CN101574530A - Novel PLGA-PEG-PLGA multipolymer microbubble ultrasound contrast agent and preparation method thereof - Google Patents
Novel PLGA-PEG-PLGA multipolymer microbubble ultrasound contrast agent and preparation method thereof Download PDFInfo
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- CN101574530A CN101574530A CNA2009101120141A CN200910112014A CN101574530A CN 101574530 A CN101574530 A CN 101574530A CN A2009101120141 A CNA2009101120141 A CN A2009101120141A CN 200910112014 A CN200910112014 A CN 200910112014A CN 101574530 A CN101574530 A CN 101574530A
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Abstract
The invention discloses a novel PLGA-PEG-PLGA multipolymer microbubble ultrasound contrast agent and preparation method thereof. The microbubble ultrasound contrast agent is provided with an outer housing prepared from the polymer material PLGA-PEG-PLGA, the components of the inner core of gas include perfluoropropane, decafluorobutane or sulphur hexafluoride, and the like, and the molecular weight of the PLGA-PEG-PLGA multipolymer ranges from 2000 to 20000 dal. The preparation of the agent adopts the double emulsion method, and after being frozen and dried, gas molecules are led into microbubbles. The multipolymer microbubble contrast agent has favorable backscattering performance, shows the enhanced effect of ultrasonic contrast during in vivo and in vitro experiments, is safe and nontoxic, and meets the requirement of the ultrasound contrast agent.
Description
Technical field:
The present invention relates to a kind of gassiness microcapsular ultrasound contrast agent of macromolecule polymer material preparation, belong to ultrasound medicine diagnosis, treatment field.
Background technology:
Conventional acoustic contrast agent is a kind of micron order contrast agent, and about 2～4 μ m of the average diameter of microvesicle do not see through blood vessel, are a kind of blood pool imaging agent.The gassiness microvesicle is to utilize its almost whole reflected ultrasound energy as acoustic contrast agent, produces the contrast image technology of notable difference behind the injection human body with surrounding tissue.Its clinical practice mainly comprises: microvesicle can show tiny and low velocity blood flow after injecting blood vessel effectively; Microvesicle can be used as tracer, situations such as organizing microcirculatory perfusion or organ blood supply state, physiological metabolism is provided and show the full situation of lesion tissue radiography and the time phase change feature, it is the milestone that ultrasonic image is learned development, also be one of focus of this area research simultaneously, have broad clinical application prospect.
The development of microvesicle acoustic contrast has been experienced the free micro air bubble ultrasonic contrast medium of the first generation, has been wrapped up the second filial generation acoustic contrast agent of air.Since nineteen ninety-five, the gas of the low dispersivity of parcel low solubility is succeeded in developing as fluorine-containing alkanes or the acoustic contrast agent of new generation that contains sulfur hexafluoride gas, has improved microvesicle in stability in blood, make the ultrasonic development effect obviously strengthen, can be used for the perfused tissue radiography.At present representative acoustic contrast agent is the SonoVue (Novi) that the Levovist (sharp sound shows) that develops of German Schering company and Italian Bracco company develop.
Problems such as the filmogen of above-mentioned preparation microbubble contrast agent adopts albumin, lipid and saccharide etc. more, and the microvesicle ubiquity body internal stability of these material preparations is not good enough, and the half-life is short in blood plasma.Recent study shows that the microbubble contrast agent of macromolecular material preparation has better body internal stability, and biodegradable, does not have irritated reaction, is a kind of more potential filmogen.In addition, the method that the preparation of present most microcapsular ultrasound contrast agents adopts the gas compound voice with filmogen and the quilt that wraps to shake, this kind preparation method all have certain limitation controlling microvesicle particle diameter, particle size distribution, membrane wrapping thickness and aspects such as elasticity and nonlinear acoustics characteristic.
