mL. An Alliance e2695 gel permeation chromatography from Waters, USA was used, with tetrahydrofuran as the mobile phase, a flow rate of 1.0 mL / min, a monodisperse PMMA as the standard, and the column temperature and detection temperature both at 35 °C.

[0059] Particle size distribution of micelle solution: The polymer was used to prepare micelles by dialysis method, and the micelle concentration was diluted to 0.5 - 1.0 mg / mL. A dynamic light scattering instrument (DLS, UK) was used to prepare micelles, with the thermosensitive particle size test range of 25 - 50 °C. After equilibration at each temperature for 30 minutes, the particle size was measured.

[0060]

Example 1

[0061] The round-bottom reaction flask after being washed and dried was purged with nitrogen three times. 8.78 g (0.017 mol) of oligoethylene glycol acrylate (OEGMA), 0.0022 g (0.000013 mol) of azobisisobutyronitrile (AIBN), 0.15 g (0.00067 mol) of cyanopropyl isopropyl dithiobenzoate, and 22 g of anhydrous methanol were mixed evenly. Under a nitrogen atmosphere, the mixed solution was added to the round-bottom flask and heated for reaction. The reaction temperature was 60 °C, and the reaction time was 3 h. Then, 3.39 g (0.030 mol) of N-isopropylacrylamide (NIPAAm) was added and the reaction continued. The reaction temperature was 60 °C, and the reaction time was 3 h. Subsequently, 1.44 g (0.020 mol) of acrylic acid was added and the reaction continued. The reaction temperature was 60 °C, and after 3 h of reaction, the reaction was stopped. It was dialyzed with ultrapure water for 3 days and then freeze-dried to obtain the thermosensitive block polymer.

[0062] The thermosensitive block polymer prepared in this example was analyzed by GPC. The weight-average molecular weight was 11340 g / mol, and the molecular weight distribution was 1.21.

[0063]

Example 2

[0064] The round-bottom reaction flask after being washed and dried was purged with nitrogen three times. 33.33 g (0.017 mol) of PEG-2000, 4.18 g (0.03 mol) of N-vinylcaprolactam, 0.0022 g (0.000013 mol) of azobisisobutyronitrile (AIBN), 0.23 g (0.00067 mol) of 2-cyano-2-propyl dodecyl trithiocarbonate, and 35 g of anhydrous methanol were mixed evenly. Under a nitrogen atmosphere, the mixed solution was added to the round-bottom flask and heated for reaction. The reaction temperature was 60 °C, and the reaction time was 3 h. Then, 1.72 g (0.020 mol) of methacrylic acid was added and stirred evenly, and the reaction continued. The reaction temperature was 60 °C, and after 3 h of reaction, the reaction was stopped. It was dialyzed with ultrapure water for 3 days and then freeze-dried to obtain the thermosensitive block polymer.

[0065] The thermosensitive block polymer prepared in this example was analyzed by GPC. The weight-average molecular weight was 11980 g / mol, and the molecular weight distribution was 1.24.

[0066]

Example 3

[0067] The round-bottom reaction flask after washing and drying was purged with nitrogen three times. 1.44 g (0.020 mol) of acrylic acid, 0.0022 g (0.000013 mol) of azobisisobutyronitrile (AIBN), 0.15 g (0.00067 mol) of cyanopropyl isopropyl dithiobenzoate, and 73 g of anhydrous methanol were mixed evenly. Under a nitrogen atmosphere, the mixed solution was added to the round-bottom flask and heated for reaction. The reaction temperature was 80 °C, and the reaction time was 2 h. Then, 3.39 g (0.030 mol) of N-isopropylacrylamide (NIPAAm) was added and stirred evenly. The reaction continued at 80 °C for 2 h. Subsequently, 8.78 g (0.017 mol) of oligo(ethylene glycol) methyl ether acrylate (OEGMA) was added and stirred evenly. The reaction was heated at 80 °C for 2 h, and then the reaction was stopped. The product was dialyzed with ultrapure water for 3 days and then freeze-dried to obtain the thermosensitive block polymer.

[0068] The thermosensitive block polymer prepared in this example was analyzed by GPC. The weight-average molecular weight was 9500 g / mol, and the molecular weight distribution was 1.17.

