CN104415359A - Organic-inorganic composite hollow ultrasound imaging microsphere material - Google Patents
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- 239000000377 silicon dioxide Substances 0.000 claims abstract description 20
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- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 14
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- 229920006037 cross link polymer Polymers 0.000 claims 1
- 229920002845 Poly(methacrylic acid) Polymers 0.000 abstract description 9
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 7
- 239000001257 hydrogen Substances 0.000 abstract description 5
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- 229910052757 nitrogen Inorganic materials 0.000 description 4
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 3
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- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 2
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Abstract
The present invention discloses an organic-inorganic composite hollow ultrasound imaging microsphere material, which has a hollow inorganic/organic/inorganic three-layer structure, wherein a cavity is positioned in the center of the microsphere, air is filled in the cavity, the outer layer of the cavity is Fe3O4 magnetic particles, the middle layer is core/shell polymer nanometer microspheres obtained by carrying out free radical copolymerization on a poly(methyl methacrylate)-polymethacrylic acid random copolymer, polymethacrylic acid and divinylbenzene, the carboxyl on the inner surface and the iron salt can form the coordination bond or ion bond so as to provide the stability between the copolymer and the Fe3O4 magnetic particles in the inner layer, the outer layer is silicon dioxide, and the carboxyl on the microsphere surface and the silanol on the silicon dioxide surface produce the hydrogen bond effect so as to connect; and the material has the following advantages that: the polymer microspheres belong to the nanoscale particles, the contrast agent can provide the targeted positioning function with the Fe3O4 magnetic nanoparticles in the inner layer, the silicon dioxide hollow microsphere has good biocompatibility and good mechanical stability, and the internal cavity can produce the strong echo signal under the contrasting mode.
Description
Technical field
The present invention relates to a kind of medical detection contrast agent, particularly relate to a kind of Nano microsphere with the multilamellar organic/inorganic composite construction of magnetic function, belong to medicine technology field.
Background technology
In recent years, molecular image technology can provide important information and be paid close attention to (Campbell R. E., Chang C. J. widely for the medical diagnosis on disease of biological tissue and monitoring due to it
curr Opin Chem Biol, 2010,14 (1): 1-2.).In numerous imaging pattern, ultra sonic imaging, as the AT biomedical imaging pattern of one, has important researching value because it has the advantages such as imaging and timely, cheap, the light and fast of diagnosis safety, utilization are extensive.But the difference of echo-signal usually can hinder the accuracy of diagnosis between different biological tissue; in order to obtain the accurate information of particular organization better; people adopt the method adding ultra sonic imaging contrast agent to realize (R. D í az-L ó PMMAz usually; Tsapisa N.; Libong D., et al.
biomaterials, 2009,30 (8): 1462-1472.).
Usually contrast agent used is mainly microvesicle, and its shell is that the amphipathic small molecules such as saccharide, protein or polymer are formed, inner filling C
3f
8, SF
6vesicle (Ferrara K. W., Borden M. A., Zhang H. is formed Deng gas
acc Chem Res, 2009,42 (7): 881-892.).These contrast agent can change or strengthen ultrasound echo signal and provide better surface or organizational information.But due to laplace pressure, blood pressure, oxidative metabolism and hyperacoustic effect, these gas microbubbles are just dissolved and are broken after injection blood a few second, and particle diameter is difficult to control (Schutt E. G., Klein D. H., Mattrey R. M., et al.
angew Chem Int Ed, 2003,42 (28): 3218-3235.).SiO 2 hollow microsphere has good biocompatibility and mechanical stability, and has larger cavity, can produce stronger echo-signal under imaging mode, can solve the problem.(Lin P. L., Eckersley R. J., the Elizabeth A. H. such as Hall
adv Mater2009,21 (38-39): 3949-3952.) with PMMA ball for template, change surface charge by polyallyl acid hydrochloride (PAH) and prepare the tiny balloon that particle diameter is 2.8 μm, shell thickness is less than 30nm, and have studied its ultra sonic imaging effect under different mechanical index condition.Linear ultrasonic imaging (B-model) result shows, this hollow SiO
2bead has very strong ultrasonic signal under water environment.But these class methods still have certain limitation, as hollow SiO
2the size of bead is too large, does not reach nanoscale structures, is difficult to for living imaging, and does not carry out modified with functional group and be difficult to connect further.Therefore, the contrast agent of current clinical middle use can't be taken into account good biocompatibility, mechanical stability, Targeting Performance, nanostructured simultaneously, can be carried out the requirements such as modified with functional group.
