CN111320732A - Amphiphilic block copolymer with near-infrared thermal responsiveness and preparation and application thereof - Google Patents

Amphiphilic block copolymer with near-infrared thermal responsiveness and preparation and application thereof Download PDF

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CN111320732A
CN111320732A CN202010224272.5A CN202010224272A CN111320732A CN 111320732 A CN111320732 A CN 111320732A CN 202010224272 A CN202010224272 A CN 202010224272A CN 111320732 A CN111320732 A CN 111320732A
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pbnma
block copolymer
pegma
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程振平
姚澜
涂凯
李海辉
张丽芬
朱秀林
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Suzhou University
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Abstract

The invention relates to an amphiphilic block copolymer with near-infrared thermal responsiveness, and a preparation method and application thereof. The invention prepares amphiphilic block copolymer PBnMA-b-P (BAPMA-co-PEGMA) by RAFT polymerization, and then reacts with croconium cyanine dye NIR800 with near-infrared photothermal response to obtain PBnMA-b-P (APMA-co-PEGMA) @ NIR 800. Self-assembly of amphiphilic block copolymers was performed separately in a solvent-in-water blend system. The self-assembly result shows that the amphiphilic block copolymer micelle with near-infrared thermal responsiveness is successfully obtained.

Description

Amphiphilic block copolymer with near-infrared thermal responsiveness and preparation and application thereof
Technical Field
The invention relates to the field of polymer synthesis, in particular to an amphiphilic block copolymer with near-infrared thermal responsiveness, and preparation and application thereof.
Background
The photo-thermal response material refers to a material which absorbs light and converts energy into heat to heat under the irradiation of a light source with a certain wavelength. Since near-infrared light can penetrate deep biological tissues and has little influence on normal cells, the nano material with near-infrared photothermal response is often applied to photothermal treatment of some tissues of a human body. Inorganic near-infrared photothermal response materials have high photothermal conversion efficiency, but are difficult to eliminate in vivo retention for a long time, and thus are not ideal photothermal reagents.
CN103002921A discloses a functional cross-linked nanostructure for combined optical imaging and therapy, wherein the optical substance comprises cross-linked block copolymers, linking groups and therapeutic agents, each block copolymer comprises hydrophilic and hydrophobic blocks, the linking groups contain optical active parts, and the optical substance forms a supermolecular structure in aqueous solution, CN103254371A discloses a synthesis method of amphiphilic block polymers with near infrared fluorescence characteristics, PNIPAM-b-PVDHBI is synthesized by RAFT synthesis method, and the side chain of PNIPAM-b-PVDHBI contains 2-benzimidazolyl- β -naphthalene chromophoric group.
Disclosure of Invention
In order to solve the above technical problems, the present invention aims to provide an amphiphilic block copolymer having near infrared thermal responsiveness, and a preparation method and an application thereof.
The invention relates to an amphiphilic block copolymer (PBnMA-b-P (APMA-co-PEGMA) @ NIR800) with near infrared thermal responsiveness, which is characterized by comprising a structure shown in a formula (1):
Figure BDA0002427127930000011
wherein x is 5-30; y is 5-30; z is 5-30; and m is 5-21.
The invention also provides a preparation method of the amphiphilic block copolymer shown in the formula (1), which comprises the following steps:
(1) in a protective atmosphere, benzyl methacrylate BnMA reacts in an organic solvent at 65-85 ℃ under the action of a RAFT regulator α -isobutylnitrile dithionaphthoate CPDN and a thermal initiator, and a polymer PBnMA is obtained after the reaction is completed, wherein the structural formula of the polymer PBnMA is as follows:
Figure BDA0002427127930000021
(2) in a protective atmosphere, taking polymer PBnMA as a macromolecular regulator, reacting methacrylamide BAPMA protected by tert-butyl carbamate and polyethylene glycol monomethyl ether methacrylate PEGMA in an organic solvent at 65-85 ℃ under the action of a thermal initiator, and obtaining a block polymer PBnMA-b-P (BAPMA-co-PEGMA) after the reaction is completed; the structural formula is as follows:
Figure BDA0002427127930000022
(3) removing a protecting group tert-butyl carbamate (BOC) on BAPMA in a block polymer PBnMA-b-P (BAPMA-co-PEGMA) to expose amino in methacrylamide to obtain PBnMA-b-P (APMA-co-PEGMA); the structural formula is as follows:
Figure BDA0002427127930000023
(4) PBnMA-b-P (APMA-co-PEGMA) and croconium cyanine dye NIR800 are reacted in an organic solvent at the temperature of 20-25 ℃, and after the reaction is completed, an amphiphilic block copolymer PBnMA-b-P (APMA-co-PEGMA) @ NIR800 is obtained; wherein the structural formula of the croconium cyanine dye NIR800 is as follows:
Figure BDA0002427127930000031
further, in step (1), the molar ratio of the BnMA, the CPDN and the thermal initiator is 5-30:1: 0.3.
