CN108392642A - A kind of nano-particle magnetic resonance imaging contrast and its preparation method and application containing gadolinium oxide - Google Patents
A kind of nano-particle magnetic resonance imaging contrast and its preparation method and application containing gadolinium oxide Download PDFInfo
- Publication number
- CN108392642A CN108392642A CN201810154654.8A CN201810154654A CN108392642A CN 108392642 A CN108392642 A CN 108392642A CN 201810154654 A CN201810154654 A CN 201810154654A CN 108392642 A CN108392642 A CN 108392642A
- Authority
- CN
- China
- Prior art keywords
- nano
- gadolinium
- particle
- solution
- oxide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/12—Macromolecular compounds
-
- 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
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/14—Peptides, e.g. proteins
- A61K49/146—Peptides, e.g. proteins the peptide being a polyamino acid, e.g. poly-lysine
-
- 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
- A61K49/1851—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 organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
- A61K49/1854—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 organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly(meth)acrylate, polyacrylamide, polyvinylpyrrolidone, polyvinylalcohol
-
- 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
- A61K49/1851—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 organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
- A61K49/1863—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 organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being a polysaccharide or derivative thereof, e.g. chitosan, chitin, cellulose, pectin, starch
-
- 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
- A61K49/1866—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 the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid
- A61K49/1872—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 the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid coated or functionalised with a polyamino acid, e.g. polylysine, polyglutamic acid
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Nanotechnology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Radiology & Medical Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention relates to a kind of nano-particle containing gadolinium oxide, kernel is nano oxidized gadolinium, and the core surface is enclosed with hydrophilic macromolecular compounds；The hydrophilic macromolecular compounds are the high-molecular compounds containing multiple carboxyls or multiple amino.The present invention also provides a kind of composite nanoparticles containing gadolinium oxide, it is made of the nano-particle containing gadolinium oxide with other Nanocomposites, it is any one in ferric oxide nano particles, manganese oxide nanoparticle, gold nanoparticle, nanometer particle or albumin nano particle that other described nano-particle outer layer covers, which have hydrophilic macromolecular compounds, kernel,.Nano-particle and composite nanoparticle of the present invention containing gadolinium oxide have good aqueous phase dispersibility, stability and biocompatibility, and the r with superelevation1Value and ultralow r2/r1Ratio can be used as the T of magnetic resonance imaging1Contrast agent.The present invention also provides a kind of methods preparing the nano-particle by Aqueous phase.
Description
Technical field
The present invention relates to magnetic resonance imaging contrasts, and in particular to a kind of nano material for magnetic resonance imaging, especially
It is related to a kind of nano-particle containing gadolinium oxide.
Technical background
Malignant tumour (cancer) is a kind of common disease for seriously endangering human life and health, some countries
As first cause of the death, have become second cause of the death for being only second to angiocardiopathy in developed country.The height of China's economic in recent years
The rising that speed development inevitably brings fine particle (PM2.5) concentration in problem of environmental pollution, especially air may
It can lead to the increase of lung cancer illness rate.Therefore, the early diagnosis of lung cancer seems especially heavy with nontoxic chemotherapy to China Today society
It wants and urgent.
Early diagnosis is the key that generally acknowledged redemption tumor patient life, however, malignant tumour lacks obviously in early stage
Symptom, majority has belonged to middle and advanced stage when discovery.As University of Virginia's radiation dean, NCI clinical test cooperations team ACRIN
Described in founder Bruce J.Hillman professors, traditional methods for clinical diagnosis is difficult to realize effective early diagnosis of tumor,
Such as：Magnetic resonance imaging (MRI), X ray computer Tomography (CT), Positron emission computed tomography imaging
(PET) etc..Therefore, developing a kind of method of early diagnosis of tumour has important scientific meaning and wide application prospect.Mesh
Before, MRI is one of the main means for diagnosing all kinds of malignant tumours.But the sensitivity that MRI detects tumour is limited, needs to use radiography
Agent improves its detection sensitivity and spatial resolution.Therefore, it to realize the early diagnosis to all kinds of tumours, need to develop all kinds of
MRI contrast agent.
MRI contrast agent can be mainly divided into two major classes：One kind is T1The MRI contrast agent of weighting, it shortens water proton
Longitudinal relaxation time, such as gadolinium chelate compound；Another kind of is T2The MRI contrast agent of weighting, it shortens the transverse relaxation of water proton
Time, such as magnetic ferric oxide nano particles (MIONs).
Since iron is human essential elements, magnetic ferric oxide nano particles (MIONs) have relatively good bio-compatible
Property.Therefore, MIONs is aroused great concern as MRI radiography materials.However, these MIONs bases T2Contrast agent also has
It has disadvantages that：1)T2The dark image of contrast agent may with the blurring under specified conditions, such as bleeding, calcification and endogenous iron
Equal metal deposits；2)T2The high magnetic moment of contrast agent may cause magnetic susceptibility type artifact (magnetic field distortion i.e. around disease area or
Background distorts), it is fuzzy so as to cause image；3)T2It is longer than T the time required to imaging1Imaging；4) MIONs bases T2Contrast agent is larger
Size (60~180nm) can cause internal checkout time longer (generally requiring several weeks or several months), long-term slow so as to cause
Property side effect.Just because of these disadvantages, the MIONs bases T listed2Contrast agent is difficult to dominate the market, so that withdrawing from the market
(such as：With), currently, only a MIONs bases T2Contrast agent is (i.e.) in the U.S. and Japan etc.
A few countries are still in print.
