CN104107440A - Novel preparation process for polyester hard-shell microbubble system with controllable particle size - Google Patents
Novel preparation process for polyester hard-shell microbubble system with controllable particle size Download PDFInfo
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- CN104107440A CN104107440A CN201310161939.1A CN201310161939A CN104107440A CN 104107440 A CN104107440 A CN 104107440A CN 201310161939 A CN201310161939 A CN 201310161939A CN 104107440 A CN104107440 A CN 104107440A
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Abstract
The invention relates to a novel polyester hard-shell gas-carried microbubble system (shown in the figure), and a new preparation process for building the polyester hard-shell gas-carried microbubble system with controllable particle size. A gas core is air; a polyester shell material is poly(n-butyl acrylate); the microbubble diameter is controlled at different particle sizes of 3.03 microns, 2.43 microns and 341.4 nanometers. The preparation process comprises the steps: with a n-butyl acrylate monomer as a preparation starting material, carrying out room temperature high speed stirring for 60 minutes in a stabilizer (polyethylene glycol octylphenol ether) solution and a high-pure water reaction system, completing a reaction, then separating the liquid, standing, washing with the stabilizer solution to obtain a crude product, then carrying out low speed centrifugation and merging concentration, and redispersing into the stabilizer solution for preservation, and thus obtaining the pure polyester hard-shell gas-carried microbubble system with higher yield. The preparation process is green and mild, generates no noise, radiation and other pollutions, has simple and convenient separation and purification operations, and easily realizes industrialized production; and the microbubble system has controllable particle size, and has good biomedical application prospects.
Description
Technical field
The present invention relates to the new preparation process of the controlled polyester duricrust carrier gas microvesicle system of a kind of structure particle diameter of novelty.
Background technology
As far back as nineteen sixty-eight, carrier gas microvesicle just learns that can be used as acoustic contrast agent is used for improving contrast and the resolution of imaging.In carrier gas microvesicle, the difference of occlusion gas and in-vivo tissue sound impedance causes carrier gas microvesicle to strengthen for hyperacoustic reflectance, the compressibility that simultaneously forms microvesicle case material has caused ultrasound wave nonlinear reflection, based on this principle, ultrasonic microbubble has become the common agents of clinical diagnosis as medical science contrast agent, in order to improve the contrast effect of radiography, strengthen the accuracy of Clinics and Practices.In today of people's growing interest health medical treatment and disease early diagnosis, apply different raw doctor's material and preparation technology and build novel ultrasonic contrast medium, in ensureing body internal contact compatibility and safety in utilization, realizing best development effect has become emphasis and the focus of these field research and development.
The construction strategy of the carrier gas microvesicle of previous literature report adopts phospholipid, albumin, saccharide etc. as microvesicle case material more, shortcoming (the Feinstein SB such as the soft shell microvesicle system body internal stability that obtains is poor, housing compressibility is bad, ultrasonic echo reflectance is weak and the radiography cycle is short, Cheirif J, Tencate FJ, et al.JAm Coll Cardiol 1990; 16:316-24.).For adopting high polymer as the report of microvesicle case material few (Yang F, Gu A, Chen Z, Gu N, Ji M Materials Letters 2008; 62:121-24.), but complicated process of preparation adopts poisonous organic solvent as reaction medium more, and the multi-step synthesis strategy successively building makes productive rate lower, and is not suitable for building the integrated contrast agent of the multi-functional diagnosis and treatment such as radiography and medicine carrying.Therefore, select suitable housing composition material, Development of Novel practicality, high-efficient simple and green ultrasonic microbubble preparation technology seem extremely important.
The particle diameter of carrier gas microvesicle is determining field and the radiography effect of its application, and micron order microvesicle is usually for angiography and targeting diagnosis and medicine carrying treatment related to this, and nanoscale microvesicle can be used for the labelling of cell and the cell transfecting of gene or medicine.Therefore, the microvesicle preparation technology of different-grain diameter produces and has important value for industrialization, and the microvesicle system of optionally efficiently preparing different-grain diameter via a kind of preparation technology broad applicability of the biomedical applications to microvesicle has great significance.
