CN106832158B - PH-responsive dynamic shell cross-linked polymer nano-particle and preparation method thereof - Google Patents
PH-responsive dynamic shell cross-linked polymer nano-particle and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a pH-responsive dynamic shell crosslinked polymer nanoparticle and a preparation method thereof, belonging to the field of functional polymer materials. The invention utilizes two block type macromolecule reversible-addition fragmentation chain transfer reagents to simultaneously adjust the dispersion polymerization under medium, and prepares the core-shell-crown type polymer nano particles by a polymerization induction self-assembly method. The chemical structure of the shell layer of the nano particle contains phenylboronic acid and ketal groups, and the phenylboronic acid and the ketal groups can perform reversible chemical reaction under the regulation and control of pH, so that the pH-responsive dynamic shell crosslinked polymer nano particle is prepared. The method has the characteristics of simplicity, convenience, environmental friendliness, high concentration of the prepared nano particles, uniform size and the like. Compared with polymer micelles, the nanoparticles have better stability, the shell layer of the nanoparticles is dynamically crosslinked by utilizing reversible chemical bonds of groups among polymer molecular chains, the preparation method is strong in feasibility, simple and convenient to operate, and the product can be repeatedly utilized. The product of the invention can effectively wrap various insoluble drugs, and is suitable for the biomedical fields of in vivo delivery of anticancer drugs, gene vectors and the like.
Description
Technical Field
The invention belongs to the technical field of chemical industry and new materials, and particularly relates to a pH-responsive dynamic shell crosslinked polymer nanoparticle and a preparation method thereof.
Background
The intelligent polymer nanoparticles with environmental responsiveness are widely applied in the biomedical field, such as medical diagnosis, biological imaging, drug delivery and the like, and thus great research interest is brought to people. Generally, the environment-responsive smart polymer nanoparticles are prepared on the basis of block copolymer micelles having temperature or pH responsiveness. However, the stability of the polymer micelle is poor, and the common stimuli-responsive block copolymer has limitations in structure, responsiveness and the like, which greatly limits the practical application of the polymer nanoparticles. Recently, the formation of stimuli-responsive nanoparticles based on dynamic covalent bonds has attracted attention as an effective method. A series of polymer materials with environmental responsiveness and adaptability can be obtained by introducing dynamic covalent bonds on or among polymer chains of a shell layer of the polymer nanoparticles, and the stability of the polymer micelle can be remarkably improved by introducing cross-linking bonds.
Dynamic covalent bonds are also referred to as reversible chemical bonds, which can undergo dynamic changes of formation and cleavage under the stimulation of an external environment. The reversible property of the dynamic covalent bond is applied to the design of the polymer material, so that the reversibility of the dynamic chemical bond can be reserved, and compared with a supramolecular compound formed by a non-covalent bond, the dynamic covalent bond has better chemical stability. Based on this idea, intelligent polymer nanoparticles having various chemical compositions containing thermally responsive alkoxyamine bonds, diels-alder bonds, acylhydrazone bonds, borate bonds, and disulfide bonds were successfully prepared. Chinese patent CN201210199661.2 reports a preparation method of a temperature and pH sensitive shell crosslinked polymer micelle, which is formed by synthesizing a temperature and pH sensitive diblock copolymer by a reversible-addition fragmentation chain transfer polymerization method and then partially crosslinking a shell structure of the self-assembled polymer micelle by using small molecular dialdehyde or diacid. The small molecular cross-linking agent is used for partially cross-linking the shell structure of the micelle, and the stability of the polymer micelle is ensured. The preparation method has the characteristics of strong feasibility, simple and convenient operation, capability of recycling the micelle and the like. McCormick et al utilizes pH regulationThe amino and the aldehyde form an imine reversible chemical bond to prepare the dynamic shell crosslinked polymer nano micelleMacromolecules, 2011, 44, 1327]. Sumerlin et al synthesized poly (3-acrylamidophenylboronic acid) -bPoly (A) and (B)N-isopropyl acrylamide) block copolymer, and utilizes the block copolymer to self-assemble and prepare the polymer nano particle with three responsibilities of pH, heat and sugarChemical Communications, 2008, 21, 2477]. Subsequently, the research group prepared another poly (A)N,N-dimethylacrylamide) -bA micelle of a block copolymer of poly (acrylamidophenylboronic acid) produced by crosslinking a segment of phenylboronic acid with a diol or triol to produce star polymer nanoparticles having a reversible borate bondJournal of the American Chemical Society, 2011, 133, 19832]. Wooley et al synthesized poly (3-acrylamidophenylboronic acid) with a bifunctional group of phenylboronic acid and aminobPoly (ethylenediamine acrylamide) and assembled to form dynamically crosslinked core-shell structured polymer nanoparticles [ poly (ethylenediamine acrylamide) ], andPolymer Chemistry, 2012, 3, 3146]. However, the polymer nanoparticles in the above-mentioned patents or documents are prepared by first synthesizing a block copolymer and then forming polymer nanoparticles by self-assembly of the block copolymer in a selective solvent. It is well known that the assembly of block copolymers in selective solvents occurs only at relatively dilute (less than 1%) polymer concentrations, which results in poor yields of micelles that produce shell-crosslinked polymers.