Above-mentioned MIONs bases T2The shortcomings that contrast agent, is derived from T2Imaging and its large-size, in order to overcome these disadvantages,
Taupitz etc. has found that the MIONs less than 5nm has T for the first time1Contrasting effects, longitudinal relaxation rate (r1) it is more than 2mM-1s-1, and
r2/r1Ratio is less than 5 (r2For transverse relaxation rate).It is referred to as minimum magnetic ferric oxide nano particles less than the MIONs of 5nm
(ES-MIONs), extensive research had been obtained in recent years.Currently, thermal decomposition method, polyol process, coprecipitation and reduction co-precipitation
Method has been developed for the synthesis of ES-MIONs.However, the r of ES-MIONs1Not high (<10mM-1s-1), and r2/r1Value is not low
(>2), this is unfavorable for T1Imaging.
Clinical widely used MRI contrast agent is gadolinium chelate compound at present, such as the gadolinium-of Schering AG companies of Germany exploitation
Gadolinium -1,4,7,10- the tetraazacyclododecanes 12 of diethylene triamine pentacetic acid (DTPA) (Gd-DTPA) and the exploitation of Guerbet SA companies of France
Alkane -1,4,7,10- tetraacethyls (Gd-DOTA).Although gadolinium chelate compound has ruled current MRI contrast agent market, research shows that gadolinium
Chelate has certain renal toxicity, for this purpose, Food and Drug Adminstration of the US (FDA) issues all gadolinium chelate compound contrast agent
Formal warning, it is proposed that all potential renal insufficiency patients are not used.
To reduce renal toxicity, the r of gadolinium base MRI contrast agent is improved1Value and reduction r2/r1Ratio becomes key, because of high r1Value
With low r2/r1Ratio can bring better T1Imaging effect (i.e. higher Δ SNR value), to reduce the use of gadolinium base MRI contrast agent
Pharmaceutical quantities.SNR value is signal-to-noise ratio (signal-to-noise ratio), and Δ SNR is signal enhancing percentage, and calculation formula is such as
Under：
Currently, ruling the r of the gadolinium chelate compound in current MRI contrast agent market1It is worth relatively low, about 4mM-1s-1.Further to carry
High r1Value, gadolinium oxide nano-particle (GdON) have obtained extensive research, have reported the r of GdON1Value is 4.4~47.2mM-1s-1,
r2/r1Ratio is 1.1~6.8.r1Value is 47.2mM-1s-1GdON r2/r1Ratio is 1.7 (magnetic fields 1.4T), synthetic method
For thermal decomposition method (oil phase method), and the common problem of oil phase method be gained nano-particle aqueous phase dispersibility it is bad.
It is analyzed, is prepared with good aqueous phase dispersibility, stability according to the domestic and international present Research of above-mentioned MRI contrast agent
With biocompatibility and with higher r1Value and lower r2/r1The T of ratio1Contrast agent is the main trend of research.
Invention content
The present invention provides a kind of magnetic resonance contrast agent based on gadolinium oxide nano-particle or gadolinium oxide composite nanoparticle
And preparation method thereof, such magnetic resonance contrast agent has good aqueous phase dispersibility, stability and biocompatibility, and with super
High r1Value (>50mM-1s-1) and ultralow r2/r1Ratio (<1.1) it, can be used for the T of magnetic resonance imaging1Contrast agent.
The solution of the present invention includes：
First, a kind of nano-particle containing gadolinium oxide is provided, kernel is nano oxidized gadolinium, and the core surface is enclosed with
Hydrophilic macromolecular compounds；The hydrophilic macromolecular compounds can be the high score containing multiple carboxyls or multiple amino
Sub- compound；It is preferred that polyacrylic acid (PAA), polyglutamic acid, poly-aspartate, sodium alginate, polylysine (PLL) or chitosan
In any one or two or more mixtures；Most preferably polyacrylic acid.
In preferred embodiments of the present invention, the nano-particle containing gadolinium oxide is hydrophilic by the way that gadolinium ion solution to be added
Property high-molecular compound solution in 60~100 DEG C and lye in the presence of be stirred to react 10 minutes it is derived above.
There is nano-particle containing gadolinium oxide of the present invention smaller size, grain size to be less than 5nm；With good water phase
Dispersibility, stability and biocompatibility；R with superelevation when for magnetic resonance radiography1Value (is more than 50mM-1s-1) and it is ultralow
r2/r1Ratio (is less than 1.1)；Embody good T1Contrasting effects can be used as T1Contrast agent is used for magnetic resonance imaging.
The present invention also provides the methods for preparing the nano-particle containing gadolinium oxide, mainly include the following steps that：
(1) hydrophilic macromolecular compounds solution is prepared, deoxygenation is spare；
(2) after solution made from step (1) being heated to 60~100 DEG C, gadolinium ion solution and aqueous slkali is added, stirring is anti-
It answers 10 minutes or more；It can be obtained the nano-particle of the present invention containing gadolinium oxide.
Hydrophilic macromolecular compounds described in step (1) need, containing multiple carboxyls or multiple amino, to have good
Water solubility can be polyacrylic acid (PAA), polyglutamic acid, poly-aspartate, sodium alginate, polylysine (PLL) or chitosan
In any one or two or more mixtures；It is preferred that polyacrylic acid (PAA), polyglutamic acid or poly-aspartate；Most preferably
Polyacrylic acid (PAA).
A concentration of 0.5~50mg/mL of hydrophilic macromolecular compounds solution described in step (1), it is more excellent be 2.0~
10mg/mL, optimal is 4.0mg/mL.
Deoxygenation described in step (1) is preferably completed by nitrogen bubbling law or freezing vacuum method.
