CN104128136B - Micro-nano gel particles and its controllable method for preparing and application - Google Patents

Micro-nano gel particles and its controllable method for preparing and application Download PDF

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CN104128136B
CN104128136B CN201310159738.8A CN201310159738A CN104128136B CN 104128136 B CN104128136 B CN 104128136B CN 201310159738 A CN201310159738 A CN 201310159738A CN 104128136 B CN104128136 B CN 104128136B
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gel particles
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CN104128136A (en
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吴德成
张健
王星
杨飞
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Institute of Chemistry CAS
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Institute of Chemistry CAS
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Abstract

The invention discloses a kind of micro-nano gel particles and its controllable method for preparing and application.The method is the carrying out of the crosslink material reaction by precise control under micro-nano-scale with special core shell structure, individual layer to the controllable preparation of the micro-nano gel particles of multilayer labyrinth is realized, and can finely regulating and the physics and chemical property for optimizing each layer gel particles.The micro-nano gel particles have a wide range of applications in many fields such as drug delivery, organizational project, bio-sensing, bio-imaging, Chemical Decomposition and catalysis, the micro-nano gel particles constructed such as are reset based on cystine linkage has good biocompatibility and biological degradability, is expected to be applied to the fields such as drug delivery and medical diagnosis on disease.

Description

Micro-nano gel particles and its controllable method for preparing and application
Technical field
The present invention relates to a kind of micro-nano gel particles and its controllable method for preparing and application.
Background technology
Colloidal particle or macromolecule in colloidal sol or solution are interconnected under certain condition, form space net structure, It is filled with structural void as the liquid (can also be gas in xerogel) of decentralized medium, the special dispersion of such a System is referred to as gel.Micro-nano gel particles are granular size in micron or the gel particles of Nano grade.
Micro-nano gel particles have been applied since its discovery in extensive field, and such as biological medicine, catalysis is anti- But many shortcomings should be still suffered from the field such as self assembly：(1) poor biocompatibility, need to can be used through processing rear；(2) do not have Standby biological degradability；(3) gel process for preparing of Nano grade is more immature；(4) preparation process is difficult to control to, it is impossible to accurate control The properties such as particle diameter, the degree of cross linking, water imbibition, the surface topography of micro-nano gel particles that system is obtained.Micro-nano gel particles kind Class is various, and two major classes can be divided into according to the degradation property of material：(1) biodegradation type；(2) not biodegradation type.It is existing Micro-nano gel particles belong to nondegradable micrometer gel particle mostly.The micro-nano gel particles of biodegradation type are main Synthesized using the degradable raw material that clinical medicine is proved and is used widely now, generally can by its material source It is divided into natural and two major classes of synthesis：(1) natural degradable macromolecule include polysaccharide (starch, cellulose, alginic acid, thoroughly Bright matter acid and chitin etc.) and polypeptide (collagen etc.) etc.；(2) the degradable macromolecule of synthesis includes polyester (lactic acid, ethanol Acid, the homopolymers of 6-caprolactone and their copolymer), polyurethane, polyaminoacid and its derivative species etc..
The technology for preparing micro-nano gel particles is a lot, including preparation technique of liquid phase, template fabrication techniques, fluid preparation skill Art, vacuum spray drying technology, technology of membrane technology, and various method use in conjunction excessively etc..Preparation technique of liquid phase can be divided into Emulsion method and self-assembly method, advantage are ripe methods, are widely used, and using molecular specific property, can prepare Various Complex structure Deng defect is the more difficult regulation and control of process, and intuitive is not strong, it is difficult to accuracy controlling etc..Template fabrication techniques can be divided into stamping method and micro- Mould prepares method, and advantage is directly perceived, and simply, outward appearance is various etc., and defect is to be limited by template, and difficulty realizes nanoscale gel particles Prepare, internal difficult realization of labyrinth regulation and control etc..Fluid preparation method is the method that micro-nano gel is prepared in the liquid of flowing, Advantage is directly perceived, and simply, outward appearance is various, and preparation amount is big etc., and defect is by equipment limit, it is difficult to realize nanoscale gel system Standby, internal labyrinth regulation and control are difficult to be realized.It is adapted to prepare the gel particles of particular/special requirement in addition with some technologies of preparing, is applicable In particular polymers etc., but generally existing Modulatory character is not strong, the wideless shortcoming of range of application.Technology above can be prepared not Same material, particle diameter from several nanometers to hundreds of microns, in single structure or loose structure, with spherical, bar-shaped, tabular, disk like, The different shapes such as taper, different structure, different size of micro-nano gel particles, can also prepare with one or more materials, be in The micro-nano gel particles of composite construction of single or multiple lift structure, to meet various different biological medicines, catalytic reaction and from group The need for the application such as dress.But prior art cannot realize the single or multiple lift structural gel particle under micro-nano-scale can Control it is standby, and gel particles physics and the accuracy controlling of chemical property, thus urgently need development one kind can realize Under micro-nano-scale can accuracy controlling physics and chemical property gel particles customization new preparation technology.
The content of the invention
It is an object of the invention to provide a kind of micro-nano gel particles and its controllable method for preparing and application.
Individual layer or the double-deck or three layers or n+3 layers controllable method for preparing of micro-nano gel particles that the present invention is provided, be as Under shown in (one), (two), (three) or (four)：
(1) method for preparing the micro-nano gel particles of individual layer, comprises the following steps：
1) the polymer I with core shell structure is prepared, in the polymer I of the core shell structure, core is with shell by stimulating The lower chemical bond connection reset of response；
2) by step 1) resulting polymers I forms polymer solution in being scattered in medium, makes the core of the composition polymer I Material cross-links react and make the shell parts of the composition polymer or leave away completely, control the cross-linking reaction when Between regulate and control the particle diameter of micro-nano gel particles, obtain the micro-nano gel particles of individual layer；
(2) method for preparing double-deck micro-nano gel particles, comprises the following steps：
3) to methods described (one) step 2) in the aqueous solution or polymer of polymer I are added in system after cross-linking reaction The aqueous solution of II, carries out cross-linking reaction and makes the shell parts of the composition polymer I or II or leave away completely, and by control The particle diameter of the micro-nano gel particles of time-controllable of cross-linking reaction, obtains double-deck micro-nano gel particles；
The polymer II is the polymer with core shell structure, wherein, core is with shell by the rearrangement under stimuli responsive Chemical bond is connected；
(3) three layers of method of micro-nano gel particles are prepared, is comprised the following steps：
4) to step 3 described in methods described (two)) in add in system after cross-linking reaction polymer I the aqueous solution or The aqueous solution of polymer II or the aqueous solution of polymer III, carry out cross-linking reaction and constitute the polymer I or II or III Shell parts or leave away completely, and by controlling the particle diameter of the micro-nano gel particles of the time-controllable of cross-linking reaction, obtain three layers Micro-nano gel particles；
The polymer III is the polymer with core shell structure, wherein, core is with shell by the rearrangement under stimuli responsive Chemical bond is connected；
(4) the n+3 layers of method of micro-nano gel particles is prepared, is comprised the following steps：
4 the step of methods described (three)) after, repeating said steps 4) n times, obtain n+3 layers of micro-nano gel particles； The n is natural number.
The preparation method with special Core-shell structure material that the invention described above is provided, is first each synthetic kernel and shell material Material, by the surface modification and the terminal groups modification of shell of core, through the chemical bond that appropraite condition will be reset between nucleocapsid by stimuli responsive Connection, forms the segregative special material of nucleocapsid.
The step of above method 1) in, the chemical bond reset under stimuli responsive is cystine linkage, double selenium keys or schiff bases key；
The step 2) -4) in, polymer is respectively formed micro-nano drop in the polymer solution；
Cross-linking reaction can be carried out by regulating and controlling environmental stimuli response；The environmental stimuli is accordingly chosen in particular from light stimulus, temperature At least one in degree stimulation, acid or the stimulation of alkali stimulation, electrical field stimulation, magnetic stimulation, ultrasound stimulation and biologically functional molecule.Core Between PJ and shell PL by stimuli responsive reset chemical bond connected, as photosensitive, temperature-sensitive, soda acid sensitivity, electroresponse, magnetic response, Ultrasound and the chemical bond of biomolecule response.By regulating and controlling environmental stimuli such as light, temperature, soda acid, electric field, magnetic field, ultrasound and life Thing functional molecular, separation that is inducible, terminating and excite again nucleocapsid causes leaving away for the Controllable cross-linking of core and shell, so as to realize The controllable preparation of gel.
The step 2) in, medium is water；
Mass percent concentrations of the polymer I in the aqueous solution of polymer I be 30-50%, specially 35%, 38%th, 40%, 41%, 43%, 44%, 45%, 50%, 35-50%, 40-50%, 30-45% or 35-45%；
Mass percent concentrations of the polymer II in the aqueous solution of polymer II be 30-50%, specially 35%, 38%th, 40%, 41%, 43%, 44%, 45%, 50%, 35-50%, 40-50%, 30-45% or 35-45%；
Mass percent concentrations of the polymer III in the aqueous solution of polymer III is 30-50%, specially 35%th, 38%, 40%, 41%, 43%, 44%, 45%, 50%, 35-50%, 40-50%, 30-45% or 35-45%.
If before environmental stimuli is implemented, by suitable dispersions technology such as (anti-phase) emulsion method, self-assembly method, micro-nano imprint System micro-nanoization is such as separated into micro-nano drop by the means such as method, micro-nano method of molding and micro-nano flow process, is then applied again Plus and regulation and control environmental stimuli, induced under micro-nano-scale, terminate and excite the separation of nucleocapsid again, cause the Controllable cross-linking of core and Shell is left away, so as to realizing the controllable preparation of micro-nano gel particles.