Summary of the invention:
The object of the present invention is to provide a kind of Novel PLGA-PEG-PLGA multipolymer microbubble ultrasound contrast agent, polylactic-co-glycolic acid-polyethylene glycol-lactic acid hydroxyacetic acid (PLGA-PEG-PLGA) that the shell of microvesicle adopts is a kind of degradable macromolecular material, histocompatibility is good, generates CO at last through metabolism
2And H
2O gets rid of external, non-immunogenicity, and safety is good.
The object of the present invention is achieved like this, described Novel PLGA-PEG-PLGA multipolymer microbubble contrast agent, its particle diameter is 1.1-7.2 μ m, mean diameter is the PLGA-PEG-PLGA copolymer microvesicle group that the PLGA-PEG-PLGA copolymer microvesicle set of the suitable number of 3.8 μ m forms, the structure of each PLGA-PEG-PLGA copolymer microvesicle is made of the shell of microvesicle and the gas kernel of microvesicle, the shell of described microvesicle is the shell that polylactic-co-glycolic acid-polyethylene glycol-lactic acid hydroxyacetic acid (PLGA-PEG-PLGA) is made, and the molecular weight of described PLGA-PEG-PLGA copolymer is 2000～20000dal; Nuclear composition is selected from and is noble gases such as gasiform perfluoropropane, perfluorinated butane or sulfur hexafluoride under the room temperature in the gas of described microvesicle, the shell of described microvesicle has charged into the noble gas kernel that is gasiform perfluoropropane, perfluorinated butane or sulfur hexafluoride etc. under the room temperature and has constituted the Novel PLGA-PEG-PLGA multipolymer microbubble contrast agent, the used macromolecular material of the shell of microvesicle is selected from Polyethylene Glycol, lactic acid/co-glycolic acid, or its binary or ternary block polymer, graft copolymer.
The technical scheme that Novel PLGA-PEG-PLGA multipolymer microbubble contrast agent its preparation method of the present invention is adopted is that water/oil/water emulsion-solvent evaporation method prepares microvesicle, 1) the PLGA-PEG-PLGA copolymer is dissolved in and forms polymer solution in the organic solvent, by the volume ratio of polymer solution and normal saline is normal saline to be joined in the polymer solution in 100: 10～100: 30, stirs 0.5～5min and obtain colostric fluid under 10000-20000 rev/min of rotating speed; 2) in colostric fluid, pour in the polyvinyl alcohol water solution of suitable concentration, under 2000～20000 rev/mins of rotating speeds, stir 0.5～5min, the polyvinyl alcohol water solution that adds Sq again, under 100～500 rev/mins of rotating speeds, magnetic agitation 2～24h makes the organic solvent volatilization fully, centrifugalize, the redistilled water washing, the shell of acquisition microvesicle; 3) shell with above-mentioned microvesicle adds antifreezing agent glycerol, charges into the noble gas kernel that is gasiform perfluoropropane, perfluorinated butane or sulfur hexafluoride etc. under the room temperature after the vacuum lyophilization, cryopreservation.Regulate by selection and preparation technology, the compressive resistance performance and the body internal stability of copolymer microvesicle obviously improve, and microvesicle size distribution homogeneous.The ultimate principle that this microbubble structure forms is that polymer is dissolved in organic solvent, mixes vibration with interior water and stirs, and along with the volatilization of organic solvent, the macromolecular material film-forming, forming the outside is that PLGA-PEG-PLGA copolymer, inside are the microgranule of water.This microgranule is the internal moisture distillation after vacuum lyophilization, forms the microvesicle of hollow, and gas molecule can enter microvesicle inside by molecular diffusion, infiltration, finally obtains gassiness microbubble contrast agent.
It is 20～200mg/ml that above-mentioned PLGA-PEG-PLGA copolymer is dissolved in the concentration that forms polymer solution in the organic solvent.Above-mentioned organic solvent is that dichloromethane is or/and ethyl acetate.The weight percent concentration of above-mentioned polyvinyl alcohol water solution is 2～5%.
The external acoustic characteristic test shows of acoustic contrast agent of the present invention, the copolymer microbubble contrast agent has good backscattering performance, and the resonant frequency that resonance produces meets the basic demand of acoustic contrast agent in diagnostic ultrasound frequency range of receiving.