In recent years, polymerization-induced self-assembly methods have been extensively studied and used for the mass production of polymer nanoparticles. The method is characterized in that a solvatable macromolecule RAFT (Macro-RAFT) reagent, an initiator and a polymerization monomer are added by a one-pot method, a block copolymer is formed in situ through heterogeneous RAFT polymerization and assembled to form polymer nanoparticles, and the concentration of the polymer nanoparticles can reach 30%. At present, no published literature report and patent application about the preparation of pH-responsive dynamic shell crosslinked polymer nanoparticles by using a polymerization-induced self-assembly method exist at home and abroad.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a preparation method of pH-responsive dynamic shell cross-linked polymer nanoparticles.
The invention provides a preparation method of pH-responsive dynamic shell cross-linked polymer nanoparticles, which is characterized in that two block-type Macro-RAFT reagents are used for simultaneously regulating and carrying out dispersion polymerization, and a core-shell-crown polymer nanoparticle is prepared by a polymerization induction self-assembly method. The shell chemical structure of the nano particle contains phenylboronic acid and ketal groups, and the phenylboronic acid and the ketal groups can form a reversible chemical reaction of a borate bond under the control of pH. Thus, the dynamic shell cross-linked polymer nano-particle with pH responsiveness is prepared.
The invention provides a preparation method of pH responsive dynamic shell cross-linked polymer nanoparticles, which comprises the following steps:
(1) synthesis of hydrophilic polymers
Synthesizing a hydrophilic polymer with a controllable molecular weight and a trithiocarbonate group at the tail end by taking trithiocarbonate as a small-molecule reversible-addition fragmentation chain transfer (RAFT) reagent and Azodiisobutyronitrile (AIBN) as an initiator through RAFT polymerization of a hydrophilic monomer in an organic solvent;
(2) hydrophilic polymers-bSynthesis of poly (3-acrylamidophenylboronic acid)
Synthesizing the hydrophilic polymer containing trithiocarbonate group by taking the synthesized hydrophilic polymer containing trithiocarbonate group at the tail end as Macro-RAFT reagent, AIBN as initiator and 3-acrylamidophenylboronic acid as chain extension monomer through solution RAFT polymerization in organic solventb-a poly (3-acrylamidophenylboronic acid) block copolymer;
(3) hydrophilic polymers-bSynthesis of methyl (2, 2-dimethyl-5-ethyl-1, 3-dioxane) acrylate
Synthesizing the hydrophilic polymer containing trithiocarbonate groups by taking the synthesized hydrophilic polymer containing trithiocarbonate groups at the tail end as a Macro-RAFT reagent, AIBN as an initiator and 2, 2-dimethyl-5-ethyl-1, 3-dioxane monomer as a chain extension monomer through solution RAFT polymerization in an organic solventbPoly (2, 2-dimethyl-5-ethyl-1, 3-dioxane) propeneA methyl ester acid block copolymer;
(4) synthesis of multicomponent 'core-shell-crown' polymer nano particle by dispersion polymerization
The Trithiocarbonate group-containing hydrophilic polymer synthesized by the above-mentioned methodbPoly (3-acrylamidophenylboronic acid) block copolymers and hydrophilic polymers containing trithiocarbonate groupsbThe poly (2, 2-dimethyl-5-ethyl-1, 3-dioxane) methyl acrylate block copolymer is Macro-RAFT reagent, AIBN is initiator, alcohol or alcohol-water mixture is selected as dispersing solvent, and hydrophilic polymer is synthesized by hydrophobic monomer dispersing RAFT polymerization under the same mediation of two Macro-RAFT reagentsbPoly (3-acrylamidophenylboronic acid) -bHydrophobic/hydrophilic polymersbPoly (2, 2-dimethyl-5-ethyl-1, 3-dioxane) acrylic acid methyl ester-b-a mixture of hydrophobic polymeric multicomponent triblock copolymers, the polymerization inducing the triblock copolymer mixture to self-assemble in situ and form multicomponent "core-shell-corona" polymeric nanoparticles due to the difference in solubility;
