CN102604310B - Water-phase preparing method of silica-coating polymer nano particles - Google Patents

Abstract

The invention belongs to the technical field of organic-inorganic hybrid nanomaterials, and specifically relates to a method for preparing a silicon-coated polymer nanoparticle in an aqueous phase. The silicon-coated polymer nanoparticle has a nanoscale structure, good thermal stability, and organic The advantages of polymers and inorganic materials have special optical, magnetic, electrical and mechanical properties. The preparation method of the present invention reduces the production cost of producing silicon-coated polymer nanoparticles, and has the advantages of simple process, high input-output ratio, high product quality, and wide application prospects. The demand for green and high-performance chemical products can be used in nano drug carriers and other fields.

Description

A kind of aqueous phase preparation method of silicon-coated polymer nanoparticles

technical field

The invention belongs to the technical field of organic-inorganic hybrid nanomaterials, and in particular relates to an aqueous phase preparation method of silicon-coated polymer nanoparticles.

Background technique

RAFT polymerization is widely used in the preparation of block polymers due to its free choice of functional monomers and good control over the polymer structure. However, since the chain transfer agent required for RAFT polymerization is easily hydrolyzed in an aqueous environment, the conversion of monomers is greatly reduced. At present, most researchers prepare block copolymers by RAFT polymerization in oil phase environment, and the addition of organic reagents in this process undoubtedly violates the current theme of green environmental protection, even if a small number of researchers have tried RAFT in water-based conditions. Amphiphilic block polymers were prepared by polymerization. After 48 hours of reaction, the conversion rate of monomers was still very low [Chen Weixing, Fan Xiaodong, Liu Yuyang. Synthesis and Characterization of Temperature Sensitive Amphiphilic Block Copolymers. Polymer Materials Science and Engineering, 2006,22:44-47; Pan Jingyun, He Junpo, Yang Yuliang, etc. Controlled free radical polymerization of MMA and synthesis of block copolymers based on RAFT process. Chemical Journal of Chinese Universities, 2004,9:1759- 1764].

In addition, during the micellar self-assembly process, when the polymer concentration is lower than the critical micelle concentration, the dilution effect of micelles seriously affects the controlled drug release efficiency. In order to improve the stability of polymer micelles and the integrity of supramolecular nanostructures for their better application in biological environments, in recent years, people have been working on the research of shell cross-linked polymer micelles. Liu's research group added a certain amount of 1,2-bis(2-iodoethoxy)ethane after preparing the amphiphilic block polymer micelles. The crosslinking agent controlled the polymer micelles well. form, but the amount of cross-linking agent is not easy to control, and all products need to be filtered through a microfiltration membrane before they can be used in the next experiment[Luo S Z, Liu S Y, Wu C, et al. Double Hydrophilic Block Copolymer Monolayer Protected Hybrid Gold Nanoparticles and Their Shell Cross-Linking. J. Phys. Chem. B, 2005, 109:22159-22166]. The Armes research group used the complexation between polyelectrolytes to obtain block polymer micelles by adjusting the pH, then added divinyl sulfone to make it cross-link with the hydroxyl groups on the polymer chain, and successfully prepared the shell cross-link Micelles, this method avoids the generation of by-products, the preparation process is non-toxic, and the reversible process of polymer micelle cross-linking and de-cross-linking can also be achieved by adding salt, but the accompanying aggregation between micelles makes this The method is not ideal [Liu S Y, Save M, Armes S P, et al. Synthesis of pH-Responsive Shell Cross-Linked Micelles and Their Use as Nanoreactors for the Preparation of Gold Nanoparticles. Langmuir, 2002, 18:8350-8357 ], which has aroused extensive attention of scholars. So far, the main methods used to prepare shell-crosslinked micelles are UV-induced cinnamoyl coupling, carbodiimide coupling, 1,2-bis(2-iodoethoxy)ethane quaternization of amines, Hydroxyl and divinyl sulfone cross-linking, click chemistry and in situ reduction of polyvalent gold ions, etc. [Li Y T, Armes S P, McCormick CL, et al. Synthesis of Reversible Shell Cross-Linked Micelles for Controlled Release of Bioactive Agents. Macromolecules, 2006, 39:2726-2728; Hernandez J R, Babin J, Lecommandoux S, et al. Preparation of Shell Cross-Linked Nano-Objects from Hybrid-Peptide Block Copolymers. Biomacromolecules, 2005, –6: 2 2213 ; Joralemon M J, Hawker C J, Wooley K L, et al. Shell Click-Crosslinked (SCC) Nanoparticles:? A New Methodology for Synthesis and Orthogonal Functionalization. J. Am. Chem. Soc., 2005, 127:16892– 16899; Liu S Y, Weaver J V M, Armes S P, et al. Synthesis of Shell Cross-Linked Micelles with pH-Responsive Cores Using ABC Triblock Copolymers. Macromolecules, 2002, 35: 6121–6131]. They are expensive and require further purification to remove small molecule by-products, limiting their large-scale use. The use of organic-inorganic hybridization under aqueous conditions to prepare silicon-coated nano-polymer micelles is being studied with the goal of simplifying the production process, environmental protection and health, and reducing costs, and the rapid development of organic-inorganic hybrid materials also makes research and development have excellent performance. The polymer micelles have become one of the research hotspots in this field.

