CN104399091B - Ultrasound/magnetic resonance bimodal contrast agent, its preparation method and application - Google Patents
Ultrasound/magnetic resonance bimodal contrast agent, its preparation method and application Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
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- 238000001694 spray drying Methods 0.000 claims description 18
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- AMWRITDGCCNYAT-UHFFFAOYSA-L hydroxy(oxo)manganese;manganese Chemical compound [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 claims description 10
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
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- SZVJSHCCFOBDDC-UHFFFAOYSA-N ferrosoferric oxide Chemical compound O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 4
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- 229910002518 CoFe2O4 Inorganic materials 0.000 description 1
- -1 Fe3O4@SiO2 Chemical compound 0.000 description 1
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Classifications
-
- 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
- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/183—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an inorganic material or being composed of an inorganic material entrapping the MRI-active nucleus, e.g. silica core doped with a MRI-active nucleus
Abstract
The present invention relates to contrast preparation field, and in particular to a kind of ultrasound/magnetic resonance bimodal contrast agent, its preparation method and application.Bimodal contrast agent of the invention with can the nanoparticle suspension of magnetic resonance development be raw material, spray-dried technique is made hollow ball shape nanometer particle congery, builds the bimodal contrast agent that ultrasound/magnetic resonance developing function rolls into one.The present invention has gathered the advantage of ultrasound and magnetic resonance imaging, has complementary advantage in terms of image sensitivity and image resolution ratio, can obtain more information about lesions position；And for quick, the efficient and controllable preparation of bimodal contrast agent open a kind of new method.
Description
Technical field
The present invention relates to the preparation of contrast agent, and in particular to a kind of ultrasound/magnetic resonance bimodal contrast agent, its preparation method
With application.
Background technology
Many major diseases（Especially cancer）Early detection be largely dependent upon the development of Medical Imaging Technology,
They are that clinician's acquisition anatomy and physiological information provide strong means, and its own is also from single dependence form
Change diagnose and is developing progressively to integrate the comprehensive diagnostic and therapeutic system of form, function and treatment.However, various medical science shadows
As technology respectively there are advantage and disadvantage at aspects such as spatial and temporal resolutions, up to the present can also be obtained without any one imaging mode
Whole biological information.
In numerous Medical Imaging Technologies, many advantages that Ultrasonic Diagnosis is protruded with it, such as sensitivity are high, directly perceived, nothing
Radiation, it is inexpensive and can real-time visualization etc., as presently most conventional iconography means, it is produced using ultrasonic wave and body
Physical phenomenon realizes the diagnosis to medical science focus.Although this imaging method has for the changes in microstructure that some diseases cause
There are diagnosis and locating effect well, but low image resolution ratio limits its application.Magnetic resonance imaging is using biology
Body different tissues produce different resonance signals to be imaged under the influence of externally-applied magnetic field, with high resolution, imaging parameters it is many,
Can arbitrarily bedding fault the advantages of, but its susceptibility is low, image taking speed is slow.
In view of both diagnostic modes have complementary advantage in terms of image sensitivity and image resolution ratio, if can realize
Both combinations, by with great clinical practice meaning.But ultrasound and magnetic resonance imaging are respectively former based on respective imaging
Reason independent development gets up, and really to realize compatibility and the fusion of diagnostic image of software and hardware, and also many technical problems are needed
Solve.
Except the combination of imaging device, another combination means of Medical Imaging Technology are to be combined both by contrast agent
Get up, various contrast agent are coupled simultaneously by a kind of contrast agent platform, using existing imaging device, ultrasound can be carried out
Radiography, can carry out magnetic resonance radiography again, complementary as the registration of the image to obtained by and fusion, obtain more relevant lesions positions
Information, this multi-mode contrast agent is the prerequisite for realizing disease early discovery, early prevention and early treatment.
