CN106237329B - Core-shell structure magnetic Hydrogel Nanoparticles and preparation method with temperature-responsive - Google Patents
Core-shell structure magnetic Hydrogel Nanoparticles and preparation method with temperature-responsive Download PDFInfo
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- CN106237329B CN106237329B CN201610634413.4A CN201610634413A CN106237329B CN 106237329 B CN106237329 B CN 106237329B CN 201610634413 A CN201610634413 A CN 201610634413A CN 106237329 B CN106237329 B CN 106237329B
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Abstract
The preparation method of present invention relates particularly to a kind of core-shell structure magnetic Hydrogel Nanoparticles with temperature-responsive.Two meta function graft copolymers of the temperature-responsive unit containing efficient absorption unit and containing crosslinking points are synthesized first；Secondly copolymer molecule is adsorbed on magnetic nano-particle surface using the efficient absorption unit in copolymer；Thirdly introducing crosslinked agent locks the molecular structure of temperature-responsive unit, forms gel layer.The present invention solves at present that the step present in the method for magnetic nano-particle surface construction hydrogel layer is cumbersome, controllability is poor, on the influential defect of magnetic nano-particle stability, comprising: 1) copolymer is high-efficient in magnetic nano-particle adsorption；2) adsorption process negatively affects magnetic nano-particle small；3) magnetic nano-particle is coated comprehensive；4) gel layer structure is adjustable；5) advantages such as hydrogel layer stable cycle performance.
Description
Technical field
The invention belongs to organic/inorganic composite functional material technical field, and in particular to a kind of with temperature-responsive
Core-shell structure magnetic Hydrogel Nanoparticles and preparation method thereof.
Background technique
Hydrogel is a kind of with space three-dimensional structure, is capable of the polymer soft material of water absorption and swelling.According to application environment
Or the difference of purposes, the performances such as its chemical property, mechanical property and biocompatibility can be adjusted as needed.Water
Gel is in bioengineered tissue, the great application prospect of field of medicine release.Hydrogel can be used as biomimetic material, in vivo
Simulation is similar to the avascular tissues such as skin, cartilage；Carrier can also be utilized it as, by empty and logical inside gel
The absorption and release of road progress drug molecule.
Temperature-responsive hydrogel is a kind of intellectual material that self performance can be adjusted according to the variation of external environment temperature.
The polymer network conformation of common temperature-responsive hydrogel can be adjusted according to temperature change, they all have one
Critical solution temperature, more than this temperature and this temperature is hereinafter, completely contraction or diastole conformation may be implemented in gel network.
Magnetic nano-particle typically refers to the zero dimensional nanometer materials that diameter is less than 100nm.They have great specific surface
Product, and since its size is smaller, usually there is superparamagnetic characteristic, therefore be widely used in nuclear-magnetism development imaging, drug targeting
The fields such as release, tumor thermotherapy.
Temperature-responsive magnetic Hydrogel Nanoparticles then combines the advantage of above-mentioned material.They include 1) lesser size
(according to the difference of preparation method, size is also different, but general diameter is both less than 500nm)；2) temperature response characteristics.Pass through
Transformation temperature, gel network conformation can change；3) certain magnetic property.By applying extraneous magnetic field, it can be realized this and receive
The displacement of rice corpuscles and enrichment.
This kind of material has extremely strong application value in drug controlled release field.Firstly, drug molecule is carried on solidifying
Glue inside nanoparticles.Secondly, moving and positioning in vivo the nanoparticle for having loaded drug by magnetic field.Finally,
Cause the conformation change of hydrogel network so that the magnetic particle of inside nanoparticles heats up by changing field strength, loads
Drug will be released, to realize the accurate Targeting delivery of drug molecule.
Currently, the method in magnetic nano-particle surface construction hydrogel layer still has following three problems to need to solve or excellent
Change: 1) it is relatively complicated to construct step；2) construction method controllability is poor；3) stability of magnetic nano-particle needs in preparation process
It keeps.Such as publication No.105251456A is reported and a kind of is made polyhydroxy based high-polymer with a kind of nitrogenous high polymer
It is support dispersion in the solution containing magnetisable material iron, cobalt and/or nickel ion, precipitating reagent hydroxide is then added into solution
Sodium, magnetic gel bead obtained.Gel layer depends entirely on intermolecular work for the absorption of magnetic nano-particle in the patent
Firmly, therefore cycle-index can only achieve 1-10 times, and it is still necessary to improve for stability.Granted patent No.102875823B is reported
One kind is by the previously prepared blocky gel of polymerization crosslinking, then grinds the method for being formed as magnetic microgel.But this method is without legal system
It is standby to obtain the magnetic gel particle of Nano grade.
Summary of the invention
The primary purpose of the present invention is that the shortcomings that overcoming the prior art and insufficient, provide a kind of with temperature-responsive
The preparation method of core-shell structure magnetic Hydrogel Nanoparticles.