In order to prepare structurally stable shell cross-linked polymer micelles, people have been making unremitting efforts. In 2005, McCormick's research group synthesized a triblock copolymer polyethylene oxide-b-(N,N-dimethylacrylamide-s-sodium aluminosilicate)-b-N-isopropyl through RAFT polymerization NIPAM (PEO-b-(DMA-s-NAS)-b-NIPAM). When the temperature is higher than the lower critical solution temperature of the thermosensitive block NIPAM, the polymer self-assembles into micelles with NIPAM as the core and hydrophilic PEO as the shell, adding diethylamine to react with the remaining NAS, Shell crosslinked micelles can be prepared [Li Y T, Lokitz B Z, McCormick C L. RAFT Synthesis of a Thermally Responsive ABC Triblock Copolymer Incorporating N-Acryloxysuccinimide for Facile in Situ Formation of Shell Cross-Linked Micelles in Maccules in Aquerom , 2006, 39:81-89]. In 2007, Wang synthesized a polymer with temperature-sensitive block NIPAM-co-NAS (N-isopropylacrylamide-co-sodium aluminosilicate) by RAFT polymerization, when the temperature was higher than the temperature-sensitive block When the critical solution temperature is low, the polymer self-assembles into micelles with NIPAM-co-NAS as the core and hydrophilic PEO as the shell, adding cystamine to react with the remaining NAS, and the shell cross-linked gel can also be prepared Beam [Wang R, Lowe A B. RAFT polymerization of tyrenic-based phosphonium monomers and a new family of well-defined statistical and block polyampholytes. J Polym Sci Polym Chem, 2007, 45:2468–2483].

