CN106883360B - Functionalized stimulus-responsive polymer and preparation method thereof - Google Patents
Functionalized stimulus-responsive polymer and preparation method thereof Download PDFInfo
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- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F293/00—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule
- C08F293/005—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- C08F222/10—Esters
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Abstract
The invention relates to a functionalized stimulus-responsive polymer and a preparation method thereof. The polymer is obtained by controllable polymerization of two free radicals of hydrophilic monomer VBOEG containing alkoxy chain and monomer containing cholesteryl. The end of the obtained amphiphilic block polymer is provided with a furan functional group which can be functionalized and modified, and the main chain is provided with a disulfide bond which can be reduced and responded. The outer layer of the hydrophilic shell of the nano material prepared by the polymer can be subjected to in-situ multifunctional modification through Diels-Alder reaction, and the hydrophobic core is connected with the disulfide bond with reduction response capability between the hydrophilic shell, so that the dissociation of the nano structure of the nano material can be realized in the presence of a reducing reagent. The polymer material has great potential application value in the field of intelligent drug delivery.
Description
Technical Field
The invention relates to a functionalized stimulus-responsive polymer and a preparation method thereof.
Background
Intelligent polymer materials are a new class of materials that have developed rapidly in the twenty-first century. Since it mimics a living system, certain properties of the polymer itself, such as shape, hydration state, surface energy, permeation rate or recognition ability, change in response when a change in the physical, chemical or even biostimulation signal of the external environment is sensed. The polymer intelligent nano material constructed by combining the development of a nano technology and integrating the response behavior of polymer intelligence and the characteristics of nano-sized materials is one of the most advanced functional materials which are developed most rapidly in recent years, has wide application potential in the fields of biomedicine, photoelectricity, green energy storage materials and the like, and particularly has immeasurable prospect in the fields of intelligent drug delivery and the like. The polymer nano material is used as a carrier of an effective component for treatment, so that the delivery of organic molecule drugs, the loading of specific proteins, gene drugs and the like is no longer impossible. The requirements of the prior carrier polymer nano material are simple, and only the prior carrier polymer nano material needs no toxicity, good biocompatibility and simple capability of coating active ingredients. With the scientific development, people have higher and higher requirements on the design of polymer nano materials, and the development of intellectualization and multifunction becomes the mainstream research and application direction. The intelligentization of the nano polymer carrier is mainly considered in the following two aspects:
1. the surface can be functionally modified. Substances with different functional properties, such as targeting molecules, proteins, antibodies and the like, can be effectively introduced on the surface of the polymer nano material coated with the effective components, so that various functional applications of the drug-carrying system are realized, the intelligent delivery effect is enhanced, and the application field is expanded.
2. The intelligent response capability is given to the polymer nanometer material. The intelligent response of the polymer material is triggered by external stimulation, so that the aim of controllably delivering the effective ingredients at fixed time, fixed point and quantity is fulfilled. In the field of preparing polymer nanomaterials with stimulus response, a plurality of polymer nanomaterials responding to different stimulus sources are developed. Such as temperature response, pH response, light response, reduction response, and the like. The reduction response polymer nano drug-carrying system can be changed differently according to the concentration difference of glutathione which is a reducing substance in different environments (inside and outside cells) in a human body, so that selective intracellular drug delivery is realized, and therefore the material is regarded as one of polymer carrier materials which can be practically applied in a large scale in the future.
Common polymer carrier nano materials often only have single stimulus response performance, but in order to really realize the intelligent delivery performance of the nano polymer nano materials, functional modification and stimulus response performance must be organically combined together, so that the real application value of the nano polymer nano materials in the fields of intelligent delivery/release of medicines and the like is brought into play.
Disclosure of Invention
It is an object of the present invention to provide a stimulus responsive polymer that can be functionalized. The polymer is an amphiphilic block polymer with furan functional groups at the ends and disulfide bonds in the main chain.
The second purpose of the invention is to provide a preparation method of the polymer nano material.