The content of the invention
It is an object of the invention to provide a kind of ultrasound/magnetic resonance bimodal contrast agent and preparation method thereof；The ultrasound for obtaining/
Magnetic resonance bimodal contrast agent has the function of ultrasonic contrast imaging and magnetic resonance radiography imaging simultaneously, solves traditional clinical practice
A kind of middle contrast agent is only used for a variety of inconvenience that a kind of iconography means inspection brings.
To achieve the above object of the invention, the technical solution adopted by the present invention is：A kind of ultrasound/magnetic resonance bimodal contrast agent
Preparation method, comprise the following steps：
（1）By can magnetic resonance development nano-particle be added in deionized water, it is 1~10% to be configured to mass concentration
Suspension；Then the pH value of regulation suspension is to 6~8；
（2）Spray drying treatment is carried out to the suspension after regulation pH value, hollow sphere nanometer particle congery is obtained, i.e.,
It is ultrasound/magnetic resonance bimodal contrast agent；
The spray drying condition is：EAT is 120~140 DEG C, and feed rate is 2.0~12.0 mL/min, pressure
Contracting gas flow is 250~350 L/h.
In the present invention, parameter during spray drying influences very big on product, the structural form of product is determined, if parameter is not
Properly, it is impossible to prepare hollow sphere nanometer particle congery, it is impossible to as ultrasound/magnetic resonance bimodal contrast agent.
In above-mentioned technical proposal, it is described can magnetic resonance development nano-particle be superparamagnetic iron oxide nano-particle
（Fe3O4）, superparamagnetic manganese oxide nanoparticle son（MnO）, cobalt ferrite（CoFe2O4）Magnetic nano-particle, Manganese Ferrite（MnFe2O4）Magnetic
The composition of one or more in property nano-particle；Or can magnetic resonance development nano-particle be core shell structure；The core
It is the one kind in superparamagnetic iron oxide nano-particle, superparamagnetic manganese oxide nanoparticle, ferrite magnetic nano-particle, shell is two
Silica；Such as Fe3O4@SiO2、MnO@SiO2.Core shell structure can the preparation of nano-particle of magnetic resonance development belong to existing
Technology, those skilled in the art can voluntarily select as needed.
In preferred technical scheme, can magnetic resonance development nano-particle by being then added to deionization after citric acid modification
In water.
In above-mentioned technical proposal, regulation can magnetic resonance development nano-particle pH value of water solution reagent be hydrochloric acid or ammonia
Water.
In preferred technical scheme, can the mass concentration of the nano-particle aqueous solution of magnetic resonance development be 1~3%；Can magnetic be total to
Shake development the nano-particle aqueous solution pH value be 7~7.5；Spray drying condition：130 DEG C of EAT, feed rate is 4.0
ML/min, compression gas flow is 250 L/h.Thus obtained hollow sphere nanometer particle congery uniformity is good, as
The ultrasound that contrast agent is obtained/magnetic resonance bimodal medical science contrast imaging figure is clear, accurately.
In preferred technical scheme, compressed gas are compressed nitrogen.
The present invention is also claimed the ultrasound/magnetic resonance bimodal contrast agent prepared according to above-mentioned preparation method.
Ultrasound disclosed by the invention/magnetic resonance bimodal contrast agent is hollow sphere nanometer particle congery, internal package
Have gas, spherical shell by can the nanometer particle congery that develops of magnetic resonance constitute；Ultrasound/magnetic resonance bimodal contrast agent it is a diameter of
0.5~8 micron, wall thickness is 10~500 nanometers.
Ultrasound disclosed by the invention/magnetic resonance bimodal contrast agent have simultaneously ultrasonic contrast imaging and magnetic resonance radiography into
The function of picture, can be used for ultrasound/magnetic resonance imaging；Ultrasonic imaging image can be obtained, magnetic resonance imaging image is can obtain again, led to
Cross complementary to the registration of gained image and fusion, obtain more information.Therefore it is double the invention also discloses above-mentioned ultrasound/magnetic resonance
Application of the mode contrast agent in ultrasound/magnetic resonance imaging.
