CN1209167C - Supersonic contrast medium and supersonic contrast medium simultaneously as medicine and gene target carrier - Google Patents
Supersonic contrast medium and supersonic contrast medium simultaneously as medicine and gene target carrier Download PDFInfo
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Abstract
The present invention discloses an ultrasonic contrast agent and a targeted ultrasound contrast agent with drugs and genetic carriers, which comprises gas microbubbles of which the diameters are 0.6 to 10 microns. The shells of the gas microbubbles are composed of lipid, high molecular degradable polymers and surface active agents, and the surfaces of the shells have positive charges. The gas microbubbles are hollow and contain nonhalocarbon gases, such as air, nitrogen, etc. An emulsion copolymerization method is used for carrying out emulsion copolymerization on acrylic acid and ramifications thereof. Under the participation of the surface active agents, the surface tension of gas phases and liquid phases is regulated, so that the gas phases enter in polymer emulsion microbubbles. The gas microbubbles of the targeted ultrasound contrast agent with the drugs and the genetic carriers are formed by that on the basis of the gas mocrobubbles, polylysine-kieselguhr or poly amino acid are contained, an active function base group is arranged, and the base group is coupled with the base groups of gene plasmids, so that carboxyl groups with the gas microbubbles are coupled with thrombus, or thrombus resistance, or the antibodies of thrombolysis materials, such as GP. IIb/IIa, etc. so as to prepare the gas microbubbles with the antibodies, such as the IIb/IIa, etc. Antitumor drugs packaged by the microbubbles are broken under ultrasonication, and are released locally at tumors.
Description
One, technical field
The invention belongs to clinical Vasculocardiology Deparment and learn, relate to substantial viscera tumor medical science such as liver, kidney, spleen, prostate and mammary gland, the acoustic contrast agent that chemistry and ultrasound medicine are used.Be particularly related to the preparation method of the acoustic contrast agent of acoustic contrast agent and double medicine, gene targeting vector.
Two, background technology
1. acoustic contrast agent is developed present situation:
Acoustic contrast is made up of the gassiness microvesicle of similar erythrocyte size, can arrive the position that erythrocyte can arrive after injecting vein, under ultrasonication, have linear scattering and nonlinear scattering characteristic, thereby can make the abundant organa parenchymatosum of blood flow when the two-dimensional ultrasound instrument detects, produce strong contrast development as cardiac muscle, liver etc.With other shadowgraph technique such as X line relatively, have noinvasive, in good time, bed is other and advantage such as inexpensive.Acoustic contrast agent is succeeded in developing, and has broad application prospects and huge economic benefit for the non-invasive diagnosis of cardiovascular and cerebrovascular disease and tumor.
External acoustic contrast agent development present situation: Albunex and Optison all are the sound albumin that shakes, the drugs approved by FDA clinical practice.Levovist ratifies clinical practice in Europe.But the myocardial visualization effect is all not good enough, belong to the 1st and the 2nd generation product.In recent years developing lipid, macromolecule polymer filmogen, flexible shell the 3rd generation acoustic contrast agent, myocardial visualization is good, also can be engulfed by liver reticuloendothelial system specificity and the liver development, experiment and the research of clinical phase have shown good prospects for application.
The development situation of domestic contrast agent: having only Germany to produce Levovist on the domestic market, is the acoustic contrast agent of unique clinical practice of being ratified by China's Ministry of Public Health, is raw material with the galactose, and myocardial visualization is not good enough, costs an arm and a leg, and is difficult for promoting the use of.The Xie Feng of Fuwai Hospital, Beijing once made a search, and did not see Related product at present yet.Nanfang Hospital of No.1 Military Medical Univ. Ultrasonography is the development sound albumin fluorocarbon gas acoustic contrast agent that shakes just, belong to the 2nd generation product, use does not at present yet put goods on the market.So far, there is not the report of homemade cardiac ultrasound contrast agent clinical practice.Therefore, development stability, reliable, inexpensive homemade acoustic contrast agent are the urgent tasks that China's medical science and correlative technology field face.