In step (1), the molecular weight of the polymer PBnMA is 2400-3600 g/mol. Molecular weight distribution index Mw/MnLess than 1.13. Polymers with different molecular weights can be designed and synthesized by regulating the ratio of the monomer to the CPDN of the RAFT reagent, and the molecular weight distribution of the polymers is narrow.
Further, in the step (1), the reaction time was 20 hours.
Further, in step (2), the molar ratio of BAPMA, PEGMA, PBnMA and thermal initiator is 10:5 to 10:1: 0.3.
In the step (2), a block polymer PBnMA-b-P (BAPMA-co-PEGMA) comprises an oleophilic segment PBnMA, and P (BAPMA-co-PEGMA) in the polymer is a random copolymer of PEGMA and BAPMA, wherein PEGMA is a hydrophilic segment, BAPMA is used as a functional segment, and after BOC protecting group is removed, an amino group is exposed and used for reacting with a carboxyl group in a croconium cyanine dye NIR800, so that a group with near infrared light responsiveness is covalently connected in the block polymer.
Further, in the step (2), the reaction time was 24 hours. The molecular weight of the block polymer PBnMA-b-P (BAPMA-co-PEGMA) is 5600-9900 g/mol. The block copolymers with different molecular weights can be synthesized by regulating the proportion of comonomers BAPMA and PEGMA and adopting PBnMA with different molecular weights, the molecular weight distribution of the polymers is mostly narrow, and the macromolecular RAFT reagent PBnMA synthesized in the step (1) has high terminal functionalization degree.
Further, in steps (1) and (2), the thermal initiator is Azobisisobutyronitrile (AIBN).
Further, in the step (3), the method for removing the tert-butyl carbamate group comprises the following steps:
the block polymer PBnMA-b-P (BAPMA-co-PEGMA) is subjected to acidolysis reaction in an organic solvent under the action of trifluoroacetic acid (TFA), and the reaction temperature is 20-25 ℃.
Further, in step (3), the reaction time was 24 hours.
Further, in the step (4), the molar ratio of PBnMA-b-P (APMA-co-PEGMA) to NIR800 is 0.1-0.5: 1.
Further, in the step (4), the reaction time was 24 hours.
In step (4), the croconium dye NIR800 is prepared as follows:
Figure BDA0002427127930000041
in step (4), since the kratocyanine dye NIR800 contains carboxyl groups at both ends, when it reacts with PBnMA-b-P (APMA-co-PEGMA), it will occur that one of the carboxyl groups reacts with an amino group on one APMA, and furthermore, it will also occur that two carboxyl groups react with amino groups on two APMAs, respectively, and since two APMAs closest to each other in the same polymer chain are separated by a longer-chain PEGMA, there is a greater probability that these two reacted APMAs are located on different polymer chains, thereby causing partial APMAs on different polymer chains to undergo crosslinking (i.e., intermolecular crosslinking) by means of NIR 800.
The invention also provides an amphiphilic block copolymer micelle with near-infrared thermal responsiveness, which comprises an amphiphilic block copolymer shown in the formula (1), wherein the amphiphilic block copolymer micelle comprises a lipophilic inner core and a hydrophilic outer shell wrapping the outer part of the inner core, the inner core comprises PBnMA, the outer shell comprises P (APMA-co-PEGMA), and the outer shell is connected with a croconium cyanine dye with near-infrared thermal responsiveness through a covalent bond.
Further, the particle size of the amphiphilic block copolymer micelle is 200-600 nm. Under the condition of keeping the length of the lipophilic chain segment PBnMA in the amphiphilic block copolymer unchanged, the chain length of the hydrophilic chain segment is prolonged, and the size of the obtained micelle is correspondingly increased. Meanwhile, the micelle size can be changed by changing the proportion of the oleophilic chain segment and the hydrophilic chain segment in the amphiphilic block copolymer.
Further, the amphiphilic block copolymer micelle is obtained by self-assembling the amphiphilic block copolymer represented by the formula (1) in a cosolvent of an organic solvent and water.