(5) preparation of dynamic shell cross-linked 'core-shell-corona' polymer nano-particle
In the multi-component core-shell-crown polymer nano particle, a core is composed of a hydrophobic polymer chain segment, a polymer side group of a shell layer contains both polyphenylboronic acid and a polyketal chain segment, a crown layer is a hydrophilic polymer chain segment, the polyketal chain segment of the shell layer can be hydrolyzed under an acidic condition to form a dihydroxyl group, and the dihydroxyl group and the phenylboronic acid group can form a reversible chemical bond under the regulation and control of pH, so that the dynamic shell crosslinked core-shell-crown polymer nano particle is prepared.
In the invention, the trithiocarbonate in the step (1) is one or two of S-n-dodecyl-S ' - (2-methyl-2-propionyloxy) trithiocarbonate, S-ethyl-S ' - (2, 2-dimethyl-2-propionyloxy) trithiocarbonate and S, S ' -bis (2-methyl-2-propionyloxy) trithiocarbonate; the hydrophilic monomer is acrylic acid,N,NOne or more of dimethylacrylamide, methacrylic acid, acrylamide, hydroxyethyl acrylate and glycidyl acrylateTwo types are adopted; the organic solvent in the steps (1), (2) and (3) is toluene, tetrahydrofuran,N,N-one or two of dimethylformamide, n-hexane or dioxane.
In the invention, the hydrophobic monomer in the step (4) is one or two of styrene, methyl methacrylate, butyl methacrylate and tert-butyl methacrylate; the alcohol or alcohol-water mixture in the step (4) can be methanol, ethanol, propanol, butanol or a mixed solvent of alcohol and water (the alcohol-water ratio is more than 70: 30).
In the invention, the pH-responsive dynamic shell cross-linked polymer nanoparticle as claimed in claim 1 can efficiently wrap various insoluble drugs, and is suitable for the biomedical fields of in vivo delivery of anticancer drugs, gene vectors and the like.
Compared with the prior art, the invention has the advantages that: 1) the invention utilizes a method combining active polymerization and dispersion polymerization to prepare the triblock copolymer polymer nanoparticles in an alcohol/water phase, and the triblock copolymer polymer nanoparticles have small polymer molecular weight polydispersion coefficient, uniform polymer nanoparticle size and good environmental protection property; 2) the polymer nano particles are prepared by a polymerization-induced self-assembly method, and compared with the traditional polymer micelle, the polymer nano particles have good stability and high reaction yield, the polymer concentration can reach up to 30 percent, and compared with the traditional method for preparing the polymer micelle by self-assembly of a block copolymer (the polymer concentration is less than 1 percent), the method has obvious advantages; 3) the polymer nanoparticles prepared by the invention have a core-shell-crown structure, the core can realize the wrapping of hydrophobic drugs, the shell layer polymer can be dynamically crosslinked to realize the controllable release of drug molecules, and the crown layer polymer plays a role in stabilizing the polymer nanoparticles. And the groups capable of undergoing dynamic chemical reaction are simultaneously fixed in the shell layer, and the dynamic crosslinking of the shell layer of the polymer nanoparticles is realized by controlling the pH value of the system.
Drawings
FIG. 1 is a chemical reaction scheme for the synthesis of a triblock copolymer.
FIG. 2 is a schematic diagram of the synthesis of a polymerization-induced self-assembly method for preparing a "core-shell-crown" polymer nanoparticle.