Gadolinium ion solution described in step (2) preferably is selected from any one in gadolinium chloride, gadolinium nitrate, gadolinium fluoride or gadolinium bromide etc.
Kind solution or two or more mixed solutions；More preferable gadolinium chloride or gadolinium nitrate solution.
A concentration of 30~1000mM of gadolinium ion solution described in step (2), more excellent is 100~300mM, optimal to be
125mM。
Aqueous slkali described in step (2) preferably be selected from ammonium hydroxide, sodium hydroxide or potassium hydroxide solution any one or
Two or more mixed solutions.
In further preferred scheme, a concentration of the 2~28% of the ammonium hydroxide, more excellent is 20~28%, optimal to be
28%.
In further preferred scheme, a concentration of 0.05~5.0M of the sodium hydroxide or potassium hydroxide is more excellent to be
0.5~2.0M, optimal is 1.0M.
The volume ratio of Polymer Solution and gadolinium ion solution described in step (2) is 500~5.0, it is more excellent be 100~
25, optimal is 50.
The volume ratio of aqueous slkali and gadolinium ion solution described in step (2) is 0.1~100, and more excellent is 2~15, optimal to be
7.5。
Stirring can be magnetic agitation or mechanical agitation described in step (2).
Reaction time described in step (2) need to be 10 minutes or more, and more excellent is 30~120 minutes, and optimal is 60 minutes.
Step (2) includes preferably further the purification process for removing unreacted high-molecular compound and gadolinium ion, described pure
Change can be any one or a few in dialysis, filtering, centrifugation or chromatography.
The method that the present invention prepares the nano-particle containing gadolinium oxide is Aqueous phase, and nano-particle obtained has ideal
Water dispersible.
On this basis, the present invention further provides a kind of composite nanoparticle containing gadolinium oxide, it is by of the present invention
Nano-particle containing gadolinium oxide constituted with other Nanocomposites, other described nano-particle outer layer covers have hydrophily
High-molecular compound, kernel be ferric oxide nano particles, manganese oxide nanoparticle, gold nanoparticle, nanometer particle or
Any one in albumin nano particle.
In composite nanoparticle of the present invention containing gadolinium oxide, the nano-particle containing gadolinium oxide can pass through idol
The mode of connection or fabricated in situ is coated on other described nanoparticle surfaces, can also wrap up to other described nano-particles
Portion；The grain size of the finally formed composite nanoparticle containing gadolinium oxide is less than 100nm；With good Aqueous dispersions
Property, stability and biocompatibility；R with superelevation1Value (is more than 50mM-1s-1) and ultralow r2/r1Ratio (is less than 1.1)；
With good T1Contrasting effects can be used as T1Contrast agent is used for magnetic resonance imaging.
The preparation principle of composite nanoparticle of the present invention containing gadolinium oxide includes mainly following several：
(1) other described nano-particles are prepared with reference to the method that the present invention prepares the nano-particle containing gadolinium oxide,
Such as：Ferric oxide nano particles, manganese oxide nanoparticle, gold nanoparticle, nanometer particle, albumin nano particle；So
Afterwards the nano-particle containing gadolinium oxide is synthesized in its surface in situ；To which the composite nanoparticle containing gadolinium oxide be made, that is, oxygen
Change gadolinium-iron oxide composite nanoparticle, gadolinium oxide-manganese oxide composite nanoparticle, gadolinium oxide-gold compound nano-particle, oxidation
Gadolinium-mesoporous silicon composite nanoparticle or gadolinium oxide-albumin compound nano-particle.
(2) other described nano-particles are prepared with reference to the method that the present invention prepares the nano-particle containing gadolinium oxide,
Such as：Ferric oxide nano particles, manganese oxide nanoparticle, gold nanoparticle, nanometer particle, albumin nano particle；So
Afterwards the nano-particle containing gadolinium oxide is coupled on its surface；To which the composite nanoparticle containing gadolinium oxide be made, that is, oxidation
Gadolinium-iron oxide composite nanoparticle, gadolinium oxide-manganese oxide composite nanoparticle, gadolinium oxide-gold compound nano-particle, gadolinium oxide-
Mesoporous silicon composite nanoparticle or gadolinium oxide-albumin compound nano-particle.
(3) the reference present invention is prepared described in the method preparation of the nano-particle containing gadolinium oxide, such as：Nanometer
Particle, albumin nano particle；Then with other nano-particles package nano-particle containing gadolinium oxide；To make
The composite nanoparticle of gadolinium oxide must be contained, that is, gadolinium oxide-mesoporous silicon composite nanoparticle or gadolinium oxide-albumin composite Nano
Particle.
The present invention also provides the nano-particle containing gadolinium oxide and the composite nanoparticles containing gadolinium oxide to prepare magnetic total
The application shaken in image-forming contrast medium.
In the prior art, the r of document report1Value is 47.2mM-1s-1Gadolinium oxide nano-particle r2/r1Ratio is 1.7,
The r2/r1Ratio is larger, influences T1Imaging effect；In addition, its oil phase synthetic method (i.e. thermal decomposition method) leads to gained nano-particle
Aqueous phase dispersibility it is bad, to limit its vivo applications.Nano-particle provided by the invention containing gadolinium oxide or containing oxidation
When the composite nanoparticle of gadolinium is used as magnetic resonance imaging contrast, there is good aqueous phase dispersibility, stability and bio-compatible
Property, and the r with superelevation1Value (is more than 50mM-1s-1) and ultralow r2/r1Ratio (is less than 1.1), meets the institute of vivo applications
It requires.The r of its superelevation1Value is derived from its ultra-small grain size and ultra-hydrophilic surface, ultralow r2/r1Ratio is derived from its extra small saturation magnetic
Change intensity.
