CN106237329A - There is nucleocapsid structure magnetic Hydrogel Nanoparticles and the preparation method of temperature-responsive - Google Patents

Abstract

The invention specifically relates to a method for preparing temperature-responsive core-shell magnetic hydrogel nanoparticles. Firstly, a binary functional graft copolymer containing high-efficiency adsorption units and temperature-responsive units containing cross-linking points was synthesized; secondly, the copolymer molecules were adsorbed on the surface of magnetic nanoparticles by using the high-efficiency adsorption units in the copolymer; and then cross-linking was introduced The agent locks the molecular structure of the temperature-responsive unit to form a gel layer. The present invention solves the defects of cumbersome steps, poor controllability, and influence on the stability of magnetic nanoparticles in the current method for constructing a hydrogel layer on the surface of magnetic nanoparticles. The surface adsorption efficiency is high; 2) The adsorption process has little negative impact on the magnetic nanoparticles; 3) The magnetic nanoparticles are fully covered; 4) The structure of the gel layer is adjustable; 5) The cycle performance of the hydrogel layer is stable and other advantages.

Description

Temperature-responsive core-shell magnetic hydrogel nanoparticles and preparation method thereof

technical field

The invention belongs to the technical field of organic/inorganic composite functional materials, and in particular relates to a temperature-responsive core-shell magnetic hydrogel nanoparticle and a preparation method thereof.

Background technique

Hydrogel is a soft polymer material with a three-dimensional structure and the ability to absorb water and swell. According to different application environments or uses, its chemical properties, mechanical properties, and biocompatibility can all be adjusted as needed. Hydrogels have great application prospects in the fields of biological tissue engineering and drug release. Hydrogel can be used as a biomimetic material to simulate non-vascular tissues such as skin and cartilage in vivo; it can also be used as a carrier to absorb and release drug molecules through the holes and channels inside the gel.

Temperature-responsive hydrogels are a class of smart materials that can adjust their properties according to changes in the external environment temperature. The conformation of the polymer network of common temperature-responsive hydrogels can be adjusted according to the temperature change, and they all have a critical solution temperature, above which and below this temperature, the gel network can achieve a complete contraction or relaxation conformation.

Magnetic nanoparticles generally refer to zero-dimensional nanomaterials with a diameter of less than 100 nm. They have a very large specific surface area, and because of their small size, they usually have superparamagnetic properties, so they are widely used in the fields of nuclear magnetic imaging, targeted drug release, and tumor hyperthermia.

Temperature-responsive magnetic hydrogel nanoparticles combine the advantages of the above materials. They have: 1) small size (depending on the preparation method, the size is also different, but usually the diameter is less than 500nm); 2) temperature response characteristics. That is, by changing the temperature, the conformation of the gel network will change; 3) Certain magnetic properties. By applying an external magnetic field, the directional movement and enrichment of the nanoparticles can be realized.

Such materials have strong application value in the field of drug controlled release. First, drug molecules are loaded inside the gel nanoparticles. Second, the drug-loaded nanoparticles are moved and positioned in the living body through a magnetic field. Finally, by changing the strength of the magnetic field, the temperature of the magnetic particles inside the nanoparticles is raised, causing a conformational change of the hydrogel network, and the loaded drug will be released, thereby realizing the precise targeted release of drug molecules.

At present, the following three problems still need to be solved or optimized in the method of constructing hydrogel layer on the surface of magnetic nanoparticles: 1) the construction steps are relatively cumbersome; 2) the construction method is poorly controllable; The stability needs to be maintained. For example, published patent No.105251456A has reported that a polyhydroxy polymer and a nitrogen-containing polymer are dispersed in a solution containing magnetic substances iron, cobalt and/or nickel ions as a carrier, and then the precipitate is added to the solution Sodium hydroxide, the prepared magnetic gel beads. In this patent, the adsorption of magnetic nanoparticles by the gel layer depends entirely on the intermolecular force, so the number of cycles can only reach 1-10 times, and the stability needs to be improved. Authorized patent No. 102875823B reports a method of pre-preparing bulk gels through polymerization and cross-linking, and then grinding them into magnetic microgels. However, this method cannot prepare nano-scale magnetic gel particles.

Contents of the invention

The primary purpose of the present invention is to overcome the shortcomings and deficiencies of the prior art, and provide a method for preparing temperature-responsive core-shell magnetic hydrogel nanoparticles.

