CN111617267A - Nano-scale ultrasonic contrast agent coated with perfluorocarbon - Google Patents
Nano-scale ultrasonic contrast agent coated with perfluorocarbon Download PDFInfo
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- CN111617267A CN111617267A CN202010649043.8A CN202010649043A CN111617267A CN 111617267 A CN111617267 A CN 111617267A CN 202010649043 A CN202010649043 A CN 202010649043A CN 111617267 A CN111617267 A CN 111617267A
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- 239000002961 echo contrast media Substances 0.000 title claims abstract description 34
- TXEYQDLBPFQVAA-UHFFFAOYSA-N tetrafluoromethane Chemical compound FC(F)(F)F TXEYQDLBPFQVAA-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 13
- 230000000694 effects Effects 0.000 claims abstract description 12
- 238000003384 imaging method Methods 0.000 claims abstract description 12
- 239000002245 particle Substances 0.000 claims abstract description 10
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 16
- 239000000463 material Substances 0.000 claims description 13
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- 239000002502 liposome Substances 0.000 claims description 7
- 239000012528 membrane Substances 0.000 claims description 6
- 238000002604 ultrasonography Methods 0.000 claims description 6
- 230000005540 biological transmission Effects 0.000 claims description 4
- 229960004692 perflenapent Drugs 0.000 claims description 3
- 229960004624 perflexane Drugs 0.000 claims description 3
- ZJIJAJXFLBMLCK-UHFFFAOYSA-N perfluorohexane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F ZJIJAJXFLBMLCK-UHFFFAOYSA-N 0.000 claims description 3
- NJCBUSHGCBERSK-UHFFFAOYSA-N perfluoropentane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F NJCBUSHGCBERSK-UHFFFAOYSA-N 0.000 claims description 3
- 230000003902 lesion Effects 0.000 claims description 2
- 239000008347 soybean phospholipid Substances 0.000 claims description 2
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- 239000002356 single layer Substances 0.000 claims 1
- 229940126585 therapeutic drug Drugs 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 11
- 238000001727 in vivo Methods 0.000 abstract description 6
- 238000003745 diagnosis Methods 0.000 abstract description 5
- 230000000149 penetrating effect Effects 0.000 abstract description 5
- 238000011160 research Methods 0.000 abstract description 2
- 210000000998 shell membrane Anatomy 0.000 description 7
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical class CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 5
- 239000002872 contrast media Substances 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002105 nanoparticle Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 210000003240 portal vein Anatomy 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 210000003556 vascular endothelial cell Anatomy 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
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- 239000004094 surface-active agent Substances 0.000 description 2
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- 206010002091 Anaesthesia Diseases 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 150000007824 aliphatic compounds Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
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- 238000006703 hydration reaction Methods 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 210000004779 membrane envelope Anatomy 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 229910052755 nonmetal Inorganic materials 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- -1 perfluorocarbon compound Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/221—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by the targeting agent or modifying agent linked to the acoustically-active agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/227—Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
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- Public Health (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Acoustics & Sound (AREA)
- Physics & Mathematics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Radiology & Medical Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Chemistry (AREA)
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Abstract
The invention discloses a nano-scale ultrasonic contrast agent coated with perfluorocarbon. The prepared nano-scale ultrasonic contrast agent internally carrying low-boiling-point perfluorocarbon is quickly gasified under the action of body temperature and ultrasonic effect to generate microbubbles, and the microbubbles resonate and scatter ultrasonic signals after receiving ultrasonic energy to achieve the effect of ultrasonic contrast. The ultrasonic contrast agent has the advantages of particle size in a nano-scale range, strong penetrating power, better imaging enhancing capability, good storage stability, high in-vivo ultrasonic stability, excellent biological safety and simple preparation method, is wrapped by multiple layers of phospholipid, can effectively improve the diagnosis and treatment efficiency, and has very high research value and wide application prospect.
Description
Technical Field
The invention relates to an ultrasonic contrast agent for ultrasonic imaging diagnosis and a preparation method thereof, belonging to the field of biomedical materials.
Background
Ultrasonic imaging, which is an imaging technique for disease diagnosis using differences in physical properties of ultrasound and acoustic properties of human organs and tissues, is of particular interest due to its non-invasive, inexpensive, simple to operate, and wide diagnostic applications. The ultrasonic contrast agent is often applied to ultrasonic diagnosis, effectively improves the contrast quality of ultrasonic images, obviously improves the resolution capability of ultrasonic waves on the forms and types of lesion areas, and enhances the sensitivity and specificity of ultrasonic diagnosis.