In the polymer I, polymer II and polymer III, core is selected from three arm polymer, multiarm polymers, tree-like At least one in polymer, natural polymer, inorganic nano-particle, metal nanoparticle and metal oxide nanoparticles；
It is chosen in particular from ultrabranching polyamide, hyperbranched poly amido acid amides, hyper-branched polyester, hyperbranched polyamine base ester, branch Shape polyamide, dendroid polyamine group acid amides (PAMAM), hyperbranched poly acrylamide (poly (BAC2-AEPZ1)), dendroid are gathered Ester, dendroid polyamine base ester, star multi-arm polystyrene (Star-PS), star multi-arm PNIPAM (Star- PNIPAM), star multi-arm methyl methacrylate (Star-PMMA), poly- cagelike silsesquioxane (POSS), solid or hollow receive At least one in rice silicon ball (SiNPs), gold and silver nano-particle (AuNPs, AgNPs) and ferroferric oxide magnetic nano-particles；
More specifically weight average molecular weight be 1.7 ten thousand poly (BAC2-AEPZ1), the PNIPAM that weight average molecular weight is 2000, Weight average molecular weight is 5000 PS or with symmetrical 8 arm cagelike structures and a diameter of 2 nanometers and weight average molecular weight is 1008 POSS；
The weight average molecular weight of the three arms polymer, multiarm polymers and tree shaped polymer is 300 to 1,000 ten thousand, specifically It is 1,000 to 500,000, more specifically 5,000 to 100,000, more specifically weight average molecular weight is 20112 PAMAM forth generations dendroid point Son；
The particle diameter of the inorganic nano-particle, metal nanoparticle and metal oxide nanoparticles is 1 nanometer to 500 micro- Rice, specially 1 nanometer to 50 microns, more specifically more specifically 1 nanometer to 1 micron, 12 nanometers；
In the polymer I, polymer II, polymer III, the shell is selected from hydrophilic or hydrophobic linear and branched polymeric At least one in thing；
Described hydrophilic or hydrophobic linear or branched polymer weight average molecular weight is 100 to 1,000,000, specially 3 hundred to 5 Ten thousand, more specifically 500 to 5,000；
It is chosen in particular from polyethylene glycol (PEG), polyacrylic acid (PAA), polymethylacrylic acid (PMAA), polymethylacrylic acid hydroxyl Ethyl ester, CMS (CMS), acetic starch, carboxymethylcellulose calcium (CMC), polyacrylamide (PAM), hydrolysis polyacrylamide Amine, poly, poly-aspartate (PASP), poly-epoxy succinic acid (PESA), cellulose ether, chitin, xanthans and plant At least one in glue；
More specifically weight average molecular weight is 500 to 5,000 or 750-1000 or 750-2000 or 750-3200 or 2000-3200 PEG, weight average molecular weight for 1200-3200 PAA, the CMS that weight average molecular weight is 5000, the PASP that weight average molecular weight is 600 Or the PESA that weight average molecular weight is 1000；
The step 1) gained have core shell structure polymer P J-PL concretely poly (BAC2-AEPZ1)-CMS, poly(BAC2-AEPZ1)-PAA、poly(BAC2-AEPZ1)-PEG、poly(BAC2-AEPZ1)-PMAA、PAMAM-PASP、 PAMAM-PESA、POSS-PAM、POSS-PEG、Star-PS-PEG、Star-PS-CMC、Star-PNIPAM-PESA、SiNPs- At least one in PEG, AuNPs-PAA, AuNPs-PEG, AgNPs-PAA and AgNPs-PEG；
More specifically, the polymer P J-PL is with 4 arm and to be weight average molecular weight be 2000 per arm The weight average molecular weight of PNIPAM and PESA is 1000 Star-PNIPAM-SeSe-PESA, attaches most importance to 4 arm and per arm Average molecular weight be 5000 PS and PEG weight average molecular weight be 2000 Star-PS-PEG or poly (BAC2-AEPZ1)-CMS；
Wherein, in poly (BAC2-AEPZ1)-PAA, the weight average molecular weight of core poly (BAC2-AEPZ1) is 5,000 to 30,000, The weight average molecular weight of more specifically 1.7 ten thousand, shell PAA is 500 to 5,000, more specifically 1200-3200；
In poly (BAC2-AEPZ1)-PEG, the weight average molecular weight of core poly (BAC2-AEPZ1) is 5,000 to 30,000, more Body is 1.7 ten thousand, and the weight average molecular weight of shell PEG is 500 to 5,000, more specifically 750-1000 or 750-2000 or 750-3200 Or 2000-3200.
In methods described (), (two), (three) or (four), the pH value of the system of the cross-linking reaction is 7-14, specifically Can for 12,12.8,13.3,13.5,13.9,12-14,12.8-13.9 or 13.3-14；
The time of the cross-linking reaction be 1-24 hours, specially 1,2,4,6,8,16,20,24,2-24,4-20,6-16, 8-24,2-20,4-24 or 8-20 hour；
In methods described (), (two), (three) or (four), the system of the cross-linking reaction by the polymer solution, Organic solvent and surfactant are constituted；
The step 2) to step 4) cross-linking reaction in, micro-nano drop is generally stablized using surfactant；It is described Surfactant is selected from fatty glyceride, fatty acid sorbitan (sapn), polysorbate (tween), lecithin, amino acid, sweet At least one in dish alkali and quaternary ammonium compound, is chosen in particular from least one in span80 and tween80.
The raw material of composition core, the raw material for constituting shell, the amount ratio between surfactant and solvent need not be limited, and only be needed The cross-linking system of stabilization can be formed.
The step 2) to step 4) in dispersion steps, scattered method is selected from emulsion method, antiphase emulsifiable method, self assembly At least one in method, micro-nano imprint method, micro-nano method of molding and micro-nano flow process.Above-mentioned process for dispersing is conventional side Method.
In methods described (), (two), (three) or (four), after cross-linking reaction completion, also comprise the following steps： System after cross-linking reaction is neutralized to neutrality, is centrifuged, remove upper oil phase, remove a layer emulsion.
The individual layer or double-deck or three layers or n+3 layers of micro-nano gel particles for preparing according to the method described above, fall within this The protection domain of invention.Wherein, the n is natural number.The pattern of the particle is spherical, bar-shaped, tabular, disk like or taper； Particle diameter is 5 nanometers to 900 microns.The particle diameter is the particle diameter after conventionally vacuum drying.
Specifically, the particle diameter of the micro-nano gel particles of individual layer concretely 79nm, 82nm, 111nm, 130nm, 133nm、150nm、155nm、190nm、16μm、28μm、32μm、50μm、85μm、79nm-85μm、150-190nm、82nm-50μ M, 111nm-32 μm, 130nm-28 μm or 133nm-16 μm；
In the double-deck micro-nano gel particles, the diameter of core can be 40-100nm, more specifically can be 80-100nm；Shell Thickness is 40-150nm, more specifically can be 100nm or 150nm；
In three layers of micro-nano gel particles, concretely 70nm-75 μm, 70nm-45 μm or 45 μm -75 of the diameter of innermost layer μm, concretely 80nm-85 μm, 80nm-45 μm or 45 μm -85 μm of the thickness in intermediate layer, outermost thickness is concretely 100nm-110 μm, 100nm-80 μm or 80 μm -110 μm.
Further certain layer will wherein be corroded by methods such as light, heat or chemical attacks, can obtain more more complicated multilayers Different engraved structures.
Material used can be the mixture of one pack system or several components in each layer, can be identical, also can be different.Each layer pattern Structure can be spherical, bar-shaped, tabular, disk like, taper, and the pattern of different layers can be identical, also can be different.Every layer of thickness is received for several Rice can freely be adjusted to hundreds of microns according to needs.
Each layer of physics and chemical property can be selected by MOLECULE DESIGN, material in gel particles, cross-linking system is selected Select and the factor such as degree of cross linking control realizes regulation and control, physics and chemical property include that pattern, density, water imbibition, medicine are released here Put speed, degradation time, color, fusing point, photosensitive, temperature-sensing property, INFRARED ABSORPTION, UV absorption, fluorescent characteristic etc..
The micro-nano gel particles that the invention described above is provided are in drug controlled release, organizational project, catalytic reaction or material Application in purifying, falls within protection scope of the present invention.
Specifically, illustrating the micro- of present invention offer by taking the material of the core shell structure of the sensitive cystine linkage connection of soda acid as an example The controllable method for preparing of nanogel particle.
The mechanism of crosslinking of such material is sulfydryl cystine linkage exchange reaction, due to the structure and performance difference of nucleocapsid, ECDC Reason design, is capable of achieving unidirectional exchange, causes the orderly separation of core and shell：The crosslinking of core and leaving away for shell.
The method is specifically sulfydryl anion attack cystine linkage in the basic conditions, forms new sulfydryl anion and double sulphur Key, trigger in the process nucleocapsid separation-shell leave away and core crosslinking, the degree of cross linking of gel structure gradually increases with the time, And nucleocapsid separation process stops, that is, the loose gel material of the low crosslinking degree stablized as system pH is reduced to neutrality Material；Loose gel material is alkalized again, said process can continue generation again, can obtain the firming gels material of high-crosslinking-degree, Therefore cross-linking process is the controllable crosslinking of activity in situ.Can be dispersed into largely relatively steady by solution using the method for emulsion dispersion Fixed micro-nano droplet, regulates and controls the acid-base value control cross-linking reaction process of micro-nano drop, realizes micro-nano gel particles Controllable preparation.The wherein physics and chemical property of gel particles such as structure, pattern, particle diameter etc. can be simply by control system soda acid Degree and crosslinking time carry out finely regulating.Meanwhile, prepare the micro- of difference in functionality also by the material of selection different IPs or shell structure Nanogel particle.