Technical scheme of the present invention is as follows:

A method for preparing temperature-responsive core-shell magnetic hydrogel nanoparticles, comprising the following steps:

(1) Synthesis of binary functional graft copolymers containing highly efficient adsorption units and temperature-responsive units containing crosslinking points;

(2), using the efficient adsorption unit in the copolymer to adsorb the copolymer molecules on the surface of the magnetic nanoparticles;

(3) Introducing a cross-linking agent to lock the molecular structure of the temperature-responsive unit to form a gel layer.

The following parts are parts by mass:

(1) Dissolve 10-30 parts of the polymer main chain, 20-40 parts of temperature-responsive units containing crosslinking points, and 5-10 parts of functional dopamine monomers in 40-120 parts of solvent A, and add 0.05- 0.2 parts of catalyst, inert gas bubbling for 10-60 minutes, then stirred and reacted at 35-60°C for 6-48 hours, using dialysis technology, dialyzed the reaction solution for 6-72 hours, and then freeze-dried to obtain binary functional grafts copolymer;

(2) Dissolve 60-120 parts of binary functional graft copolymer and 10-40 parts of magnetic nanoparticles and disperse them in 10-40 parts of solvent B, stir at room temperature for 20-80 minutes, and rotate to evaporate Remove solvent B, then disperse the precipitate in deionized water, apply magnetic suction to the dispersion, pour it to remove the unadsorbed solution, and re-inject deionized water at 5-25°C. In this step, magnetic suction-dumping-water injection- The process of magnetic attraction is repeated 2 to 5 times, and at the last time, a phosphate buffer solution with a pH of 4.0 to 8.0 is added to obtain an aqueous dispersion of magnetic nanoparticles.

(3) Add 60 to 180 parts of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 30 to 120 parts of N- Hydroxysuccinimide, stir at 5-25°C for 30-120 minutes, after the stirring is completed, magnetically absorb, pour out the unadsorbed solution, and then add a pH of 4.0-8.0 containing 5-60 parts of cross-linking agent Phosphate buffer solution, stirred and reacted at 5-25°C for 2-12 hours. After the reaction, magnetically absorb the dispersion, pour it to remove the unadsorbed solution, re-inject deionized water at 5-25°C, and heat up to 40-40°C. 60°C. In this step, the process of magnetic attraction-dumping-water injection-heating-magnetic attraction is repeated 2 to 5 times to obtain temperature-responsive core-shell magnetic hydrogel nanoparticles.

In the binary graft copolymer described in step (1), in its molecular structure, the mass ratio between the temperature-responsive unit containing the crosslinking point and the functional dopamine monomer is between 2.2:1.0～5.8:1.0;

The solvent A described in step (1) is a kind of in dimethylsulfoxide, dimethylformamide, dimethylacetamide;

The catalyst described in step (1) is N,N,N,N,N-pentamethyldivinyltriamine/cuprous chloride (PMDETA/CuCl, wherein the mass ratio of the two is preferably 1:1～5: 1), one of sodium ascorbate/copper sulfate (NaVc/CuSO ₄ , wherein the mass ratio of the two is preferably 1.5:1.0 to 7.5:1.0);

The polymerization degree of the polymer main chain described in step (1) is 2000-6000, and it is polyglycidyl methacrylate (P(GMA-N ₃ )) with an azido group at the end, and polyglycidyl methacrylate with an azide group at the end. Glycidyl acrylate (P(GA-N ₃ )), polyhydroxyethyl methacrylate with alkynyl terminal (P(HEMA-C≡CH)), polyhydroxyethyl acrylate with alkynyl terminal (P( One of HEA-C≡CH));

The degree of polymerization of the temperature-responsive unit containing the cross-linking point is 2000-12000, and the temperature-responsive unit containing the cross-linking point includes a cross-linking point monomer and a temperature-responsive monomer with a molar ratio of 1:1000-50:1000, The temperature response unit containing the crosslinking point is a random copolymer of poly N-isopropylacrylamide and acrylic acid (P(NIPAAm-co-AA)-C≡CH or P( NIPAAm-co-AA)-N ₃ ), a random copolymer of poly-N-isopropylacrylamide and glycidyl methacrylate with an alkynyl or azido terminal group (P(NIPAAm-co-GMA)- One of C≡CH or P(NIPAAm-co-GMA-N ₃ );

The functional dopamine monomer is one of alkynyl dopamine (DOPA-C≡CH) or azidodopamine (DOPA-N ₃ );

Wherein the synthesis of the polymer main chain A and the temperature response unit containing the crosslinking point refers to the published patent document No. 103755968A, and the synthesis of the functional dopamine monomer refers to the paper Chemistry-European Journal.2013,19(26):8673-8678;

The synthesis of the magnetic nanoparticles described in step (2) refers to the paper ACS Nano, 2012, 6(1):389-399;

The solvent B described in step (2) is a kind of in dichloromethane, chloroform, toluene, xylene.