In order to achieve the above object, the amphiphilic block polymer of the present invention is synthesized by combining two kinds of activity-controllable Polymerization of a styrene monomer (VBOEG) containing a short Chain of polyethylene glycol and a monomer containing a cholesterol group, wherein the VBOEG monomer is polymerized by Reversible Addition-Fragmentation Chain Transfer Polymerization (RAFT) to obtain the hydrophilic block polymer, and an Atom Transfer Radical Polymerization (ATRP) initiating group containing a disulfide bond is introduced by end functional modification to realize that an acrylate monomer containing the cholesterol group is polymerized by ATRP to obtain the target amphiphilic block polymer. On the basis, the polymer spherical nano material is prepared by a solvent replacement method, and the specific reaction formula is as follows:
according to the reaction mechanism, the invention adopts the following technical scheme:
a functionalizable stimulus responsive polymer characterized by the structural formula:
wherein m = 10-30; n =10 ~ 90.
A method for preparing the above functionalized stimulus-responsive polymer, which is characterized by comprising the following specific steps:
a. and (2) mixing a chain transfer agent, a styrene monomer containing polyethylene glycol short chain and azobisisobutyronitrile according to the weight ratio of 1: (20-50): (0.1-0.3) dissolving in dioxane, sealing, removing water and oxygen, stirring at 60-80 ℃ for 12-36 hours, and precipitating and purifying in a solvent and diethyl ether to obtain the hydrophilic block polymer PVBOEG.
b. And (c) mixing the PVBOEG and the n-hexylamine obtained in the step a according to the proportion of 1: and (5-50) dissolving in dichloromethane in a molar ratio, performing water removal and oxygen removal operation, stirring at room temperature for reaction for 10-24 hours, removing the solvent after the reaction is finished, and precipitating and purifying in diethyl ether to obtain a polymer product PVBOEG-SH with a sulfhydryl at the end.
c. The product PVBOEG-SH and ATRP micromolecule initiator containing disulfide bonds are added according to the proportion of 1: dissolving the 10-50 molar ratio in methanol, stirring at room temperature for reaction for 16-24 hours, and then precipitating and purifying in diethyl ether to obtain the target ATRP macromolecular initiator PVBOEG-SS-Br.
d. And c, under an inert atmosphere, mixing the PVBOEG-SS-Br, cuprous bromide, a monomer containing a cholesterol group and pentamethyl diethylenetriamine obtained in the step c according to the weight ratio of 1: (2-5): (20-100): (2-5) dissolving the mixture in toluene in a molar ratio, performing water removal and oxygen removal, and stirring to react for 18-48 hours at the temperature of 70-80 ℃; and removing copper salt in the product after the reaction is finished. Precipitating and purifying in methanol, and vacuum drying to obtain the target polymer functionalized stimulus responsive polymer.
The structural formula of the chain transfer agent is as follows:(ii) a The chemical structural formula of the styrene monomer containing polyethylene glycol short chain is as follows:(ii) a The chemical structural formula of the ATRP micromolecule initiator containing disulfide bonds is as follows:(ii) a The chemical structural formula of the monomer containing the cholesteryl group is as follows:。
the polymer nano material prepared by the functionalized stimulus-responsive polymer has the particle size of 30-500nm, uniform distribution and regular shape. The preparation method comprises the following specific steps: dissolving the functionalized stimulus-responsive polymer in a certain amount of tetrahydrofuran to prepare 0.1-1 wt% of solution, and slowly dropwise adding deionized water with the volume of 1-3 times of that of the polymer solution. Then dialyzed through a dialysis bag (molecular weight cut-off 3500 Da). Finally obtaining the aqueous solution of the polymer spherical nano material.
The functionalized stimulus-responsive polymer provided by the invention has a specific furan functional group capable of being functionalized and modified at the terminal, and the hydrophilic block is connected with the hydrophobic block by a reduction-responsive disulfide bond. Therefore, the polymer has the functional modification capability and the reduction stimulus response capability simultaneously in the same polymer system. The polymer nano material prepared by the solvent replacement method can be subjected to various functional modifications on the surface according to needs, has intelligent response and release capacity as an effective component carrier material, and has great potential application value in the field of intelligent drug delivery.