Technical scheme is as follows:
The preparation method of core-shell structure magnetic Hydrogel Nanoparticles with temperature-responsive, comprises the following steps:
(1), the two meta functions grafting of the temperature-responsive unit containing efficient absorption unit and containing crosslinking points is synthesized
Copolymer；
(2), copolymer molecule is adsorbed on magnetic nano-particle surface using the efficient absorption unit in copolymer；
(3) introducing crosslinked agent locks the molecular structure of temperature-responsive unit, forms gel layer.
Following numbers are mass fraction:
(1), by 10~30 parts of main polymer chain, 20~40 parts of temperature-responsive units containing crosslinking points, 5~10 parts of function
Energy DOPA amine monomers co-dissolve is in 40~120 parts of solvent As, 0.05~0.2 part of catalyst of addition, and bubbling inert gas 10~
It 60 minutes, is stirred to react at 35~60 DEG C 6~48 hours, using dialysis, reaction solution is dialysed 6~72 hours later,
It is freeze-dried again, obtains two meta function graft copolymers；
(2), simultaneously by 60~120 parts of two meta function graft copolymers and 10~40 parts of magnetic nano-particle co-dissolve
It is dispersed in 10~40 parts of solvent B, stirs 20~80 minutes at room temperature, rotary evaporation removes solvent B, then sediment is dispersed
In deionized water, magnetic is carried out to dispersion liquid, topples over and removes unadsorbed solution, refill 5~25 DEG C of deionized water,
In the step, magnetic-topples over-fills the water-and the process of magnetic operates 2~5 times repeatedly, and last time, it is 4.0~8.0 that pH, which is added,
Phosphate buffer obtains the aqueous dispersions of magnetic nano-particle.
(3), 60~180 parts 1- (3- dimethylamino-propyl) -3- second is added in the aqueous dispersions of magnetic nano-particle
Base carbodiimide hydrochloride and 30~120 parts of n-hydroxysuccinimide stir 30~120 minutes at 5~25 DEG C, stirring
After, unadsorbed solution is poured out in magnetic, adds the phosphoric acid containing 5~60 parts of crosslinking agent that pH is 4.0~8.0
Salt buffer is stirred to react at 5~25 DEG C 2~12 hours, after completion of the reaction, carries out magnetic to dispersion liquid, topple over removing and do not inhale
Attached solution refills 5~25 DEG C of deionized water, is warming up to 40~60 DEG C, and in the step, magnetic-topples over-fills the water-liter
Temperature-magnetic process operates 2~5 times repeatedly, obtains core-shell structure magnetic Hydrogel Nanoparticles with temperature-responsive.
Binary graft copolymer described in step (1), in molecular structure, temperature-responsive unit and function containing crosslinking points
Mass ratio between energy DOPA amine monomers is between 2.2:1.0~5.8:1.0；
Solvent A described in step (1) is one of dimethyl sulfoxide, dimethylformamide, dimethyl acetamide；
Catalyst described in step (1) is N, N, N, N, N- pentamethyldivinyltriamine/stannous chloride (PMDETA/
CuCl, wherein the two mass ratio is preferably 1:1~5:1), sodium ascorbate/copper sulphate (NaVc/CuSO4, wherein the two quality
One of than being preferably 1.5:1.0~7.5:1.0)；
The degree of polymerization of main polymer chain described in step (1) is 2000~6000, is the poly- methyl-prop that end is azido
Olefin(e) acid ethylene oxidic ester (P (GMA-N3)), end be azido polyglycidyl acrylate (P (GA-N3)), end be alkynes
The poly hydroxy ethyl acrylate (P (HEMA-C ≡ CH)) of base, hydroxyethyl acrylate (P (the HEA-C ≡ that end is alkynyl
One of CH))；
The degree of polymerization of the temperature-responsive unit containing crosslinking points is 2000~12000, the temperature containing crosslinking points
Response unit includes the crosslinking points monomer and temperature-responsive monomer that molar ratio is 1:1000~50:1000, the temperature containing crosslinking points
Response unit is spent, is the random copolymer (P of poly-N-isopropyl acrylamide and acrylic acid that end is alkynyl or azido
(NIPAAm-co-AA)-C ≡ CH or P (NIPAAm-co-AA)-N3), the poly-N-isopropyl propylene that end is alkynyl or azido
Random copolymer (P (NIPAAm-co-GMA)-C ≡ CH or P (NIPAAm-co- of amide and glycidyl methacrylate
GMA-N3One of)；
The function DOPA amine monomers are alkynyl dopamine (DOPA-C ≡ CH) or azido dopamine (DOPA-N3) in
One kind；
The wherein synthesized reference of main polymer chain A and the temperature-responsive unit containing crosslinking points patent document
No.103755968A, the synthesized reference paper document Chemistry-European of function DOPA amine monomers
Journal.2013,19(26):8673-8678；
The synthesized reference paper document ACS Nano of magnetic nano-particle described in step (2), 2012,6 (1): 389-
399；
Solvent B described in step (2) is one of methylene chloride, chloroform, toluene, dimethylbenzene.