The beneficial effect of copolymer microbubble contrast agent of the present invention is:
(1) manufacture method of invention microbubble contrast agent is simple and convenient, easy operating;
(2) sheathing material of invention use is biodegradable high-molecular copolymer, and degradable is that carbon dioxide and water excrete in vivo, and human body is had no side effect.
(3) the gas kernel that uses of invention can better improve the radiography effect as being noble gases such as gasiform perfluoropropane, perfluorinated butane and sulfur hexafluoride under the room temperature.
(4) Fa Ming microbubble contrast agent particle diameter 1.1-7.2 μ m, average 3.8 μ m, through the body surface intravenous injection, microbubble contrast agent can comprise the contrast examination of each systemic disease of whole body of the left heart smoothly by pulmonary circulation.
(5) microvesicle is long stabilization time, and PLGA-PEG-PLGA is as the coated fertilizer of forming the microvesicle surface, and intermolecular force is stronger, and surface tension is low, makes the stability of film and anti-stress obviously improve, and the body internal stability is good, obviously strengthens the radiography effect.
(6) microcapsular ultrasound contrast agent of the present invention is applicable to body each systemic disease, especially cardiovascular system, the ultrasonic contrast inspection of liver, biliary tract, kidney, pancreas, mammary gland, thyroid, gynecological tumor diagnosis and diseases such as therapeutic evaluation and wound.
Description of drawings:
Fig. 1 is the optical microscope figure (* 400) of PLGA-PEG-PLGA copolymer microbubble contrast agent of the present invention.
Fig. 2 is the external second harmonic quantitative analysis figure of PLGA-PEG-PLGA copolymer microbubble contrast agent of the present invention.
Fig. 3 strengthens figure for the rabbit liver radiography of PLGA-PEG-PLGA copolymer microbubble contrast agent of the present invention.
The specific embodiment:
Synthetic and the sign of embodiment 1:PLGA-PEG-PLGA copolymer
Putting into 15g (mass percent 40%) Mw in there-necked flask is 1500 Polyethylene Glycol; 150 ℃ of vacuum conditions stir 3h down; add the 3.2g Acetic acid, hydroxy-, bimol. cyclic ester; 19.3g the inferior stannum of lactide (Acetic acid, hydroxy-, bimol. cyclic ester and lactide mol ratio are 1: 4) and 0.04g octoate catalyst, nitrogen protection reaction 8hr down obtain product.Product is dissolved in the chloroform, the dehydrated alcohol deposition and purification, normal temperature drying is to constant weight.Adopting the mean molecule quantity of efficient gel permeation chromatography analysis-e/or determining copolymer is 5880dal, Fourier infrared spectrum,
1H NMR spectrum is shown as typical PLGA-PEG-PLGA structure.
The preparation of embodiment 2:PLGA-PEG-PLGA microvesicle
Adopt water/oil/water emulsion-solvent evaporation method to prepare microvesicle.1ml concentration is the PLGA-PEG-PLGA dichloromethane/ethyl acetate mixed solution of 50mg/ml, add the 0.1ml normal saline, 10000 rev/mins of rotating speeds stir 1min and obtain colostric fluid, pour in 4ml 3% polyvinyl alcohol water solution, 10000 rev/mins are stirred 1min, add 15ml 3% polyvinyl alcohol water solution again, 400 rev/mins of magnetic agitation 3h, make the organic solvent volatilization fully, centrifugalize, the redistilled water washing, the gained microvesicle adds antifreezing agent glycerol, charge into the noble gas perfluoropropane after the vacuum lyophilization, cryopreservation.
The sign of embodiment 3:PLGA-PEG-PLGA microvesicle
Microvesicle is scattered in the normal saline, and inverted microscope is observed microvesicle down and is spheroidal, smooth surface, and good dispersion, no adhesion, size is (see figure 1) evenly.Get an amount of microvesicle powder and be scattered in the normal saline, laser particle size analyzer is measured microspherulite diameter 1.1-7.2 μ m, average 3.8 μ m.
