CN104415362A - Novel ultrasonic-diagnosis medical high-molecular material - Google Patents
Novel ultrasonic-diagnosis medical high-molecular material Download PDFInfo
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- CN104415362A CN104415362A CN201310361793.5A CN201310361793A CN104415362A CN 104415362 A CN104415362 A CN 104415362A CN 201310361793 A CN201310361793 A CN 201310361793A CN 104415362 A CN104415362 A CN 104415362A
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- microsphere
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Abstract
The invention discloses a novel ultrasonic-diagnosis medical high-molecular material. A microsphere is in a hollow inorganic/organic/inorganic three-layer structure. A hollow cavity is formed in the center of the microsphere with air therein. A Fe3O4 magnetic particle is formed on an external layer of the hollow cavity. A middle layer is a core/shell polymer nano-microsphere which is formed from a polypropylene-polyacrylic acid random copolymer and polyacrylic acid and divinyl benzene through free radical polymerization. A coordinate bond or an ionic bond can be formed between the copolymer and the Fe3O4 magnetic particle, in the internal layer, through carboxyl groups and ferric salts on an internal surface so that the structure is stable. An external layer is silicon dioxide which is connected to the nano-microsphere through a hydrogen bond effect due to the carboxyl groups on the nano-microsphere and silicon hydroxyl groups on the surface of the silicon dioxide. The system is advantaged in that the polymer microsphere belongs to nano-scale particles, wherein the Fe3O4 magnetic particle in the internal layer allows targeted positioning of a contrast medium, the silicon dioxide hollow microsphere is good in biocompatibility and mechanical-stability, and the hollow cavity can generate a strong echo signal under a radiography 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 PPz 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 PP 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, there is provided herein a kind of Novel ultrasonic diagnostic medical macromolecular 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 polyacrylic 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 propylene and acrylic 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 polyacrylic 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 PP core, obtain SiO
2tiny balloon, its form keeps stable and structural integrity, has a good spherical structure.Preparation process schematic diagram as shown in Figure 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) this Novel ultrasonic diagnostic medical macromolecular material has good biocompatibility;
2) to have volume little for this Novel ultrasonic diagnostic medical macromolecular material, has nanoscale structures, can by various human body barriers;
3) this Novel ultrasonic diagnostic medical macromolecular material is due to the Fe containing superparamagnetism
3o
4, therefore there is Targeting Performance;
4) this Novel ultrasonic diagnostic medical Polymer Materials ' Structure is stable, mechanical stability is 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 Novel ultrasonic diagnostic medical macromolecular material;
Fig. 2 is the particle diameter test pattern of this Novel ultrasonic diagnostic medical macromolecular material;
Fig. 3 is the AFM scintigram of this Novel ultrasonic diagnostic medical macromolecular 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 this Novel ultrasonic diagnostic medical macromolecular 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.
Polyacrylic 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 propylene and polyacrylic acid to carry out copolymerization and obtain internal layer microsphere, then internal layer is carried out copolymerization by polyacrylic 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 this Novel ultrasonic diagnostic medical macromolecular 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 (PP-PAA) copolymer microsphere.Propylene and each 0.2mol, AIBN(azo-bis-isobutyl cyanide of acrylic 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 (PP-PAA) copolymer microsphere.
Step 2: prepare core/shell polymer microsphere by seed " from dispersion " polyreaction.By each to (PP-PAA) copolymer microsphere 3.65g, acrylic 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 PAA 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 PAA surface PP core as templated deposition SiO
2time, generally can generate the independent SiO of about 35nm
2particle.Because PP checks SiO
2adsorptivity weak, if direct PP precipitates SiO as masterplate
2, be difficult to obtain uniform SiO
2shell structurre.And when after the surface and copolymerized PAA of PP core, because of the carboxyl on PAA 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 PP 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. a Novel ultrasonic diagnostic medical macromolecular 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 polyacrylic acid and divinylbenzene;
3) between cavity and intermediate layer be ferroso-ferric oxide body magnetic nano-particle;
4) skin is Nano particles of silicon dioxide.
2. a kind of Novel ultrasonic diagnostic medical macromolecular material according to claim 1, this material is prepared as follows:
1) polypropylene-acrylic 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 Novel ultrasonic diagnostic medical macromolecular 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 polyacrylic acid as hydrophilic segment, it is characterized in that:
1) its internal layer is polypropylene-acrylic acid random copolymer;
2) its skin is polyacrylic acid and divinyl benzene crosslinked polymer.
4. a kind of Novel ultrasonic diagnostic medical macromolecular 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 Novel ultrasonic diagnostic medical macromolecular material according to claim 1 and 2, be further characterized in that: macromolecule layer is the copolymer of polyacrylic acid and divinylbenzene, macromolecule has double-deck polyacrylic acid structure, utilizes divinylbenzene bridging between molecule.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102389576A (en) * | 2011-11-11 | 2012-03-28 | 上海师范大学 | Magnetic-ultrasonic difunctional SiO2 hollow sphere contrast agent and preparation method and application thereof |
| CN103028116A (en) * | 2012-12-20 | 2013-04-10 | 中国林业科学研究院林产化学工业研究所 | Magnetic nano-composite microsphere based on cellulose base template and preparation method and use of magnetic nano-composite microsphere |
| CN104338153A (en) * | 2013-08-06 | 2015-02-11 | 成都市绿科华通科技有限公司 | Hollow type magnetic nanoparticle contrast agent. |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102389576A (en) * | 2011-11-11 | 2012-03-28 | 上海师范大学 | Magnetic-ultrasonic difunctional SiO2 hollow sphere contrast agent and preparation method and application thereof |
| CN103028116A (en) * | 2012-12-20 | 2013-04-10 | 中国林业科学研究院林产化学工业研究所 | Magnetic nano-composite microsphere based on cellulose base template and preparation method and use of magnetic nano-composite microsphere |
| CN104338153A (en) * | 2013-08-06 | 2015-02-11 | 成都市绿科华通科技有限公司 | Hollow type magnetic nanoparticle contrast agent. |
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Application publication date: 20150318 |