[0069]

Example 4

[0070] The round-bottom reaction flask after washing and drying was purged with nitrogen three times. 8.78 g (0.017 mol) of oligo(ethylene glycol) methyl ether acrylate (OEGMA), 0.0022 g (0.000013 mol) of azobisisobutyronitrile (AIBN), 0.15 g (0.00067 mol) of cyanopropyl isopropyl dithiobenzoate, and 22 g of anhydrous methanol were mixed evenly. Under a nitrogen atmosphere, the mixed solution was added to the round-bottom flask and heated for reaction. The reaction temperature was 40 °C, and the reaction time was 6 h. Then, 3.39 g (0.030 mol) of N-isopropylacrylamide (NIPAAm) was added and stirred evenly. The reaction continued at 40 °C for 6 h. Subsequently, 1.44 g (0.020 mol) of acrylic acid was added and stirred evenly. The reaction continued at 40 °C for 6 h, and then the reaction was stopped. The product was dialyzed with ultrapure water for 3 days and then freeze-dried to obtain the thermosensitive block polymer.

[0071] The thermosensitive block polymer prepared in this example was analyzed by GPC. The weight-average molecular weight was 10580 g / mol, and the molecular weight distribution was 1.23.

[0072]

Example 5

[0073] The round-bottom reaction flask after washing and drying was purged with nitrogen three times. 14.04 g (0.027 mol) of oligo(ethylene glycol) methacrylate (OEGMA), 0.0022 g (0.000013 mol) of azobisisobutyronitrile (AIBN), 0.15 g (0.00067 mol) of cyanopropyl isopropyl dithiobenzoate, and 22 g of anhydrous methanol were mixed evenly. Under a nitrogen atmosphere, the mixed solution was poured into the round-bottom flask and heated for reaction. The reaction temperature was 80 °C, and the reaction time was 2 h. Then, 3.39 g (0.030 mol) of N-isopropylacrylamide (NIPAAm) was added and stirred evenly. The reaction continued at 80 °C for 2 h. Subsequently, 1.44 g (0.020 mol) of acrylic acid was added and stirred evenly. The reaction continued at 80 °C for 2 h, and then the reaction was stopped. The product was dialyzed with ultrapure water for 3 days and then freeze-dried to obtain the thermosensitive block polymer.

[0074] The thermosensitive block polymer prepared in this example was analyzed by GPC. The weight-average molecular weight was 11,580 g / mol, and the molecular weight distribution was 1.23.

[0075]

Comparative Example 1

[0076] The difference from Example 1 was that the RAFT reagent cyanopropyl isopropyl dithiobenzoate was not added.

[0077] Except for the above difference, other conditions in Comparative Example 1 were the same as those in Example 1, and a block polymer was obtained.

[0078] The obtained block polymer was analyzed by GPC. The weight-average molecular weight was 59,340 g / mol, and the molecular weight distribution was 1.86.

[0079] Test:

[0080] A certain amount of the block polymers prepared in the examples and comparative examples was dissolved in DMF to obtain a homogeneous solution, which was loaded into a dialysis bag. Under magnetic stirring, the dialysis bag was placed in ultrapure water and stirred for 48 h. During this period, the water was changed several times until the solution in the dialysis bag changed from transparent to translucent to obtain a micelle solution. The micelle particle size was measured, and the test results are shown in Table 1.

[0081] Table 1 Particle size distribution of micelle solution

[0082] Sample Name Micelle Particle Size (nm) Example 1 112.6 Example 2 127.1 Example 3 98.9 Comparative Example 1 335.4

[0083] It can be seen from the test results of the examples and comparative examples that:

[0084] (1) For the thermosensitive block polymers obtained in Examples 1 to 5, the molecular weight distribution was narrow, with PDI < 1.30.

[0085] (2) Compared with Comparative Example 1, the thermosensitive block polymer micelles prepared in Example 1 have a smaller particle size.

[0086] (3) Compared with Comparative Example 1, the thermosensitive block polymers obtained in Examples 1 to 5 have a narrow molecular weight distribution with PDI < 1.30, indicating that block polymers with a narrow molecular weight distribution can be obtained by using the RAFT controlled radical polymerization method.

[0087] In Examples 1 to 5, thermosensitive block polymers were prepared by reversible addition-fragmentation chain transfer (RAFT) controlled radical polymerization. Compared with traditional radical polymerization, the molecular weight distribution of the block polymers was reduced. The obtained thermosensitive block polymers have a narrow molecular weight distribution, uniform polymer molecular chains, more controllable drug release rates, and the pH-responsive groups of the thermosensitive block polymers have a better effect on delivering hydrophobic drugs, improving the drug efficacy.