Crosslinking agent described in step (3) be ethylenediamine, double amino-polyethyleneglycols (weight average molecular weight is preferably 200~
One of 700Da).
The principle of the present invention is:
By binary graft copolymer synthesized by controllable polymerization means, DOPA amine unit is grafted on main chain, it is more
Distinctive catechol group can cooperate rapidly with the ion on magnetic nano-particle surface in bar amine molecule structure, will connect
Graft copolymer is adsorbed on magnetic nano-particle surface, forms core-shell structure, but only this simple absorption and unstable.It is logical
Crosslinking points contained in crosslinking temperature responsiveness unit are crossed, this core-shell structure can be solidified, so that formation temperature responsiveness is solidifying
Glue-line.
The present invention has the following advantages and effects with respect to the prior art:
(1) binary functional polymer has continuous, a large amount of adsorption site, can be rapidly on magnetic nano-particle surface
Adsorption effect is generated, adsorption process is mildly easy, will not have a negative impact to magnetic nano particle minor structure and performance；
(2) binary functional polymer is more comprehensive for the package of magnetic nano-particle, can realize substantially to magnetic Nano
The monodisperse of particle wraps up, and the cycle performance of gel particles is continuous and stable；(3) temperature of magnetic Hydrogel Nanoparticles prepared by
Response performance and swelling behavior are spent, it can be by adjusting the temperature-responsive list containing crosslinking points in two meta function graft copolymers
The structure of member realizes that the number of crosslinking points, the length of unit can be according to different needs, in the synthesis process in advance
It adjusts.
Detailed description of the invention
A kind of preparation method schematic diagram of core-shell structure magnetic Hydrogel Nanoparticles with temperature-responsive of Fig. 1；
The electron scanning micrograph (being unstained) for magnetic Hydrogel Nanoparticles that Fig. 2 is prepared by embodiment 4；
The diameter for magnetic Hydrogel Nanoparticles that Fig. 3 is prepared by embodiment 4 with temperature circulation change figure.
Specific embodiment
Further the preparation method is described in detail below in conjunction with attached drawing.
Present invention will now be described in further detail with reference to the embodiments and the accompanying drawings, but embodiments of the present invention are unlimited
In this.
Raw material used in embodiment is as follows:
Embodiment 1
A kind of core-shell structure magnetic Hydrogel Nanoparticles with temperature-responsive, comprises the following steps that (number is equal
For mass parts):
(1) by 10 parts of P (GMA-N3) (degree of polymerization 2000), 20 parts of P (NIPAAm-co-GMA)-C ≡ CH (degree of polymerization
It is 2000, crosslinking points monomer and temperature-responsive monomer mole ratio are 1:1000), 5 parts of DOPA-C ≡ CH co-dissolves are at 40 part two
In methyl sulfoxide, 0.05 part of PMDETA/CuCl is added, wherein both mass ratio be 1:1, bubbling inert gas 10 minutes, later
It is stirred to react at 35 DEG C 6 hours, using dialysis, reaction solution is dialysed 72 hours, then is freeze-dried, obtains two meta functions
Graft copolymer.
(2) by 60 parts of two meta function graft copolymers and 10 parts of magnetic nano-particle co-dissolve and 10 parts are dispersed in
Methylene chloride in, stir 20 minutes at room temperature, rotary evaporation removes methylene chloride, then disperses deionized water for sediment
In, magnetic is carried out to dispersion liquid, topples over and removes unadsorbed solution, refill 5 DEG C of deionized water, should " magnetic-topples over-
Water filling-magnetic " process operates 2 times repeatedly.For the last time, it is added in the phosphate buffer that pH is 4.0, obtains magnetic nano-particle
Aqueous dispersions.
(3) 60 parts of 1- (3- dimethylamino-propyl) -3- ethyl carbon two is added in the aqueous dispersions of magnetic nano-particle
Inferior amine salt hydrochlorate and 30 parts of n-hydroxysuccinimide stir 30 minutes at 5 DEG C, and after stirring, magnetic is poured out not
The solution of absorption adds the phosphate buffer containing 5 parts of the pH ethylenediamine for being 4.0, is stirred to react 2 hours at 5 DEG C.Instead
After answering, magnetic is carried out to dispersion liquid, topples over and removes unadsorbed solution, refill 5 DEG C of deionized water, be warming up to 40
DEG C, should " magnetic-is toppled over-water filling-heat up-magnetic " process operate repeatedly 2 times, obtain the core-shell structure magnetic with temperature-responsive
Hydrogel Nanoparticles.
The binary graft copolymer that this embodiment is prepared, temperature-responsive unit and function dopamine containing crosslinking points
The mass ratio of monomer is 4.2:1.0；Saturation swelling diameter is 120nm, 45 DEG C of swellings of going down at 15 DEG C of son of magnetic Hydrogel Nanoparticles
Diameter is 116nm.