The cross-linking agent in step (3) is one of ethylenediamine and bisaminopolyethylene glycol (weight average molecular weight is preferably 200-700Da).

Principle of the present invention is:

The binary graft copolymer synthesized by controllable polymerization has dopamine units grafted on its main chain, and the unique catechol group in the molecular structure of dopamine can quickly coordinate with the ions on the surface of magnetic nanoparticles. The graft copolymer is adsorbed on the surface of magnetic nanoparticles to form a core-shell structure, but this simple adsorption is not stable. By cross-linking the cross-linking points contained in the temperature-responsive unit, such a core-shell structure can be cured to form a temperature-responsive gel layer.

Compared with the prior art, the present invention has the following advantages and effects:

(1) Binary functional polymers have a continuous and large number of adsorption sites, which can quickly produce adsorption effects on the surface of magnetic nanoparticles. The adsorption process is gentle and simple, and will not negatively affect the structure and performance of magnetic nanoparticles;

(2) The encapsulation of magnetic nanoparticles by binary functional polymers is relatively comprehensive, and the monodisperse encapsulation of magnetic nanoparticles can be basically realized, and the cycle performance of gel particles is continuous and stable; (3) The prepared magnetic hydrogel nano The temperature response performance and swelling behavior of the particles can be realized by adjusting the structure of the temperature response unit containing the crosslinking point in the binary functional graft copolymer. The number of crosslinking points and the length of the unit can be adjusted according to different needs. , preconditioned during synthesis.

Description of drawings

Fig. 1 is a schematic diagram of the preparation method of a core-shell magnetic hydrogel nanoparticle with temperature responsiveness;

Fig. 2 is the scanning electron micrograph (undyed) of the magnetic hydrogel nanoparticle that is prepared by embodiment 4;

Fig. 3 is a diagram of the cyclic variation of the diameter of the magnetic hydrogel nanoparticles prepared in Example 4 with temperature.

detailed description

The preparation method will be further described in detail below in conjunction with the accompanying drawings.

The present invention will be further described in detail below in conjunction with the embodiments and the accompanying drawings, but the embodiments of the present invention are not limited thereto.

The raw material used in the embodiment is as follows:

Example 1

A temperature-responsive core-shell magnetic hydrogel nanoparticle comprising the following steps (the parts are parts by mass):

(1) Mix 10 parts of P(GMA-N ₃ ) (the degree of polymerization is 2000), 20 parts of P(NIPAAm-co-GMA)-C≡CH (the degree of polymerization is 2000, the crosslinking point monomer and the temperature response unit molar ratio of 1:1000), 5 parts of DOPA-C≡CH were dissolved in 40 parts of dimethyl sulfoxide, 0.05 parts of PMDETA/CuCl was added, and the mass ratio of the two was 1:1, and the inert gas was bubbled for 10 Minutes, then stirred and reacted at 35°C for 6 hours, using dialysis technology, dialyzed the reaction solution for 72 hours, and then freeze-dried to obtain a binary functional graft copolymer.

(2) Dissolve and disperse 60 parts of binary functional graft copolymers and 10 parts of magnetic nanoparticles in 10 parts of methylene chloride, stir at room temperature for 20 minutes, remove methylene chloride by rotary evaporation, and remove the precipitate Disperse the substance in deionized water, apply magnetic suction to the dispersion, pour it to remove the unadsorbed solution, and re-inject the deionized water at 5°C. The process of "magnetic suction-dumping-water injection-magnetic suction" is repeated twice. For the last time, it was added to a phosphate buffer solution with a pH of 4.0 to obtain an aqueous dispersion of magnetic nanoparticles.

(3) Add 60 parts of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 30 parts of N-hydroxysuccinimide to the aqueous dispersion of magnetic nanoparticles , stirred at 5°C for 30 minutes, after the stirring was completed, magnetically sucked, poured out the unadsorbed solution, and then added phosphate buffer containing 5 parts of ethylenediamine with a pH of 4.0, and stirred and reacted at 5°C for 2 hours. After the reaction is completed, apply magnetic suction to the dispersion, pour it to remove the unadsorbed solution, re-inject deionized water at 5°C, and raise the temperature to 40°C. The process of "magnetic suction-dumping-water injection-heating-magnetic suction" is repeated for 2 Second, temperature-responsive core-shell magnetic hydrogel nanoparticles were obtained.