Because above-mentioned technical proposal is used, the present invention has following advantages compared with prior art:
1. be applied to for spray drying process first prepare contrast agent by the present invention, has successfully obtained hollow nanometer particle congery
The ultrasound of structure/magnetic resonance bimodal contrast agent；Preparation process is simple, quick；Products obtained therefrom stabilization, difference is small.
2. ultrasound disclosed in this invention/magnetic resonance bimodal contrast agent is hollow nanometer particle congery structure, can be used
In ultrasound/magnetic resonance imaging；It is registering with magnetic resonance imaging image by the ultrasonic imaging image for obtaining and fusion is complementary, can be with
More, more accurately detection information is obtained, is conducive to clinical judgment.
3. the present invention using citric acid increase can magnetic resonance development nano-particle dispersiveness in deionized water, have
It is uniform and stable beneficial to the hollow sphere nanometer particle congery for being formed；Using nitrogen pair can magnetic resonance develop nano-particle be suspended
Liquid is spray-dried, and efficiently avoid the oxidation of nano-particle.
4. method disclosed by the invention is applied widely, and raw material is easy to get, pollution-free；And products obtained therefrom has ultrasound simultaneously
Contrast imaging and the function of magnetic resonance radiography imaging, application prospect are wide.
Brief description of the drawings
Fig. 1 is the grain size distribution of ultrasound/magnetic resonance bimodal contrast agent that embodiment two is obtained；
Fig. 2 is ultrasound/magnetic resonance bimodal contrast agent external supersonic contrast imaging figure that embodiment two is obtained；
The external magnetic resonance radiography image of the ultrasound that Fig. 3 embodiments two are obtained/magnetic resonance bimodal contrast agent.
Specific embodiment
With reference to embodiment, accompanying drawing, the invention will be further described:
Embodiment one：A kind of preparation method of ultrasound/magnetic resonance bimodal contrast agent, comprises the following steps：
（1）Weigh 1.0 g superparamagnetic iron oxide nano-particles to be scattered in 99 g deionized waters, the min of water bath sonicator 5 makes
It is uniformly dispersed, and with salt acid for adjusting pH value to 6.0, is configured to stabilization, the uniform, suspension of good fluidity；
（2）Above-mentioned suspension is delivered into spray dryer through self-priming peristaltic pump carries out spray drying treatment, and spraying is dry
Dry condition：140 DEG C of EAT, feed rate is 5.0 mL/min, and compressed nitrogen flow is 280 L/h.
Collect spray drying gained hollow sphere nanometer particle congery, as ultrasound/magnetic resonance bimodal contrast agent.
Embodiment two：A kind of preparation method of ultrasound/magnetic resonance bimodal contrast agent, comprises the following steps：
（1）The superparamagnetic iron oxide nano-particle of citric acid modification is prepared using coprecipitation；
Weigh 0.86gFeCl2And 2.35gFeCl3Into four-hole boiling flask, the ultrasonically treated 5min of the 40mL that adds water；Nitrogen protection
Under the conditions of be stirred；Heating-up temperature reaches 80 DEG C, is slowly added dropwise 5mL ammoniacal liquor, continues to react 30min；Delay in reaction system
It is slow that citric acid solution is added dropwise；Then high reaction temperature is risen to 95 DEG C, continues to react 90min.Washed reaction gained black precipitate be
Obtain the superparamagnetic iron oxide nano-particle of citric acid modification；
（2）The superparamagnetic iron oxide nano-particle for weighing the above-mentioned citric acid modifications of 1.5 g is scattered in 98.5 g deionized waters
In, the min of water bath sonicator 5 makes it be uniformly dispersed, and pH value is adjusted to 7.0 with ammoniacal liquor, be configured to stabilization, uniform, good fluidity it is mixed
Suspension；
（3）Above-mentioned suspension is delivered into spray dryer through self-priming peristaltic pump carries out spray drying treatment, and spraying is dry
Dry condition：130 DEG C of EAT, feed rate is 4.0 mL/min, and compressed nitrogen flow is 250 L/h.