Specifically, when preparing micelles, the amphiphilic block copolymer shown in the formula (1) is dissolved in an organic solvent, the obtained organic solution is slowly dripped into water, or water is slowly dripped into the obtained organic solution, the volume ratio of the water to the organic solvent is more than 10:1, and under the condition that the volume of the water is excessive, the amphiphilic block copolymer shown in the formula (1) is subjected to self-assembly in the cosolvent of the organic solvent and the water by means of hydrophilic and hydrophobic acting force, so that the amphiphilic block copolymer micelle with the hydrophilic shell and the hydrophobic core is obtained.
Further, when preparing the amphiphilic block copolymer micelle, the method also comprises the steps of dialyzing and centrifuging after finishing the dripping so as to remove the excessive NIR 800.
The invention also discloses application of the amphiphilic segmented copolymer micelle with near-infrared thermal responsiveness in preparation of a near-infrared responsive material.
Further, the near-infrared light response material is a near-infrared light response photothermal therapy preparation.
The amphiphilic block copolymer micelle contains the croconium cyanine dye, can absorb near infrared light and convert light energy into heat, so that the amphiphilic block copolymer micelle is suitable for preparing a near infrared light response material for non-medical use, even can be used for preparing a photo-thermal treatment preparation for medical use, and exerts the treatment function by utilizing the photo-thermal effect of the preparation.
By the scheme, the invention at least has the following advantages:
the invention prepares amphiphilic block copolymer PBnMA-b-P (BAPMA-co-PEGMA) with PEGMA as hydrophilic monomer by RAFT polymerization, and carries out post-modification on the block copolymer by utilizing kreocyanine dye NIR800 to obtain amphiphilic block copolymer PBnMA-b-P (APMA-co-PEGMA) @ NIR800 with near infrared photothermal responsiveness.
The PBnMA-b-P (APMA-co-PEGMA) @ NIR800 can be self-assembled in a blending solvent system of organic solvent/water, so that the amphiphilic block copolymer micelle with near infrared thermal responsiveness is obtained, and the micelle can be used for preparing a near infrared response material.
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood and to implement them in accordance with the contents of the description, the following detailed description is given with reference to the preferred embodiments of the present invention and the accompanying drawings.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum (DMSO-d) of intermediate PT-1 synthesized in example 16)；
FIG. 2 is a nuclear magnetic hydrogen spectrum (DMSO-d) of the intermediate PT-2 synthesized in example 16)；
FIG. 3 is a nuclear magnetic hydrogen spectrum (DMSO-d) of NIR800, a near-infrared dye synthesized in example 16)；
FIG. 4 is a graph of UV-Vis absorption spectra and absorption intensity versus concentration for the NIR dye NIR800 synthesized in example 1 in different solutions;
FIG. 5 is nuclear magnetic hydrogen spectra (CDCl) of PBnMA synthesized in example 2, PBnMA-b-P (BAPMA-co-PEGMA) synthesized in example 3, and PBnMA-b-P (BAPMA-co-PEGMA) synthesized in example 43)；
FIG. 6 is a hydraulic diameter, TEM image and TEM image of P7 self-assembly of a post-NIR modified P7 sample;
fig. 7 is an absorption curve of UV-Vis and a photothermal conversion temperature versus time curve for the NIR post-modification P7 sample.
Detailed Description
The following detailed description of embodiments of the present invention is provided in connection with the accompanying drawings and examples. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Chemical reagents used in the following examples of the invention: benzyl methacrylate (BnMA), polyethylene glycol monomethylether methacrylate (PEGMA, M)n500g/mol), azobisisoButyronitrile (AIBN), acetic acid (CH)3COOH), 2-mercaptothiophene, N- (3-hydroxypropyl) carbamic acid tert-butyl ester, anhydrous sodium sulfate (Na)2SO4) Tetrahydrofuran (THF), N-Dimethylformamide (DMF), toluene, methacryloyl chloride and trifluoroacetic acid (TFA) were mainly purchased from Jiangsu Qiangsheng chemical Co., Ltd and used as they are.