In the binary graft copolymer prepared in this example, the mass ratio of the temperature-responsive unit containing the cross-linking point to the functional dopamine monomer is 4.2:1.0; The swelling diameter at ℃ is 116nm.

Example 2

A temperature-responsive core-shell magnetic hydrogel nanoparticle comprising the following steps (the parts are parts by mass):

(1) Mix 10 parts of P(GMA-N ₃ ) (the degree of polymerization is 3000), 20 parts of P(NIPAAm-co-GMA)-C≡CH (the degree of polymerization is 6000, the cross-linking point monomer and the temperature response unit molar ratio of 4:1000), 5 parts of DOPA-C≡CH were dissolved in 60 parts of dimethyl sulfoxide, 0.05 parts of PMDETA/CuCl was added, and the mass ratio of the two was 2:1, and the inert gas was bubbled for 20 Minutes, then stirred and reacted at 35°C for 12 hours, using dialysis technology, dialyzed the reaction solution for 66 hours, and then freeze-dried to obtain a binary functional graft copolymer.

(2) Dissolve and disperse 60 parts of binary functional graft copolymers and 10 parts of magnetic nanoparticles in 10 parts of methylene chloride, stir at room temperature for 20 minutes, remove methylene chloride by rotary evaporation, and remove the precipitate Disperse the substance in deionized water, apply magnetic suction to the dispersion, pour it to remove the unadsorbed solution, and re-inject the deionized water at 5°C. The process of "magnetic suction-dumping-water injection-magnetic suction" is repeated twice. For the last time, it was added to a phosphate buffer solution with a pH of 4.0 to obtain an aqueous dispersion of magnetic nanoparticles.

(3) Add 60 parts of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 30 parts of N-hydroxysuccinimide to the aqueous dispersion of magnetic nanoparticles , stirred at 5°C for 30 minutes, after the stirring was completed, magnetically sucked, poured out the unadsorbed solution, then added 5 parts of phosphate buffer containing ethylenediamine with a pH of 5.0, and stirred and reacted at 5°C for 2 hours. After the reaction is completed, apply magnetic suction to the dispersion, pour it to remove the unadsorbed solution, re-inject deionized water at 5°C, and raise the temperature to 40°C. The process of "magnetic suction-dumping-water injection-heating-magnetic suction" is repeated for 2 Second, temperature-responsive core-shell magnetic hydrogel nanoparticles were obtained.

In the binary graft copolymer prepared in this example, the mass ratio of the temperature-responsive unit containing the cross-linking point to the functional dopamine monomer is 3.6:1.0; The swelling diameter at ℃ is 116nm.

Example 3

A temperature-responsive core-shell magnetic hydrogel nanoparticle comprising the following steps (the parts are parts by mass):

(1) Mix 10 parts of P(GMA-N ₃ ) (the degree of polymerization is 4000), 20 parts of P(NIPAAm-co-GMA)-C≡CH (the degree of polymerization is 10000, the crosslinking point monomer and the temperature response unit The volume molar ratio is 8:1000), 6 parts of DOPA-C≡CH are dissolved in 60 parts of dimethyl sulfoxide, 0.1 part of PMDETA/CuCl is added, and the mass ratio of the two is 3:1, and the inert gas is bubbled for 20 Minutes, then stirred and reacted at 45°C for 24 hours, using dialysis technology, dialyzed the reaction solution for 60 hours, and then freeze-dried to obtain a binary functional graft copolymer.

(2) Dissolve and disperse 70 parts of binary functional graft copolymers and 20 parts of magnetic nanoparticles in 20 parts of chloroform, stir at room temperature for 40 minutes, remove chloroform by rotary evaporation, and then remove the precipitate The substance was dispersed in deionized water, magnetically sucked the dispersion, poured to remove the unadsorbed solution, and re-injected with 10°C deionized water. The process of "magnetic suction-dumping-water injection-magnetic suction" was repeated 3 times. For the last time, it was added to a phosphate buffer solution with a pH of 5.0 to obtain an aqueous dispersion of magnetic nanoparticles.

(3) Add 100 parts of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 60 parts of N-hydroxysuccinimide to the aqueous dispersion of magnetic nanoparticles , stirred at 10°C for 60 minutes, after the stirring was completed, magnetically sucked, poured out the unadsorbed solution, and then added phosphate buffer containing 20 parts of bisaminopolyethylene glycol (M _w =200) with a pH of 5.0 , and stirred at 10°C for 4 hours. After the reaction is completed, apply magnetic suction to the dispersion, pour it to remove the unadsorbed solution, re-inject deionized water at 10°C, and raise the temperature to 40°C. The process of "magnetic suction-dumping-water injection-heating-magnetic suction" is repeated for 3 Second, temperature-responsive core-shell magnetic hydrogel nanoparticles were obtained.