Summary of the invention
The object of the present invention is to provide a kind of new method that builds and prepare the polyesters duricrust microvesicle system of different-grain diameter, thereby select for bio-imaging, the personalized different application field such as medical image and clinical diagnosis and treatment in experimental medicine provide acoustic contrast agent widely.
Preparation technology of the present invention is green gentle, do not produce the pollutions such as noise radiation, separating-purifying is easy and simple to handle, easily realizing industrialization produces, the positive butyl ester of polyacrylic acid that forms housing has good biocompatibility and safety, gained microvesicle system particle diameter is controlled, is expected to build at ultrasound medicine radiography, targeted drug, is used widely in the research such as the diagnosis of Image-aided and clinical integrated diagnosis and treatment, has good biomedical applications prospect.
The present invention relates to novel polyesters duricrust carrier gas microvesicle system, its universal architecture as shown in Figure 1.
Wherein gas core is air; Polyester shell material is that the positive butyl ester of polyacrylic acid is cured material this all one's life, and microvesicle diameter is controlled in different-grain diameters such as 3.03 microns, 2.43 microns and 341.4 nanometers.
For achieving the above object, the invention provides the new preparation process that builds the controlled polyesters duricrust carrier gas microvesicle system of particle diameter, that is: with n-butyl acrylate monomer for preparing starting material, in stabilizing agent (Triton X-100) solution and high purity water reaction system, room temperature high-speed stirred completes reaction for 60 minutes,, stabiliser solution washing standing by separatory obtains crude product, concentrate, be again dispersed in stabiliser solution and preserve through low-speed centrifugal, merging again, can higher yields obtain pure polyester duricrust carrier gas microvesicle system.This preparation feedback formula and technological process (Fig. 2) can be as follows:
This preparation technology mainly comprises the following steps:
A. n-butyl acrylate, stabilizing agent (Triton X-100), high purity water were fed intake according to 1: 1: 100;
B. when question response system pH is down to faintly acid (approximately 2.5), in room temperature high-speed stirred 60 minutes;
C. after reaction terminating, system is transferred to separatory funnel and leaves standstill 5 hours, discard bottom, retain top layer microvesicle, obtain crude product three times with 0.02% Triton X-100 solution washing;
D. microvesicle product is divided to centrifuge tube to centrifugal 20 minutes of purification;
E. collect centrifugal gained upper strata microvesicle product, repeated centrifugation three times, merges upper strata microscopic bubble layer, is again dispersed in 0.02% Triton X-100 stabiliser solution and preserves, and obtains pure polyester duricrust carrier gas microvesicle system.
The polyester duricrust carrier gas microvesicle system of the different-grain diameter that the present invention obtains, after centrifugal purification, productive rate can reach 67-91%.The each product component of gained has obtained the accurate confirmation of component and structure through nmr spectrum (NMR, Fig. 3) and infrared spectrum (IR, Fig. 4).
The nuclear magnetic resonance spectroscopy data of polyester duricrust carrier gas microvesicle system:
1hNMR (300MHz, CDCl
3): 60.98 (m ,-C
h 3) 1.47 (br ,-C
h 2cH
3) 1.76 (br ,-C
h 2cH
2cH
3) 2.49-2.81 (br ,-C
h 2c (CN) (CO
2bu)-) 4.28 (br ,-OC
h 2-)
Microvesicle system particle diameter and microscopic appearance are accurately observed through means such as scanning electron microscope (SEM) and transmission electron microscopes (TEM).The polyester carrier gas microvesicle of different-grain diameter is accurately verified by clinical ultrasound instrument hyperacoustic usable reflection and development effect in ultrasonic contrast.