The test apparatus used in the following examples of the invention: the near infrared absorption intensity of the compound NIR800 and the post-modified micelle PBnMA-b-P (APMA-co-PEGMA) @ NIR800 was measured by an ultraviolet spectrophotometer (UV-2600 spectrophotometer). Number average molecular weight (M) of homopolymer PBnMA obtained by RAFT polymerization and amphiphilic block copolymer PBnMA-b-P (APMA-co-PEGMA)n，GPC) And molecular weight distribution (M)w/Mn) Measured by gel permeation chromatography (GPC, TOSOH, HLC-8320) equipped with a differential refractometer (TOSOH). The instrument is equipped with a protective column (TSKgel SuperMP-N type, 4.6 × 20mm), two separation columns (TSKgel SuperMultiporeHZ-N type, 4.6 × 150mm), a test column (molecular weight determination range 5 × 102To 1.9 × 105g/mol). The temperature of the instrument is 40 ℃, DMF is selected as a mobile phase, and the flow rate is 0.35 mL/min. GPC samples were injected using a TOSOH plus autosampler and sample molecular weights were calculated from PS standards purchased from TOSOH. The real-time temperature of the NIR800 and the post-modified micelles under near infrared light irradiation is measured by a thermal imager. Synthesis of the Compound NIR800, BAPMA, homopolymers obtained by polymerization, block copolymers and acid hydrolysis products1The H NMR spectra were determined by means of a nuclear magnetic resonance apparatus (Bruker 300MHz) in DMSO-d6Or CDCl3As solvent, TMS as internal standard. The self-assembled micelles, whose particle size and particle size polydispersity index were determined by dynamic light scattering (DLS, nanobook 90Plus), were dispersed in water at a test temperature of 25 ℃. The self-assembled micelle morphology and size were measured by transmission electron microscopy (TEM, HITACHI HT7700) at an accelerating voltage of 120 kV. Using a micropipette to remove 20uL of the dialyzed micelle aqueous solution, carefully dripping the micelle aqueous solution at the center of the carbon-coated copper mesh, standing for one minute, and then sucking away the excessive liquid by using filter paper. Again 20uL of aqueous phosphotungstic acid (1.0 wt.%) was transferred dropwise onto the copper grid, waiting for half a minuteAfter this time, the excess liquid was aspirated. The phosphotungstic acid aqueous solution has a dyeing effect, and the appearance can be better observed. The copper mesh after sample preparation can be baked for a moment under an infrared lamp so as to thoroughly evaporate water.
Example 1: synthesis of croconium cyanine NIR800
Figure BDA0002427127930000061
(1) Synthesis of PT-1
Under an argon atmosphere, 2-mercaptothiophene (4.87g, 41.9mmol) and methyl 4-piperidinecarboxylate (9.02g, 63.0mmol) were dissolved in 50mL of toluene, and the mixture was heated under reflux at 110 ℃ for 2 hours. And after the reaction is finished, removing the reaction solvent toluene by rotary evaporation. Preparation of a chromatography System Using an Intelligent fast liquid phase (eluent V)Petroleum ether：VEthyl acetateYield 73.1% of product PT-1 isolated as 9: 1);1H NMR(300MHz，CDCl3) δ 6.76(d, 1H), δ 6.62(d, 1H), δ 6.14(d, 1H), δ 3.71(s, 3H), δ 3.55 to 3.46(m, 2H), δ 3.06 to 2.79(m, 2H), δ 2.49 to 2.39(m, 1H), δ 2.05 to 2.00(m, 2H), δ 1.96 to 1.83(m, 2H) (FIG. 1).
(2) Synthesis of PT-2
PT-1(5.02g, 22.3mmol) was dissolved in a defined amount of aqueous sodium hydroxide (0.50mol/L, 2.93g NaOH in 146mL H2O) at 90 ℃ for 4 hours. After the reaction solution was cooled to room temperature, an aqueous acetic acid solution (1.7mmol/L, 7.00g of CH) was added dropwise thereto3COOH was dissolved in 70mL H2O) until a white precipitate appears. And (3) detecting the pH value of the mixed solution by using a wide pH test paper in the dripping process, and stopping dripping the acetic acid aqueous solution if the pH value of the solution is reduced to about 2. Removing excessive acetic acid and other water-soluble impurities through suction filtration and multiple water washing processes, and placing the product in a vacuum oven for overnight drying to obtain a light blue solid product PT-2 with a yield of 59.9%;1H NMR(300MHz，DMSO-d6) δ 6.73(d, 1H), δ 6.70(d, 1H), δ 6.13(d, 1H), δ 3.45 to 3.38(m, 2H), δ 2.82 to 2.73(m, 2H), δ 2.42 to 2.33(m, 1H), δ 1.93 to 1.88(m, 2H), δ 1.73 to 1.59(m, 2H) (FIG. 2).
(3) Synthesis of NIR800
PT-2(1.95g, 9.2mmol) and croconic acid (0.65g, 4.6mmol) were added to a mixed solvent of toluene and n-butanol in this order under an argon atmosphere (V)Toluene:VCroconic acid50mL:50mL), and refluxed at 90 ℃ for 2 hours. The reaction solvent was removed by suction filtration and washed several times with anhydrous methanol to remove soluble impurities. Drying overnight in a vacuum oven gave a solid powder with a metallic luster, 84.3% yield.1H NMR(300MHz，DMSO-d6) δ 12.44(d, 2H), δ 8.54(d, 2H), δ 7.05(d, 2H), δ 4.03 to 3.99(m, 4H), δ 3.51 to 3.53(m, 2H), δ 3.33 to 3.31(m, 4H), δ 2.27 to 2.03(m, 4H), δ 1.75 to 1.72(m, 4H) (FIG. 3).