Claims

1. A thermosensitive block polymer, comprising a thermosensitive unit, a hydrophilic unit and a pH-responsive unit; The weight-average molecular weight of the thermosensitive block polymer is 1×10 3 g / mol to 2.5×10 5 g / mol, preferably 8×10 3 g / mol to 2.0×10 4 g / mol; the molecular weight distribution is <1.50, preferably <1.

30.

2. The thermosensitive block polymer according to claim 1, characterized in that: The thermosensitive unit comprises a thermosensitive group, and the thermosensitive group is at least one of an amide bond and an ether bond; and / or, The hydrophilic unit comprises a hydrophilic group, and the hydrophilic group is at least one of a hydroxyl group, a sulfate group and an amino group; and / or, The pH-responsive unit comprises a pH-sensitive group, and the pH-sensitive group is at least one of a carboxyl group, a pyridyl group and an imidazolyl group.

3. The thermosensitive block polymer according to claim 1, characterized in that: The thermosensitive unit is polymerized from a thermosensitive monomer, and the thermosensitive monomer is at least one of N-isopropylacrylamide, N-vinylcaprolactam, N-propylacrylamide, N-ethyl-N-methylacrylamide, dimethylaminoethyl methacrylate, N-ethyl-N-ethylacrylamide, 1-(allyl)pyrrolidin-2-one, 1-(piperidin-1-yl)prop-2-en-1-one; and / or, The hydrophilic unit is polymerized from a hydrophilic polymer or a hydrophilic monomer; the hydrophilic polymer is at least one of polyvinyl alcohol, polysaccharide and polypeptide, and the polysaccharide is preferably at least one of cellulose, starch, carboxymethyl cellulose, hydroxymethyl cellulose and carboxymethyl starch; the hydrophilic monomer is at least one of ethylene oxide, vinyl alcohol, hydroxyethyl methacrylate and oligoethylene glycol methacrylate; and / or, The pH-responsive unit is polymerized from a pH-responsive monomer, and the pH-responsive monomer is at least one of acrylic acid, methacrylic acid, L-glutamic acid, 4-vinylpyridine and methacrylic acid-(2-N,N)dimethylaminoethyl ester.

4. A method for preparing the thermosensitive block polymer according to any one of claims 1 to 3, comprising: Mixing a RAFT reagent, an initiator, a thermosensitive monomer, a hydrophilic polymer or a hydrophilic monomer, a pH-responsive monomer and a solvent, and carrying out a living radical polymerization reaction under a protective gas atmosphere, and the product is post-treated to obtain the thermosensitive block polymer; preferably, The reaction temperature is 0°C to 100°C, more preferably 40 to 80°C; and / or, The reaction time is 1 to 24 h, more preferably 4 to 18 h.

5. The preparation method of the thermosensitive block polymer according to claim 4, characterized in that, The preparation method is Method 1 or Method 2; Method 1 includes: Adding a RAFT reagent, an initiator, a hydrophilic polymer and a thermosensitive monomer into a solvent, carrying out a first living radical polymerization reaction under a protective gas atmosphere, and then adding a pH-responsive monomer to carry out a second living radical polymerization reaction, and the product is post-treated and dried to obtain the thermosensitive block polymer; wherein, the addition order of the thermosensitive monomer and the pH-responsive monomer can be arbitrarily interchanged; Method 2 includes: Add the RAFT reagent, initiator, and pH-responsive monomer to a solvent. Under a protective gas atmosphere, conduct the living radical polymerization reaction III. Then add the thermosensitive monomer to conduct the living radical polymerization reaction IV. After that, add the hydrophilic monomer to conduct the living radical polymerization reaction V. The product is obtained by post-treatment and drying to obtain the thermosensitive block polymer; wherein, the addition order of the pH-responsive monomer, thermosensitive monomer, and hydrophilic monomer can be arbitrarily interchanged.