Description of the drawings
Fig. 1,2 are the GdON5 of the preparation of embodiment 1, commercial product magnevistAnd the T of pure water1Weighting
MRI image.TR=250ms in wherein Fig. 1；TE=10ms；TR=100ms in Fig. 2；TE=10ms.
Fig. 3 is the opposite MRI signal intensity of GdON5, magnevist and pure water in Fig. 1,2；*P<0.001.
Fig. 4 is transmission electron microscope (TEM) photo, the high-resolution transmission electron microscopy of GdON1-5 prepared by embodiment 1
Mirror (HR-TEM) photo.
Fig. 5-Fig. 7 be respectively embodiment 1 prepare the particle diameter distribution of GdON5, energy dispersion X-ray spectrum (EDS) and
The magnetization curve of the magnetic field dependence of GdON3, GdON5.
Fig. 8 is the scanning transmission electronics of FeGd-HN1 (a), FeGd-HN3 (b) prepared by embodiment 2 and FeGd-HN6 (c)
Microscope (STEM) figure.
Fig. 9 embodies the characterization result of electron energy loss light spectrum image-forming (EELS) corresponding with Fig. 8.
Figure 10-Figure 13 is the characterization result of FeGd-HN3 prepared by embodiment 2 and FeGd-HN3-RGD2.In wherein Figure 10
(a), (b) is the HR-TEM photos of FeGd-HN3 and FeGd-HN3-RGD2 respectively；Figure 11 is the FeGd-HN3 (d that DLS is measuredh=
6.5nm) and FeGd-HN3-RGD2 (dh=8.5nm) particle diameter distribution；Figure 12 is the energy dispersion X-ray spectrum of FeGd-HN3
(EDS)；Figure 13 is the magnetization curve of the magnetic field dependence of FeGd-HN3 and FeGd-HN3-RGD2.
The FeGd-HN3 or FeGd- that Figure 14 embodies tail vein injection magnevist (Magnevist), prepared by embodiment 2
The internal T of U-87MG tumours mice with tumor after HN3-RGD21Weighted magnetic resonance imaging.
The FeGd-HN3 or FeGd- that Figure 15 embodies tail vein injection magnevist (Magnevist), prepared by embodiment 2
The tumor signal of U-87MG tumours mice with tumor enhances quantitative analysis after HN3-RGD2.
Specific implementation mode
The present invention is further described below by specific embodiment, but does not limit present disclosure.
Embodiment 1
The preparation of gadolinium oxide nano-particle (GdON)
Prepare the polyacrylic acid solution (molecular weight 1800) of 40mL, a concentration of 4.0mg/mL.Logical nitrogen is bubbled 50 minutes
(deoxygenation), then solution is heated to 100 DEG C.0.8mL gadolinium nitrates solution (62.5~1000mM) is first added by syringe, then
6.0mL ammonia spirits (28%) are added immediately, are reacted 60 minutes under magnetic agitation.After being cooled to room temperature, pass through dialysis (molecular weight
Retain 6-8kDa) it purifies, again by ultrafiltration (molecular weight retains 3kDa) concentration, you can obtain GdON.1000,750,500,250,
Nano-particle is respectively GdON1-6 obtained by 125,62.5mM gadolinium nitrate solution, related synthesis condition and its characterization result such as table 1
It is shown.
The synthesis condition and its characterization result of table 1.GdON nano-particles
aThe concentration of reactant gadolinium nitrate, PAA and ammonium hydroxide；
bGadolinium concentrations account for the molar percentage that raw material gadolinium is added in nano-particle.
Take sample GdON2, GdON3, GdON5 manufactured in the present embodiment and commercially available MRI contrast agent magnevist (i.e.
Magnevist) T is measured respectively as MRI contrast agent1Relaxation rate (1/T1) and T2Relaxation rate (1/T2), wherein the present embodiment
Three samples GdON2, GdON3, GdON5 take the product that three batches synthesize under the same terms to measure respectively；Magnevist takes three parts
Different bottled products measure；It is 1.5T to measure magnetic field used.According to T1Relaxation rate and T2Relaxation rate is with gadolinium concentration (CGd) change
Change and calculates its slope, as r1And r2Value.The results show that sample GdON2, GdON3 and GdON5's manufactured in the present embodiment is averaged
r1Value is respectively 54.2 ± 3.0,60.7 ± 1.9,70.2 ± 1.8mM-1s-1, it is far above the average r of magnevist1Value (4.20
±0.16mM-1s-1).Wherein, the average r of GdON3 and GdON52/r1Ratio is respectively 1.03 ± 0.02 and 1.02 ± 0.03,
Less than the average r of magnevist2/r1Ratio (1.08 ± 0.06).
Fig. 1 and Fig. 2 is GdON5, commercial product magnevistAnd the T of pure water1Weighted mri image (magnetic field
For 7.0T).TR=250ms in wherein Fig. 1；TE=10ms；TR=100ms in Fig. 2；TE=10ms.Fig. 3 is in Fig. 1,2
The opposite MRI signal intensity of GdON5, magnevist and pure water；*P<0.001.The results show that the MRI signal intensity of GdON5 is remote
Higher than magnevist.These the experimental results showed that, compare magnevist, sample GdON5 is more excellent T1Contrast agent.