On this basis, with gel particles as seed, another component is added in system, can is same material or not Same material, controls the crosslinking time and system acid-base value of each component, can obtain the micro-nano gel particles of two-layer.
Similarly, with the micro-nano gel particles of this double-layer structure as seed, then third component is added in system, controls each layer Crosslinking time and system acid-base property, three layers of micro-nano gel particles can be obtained.
The rest may be inferred, can obtain the micro-nano gel particles of more layers.
The micro-nano gel particles that the present invention is provided, specially designed to may be such that core and shell are respectively provided with good biological compatible Property, the micro-nano gel particles of gained are crosslinked by the chemical bond such as cystine linkage, and cystine linkage under extracellular environment can stable existence, But it is broken so as to realize the disintegration of gel particles under the glutathione effect in the cell, so the method can prepare biological drop Micro-nano gel particles of the individual layer of solution type to multilayer labyrinth.By regulating and controlling and optimize the thing of each layer each component of gel particles Reason and chemical property such as degradability, particle diameter etc., are expected to be widely applied in the acquirement of the aspect such as drug delivery and medical diagnosis on disease.
The present invention is that have entering for the crosslink material reaction of special core shell structure by precise control under micro-nano-scale OK, individual layer to the preparation of the micro-nano gel particles of multilayer labyrinth is realized, and can finely regulating and each layer gel particles of optimization The physics and chemical property of son.The micro-nano gel particles drug delivery, bio-sensing, bio-imaging, Chemical Decomposition and Many fields such as catalysis have a wide range of applications, and the micro-nano gel particles constructed such as are reset based on cystine linkage has good life Thing compatibility and biological degradability, are expected to be applied to the fields such as drug delivery and medical diagnosis on disease.
Brief description of the drawings
Fig. 1 is the relation of the nanogel particle diameter that dynamic light scattering is characterized and crosslinking time.
Fig. 2 is the transmission electron microscope photo of nanogel particle that crosslinking time is 1,4 and 16 hours.
Fig. 3 is the relation of the nanogel particle diameter that AFM is characterized and crosslinking time.
Fig. 4 is the nanogel particle degraded transmission electron microscope photo that changes with crosslinking time of situation of different crosslinking times.
Fig. 5 is the crosslinking time nanogel particle of 1 hour in a) BHK21, b) HEK293 and c) survival in L929 cells The relation of rate and particle concentration.
Fig. 6 is the transmission electron microscope photo of the different crosslinking time bilayer spherical degradable nanogels of bi-component layer by layer, its In, a is that internal layer is crosslinked the double-deck nucleocapsid nanogel particle that 6 hours-outer layer is crosslinked 1 hour, and b is that internal layer is crosslinked 6 hours-outer layer The double-deck nucleocapsid nanogel particle of crosslinking 2 hours.
Specific embodiment
With reference to specific embodiment, the present invention is further elaborated, but the present invention is not limited to following examples.Institute State method and be conventional method unless otherwise instructed.The raw material can be obtained from open commercial sources unless otherwise instructed. Molecular weight unless otherwise instructed, is weight average molecular weight described in following embodiments.
Embodiment 1, prepare the micro-nano gel particles of individual layer
1) the polymer P J with core shell structure is preparedI-PLINamely poly (BAC2-AEPZ1)-PEG：
Core PJ will be prepared in methyl alcoholIRaw material namely N, N '-bis- acryloyl cystamines (BAC, 20mmol) and N- aminoethyls Piperazine (AEPZ, 10mmol) mixing is heated to 50 DEG C and reacts 6 days, adds and prepares shell PLIRaw material amido polyethylene glycol (PEG- NH2, 15mmol), be heated to 60 DEG C react 7 days, in a large amount of ether precipitate, then by sediment with a small amount of methyl alcohol dissolving after, in Volume ratio is to carry out protonation reaction 5 minutes in 1: 20 concentrated hydrochloric acid and the mixed liquor of acetone, will be between core and shell with double sulphur Key is connected together, collect gained precipitation vacuum drying obtain the polymer poly (BAC2-AEPZ1) with core shell structure- PEG, is designated as PJI-PLI。
The polymer has crosslinkable core PJIPoly (BAC2-AEPZ1), molecular weight is 1.7 ten thousand, and the shell that can be left away PLIThe molecular weight of PEG, single PEG is 750, is connected with each other by cystine linkage between nucleocapsid, while the polymer has biological drop The characteristic of solution.
2) the micro-nano gel particles of individual layer are prepared：
By step 1) gained PJI-PLINamely poly (BAC2-AEPZ1)-PEG is dispersed in water and obtains PJI-PLIIt is water-soluble Liquid, PJI-PLIMicro-nano drop is formed in water, its mass percentage concentration is 40%；
N-decane, the surfactant span80 and tween80 solution that constitutes of the 31mL by mass ratio for 98: 1: 1 are prepared, Wherein, n-decane is organic solvent and dispersed phase, and setting speed of agitator is 1400rpm, and 31 μ L gained is added in this solution PJ1-PLIThe aqueous solution, the pH value for adding appropriate 5M NaOH regulation systems is 12.1, cross-linking reaction after 1 hour will crosslinking it is anti- Gained emulsion system is answered to pour into 4mL saturations NH4In the aqueous solution of Cl, neutralization reaction system to neutrality, with the rotating speed of 1000rpm from The heart 1 minute, removes upper oil phase, and lower floor's emulsion dialysis 3 days in water obtain the micro-nano gel particles of individual layer.
The hydrodynamic radius of the micro-nano gel particles of the individual layer are 800nm, a diameter of 190nm after vacuum drying, are filled The a diameter of 850nm divided after water suction.
Prepare the micro-nano gel particles of individual layer according to upper identical method, crosslinking time is only replaced with 2,4,8, 16 and 24 hours.
Gained crosslinking time is that the hydrodynamic radius of the micro-nano gel particles of individual layer of 2 hours are 610nm, vacuum drying A diameter of 736nm after a diameter of 155nm afterwards, fully water suction；
Gained crosslinking time is that the hydrodynamic radius of the micro-nano gel particles of individual layer of 4 hours are 470nm, vacuum drying A diameter of 510nm after a diameter of 133nm afterwards, fully water suction；
Gained crosslinking time is that the hydrodynamic radius of the micro-nano gel particles of individual layer of 8 hours are 272nm, vacuum drying A diameter of 368nm after a diameter of 111nm afterwards, fully water suction；
Gained crosslinking time is that the hydrodynamic radius of the micro-nano gel particles of individual layer of 16 hours are 122nm, and vacuum is done A diameter of 199nm after a diameter of 82nm after dry, fully water suction；
Gained crosslinking time is that the hydrodynamic radius of the micro-nano gel particles of individual layer of 24 hours are 112nm, and vacuum is done A diameter of 173nm after a diameter of 79nm after dry, fully water suction.
Dynamic light scattering (DLS) table of embodiment gained poly (BAC2-AEPZ1) micro-nano gel particles of-PEG individual layers Levy result statistics as shown in Figure 1.
As seen from the figure, by controlling different crosslinking times, the individual layer that hydrodynamic radius are 180-850nm can be obtained Micro-nano gel particles, crosslinking time is more long, and the particle diameter of the micro-nano gel particles of gained is smaller, therefore can freely adjust as needed The properties such as the degree of cross linking and hydrodynamic radius of the micro-nano gel particles of individual layer.
Transmission electron microscope (TEM) photo of embodiment gained poly (BAC2-AEPZ1) micro-nano gel particles of-PEG individual layers As shown in Fig. 2 from left to right crosslinking time is followed successively by the gel particles of 1,4 and 16 hours.
As seen from the figure, by controlling different crosslinking times, a diameter of 79-190nm's after being vacuum dried The micro-nano gel particles of individual layer with the property such as the different degrees of cross linking and particle diameter.
The AFM (AFM) of embodiment gained poly (BAC2-AEPZ1) micro-nano gel particles of-PEG individual layers Characterization result count as shown in figure 3, be gel particles particle diameter with crosslinking time 1-24 hour change curve.
As seen from the figure, by controlling different crosslinking times, can obtain a diameter of 180-850nm's after fully water suction The micro-nano gel particles of individual layer with the property such as the different degrees of cross linking and particle diameter.
The transmission electricity of the degraded situation of embodiment gained poly (BAC2-AEPZ1) micro-nano gel particles of-PEG individual layers Mirror (TEM) photo is as shown in figure 4, for nanogel particle that crosslinking time from top to bottom is followed successively by 1,8 and 24 hours is degraded feelings The photo that condition changes with crosslinking time.
As seen from the figure, by controlling different crosslinking times, can obtain what the degradable time was incremented by with crosslinking time The micro-nano gel particles of individual layer, can freely adjust degradation time and palliating degradation degree of the micro-nano gel particles of individual layer etc. as needed Property.
The cytotoxicity very little of embodiment gained poly (BAC2-AEPZ1) micro-nano gel particles of-PEG individual layers, a) BHK21, b) HEK293and c) cell survival rate is dense in L929 (be purchased from Beijing consonance cell resource center) cell culture Line of writing music is as shown in Figure 5, it was demonstrated that in the method, by controlling different crosslinking times, can obtain biocompatibility fine The micro-nano gel particles of individual layer.
Can to sum up obtain, the water imbibition that the embodiment prepares gained individual layer nanogel particle has with the increase of crosslinking time And regular reduction, and according to profit phase and the difference of surfactant, by controlling different crosslinking times, can be had There is the nanogel particle of different water imbibitions.