FIG. 3 is a nuclear magnetic hydrogen spectrum of Macro-RAFT agent.
FIG. 4 is an infrared spectrum of multi-component core-shell-corona polymeric nanoparticles prepared in example 1.
Fig. 5 is a transmission electron micrograph of the multi-component core-shell-corona polymeric nanoparticles prepared in example 1.
Fig. 6 is a graph of the particle size distribution of the multi-component core-shell-corona polymer nanoparticles prepared in example 1 in aqueous solutions of different pH.
Fig. 7 is a transmission electron micrograph of the multi-component core-shell-corona polymeric nanoparticles prepared in example 2.
Fig. 8 is a transmission electron micrograph of the multi-component core-shell-corona polymeric nanoparticles prepared in example 3.
Fig. 9 is a transmission electron microscope image of multi-component core-shell-corona polymeric nanoparticles prepared in comparative example 1.
Fig. 10 is a transmission electron micrograph of a multi-component core-shell-corona polymeric nanoparticle prepared in comparative example 2.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention discloses a method for preparing a core-shell-crown structure pH responsive dynamic shell cross-linked polymer nano particle by a polymerization-induced self-assembly method through dispersion polymerization under the simultaneous mediation of two block type Macro-RAFT reagents and a preparation method thereof. To further illustrate the technical solutions of the present invention, the following preferred embodiments of the present invention are described with reference to examples, but it should be understood that the descriptions are only for further illustrating the features and advantages of the present invention and are not to be construed as limiting the claims of the present invention.
Example 1: poly(s) are polymerizedN,N-dimethylacrylamide-bPoly (3-acrylamidophenylboronic acid) -bPolystyrene/poly (E-styrene)N,N-dimethylacrylamide-bMethyl (2, 2-dimethyl-5-ethyl-1, 3-dioxane) acrylate-bPreparation of-polystyrene 'core-shell-crown' polymer nanoparticles
Poly(s) are polymerizedN,N-dimethylacrylamide-bPoly (3-acrylamidophenylboronic acid) -bPolystyrene/poly (E-styrene)N,N-dimethylacrylamide-bMethyl (2, 2-dimethyl-5-ethyl-1, 3-dioxane) acrylate-bThe chemical equation and schematic diagram of the synthesis of the polystyrene "core-shell-crown" polymer nanoparticle are respectively shown in fig. 1 and 2, and the synthesis comprises the following steps:
(1) poly(s) are polymerizedN,NSynthesis of (E) -dimethylacrylamide
Will be provided withN,N-dimethylacrylamide monomer (10.0 g, 0.10 mol), chain transfer agent S-ethyl-S' - (2, 2-dimethyl-2-propionyloxy) trithiocarbonate (0.37 g, 1.65 mmol) and initiator azobisisobutyronitrile (0.012 g, 7.50X 10 mol)-2mmol) of the componentsN,N-dimethylacrylamide monomer (10.0 g, 0.10 mol), chain transfer agent S-ethyl-S' - (2, 2-dimethyl-2-propionyloxy) trithiocarbonate (0.37 g, 1.65 mmol) and initiator azobisisobutyronitrile (0.012 g, 7.50X 10 mol)-2mmol) is dissolved in 20 mL dioxane, stirred and mixed evenly, and the mixture is put in a nitrogen atmosphere in the systemN,NThe mol ratio of the dimethylacrylamide monomer to the chain transfer agent to the initiator is 60:1:0.05, the mixture is stirred and reacted for 4 hours, the temperature of the reaction system is 70 ℃, and the poly-containing trithiocarbonate group at the terminal is obtainedN,N-dimethylacrylamide, nuclear magnetic hydrogen spectrum as shown in figure 3A;
(2) poly(s) are polymerizedN,N-dimethylacrylamide-bSynthesis of poly (3-acrylamidophenylboronic acid)