In the binary graft copolymer prepared in this example, the mass ratio of the temperature-responsive unit containing the cross-linking point to the functional dopamine monomer is 2.7:1.0; The swelling diameter at ℃ is 120nm.

Example 4

A temperature-responsive core-shell magnetic hydrogel nanoparticle comprising the following steps (the parts are parts by mass):

(1) Mix 20 parts of P(GMA-N ₃ ) (the degree of polymerization is 6000), 30 parts of P(NIPAAm-co-GMA)-C≡CH (the degree of polymerization is 12000, the crosslinking point monomer and the temperature response unit The volume molar ratio is 16:1000), 6 parts of DOPA-C≡CH are dissolved in 80 parts of dimethylformamide, 0.1 part of PMDETA/CuCl is added, and the mass ratio of the two is 5:1, and the inert gas is bubbled for 30 Minutes, then stirred and reacted at 45°C for 24 hours, using dialysis technology, dialyzed the reaction solution for 48 hours, and then freeze-dried to obtain a binary functional graft copolymer.

(2) Dissolve and disperse 70 parts of binary functional graft copolymers and 20 parts of magnetic nanoparticles in 20 parts of chloroform, stir at room temperature for 40 minutes, remove chloroform by rotary evaporation, and then remove the precipitate The substance was dispersed in deionized water, magnetically sucked the dispersion, poured to remove the unadsorbed solution, and re-injected with 10°C deionized water. The process of "magnetic suction-dumping-water injection-magnetic suction" was repeated 3 times. For the last time, it was added to a phosphate buffer solution with a pH of 5.0 to obtain an aqueous dispersion of magnetic nanoparticles.

(3) Add 100 parts of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 60 parts of N-hydroxysuccinimide to the aqueous dispersion of magnetic nanoparticles , stirred at 10°C for 60 minutes, after the stirring was completed, magnetically sucked, poured out the unadsorbed solution, and then added phosphate buffer containing 20 parts of bisaminopolyethylene glycol (M _w =200) with a pH of 6.0 , and stirred at 10°C for 4 hours. After the reaction is completed, apply magnetic suction to the dispersion, pour it to remove the unadsorbed solution, re-inject 10°C deionized water, and raise the temperature to 50°C. The process of "magnetic suction-dumping-water injection-heating-magnetic suction" is repeated for 3 Second, temperature-responsive core-shell magnetic hydrogel nanoparticles were obtained.

In the binary graft copolymer prepared in this example, the mass ratio of the temperature-responsive unit containing the cross-linking point to the functional dopamine monomer is 5.2:1.0; The swelling diameter at ℃ is 124nm.

Example 5

A temperature-responsive core-shell magnetic hydrogel nanoparticle comprising the following steps (the parts are parts by mass):

(1) Mix 20 parts of P(HEMA-C≡CH) (the degree of polymerization is 2000), 30 parts of P(NIPAAm-co-GMA-N ₃ ) (the degree of polymerization is 2000, the crosslinking point monomer and the temperature response unit Volume molar ratio is 24:1000), 7 parts of DOPA-N ₃ are dissolved in 80 parts of dimethylformamide, 0.15 parts of NaVc/CuSO ₄ is added, the mass ratio of the two is 1.5:1.0, and inert gas is bubbled for 30 Minutes, then stirred and reacted at 50°C for 24 hours, using dialysis technology, dialyzed the reaction solution for 40 hours, and then freeze-dried to obtain a binary functional graft copolymer.

(2) Dissolve and disperse 80 parts of binary functional graft copolymers and 30 parts of magnetic nanoparticles in 30 parts of toluene, stir at room temperature for 60 minutes, remove toluene by rotary evaporation, and then disperse the precipitate in In deionized water, apply magnetic suction to the dispersion, pour it to remove the unadsorbed solution, and re-inject deionized water at 20°C. The process of "magnetic suction-dumping-water injection-magnetic suction" is repeated 4 times. For the last time, it was added to a phosphate buffer solution with a pH of 6.0 to obtain an aqueous dispersion of magnetic nanoparticles.