Fig. 4 shows the UV-Vis absorption spectrum of the NIR800 near-infrared dye in (a) buffer solution (pH 8.0) and (b) DMF, and (c) the intensity of absorption as a function of concentration (λ 780nm, pH 8.0 buffer solution). The result shows that the nano-silver nano-particles can absorb near infrared light, and the absorption capacity is in direct proportion to the concentration.
Example 2: synthesis of PBnMA
PBnMA was synthesized by altering [ BnMA]0:[CPDN]0:[AIBN]0Respectively synthesizing products P1, P2 and P3 according to the molar ratio of the components [ BnMA ]]0:[CPDN]0:[AIBN]0For example, the process is as follows:
monomer BnMA (0.5mL, 3.0mmol), RAFT modulator CPDN (0.1623g, 0.6mmol), initiator AIBN (29.6mg, 0.18mmol), solvent toluene (1.0mL), and a crystalline and dry magnetic stirrer were placed in succession in a 5mL ampoule. Oxygen in the ampoule bottle is removed through three cycles of freezing, air extraction and unfreezing on a double-row pipe device, and a pipe is sealed by using flame fusion. After the oil bath pan was warmed to 80 ℃, the ampoule was placed in it and in stirring mode. After reacting for 20h, taking out the ampoule bottle, and cooling and quenching the reaction under running water. After the tube is broken, a proper amount of THF is added into the ampoule bottle to dissolve the polymer, and the diluent is dropwise added into a large amount of petroleum ether to precipitate. After sufficient precipitation time, the polymer is obtained by suction filtration. Drying the polymer after suction filtration in a vacuum oven at 35 ℃ to constant weightAnd calculating the monomer conversion rate by a weighing method. The performance test results of the synthesized PBnMA are shown in Table 1, and the polymers with different molecular weights can be designed and synthesized by regulating the ratio of the monomer to the RAFT reagent CPDN, and the molecular weight distribution of the polymers is narrow (M)w/MnLess than 1.13).
Table 1: performance test results of PBnMA
Figure BDA0002427127930000081
In Table 1, R ═ BnMA]0/[CPDN]0/[AIBN]0The molar ratio.aIndicating the molecular weight and molecular weight distribution were determined by GPC using PS as a standard in DMF (0.1 wt.% LiBr) solution,bthe molecular weight is represented by calculation of nuclear magnetic hydrogen spectrum.
Example 3: synthesis of PBnMA-b-P (BAPMA-co-PEGMA)
Different PBnMA (P1, P2 and P3) synthesized in example 2 are taken as macromolecular regulators respectively, and BAPMA and PEGMA are taken as monomers to synthesize different PBnMA-b-P (BAPMA-co-PEGMA) (P4-P9), wherein the molecular weight of PEGMA is 500g/mol, and [ BAPMA]0:[PEGMA]0:[PBnMA]0:[AIBN]0For example, the synthesis method is as follows:
BAPMA (0.1013g, 0.42mmol), PEGMA (0.2083g, 0.42mmol), PBnMA (0.10g, 0.042mmol), AIBN (2.1mg, 0.013mmol), toluene (3mL) and a clean dry magneton were added to a 5mL ampoule in this order. After three freezing-air extraction-unfreezing cycles, a flame is used for sealing the tube, and the ampoule bottle is placed in an oil bath kettle at the temperature of 80 ℃ for reaction for 24 hours. After the reaction was completed, the ampoule was taken out and cooled to room temperature. Breaking the tube, adding a proper amount of THF into the ampoule bottle to dissolve the polymer, and dropwise adding the diluent into a large amount of petroleum ether to precipitate. After sufficient precipitation time, the polymer is obtained by suction filtration. And drying the polymer subjected to suction filtration in a vacuum oven at 35 ℃ to constant weight, and calculating by a weighing method to obtain the monomer conversion rate. As shown in Table 2, the synthesized PBnMA-b-P (BAPMA-co-PEGMA) can be used for synthesizing block copolymers with different molecular weights by regulating the proportion of comonomers BAPMA and PEGMA and adopting PBnMA (P1, P2 and P3) with different molecular weights, and the molecular weight distribution of the polymers is mostly narrow, so that the macromolecular RAFT reagent PBnMA has high terminal functionalization degree.