Collect spray drying gained hollow sphere nanometer particle congery, as ultrasound/magnetic resonance bimodal contrast agent.Figure
1 is the grain size distribution of above-mentioned ultrasound/magnetic resonance bimodal contrast agent.
External supersonic contrast imaging effect assessment：By elastic transparent medical grade silicone pipe（The mm of internal diameter about 5）It is partially disposed in water
Below tank liquor face, to inject the ultrasonogram of physiological saline as control, preparation is slowly pushed into from one end of silicone tube with syringe
Ultrasound/magnetic resonance bimodal contrast agent, the cross section of silicone tube is observed with Pulse inversion harmonic wave pattern, injected
The contrast effect observation of ultrasound/magnetic resonance bimodal contrast agent.Fig. 2 surpasses in vitro for above-mentioned ultrasound/magnetic resonance bimodal contrast agent
Sound contrast imaging figure（A, the ultrasonogram for injecting physiological saline；B, the ultrasonogram for injecting bimodal contrast agent prepared by the present invention）,
It can be seen that the silicone tube for injecting physiological saline is hardly visible any echo signal, and injects ultrasound/magnetic resonance bimodal and make
The silica gel of shadow agent has been in control obvious enhancing, and tube chamber inside is presented solid echopattern, and echo luminous point is tiny, uniform.
External magnetic resonance radiography imaging effect is evaluated：Obtained ultrasound/magnetic resonance bimodal contrast agent is buffered using PBS
Solution is according to finite concentration gradient（0.5,0.25,0.1,0.05,0.01 mg/mL）Series of samples is prepared, with control sample PBS
Buffer solution（0 mg/mL）Together, it is placed on the scanning platform of the T toy magnetic resonance imagers of Bruker Biospec 7, uses
Following parameter is scanned：The cm of 3 cm ' of field area 3, pixel count 256 ' 256, repetition time TR=750 ms, echo time
TE=60 ms, pulse train MSME, writing scan data are simultaneously rebuild, and obtain T2The magnetic resonance radiography image of weighting.Fig. 3 is upper
State the external magnetic resonance radiography image of ultrasound/magnetic resonance bimodal contrast agent（0th, physiological saline；1st, bimodal contrast concentration is
0.01 mg/mL；2nd, bimodal contrast concentration is 0.05 mg/mL；3rd, bimodal contrast concentration is 0.1 mg/mL；4th, it is double
Mode contrast concentration is 0.25 mg/mL；5th, bimodal contrast concentration is 0.5 mg/mL）, it can be seen that ultrasound/magnetic resonance
The rising of bimodal contrast concentration（From sample 0 to sample 5）, in T2It is presented gradually dimmed in the magnetic resonance radiography figure of weighting
Trend.
Embodiment three：A kind of preparation method of ultrasound/magnetic resonance bimodal contrast agent, comprises the following steps：
（1）Superparamagnetic manganese oxide nanoparticle for weighing 3 g citric acid modifications is scattered in 97 g deionized waters, and water-bath surpasses
The min of sound 5 makes it be uniformly dispersed, and regulation pH value is configured to stabilization, the uniform, suspension of good fluidity to 7.5.
（2）Above-mentioned suspension is delivered into spray dryer through self-priming peristaltic pump carries out spray drying treatment, and spraying is dry
Dry condition：130 DEG C of EAT, feed rate is 5.0 mL/min, and compressed nitrogen flow is 280 L/h.
Collect spray drying gained hollow sphere nanometer particle congery, as ultrasound/magnetic resonance bimodal contrast agent.