Embodiment 2, prepare the micro-nano gel particles of individual layer
1) POSS-PEG is prepared：
1mmol mercapto-polyglycols (PEG-SH, can be from open approach purchase) are mixed in first with the pyridine of bis- sulphur of 6mmol two Be heated in alcohol 50 DEG C reaction 5 days after, in a large amount of ether precipitate.By 1mmol sediments and the sulfydryls of 20mmol eight after purified POSS(POSS-(SH)8, can be from open approach purchase) mix in chloroform after be heated to 50 DEG C of reactions 7 days after, in a large amount of ether Middle precipitation, vacuum drying obtains the polymer P OSS-PEG with core shell structure, is designated as PJI-PLI。
The polymer has crosslinkable core PJIThe POSS and shell PL that can be left awayIPEG, it is mutual by cystine linkage between nucleocapsid Connection, core POSS is 8 symmetrical arm cagelike structures, and a diameter of 2 nanometers, molecular weight is 1008, and the molecular weight of shell PEG is 1000, The polymer has biodegradable characteristic simultaneously.
2) the micro-nano gel particles of individual layer are prepared：
By step 1) gained PJI-PLINamely POSS-PEG is dispersed in water and obtains PJI-PLIThe aqueous solution, PJI-PLI Micro-nano drop, PJ are formed in waterI-PLIMass percentage concentration in aqueous is 30%；
Prepare 32mL by mass ratio for 98: 1: 1 n-decane (organic solvent and dispersed phase) and surfactant span80 And the solution of tween80 compositions, setting speed of agitator is 1000rpm, and 30 μ LPJ are added in this solutionI-PLIThe aqueous solution, plus It is 13.5 to enter the pH value of appropriate 5M NaOH regulation systems, and cross-linking reaction neutralisation reaction system after 2 hours will also be crosslinked Reaction gained emulsion pours into 4mL saturations NH4In Cl solution, it is centrifuged 1 minute with the rotating speed of 1000rpm, removes upper oil phase, lower floor Emulsion dialysis 3 days in water, obtain the micro-nano gel particles of individual layer.
The hydrodynamic radius of the micro-nano gel particles of the individual layer are 600nm, a diameter of 150nm after vacuum drying, are filled The a diameter of 730nm divided after water suction.
Embodiment 3, prepare the micro-nano gel particles of individual layer
1) the polymer P J with core shell structure is preparedI-PLINamely PAMAM-PASP：
1mmolPAMAM and 20mmol3,3 '-two hydrogen-oxygen quinolines acid (can be from open approach purchase) are obtained by amidation process The product for arriving, by carrying out amidation process again with 20mmolPASP after purification of dialysing, after dialysing 2 days, vacuum drying is had There is the polymer P AMAM-PASP of core shell structure, be designated as PJI-PLI；
In the polymer, core PAMAM is forth generation dendrimer, and molecular weight is 20112, and the molecular weight of shell PASP is 600。
The polymer has crosslinkable core PJIThe PAMAM and shell PL that can be left awayIPASP, passes through cystine linkage phase between nucleocapsid Connect, while the polymer has biodegradable characteristic.
2) the micro-nano gel particles of individual layer are prepared：
By step 1) gained PJI-PLINamely PAMAM-PASP is dispersed in water and obtains PJI-PLIThe aqueous solution, PJI-PLI Micro-nano drop, PJ are formed in waterI-PLIMass percentage concentration in aqueous is 35%；
Prepare 33mL by mass ratio for 98: 1: 1 n-decane (organic solvent and dispersed phase) and surfactant span80 And the solution of tween80 compositions, setting speed of agitator is 900rpm, and 29 μ LPJ are added in this solutionI-PLIThe aqueous solution, plus It is 14 to enter the pH value of appropriate 5M NaOH regulation systems, and cross-linking reaction neutralisation reaction system after 4 hours will also be crosslinked anti- Gained emulsion is answered to pour into 4mL saturations NH4In Cl solution, it is centrifuged 1 minute with the rotating speed of 1000rpm, removes upper oil phase, lower floor's breast Liquid dialysis 3 days in water, obtain the micro-nano gel particles of individual layer.
The hydrodynamic radius of the micro-nano gel particles of the individual layer are 500nm, a diameter of 130nm after vacuum drying, are filled The a diameter of 510nm divided after water suction.
Embodiment 4, prepare the micro-nano gel particles of individual layer
1) the polymer P J with core shell structure is preparedI-PLINamely Star-PNIPAM-SeSe-PESA：
The COOH-PNIPAM-SH that the method being polymerized using reversible addion-fragmentation chain transfer is prepared, with pentaerythrite Can reach the core of four arms after reaction, then with 2,2 '-two selenium diethanols, maleic anhydride and PESA esterifications, it is purified simultaneously The polymer Star-PNIPAM-SeSe-PESA with core shell structure can be obtained after vacuum drying, PJ is designated asI-PLI。
The polymer has 4 arm, and the PNIPAM that molecular weight is 2000 is per arm, and the molecular weight of PESA is 1000.
The polymer has crosslinkable core PJIThe PNIPAM and shell PL that can be left awayIPESA, by double selenium between nucleocapsid Key is connected with each other, while the polymer has biodegradable characteristic.
2) the micro-nano gel particles of individual layer are prepared：
By step 1) gained PJI-PLINamely Star-PNIPAM-SeSe-PESA is dispersed in water and obtains PJI-PLIWater Solution, PJI-PLIMicro-nano drop, PJ are formed in waterI-PLIMass percentage concentration in aqueous is 40%；
N-hexane, the span80 and tween80 solution that constitute of the 50mL by mass ratio for 96: 2: 2 are prepared, ultrasound work(is set Rate is 220 watts, and 36 μ LPJ are added in this solutionI-PLIThe aqueous solution, the pH value for adding appropriate 5M NaOH regulation systems is 14, cross-linking reaction neutralisation reaction system after 1 hour, also will cross-linking reaction gained emulsion pour into 4mL saturations NH4Cl solution In, it is centrifuged 1 minute with the rotating speed of 1000rpm, upper oil phase is removed, lower floor's emulsion dialysis 3 days in water obtain individual layer micro-nano Gel particles.
The hydrodynamic radius of the micro-nano gel particles of the individual layer are 600nm, a diameter of 150nm after vacuum drying, are filled The a diameter of 450nm divided after water suction.
Embodiment 5, prepare the micro-nano gel particles of individual layer
1) the polymer P J with core shell structure is preparedI-PLINamely AuNPs-PAA, wherein, AuNPs is gold nano grain：
Preparing surface with cysteamine reaction by AuNPs first has the gold nano grain AuNPs-SH of sulfydryl, so The method being polymerized using reversible addion-fragmentation chain transfer afterwards prepares PAA-SH, and it is rubbed with the pyridine of two sulphur two according to 1: 6 You are reacted at ratio, and products therefrom is fully reacted with AuNPs-SH again, can be obtained with core after purified and vacuum drying The polymer AuNPs-PAA of shell structure, is designated as PJI-PLI；
In the polymer, core is the golden nanometer particle of a diameter of 12nm, and shell is PAA, and molecular weight is 3200.
The polymer has crosslinkable PJIThe AuNPs and shell PL that can be left awayIIt is mutual by cystine linkage between PAA nucleocapsids Connection, while the polymer has biodegradable characteristic.
2) the micro-nano gel particles of individual layer are prepared：
By step 1) gained PJI-PLINamely AuNPs-PAA is dispersed in water and obtains PJI-PLIThe aqueous solution, PJI-PLI Micro-nano drop, PJ are formed in waterI-PLIMass percentage concentration in aqueous is 40%；
Hexamethylene, the span80 and tween80 solution that constitute of the 3.5mL by mass ratio for 90: 5: 5 are prepared, sets ultrasonic Power is 400 watts, and 55 μ LPJ are added in this solutionI-PLIThe aqueous solution, add the pH value of appropriate 5M NaOH regulation systems It is 12.8, cross-linking reaction neutralisation reaction system after 1 hour stops stirring, stands 1 minute, removes supernatant liquid, precipitation dispersion In 4mL saturations NH4In Cl solution, gained suspension stirs dialysis 3 days in water, obtains the micro-nano gel particles of individual layer.
The hydrodynamic radius of the micro-nano gel particles of the individual layer be 77 μm, a diameter of 16 μm after vacuum drying, fully A diameter of 78 μm after water suction.
Embodiment 6, prepare the micro-nano gel particles of individual layer
1) the polymer P J with core shell structure is preparedI-PLINamely Star-PS-PEG：
The method being polymerized using reversible addion-fragmentation chain transfer prepares COOH-PS-SH, after pentaerythrite reaction The core of four arms is can reach, the exchange reaction of sulfydryl disulfide bond is then carried out with the PEG-SH being modified with the pyridine of two sulphur two, passed through The polymer Star-PS-PEG with core shell structure can be obtained after purifying and being vacuum dried, PJ is designated asI-PLI
The polymer has 4 arm, and the PS that molecular weight is 5000 is per arm, and the molecular weight of PEG is 2000.
The polymer has crosslinkable core PJIThe Star-PS and shell PL that can be left awayIPEG, by double sulphur between nucleocapsid Key is connected with each other, while the polymer has biodegradable characteristic.