2. the acoustic contrast agent development present situation of double gene or drug targeting carrier
(1) genophore development present situation
Along with the continuous discovery of composition and the Disease-causing gene of human gene figure, the deepening continuously of gene therapy research, cardiovascular and cerebrovascular disease and genetic treatment of tumor have become one of most active fields in the gene therapy research.Naked DNA is owing to easily hindered removing by barrier in body born of the same parents external shield and the born of the same parents, main by direct physics and mechanical means importing position, though can effectively transport and express genes of interest, but lack targeting, can only local action, and may also need carry out surgical operation to expose target organ, clinical practice is limited.People more and more recognize the selection appropriate carriers, make gene target and specific in some soma's position expression, are the keys of gene therapy success.At present, be applied to Vectors in Gene Therapy and mainly contain viral vector and non-virus carrier.Wherein the clinical project of 85% gene therapy is to adopt viral vector, has many deficiencies or danger, is mainly reflected in that immunogenicity height, toxicity are big, the property inserted gene mutation, the genes of interest capacity is little, specially property is poor, preparation is more high than complexity and expense for targeting.So just actively develop non-virus carrier.Liposome is as carrier, though shortcoming such as direct injection safety, non-immunogenicity behind the parcel DNA do not have targeting and specificity, and vivo gene transfer efficient is low.Nanoparticle is a carrier likely, but targeting still awaits researching and solving.Over 10 years, though many new targeting specific gene therapies are arranged, successful gene therapy remains unpredictable and challenging, topmost obstacle be lack noinvasive, effectively, the carrier delivery system of targeting special organ and tissue.
(2) thrombolytic drug and antitumor drug carrier development present situation
Thrombotic disease and tumor have become the principal disease of harm humans.Many thrombotic disease are by due to the thrombosis, as myocardium infarction, peripheral blood vessel thrombosis, cerebral infarction, need thrombolytic and/or anticoagulation therapy.But, present thrombolytics and antithrombotic reagent such as r-tPA, streptokinase, urokinase does not all have the thrombosis specificity, causes the hemorrhage serious side effects in other position of health easily.Still do not find the specific medicine that acts on the thrombosis position so far.Therefore, thrombolytic medicine and antiplatelet drug are carried in development, and the carrier delivery system of selectively targeted thrombosis has important clinical significance.In like manner, present anticarcinogen is kill cancer cell not only, and destroys normal histiocyte.But still there is not ideal medicament carrier delivery system specific, targeting at present.
Myocardium acoustic contrast is a kind of image new technique of developed recently, the contrast agent that will contain microbubble injects vein, when by myocardium capillary bed, use the two dimensional echocardiogram myocardial visualization, because microbubble remains in the blood vessel during by cardiac muscle fully, so it not only can estimate arteria coronaria microcirculation and myocardium viability on dancing heart, and the feeble QI bubble is as carrier, can take to myocardium microcirculation such as the gene that carries or medicine, ultrasonic cavitation feeble QI bubble destroys, and makes entrained gene or medicine be released in the particular organization position.The external existing relevant experimental papers that carries the acoustic contrast agent of antiplatelet antibody is delivered domestic rare relevant research.Therefore, study biodegradable macromolecule polymer acoustic contrast agent, its feeble QI bubble is as the carrier that carries several genes or medicine, and ultrasonic mediation is filled up the blank of gene importing and drug targeting release at particular organization's position gene transfection or drug release.It will have broad application prospects and huge economic benefit undoubtedly.
Three, summary of the invention:
At defective or deficiency that above-mentioned prior art exists, the object of the invention is, develops simple acoustic contrast agent, and the preparation method of the targeted ultrasound contrast agent that has medicine, genophore concurrently on simple acoustic contrast agent basis.