Drawings
FIG. 1 shows a block copolymer PVBOEG-SS-PAChol of the invention1HNMR spectrogram.
FIG. 2 is a GPC chart showing the change in molecular weight of the block polymer PVBOEG-SS-PChol of the present invention after exposure to dithiothreitol over time.
FIG. 3 is a TEM photograph of spherical nanomaterials prepared from the block polymer PVBEOG-SS-PAChol of the present invention.
Detailed Description
The preferred embodiments of the invention are detailed below:
the first embodiment is as follows:
(1) a dry 25 mL Schlenk reaction flask was charged with a styrenic monomer containing polyethylene glycol short chain (3.65 g), Furan-RAFT reagent (95.5 m)g) Azobisisobutyronitrile (8.8 mg) and 5 mL of dioxane. After the rubber plug is used for sealing, the reaction bottle is immersed into preheated 65 after the operation of removing water and oxygenoC, heating and stirring in an oil bath kettle to react for 24 hours. After the reaction is finished, the solvent is removed by rotary evaporation, and the product PVBOEG is obtained after precipitation and purification in 40 mL of diethyl ether.
(2) PVBOEG (700 mg), n-hexylamine (90 mg), 3 mL of methylene chloride were added to a 10 mL reaction flask after water removal and oxygen removal. Stirred for 24 hours. After removal of the solvent by rotary evaporation, it was precipitated three times in 40 mL of diethyl ether to give the product PVBOEG-SH. PVBOEG-SH and small ATRP initiator, 3 mL of methanol were added to a 10 mL Schlenk reaction flask. Stirring for 24 hours, removing the solvent by rotary evaporation, precipitating in 40 mL of diethyl ether for three times, purifying, and drying in vacuum to obtain the target macroinitiator PVBOEG-SS-Br.
(3) PVBOEG-SS-Br (60 mg), cuprous bromide (3.2 mg) and monomer containing a cholesterol group (373 mg) were charged to a dry 10 mL Schlenk reaction tube, and a solution of pentamethyldiethylenetriamine (5.2 mg) in toluene (0.6 mL) was added to the reaction tube under nitrogen. After the water and oxygen removal operation, the reaction tube is immersed into the preheated 80oC, oil bath, stirring for 24 hours. After the reaction is finished, the reaction solution is passed through an alkaline alumina column to remove copper salts in the product. Precipitating and purifying in methanol, and vacuum drying to obtain the target polymer. Nuclear magnetization is shown in figure 1.
Example two:
in this example, dithiothreitol was used as a reducing agent to investigate the reduction response capability of the block polymer. The specific implementation process is as follows: the block polymer (2 mg) was dissolved in methylene chloride (1 mL) with dithiothreitol (2.5 mg). The system was deoxygenated and the reaction was started with stirring. Samples were taken 24 hours and 8 hours after the start of the reaction and subjected to molecular weight measurement by gel permeation chromatography in the tetrahydrofuran phase. See fig. 2. Compared with the original polymer, after the PVBOEG-SS-PAChol reacts with dithiothreitol for 24 hours, the molecular weight of the polymer is reduced due to the breakage of disulfide bonds after the peak-off time is prolonged. When the reaction time was 48 hours, the degree of molecular weight reduction of the polymer was increased, and the block polymer was decomposed into two kinds of homopolymers. This demonstrates the ability of the block polymer to respond to a reducing environment.
Example three:
a method for preparing spherical polymer nano material by solvent displacement method. The specific implementation process is as follows: the above amphiphilic block polymer (0.5 mg) was dissolved in tetrahydrofuran (1 mL) to prepare a solution, and deionized water (1 mL) was added to the polymer solution at a dropping rate of 10. mu.L/min. And in the dropping process, continuously shaking to uniformly mix the solution until the dropping of the deionized water is finished. Then dialyzing by a dialysis bag (molecular weight cut-off is 3500 Da) to finally obtain the aqueous solution of the polymer spherical nano material. The microscopic morphology of the polymeric nanomaterial is observed by a transmission electron microscope, and the microscopic morphology is spherical with the size of 60-100 nm, the size is relatively consistent and the distribution is uniform, as shown in FIG. 3.