Fig. 4 is transmission electron microscope (TEM) photo, the high resolution transmission electron microscopy (HR- of sample GdON1-5
TEM) photo.Wherein Fig. 4 (a)-Fig. 4 (e) is transmission electron microscope (TEM) photo of GdON1-5 respectively.Fig. 4 (f) is
High resolution transmission electron microscopy (HR-TEM) photo of GdON5.
Fig. 5-Fig. 7 is the particle diameter distribution of sample GdON5, energy dispersion X-ray spectrum (EDS) and GdON3, GdON5 respectively
Magnetic field dependence magnetization curve, wherein Fig. 5 embodies the grain size point of the GdON5 measured from the HR-TEM photos of Fig. 4 (f)
Cloth.The result shows that the sample GdON1-5 of the present embodiment has good aqueous phase dispersibility, uniform particle diameter；GdON5 average grain diameters
For 1.9nm；GdON5 is mainly made of Gd and O, therefore component should be Gd2O3；The saturation magnetization of GdON5 is 0.09emu/g.
Embodiment 2
The preparation of gadolinium oxide-iron oxide composite nanoparticle (FeGd-HN)
Prepare the polyacrylic acid solution (molecular weight 1800) of 40mL, a concentration of 4.0mg/mL.Logical nitrogen is bubbled 50 minutes
(deoxygenation), then solution is heated to 100 DEG C.0.8mL ferric ion solutions (500mM iron chloride, 250mM are first added by syringe
Ferrous sulfate), 12mL ammonia spirits (28%) are immediately added, are reacted 30 minutes under magnetic agitation.Added again by syringe
Enter 0.8mL gadolinium nitrates solution (62.5~1000mM), immediately addition 6.0mL ammonia spirits (28%), it is anti-under magnetic agitation
It answers 90 minutes.After being cooled to room temperature, by dialysis (molecular weight retains 6-8kDa) purifying, by ultrafiltration, (molecular weight retains again
It 3kDa) concentrates, you can obtain FeGd-HN.1000,750,500,250,125,62.5mM nano-particle obtained by gadolinium nitrate solution
Respectively FeGd-HN1-6, related synthesis condition and its characterization result are as shown in table 2.
The active targeting of tumour is acted on to improve nano-particle FeGd-HN3, nano-particle can be activated by EDC/NHS
Surface carboxyl groups are allowed to and target molecule RGD dimers (RGD2, Glu- { Cyclo [Arg-Gly-Asp- (D-Phe)-Lys] }2) anti-
It answers, has the FeGd-HN3 (i.e. FeGd-HN3-RGD2) of RGD2 to obtain coupling.
The synthesis condition and characterization result of table 2.FeGd-HN nano-particles
aThe concentration of reactant gadolinium nitrate, iron chloride and ferrous sulfate；
bHydraulic diameter (the d that dynamic light scattering (DLS) measuresh)；
cIron or gadolinium concentrations, which account for, in nano-particle is added the molar percentage of iron or gadolinium in raw material；
dThe molar ratio of iron gadolinium in gained nano-particle.
Fig. 8 is sample F eGd-HN1, FeGd-HN3 and scanning transmission electron microscope (STEM) figure of FeGd-HN6；Fig. 9
Embody the characterization of the corresponding electron energy loss light spectrum image-forming (EELS) of FeGd-HN1, FeGd-HN3 and FeGd-HN6 in Fig. 8
As a result.EELS data white box selected areas from STEM pictures obtains.The results show that sample F eGd-HN1, FeGd-HN3
And Gd contents are different in FeGd-HN6, structure is core shell structure, core Fe3O4, shell Gd2O3。
Figure 10-13 be FeGd-HN3 and FeGd-HN3-RGD2 HR-TEM photos, DLS measure particle diameter distribution, FeGd-
The magnetization curve of the energy dispersion X-ray spectrum (EDS) of HN3, the magnetic field dependence of FeGd-HN3 and FeGd-HN3-RGD2.As a result
It has been shown that, FeGd-HN3 and FeGd-HN3-RGD2 all have good aqueous phase dispersibility, hydraulics grain size be respectively 6.5nm and
8.5nm.Main group of FeGd-HN3 becomes Fe, Gd, O, therefore component should be Fe3O4And Gd2O3.FeGd-HN3 and FeGd-HN3-
The saturation magnetization of RGD2 is respectively 11.5 and 12.4emu/g.
Take sample F eGd-HN3, FeGd-HN3-RGD2 manufactured in the present embodiment and commercially available MRI contrast agent magnevist (i.e.
Magnevist) T is measured respectively as MRI contrast agent1Relaxation rate (1/T1) and T2Relaxation rate (1/T2), wherein the present embodiment
FeGd-HN3 and FeGd-HN3-RGD2 takes the product that three batches synthesize under the same terms to measure respectively；Magnevist take three parts not
It is measured with bottled product；It is 1.5T to measure magnetic field used.According to T1Relaxation rate and T2Relaxation rate is with gadolinium concentration (CGd) or iron it is dense
Spend (CFe) variation calculate its slope, as r1And r2Value.The results show that FeGd-HN3 manufactured in the present embodiment and FeGd-
The r of HN3-RGD21Value is respectively 73.5 ± 2.6 and 70.0mM-1s-1, it is far above the r of magnevist1It is worth (4.25 ± 0.07mM- 1s-1).The r of FeGd-HN3 and FeGd-HN3-RGD2 manufactured in the present embodiment2/r1Ratio is respectively 1.01 ± 0.04 and 1.03,
Less than the r of magnevist2/r1Ratio (1.06 ± 0.02).