Weighing the polymer prepared in the step (1)N,NDimethylacrylamide (1.50 g, 0.25 mmol), 3-acrylamidophenylboronic acid monomer (3.34 g, 17.50 mmol), azobisisobutyric acidNitrile (4.1 mg, 2.50X 10)-2mmol) dissolved in 20 mLN,N3-acrylamidophenylboronic acid and poly (p-acrylamide) in a mixed solvent of-dimethylformamide and waterN,NThe mol ratio of the dimethylacrylamide to the initiator is 70:1:0.1, the mixture is stirred and reacted for 1 hour under nitrogen atmosphere, the temperature of the reaction system is 65 ℃, and the poly containing trithiocarbonate groups at the tail end is obtainedN,N-dimethylacrylamide-b-a poly (3-acrylamidophenylboronic acid) block copolymer having a nuclear magnetic hydrogen spectrum as shown in fig. 3B;
(3) poly(s) are polymerizedN,N-dimethylacrylamide-bSynthesis of methyl (2, 2-dimethyl-5-ethyl-1, 3-dioxane) acrylate
Weighing the hydrophilic polymer (1.20 g, 0.20 mmol) prepared in the step (1), 2-dimethyl-5-ethyl-1, 3-dioxane monomer (3.20 g, 14.00 mmol) and azobisisobutyronitrile (3.3 mg, 0.02 mmol), dissolving in 20 mL of 1, 4-dioxane to obtain poly (A) (B)N,N-dimethylacrylamide), 2-dimethyl-5-ethyl-1, 3-dioxane and an initiator in a molar ratio of 70:1:0.1, and the mixture is stirred and reacted for 1.5 hours under nitrogen atmosphere, wherein the temperature of the reaction system is 70 ℃ to obtain the polythiocarbonate group-terminated polymerN,N-dimethylacrylamide-b-poly (2, 2-dimethyl-5-ethyl-1, 3-dioxane) methyl acrylate block copolymer with nuclear magnetic hydrogen spectrum as shown in figure 3C;
(4) synthesis of multicomponent 'core-shell-crown' polymer nano particle by dispersion polymerization
0.944 g of the polymer obtained in step (2) was weighed out separatelyN,N-dimethylacrylamide-bPoly (3-acrylamidophenylboronic acid) block copolymer, about 0.08 mmol, 0.8 g of the poly obtained in step (3)N,N-dimethylacrylamide-bPoly (methyl 2, 2-dimethyl-5-ethyl-1, 3-dioxane) acrylate block copolymer, about 0.08 mmol, hydrophobic monomers styrene (5.0 g, 48 mmol), azobisisobutyronitrile 4.5 mg (2.67X 10)-2mmol) dissolved in 33.3 g of methanol-water (85/15 v/v) solvent, the molar ratio of the monomer, the Macro-RAFT reagent and the initiator in the system is 1800:3:3:1, the mass fraction of the monomer in the solvent is 15 percent, and the reaction is stirred under nitrogen atmosphereAnd (3) obtaining the multi-component core-shell-crown polymer nano particles through a polymerization induction self-assembly process at the temperature of 70-80 ℃ in 24 hours. After the reaction is finished, firstly dialyzing the reaction solution in methanol, then dialyzing the reaction solution in deionized water, and removing unreacted monomers and organic solvents to obtain a suspension of the multi-component core-shell-crown polymer nanoparticles dispersed in water, wherein an infrared spectrogram and a Transmission Electron Microscope (TEM) image of the core-shell-crown polymer nanoparticles are respectively shown in FIGS. 4 and 5, and the average size of the core-shell-crown polymer nanoparticles is 34 nm;
(5) dynamic shell crosslinking of pH-regulated 'core-shell-corona' polymer nanoparticles
And (3) placing the polymer nanoparticles prepared in the step (4) into a single-mouth bottle, adding an inorganic acid to adjust the pH value of the system to 1.0, stirring the system at 50 ℃ for reaction for 12 hours, and hydrolyzing ketal groups on the shell layer of the core-shell-crown polymer nanoparticles to form dihydroxy groups. Diluting the newly obtained core-shell-crown polymer nanoparticle suspension to 1.0 mg/mL, and then dropwise adding acetic acid or triethylamine to adjust the pH value of the system to obtain the dynamic shell crosslinked polymer nanoparticles, wherein the pH is 3.8-7.0, the polymer nanoparticles are subjected to shell crosslinking, and when the pH is more than 7.0 or less than 3.8, the shell layer is subjected to crosslinking release, as shown in FIG. 6.