2) the micro-nano gel particles of individual layer are prepared：
By step 1) gained PJI-PLINamely Star-PS-PEG is dispersed in water and obtains PJI-PLIThe aqueous solution, PJI-PLI Micro-nano drop, PJ are formed in waterI-PLIMass percentage concentration in aqueous is 40%；
Hexamethylene, the span80 and tween80 solution that constitute of the 3.5mL by mass ratio for 90: 5: 5 are prepared, sets ultrasonic Power is 260 watts, and 40 μ L PJ are added in this solutionI-PLIThe aqueous solution and the μ L of assistant crosslinking agent ethylenediamine 1, add appropriate 5M The pH value of NaOH regulation systems is 14, cross-linking reaction neutralisation reaction system after 8 hours, namely stops stirring, stands 1 minute, Supernatant liquid is removed, precipitation is scattered in 4mL saturations NH4In Cl solution.Gained suspension stirs dialysis 3 days in water, obtains list The micro-nano gel particles of layer.
The hydrodynamic radius of the micro-nano gel particles of the individual layer be 311 μm, a diameter of 50 μm after vacuum drying, fully A diameter of 300 μm after water suction.
Embodiment 7, prepare individual layer and double-deck micro-nano gel particles
1) the polymer P J with core shell structure is preparedI-PLINamely poly (BAC2-AEPZ1)-PEG：
The step is with the step 1 of embodiment 1)；
2) the micro-nano gel particles of individual layer are prepared：
By step 1) gained PJI-PLINamely poly (BAC2-AEPZ1)-PEG is dispersed in water and obtains PJI-PLIIt is water-soluble Liquid, PJI-PLIMicro-nano drop, PJ are formed in waterI-PLIMass percentage concentration in aqueous is 44%；
Prepare 34mL by mass ratio for 98: 1: 1 n-decane (organic solvent and dispersed phase) and surfactant span80 And the solution of tween80 compositions, setting speed of agitator is 1500rpm, and 30 μ L PJ are added in this solutionI-PLIThe aqueous solution, The pH value for adding appropriate 5M NaOH regulation systems is 12.8, cross-linking reaction neutralisation reaction system after 6 hours, namely is stopped Stirring, stands 1 minute, removes supernatant liquid, and precipitation is scattered in 4mL saturations NH4In Cl solution.Gained suspension is stirred in water Dialysis 3 days, obtains the micro-nano gel particles of individual layer；
3) double-deck micro-nano gel particles are prepared：
Using step 2) gained the micro-nano gel particles of individual layer as seed, to step 2) gained contain individual layer micro-and nano-particles Solution in add 25 μ L steps 1) gained has the polymer of core shell structure, namely PJI-PLIThe aqueous solution (PJI-PLIIn water Mass percentage concentration in solution is 12, cross-linking reaction 1 hour 40%), to add the pH value of appropriate 5M NaOH regulation systems Neutralisation reaction system afterwards, also will cross-linking reaction gained emulsion system pour into 4mL saturations NH4In the aqueous solution of Cl, with The rotating speed of 1000rpm is centrifuged 1 minute, removes upper oil phase, and lower floor's emulsion dialysis 3 days in water obtain double-deck micro-nano gel Particle.
In the double-deck micro-nano gel particles, a diameter of 100nm of core, the thickness of shell is 150nm.
Transmission electron microscope (TEM) photo of the double-deck micro-nano gel particles of embodiment gained is as shown in Figure 6.From left to right according to Secondary to be crosslinked 6 hours with outer layer crosslinking 1 hour for crosslinking time is respectively internal layer, internal layer is crosslinked 6 hours-outer layer and is crosslinked 2 hours Double-deck nucleocapsid nanogel particle.
As seen from the figure, according to profit phase and the difference of surfactant, by controlling different crosslinking times, can obtain Double-deck micro-nano gel particles.In double-deck micro-nano gel particles after vacuum drying, the diameter of core can be 40-100nm, shell Thickness can be 40-150nm, and the properties such as every layer of the degree of cross linking, thickness can be freely adjusted as needed.
Similarly, three layer of three spherical degradable nanogel particle of component can be obtained, and can freely adjusts as needed The properties such as every layer of the degree of cross linking and thickness.
Embodiment 8, prepare double-deck micro-nano gel particles
1) the polymer P J with core shell structure is preparedI-PLINamely AuNPs-PEG：
Preparing surface with cysteamine reaction by AuNPs first has the gold nano grain AuNPs-SH of sulfydryl, so The exchange reaction of sulfydryl disulfide bond is carried out with the PEG-SH being modified with the pyridine of two sulphur two afterwards, after purified and vacuum drying The polymer AuNPs-PEG with core shell structure is obtained, PJ is designated asI-PLI；
In the polymer, core is a diameter of 12 nanometers of golden nanometer particle, and shell is PEG, and molecular weight is 2000.
The polymer has crosslinkable core PJIThe AuNPs and shell PL that can be left awayIPEG, passes through cystine linkage between nucleocapsid It is connected with each other, while the polymer has biodegradable characteristic.
2) the micro-nano gel particles of individual layer are prepared：
The step is with the step 2 of embodiment 7), only by n-decane (organic solvent and dispersed phase) and surfactant span80 And the volume of the solution of tween80 compositions replaces with 30ml；Speed of agitator replaces with 1100rpm；Step 1 in embodiment 7) gained PJI-PLIReplace with the embodiment step 1) gained PJI-PLI；Mass percentage concentration in aqueous replaces with 44%；System PH value replace with 13.4；Cross-linking reaction time is replaced with 4 hours.
3) double-deck micro-nano gel particles are prepared：
Using step 2) the gained micro-nano gel particles of individual layer as seed, afterwards according to the step 3 of embodiment 7) identical Step, only does following replacement：By the step 3 of embodiment 7) used by PJI-PLIReplace with the step 1 of embodiment 2) gained have nucleocapsid knot The polymer P J of structureII-PLII, and the mass percentage concentration of its aqueous solution is replaced with 41%, it is small that cross-linking reaction time replaces with 2 When；
In the double-deck micro-nano gel particles, a diameter of 100nm of core, the thickness of shell is 100nm.
Embodiment 9, prepare individual layer and double-deck micro-nano gel particles
1) the polymer P J with core shell structure is preparedI-PLINamely PAMAM-PASP：
The step is with the step 1 of embodiment 3)；
In the polymer, core PAMAM is forth generation dendrimer, and molecular weight is 20112, and the molecular weight of shell PASP is 600。
The polymer has crosslinkable core PJIThe PAMAM and shell PL that can be left awayIPASP, passes through cystine linkage between nucleocapsid It is connected with each other, while the polymer has biodegradable characteristic.
2) the micro-nano gel particles of individual layer are prepared：
The step is with the step 2 of embodiment 7), only by n-decane (organic solvent and dispersed phase) and surfactant span80 And the volume of the solution of tween80 compositions replaces with 36ml；Speed of agitator replaces with 1400rpm；Step 1 in embodiment 7) gained PJI-PLIReplace with the embodiment step 1) gained PJI-PLI；Step 1) gained PJI-PLINamely PAMAM-PASP is in the aqueous solution In mass percentage concentration replace with 43%；The pH value of system replaces with 12.7；Cross-linking reaction time is replaced with 8 hours.
3) double-deck micro-nano gel particles are prepared：
A, first prepare the polymer P J with core shell structureII-PLIINamely AgNPs (silver nano-grain, can be from open approach Purchase)-PAA：
Surface can be prepared with cysteamine reaction by AgNPs first has the silver nano-grain AgNPs-SH of sulfydryl, Then the method being polymerized using reversible addion-fragmentation chain transfer prepares PAA-SH, and it is obtained with the pyridine of two sulphur two according to 1: 6 To product fully reacted with AgNPs-SH again, it is purified and be vacuum dried after can obtain the polymer with core shell structure AgNPs-PAA, is designated as PJI-PLI；
In the polymer, core is the Nano silver grain of a diameter of 12nm, and shell is PAA, and molecular weight is 3200.
The polymer has crosslinkable PJIThe AgNPs and shell PL that can be left awayIMutually interconnected by cystine linkage between PAA nucleocapsids Connect, while the polymer has biodegradable characteristic.
B, again using step 2) the gained micro-nano gel particles of individual layer as seed, afterwards according to the step 3 of embodiment 7) phase Same step, only does following replacement：By the step 3 of embodiment 7) used by PJI-PLIReplace with the step 1 of embodiment 2) gained have core The polymer P J of shell structureII-.PLIINamely AgNPs (silver nano-grain)-PAA, cross-linking reaction time replaces with 2 hours；
In the double-deck micro-nano gel particles, a diameter of 80nm of core, the thickness of shell is 100nm.
Embodiment 10, prepare individual layer, double-deck and three layers of micro-nano gel particles
1) the polymer P J with core shell structure is preparedI-PLINamely poly (BAC2-AEPZ1)-CMS：
Core PJ will be constituted in methyl alcoholIMaterial namely N, N '-bis- acryloyl cystamines (BAC, 20mmol) and N- aminoethyls Piperazine (AEPZ, 10mmol) mixing is heated to 50 DEG C and reacts 6 days, adds composition shell PLIIt is material modified (CMS-NH2, 15mmol) (can be from open approach purchase), be heated to 60 DEG C and reacts 7 days, is precipitated in a large amount of ether, then sediment is used into a small amount of After methyl alcohol dissolving, protonation reaction is carried out 5 minutes in volume ratio is for 1: 20 concentrated hydrochloric acid and the mixed liquor of acetone, by core and Connected together with cystine linkage between shell, collect gained precipitation vacuum drying and obtain the polymer poly with core shell structure (BAC2-AEPZ1)-CMS, is designated as PJI-PLI。
In the polymer, the molecular weight of core poly (BAC2-AEPZ1) is 5000 for the molecular weight of 1.7 ten thousand, CMS.