One of purpose of the present invention: develop a kind of intravenous acoustic contrast agent that is applicable to.This contrast agent has following effect:
1) early diagnosis of acute myocardial infarction, infarction size reach and pour into curative effect damage evaluation again;
2) diagnosis of chronic ischemia cardiac muscle;
3) cardiac function evaluation: ultrasoundcardiogram is estimated cardiac function needs endocardium circle clearly.And many patients, simple ultrasoundcardiogram can not clearly be differentiated endocardial surface, has influenced cardiac determination.Acoustic contrast agent has strengthened endocardium circle, makes the cardiac function evaluation more accurate.
4) parenchymal viscera tumors such as diagnosis and differential diagnosis liver, kidney, spleen, prostate, mammary gland.
Two of purpose of the present invention: developing a kind of existing ultrasonic contrast effect, is again the targeted ultrasound contrast agent of medicine, genophore.
This contrast agent has following effect:
1) carries polygenic acoustic contrast agent feeble QI bubble such as VEGF, bFGF, under ultransonic effect, at myocardial ischemia slough position feeble QI follicular rupture, polygenes such as VEGF are released in the ischemic myocardium part by targeting, transfection cardiac muscle endotheliocyte, promote myocardium blood capillary and collateral blood vessels logical again, promptly the noinvasive therapeutic transgene is realized blood capillary " bridging " in the non-invasive cardiac muscle.
2) thrombosis in the target vascular therapy.In the cause of disease of acute coronary artery syndrome, being rich in hematoblastic thrombosis is main cause.Platelet activation plays a part crucial in the pathophysiological process of acute coronary artery syndrome.Platelet membrane glycoprotein IIb/IIIa (GPIIb/IIIa) receptor is a medium final in the platelet activation process, and its blocking-up can make the acute coronary artery syndrome patient reduce cardiac complication.That human platelet antigen research is maximum is GPIIIa and IIb.Acoustic contrast agent feeble QI bubble carries IIb/IIIa antibody and thrombolytic medicine, under the local ultrasonication of breast ultrasonic cardiography, destruction feeble QI bubble, make the IIb/IIIa antibody that carries and the thrombolytic medicine is specific discharges at the thrombosis position, utilize antibody to combine with the IIb/IIIa antigenic specificity of thrombosis, the side effect of systemic bleeding is avoided and reduced to specific antiplatelet and thrombolytic.
3) carry specific antibody or gene or specificity antineoplastic medicine, targeting organa parenchymatosum's tumor, organa parenchymatosum's tumors such as specific treatment liver, kidney, spleen, prostate, mammary gland are avoided the toxic and side effects of systemic administration.
To achieve these goals, the technical solution used in the present invention is:
A kind of preparation method of intravenous acoustic contrast agent is characterized in that, adopts the emulsion polymerization preparation, and its prescription is:
100 parts of cyanoacrylates
2.0 parts in alkylphenol-polyethenoxy (10) ether
1.5 parts in N-acyl glutamic acid sodium
1.5 parts in poly cystine sodium
4 parts of peracetic acid
300 parts of distilled water
Above-mentioned prescription is carried out emulsion polymerisation under brute force stirs, and feed nitrogen in feed liquid, polyreaction is reacted under 65 ℃-78 ℃, and the time is 6h-8h; Promptly obtain feeble QI bubble particle diameter and be 0.6 micron～10.0 microns acoustic contrast agent.
The preparation method of a kind of double medicine or gene targeting vector acoustic contrast agent is characterized in that, carries out according to the following steps:
1) at first prepares above-mentioned intravenous acoustic contrast agent;
2) intravenous acoustic contrast agent and VEGF, alkali fibroblast growth factor plasmid are recombinated, with 40-100: 1 weight ratio is mixed and is stirred, under 15 ℃ of conditions, react, be prepared into the acoustic contrast agent of the gassiness microvesicle that carries VEGF, alkali fibroblast growth factor gene;
Or with intravenous acoustic contrast agent and GPIIb/IIIa antibody with 30-100: 1 weight ratio is mixed stirring, reacts under 15 ℃ of conditions, makes the double medicine or the gene targeting vector acoustic contrast agent that carry IIb/IIIa antibody;
Or intravenous acoustic contrast agent mixed stirring with fibrinolysis activation of zymogen thing t-PA monoclonal antibody by above-mentioned weight ratio, make the double medicine or the gene targeting vector acoustic contrast agent that carry thrombolytic drug;
Or intravenous acoustic contrast agent mixed stirring with the active group of microvesicle wall by above-mentioned weight ratio with the sulfide linkage isoreactivity group of antibody, make multiple double medicine or gene targeting vector acoustic contrast agent with the specific antithrombotic agents of thrombosis.
