CN101979097A - Gadolinium-containing magnetic resonance contrast agent and preparation method thereof - Google Patents
Gadolinium-containing magnetic resonance contrast agent and preparation method thereof Download PDFInfo
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- CN101979097A CN101979097A CN 201010512605 CN201010512605A CN101979097A CN 101979097 A CN101979097 A CN 101979097A CN 201010512605 CN201010512605 CN 201010512605 CN 201010512605 A CN201010512605 A CN 201010512605A CN 101979097 A CN101979097 A CN 101979097A
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Abstract
The invention relates to the field of magnetic resonance imaging, in particular to a gadolinium-containing magnetic resonance contrast agent and a preparation method thereof. The gadolinium-containing magnetic resonance contrast agent of the invention mainly comprises a gadolinium chelate, hydroxyapatite and sodium alginate, wherein the contrast agent is prepared by wrapping the gadolinium chelate-supported hydroxyapatite with the sodium alginate. The magnetic resonance contrast agent of the invention has small toxic or side effect on human body; the particle diameter of the particles is controllable (0.1 to 2.0mu m); the specificity of the liver part and the spleen part can be realized through passive targeting; and the contrast agent carries 12.5 to 20 mass percent of gadolinium chelate, has high sustained-release performance and can improve the development effect.
Description
Technical field
The present invention relates to the magnetic resonance contrast agent of infantile tumour diagnosis, be specifically related to a kind of gadolinium magnetic resonance contrast agent and preparation method thereof that contains.
Background technology
Nmr imaging technique (MRI) has been widely used in clinical, in order to improve the effect of NMR (Nuclear Magnetic Resonance)-imaging, needs to use mri contrast agent usually.Contrast agent is the intensity that is used to strengthen image, by changing tissue local magnetic field intensity or relaxation time, or comes the difference of Enhanced Imaging factor by contrast agent physiology, biochemical characteristic, reaches the radiography purpose.Free gadolinium has high toxicity, is distributed in skeleton and liver in vivo, and can cause hepatic necrosis rapidly.So all gadolinium contrast agent that contain all are chelates, can change its distribution in vivo behind the chelating to improve picture contrast, improve its toxic and side effects simultaneously.Gd-DTPA (Magnevist Solution) is research and uses maximum contrast agent, because it mainly passes through renal metabolism, and accretion rate is too fast, be not suitable for the imaging of tumor tissues such as liver, spleen, therefore need be made into slow release formulation and demanding year gadolinium amount, can strengthen the development effect of gadolinium like this, can reduce dosage and number of times again, reduce toxic action tissue.
Hydroxyapatite nano particle has advantages such as nontoxic, that dissolubility is higher, surface energy is big, biological activity is good as carrier.Drug molecule can be adsorbed and overall structure that can change itself easily.The cavity structure of hydroxyapatite has increased its load capacity to medicine greatly.Natural polymer sodium alginate good biocompatibility, degradable, tissue and cell are had no side effect, be the focus of biomedical sector research always.Sodium alginate is compound with carrying the gadolinium hydroxyapatite, because sodium alginate can be crosslinked rapidly with calcium ion, therefore reduced the loss of water solublity gadolinium medicine in the coating process.Can effectively improve the prominent phenomenon of releasing of Gd-DTPA after coating simultaneously, help the raising of carrier contrast agent development effect.
Anusha Ashokan (Anusha Ashokan, Deepthy Menon.A molecular receptor targeted, hydroxyapatite nanocrystal based multi-modal contrast agent [J] .Biomaterials, 2010,31 (9): be matrix gadolinium-doped ion with the nanometer hydroxyapatite after modifying 2606-2616), the gadolinium-contained nano material particle size for preparing is less and have a higher magnetic susceptibility.But gadolinium ion has drug toxicity, is unfavorable for intravital application.CN101549161A (a kind of liver, spleen specific hylon mr contrast agent and preparation method thereof) directly is coated to Gd-DTPA on the nanometer hydroxyapatite particle, waits through the human serum albumin and modifies.Though this kind preparation method can improve whole biocompatibility, has liver, spleen specific, the raising of the drug loading of nano-particle is restricted.