Brief description of the drawings
The universal architecture of Fig. 1 polyester duricrust carrier gas microvesicle system involved in the present invention
Preparation technology's flow process of the controlled polyester duricrust microvesicle system of the novel particle diameter of Fig. 2
The 1HNMR spectrogram of Fig. 3 polyester duricrust carrier gas microvesicle
The IR spectrogram of Fig. 4 polyester duricrust carrier gas microvesicle
Fig. 5 particle diameter is polyester carrier gas microvesicle TEM (a), SEM (b) and the ultrasonic contrast analysis diagram (c) of 3.03 microns
Fig. 6 particle diameter is polyester carrier gas microvesicle TEM (a), SEM (b) and the ultrasonic contrast analysis diagram (c) of 2.43 microns
Fig. 7 particle diameter is polyester carrier gas microvesicle TEM (a), SEM (b) and the ultrasonic contrast analysis diagram (c) of 341.4 nanometers
Detailed description of the invention
Raw materials of the present invention is commodity and obtains.
Embodiment 1: n-butyl acrylate, Triton X-100, high purity deionized water were fed intake in 2 liters of beakers according to 1: 1: 100, pH value of reaction system downgrades faintly acid (approximately 2.5), under room temperature, (rpm=10000) stirs 60 minutes at a high speed, after question response stops, crude product is transferred to separatory funnel and leaves standstill 5 hours, discard bottom residue, retain top layer microvesicle, and with 0.02% Triton X-100 solution washing three times.Products therefrom is sub-packed in centrifuge tube, centrifugal 20 minutes of purification, and carefully collect centrifuge tube top layer microvesicle product layer, after repeated centrifugation three times, merge microscopic bubble layer, again be dispersed in 0.02% Triton X-100 aqueous solution in 4 DEG C of preservations, obtain pure polyester duricrust carrier gas microvesicle system (productive rate: 91%).Through measuring, microvesicle particle diameter d=3.03 ± 0.98 micron, microvesicle microscopic appearance obtains picture rich in detail by scanning electron microscope (SEM) and transmission electron microscope (TEM) analysis, microvesicle has good reflection and imaging results for ultrasound wave in ultrasonic field, and the analysis of applying clinical Vltrasonic device obtains blur-free imaging spectrogram (Fig. 5).
Embodiment 2: n-butyl acrylate, Triton X-100, high purity deionized water were fed intake in 2 liters of beakers according to 1: 1: 100, pH value of reaction system downgrades faintly acid (approximately 2.5), under room temperature, (rpm=8000) stirs 60 minutes at a high speed, after question response stops, crude product is transferred to separatory funnel and leaves standstill 5 hours, discard bottom residue, retain top layer microvesicle, and with 0.02% Triton X-100 solution washing three times.Products therefrom is sub-packed in centrifuge tube, centrifugal 20 minutes of purification, and carefully collect centrifuge tube top layer microvesicle product layer, after repeated centrifugation three times, merge microscopic bubble layer, again be dispersed in 0.02% Triton X-100 aqueous solution in 4 DEG C of preservations, obtain pure polyester duricrust carrier gas microvesicle system (productive rate: 86%).Through measuring, microvesicle particle diameter d=2.43 ± 0.46 micron, microvesicle microscopic appearance obtains picture rich in detail by scanning electron microscope (SEM) and transmission electron microscope (TEM) analysis, microvesicle has good reflection and imaging results for ultrasound wave in ultrasonic field, and the analysis of applying clinical Vltrasonic device obtains blur-free imaging spectrogram (Fig. 6).
Embodiment 3: n-butyl acrylate, Triton X-100, high purity deionized water were fed intake in 2 liters of beakers according to 1: 1: 100, pH value of reaction system downgrades faintly acid (approximately 2.5), under room temperature, (rpm=4000) stirs 60 minutes at a high speed, after question response stops, crude product is transferred to separatory funnel and leaves standstill 5 hours, discard bottom residue, retain top layer microvesicle, and with 0.02% Triton X-100 solution washing three times.Products therefrom is sub-packed in centrifuge tube, centrifugal 20 minutes of purification, and carefully collect centrifuge tube top layer microvesicle product layer, after repeated centrifugation three times, merge microscopic bubble layer, again be dispersed in 0.02% Triton X-100 aqueous solution in 4 DEG C of preservations, obtain pure polyester duricrust carrier gas microvesicle system (productive rate: 67%).Through measuring, microvesicle particle diameter d=341.4 ± 27.6 nanometer, microvesicle microscopic appearance obtains picture rich in detail by scanning electron microscope (SEM) and transmission electron microscope (TEM) analysis, microvesicle has good reflection and imaging results for ultrasound wave in ultrasonic field, and the analysis of applying clinical Vltrasonic device obtains blur-free imaging spectrogram (Fig. 7).