Example 2:
the other conditions were the same as in example 1 except that the amount of the methanol-water (85/15 v/v) solvent was adjusted to 50.0 g and the mass fraction of the monomer in the solvent was 10%. The infrared spectroscopy, nuclear magnetic hydrogen spectroscopy, transmission electron microscopy and the nanometer particle sizer prove that the dynamic shell cross-linked polymer nanoparticles are successfully prepared, wherein TEM pictures of the prepared 'core-shell-crown' polymer nanoparticles with the average size of 26 nm are shown in FIG. 7.
Example 3:
the other conditions were the same as in example 1 except that the amount of the methanol-water (85/15 v/v) solvent was adjusted to 25.0 g and the mass fraction of the monomer in the solvent was 20%. The infrared spectroscopy, nuclear magnetic hydrogen spectroscopy, transmission electron microscopy and the nanometer particle sizer prove that the dynamic shell cross-linked polymer nanoparticles are successfully prepared, wherein TEM pictures of the prepared 'core-shell-crown' polymer nanoparticles with the average size of 37 nm are shown in FIG. 8.
Example 4:
the other conditions were the same as in example 1, except that the molar ratio of the monomer, Macro-RAFT agent and initiator in the system was 1200:3:3:1, and infrared spectroscopy, nuclear magnetic hydrogen spectroscopy, transmission electron microscopy and nano-particle sizer demonstrated successful preparation of dynamic shell cross-linked polymer nanoparticles.
Example 5:
the other conditions were the same as in example 1 except that the molar ratio of the monomer, Macro-RAFT agent and initiator in the system was 2400:3:3:1, and the infrared spectroscopy, nuclear magnetic hydrogen spectroscopy, transmission electron microscopy and nano-particle sizer demonstrated successful preparation of dynamic shell cross-linked polymer nanoparticles.
Comparative example 1:
otherwise, as in example 1, a single poly was selected in step (4)N,N-dimethylacrylamide-bThe poly (3-acrylamidophenylboronic acid) block copolymer is Macro-RAFT reagent, the molar ratio of the monomer, the Macro-RAFT reagent and the initiator is 1800:3:1, TEM images of the prepared core-shell-crown polymer nanoparticles with the average size of 43 nm are shown in FIG. 9, and the characterization of a nanogranometer shows that the core-shell-crown polymer nanoparticles only contain phenylboronic acid groups in the shell layer and do not have the dynamic shell crosslinking characteristic.
Comparative example 2:
otherwise, as in example 1, a single poly was selected in step (4)N,N-dimethylacrylamide-bThe TEM picture of the prepared core-shell-crown polymer nanoparticles with the average size of 28 nm is shown in FIG. 10, and the characterization of a nanogranometer shows that the core-shell-crown polymer nanoparticles only contain phenylboronic acid groups in the shell layer do not have the dynamic shell crosslinking characteristic.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (4)
1. A preparation method of pH-responsive dynamic shell cross-linked polymer nanoparticles is characterized in that two block-type macromolecule reversible-addition fragmentation chain transfer (Macro-RAFT) reagents are used for simultaneously adjusting and carrying out dispersion polymerization, and a core-shell-crown polymer nanoparticle is prepared by a polymerization-induced self-assembly method, and comprises the following steps:
(1) synthesis of hydrophilic polymers
Synthesizing a hydrophilic polymer with a controllable molecular weight and a trithiocarbonate group at the tail end by taking trithiocarbonate as a small-molecule reversible-addition fragmentation chain transfer (RAFT) reagent and Azodiisobutyronitrile (AIBN) as an initiator through RAFT polymerization of a hydrophilic monomer in an organic solvent;
(2) synthesis of hydrophilic polymer-b-poly (3-acrylamidophenylboronic acid)
Synthesizing a hydrophilic polymer-b-poly (3-acrylamidophenylboronic acid) block copolymer containing trithiocarbonate groups by taking a synthesized hydrophilic polymer containing trithiocarbonate groups at the tail end as a Macro-RAFT reagent, AIBN as an initiator and 3-acrylamidophenylboronic acid as a chain extension monomer through solution RAFT polymerization in an organic solvent;