Embodiment 2
A kind of core-shell structure magnetic Hydrogel Nanoparticles with temperature-responsive, comprises the following steps that (number is equal
For mass parts):
(1) by 10 parts of P (GMA-N3) (degree of polymerization 3000), 20 parts of P (NIPAAm-co-GMA)-C ≡ CH (degree of polymerization
It is 6000, crosslinking points monomer and temperature-responsive monomer mole ratio are 4:1000), 5 parts of DOPA-C ≡ CH co-dissolves are at 60 part two
In methyl sulfoxide, 0.05 part of PMDETA/CuCl is added, wherein both mass ratio be 2:1, bubbling inert gas 20 minutes, later
It is stirred to react at 35 DEG C 12 hours, using dialysis, reaction solution is dialysed 66 hours, then is freeze-dried, obtains two elementary works
It can graft copolymer.
(2) by 60 parts of two meta function graft copolymers and 10 parts of magnetic nano-particle co-dissolve and 10 parts are dispersed in
Methylene chloride in, stir 20 minutes at room temperature, rotary evaporation removes methylene chloride, then disperses deionized water for sediment
In, magnetic is carried out to dispersion liquid, topples over and removes unadsorbed solution, refill 5 DEG C of deionized water, should " magnetic-topples over-
Water filling-magnetic " process operates 2 times repeatedly.For the last time, it is added in the phosphate buffer that pH is 4.0, obtains magnetic nano-particle
Aqueous dispersions.
(3) 60 parts of 1- (3- dimethylamino-propyl) -3- ethyl carbon two is added in the aqueous dispersions of magnetic nano-particle
Inferior amine salt hydrochlorate and 30 parts of n-hydroxysuccinimide stir 30 minutes at 5 DEG C, and after stirring, magnetic is poured out not
The solution of absorption adds the phosphate buffer containing 5 parts of the pH ethylenediamine for being 5.0, is stirred to react 2 hours at 5 DEG C.Instead
After answering, magnetic is carried out to dispersion liquid, topples over and removes unadsorbed solution, refill 5 DEG C of deionized water, be warming up to 40
DEG C, should " magnetic-is toppled over-water filling-heat up-magnetic " process operate repeatedly 2 times, obtain the core-shell structure magnetic with temperature-responsive
Hydrogel Nanoparticles.
The binary graft copolymer that this embodiment is prepared, temperature-responsive unit and function dopamine containing crosslinking points
The mass ratio of monomer is 3.6:1.0；Saturation swelling diameter is 128nm, 45 DEG C of swellings of going down at 15 DEG C of son of magnetic Hydrogel Nanoparticles
Diameter is 116nm.
Embodiment 3
A kind of core-shell structure magnetic Hydrogel Nanoparticles with temperature-responsive, comprises the following steps that (number is equal
For mass parts):
(1) by 10 parts of P (GMA-N3) (degree of polymerization 4000), 20 parts of P (NIPAAm-co-GMA)-C ≡ CH (degree of polymerization
It is 10000, crosslinking points monomer and temperature-responsive monomer mole ratio are 8:1000), 6 parts of DOPA-C ≡ CH co-dissolves are at 60 part two
In methyl sulfoxide, 0.1 part of PMDETA/CuCl is added, wherein both mass ratio be 3:1, bubbling inert gas 20 minutes, Zhi Hou
It is stirred to react at 45 DEG C 24 hours, using dialysis, reaction solution is dialysed 60 hours, then is freeze-dried, obtains two meta functions
Graft copolymer.
(2) by 70 parts of two meta function graft copolymers and 20 parts of magnetic nano-particle co-dissolve and 20 parts are dispersed in
Chloroform in, stir 40 minutes at room temperature, rotary evaporation removes chloroform, then disperses deionized water for sediment
In, magnetic is carried out to dispersion liquid, topples over and removes unadsorbed solution, refill 10 DEG C of deionized water, should " magnetic-topples over-
Water filling-magnetic " process operates 3 times repeatedly.For the last time, it is added in the phosphate buffer that pH is 5.0, obtains magnetic nano-particle
Aqueous dispersions.
(3) 100 parts of 1- (3- dimethylamino-propyl) -3- ethyl carbon two is added in the aqueous dispersions of magnetic nano-particle
Inferior amine salt hydrochlorate and 60 parts of n-hydroxysuccinimide stir 60 minutes at 10 DEG C, and after stirring, magnetic is poured out
Unadsorbed solution adds the double amino-polyethyleneglycols (M for being 5.0 containing 20 parts of pHw=200) phosphate buffer,
It is stirred to react at 10 DEG C 4 hours.After completion of the reaction, magnetic is carried out to dispersion liquid, topples over and remove unadsorbed solution, refills
10 DEG C of deionized water is warming up to 40 DEG C, should " magnetic-is toppled over-water filling-heat up-magnetic " process operate 3 times, had repeatedly
There is core-shell structure magnetic Hydrogel Nanoparticles of temperature-responsive.