The external second harmonic imaging of embodiment 4:PLGA-PEG-PLGA microvesicle
A certain amount of PLGA-PEG-PLGA microvesicle freeze-dried powder is scattered in the normal saline, concentration is 1.0mg/ml, the fixing degree of depth (50mm) of the position of ultrasonic probe, angle and distance sample, regulate ultrasonic output intensity MI in 0.03～1.0 range, other parameters of instrument remain unchanged in experiment.GTG change in signal strength under the more different mechanical index conditions, and draw time-activity curve.Obtain the harmonic mode image of diluted concentration after progressively diluting 2,5,10 times with normal saline.System analyzes with ultrasonic image quantitatively analyzing, the result with the acoustics intensity of microvesicle under the concentration with the increase of MI the rising (see figure 2).
The body interimage of embodiment 5:PLGA-PEG-PLGA microvesicle
New zealand white rabbit is with 3% Nembutal vein anesthetic (1ml/kg), microcapsular ultrasound contrast agent 0.1ml/kg annotates in group through auricular vein, show that rabbit liver, ventral aorta etc. carry out the observation of development effect in the body, real-time video record, with the DICOM format conversion is digital signal, carries out quantitative analysis.The result shows: rabbit liver ultrasonic findings before radiography is more uniform echo on the low side, inject the interior tremulous pulse of the visible mutually liver of contrast agent artery and be streak enhancing, portal vein is met each other, and portal vein and liver parenchyma all strengthen in the liver, the liver parenchyma echo that postpones to meet each other obviously strengthens, and ventral aorta is arterial phase and significantly strengthens the performance (see figure 3).
Claims (7)
1, a kind of Novel PLGA-PEG-PLGA multipolymer microbubble ultrasound contrast agent, it is characterized in that by particle diameter be 1.1-7.2 μ m, mean diameter is the PLGA-PEG-PLGA copolymer microvesicle group that the PLGA-PEG-PLGA copolymer microvesicle set of the suitable number of 3.8 μ m forms, the structure of each PLGA-PEG-PLGA copolymer microvesicle is made of the shell of microvesicle and the gas kernel of microvesicle, the shell of described microvesicle is the shell that polylactic-co-glycolic acid-polyethylene glycol-lactic acid hydroxyacetic acid (PLGA-PEG-PLGA) is made, and the molecular weight of described PLGA-PEG-PLGA copolymer is 2000～20000dal; Nuclear composition is selected from and is noble gases such as gasiform perfluoropropane, perfluorinated butane or sulfur hexafluoride under the room temperature in the gas of described microvesicle, and described microvesicle envelope filled gone into the Novel PLGA-PEG-PLGA multipolymer microbubble contrast agent that is the noble gas kernel of gasiform perfluoropropane, perfluorinated butane or sulfur hexafluoride etc. under the room temperature and constitutes.
2, a kind of Novel PLGA-PEG-PLGA multipolymer microbubble ultrasound contrast agent according to claim 1, the used macromolecular material of shell that it is characterized in that microvesicle is selected from Polyethylene Glycol, lactic acid/co-glycolic acid, or its binary or ternary block polymer, graft copolymer.
3, the preparation method of the described a kind of Novel PLGA-PEG-PLGA multipolymer microbubble ultrasound contrast agent of claim 1, comprise the steps: to adopt water/oil/water emulsion-solvent evaporation method to prepare microvesicle, 1) the PLGA-PEG-PLGA copolymer is dissolved in and forms polymer solution in the organic solvent, by the volume ratio of polymer solution and normal saline is normal saline to be joined in the polymer solution in 100: 10～100: 30, stirs 0.5～5min and obtain colostric fluid under 10000-20000 rev/min of rotating speed; 2) in colostric fluid, pour in the polyvinyl alcohol water solution of suitable concentration, under 2000～20000 rev/mins of rotating speeds, stir 0.5～5min, the polyvinyl alcohol water solution that adds Sq again, under 100～500 rev/mins of rotating speeds, magnetic agitation 2～24h makes the organic solvent volatilization fully, centrifugalize, the redistilled water washing, the shell of acquisition microvesicle; 3) shell with above-mentioned microvesicle adds antifreezing agent glycerol, charges into the noble gas kernel that is gasiform perfluoropropane, perfluorinated butane or sulfur hexafluoride etc. under the room temperature after the vacuum lyophilization, cryopreservation.