To U-87MG tumour lotus knurl tail vein injection magnevists (Magnevist), FeGd-HN3 or FeGd-HN3-
RGD2, gadolinium injection dosage are 5.0mg/kg.The internal T of U-87MG tumour mice with tumor is carried out after injection1Weighted magnetic resonance imaging and
Its tumor signal enhances quantitative analysis.As a result (as shown in Figure 14,15) are shown, tail vein injection magnevist (Magnevist),
Tumour peak signal enhancing (Δ SNR) is respectively 75 ± 11%, 342 ± 47% and 477 after FeGd-HN3 or FeGd-HN3-RGD2
± 44%.These the experimental results showed that, compare magnevist, FeGd-HN3 or FeGd-HN3-RGD2 manufactured in the present embodiment are
More excellent T1Contrast agent.
Embodiment 3
The preparation of gadolinium oxide-manganese oxide composite nanoparticle (GdMn-HN)
Prepare the polyacrylic acid solution (molecular weight 1800) of 40mL, a concentration of 4.0mg/mL.Logical nitrogen is bubbled 50 minutes
(deoxygenation), then solution is heated to 100 DEG C.0.8mL manganese oxide nanoparticles sub- solution (MnO, MnO are first added by syringe2Or
Mn3O4, CMn=500mM), magnetic agitation adds 0.8mL gadolinium nitrates solution (400mM), is immediately added after 30 minutes
6.0mL ammonia spirits (28%) react 90 minutes under magnetic agitation.After being cooled to room temperature, by dialysis, (molecular weight retains 6-
It 8kDa) purifies, pass through ultrafiltration (molecular weight retains 3kDa) concentration again, you can obtain GdMn-HN.
Embodiment 4
The preparation of gadolinium oxide-gold compound nano-particle (GdAu-HN)
Prepare the polyacrylic acid solution (molecular weight 1800) of 40mL, a concentration of 4.0mg/mL.Logical nitrogen is bubbled 50 minutes
(deoxygenation), then solution is heated to 100 DEG C.0.8mL solution of gold nanoparticles (C is first added by syringeAu=50mM), magnetic force
After stirring 30 minutes, 0.8mL gadolinium nitrates solution (100mM) is added, 6.0mL ammonia spirits (28%), magnetic is immediately added
The lower reaction of power stirring 90 minutes.After being cooled to room temperature, (divide by dialysis (molecular weight retains 6-8kDa) purifying, again by ultrafiltration
Son amount retention 3kDa) concentration, you can obtain FeMn-HN.
Embodiment 5
The preparation of gadolinium oxide-mesoporous silicon composite nanoparticle (GdSi-HN)
Prepare the polyacrylic acid solution (molecular weight 1800) of 40mL, a concentration of 4.0mg/mL.Logical nitrogen is bubbled 50 minutes
(deoxygenation), then solution is heated to 100 DEG C.0.8mL nanometers particle solution (10mg/mL) is first added by syringe,
After magnetic agitation 30 minutes, 0.8mL gadolinium nitrates solution (400mM) is added, 6.0mL ammonia spirits are immediately added
(28%), it is reacted 90 minutes under magnetic agitation.After being cooled to room temperature, by dialysis (molecular weight retains 6-8kDa) purifying, lead to again
Cross ultrafiltration (molecular weight retains 3kDa) concentration, you can obtain GdSi-HN.
Embodiment 6
The preparation of gadolinium oxide-albumin compound nano-particle (GdAN-HN)
Prepare the polyacrylic acid solution (molecular weight 1800) of 40mL, a concentration of 4.0mg/mL.Logical nitrogen is bubbled 50 minutes
(deoxygenation), then solution is heated to 100 DEG C.0.8mL albumin nano particle solution (AN, 10mg/ are first added by syringe
ML), magnetic agitation adds 0.8mL gadolinium nitrates solution (400mM) after 30 minutes, and 6.0mL ammonia spirits are immediately added
(28%), it is reacted 90 minutes under magnetic agitation.After being cooled to room temperature, by dialysis (molecular weight retains 6-8kDa) purifying, lead to again
Cross ultrafiltration (molecular weight retains 3kDa) concentration, you can obtain GdAN-HN.
Claims (8)
1. a kind of nano-particle containing gadolinium oxide, kernel is nano oxidized gadolinium, and the core surface is enclosed with hydrophily high score
Sub- compound；The hydrophilic macromolecular compounds are the high-molecular compounds containing multiple carboxyls or multiple amino；It is preferred that
Any one in polyacrylic acid (PAA), polyglutamic acid, poly-aspartate, sodium alginate, polylysine (PLL) or chitosan
Or two or more mixture；Most preferably polyacrylic acid.
2. the nano-particle described in claim 1 containing gadolinium oxide, it is characterised in that：The nano-particle containing gadolinium oxide is
By the way that gadolinium ion solution to be added in hydrophilic macromolecular compounds solution 10 are stirred to react in the presence of 60~100 DEG C and lye
Minute is derived above.
3. a kind of method preparing the nano-particle described in claim 1 containing gadolinium oxide, mainly includes the following steps that：
(1) compound concentration is 0.5~50mg/mL, preferably 2.0~10mg/mL, the hydrophilic macromolecule of more preferable 4.0mg/mL
Polymer solution, deoxygenation are spare；The hydrophilic macromolecular compounds are selected from polyacrylic acid (PAA), polyglutamic acid, poly- asparagus fern ammonia
Any one in acid, sodium alginate, polylysine (PLL) or chitosan or two or more mixtures；It is preferred that polyacrylic acid
(PAA), polyglutamic acid or poly-aspartate；Most preferably polyacrylic acid (PAA)；
(2) after solution made from step (1) being heated to 60~100 DEG C, it is added a concentration of 30~1000mM, preferably 100~
The gadolinium ion solution and aqueous slkali of 300mM, more preferable 125mM；Make the volume ratio of the Polymer Solution and gadolinium ion solution
It is 500~5.0, preferably 100~25, more preferable 50；It is 0.1~100 to make the volume ratio of the aqueous slkali and gadolinium ion solution, excellent
Select 2~15, more preferable 7.5；It is stirred to react 10 minutes or more, preferably 30~120 minutes, more preferable 60 minutes；It obtains described
The nano-particle containing gadolinium oxide.