The binary graft copolymer that this embodiment is prepared, temperature-responsive unit and function dopamine containing crosslinking points
The mass ratio of monomer is 2.7:1.0；Saturation swelling diameter is 134nm, 45 DEG C of swellings of going down at 15 DEG C of son of magnetic Hydrogel Nanoparticles
Diameter is 120nm.
Embodiment 4
A kind of core-shell structure magnetic Hydrogel Nanoparticles with temperature-responsive, comprises the following steps that (number is equal
For mass parts):
(1) by 20 parts of P (GMA-N3) (degree of polymerization 6000), 30 parts of P (NIPAAm-co-GMA)-C ≡ CH (degree of polymerization
It is 12000, crosslinking points monomer and temperature-responsive monomer mole ratio are 16:1000), 6 parts of DOPA-C ≡ CH co-dissolves are at 80 parts
In dimethylformamide, 0.1 part of PMDETA/CuCl is added, wherein both mass ratio be 5:1, bubbling inert gas 30 minutes, it
It is stirred to react at 45 DEG C afterwards 24 hours, using dialysis, reaction solution is dialysed 48 hours, then is freeze-dried, obtains binary
Function graft copolymer.
(2) by 70 parts of two meta function graft copolymers and 20 parts of magnetic nano-particle co-dissolve and 20 parts are dispersed in
Chloroform in, stir 40 minutes at room temperature, rotary evaporation removes chloroform, then disperses deionized water for sediment
In, magnetic is carried out to dispersion liquid, topples over and removes unadsorbed solution, refill 10 DEG C of deionized water, should " magnetic-topples over-
Water filling-magnetic " process operates 3 times repeatedly.For the last time, it is added in the phosphate buffer that pH is 5.0, obtains magnetic nano-particle
Aqueous dispersions.
(3) 100 parts of 1- (3- dimethylamino-propyl) -3- ethyl carbon two is added in the aqueous dispersions of magnetic nano-particle
Inferior amine salt hydrochlorate and 60 parts of n-hydroxysuccinimide stir 60 minutes at 10 DEG C, and after stirring, magnetic is poured out
Unadsorbed solution adds the double amino-polyethyleneglycols (M for being 6.0 containing 20 parts of pHw=200) phosphate buffer,
It is stirred to react at 10 DEG C 4 hours.After completion of the reaction, magnetic is carried out to dispersion liquid, topples over and remove unadsorbed solution, infuses again
The deionized water for entering 10 DEG C is warming up to 50 DEG C, should " magnetic-is toppled over-water filling-heat up-magnetic " process operate 3 times, obtain repeatedly
Core-shell structure magnetic Hydrogel Nanoparticles with temperature-responsive.
The binary graft copolymer that this embodiment is prepared, temperature-responsive unit and function dopamine containing crosslinking points
The mass ratio of monomer is 5.2:1.0；Saturation swelling diameter is 142nm, 45 DEG C of swellings of going down at 15 DEG C of son of magnetic Hydrogel Nanoparticles
Diameter is 124nm.
Embodiment 5
A kind of core-shell structure magnetic Hydrogel Nanoparticles with temperature-responsive, comprises the following steps that (number is equal
For mass parts):
(1) by 20 parts of P (HEMA-C ≡ CH) (degree of polymerization 2000), 30 parts of P (NIPAAm-co-GMA-N3) (the degree of polymerization
It is 2000, crosslinking points monomer and temperature-responsive monomer mole ratio are 24:1000), 7 parts of DOPA-N3Co-dissolve is in 80 parts of diformazans
In base formamide, 0.15 part of NaVc/CuSO is added4, wherein both mass ratio be 1.5:1.0, bubbling inert gas 30 minutes, it
It is stirred to react at 50 DEG C afterwards 24 hours, using dialysis, reaction solution is dialysed 40 hours, then is freeze-dried, obtains binary
Function graft copolymer.
(2) by 80 parts of two meta function graft copolymers and 30 parts of magnetic nano-particle co-dissolve and 30 parts are dispersed in
Toluene in, stir 60 minutes at room temperature, rotary evaporation removes toluene, then disperses sediment in deionized water, to dispersion
Liquid carries out magnetic, topples over and removes unadsorbed solution, refills 20 DEG C of deionized water, and "-magnetic is toppled over-filled the water to magnetic-for this
Suction " process operates 4 times repeatedly.For the last time, it is added in the phosphate buffer that pH is 6.0, obtains the moisture of magnetic nano-particle
Dispersion liquid.