Organic/inorganic hybrid materials, especially silicon-containing nanomaterials, have attracted widespread attention due to their attractive nanoscale optical, magnetic, and electrical properties. In recent years, there have been reports describing the preparation methods of silicon-coated shell cross-linked micelles. In 2008, the research group of Professor Zhang Xianzheng and Zhuo Renxi of Wuhan University first selected functional monomers containing silicon-oxygen (Si-O) bonds in the polymerization process, and then formed Si- O-Si network structure, the first to prepare shell cross-linked thermoresponsive hybrid polymer micelles [Wei H, Chang C, Zhuo R X, et al. Synthesis and Applications of Shell Cross-Linked Thermoresponsive Hybrid Micelles Based on Poly ( N -isopropylacrylamide- co -3-(trimethoxysilyl)propyl methacrylate)- b -poly(methyl methacrylate). Langmuir, 2008, 24:4564-4570]; Ethyl methacrylic acid)-b-(2-(diisopropylamine) ethyl methacrylic acid)) (PDMA-b-PDPA) polymer micelles react with silane coupling agent and hydrolyze with silane coupling agent The network structure formed by condensation covers the polymer micelles, and the morphology of the polymer micelles is well controlled [Li Y T, Du J Z, Armes S P. Shell Cross-Linked Micelles as Cationic Templates for the Preparation of Silica- Coated Nanoparticles: Strategies for Controlling the Mean Particle Diameter. Macromol. Rapid. Commun., 2009, 30:464–468]. The shell cross-linked micelles prepared by using the silicon cross-linking system have both the structure of the organic polymer and the characteristics of the inorganic material, which has the following advantages: First, introducing the inorganic silicon network structure into the organic polymer chain can improve the shell cross-linking. The rigidity of the micelles makes them more stable; second, compared to other organic "small molecule" crosslinking agents, silane coupling agents are less costly and less toxic, making the commercial application of shell crosslinked micelles more efficient. Possibility, which is also consistent with the concept of green chemistry; third, no organic small molecule reagents need to be added, and the purification process is simple and convenient. Therefore, silicon-coated shell cross-linked micelles not only have the optical, magnetic, electrical and mechanical properties of inorganic substances, but also have the processability, compatibility and stimuli response properties of polymers, and have broad development space. These new ideas break the inertia of traditional design and provide greater convenience for material synthesis. However, the shell cross-linked block polymer micelles obtained by these methods have a relatively simple response to external environments such as temperature and pH, and there is no research on the preparation of silicon-coated shell cross-linked polymer micelles in an aqueous environment at home and abroad. literature and patents.

Contents of the invention

The purpose of the present invention is to overcome the deficiencies in the prior art and provide a method for preparing a silicon-coated polymer nanoparticle in water.

The aqueous phase preparation method of a kind of silicon-coated polymer nanoparticles proposed by the present invention adopts RAFT polymerization method, takes water as medium, dimethylaminoethyl methacrylate (DMAEMA) and N-isopropylacrylamide (NIPAM ) as a functional monomer to synthesize a PDMAEMA-b-NIPAM block polymer, by adjusting the molar ratio of the two monomers to control the micelle or Capsule form; then use the block polymer micelles as a template to react with the silane coupling agent, and the Si-O-Si network structure formed by the hydrolysis and condensation of the silane coupling agent is well coated on the polymer micelles On the surface, this process neither introduces organic reagents nor completely preserves the nanoscale precise structure of block polymer micelles; the specific steps are as follows:

(1) Add 1-2 g of pH-sensitive monomer into a 25 mL reaction bottle, adjust the pH to 5-6 with concentrated hydrochloric acid, and store at 0°C; add 19-20 mg of chain transfer agent and 4- 5 mg of water-soluble initiator, slowly add 0.5-1 mL of solvent to dissolve the chain transfer agent, then add 4-5 mL of ice deionized water; after all the substances in the sample bottle are dissolved, pour the mixed solution into the reaction bottle 30 min at 0°C under nitrogen, magnetically stirred and reacted at 75-80°C for 3-6 h at 75-80°C under nitrogen protection. When the reaction was over, the reaction bottle was cooled to room temperature, ventilated to the atmosphere, and the product was placed in deionized water with a pH of 6-7 Dialysis for 3 days, rotary evaporation, and vacuum drying at 25°C for 12-48 h, a macromolecular chain transfer agent was obtained with a yield of 75%-95%. Wherein: the chain transfer agent is tetracyanovaleric acid dithiobenzoic acid, and the water-soluble initiator is 4,4 ^, -azo-4-cyanovaleric acid.

(2) Combine 1-1.5g of the macromolecular chain transfer agent prepared in step (1), 0.5-2 g of temperature-sensitive monomer, 5-15 mg of water-soluble azo initiator and 2-8 mL of deionized Add water into the reaction flask, pass nitrogen gas for 30 min, and react for 6-8 h under the protection of nitrogen with magnetic stirring at room temperature. -48 h, the block polymer was obtained with a yield of 80%-96%. Wherein: the water-soluble azo initiator is azobisisobutylimidazoline hydrochloride.