Endovascular thrombosis mainly is made up of fibrin, platelet and hemocyte, and wherein many materials can be cloned and are antibody.
Gassiness microvesicle parcel antitumor drug can discharge under ultrasonication.
The acoustic contrast agent of acoustic contrast agent of the present invention and double medicine, gene targeting vector has following effect:
(1) heart and myocardium ultrasonic contrast:
1. the scope of can be clearly downright bad, the ischemic myocardium of the acoustic contrast agent of being invented;
2. reperfusion injury of cardiac muscle scoring;
3. strengthen the definition at endocardium interface, improved the accuracy that the ultrasoundcardiogram cardiac function is estimated;
4. particularly thrombosis diagnosis in the transthoracic echocardiography auricle that is difficult for detecting in the trunk intracavity that can detect (as neck and burst arteriovenous etc.), the chambers of the heart;
(2) carrier of ideal medicine and gene has targeting and specificity:
1. carrier carries platelet and thrombosis specific antibody targeting platelet and thrombosis, is used for the dissolving of interior thrombosis of blood vessel and coronary artery thrombus.
2. carrier carries VEGF (VEGF), alkali fibroblast growth factor (bFGF) gene, under ultrasonication, discharge gene and transfection cardiac muscle endotheliocyte at regional myocardial, promote ischemia, necrotic myocardium to organize blood capillary regeneration, i.e. " blood capillary bridging ".
3. carry specific antibody or antitumor drug, under ultrasonication, in organa parenchymatosums' such as liver, kidney tumor locus release.
Four, description of drawings
Fig. 1 is biodegradable polymer feeble QI alveolation polymerization sketch map.
Fig. 2 is the acoustic contrast agent embodiment schematic flow sheet of double medicine, gene targeting vector.
Five, the specific embodiment
The present invention is described in further detail below in conjunction with specific embodiment that accompanying drawing and inventor provide.
Fig. 1 is biodegradable polymer feeble QI alveolation polymerization sketch map; By technical scheme of the present invention, the preparation method of intravenous acoustic contrast agent, carry out according to the following steps:
Preparation contains the intravenous acoustic contrast agent of the gassiness microvesicle of diameter 1-10 micron; Adopt emulsion polymerization to prepare, its prescription is:
100 parts of cyanoacrylates
2.0 parts in alkylphenol-polyethenoxy (10) ether
1.5 parts in N-acyl glutamic acid sodium
1.5 parts in poly cystine sodium
4 parts of peracetic acid
300 parts of distilled water
Carry out emulsion polymerisation under brute force stirs, and feed nitrogen in feed liquid, polyreaction is reacted under 65 ℃-78 ℃, and the time is 6h-8h; The particle diameter of feeble QI bubble is 0.6 micron～10.0 microns.