(3) 120 parts of 1- (3- dimethylamino-propyl) -3- ethyl carbon two is added in the aqueous dispersions of magnetic nano-particle
Inferior amine salt hydrochlorate and 90 parts of n-hydroxysuccinimide stir 90 minutes at 20 DEG C, and after stirring, magnetic is poured out
Unadsorbed solution adds the double amino-polyethyleneglycols (M for being 6.0 containing 40 parts of pHw=400) phosphate buffer,
It is stirred to react at 20 DEG C 8 hours.After completion of the reaction, magnetic is carried out to dispersion liquid, topples over and remove unadsorbed solution, refills
20 DEG C of deionized water is warming up to 50 DEG C, should " magnetic-is toppled over-water filling-heat up-magnetic " process operate 4 times, had repeatedly
There is core-shell structure magnetic Hydrogel Nanoparticles of temperature-responsive.
The binary graft copolymer that this embodiment is prepared, temperature-responsive unit and function dopamine containing crosslinking points
The mass ratio of monomer is 5.8:1.0；Saturation swelling diameter is 123nm, 45 DEG C of swellings of going down at 15 DEG C of son of magnetic Hydrogel Nanoparticles
Diameter is 112nm.
Embodiment 6
A kind of core-shell structure magnetic Hydrogel Nanoparticles with temperature-responsive, comprises the following steps that (number is equal
For mass parts):
(1) by 20 parts of P (HEMA-C ≡ CH) (degree of polymerization 3000), 30 parts of P (NIPAAm-co-GMA-N3) (the degree of polymerization
It is 6000, crosslinking points monomer and temperature-responsive monomer mole ratio are 36:1000), 8 parts of DOPA-N3Co-dissolve is in 100 parts of diformazans
In base formamide, 0.15 part of NaVc/CuSO is added4, wherein both mass ratio be 3.5:1.0, bubbling inert gas 40 minutes, it
It is stirred to react at 50 DEG C afterwards 32 hours, using dialysis, reaction solution is dialysed 32 hours, then is freeze-dried, obtains binary
Function graft copolymer.
(2) by 90 parts of two meta function graft copolymers and 30 parts of magnetic nano-particle co-dissolve and 30 are dispersed in
Part toluene in, stir 60 minutes at room temperature, rotary evaporation removes toluene, then disperse sediment in deionized water, to point
Dispersion liquid carries out magnetic, topples over and removes unadsorbed solution, refills 20 DEG C of deionized water, and "-magnetic is toppled over-filled the water to magnetic-for this
Suction " process operates 4 times repeatedly.For the last time, it is added in the phosphate buffer that pH is 6.0, obtains the moisture of magnetic nano-particle
Dispersion liquid.
(3) 120 parts of 1- (3- dimethylamino-propyl) -3- ethyl carbon two is added in the aqueous dispersions of magnetic nano-particle
Inferior amine salt hydrochlorate and 90 parts of n-hydroxysuccinimide stir 90 minutes at 20 DEG C, and after stirring, magnetic is poured out
Unadsorbed solution adds the double amino-polyethyleneglycols (M for being 7.0 containing 40 parts of pHw=400) phosphate buffer,
It is stirred to react at 20 DEG C 8 hours.After completion of the reaction, magnetic is carried out to dispersion liquid, topples over and remove unadsorbed solution, refills
20 DEG C of deionized water is warming up to 50 DEG C, should " magnetic-is toppled over-water filling-heat up-magnetic " process operate 4 times, had repeatedly
There is core-shell structure magnetic Hydrogel Nanoparticles of temperature-responsive.
The binary graft copolymer that this embodiment is prepared, temperature-responsive unit and function dopamine containing crosslinking points
The mass ratio of monomer is 2.2~1.0；Saturation swelling diameter is 126nm, 45 DEG C of swellings of going down at 15 DEG C of son of magnetic Hydrogel Nanoparticles
Diameter is 114nm.
Embodiment 7
A kind of core-shell structure magnetic Hydrogel Nanoparticles with temperature-responsive, comprises the following steps that (number is equal
For mass parts):
(1) by 30 parts of P (HEMA-C ≡ CH) (degree of polymerization 4000), 40 parts of P (NIPAAm-co-GMA-N3) (the degree of polymerization
It is 10000, crosslinking points monomer and temperature-responsive monomer mole ratio are 42:1000), 9 parts of DOPA-N3Co-dissolve is at 100 part two
In methylacetamide, 0.2 part of NaVc/CuSO is added4, wherein both mass ratio be 5.5:1.0, bubbling inert gas 50 minutes,
It is stirred to react at 60 DEG C later 40 hours, using dialysis, reaction solution is dialysed 16 hours, then is freeze-dried, obtains two
Meta function graft copolymer.
(2) by 100 parts of two meta function graft copolymers and 40 parts of magnetic nano-particle co-dissolve and 40 are dispersed in
In the dimethylbenzene of part, stirring 80 minutes at room temperature, rotary evaporation removes removal xylene, then disperses sediment in deionized water,
Magnetic is carried out to dispersion liquid, topples over and removes unadsorbed solution, refill 25 DEG C of deionized water, " magnetic-is toppled over-infused for this
Water-magnetic " process operates 5 times repeatedly.For the last time, it is added in the phosphate buffer that pH is 7.0, obtains magnetic nano-particle
Aqueous dispersions.
