CN104436223A - Medical high-molecular polymer microspheres containing magnetic particles - Google Patents
Medical high-molecular polymer microspheres containing magnetic particles Download PDFInfo
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- CN104436223A CN104436223A CN201310421748.4A CN201310421748A CN104436223A CN 104436223 A CN104436223 A CN 104436223A CN 201310421748 A CN201310421748 A CN 201310421748A CN 104436223 A CN104436223 A CN 104436223A
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Abstract
The invention discloses medical high-molecular polymer microspheres containing magnetic particles. The high-molecular polymer microspheres is in a hollow-type inorganic/organic/inorganic three layer structure, a cavity is positioned at center of microspheres, air is filled in the cavity, an external layer of the cavity is alpha-Fe2O3 magnetic particles; an interface layer is a shell/core polymer nano microsphere of a polyvinyl acetate-polymethacrylic acid random copolymer, polymethacrylic acid and divinyl benzene through free radical copolymerization, the copolymer and the internal layer alpha-Fe2O3 magnetic particles enable stabilization by a coordination bond or an ionic bond formed by carboxyl on interior surface and ferric salt; and the external layer is silica, the silica can be connected to the external layer through hydrogen-bond interaction generated by carboxyl on surface of microspheres and silicon hydroxyl on surface of silica. The medical high-molecular polymer microspheres have the advantages that the polymer microspheres belong the nano-level particles; the internal layer alpha-Fe2O3 magnetic particles enable targeted positioning of a contrast agent; silica hollow microspheres have good biocompatibility and mechanical stability, and a strong echo signal can be generated in the cavity under a 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 PAcz 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 PAc 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 medical high polymer microsphere containing magnetic particle, 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;
Between cavity and intermediate layer be
-Fe
2o
3magnetic nano-particle, is 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 vinylacetate 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 PAc 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
Because Nano microsphere prepared in above-mentioned steps inside exists a large amount of carboxyls, there is a large amount of micropore at silica surface simultaneously.Therefore, this micropore can be utilized as passage, by Fe
3+after adding reaction system, utilize microchannel to enter hollow ball inside, add PEG simultaneously, NaOH, adjust ph, internal layer is combined
-Fe
2o
3magnetic particle.Nano microsphere internal layer macromolecule exists
-Fe
2o
3surface defines Fe-O-C key, and forms internal magnetization particle layer.
By above technical scheme, tool of the present invention has the following advantages: the medical high polymer microsphere 1) containing magnetic particle has good biocompatibility;
2) containing the medical high polymer microsphere of magnetic particle, there is volume little, there is nanoscale structures, can by various human body barriers;
3) containing the medical high polymer microsphere of magnetic particle due to containing superparamagnetism
-Fe
2o
3, therefore there is Targeting Performance;
4) high containing the medical high polymer micro-sphere material Stability Analysis of Structures of magnetic particle, mechanical stability.
This type of is containing can overcome the problems such as traditional contrast agent poor stability, echo signal are weak, poor biocompatibility containing medical high polymer microsphere of magnetic particle.
Accompanying drawing explanation
Fig. 1 is the structural representation of this magnetic Nano microsphere;
Fig. 2 is the particle diameter test pattern of this magnetic Nano microsphere;
Fig. 3 is the AFM scintigram of this magnetic Nano microsphere;
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 the medical high polymer microsphere containing magnetic particle.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 is
-Fe
2o
3magnetic nano-particle 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.
As macromolecule layer 2., outside adsorbs silica particle 1. simultaneously for polymethylacrylic acid-divinylbenzene crosslinking copolymerization macromolecule, and internal layer combines
-Fe
2o
3magnetic nano-particle is 3. as a preferably embodiment: utilize vinylacetate 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, internal layer is combined
-Fe
2o
3magnetic 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 the medical high polymer microsphere containing magnetic particle.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 (PAc-PMAA) copolymer microsphere.Vinylacetate 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 (PAc-PMAA) copolymer microsphere.
Step 2: prepare core/shell polymer microsphere by seed " from dispersion " polyreaction.By each to (PAc-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 PAc core as templated deposition SiO
2time, generally can generate the independent SiO of about 35nm
2particle.Because PAc checks SiO
2adsorptivity weak, if direct PAc precipitates SiO as masterplate
2, be difficult to obtain uniform SiO
2shell structurre.And when after the surface and copolymerized PMAA of PAc 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 PAc 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 1g, the FeCl of gained in above-mentioned reactions steps is added in 250mL tri-mouthfuls of round bottom reaction bulbs
36H
2o 6g, deionized water 150mL, then add 5 mL PEG-400, under magnetic stirring, with dilute NaOH solution, the pH value of mixed solution is adjusted to 3.After reaction terminates, product through centrifugalize, and with distilled water and washing with alcohol repeatedly, dry in 60 DEG C of vacuum tanks.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. containing the medical high polymer microsphere of magnetic particle, 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
-Fe
2o
3magnetic nano-particle;
4) skin is Nano particles of silicon dioxide.
2. a kind of medical high polymer microsphere containing magnetic particle according to claim 1, this material is prepared as follows:
1) polyvinyl acetate-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 medical high polymer microsphere containing magnetic particle 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 polyvinyl acetate-methacrylic acid random copolymer;
2) its skin is polymethylacrylic acid and divinyl benzene crosslinked polymer.
4. a kind of medical high polymer microsphere containing magnetic particle 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 medical high polymer microsphere containing magnetic particle 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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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109153073A (en) * | 2016-05-13 | 2019-01-04 | 意大利学院科技基金会 | Prepare the method with the Hollow Nanoparticles of metal core |
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2013
- 2013-09-16 CN CN201310421748.4A patent/CN104436223A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| K. ZHANG 等: "Magnetic polymer enhanced hybrid capsules prepared from a novel Pickering emulsion polymerization and their application in controlled drug release", 《COLLOIDS AND SURFACES A: PHYSICOCHEMICAL AND ENGINEERING ASPECTS》 * |
| NAM SEON KIM 等: "Core-shell polymerization for monodispersed hollow polymer spheres embedded with magnetic nanoparticles", 《JOURNAL OF INDUSTRIAL AND ENGINEERING CHEMISTRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109153073A (en) * | 2016-05-13 | 2019-01-04 | 意大利学院科技基金会 | Prepare the method with the Hollow Nanoparticles of metal core |
| CN109153073B (en) * | 2016-05-13 | 2020-08-25 | 意大利学院科技基金会 | Method for producing hollow nanoparticles having a metal core |
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Application publication date: 20150325 |