Example four:
in this embodiment, fluorescein 5-maleimide is selected as a surface-modified model molecule to perform in-situ functional modification on the surface of the polymer nanomaterial. The specific implementation process is as follows: fluorescein 5-maleimide (0.5 mg) was dissolved in DMF (30. mu.L), mixed with the above aqueous solution of the nanosphere, and after 12 hours, unreacted model molecule was removed by dialysis. Before and after the contrast reaction, the assembly solution after the reaction obviously has a fluorescent color, and the polymer nano material is proved to have the capability of modifying the functionalized substances on the surface in situ. The polymer carrier with the surface modification has great application prospect in the aspect of realizing the targeted delivery of a drug-carrying system.
The embodiments of the present invention have been described above with reference to the accompanying drawings, but the present invention is not limited to the above embodiments, and various changes can be made according to the purpose of the present invention, and all changes, modifications, substitutions, combinations, and simplifications made according to the spirit and principle of the technical solution of the present invention shall be equivalent substitution ways, so long as the purpose of the present invention is met, and the present invention shall fall within the protection scope of the present invention as long as the technical principle and the inventive concept of the synthesis method of the block polymer and the preparation method and application of the spherical nano material of the present invention are not departed.
Claims (4)
2. A method for preparing a functionalizable stimuli-responsive polymer, characterized in that the method comprises the following specific steps:
a. and (2) mixing a chain transfer agent, a styrene monomer containing polyethylene glycol short chain and azobisisobutyronitrile according to the weight ratio of 1: (20-50): (0.1-0.3) dissolving in dioxane in a molar ratio, sealing, performing water removal and oxygen removal operation, stirring at the temperature of 60-80 ℃ for reaction for 12-36 hours, removing the solvent by rotary evaporation after the reaction is finished, and precipitating and purifying in ether to obtain a product PVBOEG;
b. and (c) mixing the PVBOEG and the n-hexylamine obtained in the step a according to the proportion of 1: (5-50) dissolving in dichloromethane in a molar ratio, performing water removal and oxygen removal operation, stirring at room temperature for reaction for 10-24 hours, removing the solvent after the reaction is finished, and precipitating and purifying in diethyl ether to obtain a product PVBOEG-SH;
c. the product PVBOEG-SH and ATRP micromolecule initiator containing disulfide bonds are added according to the proportion of 1: dissolving the 10-50 molar ratio in methanol, stirring at room temperature for reaction for 16-24 hours, and then precipitating and purifying in diethyl ether to obtain a target ATRP macromolecular initiator PVBOEG-SS-Br;
d. and c, under an inert atmosphere, mixing the PVBOEG-SS-Br, cuprous bromide, a monomer containing a cholesterol group and pentamethyl diethylenetriamine obtained in the step c according to the weight ratio of 1: (2-5): (20-100): (2-5) dissolving the mixture in toluene in a molar ratio, performing water removal and oxygen removal, and stirring to react for 18-48 hours at the temperature of 70-80 ℃; removing copper salt in the product after the reaction is finished; precipitating and purifying in methanol, and vacuum drying to obtain the target polymer functionalized stimulus responsive polymer.
3. A polymer spherical nano material prepared by using the block polymer as the raw material according to claim 1, wherein the size of the nano microsphere is between 30 and 500 nm; the hydrophilic shell and the hydrophobic core of the nano microsphere are connected by a disulfide bond, and the surface of the nano microsphere is provided with a furan group capable of being functionally modified.
4. A method for preparing nano-microspheres according to claim 3, characterized in that the method comprises the following specific steps: dissolving the amphiphilic block polymer in tetrahydrofuran to prepare 0.1-1 wt% solution, and slowly dripping 1-3 times of volume of deionized water into the polymer solution; and dialyzing with deionized water to obtain the polymer spherical nano material.
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