The polymer has crosslinkable core PJIPoly (BAC2-AEPZ1) and the shell PL that can be left awayICMS, between nucleocapsid It is connected with each other by cystine linkage, while the polymer has biodegradable characteristic.
2) the micro-nano gel particles of individual layer are prepared：
The step is with the step 2 of embodiment 7), only by n-decane (organic solvent and dispersed phase) and surfactant span80 And the volume of the solution of tween80 compositions replaces with 33ml；Speed of agitator replaces with 1300rpm；Step 1 in embodiment 7) gained PJI-PLIReplace with the embodiment step 1) gained PJI-PLI；Step 1) gained PJI-PLINamely poly (BAC2-AEPZ1)- CMS mass percentage concentrations in aqueous replace with 38%；The pH value of system replaces with 12.3；Cross-linking reaction time is replaced with 8 hours.
3) double-deck micro-nano gel particles are prepared：
A, first prepare the polymer P J with core shell structureII-PLIINamely poly (BAC2-AEPZ1)-PAA：
In methyl alcohol, by N, N '-bis- acryloyl cystamines (BAC, 20mmol) and N- aminoethyl piperazines (AEPZ, 10mmol) press than Example mixing, is heated to 50 DEG C and reacts 6 days, adds a certain proportion of sulfydryl PAA, is heated to 60 DEG C and reacts 7 days, in a large amount of ether Middle precipitation, then by sediment with a small amount of methyl alcohol dissolve after, in volume ratio for 1: 20 concentrated hydrochloric acid and acetone composition mixed liquor in Precipitation fully protonation, vacuum drying can obtain poly (BAC2-AEPZ1)-PAA.
The polymer has crosslinkable core and the shell that can be left away, and is connected with each other by cystine linkage between nucleocapsid, while should Polymer has biodegradable characteristic.
In the polymer, the molecular weight of core poly (BAC2-AEPZ1) is 2300 for the molecular weight of 1.7 ten thousand, PAA.
B, by gained PJII-PLIINamely poly (BAC2-AEPZ1)-PAA is dispersed in water and obtains PJII-PLIIIt is water-soluble Liquid, PJII-PLIIMicro-nano drop, PJ are formed in waterII-PLIIMass percentage concentration in aqueous is 40%；
Using step 2) gained the micro-nano gel particles of individual layer as seed, to step 2) gained contain the micro-nano gel of individual layer 25 μ LPJ are added in the solution of particleII-PLIIThe aqueous solution, the pH value of system is 12, neutralisation reactant after crosslinking 4 hours System, also will emulsion pour into 4mL saturations NH4In Cl solution, it is centrifuged 1 minute with the rotating speed of 1000rpm, removes upper oil phase, under Layer emulsion dialysis 3 days in water, obtain double-deck micro-nano gel particles；
4) three layers of micro-nano gel particles are prepared：
With step 3) the double-deck micro-nano gel particles of gained are new seed, to step 3) gained is containing double-deck micro-nano solidifying 25 μ L are added in the solution of micelle has the polymer P J of core shell structureIII-PLIII, namely the step 1 of embodiment 2) gained The aqueous solution (mass percentage concentration of POSS-PEG is 40%) of POSS-PEG, the pH value of system is 13, cross-linking reaction 1 hour Afterwards, emulsion is poured into 4mL saturations NH4In Cl solution, it is centrifuged 1 minute with the rotating speed of 1000rpm, removes upper oil phase, lower floor's breast Liquid dialysis 3 days in water, obtain three layers of micro-nano gel particles.
In three layers of micro-nano gel particles, a diameter of 70nm of innermost layer, the thickness in intermediate layer is 80nm, outermost Thickness is 100nm.
Embodiment 11, prepare individual layer, double-deck and three layers of micro-nano gel particles
1) the polymer P J with core shell structure is preparedI-PLINamely AgNPs (silver nano-grain, can be from open approach purchase Buy)-PEG：
Surface can be prepared with cysteamine reaction by AgNPs first has the silver nano-grain AgNPs-SH of sulfydryl, Then the exchange reaction of sulfydryl disulfide bond is carried out with the PEG-SH being modified with the pyridine of two sulphur two, after purified and vacuum drying i.e. The polymer AgNPs-PEG with core shell structure can be obtained, PJ is designated asI-PLI；
In the polymer, core is a diameter of 12 nanometers of Nano silver grain, and shell is PEG, and molecular weight is 3200.
The polymer has crosslinkable PJIThe AgNPs and shell PL that can be left awayIPEG, it is mutual by cystine linkage between nucleocapsid Connection, while the polymer has biodegradable characteristic.
2) the micro-nano gel particles of individual layer are prepared：
The step is with the step 2 of embodiment 7), only by 34ml n-decanes (organic solvent and dispersed phase) and surfactant Span80 and tween80 composition solution replace with 3.3ml by mass ratio for 90: 5: 5 hexamethylene, span80 and tween80 The solution of composition；Speed of agitator replaces with 700rpm；By step 1 in embodiment 7) gained PJI-PLIReplace with the embodiment step 1) gained PJI-PLI；Step 1) gained PJI-PLINamely the consumption of the aqueous solution of AgNPs-PEG replaces with 50 μ L；Cross-linking reaction Time replaces with 8 hours；
3) double-deck micro-nano gel particles are prepared：
A, first prepare the polymer P J with core shell structureII-PLIINamely poly (BAC2-AEPZ1)-PMAA：
Core PJ will be constituted in methyl alcoholIMaterial namely N, N '-bis- acryloyl cystamines (BAC, 20mmol) and N- aminoethyls Piperazine (AEPZ, 10mmol) mixing is heated to 50 DEG C and reacts 6 days, adds composition shell PLIMaterial modified (PMAA-NH2, 15mmol) (can be from open approach purchase), be heated to 60 DEG C and reacts 7 days, is precipitated in a large amount of ether, then sediment is used into a small amount of After methyl alcohol dissolving, protonation reaction is carried out 5 minutes in volume ratio is for 1: 20 concentrated hydrochloric acid and the mixed liquor of acetone, by core and Connected together with cystine linkage between shell, collect gained precipitation vacuum drying and obtain the polymer poly with core shell structure (BAC2-AEPZ1)-PMAA, is designated as PJI-PLI。
In the polymer, the molecular weight of core BAC2-AEPZ1 is 2000 for the molecular weight of 1.7 ten thousand, PMAA.
The polymer has crosslinkable core PJIPoly (BAC2-AEPZ1) and the shell PL that can be left awayIPMAA, nucleocapsid it Between by cystine linkage be connected with each other, while the polymer has biodegradable characteristic.
B, by gained PJII-PLIINamely poly (BAC2-AEPZ1)-PMAA is dispersed in water and obtains PJII-PLIIIt is water-soluble Liquid, PJII-PLIIMicro-nano drop, PJ are formed in waterII-PLIIMass percentage concentration in aqueous is 40%；
Using step 2) gained the micro-nano gel particles of individual layer as seed, to step 2) gained contain the micro-nano gel of individual layer 50 μ LPJ are added in the solution of particleII-PLIIThe aqueous solution, the pH value of system is 12, neutralisation reactant after crosslinking 4 hours System, also will emulsion pour into 4mL saturations NH4In Cl solution, it is centrifuged 1 minute with the rotating speed of 1000rpm, removes upper oil phase, under Layer emulsion dialysis 3 days in water, obtain double-deck micro-nano gel particles；
4) three layers of micro-nano gel particles are prepared：
The polymer P J of a, preparation with core shell structureIII-PLIIINamely Star-PS-CMC：
The method being polymerized using reversible addion-fragmentation chain transfer prepares COOH-PS-SH, then is reacted with pentaerythrite The core of four arms being obtained afterwards, then it being reacted with the CMC-SH being modified with the pyridine of two sulphur two, purified and vacuum is dry The polymer Star-PS-CMC with core shell structure can be obtained after dry, PJ is designated asI-PLI；
The polymer has 4 arm, and the PS that molecular weight is 5000 is per arm, and the molecular weight of CMC is 5000；
The polymer has crosslinkable core PJIThe Star-PS and shell PL that can be left awayIPass through cystine linkage phase between CMC nucleocapsids Connect, while the polymer has biodegradable characteristic.
B, with step 3) the double-deck micro-nano gel particles of gained are new seed, to step 3) gained is containing double-deck micro-nano 25 μ L are added in the solution of gel particles has the polymer P J of core shell structureIII-PLIIINamely the aqueous solution of Star-PS-CMC (mass percentage concentration of Star-PS-CMC is 40%), the pH value of system is 12, and cross-linking reaction poured into emulsion after 1 hour 4mL saturations NH4In Cl solution, it is centrifuged 1 minute with the rotating speed of 1000rpm, removes upper oil phase, lower floor's emulsion dialysis 3 in water My god, obtain three layers of micro-nano gel particles.
In three layers of micro-nano gel particles, a diameter of 75 μm of innermost layer, the thickness in intermediate layer is 85 μm, outermost Thickness is 110 μm.
Embodiment 12, prepare individual layer, double-deck and three layers of micro-nano gel particles
1) the polymer P J with core shell structure is preparedI-PLINamely PAMAM-PESA：
By PAMAM, 2, there is esterification in 2 '-two selenium diethanols, maleic anhydride and PESA, and vacuum drying is obtained with core The polymer P AMAM-PESA of shell structure, is designated as PJI-PLI；
In the polymer, core PAMAM is forth generation dendrimer, and molecular weight is 20112, and the molecular weight of shell PESA is 1000。
The polymer has crosslinkable core PJIThe PAMAM and shell PL that can be left awayIPESA, passes through cystine linkage between nucleocapsid It is connected with each other, while the polymer has biodegradable characteristic.