Summary of the invention
The present invention is directed to above problem, provide a kind of organic-inorganic composite hollow ultra sonic imaging micro-sphere material, it is a kind of multilamellar organic/inorganic composite construction magnetic Nano microsphere, have hollow type inorganic/organic/inorganic three-layer composite structure:
What be positioned at microsphere center is cavity, inner filling air;
Intermediate layer is macromolecule layer, is the copolymer of polymethylacrylic acid and divinylbenzene;
Be four oxidation three body magnetic nano-particles between cavity and intermediate layer, be deposited on macromolecule layer inner surface by coordinate bond or ionic bond;
Outer for there being mesoporous Nano particles of silicon dioxide, outside with macromolecule layer by hydrogen bond action absorption.
The technical solution adopted for the present invention to solve the technical problems is:
1) preparation of core/shell polymer microsphere double-layer nanometer microsphere
This microsphere is prepared based on a kind of core/shell polymer microsphere double-layer nanometer microsphere.First utilize methyl methacrylate and methacrylic acid to carry out copolymerization and obtain dispersed nano microsphere, it is structure shown in following chemical formula:
Wherein x is the integer of 5 ~ 50;
Y is the integer of 0 ~ 15;
2) the outer cross-linked structure of double-layer nanometer microsphere is prepared
Then by above-mentioned dispersed nano microsphere and polymethylacrylic acid, divinylbenzene, by Solution Free Radical copolymerization process, obtain microsphere layer structure, it is structure shown in following chemical formula:
Wherein n is the integer of 0 ~ 50
3) core/shell polymer microsphere double-layer nanometer microsphere is prepared by " from dispersion " polyreaction
Utilize the carboxyl on the surface of double-layer nanometer microsphere can produce hydrogen bond action with the silicone hydroxyl of silica surface, make silicon dioxide in aggregate surface hydrolysis and polycondensation formation shell structurre.Its interaction chemical formula is as follows:
4) preparation of hollow polymeric-silicon dioxide nanosphere
Utilize acetone to extract kernel and form hollow polymeric-silicon dioxide nanosphere structure.In reaction system, add chloroform dissolve, stirred for several hour, after utilizing chloroform to dissolve PMMA core, obtain SiO
2tiny balloon, its form keeps stable and structural integrity, has a good spherical structure.Preparation process schematic diagram is as shown in Figure of description 4;
5) preparation of magnetic macromolecular microsphere
Finally, utilize microsphere inner surface carboxyl and the iron salt being entered internal layer by silicon dioxide micropore permeation, form coordinate bond or ionic bond, by adsorbing the Fe of hollow ball inside
2+and Fe
3+deng reactant, make internal layer in conjunction with Fe 3 O 4 magnetic particle.Its reaction principle is as follows:
By above technical scheme, tool of the present invention has the following advantages: 1) organic-inorganic composite hollow ultra sonic imaging micro-sphere material has good biocompatibility;
2) to have volume little for organic-inorganic composite hollow ultra sonic imaging micro-sphere material, has nanoscale structures, can by various human body barriers;
3) organic-inorganic composite hollow ultra sonic imaging micro-sphere material is due to the Fe containing superparamagnetism
3o
4, therefore there is Targeting Performance;
4) organic-inorganic composite hollow ultra sonic imaging micro-sphere material Stability Analysis of Structures, mechanical stability are high.
This type of organic-inorganic composite hollow ultra sonic imaging micro-sphere material can overcome the problems such as traditional contrast agent poor stability, echo signal are weak, poor biocompatibility.
Accompanying drawing explanation
Fig. 1 is the structural representation of this organic-inorganic composite hollow ultra sonic imaging micro-sphere material;
Fig. 2 is the particle diameter test pattern of this organic-inorganic composite hollow ultra sonic imaging micro-sphere material;
Fig. 3 is the AFM scintigram of this organic-inorganic composite hollow ultra sonic imaging micro-sphere material;
Fig. 4 is the preparation flow schematic diagram of hollow polymeric microspheres.