With the rapid development of the ultrasonic imaging technology and the biological nanometer technology, the development of the nanometer ultrasonic contrast agent is rapid. Compared with the traditional micron-sized ultrasonic contrast agent, the nano-sized ultrasonic contrast agent has small particle size and stronger tissue penetration capability, and can penetrate blood vessels to reach the focus of the tissue more easily. In addition, the nano-scale particles have large surface area and strong adsorption capacity, can be gathered and imaged, can obviously enhance signals in a target area, and reduces background noise.
The shell membrane material of the ultrasonic contrast agent mainly comprises lipid, high molecular polymer, surfactant, inorganic nonmetal and the like. Wherein, the shell layer prepared by the high molecular polymer is hard and has poor elasticity, and is easy to form fragments under ultrasonic explosion or natural erosion to generate non-therapeutic damage; the contrast agent prepared by the surfactant has poor stability and is not easy to modify; inorganic nanoparticle materials are rigid and require high ultrasound output. The lipid material has higher toughness, the shell membrane can form liquid crystal in an aqueous medium, the stability is good, the imaging effect is good, and the material is an ideal shell membrane material of the ultrasonic contrast agent. The bilayer shell membrane prepared by adopting the mixed lipid material has better biocompatibility, better stability and stronger entrapment capability, can better entrap the imaging agent and carry out in vivo delivery, and has very high research value.
Perfluorocarbon is a fluorinated aliphatic compound with a low boiling point, and undergoes liquid-gas phase transformation under the action of body temperature and ultrasonic effect after entering the body to form microbubbles, so that the imaging effect is enhanced. Compared with the direct encapsulated gaseous fluorocarbon, the perfluorocarbon encapsulated contrast agent has better storage stability, longer circulation time in tissues, higher biological safety and capability of resisting external pressure and mechanical stress change more durably, can realize the in-vivo long-acting ultrasonic imaging effect and is more favorable for detecting and observing the focus part.
The nano-scale liposome is adopted to encapsulate the perfluorocarbon, the strong penetrating power of the nano-particles can be utilized to penetrate through vascular endothelial cells to enable the vascular endothelial cells to reach extravascular diseased tissue organs, and the perfluorocarbon is subjected to phase transition to form microbubbles after the ultrasonic action, so that a strong ultrasonic imaging effect is generated; in addition, the formed multilayer phospholipid stabilizing layer can effectively improve the storage stability of the ultrasonic contrast agent, but does not influence the in-vivo ultrasonic responsiveness, and is convenient for clinical use.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a perfluorocarbon-coated nanoscale ultrasound contrast agent. The nano-scale ultrasonic contrast agent consists of perfluorocarbon coated by lipid and other effective components. The prepared nano-scale ultrasonic contrast agent has better biocompatibility, stronger penetrating power and longer in-vivo circulation time. The encapsulated perfluorocarbon generates microbubbles through liquid-gas phase transformation under the action of body temperature and ultrasonic effect, and can achieve the effect of enhanced ultrasonic development.
The lipid envelope is composed of one or more lipid materials, such as hydrogenated soybean phospholipids, pegylated phospholipids, cholesterol, and the like, but is not limited to these examples.
The perfluorocarbon is any one of perfluoropentane and perfluorohexane, but is not limited to the illustrative range.
The invention adopts the following technical scheme:
a nano-class ultrasonic contrast agent coated with perfluorocarbon is prepared from hydrogenated soybean phosphatide, PEG phosphatide and cholesterol as lipid through preparing shell membrane, and coating perfluorocarbon in it. The particle size distribution range of the prepared liposome is 80-400 nm, an obvious phospholipid layer can be observed by a transmission electron microscope, the surface is negatively charged, and the absolute value of the potential is about 30 mV.
The preferable perfluorocarbon to be encapsulated in the present invention is any one of perfluoropentane and perfluorohexane.
The preferable lipid material for forming the shell membrane is a mixture of hydrogenated soybean phospholipid, PEG phospholipid and cholesterol, and the mass ratio of the hydrogenated soybean phospholipid, the PEG phospholipid and the cholesterol is 10: 3: 1.
Preferred perfluorocarbons for use in the present invention are added at 1% to 10% (v: v).
The perfluorocarbon encapsulated in the liposome prepared by the invention is gasified to generate microbubbles under the action of body temperature and ultrasonic effect, generates resonance after receiving ultrasonic energy and scatters ultrasonic signals, and has the capability of enhancing imaging.