2) the micro-nano gel particles of individual layer are prepared：
According to the step 2 of embodiment 11) identical step, only by step 1 in embodiment 11) gained PJI-PLIReplace with this Embodiment step 1) gained PJI-PLI；Speed of agitator replaces with 800rpm；The pH value of system replaces with 14；PJI-PLIIt is water-soluble PJ in liquidI-PLIMass percentage concentration replace with 41%；Cross-linking reaction time is replaced with 20 hours；
3) double-deck micro-nano gel particles are prepared：
According to the step 3 of embodiment 11) identical step, only by the step 3 of embodiment 11) in it is poly- with core shell structure Compound PJII-PLIIReplace with POSS-PAM；PJII-PLIIThe aqueous solution in PJII-PLIIMass percentage concentration replace with 46%； Cross-linking reaction time is replaced with 8 hours；
Wherein, the polymer P J with core shell structureII-PLIINamely the preparation method of POSS-PAM is as follows：
1mmol sulfydryls polyacrylamide (PAM-SH, open approach purchase) is mixed in methyl alcohol with the pyridine of bis- sulphur of 6mmol two In be heated to 50 DEG C reaction 5 days after, in a large amount of ether precipitate.By 1mmol sediments and the sulfydryls of 20mmol eight after purified POSS(POSS-(SH)8, open approach purchase) mix in chloroform after be heated to 50 DEG C of reactions 7 days after, sunk in a large amount of ether Form sediment, vacuum drying obtains the polymer P OSS-PAM with core shell structure, is designated as PJI-PLI。
In the polymer, core POSS is 8 symmetrical arm cagelike structures, and a diameter of 2 nanometers, molecular weight is 1008, shell PEG's Molecular weight is 1000.
The polymer has crosslinkable core PJIThe POSS and shell PL that can be left awayIPEG, it is mutual by cystine linkage between nucleocapsid Connection, while the polymer has biodegradable characteristic.
4) three layers of micro-nano gel particles are prepared：
The polymer P J of a, preparation with core shell structureIII-PLIIINamely SiNPs (nano silicon particles)-PEG：
SiNPs surfaces sulfhydrylation is obtained nano silicon particles SiNPs-SH with silica coupling agent first, then with use two sulphur The PEG-SH that two pyridines were modified carries out the exchange reaction of sulfydryl disulfide bond, can be obtained with core after purified and vacuum drying The polymer SiNPs-PEG of shell structure, is designated as PJI-PLI；
In the polymer, core is a diameter of 12 nanometers of silicon nano, and shell is PEG, and molecular weight is 3200.
The polymer has crosslinkable core PJISilicon nano, particle diameter is 350 nanometers, and the shell PL for leaving awayIPEG, point Son amount is 5000, is connected with each other by cystine linkage between nucleocapsid, while the polymer has biodegradable characteristic.
B, according to the step 4 of embodiment 11) the identical steps of b, only by step 4 in embodiment 11) PJ used in bIII- PLIIIReplace with the embodiment step 4) gained PJIII-PLIII；Cross-linking reaction time is replaced with 2 hours；
In three layers of micro-nano gel particles, a diameter of 45 μm of innermost layer, the thickness in intermediate layer is 45 μm, outermost Thickness is 80 μm.
Embodiment 13, prepare the micro-nano gel particles of individual layer
1) the polymer P J with core shell structureI-PLINamely the preparation method of POSS-PAA is as follows：
1mmol sulfydryls polyacrylic acid (PAA-SH, can be from open approach purchase) is mixed in first with the pyridine of bis- sulphur of 6mmol two Be heated in alcohol 50 DEG C reaction 5 days after, in a large amount of ether precipitate.By 1mmol sediments and the sulfydryls of 20mmol eight after purified POSS(POSS-(SH)8, open approach purchase) mix in chloroform after be heated to 50 DEG C of reactions 7 days after, sunk in a large amount of ether Form sediment, vacuum drying obtains the polymer P OSS-PAA with core shell structure, is designated as PJI-PLI。
In the polymer, core POSS is 8 symmetrical arm cagelike structures, and a diameter of 2 nanometers, molecular weight is 1008, shell PAA's Molecular weight is 1200.
The polymer has crosslinkable core PJIThe POSS and shell PL that can be left awayIPAA, it is mutual by cystine linkage between nucleocapsid Connection, while the polymer has biodegradable characteristic.
2) the micro-nano gel particles of individual layer are prepared：
By step 1) gained PJI-PLINamely POSS-PAA is dispersed in water and obtains PJI-PLIThe aqueous solution, PJI-PLI Micro-nano drop, PJ are formed in waterI-PLIMass percentage concentration in aqueous is 50%；
It is the solution of 90: 10 hexamethylene (organic solvent and dispersed phase) and span80 composition to prepare mass ratio, and this is molten (cross-sectional area is 32000 μm to liquid injection microfluidic device outer tunnel2).In microfluidic device internal channel, (cross-sectional area is 10000 μm2) middle injection PJI-PLIThe aqueous solution, the pH value of system is 13.3, control outer tunnel flow rate of liquid for 500L/h, is led in control Road flow rate of liquid is 300L/h.Internal and external channel liquid is mixed to form drop of uniform size in pipeline is crosslinked.Mixed liquor is being handed over Cross-linking reaction is carried out in union road after 4 hours, 40mL saturations NH is passed through4With neutralisation reaction system in Cl solution, with 1000rpm Rotating speed be centrifuged 1 minute, remove upper oil phase, lower floor's emulsion dialysis 3 days in water, vacuum drying obtain the micro-nano gel of individual layer Particle.
The hydrodynamic radius of the micro-nano gel particles of the individual layer be 49 μm, a diameter of 85 μm after vacuum drying, fully A diameter of 96 μm after water suction.
The micro-nano gel particles of embodiment 14, individual layer
1) the polymer P J with core shell structure is preparedI-PLINamely poly (BAC2-AEPZ1)-PEG：
The step is with the step 1 of embodiment 1)；
2) the micro-nano gel particles of individual layer are prepared：
By step 1) gained PJI-PLINamely poly (BAC2-AEPZ1)-PEG is dispersed in water and obtains PJI-PLIIt is water-soluble Liquid, PJI-PLIMicro-nano drop, PJ are formed in waterI-PLIMass percentage concentration in aqueous is 45%；
Prepare by the n-decane that mass ratio is 87: 13 and the solution that span80 is constituted, this solution is injected into microfluidic device (cross-sectional area is 35000m to outer tunnel2).In microfluidic device internal channel, (cross-sectional area is 12000m2) middle injection PJI-PLI's The aqueous solution, the pH value of system is 12.3, controls the flow velocity of outer tunnel liquid for 530L/h, and the flow velocity of internal channel liquid is 320L/ H, internal and external channel liquid is mixed to form drop of uniform size in pipeline is crosslinked.Mixed liquor carries out being crosslinked instead in pipeline is crosslinked After answering 24 hours, 40mL saturations NH is poured into4The aqueous solution of Cl is centrifuged 1 point with neutralisation reaction system, then with the rotating speed of 1000rpm Clock, removes upper oil phase, and lower floor's emulsion dialysis 3 days in water obtain the micro-nano gel particles of individual layer.
The hydrodynamic radius of the micro-nano gel particles of the individual layer be 41 μm, a diameter of 32 μm after vacuum drying, fully A diameter of 66 μm after water suction.
Embodiment 15, prepare the micro-nano gel particles of individual layer
Mass ratio is prepared for hexamethylene (organic solvent and dispersed phase), span80 and tween80 be made up of at 90: 5: 5 Solution, by this solution injection microfluidic device outer tunnel, (cross-sectional area is 30000m2).It is (transversal in microfluidic device internal channel Area is 8400m2) middle injection embodiment 3 step 1) gained PAMAM-PASP (namely PJI-PLI) the aqueous solution, the pH value of system It is 13.9, controls outer tunnel flow rate of liquid for 550L/h, it is 200L/h to control internal channel flow rate of liquid.Internal and external channel liquid is in friendship Drop of uniform size is mixed to form in union road.After mixed liquor carries out cross-linking reaction 8 hours in crosslinking pipeline, 40mL is passed through Saturation NH4With neutralisation reaction system in Cl solution, then it is centrifuged 1 minute with the rotating speed of 1000rpm, removes upper oil phase, lower floor Emulsion dialysis 3 days in water, obtain the micro-nano gel particles of individual layer.
The hydrodynamic radius of the micro-nano gel particles of the individual layer be 39 μm, a diameter of 28 μm after vacuum drying, fully A diameter of 77 μm after water suction.
Result above shows, the present invention can prepare individual layer to the micro-nano gel particles of multilayer labyrinth, and The physics and chemical property of accuracy controlling gel particles under micro-nano-scale.The gel particles have biological degradability, it is expected to Applied in the field such as biological medicine and catalytic reaction.