(3) React 0.1-0.2 g of the block polymer prepared in step (2), 20-30 mg of cross-linking agent and 2-3 mL of deionized water with magnetic stirring at room temperature for 3 days, and dissolve the product in deionized water Dialysis for 3 days, rotary evaporation, and vacuum drying at 25°C for 12-48 h to obtain a shell-crosslinked block polymer. Wherein: the crosslinking agent is 1,2-bis(2-iodoethoxy)ethane.

(4) Dissolve 0.1-0.2 g of the shell-crosslinked block polymer prepared in step (3) in 2 mL of deionized water and react with 0.2-0.4 g of silane coupling agent under magnetic stirring at room temperature for 20 min. Dialyzed in deionized water for 3 days to obtain silicon-coated polymer nanoparticles.

In the present invention, the pH-sensitive monomer in step (1) may contain a large number of ionizable groups (COO ^- , -NR ₃ ⁺ , -NR ₂ H ⁺ , -NRH ₂ ^{+ ,} etc.), such as acrylic acid, Dimethylaminoethyl methacrylate or dimethylaminomethyl methacrylate, etc.

In the present invention, the temperature-sensitive monomer in step (2) may be N-substituted acrylamide or similar monomers, such as N-isopropylacrylamide, N-n-propylacrylamide or N,N -Dimethacrylamide, etc.

In the present invention, the solvent described in step (1) can be dioxane, a mixed solution of water and dioxane, a mixed solution of water and tetrahydrofuran, a mixed solution of water and methanol or water and dimethylformamide mixed solution.

In the present invention, the silane coupling agent described in step (4) can be aminopropyltriethoxysilane, 3-glycidyloxypropyltrimethoxysilane, γ-methacryloxypropyl Either of trimethoxysilane or tetraethyl orthosilicate.

In the present invention, the treatment of the product after the reaction described in step (4) may be dialysis and rotary evaporation, or freeze-drying after dialysis, or drying after precipitant precipitation.

The advantages of the present invention are: ① The present invention is a water-phase preparation method of silicon-coated polymer nanoparticles. The block copolymer is prepared in an aqueous environment without the addition of a large amount of organic solvents, and the reaction conditions are more environmentally friendly and healthy. The bulk conversion rate is high again, can conveniently obtain the ideal block polymer of narrow distribution and the silicon-coated nanoparticle product (PDI coefficient is 1.07) of template thereof; 2. the silicon-coated polymer nanoparticle product prepared by the present invention has Nano-scale precise structure, more stable performance, and both organic polymers and inorganic materials special optical, magnetic, electrical and mechanical properties; ③The preparation method of the present invention reduces the production cost of producing shell cross-linked micelles, and has the advantages of process With the advantages of simplicity, high input-output ratio, high product quality, and wide application prospects, the products prepared by the present invention meet the needs of today's society for green, environmentally friendly and high-performance chemical products, and can be used in fields such as nano-biomedical materials.

Description of drawings

Figure 1 is the proton magnetic spectrum of the block polymer polydimethylaminoethyl methacrylate-b-N-isopropylacrylamide.

Fig. 2 is a dynamic light scattering spectrum of the particle size of block polymer PDMAEMA ₅₀ -b-PNIPAM ₁₇₀ aggregates changing with pH at 25°C.

Fig. 3 is the dynamic light scattering spectrum of the particle size of block polymer PDMAEMA ₅₀ -b-PNIPAM ₁₇₀ aggregates changing with temperature at pH=7.

Figure 4 is the TEM spectrum of silicon-coated nanoparticles at 25°C and pH=9: (a) silicon-coated polymer nanoparticles with block polymer PDMAEMA ₅₀ -b-PNIPAM ₁₇₀ as template; (b) with Block polymer PDMAEMA ₅₀ -b-PNIPAM ₈₀ templated silicon-coated polymer nanoparticles.