4. the method described in claim 3, it is characterised in that：Gadolinium ion solution described in step (2) is selected from gadolinium chloride, nitric acid
Any one solution in gadolinium, gadolinium fluoride or gadolinium bromide etc. or two or more mixed solutions；More preferable gadolinium chloride or gadolinium nitrate
Solution.
5. the method described in claim 3, it is characterised in that：Aqueous slkali described in step (2) be selected from ammonium hydroxide, sodium hydroxide or
Any one in potassium hydroxide solution or two or more mixed solutions.
6. the method described in claim 3, which is characterized in that include the following steps：
(1) compound concentration is the polyacrylic acid solution of 4.0mg/mL, and deoxygenation is spare；
(2) after solution made from step (1) being heated to 100 DEG C, the gadolinium nitrate solution and a concentration of 20 of a concentration of 125mM is added
~28% ammonia spirit；It is 50 to make the polyacrylic acid solution and the volume ratio of gadolinium nitrate solution；Make the ammonia spirit
Volume ratio with gadolinium nitrate solution is 7.5；It is stirred to react 60 minutes；Obtain the nano-particle containing gadolinium oxide.
7. a kind of composite nanoparticle containing gadolinium oxide, it is by described in claim 1 containing the nano-particle of gadolinium oxide and other
Nanocomposites are constituted, and it is iron oxide that other described nano-particle outer layer covers, which have hydrophilic macromolecular compounds, kernel,
It is any one in nano-particle, manganese oxide nanoparticle, gold nanoparticle, nanometer particle or albumin nano particle
Kind.
8. the composite nanoparticle containing gadolinium oxide described in nano-particle and claim 7 containing gadolinium oxide described in claim 1
Application in preparing magnetic resonance imaging contrast.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810154654.8A CN108392642B (en) | 2018-02-23 | 2018-02-23 | Gadolinium oxide-containing nanoparticle magnetic resonance imaging contrast agent and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810154654.8A CN108392642B (en) | 2018-02-23 | 2018-02-23 | Gadolinium oxide-containing nanoparticle magnetic resonance imaging contrast agent and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108392642A true CN108392642A (en) | 2018-08-14 |
| CN108392642B CN108392642B (en) | 2020-10-09 |
Family
ID=63096753
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810154654.8A Active CN108392642B (en) | 2018-02-23 | 2018-02-23 | Gadolinium oxide-containing nanoparticle magnetic resonance imaging contrast agent and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108392642B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109589334A (en) * | 2018-11-28 | 2019-04-09 | 内蒙古大学 | A kind of nano enzyme antioxidant and preparation method thereof |
| CN109675065A (en) * | 2018-12-20 | 2019-04-26 | 上海交通大学 | Nanometer magnetic bead and preparation method thereof for T1 and T2 magnetic resonance bimodal radiography |
| CN114949261A (en) * | 2022-05-05 | 2022-08-30 | 南方医科大学南方医院 | Iron-gadolinium nano-composite and preparation method and application thereof |
| WO2022247142A1 (en) * | 2021-05-24 | 2022-12-01 | 南方医科大学 | Organic gadolinium nanoparticles, preparation method therefor, and use thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103041407A (en) * | 2012-12-19 | 2013-04-17 | 深圳先进技术研究院 | Core-shell type nano-contrast agent, preparation method and application thereof |
| CN103463648A (en) * | 2013-08-23 | 2013-12-25 | 南京大学 | Surface modified ferric oxide nucleus-gadolinium oxide shell composite nano particle, as well as preparation method and application of particle |
| CN104043137A (en) * | 2014-05-28 | 2014-09-17 | 上海纳米技术及应用国家工程研究中心有限公司 | Intestinal-tract targeted magnetic resonance contrast agent based on mesoporous silica and preparation method thereof |
-
2018
- 2018-02-23 CN CN201810154654.8A patent/CN108392642B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103041407A (en) * | 2012-12-19 | 2013-04-17 | 深圳先进技术研究院 | Core-shell type nano-contrast agent, preparation method and application thereof |
| CN103463648A (en) * | 2013-08-23 | 2013-12-25 | 南京大学 | Surface modified ferric oxide nucleus-gadolinium oxide shell composite nano particle, as well as preparation method and application of particle |
| CN104043137A (en) * | 2014-05-28 | 2014-09-17 | 上海纳米技术及应用国家工程研究中心有限公司 | Intestinal-tract targeted magnetic resonance contrast agent based on mesoporous silica and preparation method thereof |
Non-Patent Citations (5)
| Title |
|---|
| TIRUSEW TEGAFAW等: "Ligand-size and ligand-chain hydrophilicity effects on the relaxometric properties of ultrasmall Gd2O3 nanoparticles", 《AIP ADVANCES》 * |
| XU MIAO等: "Stable and non-toxic ultrasmall gadolinium oxide nanoparticle colloids (coating material = polyacrylic acid) as high-performance T1 magnetic resonance imaging contrast agents", 《RSC ADV.》 * |