Claims (6)
1. the polyesters duricrust carrier gas microvesicle system of universal architecture shown in Fig. 1:
Wherein gas core is air; Polyester shell material is that the positive butyl ester of polyacrylic acid is cured material this all one's life.
2. according to the carrier gas microvesicle system of claim 1, wherein gas core is air; Polyester shell material is the positive butyl ester of polyacrylic acid, and microvesicle particle diameter is 3.03 ± 0.98 microns.
3. according to the carrier gas microvesicle system of claim 1, wherein gas core is air; Polyester shell material is the positive butyl ester of polyacrylic acid, and microvesicle particle diameter is 2.43 ± 0.37 microns.
4. according to the carrier gas microvesicle system of claim 1, wherein gas core is air; Polyester shell material is the positive butyl ester of polyacrylic acid, and microvesicle particle diameter is 341.4 ± 27.6 nanometers.
5. the preparation technology of the carrier gas microvesicle system of claim 2-4, this technique comprises the following steps:
A. n-butyl acrylate, stabilizing agent (Triton X-100), high purity water were fed intake according to 1: 1: 100;
B. when question response system pH is down to faintly acid (approximately 2.5), in room temperature high-speed stirred 60 minutes;
C. after reaction terminating, system is transferred to separatory funnel and leaves standstill 5 hours, discard bottom, retain top layer microvesicle, obtain crude product three times with 0.02% Triton X-100 solution washing;
D. microvesicle product is divided to centrifuge tube to centrifugal 20 minutes of purification;
E. collect centrifugal gained upper strata microvesicle product, repeated centrifugation three times, merges upper strata microscopic bubble layer, is again dispersed in 0.02% Triton X-100 stabiliser solution and preserves, and obtains pure polyester duricrust carrier gas microvesicle system.
6. the preparation technology of claim 5, it is characterized in that: reaction condition gentleness, technique green are easy, noiselessness radiation waste pollution, productive rate ideal, separating-purifying are easy and simple to handle, easily realize industrialization and produce, gained microvesicle system particle diameter is controlled, and has good biomedical applications prospect.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104984364A (en) * | 2015-03-31 | 2015-10-21 | 温州生物材料与工程研究所 | Composite nanometer photoacoustic contrast agent based on polybutyl acrylate, and preparation process thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997022409A1 (en) * | 1995-12-21 | 1997-06-26 | Drexel University | Hollow polymer microcapsules and method of producing |
| CN1424919A (en) * | 2000-03-15 | 2003-06-18 | 舍林股份公司 | Microcapsules comprising functionalised polyalkylcyanoacrylates |
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2013
- 2013-04-17 CN CN201310161939.1A patent/CN104107440A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997022409A1 (en) * | 1995-12-21 | 1997-06-26 | Drexel University | Hollow polymer microcapsules and method of producing |
| CN1424919A (en) * | 2000-03-15 | 2003-06-18 | 舍林股份公司 | Microcapsules comprising functionalised polyalkylcyanoacrylates |
Non-Patent Citations (1)
| Title |
|---|
| 郭生伟: "超声辐照乳液聚合制备聚丙烯酸正丁酯空心微球", 《高分子学报》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104984364A (en) * | 2015-03-31 | 2015-10-21 | 温州生物材料与工程研究所 | Composite nanometer photoacoustic contrast agent based on polybutyl acrylate, and preparation process thereof |
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Application publication date: 20141022 |