Detailed ways

Example 1

Add 2 g of dimethylaminoethyl methacrylate monomer to a 25 mL reaction bottle, adjust the pH to 5 with concentrated hydrochloric acid, and store at 0°C; add 19 mg of chain transfer agent tetracyanovaleric acid disulfide to another sample bottle Substituted benzoic acid, 5 mg of water-soluble initiator azobiscyanovaleric acid, slowly added 0.5 mL of dioxane to dissolve the chain transfer agent, and then added 5 mL of ice deionized water. After all the substances in the sample bottle were dissolved, the mixed solution was poured into the reaction bottle, nitrogen gas was passed at 0°C for 30 min, and the reaction was carried out at 80°C for 6 h under the protection of magnetic stirring under nitrogen, and the reaction bottle was cooled to room temperature when the reaction was completed. In contact with air, the product was dialyzed in deionized water with a pH of 6-7 for 3 days, rotary evaporated, and vacuum-dried at 25°C for 48 hours to obtain a macromolecular chain transfer agent polydimethylaminoethyl methacrylate. 90%.

Mix 1 g of the above-mentioned macromolecular chain transfer agent polydimethylaminoethyl methacrylate, 0.4 g of monomer N-isopropylacrylamide, and 5 mg of room temperature water-soluble azo initiator azobisisobutylimidazoline hydrochloride Add salt and 4 mL deionized water into the reaction bottle, pass nitrogen gas for 30 min, and react for 6 h under the protection of nitrogen with magnetic stirring at room temperature. After vacuum drying at ℃ for 48 h, the block polymer polydimethylaminoethyl methacrylate-b-N-isopropylacrylamide was obtained with a number average molecular weight of 9699 and a yield of 88%.

Mix 0.1 g of the above block polymer polydimethylaminoethyl methacrylate-b-N-isopropylacrylamide with 20 mg of cross-linking agent 1,2-bis(2-iodoethoxy)ethane, 2 mL Magnetic stirring reaction was carried out under deionized water at room temperature for 3 days, the product was dialyzed in deionized water for 3 days, rotary evaporated, and vacuum dried at 25 °C for 48 h to obtain a shell crosslinked block polymer.

Dissolve 0.1 g of the above block polymer in 2 mL of deionized water and react with 0.2 g of silane coupling agent γ-(methacryloyloxy)propyltrimethoxysilane under magnetic stirring at room temperature for 20 min. Dialyzed in water for 3 days to obtain silicon-coated polymer nanoparticles.

The proton magnetic spectrum of this polydimethylaminoethyl methacrylate-b-N-isopropylacrylamide is shown in Figure 1, and Figure 2 and Figure 3 are the particles of block polymer micelles at different temperatures and pHs respectively. Figure 4 is a transmission electron microscope image of silicon-coated nanoparticles with block polymer micelles as templates under normal temperature and neutral conditions.

Example 2

Same as Example 1, but the dioxane solvent was changed to tetrahydrofuran, and the volume ratio between it and water remained 1:5~1:10.

Example 3

Same as Example 1, but the molar ratio of dimethylaminoethyl methacrylate to N-isopropylacrylamide is changed to 60:30.

Example 4

Same as Example 1, but the molar ratio of dimethylaminoethyl methacrylate to N-isopropylacrylamide is changed to 70:40.

Example 5

Same as Example 1, but the molar ratio of dimethylaminoethyl methacrylate and N-isopropylacrylamide is changed to 80:50.

Example 6

Same as Example 1, but the molar ratio of dimethylaminoethyl methacrylate to N-isopropylacrylamide is changed to 20:110.

Example 7

Same as Example 1, but the molar ratio of dimethylaminoethyl methacrylate and N-isopropylacrylamide is changed to 30:100.

Example 8

Same as Example 1, but the molar ratio of dimethylaminoethyl methacrylate to N-isopropylacrylamide is changed to 40:90.

Example 9

Same as Example 1, but the molar ratio of dimethylaminoethyl methacrylate to N-isopropylacrylamide was changed to 50:80.