(3) Add 120 parts of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 90 parts of N-hydroxysuccinimide to the aqueous dispersion of magnetic nanoparticles , stirred at 20°C for 90 minutes, after the stirring was completed, magnetically sucked, poured out the unadsorbed solution, and then added phosphate buffer containing 40 parts of bisaminopolyethylene glycol (M _w =400) with a pH of 6.0 , and stirred at 20°C for 8 hours. After the reaction is completed, apply magnetic suction to the dispersion, pour it to remove the unadsorbed solution, re-inject deionized water at 20°C, and raise the temperature to 50°C. The process of "magnetic suction-dumping-water injection-heating-magnetic suction" is repeated for 4 Second, temperature-responsive core-shell magnetic hydrogel nanoparticles were obtained.

In the binary graft copolymer prepared in this example, the mass ratio of the temperature-responsive unit containing the cross-linking point to the functional dopamine monomer is 5.8:1.0; The swelling diameter at ℃ is 112nm.

Example 6

A temperature-responsive core-shell magnetic hydrogel nanoparticle comprising the following steps (the parts are parts by mass):

(1) Mix 20 parts of P(HEMA-C≡CH) (degree of polymerization 3000), 30 parts of P(NIPAAm-co-GMA-N ₃ ) (degree of polymerization 6000, crosslink point monomer and temperature response unit The volume molar ratio is 36:1000), 8 parts of DOPA-N ₃ are dissolved in 100 parts of dimethylformamide, 0.15 parts of NaVc/CuSO ₄ is added, and the mass ratio of the two is 3.5:1.0, and the inert gas is bubbled for 40 Minutes, then stirred and reacted at 50°C for 32 hours, using dialysis technology, dialyzed the reaction solution for 32 hours, and then freeze-dried to obtain a binary functional graft copolymer.

(2) Dissolve and disperse 90 parts of binary functional graft copolymers and 30 parts of magnetic nanoparticles in 30 parts of toluene, stir at room temperature for 60 minutes, remove toluene by rotary evaporation, and then disperse the precipitate in In deionized water, apply magnetic suction to the dispersion, pour it to remove the unadsorbed solution, and re-inject deionized water at 20°C. The process of "magnetic suction-dumping-water injection-magnetic suction" is repeated 4 times. For the last time, it was added to a phosphate buffer solution with a pH of 6.0 to obtain an aqueous dispersion of magnetic nanoparticles.

(3) Add 120 parts of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 90 parts of N-hydroxysuccinimide to the aqueous dispersion of magnetic nanoparticles , stirred at 20°C for 90 minutes, after the stirring was completed, magnetically sucked, poured out the unadsorbed solution, and then added phosphate buffer containing 40 parts of bisaminopolyethylene glycol (M _w =400) with a pH of 7.0 , and stirred at 20°C for 8 hours. After the reaction is completed, apply magnetic suction to the dispersion, pour it to remove the unadsorbed solution, re-inject deionized water at 20°C, and raise the temperature to 50°C. The process of "magnetic suction-dumping-water injection-heating-magnetic suction" is repeated for 4 Second, temperature-responsive core-shell magnetic hydrogel nanoparticles were obtained.

In the binary graft copolymer prepared in this example, the mass ratio of the temperature-responsive unit containing the cross-linking point to the functional dopamine monomer is 2.2-1.0; The swelling diameter at ℃ is 114nm.

Example 7

A temperature-responsive core-shell magnetic hydrogel nanoparticle comprising the following steps (the parts are parts by mass):

(1) Mix 30 parts of P(HEMA-C≡CH) (degree of polymerization 4000), 40 parts of P(NIPAAm-co-GMA-N ₃ ) (degree of polymerization 10000, crosslink point monomer and temperature response unit Volume molar ratio is 42:1000), 9 parts of DOPA-N ₃ are dissolved in 100 parts of dimethylacetamide, 0.2 parts of NaVc/CuSO ₄ is added, the mass ratio of the two is 5.5:1.0, and inert gas is bubbled for 50 Minutes, then stirred and reacted at 60°C for 40 hours, using dialysis technology, dialyzed the reaction solution for 16 hours, and then freeze-dried to obtain a binary functional graft copolymer.

(2) Dissolve and disperse 100 parts of binary functional graft copolymers and 40 parts of magnetic nanoparticles in 40 parts of xylene, stir at room temperature for 80 minutes, remove xylene by rotary evaporation, and then disperse the precipitate In deionized water, magnetically absorb the dispersion, pour to remove the unadsorbed solution, and re-inject deionized water at 25°C. The process of "magnetic suction-dumping-water injection-magnetic suction" is repeated 5 times. For the last time, it was added to a phosphate buffer solution with a pH of 7.0 to obtain an aqueous dispersion of magnetic nanoparticles.