The preparation method of the perfluorocarbon-loaded nanoscale ultrasonic contrast agent comprises the following steps:
(1) dispersing lipid material hydrogenated soybean phospholipid, PEGylated phospholipid and cholesterol in organic solvent, removing organic solvent by rotary evaporation to obtain film, hydrating with normal saline at 37 deg.C for 30min to obtain lipid vesicle;
(2) taking the lipid vesicle prepared in the step (1), adding perfluorocarbon, and ultrasonically crushing by using a probe to obtain a coarse suspension;
(3) and (3) mixing the crude mixed suspension prepared in the step (2) with the lipid vesicle prepared in the step (1), sequentially extruding the mixture through cellulose membranes of 400nm, 200nm and 100nm, extruding each layer for at least 13 times, taking the subsequent filtrate, and diluting to obtain the ultrasonic contrast agent.
In the step (1), the organic solvent is one or more of methanol, ethanol, acetone, dichloromethane and chloroform, but is not limited to the illustrative range.
In the step (2), the ultrasonic intensity of the probe is 50%, and the ultrasonic time is 10min, but the method is not limited to the exemplary range. In the preferable step (3), the dilution factor is 3-6 times.
Compared with the prior art, the invention has the following advantages:
(1) the shell membrane is prepared by adopting the mixture of hydrogenated soybean phospholipid, PEG phospholipid and cholesterol, the preparation method is mature, the process is simple, and the preparation has the characteristics of good in vivo biocompatibility and good in vitro stability, and is beneficial to the clinical application of the preparation.
(2) The nano-scale ultrasonic contrast agent has strong penetrating power after intravenous injection, and can reach extravascular diseased tissue and organs after penetrating through vascular endothelial cells.
(3) The encapsulated perfluorocarbon compound has higher safety, longer circulation time in tissues and capability of resisting external pressure and mechanical stress change for a longer time compared with gaseous fluorocarbon. The gaseous fluorocarbon can be quickly discharged out of the body through breathing finally, so that interference signals are minimized.
(4) Can form a nano preparation coated by a plurality of phospholipid layers, and improves the storage stability and the ultrasonic response stability.
Drawings
FIG. 1 is a transmission electron microscope image of a nano-scale ultrasound contrast agent coated with perfluorocarbon.
Fig. 2 is a graph showing a particle size potential distribution of a perfluorocarbon-encapsulated nanoscale ultrasound contrast agent.
Fig. 3 is a graph showing the storage stability of a perfluorocarbon-encapsulated nanoscale ultrasound contrast agent.
Fig. 4 is a photograph of a contrast-free portal vein image taken by an ultrasound apparatus.
Figure 5 is an imaging of a portal vein contrast intravenously injected with a perfluorocarbon-encapsulated nanoscale ultrasound contrast agent.
Detailed Description
The embodiments of the present invention are described in detail below for the purpose of illustration only, and are not intended to limit the scope of the invention.
Example 1
A preparation method of a nano-scale ultrasonic contrast agent coated with perfluorocarbon comprises the following steps:
(1) dissolving hydrogenated soybean phospholipid, PEG phospholipid and cholesterol in chloroform according to mol ratio, ultrasonic dissolving completely, and evaporating at 40 deg.C under reduced pressure to remove organic solvent to obtain lipid film. Adding appropriate amount of normal saline as hydration medium, and hydrating at 37 deg.C for 30min to obtain lipid vesicle.
(2) And (2) adding perfluorocarbon into the liposome prepared in the step (1), carrying out probe ultrasonic crushing at the intensity of 50%, and carrying out ultrasonic crushing for 10min to obtain a coarse suspension.
(3) And (3) mixing the crude mixed suspension prepared in the step (2) with the lipid vesicle prepared in the step (1), sequentially extruding the mixture through cellulose membranes of 400nm, 200nm and 100nm, extruding each layer for at least 13 times, taking the subsequent filtrate, and diluting to obtain the ultrasonic contrast agent.
The prepared preparation is scanned by a transmission electron microscope, the appearance of the preparation is in a spherical shape with uniform size, an obvious shell-core structure can be seen, and a phospholipid shell has an obvious multilayer structure, which is shown in figure 1. The particle size measurement and Zeta potential evaluation are carried out, the mean value of the particle size of the preparation is 200nm, the particle size distribution range is 80-400 nm, the surface is negatively charged, the absolute value of the potential is about 25mV, and the particle size potential distribution is shown in figure 2.
Example 2
The evaluation of the storage stability of the ultrasound contrast agent prepared in example 1 mainly comprises the following steps:
the prepared contrast agent is placed at 4 ℃, samples are taken on days 1, 2, 3, 4, 5, 6 and 7, and particle size measurement and Zeta potential evaluation are carried out on the samples.