TABLE 2 Synthesis of PBnMA-b-P (BAPMA-co-PEGMA)
Figure BDA0002427127930000091
Example 4: synthesis of PBnMA-b-P (BAPMA-co-PEGMA)
The different products synthesized in example 3 were post-modified by removing the tert-butyl carbamate group from the monomer BAPMA in order to expose the amino group for reaction with the carboxyl group in NIR 800. Namely, PBnMA-b-P (APMA-co-PEGMA) can be obtained by acid hydrolysis of PBnMA-b-P (BAPMA-co-PEGMA). The method comprises the following specific steps:
the polymer PBnMA-b-P (BAPMA-co-PEGMA) (100mg, 0.042mmol) synthesized above was dissolved in 2.0mL of methylene chloride, 0.5mL of trifluoroacetic acid (TFA) was rapidly added thereto, and the reaction mixture was stirred under sealed conditions at room temperature overnight. After the reaction is finished, precipitating the reaction mixed solution for 2-3 times by using petroleum ether, and drying the precipitate in a constant-temperature vacuum oven at 35 ℃. From the hydrogen nuclear magnetic resonance spectrum (FIG. 5(c), a complete disappearance of peaks at 1.40ppm to 1.50ppm was observed, thereby confirming successful removal of the t-butoxycarbonyl group (BOC) and successful acquisition of PBnMA-b-P (APMA-co-PEGMA).
Example 5: synthesis of PBnMA-b-P (APMA-co-PEGMA) @ NIR800
PBnMA-b-P (APMA-co-PEGMA) @ NIR800 was prepared by post-modification reaction of PBnMA-b-P (APMA-co-PEGMA) and NIR 800. concretely, the different acid hydrolysis products PBnMA-b-P (APMA-co-PEGMA) (2mg) prepared in example 4 and a suitable amount of croconium dye NIR800 (0.6mg, 1.14 × 10)-3mmol) is dissolved in 1.0mL DMF at the same time, and the reaction is carried out overnight until the reaction is complete, so as to achieve the post-modification purpose, and obtain PBnMA-b-P (APMA-co-PEGMA) @ NIR 800.
Example 6: preparation of micelles
PBnMA-b-P (APMA-co-PEGMA) @ NIR800 synthesized by taking the product P7 synthesized in example 3 as a raw material is used for preparing micelles and is assembled by a selective solvent, and the method comprises the following steps:
first, the polymer PBnMA-b-P (APMA-co-PEGMA) @ NIR800(2mg) is dissolved in 1.0mL DMF, and the solution is fully shaken in a sonicator for half an hour to obtain a completely dissolved polymer solution. 10mL of deionized water were added dropwise to the polymer solution over 2 hours by means of a syringe pump, the process being carried out at a constant temperature of 25 ℃ with gentle stirring. The solution obtained after the completion of the dropwise addition was placed in a dialysis bag having a molecular weight cutoff of 3500g/mol, and dialyzed in deionized water for 24 hours with continuous water exchange to remove DMF from the reaction solution. Since the mixed solution gradually changed from alkaline to neutral, the excess NIR800 not participating in the reaction precipitated from the solution, and was centrifuged at 10000r/min for 10 minutes in a high-speed centrifuge to remove the precipitate. The supernatant after centrifugation, i.e., the assembly solution, was dialyzed again against a buffer solution having a pH of 8.0 for 12 hours to remove the NIR800 entrapped in the micelle. Finally dialyzing in deionized water for 24 hours, wherein all NIR800 structures in the micellar aqueous solution are chemically combined on the micellar nucleocapsid structure, and no physical embedding form exists.
For comparison, PBnMA-b-P (BAPMA-co-PEGMA) synthesized in example 3 and PBnMA-b-P (BAPMA-co-PEGMA) synthesized in example 4 were prepared into micelles in the same manner, respectively, and the polymer was dissolved in 1.0mL of DMF and sufficiently shaken in a sonicator for half an hour to obtain a completely dissolved polymer solution. 10mL of deionized water were added dropwise to the polymer solution over 2 hours by means of a syringe pump, the process being carried out at a constant temperature of 25 ℃ with gentle stirring. The solution obtained after the completion of the dropwise addition was placed in a dialysis bag having a molecular weight cutoff of 3500g/mol, and dialyzed in deionized water for 24 hours with continuous water exchange to remove DMF from the reaction solution.