Detailed description of the invention
For making enforcement object of the present invention, technical scheme and advantage more clear, below in conjunction with the drawings and specific embodiments of the present invention, the present invention is described in detail:
As shown in Figure 1, be the structural representation of organic-inorganic composite hollow ultra sonic imaging micro-sphere material.This Nano microsphere has hollow type machine/organic/inorganic three-layer composite structure, has successively: outermost layer be Nano particles of silicon dioxide 1.; Intermediate layer be macromolecule layer 2.; Internal layer be four oxidation three body magnetic nano-particles 3.; Be positioned at microsphere center be cavity 4., inner fill air.Wherein Nano particles of silicon dioxide layer 1. in should have meso-hole structure.
Polymethylacrylic acid-divinylbenzene crosslinking copolymerization macromolecule as macromolecule layer 2., outside adsorbs silica particle 1. simultaneously, and internal layer in conjunction with four oxidation three body magnetic nano-particles 3. as a preferably embodiment: utilize methyl methacrylate and polymethylacrylic acid to carry out copolymerization and obtain internal layer microsphere, then internal layer is carried out copolymerization by polymethylacrylic acid and divinylbenzene, obtain double-deck solid nano polymer microspheres.Utilize the carboxyl on the surface of double-layer nanometer microsphere can produce hydrogen bond action with the silicone hydroxyl of silica surface, make silicon dioxide be hydrolyzed also polycondensation in aggregate surface and form shell structurre 1..Meanwhile, utilize the meso-hole structure of Nano particles of silicon dioxide, with an organic solvent method (acetone) extracts kernel and forms hollow polymeric-silicon dioxide double-layer nanometer micro-sphere structure.Finally, utilize microsphere inner surface carboxyl and iron salt can form coordinate bond or ionic bond, entered the Fe of hollow ball inside by adsorption and permeation
2+and Fe
3+deng reactant, make internal layer in conjunction with Fe 3 O 4 magnetic particle 3..
Figure 2 shows that the particle diameter test pattern utilizing dynamic light scattering method to magnetic Nano microsphere, can find out, Nano microsphere particle diameter is less than 1 micron, and particle size distribution is narrower, proves that this Nano microsphere volume is little, good dispersion.
Figure 3 shows that the AFM scanogram of organic-inorganic composite hollow ultra sonic imaging micro-sphere material.Prove that macromolecule forms globular micelle structure homogeneous, good dispersion, does not reunite in aqueous.Be conducive to the targeting of contrast agent in body fluid to locate and dispersion.
Provide embodiment below to be specifically described the present invention; but it is worthy of note that following examples are only used to further illustrate the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that the person skilled in the art in this field makes the present invention according to the invention described above content and adjustment still belong to protection scope of the present invention.
Embodiment 1:
The preparation of 1. core/shell polymeric Nano microsphere
Step one: the method first adopting " from dispersion " to be polymerized prepares single dispersing (PMMA-PMAA) copolymer microsphere.Methyl methacrylate and each 0.2mol, AIBN(azo-bis-isobutyl cyanide of methacrylic acid is added in 500mL tri-mouthfuls of round bottom reaction bulbs) 0.98g, butyl acetate 280 mL; under nitrogen protection; constant temperature 70 DEG C reaction 12 hours; product is dried in 55 DEG C of baking ovens, obtains single dispersing (PMMA-PMAA) copolymer microsphere.
Step 2: prepare core/shell polymer microsphere by seed " from dispersion " polyreaction.By each to (PMMA-PMAA) copolymer microsphere 3.65g, methacrylic acid and divinylbenzene 0.038mol, AIBN 0.09 g, butyl acetate 100 mL, normal hexane 35 mL; add in reaction bulb; under nitrogen protection; constant temperature 75 DEG C reaction 13 hours, obtains two-layer core/shell polymeric Nano microsphere.
2. silicon dioxide carries out gathering at microsphere surface and forms shell structurre
With the two-layer core prepared in above-mentioned steps/shell polymeric Nano microsphere for template, generate the homogeneous and SiO of regular appearance of thickness by sol-gel process at PMAA surface in situ
2shell.Adopt St ber method (St ber W., Fink A., Bohn E.
j Colloid Interface Sci, 1968,26 (1): 62-69.), adding 55mL ammonia is catalyst, utilizes ethyl orthosilicate (TEOS) 16.5g, after poly-condensation and hydrolysis, synthesizes SiO
2.