Feeble QI cell-shell layer (being the bubble wall of feeble QI bubble) is by lipid, biodegradable polymer (as polybutylcyanoacrylate, cyanoacrylate---acrylamide copolymer etc.), and surfactant (as phospholipid, alkylphenol-polyethenoxy (10) ether, N-acyl glutamic acid sodium, poly cystine sodium etc.) is formed.Surfactant (this also is called emulsifying agent again), we adopt the compound use of kinds of surface activating agent.The ratio of polymer monomer and dosage of surfactant is 100: 4-6 (weight portion).Contain a bigger neutral hydrocarbon based structures and polarity end in the molecule of surfactant, the neutral hydrocarbon based structures can be dissolved in the polymeric monomer, and air, nitrogen are also had affinity, and its polar end is then hydrophilic.Adopting water in emulsion polymerisation is disperse medium, surfactant is in order to reduce the interfacial tension between monomer and disperse medium, make monomer emulsifying become the monomer emulsion particle, and increase monomer, make the monomer that is contained in the surface activity agent capsules become solubilising solution in the dissolubility of aqueous phase.Also reduce simultaneously the interfacial tension between gas (air, nitrogen) and disperse medium, gas can more be contained in the capsule of surfactant, entered again in polymer-monomer emulsion particle, and formed feeble QI bubble latex particle at last.In aqueous solution surfactant with hydrophobic group towards monomer droplet or polymer particle; around them, cause protective layer; stop particle and close and guaranteed also to provide the more stable environment of gas in polymer-monomer emulsion particle simultaneously by the stable of emulsion.(accompanying drawing 1).
The preparation method of double medicine or gene targeting vector acoustic contrast agent, carry out according to the following steps:
1) at first prepares above-mentioned intravenous acoustic contrast agent; The skin of feeble QI in intravenous acoustic contrast agent bubble surfactant alkylphenol-polyethenoxy (10) ether that distributing, the molecular beam of N-acyl glutamic acid sodium and poly cystine sodium, make the bubble wall of feeble QI bubble have amido, amide groups, carboxyl, ether and sulfide linkage, polyamino acid, VEGF (VEGF), alkali fibroblast growth factor (bFGF) gene are all had affinity interaction, and valency force carries out combination in due order; Making the feeble QI bubble is acoustic contrast agent, also can become gene, drug targeting carrier simultaneously;
2) simultaneously the various active functional group that has of the bubble wall of feeble QI bubble reacts under 15 ℃ of conditions with the active functional group in poly-D-lysine, the genes such as VEGF, bFGF, take place in conjunction with or the generation chemical bond; Making the feeble QI bubble is acoustic contrast agent, also can become gene, drug targeting carrier simultaneously;
3) positively charged feeble QI bubble mixes with electronegative VEGF, bGFG gene plasmid; Perhaps the bubble wall of feeble QI bubble has amido, amide groups, carboxyl, ether and sulfide linkage, perhaps the lipid of feeble QI bubble has hydroxyl, amino group coupling connection with VEGF, bGFG is prepared into the gassiness microvesicle that carries VEGF, bGFG gene, is intravenous acoustic contrast agent;
1. the feeble QI bubble is mixed with VEGF (VEGF), alkali fibroblast growth factor (bFGF) gene plasmid, with 40-100: 1 weight ratio is mixed and is stirred, being prepared into the carrier of the gassiness microvesicle that carries VEGF, alkali fibroblast growth factor gene plasmid, also is acoustic contrast agent simultaneously;
2. or make gassiness microvesicle and platelet GPIIb/IIIa antibody Rhizoma Nelumbinis connection
3. or with microvesicle and GPIIb/IIIa antibody with 30-100: 1 weight ratio is mixed stirring, makes the feeble QI bubble that carries IIb/IIIa antibody, is hold concurrently medicine or gene targeting vector acoustic contrast agent;
4. or make the gassiness microvesicle mix stirring, make the carrier that carries thrombolytic drug, be hold concurrently medicine or gene targeting vector acoustic contrast agent with fibrinolysis activation of zymogen thing t-PA monoclonal antibody;
5. or utilize the sulfide linkage isoreactivity group of antibody, mix, produce chemical bond, thereby make multiple feeble QI bubble, be hold concurrently medicine or gene targeting vector acoustic contrast agent with the specific antithrombotic agents of thrombosis with the active group of microvesicle wall.
Fig. 2 is the embodiment schematic flow sheet of the acoustic contrast agent of double medicine, gene targeting vector.