(3) synthesis of hydrophilic polymer-b-poly (2, 2-dimethyl-5-ethyl-1, 3-dioxane) methyl acrylate
Taking a synthesized hydrophilic polymer with trithiocarbonate groups at the tail end as a Macro-RAFT reagent, AIBN as an initiator, and taking a (2, 2-dimethyl-5-ethyl-1, 3-dioxane) methyl acrylate monomer as a chain extension monomer, and synthesizing a trithiocarbonate group-containing hydrophilic polymer-b-poly (2, 2-dimethyl-5-ethyl-1, 3-dioxane) methyl acrylate block copolymer in an organic solvent through solution RAFT polymerization;
(4) synthesis of multicomponent 'core-shell-crown' polymer nano particle by dispersion polymerization
The hydrophilic polymer-b-poly (3-acrylamidophenylboronic acid) block copolymer containing trithiocarbonate groups and the hydrophilic polymer-b-poly (2, 2-dimethyl-5-ethyl-1, 3-dioxane) methyl acrylate block copolymer containing trithiocarbonate groups, which are synthesized by the method are Macro-RAFT reagents, AIBN is an initiator, alcohol or an alcohol-water mixture is selected as a dispersing solvent, and the hydrophilic polymer-b-poly (3-acrylamidophenylboronic acid) -b-hydrophobic polymer/hydrophilic polymer-b-poly (2, 2-dimethyl-5-ethyl-1) is synthesized by dispersing RAFT polymerization of hydrophobic monomers under the same adjustment of the two Macro-RAFT reagents, 3-dioxane) methyl acrylate-b-hydrophobic polymer multi-component triblock copolymer mixture, and due to the difference of dissolubility, the polymerization induces the triblock copolymer mixture to carry out in-situ self-assembly and form multi-component core-shell-crown polymer nanoparticles;
(5) preparation of dynamic shell cross-linked 'core-shell-corona' polymer nano-particle
In the multi-component core-shell-crown polymer nanoparticle, a core is composed of a hydrophobic polymer chain segment, a polymer side group of a shell layer contains both phenylboronic acid and a polyketal chain segment, a crown layer is a hydrophilic polymer chain segment, the ketal group in the polyketal chain segment of the shell layer can be hydrolyzed under an acidic condition to form a dihydroxyl group, and the dihydroxyl group and the phenylboronic acid group can form a reversible chemical bond under the regulation and control of pH, so that the dynamic shell crosslinked core-shell-crown polymer nanoparticle is prepared, and has a core-shell-crown structure as shown in the following figure:
wherein, the core is composed of hydrophobic polymer chain segments, the polymer side group of the shell layer contains both polyphenylboronic acid and polyketide chain segments, and the crown layer is a hydrophilic polymer chain segment.
2. The method for preparing pH-responsive dynamic shell crosslinked polymeric nanoparticles according to claim 1, wherein said trithiocarbonate in step (1) is one or two of S-n-dodecyl-S ' - (2-methyl-2-propanoyl) trithiocarbonate, S-ethyl-S ' - (2, 2-dimethyl-2-propanoyl) trithiocarbonate, S ' -bis (2-methyl-2-propanoyl) trithiocarbonate; the hydrophilic monomer is one or two of acrylic acid, N-dimethylacrylamide, methacrylic acid, acrylamide, hydroxyethyl acrylate and glycidyl acrylate; the organic solvent in the steps (1), (2) and (3) is one or two of toluene, tetrahydrofuran, N-dimethylformamide, N-hexane or dioxane.
3. The method for preparing pH-responsive dynamic shell cross-linked polymer nanoparticles according to claim 1, wherein the hydrophobic monomer in step (4) is one or two of styrene, methyl methacrylate, butyl methacrylate and tert-butyl methacrylate; the alcohol or the alcohol-water mixture in the step (4) is methanol, ethanol, propanol, butanol or a mixed solvent of alcohol and water; the alcohol-water ratio of the alcohol-water mixture is greater than 70: 30.
4. The method for preparing the pH-responsive dynamic shell-crosslinked polymer nanoparticles according to claim 1, wherein the pH-responsive dynamic shell-crosslinked polymer nanoparticles prepared by the method can efficiently wrap various insoluble drugs, and are suitable for the fields of in vivo delivery of anticancer drugs and biomedicine of gene vectors.
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