The particle size and particle size distribution of each micelle are shown in Table 3, wherein in Table 3, the particle size and particle size distribution are obtained by DLS test, wherein polymers 1 to 3 are respectively obtained by taking P4-P9 synthesized in example 3 as raw materials, and polymer 1 represents a micelle formed by PBnMA-b-P (BAPMA-co-PEGMA) synthesized in example 3; polymer 2 represents micelles formed by the product PBnMA-b-P (APMA-co-PEGMA) synthesized in example 4; polymer 3 represents micelles formed by the product PBnMA-b-P (APMA-co-PEGMA) @ NIR800 synthesized in example 5.
TABLE 3 self-Assembly of different block polymers
Figure BDA0002427127930000101
The self-assembly result (table 3) shows that the longer the chain length of the hydrophilic chain PPEGMA is, the larger the micelle size obtained by self-assembly of the amphiphilic block copolymer PBnMA-b-P (BAPMA-co-PEGMA) is, and the same tendency is shown in the assembled micelle size of the block copolymer after acid hydrolysis, under the condition that the lipophilic chain length and the polymerization degree of BAPMA are the same. This is caused by the increased repulsive force between hydrophilic shells after the hydrophilic chain length is increased. The block copolymer P7, which forms smaller size micelles, was selected for post-modification of NIR 800. FIG. 6(c) is a TEM image of micelles formed by the block copolymer P7, and FIG. 6b is a TEM image of micelles formed by the polymer modified by NIR 800P 7, which shows that the micelle size of the post-modified block copolymer is further reduced after the same assembly. The reason is presumed to be as follows: in the amidation reaction process, one carboxyl group of NIR800 is chemically bonded to a copolymer chain, and the other hydroxyl group reacts with an amino group, the amino group is positioned on different copolymer chains with high probability, so that the different copolymer chains are slightly crosslinked, the micelle structure obtained by subsequent assembly is more compact, and the particle size of an assembly is reduced to 114 nm. From the TEM image (FIG. 6(b)) it can be seen that the assembly is a spherical particle with a corresponding diameter of about 38nm, which is much lower than the 114nm measured with DLS (FIG. 6 (a)). This is mainly due to the TEM measurements of the diameter of the self-assembly in dry state.
FIG. 7(a) is the UV absorption curve of NIR800 post-modified polymer PBnMA-b-P (APMA-co-PEGMA) @ NIR800 micelle after 5-fold dilution, where CNIR 800From 0.07mg/mL, we calculated NIR800 to be 39.3% efficient in modifying the deprotected block copolymer PBnMA-b-P (APMA-co-PEGMA). The post-modified micelle aqueous solution is irradiated by near infrared light at 810nm (0.028W/cm)2) The temperature increased from 20 ℃ to about 55 ℃ in one hour from the initial ambient temperature (FIG. 7 (b)). This shows that the micelles formed by PBnMA-b-P (APMA-co-PEGMA) @ NIR800 have the same effectHas good near-infrared photo-thermal response capability.
The invention adopts RAFT polymerization method to synthesize amphiphilic block copolymer PBnMA-b-P (BAPMA-co-PEGMA), wherein benzyl methacrylate (BnMA) is respectively used as a lipophilic monomer, and polyethylene glycol monomethyl ether methacrylate (PEGMA) with molecular weight of 500500) The self-assembly research is carried out on the obtained amphiphilic block copolymer by adopting a solution self-assembly method, and the experimental result shows that the micelle particle size is increased along with the increase of a hydrophilic chain segment under the condition that the length of the lipophilic chain segment and the doping amount of the functional monomer are not changed, the repulsion force between micelle shells is increased due to the increase of the hydrophilic chain segment, so that the size of the micelle is changed.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, it should be noted that, for those skilled in the art, many modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.

Claims (10)

1. An amphiphilic block copolymer having near-infrared thermal responsiveness, characterized in that it comprises a structure represented by formula (1):
Figure FDA0002427127920000011
wherein x is 5-30; y is 5-30; z is 5-30; and m is 5-21.
2. A method for preparing the amphiphilic block copolymer according to claim 1, comprising the steps of:
(1) in a protective atmosphere, reacting benzyl methacrylate BnMA in an organic solvent at 65-85 ℃ under the action of a RAFT regulator α -isobutylnaphthoate CPDN and a thermal initiator, and obtaining a polymer PBnMA after complete reaction;
(2) in a protective atmosphere, taking the polymer PBnMA as a macromolecular regulator, reacting methacrylamide BAPMA protected by tert-butyl carbamate and polyethylene glycol monomethyl ether methacrylate PEGMA in an organic solvent at 65-85 ℃ under the action of a thermal initiator, and obtaining a block polymer PBnMA-b-P (BAPMA-co-PEGMA) after the reaction is completed;
(3) removing a protecting group tert-butyl carbamate group on BAPMA in the block polymer PBnMA-b-P (BAPMA-co-PEGMA) to expose amino in methacrylamide to obtain PBnMA-b-P (APMA-co-PEGMA);
(4) reacting the PBnMA-b-P (APMA-co-PEGMA) and croconium cyanine dye NIR800 in an organic solvent at the temperature of 20-25 ℃ to obtain the amphiphilic block copolymer after the reaction is completed; wherein the structural formula of the croconium cyanine dye NIR800 is as follows:
Figure FDA0002427127920000012
3. the method of claim 2, wherein: in step (1), the molar ratio of BnMA, CPDN and thermal initiator is 5-30:1: 0.3.