With PMAA surface PMMA core as templated deposition SiO
2time, generally can generate the independent SiO of about 35nm
2particle.Because PMMA checks SiO
2adsorptivity weak, if direct PMMA precipitates SiO as masterplate
2, be difficult to obtain uniform SiO
2shell structurre.And when after the surface and copolymerized PMAA of PMMA core, because of the carboxyl on PMAA chain or carboxylate radical can with the hydrolyzate of ethyl orthosilicate and SiO
2the hydroxyl of particle surface forms hydrogen bond, thus induction SiO
2nucleating growth, finally forms regular shell structurre.
3. hollow type polymer-SiO
2the preparation of Nano microsphere
Get the SiO prepared in 2.7g above-mentioned steps
2core/shell polymeric Nano microsphere, adds 15mL chloroform and dissolves, stir 7 hours in reaction system, obtains SiO after utilizing chloroform to dissolve PMMA core
2tiny balloon, its form keeps stable and structural integrity, has a good spherical structure.
4. the preparation of hollow type magnetic Nano microsphere contrast agent
Hollow polymer microsphere 1.2g, the FeCl of gained in above-mentioned reactions steps is added in 250mL tri-mouthfuls of round bottom reaction bulbs
3 .6H
2o 5.8g, FeCl
24H
2o 3.3g, deionized water 180mL, under nitrogen protection, stir 1h, ultrasonic 2.5h, sucking filtration, deionized water rinsing 3 ~ 5 times.Then by filter microsphere adds in deoxygenation deionized water, in 85 DEG C, drip NH under high-speed stirred
3 .h
2o adjust ph is 11 ~ 12, under nitrogen protection, and isothermal reaction 2 h.Above-mentioned microsphere is added in bag filter, with 1000 mL pure water dialysis, refreshes the water periodically.After dialysis solution membrane filtration, lyophilization obtains hollow type magnetic Nano microsphere contrast agent.
Finally it should be noted that, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art should understand, can a point technical scheme for invention be modified or be replaced on an equal basis, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in the middle of right of the present invention.
Claims (5)
1. an organic-inorganic composite hollow ultra sonic imaging micro-sphere material, it is characterized in that having hollow type inorganic/organic/inorganic three-layer composite structure:
1) what be positioned at microsphere center is cavity, inner filling air;
2) intermediate layer is macromolecule layer, is the copolymer of polymethylacrylic acid and divinylbenzene;
3) between cavity and intermediate layer be ferroferric oxide magnetic nano-particles;
4) skin is Nano particles of silicon dioxide.
2. a kind of organic-inorganic composite hollow ultra sonic imaging micro-sphere material according to claim 1, this material is prepared as follows:
1) polymethyl methacrylate-methacrylic acid random copolymerization single dispersing core/shell polymeric Nano microsphere is prepared;
2) silicon dioxide is assembled at microsphere surface;
3) hollow type polymer-SiO is prepared
2nano microsphere;
4) preparation of hollow type magnetic Nano microsphere contrast agent.
3. a kind of organic-inorganic composite hollow ultra sonic imaging micro-sphere material according to claim 1 and 2, be further characterized in that above-mentioned steps 1) in core/shell polymeric Nano microsphere of being formed be double-decker, and be all adopt polymethylacrylic acid as hydrophilic segment, it is characterized in that:
1) its internal layer is polymethyl methacrylate-methacrylic acid random copolymer;
2) its skin is polymethylacrylic acid and divinyl benzene crosslinked polymer.
4. a kind of organic-inorganic composite hollow ultra sonic imaging micro-sphere material according to claim 1 and 2, is further characterized in that: have meso-hole structure in outermost Nano particles of silicon dioxide.
5. a kind of organic-inorganic composite hollow ultra sonic imaging micro-sphere material according to claim 1 and 2, be further characterized in that: macromolecule layer is the copolymer of polymethylacrylic acid and divinylbenzene, macromolecule has double-deck polymethylacrylic acid structure, utilizes divinylbenzene bridging between molecule.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104415364A (en) * | 2013-08-27 | 2015-03-18 | 成都市绿科华通科技有限公司 | Polyacrylonitrile-containing medical high-molecular contrast agent microballoon |
| CN105169417A (en) * | 2015-08-18 | 2015-12-23 | 王新强 | Contrast agent used for NMR imaging |
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Application publication date: 20150318 |