At first monomer, compound emulsifying agent, initiator, disperse medium and water are mixed; Emulsion polymerisation under brute force stirs, generate the bubble wall various active functional group is arranged, bubble contains the feeble QI bubble emulsion particle of polymer and gas, add the gene (VEGF, bFGF plasmid) that active group is arranged, be prepared into the feeble QI bubble that can carry gene, be hold concurrently medicine or gene targeting vector acoustic contrast agent; Go into blood circulation through intravenous injection, through heart arteria coronaria and microcirculation thereof, continue under the ultrasonication at the body-surface heart position, the feeble QI bubble discharges, and reaches following effect: 1, myocardial visualization; 2, feeble QI bubble release gene is gone into cardiac muscle, and gene transfection cardiac muscle endotheliocyte is expressed in cardiac muscle, makes ischemia, necrotic myocardium revascularization.
Embodiment:
The feeble QI bubble is to adopt the emulsion polymerization preparation, and its prescription is:
100 parts of cyanoacrylates
2.0 parts in alkylphenol-polyethenoxy (10) ether
1.5 parts in N-acyl glutamic acid sodium
1.5 parts in poly cystine sodium
4 parts of peracetic acid
300 parts of distilled water
Carry out emulsion polymerisation under brute force stirs, and feed nitrogen in feed liquid, polyreaction is carried out under 65 ℃-78 ℃.The product Electronic Speculum analytical test that the reaction back obtains, the particle diameter of latex particle (being the feeble QI bubble) is essentially 0.6 micron～10.0 microns.Emulsion particle is inclusive with air in certain amount such as nitrogen, and the polymer of emulsion particle is that polybutylcyanoacrylate is biodegradable polymer.The skin of latex particle emulsifying agent (being surfactant) alkylphenol-polyethenoxy (10) ether that distributing; the molecular beam of N-acyl glutamic acid sodium and poly cystine sodium; make the bubble wall of feeble QI bubble have amido; amide groups; carboxyl; ether and sulfide linkage; to polyamino acid; VEGF (VEGF); (annotate: VEGF and bFGF are angiogenic growth factors to alkali fibroblast growth factor (bFGF) gene; confirmed VEGF; angiogenesis factor gene specific ground such as bFGF promote endothelial cell division propagation; vascular permeability increases; for the migration and the vascularization of vascular endothelial cell provides substrate; it is the initiating agent of new vessels; promote the growth of ischemic tissue's revascularization and side shoot blood capillary, make and suffer that blood capillary is rebuild in the destructive cardiac muscle.) all having affinity interaction, valency force carries out combination in due order.Active functional group in various active functional group that the bubble wall of while feeble QI bubble has and poly-D-lysine, the genes such as VEGF, bFGF also can be reacted under proper condition, combination takes place or generate chemical bond.Therefore the feeble QI bubble is an acoustic contrast agent, also can become gene, drug targeting carrier simultaneously.
With feeble QI bubble and VEGF; the bFGF gene plasmid mixes; because the bubble wall of feeble QI bubble has the various polarity functional group; and also contain polarity gene in the gene plasmid; promptly have the effect of Van der Waals force between bubble wall and gene plasmid and the possibility that generates hydrogen bond is arranged; the bubble amino acid whose carboxylic group had of wall and can with VEGF; the active group Rhizoma Nelumbinis connection of bFGF gene plasmid; perhaps positively charged feeble QI bubble and electronegative VEGF; the combination of bFGF gene plasmid; with microvesicle and VEGF; the bFGF plasmid is recombinated with 40-100: 1 weight ratio is mixed stirring at a slow speed; be prepared into and carry VEGF; the carrier of the gassiness microvesicle of alkali fibroblast growth factor gene plasmid also is an acoustic contrast agent simultaneously.