4. The method of claim 2, wherein: in step (2), the molar ratio of BAPMA, PEGMA, PBnMA and thermal initiator is 10:5 to 10:1: 0.3.
5. The production method according to claim 2, wherein in the step (3), the method for removing a tert-butylcarbamate group comprises the steps of:
the block polymer PBnMA-b-P (BAPMA-co-PEGMA) is subjected to acidolysis reaction in an organic solvent under the action of trifluoroacetic acid, and the reaction temperature is 20-25 ℃.
6. The method of claim 2, wherein: in step (4), the molar ratio of PBnMA-b-P (APMA-co-PEGMA) to NIR800 is 0.1-0.5: 1.
7. An amphiphilic block copolymer micelle with near-infrared thermal responsiveness, which is characterized in that: the amphiphilic block copolymer of claim 1, wherein the amphiphilic block copolymer micelle comprises a lipophilic inner core and a hydrophilic outer shell wrapping the outer part of the inner core, wherein the inner core comprises PBnMA, the outer shell comprises P (APMA-co-PEGMA), and the outer shell is connected with croconium cyanine dye with near infrared photo-responsiveness through covalent bonds.
8. The amphiphilic block copolymer micelle having near-infrared thermal responsiveness according to claim 7, wherein: the particle size of the amphiphilic block copolymer micelle is 100-600 nm.
9. The amphiphilic block copolymer micelle having near-infrared thermal responsiveness according to claim 7, wherein: the amphiphilic block copolymer micelle is obtained by self-assembling the amphiphilic block copolymer according to claim 1 in a co-solvent of an organic solvent and water.
10. Use of the amphiphilic block copolymer micelle having a near-infrared thermo-responsiveness according to claim 7 in preparation of a near-infrared photo-responsive material.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112999348A (en) * 2021-03-31 2021-06-22 西南交通大学 Polypeptide-dye conjugate with variable morphology, preparation method and application
CN115010850A (en) * 2022-06-08 2022-09-06 上海大学 Near-infrared photo-thermal polymer functional material with cross-linked stable structure, preparation method and application thereof
CN116496646A (en) * 2022-01-18 2023-07-28 苏州大学 Super-hydrophobic photo-thermal coating, preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110010896A (en) * 2019-04-03 2019-07-12 北京科技大学 A kind of lithium ion battery ionic conduction type cross-linked binder and preparation method thereof
CN110128578A (en) * 2019-06-14 2019-08-16 苏州大学 The light-operated reversible complexing of aqueous solution polymerize and the preparation of polymer nano-particle
CN110194834A (en) * 2019-05-07 2019-09-03 西南交通大学 A kind of visualization light-induced shape-memory polymer and preparation method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110010896A (en) * 2019-04-03 2019-07-12 北京科技大学 A kind of lithium ion battery ionic conduction type cross-linked binder and preparation method thereof
CN110194834A (en) * 2019-05-07 2019-09-03 西南交通大学 A kind of visualization light-induced shape-memory polymer and preparation method thereof
CN110128578A (en) * 2019-06-14 2019-08-16 苏州大学 The light-operated reversible complexing of aqueous solution polymerize and the preparation of polymer nano-particle

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XIANGZHI SONG等: "A new water-soluble near-infrared croconium dye", 《DYES AND PIGMENTS》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112999348A (en) * 2021-03-31 2021-06-22 西南交通大学 Polypeptide-dye conjugate with variable morphology, preparation method and application
CN116496646A (en) * 2022-01-18 2023-07-28 苏州大学 Super-hydrophobic photo-thermal coating, preparation method and application thereof
CN115010850A (en) * 2022-06-08 2022-09-06 上海大学 Near-infrared photo-thermal polymer functional material with cross-linked stable structure, preparation method and application thereof
CN115010850B (en) * 2022-06-08 2023-09-15 上海大学 Near-infrared photo-thermal polymer functional material with cross-linked stable structure, preparation method and application thereof

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