(3) Add 180 parts of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 120 parts of N-hydroxysuccinimide in the aqueous dispersion of magnetic nanoparticles , stirred at 25°C for 120 minutes, after the stirring was completed, magnetically sucked, poured out the unadsorbed solution, and then added phosphate buffer containing 60 parts of bisaminopolyethylene glycol (M _w =700) with a pH of 7.0 , and stirred at 25°C for 12 hours. After the reaction is completed, apply magnetic suction to the dispersion, pour it to remove the unadsorbed solution, re-inject deionized water at 25°C, and raise the temperature to 60°C. The process of "magnetic suction-dumping-water injection-heating-magnetic suction" is repeated for 5 Second, temperature-responsive core-shell magnetic hydrogel nanoparticles were obtained.

In the binary graft copolymer prepared in this example, the mass ratio of the temperature-responsive unit containing the cross-linking point to the functional dopamine monomer is 2.8:1.0; The swelling diameter at ℃ is 119nm.

Example 8

A temperature-responsive core-shell magnetic hydrogel nanoparticle comprising the following steps (the parts are parts by mass):

(1) Mix 30 parts of P(HEMA-C≡CH) (6000 degree of polymerization), 40 parts of P(NIPAAm-co-GMA-N ₃ ) (12000 degree of polymerization, cross-link monomer and temperature response unit Volume molar ratio is 50:1000), 10 parts of DOPA-N ₃ are dissolved in 120 parts of dimethylacetamide, 0.2 parts of NaVc/CuSO ₄ is added, the mass ratio of the two is 7.5:1.0, and inert gas is bubbled for 60 Minutes, then stirred and reacted at 60°C for 48 hours, using dialysis technology, dialyzed the reaction solution for 6 hours, and then freeze-dried to obtain a binary functional graft copolymer.

(2) Dissolve and disperse 120 parts of binary functional graft copolymers and 40 parts of magnetic nanoparticles in 40 parts of xylene, stir at room temperature for 80 minutes, remove xylene by rotary evaporation, and then disperse the precipitate In deionized water, magnetically absorb the dispersion, pour to remove the unadsorbed solution, and re-inject deionized water at 25°C. The process of "magnetic suction-dumping-water injection-magnetic suction" is repeated 5 times. For the last time, it was added to a phosphate buffer solution with a pH of 8.0 to obtain an aqueous dispersion of magnetic nanoparticles.

(3) Add 180 parts of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 120 parts of N-hydroxysuccinimide in the aqueous dispersion of magnetic nanoparticles , stirred at 25°C for 120 minutes, after the stirring was completed, magnetically sucked, poured out the unadsorbed solution, and then added phosphate buffer containing 60 parts of bisaminopolyethylene glycol (M _w =700) with a pH of 8.0 , and stirred at 25°C for 12 hours. After the reaction is completed, apply magnetic suction to the dispersion, pour it to remove the unadsorbed solution, re-inject deionized water at 25°C, and raise the temperature to 60°C. The process of "magnetic suction-dumping-water injection-heating-magnetic suction" is repeated for 5 Second, temperature-responsive core-shell magnetic hydrogel nanoparticles were obtained.

In the binary graft copolymer prepared in this example, the mass ratio of the temperature-responsive unit containing the cross-linking point to the functional dopamine monomer is 3.8:1.0; The swelling diameter at ℃ is 123nm.

The specific embodiments described above are intended to further describe the use of the present invention in detail and to help further understanding of the present invention, rather than to limit the scope of the present invention. Those skilled in the art should understand that without departing from the spirit and principles of the present invention, various modifications and substitutions should be included within the protection scope of the present invention.

Claims (10)

1. there is the preparation method of nucleocapsid structure magnetic Hydrogel Nanoparticles of temperature-responsive, it is characterised in that: (1), synthesis Containing efficient absorption unit and two meta function graft copolymers of the temperature-responsive unit containing crosslinking points；

(2) the efficient absorption unit in copolymer, is utilized to adsorb copolymer molecule in magnetic nano particle sub-surface；

(3) introduce cross-linking agent, the molecular structure of temperature-responsive unit is locked, form gel layer.