Example IV：A kind of preparation method of ultrasound/magnetic resonance bimodal contrast agent, comprises the following steps：
（1）Weigh 3.0 g cobalt ferrite magnetics nano-particles and 3.0 g Manganese Ferrite magnetic nano-particles be scattered in 94g go from
In sub- water, the min of water bath sonicator 5 makes it be uniformly dispersed, and with salt acid for adjusting pH value to 6.5, is configured to stabilization, uniform, good fluidity
Suspension；
（2）Above-mentioned suspension is delivered into spray dryer through self-priming peristaltic pump carries out spray drying treatment, and spraying is dry
Dry condition：140 DEG C of EAT, feed rate is 5.0 mL/min, and compressed nitrogen flow is 280 L/h.
Collect spray drying gained hollow sphere nanometer particle congery, as ultrasound/magnetic resonance bimodal contrast agent.
Embodiment five：A kind of preparation method of ultrasound/magnetic resonance bimodal contrast agent, comprises the following steps：
（1）Weigh 1.5g SiO2The superparamagnetic iron oxide nano-particle of cladding is scattered in 98.5g deionized waters, water-bath
Ultrasonic 5min, makes it be uniformly dispersed, and regulation pH value is configured to stabilization, the uniform, suspension of good fluidity to 7.5；
（2）Above-mentioned suspension is delivered into spray dryer through self-priming peristaltic pump carries out spray drying treatment, and spraying is dry
Dry condition：130 DEG C of EAT, feed rate is 5.0 mL/min, and compressed air require is 260 L/h.Collect spray drying
Gained hollow sphere nanometer particle congery, as ultrasound/magnetic resonance bimodal contrast agent.
Claims (5)
1. the preparation method of a kind of ultrasound/magnetic resonance bimodal contrast agent, it is characterised in that comprise the following steps：
（1）By can magnetic resonance development nano-particle by being added in deionized water after citric acid modification, be configured to quality dense
Spend the suspension for 1~10%；Then the pH value of regulation suspension is to 6~8；
（2）Spray drying treatment is carried out to the suspension after regulation pH value, hollow sphere nanometer particle congery is obtained, as surpassed
Sound/magnetic resonance bimodal contrast agent；
The spray drying condition is：EAT is 120~140 DEG C, and feed rate is 2.0~12.0 mL/min, compressed gas
Body flow is 250~350 L/h；The compressed gas are compressed nitrogen；
It is described can magnetic resonance development nano-particle for superparamagnetic iron oxide nano-particle, superparamagnetic manganese oxide nanoparticle son, iron
The composition of one or more in sour cobalt magnetic nano-particle, Manganese Ferrite magnetic nano-particle；Or it is described can magnetic resonance show
The nano-particle of shadow is core shell structure, and the core is superparamagnetic iron oxide nano-particle, superparamagnetic manganese oxide nanoparticle, ferrous acid
One kind in cobalt magnetic nano-particle, Manganese Ferrite magnetic nano-particle, shell is silica.
2. the preparation method of ultrasound/magnetic resonance bimodal contrast agent according to claim 1, it is characterised in that:Step（1）
In, the reagent for adjusting suspension pH value is hydrochloric acid or ammoniacal liquor.
3. the preparation method of ultrasound/magnetic resonance bimodal contrast agent according to claim 1, it is characterised in that:Step（1）
In, the mass concentration of suspension is 1~3%, and pH value is 7~7.5；Step（2）In, spray drying condition is EAT 130
DEG C, feed rate is 4.0 mL/min, and compression gas flow is 250 L/h.
4. the ultrasound that any one preparation method according to claims 1 to 3 is prepared/magnetic resonance bimodal radiography
Agent.
5. ultrasound/magnetic resonance bimodal contrast agent according to claim 4, it is characterised in that:The ultrasound/magnetic resonance bimodulus
A diameter of 0.5~8 micron of state contrast agent；The wall thickness of the ultrasound/magnetic resonance bimodal contrast agent is 10~500 nanometers.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410600719.9A CN104399091B (en) | 2014-10-31 | 2014-10-31 | Ultrasound/magnetic resonance bimodal contrast agent, its preparation method and application |
| CN201710101062.5A CN106668880B (en) | 2014-10-31 | 2014-10-31 | The application of ultrasound/magnetic resonance bimodal contrast agent |
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