The evaluation results are shown in FIG. 3
Example 3
The evaluation of the in-vivo imaging effect of the ultrasonic contrast agent prepared in example 1 mainly comprises the following steps:
(1) selecting male SD rats, removing abdominal hair, and performing intraperitoneal injection of barbiturates for anesthesia. The abdomen was coated with ultrasound coupling agent, and the portal vein contrast without contrast agent was performed with ultrasound apparatus, and the stored image is shown in fig. 4.
(2) The contrast agent described in example 1 was diluted 5-10 times with physiological saline, and was injected via the tail vein, and the portal vein contrast was performed, and the stored image is shown in fig. 5.
Claims (7)
1. A nanoscale ultrasound contrast agent containing liquid perfluorocarbon, characterized by: the envelope is mainly composed of lipid materials, and perfluorocarbons or other therapeutic drugs and the like are encapsulated inside, but not limited to the range.
2. The envelope of nanoscale ultrasound contrast agent as claimed in claim 1, comprising a plurality of lipid materials and cell biofilm. Various lipid materials include, for example, hydrogenated soybean phospholipids, pegylated phospholipids, cholesterol, and the like, and cell biological membranes include, but are not limited to, erythrocyte membranes, platelet membranes, neutrophil membranes, tumor cell membranes, and the like.
3. The envelope of the nanoscale ultrasound contrast agent of claim 1 being a monolayer or multilayer lipid.
4. The nanoscale ultrasound contrast agent-encapsulated perfluorocarbon as claimed in claim 1 is any one of perfluoropentane and perfluorohexane, but not limited to the examples.
5. The nanoscale ultrasound contrast agent according to claim 1, characterized in that: the particle size of the prepared liposome is 20-400 nm, an obvious phospholipid layer can be observed by a transmission electron microscope, and the surface potential of the liposome is +/-50 mV.
6. The ultrasound contrast agent according to claim 1, characterized in that: the perfluorocarbon entrapped in the liposome is gasified under the action of body temperature and ultrasonic effect to generate microbubbles, and the microbubbles resonate and scatter ultrasonic signals after receiving ultrasonic energy, thereby enhancing the imaging capability.
7. Use of the nanoscale ultrasound contrast agent as claimed in claims 1 to 6 for the detection of lesions.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010649043.8A CN111617267A (en) | 2020-07-07 | 2020-07-07 | Nano-scale ultrasonic contrast agent coated with perfluorocarbon |
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| CN202010649043.8A CN111617267A (en) | 2020-07-07 | 2020-07-07 | Nano-scale ultrasonic contrast agent coated with perfluorocarbon |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114588125A (en) * | 2022-02-25 | 2022-06-07 | 北京科技大学 | Targeted drug-loaded thrombolytic microvesicles and preparation method thereof |
| CN115944752A (en) * | 2022-12-27 | 2023-04-11 | 南京邮电大学 | Engineered fused membrane bubble, preparation method and application thereof |
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| CN1125389A (en) * | 1993-06-11 | 1996-06-26 | ImaRx药物公司 | Methods of preparing gas and gaseous precursor-filled microspheres |
| CN101732343A (en) * | 2009-12-24 | 2010-06-16 | 上海纳米技术及应用国家工程研究中心有限公司 | Nano perfluocarbon liposome particles and preparation method thereof |
| CN110237276A (en) * | 2019-07-10 | 2019-09-17 | 香港大学深圳医院 | A kind of nanoparticle and its preparation method and application |
| CN111330025A (en) * | 2020-03-03 | 2020-06-26 | 中山大学附属第三医院 | Bionic microbubble ultrasound contrast agent and preparation method thereof |
-
2020
- 2020-07-07 CN CN202010649043.8A patent/CN111617267A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1125389A (en) * | 1993-06-11 | 1996-06-26 | ImaRx药物公司 | Methods of preparing gas and gaseous precursor-filled microspheres |
| CN101732343A (en) * | 2009-12-24 | 2010-06-16 | 上海纳米技术及应用国家工程研究中心有限公司 | Nano perfluocarbon liposome particles and preparation method thereof |
| CN110237276A (en) * | 2019-07-10 | 2019-09-17 | 香港大学深圳医院 | A kind of nanoparticle and its preparation method and application |
| CN111330025A (en) * | 2020-03-03 | 2020-06-26 | 中山大学附属第三医院 | Bionic microbubble ultrasound contrast agent and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114588125A (en) * | 2022-02-25 | 2022-06-07 | 北京科技大学 | Targeted drug-loaded thrombolytic microvesicles and preparation method thereof |
| CN115944752A (en) * | 2022-12-27 | 2023-04-11 | 南京邮电大学 | Engineered fused membrane bubble, preparation method and application thereof |
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Application publication date: 20200904 |