(3) 180 parts of 1- (3- dimethylamino-propyl) -3- ethyl carbon two is added in the aqueous dispersions of magnetic nano-particle
Inferior amine salt hydrochlorate and 120 parts of n-hydroxysuccinimide stir 120 minutes at 25 DEG C, and after stirring, magnetic is toppled over
Unadsorbed solution out adds the double amino-polyethyleneglycols (M for being 7.0 containing 60 parts of pHw=700) phosphate-buffered
Liquid is stirred to react 12 hours at 25 DEG C.After completion of the reaction, magnetic is carried out to dispersion liquid, topples over and remove unadsorbed solution, again
25 DEG C of deionized water of injection, is warming up to 60 DEG C, should " magnetic-is toppled over-water filling-heat up-magnetic " process operate 5 times, obtain repeatedly
To core-shell structure magnetic Hydrogel Nanoparticles with temperature-responsive.
The binary graft copolymer that this embodiment is prepared, temperature-responsive unit and function dopamine containing crosslinking points
The mass ratio of monomer is 2.8:1.0；Saturation swelling diameter is 135nm, 45 DEG C of swellings of going down at 15 DEG C of son of magnetic Hydrogel Nanoparticles
Diameter is 119nm.
Embodiment 8
A kind of core-shell structure magnetic Hydrogel Nanoparticles with temperature-responsive, comprises the following steps that (number is equal
For mass parts):
(1) by 30 parts of P (HEMA-C ≡ CH) (degree of polymerization 6000), 40 parts of P (NIPAAm-co-GMA-N3) (the degree of polymerization
It is 12000, crosslinking points monomer and temperature-responsive monomer mole ratio are 50:1000), 10 parts of DOPA-N3Co-dissolve is at 120 part two
In methylacetamide, 0.2 part of NaVc/CuSO is added4, wherein both mass ratio be 7.5:1.0, bubbling inert gas 60 minutes,
It is stirred to react at 60 DEG C later 48 hours, using dialysis, reaction solution is dialysed 6 hours, then is freeze-dried, obtains binary
Function graft copolymer.
(2) by 120 parts of two meta function graft copolymers and 40 parts of magnetic nano-particle co-dissolve and 40 are dispersed in
In the dimethylbenzene of part, stirring 80 minutes at room temperature, rotary evaporation removes removal xylene, then disperses sediment in deionized water,
Magnetic is carried out to dispersion liquid, topples over and removes unadsorbed solution, refill 25 DEG C of deionized water, " magnetic-is toppled over-infused for this
Water-magnetic " process operates 5 times repeatedly.For the last time, it is added in the phosphate buffer that pH is 8.0, obtains magnetic nano-particle
Aqueous dispersions.
(3) 180 parts of 1- (3- dimethylamino-propyl) -3- ethyl carbon two is added in the aqueous dispersions of magnetic nano-particle
Inferior amine salt hydrochlorate and 120 parts of n-hydroxysuccinimide stir 120 minutes at 25 DEG C, and after stirring, magnetic is toppled over
Unadsorbed solution out adds the double amino-polyethyleneglycols (M for being 8.0 containing 60 parts of pHw=700) phosphate-buffered
Liquid is stirred to react 12 hours at 25 DEG C.After completion of the reaction, magnetic is carried out to dispersion liquid, topples over and remove unadsorbed solution, again
25 DEG C of deionized water of injection, is warming up to 60 DEG C, should " magnetic-is toppled over-water filling-heat up-magnetic " process operate 5 times, obtain repeatedly
To core-shell structure magnetic Hydrogel Nanoparticles with temperature-responsive.
The binary graft copolymer that this embodiment is prepared, temperature-responsive unit and function dopamine containing crosslinking points
The mass ratio of monomer is 3.8:1.0；Saturation swelling diameter is 140nm, 45 DEG C of swellings of going down at 15 DEG C of son of magnetic Hydrogel Nanoparticles
Diameter is 123nm.
Specific embodiment described above, it is intended to which the use that present invention be described in more detail, help further understand this hair
Range that is bright, being not intended to be limiting of the invention.It should be appreciated by those skilled in the art, do not depart from spirit of the invention and
In the case where principle, various modifications and replacement be should all be included in the protection scope of the present invention.