The most according to claim 1, there is the preparation method of nucleocapsid structure magnetic Hydrogel Nanoparticles of temperature-responsive, its Being characterised by, following number is weight portion:

(1) by the main polymer chain of 10～30 parts, 20～40 parts of temperature-responsive unit containing crosslinking points, 5～10 parts of functions are many Bar amine monomers is dissolved in 40～120 parts of solvent orange 2 As jointly, adds 0.05～0.2 part of catalyst, bubbling inert gas 10～60 points Clock, stirring reaction 6～48 hours at 35～60 DEG C, utilize dialysis, are dialysed 6～72 hours by reactant liquor afterwards, colder Lyophilizing is dry, obtains two meta function graft copolymers；

(2) the two meta function graft copolymers of 60～120 parts and the magnetic nano-particle of 10～40 parts are jointly dissolved and disperse In the solvent B of 10～40 parts, stirring 20～80 minutes under room temperature, rotary evaporation removes solvent B, then is scattered in by precipitate In ionized water, dispersion liquid is carried out magnetic, topple over and remove unadsorbed solution, refill the deionized water of 5～25 DEG C, this step In Zhou, the process repeatable operation 2 of magnetic-topple over-water filling-magnetic～5 times.For the last time, the phosphoric acid that pH is 4.0～8.0 is added Buffer, obtains the aqueous dispersions of magnetic nano-particle；

(3) in the aqueous dispersions of magnetic nano-particle, add 1-(3-the dimethylamino-propyl)-3-ethyl carbon two of 60～180 parts Inferior amine salt hydrochlorate and the N-hydroxy-succinamide of 30～120 parts, stir 30～120 minutes at 5～25 DEG C, stir complete After, magnetic, pour out unadsorbed solution, add the phosphate containing the cross-linking agent of 5～60 parts that pH is 4.0～8.0 and delay Rushing liquid, at 5～25 DEG C, stirring reaction 2～12 hours, after completion of the reaction, carry out magnetic to dispersion liquid, topple over removing unadsorbed Solution, refills the deionized water of 5～25 DEG C, is warming up to 40～60 DEG C, in this step, and magnetic-topple over-water filling-intensification-magnetic The process repeatable operation 2 inhaled～5 times, obtain having nucleocapsid structure magnetic Hydrogel Nanoparticles of temperature-responsive.

Nucleocapsid structure magnetic Hydrogel Nanoparticles with temperature-responsive the most according to claim 2, it is characterised in that The quality between temperature-responsive unit and function dopamine monomer in the molecular structure of binary graft copolymer, containing crosslinking points Ratio is between 2.2:1.0～5.8:1.0, and function dopamine monomer is the one in alkynyl dopamine or azido dopamine.

Nucleocapsid structure magnetic Hydrogel Nanoparticles with temperature-responsive the most according to claim 2, it is characterised in that Solvent orange 2 A is the one in dimethyl sulfoxide, dimethylformamide, dimethyl acetylamide.

5., according to nucleocapsid structure magnetic Hydrogel Nanoparticles with temperature-responsive described in claim 2, its feature exists In, catalyst be mass ratio be the N of 1:1～5:1, N, N, N, N-PMDETA/Cu-lyt. or mass ratio are Sodium ascorbate/the copper sulfate of 1.5:1.0～7.5:1.0.

Nucleocapsid structure magnetic Hydrogel Nanoparticles with temperature-responsive the most according to claim 2, it is characterised in that The main polymer chain degree of polymerization is 2000～6000, this main polymer chain be end be the polymethyl acid glycidyl of azido Ester, end be the polyglycidyl acrylate of azido, end be the poly hydroxy ethyl acrylate of alkynyl, end be alkynyl Poly(Hydroxyethyl Methacrylate) in one.

Nucleocapsid structure magnetic Hydrogel Nanoparticles with temperature-responsive the most according to claim 2, it is characterised in that The degree of polymerization of the temperature-responsive unit containing crosslinking points is 2000～12000, including the friendship that mol ratio is 1:1000～50:1000 Connection point monomer and temperature-responsive monomer；

Should containing temperature-responsive unit of crosslinking points be end be alkynyl or the poly-N-isopropyl acrylamide of azido and propylene The random copolymer of acid or end are alkynyl or the poly-N-isopropyl acrylamide of azido and glycidyl methacrylate Random copolymer.

Described nucleocapsid structure magnetic Hydrogel Nanoparticles with temperature-responsive the most according to claim 2, its feature exists In, solvent B is the one in dichloromethane, chloroform, toluene, dimethylbenzene.

9., according to nucleocapsid structure magnetic Hydrogel Nanoparticles with temperature-responsive described in claim 2, its feature exists In, the weight average molecular weight of cross-linking agent is 200～700Da, for the one in ethylenediamine, double amino-polyethyleneglycols.

10. nucleocapsid structure magnetic Hydrogel Nanoparticles with temperature-responsive, it is characterised in that be by claim 1 ～the preparation method that 9 described in any one obtains.