6. The preparation method of the thermosensitive block polymer according to claim 4 or 5, It is characterized in that; The RAFT reagent is at least one of dithiocarbonates, trithiocarbonates, xanthates, dithiocarbamates, aryl dithiol esters, cyano disulfates, cyano dithioesters, and disulfiram-like compounds. Preferably, it is at least one of bis(dodecylthioalkylthio-carbonyl) disulfide, benzonitrile disulfuric acid, cyanopropyl isopropyl dithiobenzoate, 2-cyano-2-propyl dodecyl trithiocarbonate, 2-phenethylbenzene dithiol ester, benzyl dithiobenzoate, 2-cyano-2-butylbenzene dithioester, N-hydroxysuccinimide ester of 2-dodecylthiocarbonylthio-2-methylpropanoic acid, tetramethylthiuram disulfide, and tetraethylthiuram disulfide; and / or, The initiator is at least one of azo initiators and organic peroxide initiators. Preferably, it is at least one of azobisisobutyronitrile, azobisisoheptonitrile, azobisisopentanenitrile, azobis(2-methylpropionamidine) dihydrochloride, azobis(2-methylimidazoline) dihydrochloride, dimethyl azobis(2-methylpropionate), azoisobutyronitrile formamide, azodicyanovaleric acid, azodicyclohexylcarbonitrile, benzoyl peroxide, tert-butyl hydroperoxide, di-tert-butyl peroxide, tert-butyl peroxybenzoate, lauroyl peroxide, 2,5-di-tert-butylperoxy-2,5-dimethylhexane, and diisopropyl peroxydicarbonate; and / or, The solvent is at least one of hydroxyl-containing solvents, ester solvents, ketone solvents, ether solvents, aromatic solvents, and cyclic solvents with polar groups. Preferably, it is at least one of methanol, ethanol, isopropanol, methyl formate, ethyl acetate, methyl acetate, n-propyl acetate, acetone, methyl ethyl ketone, cyclohexanone, tetrahydrofuran, toluene, and N,N-dimethylformamide; and / or, The protective gas is at least one of nitrogen and inert gases; the inert gas is preferably argon.

7. The preparation method of the thermosensitive block polymer according to claim 4 or 5, characterized in that ； Based on the total molar amount of the hydrophilic monomer or hydrophilic polymer, pH-responsive monomer, and thermosensitive monomer being 100%, it includes 0.01 - 50% of the hydrophilic monomer or hydrophilic polymer, 0.01 - 50% of the pH-responsive monomer, and 0.01 - 50% of the thermosensitive monomer; preferably, it includes 1 - 50% of the hydrophilic monomer or hydrophilic polymer, 1 - 50% of the pH-responsive monomer, and 1 - 50% of the thermosensitive monomer; more preferably, it includes 25 - 40% of the hydrophilic monomer or hydrophilic polymer, 25 - 40% of the pH-responsive monomer, and 30 - 50% of the thermosensitive monomer; and / or, The molar ratio of the initiator to the total monomers is (0.01 - 10):100, preferably (0.01 - 5):100, and more preferably (0.01 - 0.1):100; and / or, The molar ratio of the RAFT reagent to the initiator is 1:(0.001 - 1), preferably 1:(0.01 - 0.2), more preferably 1:(0.01 - 0.05); and / or, The mass ratio of the solvent to the total mass of the monomers is (0.1 - 50):1, preferably (0.5 - 25):1, more preferably (0.8 - 6):1; and / or, The post-treatment is drying after being treated by at least one of precipitation, dialysis, and rotary evaporation; the drying is at least one of freeze-drying, vacuum drying, and microwave drying.

8. The preparation method of the thermosensitive block polymer according to claim 5, characterized in that ； The temperature of the first reaction is 0°C to 100°C, preferably 40 - 80°C; and / or, The time of the first reaction is 1 - 12 h, preferably 2 - 6 h; and / or, The temperature of the second reaction is 0°C to 100°C, preferably 40 - 80°C; and / or, The time of the second reaction is 1 - 12 h, preferably 2 - 6 h; and / or, The temperature of the third reaction is 0°C to 100°C, preferably 40 - 80°C; and / or, The time of the third reaction is 1 - 12 h, preferably 2 - 6 h; and / or, The temperature of the fourth reaction is 0°C to 100°C, preferably 40 - 80°C; and / or, The time of the fourth reaction is 1 - 12 h, preferably 2 - 6 h; and / or, The temperature of the fifth reaction is 0°C to 100°C, preferably 40 - 80°C; and / or, The time of the fifth reaction is 1 - 12 h, preferably 2 - 6 h.

9. A thermosensitive block polymer obtained by the preparation method according to any one of claims 4 - 8.

10. An application of the thermosensitive block polymer according to any one of claims 1 - 3, 9 in drug sustained release or controlled release.