Claims (7)
1. the preparation method of core-shell structure magnetic Hydrogel Nanoparticles with temperature-responsive includes the following steps: (1), closes
At two meta function graft copolymers of the temperature-responsive unit containing efficient absorption unit and containing crosslinking points；
(2), copolymer molecule is adsorbed on magnetic nano-particle surface using the efficient absorption unit in copolymer；
(3) introducing crosslinked agent locks the molecular structure of temperature-responsive unit, forms gel layer；
It is characterized in that, the specific steps are as follows: following number is parts by weight:
(1) by 10 ~ 30 parts of main polymer chain, 20 ~ 40 parts of temperature-responsive units containing crosslinking points, 5 ~ 10 parts of function dopamines
Monomer co-dissolve is in 40 ~ 120 parts of solvent As, 0.05 ~ 0.2 part of catalyst of addition, and bubbling inert gas 10 ~ 60 minutes, later
It is stirred to react at 35 ~ 60 DEG C 6 ~ 48 hours, using dialysis, reaction solution is dialysed 6 ~ 72 hours, then is freeze-dried, is obtained
Two meta function graft copolymers；
(2) it by 60 ~ 120 parts of two meta function graft copolymers and 10 ~ 40 parts of magnetic nano-particle co-dissolve and is dispersed in
It in 10 ~ 40 parts of solvent B, stirs 20 ~ 80 minutes at room temperature, rotary evaporation removes solvent B, then disperses deionization for sediment
In water, magnetic is carried out to dispersion liquid, topples over and removes unadsorbed solution, refill 5 ~ 25 DEG C of deionized water, in the step,
Magnetic-topples over-fills the water-and the process of magnetic operates 2 ~ 5 times repeatedly, and the phosphate buffer that pH is 4.0 ~ 8.0 is added in last time,
Obtain the aqueous dispersions of magnetic nano-particle；
(3) 60 ~ 180 parts of 1- (3- dimethylamino-propyl) -3- ethyl carbon two is added in the aqueous dispersions of magnetic nano-particle
Inferior amine salt hydrochlorate and 30 ~ 120 parts of n-hydroxysuccinimide stir 30 ~ 120 minutes at 5 ~ 25 DEG C, after stirring,
Unadsorbed solution is poured out in magnetic, adds the phosphate buffer containing 5 ~ 60 parts of crosslinking agent that pH is 4.0 ~ 8.0, and 5
It is stirred to react at ~ 25 DEG C 2 ~ 12 hours, after completion of the reaction, magnetic is carried out to dispersion liquid, topples over and removes unadsorbed solution, again
5 ~ 25 DEG C of deionized water of injection, is warming up to 40 ~ 60 DEG C, and in the step, magnetic-, which is toppled over ,-water filling-heats up-and the process of magnetic is anti-
It operates 2 ~ 5 times again, obtains core-shell structure magnetic Hydrogel Nanoparticles with temperature-responsive；
Solvent A is one of dimethyl sulfoxide, dimethylformamide, dimethyl acetamide；
Solvent B is one of methylene chloride, chloroform, toluene, dimethylbenzene；
Function DOPA amine monomers are one of alkynyl dopamine or azido dopamine；
The main polymer chain is that end is the poly (glycidyl methacrylate) of azido, the polyacrylic acid that end is azido
Ethylene oxidic ester, end are the poly hydroxy ethyl acrylate of alkynyl, end be in the hydroxyethyl acrylate of alkynyl one
Kind；
The temperature-responsive unit for containing crosslinking points is the poly-N-isopropyl acrylamide and propylene that end is alkynyl or azido
The random copolymer of acid or end are the poly-N-isopropyl acrylamide and glycidyl methacrylate of alkynyl or azido
Random copolymer；
Crosslinking agent is one of ethylenediamine, double amino-polyethyleneglycols.
2. the preparation method of core-shell structure magnetic Hydrogel Nanoparticles according to claim 1 with temperature-responsive,
It is characterized in that, in the molecular structure of binary graft copolymer, the temperature-responsive unit containing crosslinking points and function dopamine list
Mass ratio between body is between 2.2:1.0 ~ 5.8:1.0.
3. the preparation side of core-shell structure magnetic Hydrogel Nanoparticles according to claim 1 with temperature-responsive
Method, which is characterized in that catalyst is the N that mass ratio is 1:1 ~ 5:1, N, N, N, N- pentamethyldivinyltriamine/stannous chloride
Or mass ratio is sodium ascorbate/copper sulphate of 1.5:1.0 ~ 7.5:1.0.
4. the preparation method of core-shell structure magnetic Hydrogel Nanoparticles according to claim 1 with temperature-responsive,
It is characterized in that, the main polymer chain degree of polymerization is 2000 ~ 6000.
5. the preparation method of core-shell structure magnetic Hydrogel Nanoparticles according to claim 1 with temperature-responsive,
It is characterized in that, the degree of polymerization of the temperature-responsive unit containing crosslinking points be 2000 ~ 12000, including molar ratio be 1:1000 ~
The crosslinking points monomer and temperature-responsive monomer of 50:1000.
6. the preparation side of core-shell structure magnetic Hydrogel Nanoparticles according to claim 1 with temperature-responsive
Method, which is characterized in that the weight average molecular weight of crosslinking agent is 200 ~ 700 Da.
7. a kind of core-shell structure magnetic Hydrogel Nanoparticles with temperature-responsive, which is characterized in that be by claim 1 ~ 6
Described in any item preparation methods obtain.
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