Feeble QI bubble as the acoustic contrast agent of the carrier that carries angiogenesis factor is injected into vein, with blood flow through cardiac muscle, under ultrasonic cavitation, the feeble QI bubble destroys at regional myocardial, discharge the gas in it, not only producing linear scattering and nonlinear scattering, develops and strengthens in the zone that myocardial blood is poured into, and does not then develop or develop bad in the bad zone of myocardial blood perfusion.Thereby the realization cardiomyography can become noinvasive, bed is other, in good time and repeatably acute or chronic ischemic heart disease is new good diagnostic techniques.And ultrasonic cavitation destroys the feeble QI bubble, make the entrained angiogenesis factor gene of feeble QI bubble be discharged into regional myocardial, the transfection vascular endothelial cell, build the microenvironment of revascularization, promote vascular endothelial cell to increase, ischemia, downright bad myocardial vascular are regenerated, realize blood capillary " bridging " in the non-invasive cardiac muscle.
Claims (2)
1. the preparation method of an intravenous acoustic contrast agent adopts the emulsion polymerization preparation, it is characterized in that its prescription consists of:
100 parts of cyanoacrylates
2.0 parts in alkylphenol-polyethenoxy (10) ether
1.5 parts in N-acyl glutamic acid sodium
1.5 parts in poly cystine sodium
4 parts of peracetic acid
300 parts of distilled water
Above-mentioned prescription is carried out emulsion polymerisation under brute force stirs, and feed nitrogen in feed liquid, polyreaction is reacted under 65 ℃-78 ℃, and the time is 6h-8h; Promptly obtain feeble QI bubble particle diameter and be 0.6 micron～10.0 microns acoustic contrast agent.
2. the preparation method of double medicine or gene targeting vector acoustic contrast agent is characterized in that, carries out according to the following steps:
1) at first prepares intravenous acoustic contrast agent as claimed in claim 1;
2) above-mentioned acoustic contrast agent and VEGF, alkali fibroblast growth factor plasmid are recombinated, with 40-100: 1 weight ratio is mixed and is stirred, under 15 ℃ of conditions, react, be prepared into the acoustic contrast agent of the gassiness microvesicle that carries VEGF, alkali fibroblast growth factor gene;
Or feeble QI bubble mixed stirring with fibrinolysis activation of zymogen thing t-PA monoclonal antibody by above-mentioned weight ratio, make the double medicine or the gene targeting vector acoustic contrast agent that carry thrombolytic drug;
Or feeble QI bubble mixed stirring with the active group of microvesicle wall by above-mentioned weight ratio with the sulfide linkage isoreactivity group of antibody, make multiple double medicine or gene targeting vector acoustic contrast agent with the specific antithrombotic agents of thrombosis;
Or with feeble QI bubble and GP IIb/IIIa antibody with 30-100: 1 weight ratio is mixed stirring, reacts under 15 ℃ of conditions, makes the double medicine that carries IIb/IIIa antibody or the acoustic contrast agent of gene targeting vector.
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| WO2023156806A1 (en) * | 2022-02-21 | 2023-08-24 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method for manufacturing bubbles having a polymeric shell using sound waves for generating the bubbles |
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| CN101028524B (en) * | 2006-03-03 | 2010-10-20 | 重庆融海超声医学工程研究中心有限公司 | Supersonic microvesicle target positioning controlled-release/gene device and target transferring method |
| CN1943541B (en) * | 2006-10-18 | 2010-05-12 | 许川山 | Supersonic micro bubble skin permeate promotor |
| CN101314049B (en) * | 2008-06-13 | 2010-11-10 | 许川山 | Novel targeted microbubble contrast medium |
| CN101780284B (en) * | 2009-01-15 | 2012-05-30 | 南方医科大学南方医院 | Magnetic molecular targeted ultrasound contrast agent microsphere and preparation method thereof |
| CN101711736B (en) * | 2009-12-17 | 2011-09-14 | 重庆医科大学 | Method for preparing medicine-carrying microvesicle |
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| WO2023156806A1 (en) * | 2022-02-21 | 2023-08-24 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method for manufacturing bubbles having a polymeric shell using sound waves for generating the bubbles |
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