4, the preparation method of a kind of Novel PLGA-PEG-PLGA multipolymer microbubble ultrasound contrast agent according to claim 3 is characterized in that it is 20～200mg/ml that the PLGA-PEG-PLGA copolymer is dissolved in the concentration that forms polymer solution in the organic solvent.
5,, it is characterized in that described organic solvent is that dichloromethane is or/and ethyl acetate according to the preparation method of claim 3 or 4 described a kind of Novel PLGA-PEG-PLGA multipolymer microbubble ultrasound contrast agents.
6, according to the preparation method of claim 3 or 4 described a kind of Novel PLGA-PEG-PLGA multipolymer microbubble ultrasound contrast agents, the weight percent concentration that it is characterized in that described polyvinyl alcohol water solution is 2～5%.
7, the microbubble contrast agent used as diseases such as diagnosis various tumors, cardiovascular of the described a kind of Novel PLGA-PEG-PLGA multipolymer microbubble ultrasound contrast agent of claim 1-2.
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| CN102861345A (en) * | 2012-10-22 | 2013-01-09 | 南京林业大学 | Preparation method of polymer microvesicle ultrasonic contrast agent |
| CN103432601A (en) * | 2013-08-26 | 2013-12-11 | 福建医科大学附属协和医院 | Perfluorooctylbromide coated block polymer ultrasound microbubble contrast agent and preparation method thereof |
| EP2708244A1 (en) | 2012-09-14 | 2014-03-19 | Stichting Katholieke Universiteit | Contrast agent and its use for imaging. |
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| EP2708244A1 (en) | 2012-09-14 | 2014-03-19 | Stichting Katholieke Universiteit | Contrast agent and its use for imaging. |
| WO2014041150A1 (en) | 2012-09-14 | 2014-03-20 | Stichting Katholieke Universiteit | Contrast agent and its use for imaging |
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| CN102861345A (en) * | 2012-10-22 | 2013-01-09 | 南京林业大学 | Preparation method of polymer microvesicle ultrasonic contrast agent |
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| CN103432601B (en) * | 2013-08-26 | 2015-01-07 | 福建医科大学附属协和医院 | Perfluorooctylbromide coated block polymer ultrasound microbubble contrast agent and preparation method thereof |
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| JP6997717B2 (en) | 2016-03-11 | 2022-02-04 | スティヒティング ラドバウド ユニヴェルシテール メディッシュ セントルム | Methods for preparing beads for imaging |
| EP3216464A1 (en) | 2016-03-11 | 2017-09-13 | Stichting Katholieke Universiteit Nijmegen | Process for preparation of beads for imaging |
| WO2017153605A1 (en) * | 2016-03-11 | 2017-09-14 | Stichting Katholieke Universiteit | Process for preparation of beads for imaging |
| JP2019510759A (en) * | 2016-03-11 | 2019-04-18 | スティヒティング カトリーケ ユニヴェルシテイト | Method for the preparation of beads for imaging |
| US11286352B2 (en) | 2016-03-11 | 2022-03-29 | Stichting Radboud Universitair Medisch Centrum | Process for preparation of beads for imaging |
| CN107669658A (en) * | 2017-09-20 | 2018-02-09 | 华中科技大学同济医学院附属协和医院 | A kind of load enzyme nanometer microvesicle of folacin receptor targeting and preparation method thereof |
| CN111358956A (en) * | 2020-03-25 | 2020-07-03 | 南京鼓楼医院 | Nano switch molecule and solid tumor targeting CAR-T cell for controlling activation of nano switch molecule |
| CN113929740A (en) * | 2020-06-29 | 2022-01-14 | 中国科学技术大学 | Amphiphilic polypeptide and preparation method and application thereof |
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