| XU MIAO等: "Ultrasmall Gd2O3 nanoparticles surface-coated by polyacrylic acid (PAA) and their PAA-size dependent relaxometric properties", 《APPLIED SURFACE SCIENCE》 * |
| YASIR LOAI等: "Concurrent Dual Contrast for Cellular Magnetic Resonance Imaging Using Gadolinium Oxide and Iron Oxide Nanoparticles", 《INTERNATIONAL JOURNAL OF MOLECULAR IMAGING》 * |
| ZHEYU SHEN等: "Multifunctional Theranostic Nanoparticles Based on Exceedingly Small Magnetic Iron Oxide Nanoparticles for T1-Weighted Magnetic Resonance Imaging and Chemotherapy", 《ACS NANO》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109589334A (en) * | 2018-11-28 | 2019-04-09 | 内蒙古大学 | A kind of nano enzyme antioxidant and preparation method thereof |
| CN109589334B (en) * | 2018-11-28 | 2021-02-09 | 内蒙古大学 | Nano enzyme antioxidant and preparation method thereof |
| CN109675065A (en) * | 2018-12-20 | 2019-04-26 | 上海交通大学 | Nanometer magnetic bead and preparation method thereof for T1 and T2 magnetic resonance bimodal radiography |
| WO2022247142A1 (en) * | 2021-05-24 | 2022-12-01 | 南方医科大学 | Organic gadolinium nanoparticles, preparation method therefor, and use thereof |
| CN114949261A (en) * | 2022-05-05 | 2022-08-30 | 南方医科大学南方医院 | Iron-gadolinium nano-composite and preparation method and application thereof |
| CN114949261B (en) * | 2022-05-05 | 2024-06-04 | 南方医科大学南方医院 | Iron gadolinium nano-composite and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108392642B (en) | 2020-10-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Bolskar | Gadofullerene MRI contrast agents | |
| Huang et al. | Gadolinium-doped carbon quantum dots loaded magnetite nanoparticles as a bimodal nanoprobe for both fluorescence and magnetic resonance imaging | |
| Ahmad et al. | Potential dual imaging nanoparticle: Gd2O3 nanoparticle | |
| Patel et al. | The cell labeling efficacy, cytotoxicity and relaxivity of copper-activated MRI/PET imaging contrast agents | |
| Xu et al. | Paramagnetic nanoparticle T 1 and T 2 MRI contrast agents | |
| Cheung et al. | Polymer-stabilized lanthanide fluoride nanoparticle aggregates as contrast agents for magnetic resonance imaging and computed tomography | |
| CN108392642A (en) | A kind of nano-particle magnetic resonance imaging contrast and its preparation method and application containing gadolinium oxide | |
| US7396589B2 (en) | Core-shell magnetic nanoparticles comprising an inner-transition element | |
| Yang et al. | Albumin-constrained large-scale synthesis of renal clearable ferrous sulfide quantum dots for T1-Weighted MR imaging and phototheranostics of tumors | |
| Xue et al. | Upconversion optical/magnetic resonance imaging-guided small tumor detection and in vivo tri-modal bioimaging based on high-performance luminescent nanorods | |
| US8092783B2 (en) | Gadolinium containing prussian blue nanoparticles as nontoxic MRI contrast agents having high relaxivity | |
| CN102294038B (en) | Method for preparing computed tomography (CT)/magnatic resonance imaging (MRI) bimodal imaging contrast agent based on dendrimers | |
| Hu et al. | High-performance nanostructured MR contrast probes | |
| Azizian et al. | Synthesis route and three different core-shell impacts on magnetic characterization of gadolinium oxide-based nanoparticles as new contrast agents for molecular magnetic resonance imaging | |
| Liu et al. | Stable gadolinium based nanoscale lyophilized injection for enhanced MR angiography with efficient renal clearance | |
| Hoffman et al. | Intrinsically radiolabelled [59Fe]-SPIONs for dual MRI/radionuclide detection | |
| Haribabu et al. | Magneto-silver core–shell nanohybrids for theragnosis | |
| Deng et al. | Size and PEG length-controlled PEGylated monocrystalline superparamagnetic iron oxide nanocomposite for MRI contrast agent | |
| Liu et al. | Sequential growth of CaF 2: Yb, Er@ CaF 2: Gd nanoparticles for efficient magnetic resonance angiography and tumor diagnosis | |
| Li et al. | The renal clearable magnetic resonance imaging contrast agents: state of the art and recent advances | |
| CN103007303A (en) | Core-shell type tri-modal nano contrast agent as well as preparation method and application thereof | |
| US20180161461A1 (en) | Rare Earth Oxide Particles and Use Thereof in Particular In Imaging | |
| CN102380109B (en) | Magnetic resonance contrast agent constructed by amphipathic polysaccharide-wrapped super-paramagnetic nanoparticles and preparation method thereof | |
| Yue et al. | Ultrasmall europium, gadolinium, and dysprosium oxide nanoparticles: Polyol synthesis, properties, and biomedical imaging applications | |
| Lee et al. | Ultrasmall lanthanide oxide nanoparticles for biomedical imaging and therapy |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210630 Address after: 215100 Room 201, building 1, 168 Majian Road, high tech Zone, Suzhou City, Jiangsu Province Patentee after: Suzhou zeci Medical Technology Co.,Ltd. Address before: 402, No.13, Lane 2001, Jianhe Road, Changning District, Shanghai, 200336 Patentee before: SHAMU (SHANGHAI) BIOTECHNOLOGY Co.,Ltd. |
|
| TR01 | Transfer of patent right |