Claims (20)

1. a kind of individual layer or the double-deck or three layers or n+3 layer controllable method for preparing of micro-nano gel particles, be as follows (one), (2), shown in (three) or (four)：
(1) method for preparing the micro-nano gel particles of individual layer, comprises the following steps：
1) polymer I with core shell structure is prepared, in the polymer I of the core shell structure, core is with shell by stimuli responsive The chemical bond connection of lower rearrangement；
The step 1) in, the chemical bond reset under stimuli responsive is cystine linkage, double selenium keys or schiff bases key；
2) by step 1) resulting polymers I forms polymer solution in being scattered in medium, makes the material of the core of the composition polymer Material crosslinks and reacts and make the shell parts of the composition polymer I or leave away completely, controls the time of the cross-linking reaction To regulate and control the particle diameter of micro-nano gel particles, the micro-nano gel particles of individual layer are obtained；
The cross-linking reaction is carried out by regulating and controlling environmental stimuli response；System is divided by dispersion technology before environmental stimuli is implemented It is micro-nano drop to dissipate；
(2) method for preparing double-deck micro-nano gel particles, comprises the following steps：
3) to methods described (one) step 2) in the aqueous solution or polymer II of polymer I are added in system after cross-linking reaction The aqueous solution, carries out cross-linking reaction and makes the shell parts of the composition polymer I or II or leave away completely, and by controlling to be crosslinked The particle diameter of the micro-nano gel particles of time-controllable of reaction, obtains double-deck micro-nano gel particles；
The polymer II is the polymer with core shell structure, wherein, the chemistry that core passes through the rearrangement under stimuli responsive with shell It is bonded and connects；
(3) three layers of method of micro-nano gel particles are prepared, is comprised the following steps：
4) to step 3 described in methods described (two)) in the aqueous solution or the polymerization of polymer I are added in system after cross-linking reaction The aqueous solution of thing II or the aqueous solution of polymer III, carry out cross-linking reaction and constitute the shell portion of the polymer I or II or III Point or leave away completely, and by controlling the particle diameter of the micro-nano gel particles of the time-controllable of cross-linking reaction, obtain three layers it is micro-nano Gel particles；
The polymer III is the polymer with core shell structure, wherein, the chemistry that core passes through the rearrangement under stimuli responsive with shell It is bonded and connects；
(4) the n+3 layers of method of micro-nano gel particles is prepared, is comprised the following steps：
4 the step of methods described (three)) after, repeating said steps 4) n times, obtain n+3 layers of micro-nano gel particles；It is described N is natural number；
In methods described (), (two), (three) or (four), the pH value of the system of the cross-linking reaction is 7-14；
The step 2) to step 4) in dispersion steps, scattered method is selected from emulsion method, antiphase emulsifiable method, self-assembly method, micro- At least one in nano-imprint method, micro-nano method of molding and micro-nano flow process；
In methods described (), (two), (three) or (four), the system of the cross-linking reaction is by the polymer solution, organic Solvent and surfactant are constituted；
The surfactant is selected from fatty glyceride, sapn, tween, lecithin, amino acid, glycine betaine and quaternary ammonium compound At least one.
2. method according to claim 1, it is characterised in that：The step 2) in, medium is water；
Mass percent concentration of the polymer I in the aqueous solution of polymer I is 30-50%；
Mass percent concentration of the polymer II in the aqueous solution of polymer II is 30-50%；
Mass percent concentration of the polymer III in the aqueous solution of polymer III is 30-50%.
3. method according to claim 1 and 2, it is characterised in that：In the polymer I, polymer II and polymer III, Core is selected from least one in three arm polymer, multiarm polymers, tree shaped polymer, natural polymer, inorganic nano-particle.
4. method according to claim 3, it is characterised in that：The three arms polymer, multiarm polymers and tree-like polymerization The weight average molecular weight of thing is 300 to 1,000 ten thousand.
5. method according to claim 3, it is characterised in that：In the polymer I, polymer II and polymer III, core Selected from the PAMAM forth generation dendrimers that weight average molecular weight is 20112.
6. method according to claim 3, it is characterised in that：The particle diameter of the inorganic nano-particle is 1 nanometer to 1 micro- Rice.
7. method according to claim 1 and 2, it is characterised in that：In the polymer I, polymer II and polymer III, Core be selected from ultrabranching polyamide, hyperbranched poly amido acid amides, hyper-branched polyester, hyperbranched polyamine base ester, dendroid polyamide, Dendroid polyamine group acid amides, hyperbranched poly acrylamide, dendritic polyester, dendroid polyamine base ester, star multi-arm polystyrene, It is star multi-arm PNIPAM, star multi-arm methyl methacrylate, poly- cagelike silsesquioxane, solid or hollow receive At least one in rice silicon ball, golden nanometer particle, Nano silver grain and ferroferric oxide magnetic nano-particles.
8. method according to claim 1 and 2, it is characterised in that：In the polymer I, polymer II and polymer III, Core is selected from poly (BAC2-AEPZ1), the PNIPAM that weight average molecular weight is 2000, the Weight-average molecular that weight average molecular weight is 1.7 ten thousand Measure for 5000 polystyrene or with symmetrical 8 arm cagelike structures and a diameter of 2 nanometers and weight average molecular weight be 1008 it is poly- Cagelike silsesquioxane.
9. method according to claim 1 and 2, it is characterised in that：In the polymer I, polymer II, polymer III, The shell is selected from least one in hydrophilic or hydrophobic linear and branched polymer；
Described hydrophilic or hydrophobic linear or branched polymer weight average molecular weight is 100 to 1,000,000.
10. method according to claim 1 and 2, it is characterised in that：In the polymer I, polymer II, polymer III, The shell is selected from polyethylene glycol, polyacrylic acid, polymethylacrylic acid, poly hydroxy ethyl acrylate, CMS, acetic acid and forms sediment Powder, carboxymethylcellulose calcium, polyacrylamide, hydrolyzed polyacrylamide, poly, poly-aspartate, poly-epoxy succinic acid, fibre At least one in the plain ether of dimension, chitin, xanthans and natural plant gum.
11. methods according to claim 1 and 2, it is characterised in that：In the polymer I, polymer II, polymer III, The shell is 500 to 5,000 or the PEG of 750-1000 or 750-2000 or 750-3200 or 2000-3200, weight for weight average molecular weight Average molecular weight is the PAA of 1200-3200, the CMS that weight average molecular weight is 5000, the PASP that weight average molecular weight is 600 or divide equally again Son amount is 1000 PESA.
12. methods according to claim 1 and 2, it is characterised in that：The polymer I, polymer II, polymer III are Polymer P J-PL；The polymer P J-PL is poly (BAC2-AEPZ1)-CMS, poly (BAC2-AEPZ1)-PAA, poly (BAC2-AEPZ1)-PEG、poly(BAC2-AEPZ1)-PMAA、PAMAM-PASP、PAMAM-PESA、POSS-PAM、POSS- PEG、Star-PS-PEG、Star-PS-CMC、Star-PNIPAM-PESA、SiNPs-PEG、AuNPs-PAA、AuNPs-PEG、 At least one in AgNPs-PAA and AgNPs-PEG.
13. methods according to claim 12, it is characterised in that：The polymer P J-PL is with 4 arm and per arm The weight average molecular weight for being PNIPAM that weight average molecular weight is 2000 and PESA be 1000 Star-PNIPAM-SeSe-PESA, The weight average molecular weight that PS that weight average molecular weight is 5000 and PEG are with 4 arm and per arm is 2000 Star-PS-PEG Or poly (BAC2-AEPZ1)-CMS；
Wherein, in poly (BAC2-AEPZ1)-PAA, the weight average molecular weight of core poly (BAC2-AEPZ1) is 5,000 to 30,000, shell The weight average molecular weight of PAA is 500 to 5,000；
In poly (BAC2-AEPZ1)-PEG, the weight average molecular weight of core poly (BAC2-AEPZ1) is 5,000 to 30,000, shell PEG's Weight average molecular weight is 500 to 5,000.
14. methods according to claim 1 and 2, it is characterised in that：In methods described (), (two), (three) or (four), The time of the cross-linking reaction is 1-24 hours.
15. methods according to claim 14, it is characterised in that：The pH value of the system of the cross-linking reaction is 12.
16. methods according to claim 1, it is characterised in that：The surfactant is selected from span80 and tween80 At least one.
17. methods according to claim 1 and 2, it is characterised in that：In methods described (), (two), (three) or (four), After cross-linking reaction completion, also comprise the following steps：System after cross-linking reaction is neutralized to neutrality, is centrifuged, removed Upper oil phase, removes a layer emulsion.
18. individual layers prepared using any methods describeds of claim 1-17 or it is double-deck or three layers or n+3 layer micro-nano coagulate Micelle；The n is natural number.
19. particles according to claim 18, it is characterised in that：The pattern of the micro-nano gel particles is spherical, rod Shape, tabular, disk like or taper；
Particle diameter is 5 nanometers to 900 microns.
The answering in the purifying of drug controlled release, organizational project, catalytic reaction or material of particle described in 20. claims 18 or 19 With.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101721349A (en) * 2008-10-16 2010-06-09 常州百瑞吉生物医药有限公司 Injectable in-situ crosslinking aquogel and preparation method and application thereof
CN102070784A (en) * 2010-12-08 2011-05-25 苏州同科生物材料有限公司 pH-responsive degradable hydrogel and preparation method thereof
CN102399295A (en) * 2010-09-09 2012-04-04 常州百瑞吉生物医药有限公司 Low-sulfhydrylation-modification-degree biocompatible high-molecular sulfhydrylation derivatives, cross-linking material thereof, and purpose thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101340290B1 (en) * 2011-09-14 2013-12-11 한국과학기술원 NANOSTRUCTURED siRNA HYDROGELS FOR GENE SILENCING AND PREPARING METHOD THEREOF

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101721349A (en) * 2008-10-16 2010-06-09 常州百瑞吉生物医药有限公司 Injectable in-situ crosslinking aquogel and preparation method and application thereof
CN102399295A (en) * 2010-09-09 2012-04-04 常州百瑞吉生物医药有限公司 Low-sulfhydrylation-modification-degree biocompatible high-molecular sulfhydrylation derivatives, cross-linking material thereof, and purpose thereof
CN102070784A (en) * 2010-12-08 2011-05-25 苏州同科生物材料有限公司 pH-responsive degradable hydrogel and preparation method thereof

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