The block polymers obtained in Examples 2-9 have a similar narrow distribution to Example 1, and the block polymers prepared in Examples 3, 4, 5 and Example 1 form different particle sizes under the stimulation of changes in the external environment The micelles, the block polymers prepared in Examples 6, 7, 8, and 9 form capsules of different particle sizes under the stimulation of changes in the external environment.

Claims (4)

1. an aqueous phase preparation method for silicon coated polymer nanoparticle, is characterized in that concrete steps are as follows:

(1) 1-2 g pH sensitive monomer is added in 25 mL reaction flasks, concentrated hydrochloric acid regulates pH to 5-6, at 0 ℃, preserves; In another sample bottle, add 19-20 mg chain-transfer agent and 4-5 mg water soluble starter, slowly add 0.5-1 mL solvent that chain-transfer agent is dissolved, then add 4-5 mL deionized water; After all substances in sample bottle are all dissolved, this mixing solutions is poured in reaction flask into 0 ℃ of logical nitrogen 30 min; under magnetic agitation nitrogen protection, in 75-80 ℃, react 3-6 h; while finishing reaction, reaction flask is cooled to room temperature, logical atmosphere, dialyses in the deionized water that is 6-7 3 days by product at pH; revolve steaming; 25 ℃ of vacuum-drying 12-48 h, obtain a kind of macromolecular chain transfer agent, wherein: chain-transfer agent is four cyano valeric acid dithiobenzoic acid; water soluble starter is 4,4 ^,-azo-4-cyanopentanoic acid; Described pH sensitive monomer be in vinylformic acid, dimethylaminoethyl acrylate methyl ammonia ethyl ester or dimethylaminoethyl acrylate methyl ammonia methyl esters any;

(2) by the prepared macromolecular chain transfer agent of 1-1.5g step (1), 0.5-2 g temperature sensitivity monomer, 5-15 mg water-soluble azo class initiator and 2-8 mL deionized water add in reaction flask, logical nitrogen 30 min, under the nitrogen protection of normal temperature magnetic agitation, react 6-8 h, while finishing reaction, make reaction flask lead to atmosphere, product is dialysed in deionized water 3 days, revolve steaming, 25 ℃ of vacuum-drying 12-48 h, obtain block polymer, wherein: water-soluble azo class initiator is azo two isobutyl imidazoline salt hydrochlorates; Described temperature sensitivity monomer is the acrylamide being replaced by N;

(3) by the prepared block polymer of 0.1-0.2 g step (2), 20-30 mg linking agent and 2-3 mL deionized water normal temperature lower magnetic force stirring reaction 3 days, product is dialysed in deionized water 3 days, revolve steaming, 25 ℃ of vacuum-drying 12-48 h, obtain the crosslinked block polymer of shell; Wherein: described linking agent is two (the 2-iodo oxyethyl group) ethane of 1,2-;

(4) the crosslinked block polymer of the prepared shell of 0.1-0.2g step (3) is dissolved in 2 mL deionized waters and 0.2-0.4 g silane coupling agent normal temperature lower magnetic force stirring reaction 20 min, product is dialysed in deionized water 3 days, obtain silicon coated polymer nanoparticle.

2. the aqueous phase preparation method of silicon coated polymer nanoparticle according to claim 1, it is characterized in that described in step (1), solvent is the mixing solutions of dioxane, water and dioxane, the mixing solutions of the mixing solutions of the mixing solutions of water and tetrahydrofuran (THF), water and methyl alcohol or water and dimethyl formamide.

3. the aqueous phase preparation method of silicon coated polymer nanoparticle according to claim 1, it is characterized in that silane coupling agent described in step (4) be in aminopropyl triethoxysilane, 3-glycidyl ether oxygen base propyl trimethoxy silicane, γ-methacryloxypropyl trimethoxy silane or tetraethoxy any.

4. the aqueous phase preparation method of silicon coated polymer nanoparticle according to claim 1, is characterized in that the described reaction of step (4) is that steaming is revolved in dialysis while finishing after-treatment products, or dialysis postlyophilization, or dry after precipitation agent precipitation.

Images