Summary of the invention
The invention provides a kind of gadolinium magnetic resonance contrast agent and preparation method thereof that contains, be intended to by cavity mesoporous inorganic carrier hydroxyapatite and the high inorganic/composite nano-polymers particle of a kind of gadolinium chelate compound content of the compound acquisition of natural polymer sodium alginate, thereby it is controlled to obtain a kind of particle diameter, realize liver, spleen specificity by passive target, good biocompatibility, the mri contrast agent of no cytotoxicity.The high had good sustained release effect of this mri contrast agent drug loading can realize the lasting release of developing agent in blood, has prolonged the circulation time of developing agent in blood, thereby can reduce amount of drug, improves the development effect of developing agent.Preparation technology is simple for this contrast agent, and the preparation condition gentleness has good potentiality aspect medical applications.
The invention discloses a kind of gadolinium magnetic resonance contrast agent that contains, it is characterized in that mainly being made up of gadolinium chelate compound, hydroxyapatite and sodium alginate, its weight ratio is as follows:
1 part of gadolinium chelate compound
Hydroxyapatite 1-10 part
Sodium alginate 1-10 part
Preferred weight ratio is as follows:
1 part of gadolinium chelate compound
Hydroxyapatite 3-5 part
Sodium alginate 1-2 part
Described gadolinium chelate compound is Gd-DTPA (Magnevist Solution), Gd-DTPA-BMA (gadodiamide), Gd-DO3A-HP (gadolinium is for alcohol) or Gd-DOTA (Dotarem), preferred Gd-DTPA.
Described hydroxyapatite has mesoporous cavity spherical structure, and grain diameter is 100～2000nm, and shell thickness is 10～100nm, and specific surface area is 130～230m
2/ g, surface mesoporous aperture is 10～50nm.
Its 1% viscosity in aqueous solution of described sodium alginate 〉=20cp.
The preparation method that contains the gadolinium magnetic resonance contrast agent of the present invention comprises the steps:
(1) hydroxyapatite is joined in the sodium hydrate aqueous solution that pH is 6～8 gadolinium chelate compound, behind supersound process 3～10min, soak 15～24h again under stirring condition, the solution lyophilization obtains the hydroxyapatite powder of load gadolinium chelate compound;
(2) hydroxyapatite powder with the load gadolinium chelate compound joins in the sodium alginate soln of 1～7mg/ml, reaction 20～30min, and high speed centrifugation takes out the precipitate lyophilization, can make to contain gadolinium magnetic resonance contrast agent lyophilized powder.
It is little that the present invention contains gadolinium magnetic resonance contrast agent pair cell toxic and side effects, and grain diameter is 0.1～2.0 μ m, can realize liver, position, spleen specificity by passive target.Utilize sodium alginate to solve as clad that water soluble drug loses in the coating process and dispose procedure in the prominent problem of releasing.This contrast agent has improved the load capacity of gadolinium chelate compound, and the good slow release performance is arranged, and improves the MRI contrast of target pathological tissues and normal structure, in the early diagnosis of tumor application facet good potentiality is arranged.
Description of drawings
Fig. 1 is for containing gadolinium magnetic resonance contrast agent stereoscan photograph.
Fig. 2 is for containing gadolinium magnetic resonance contrast agent particle size distribution figure.
Fig. 3 is a gadolinium chelate compound, the hydroxyapatite powder of load gadolinium chelate compound with contain the gadolinium release profiles comparison in PBS buffer solution (pH=7.4) of gadolinium magnetic resonance contrast agent.
The specific embodiment
Embodiment 1
Take by weighing the mesoporous cavity spherical structure of 140mg hydroxyapatite (HAP), add 10ml 30mg/ml to, pH is in 7.0 the Gd-DTPA aqueous solution, supersound process 10min.Stirring condition soaks 24h down, and lyophilization is handled.Compound concentration is the sodium alginate soln of 4mg/ml, then the Gd-DTPA/HAP lyophilized powder is joined 20ml sodium alginate soln ultrasound condition and disperses, and electromagnetic agitation reaction 20min obtains the suspension system.The suspension ultracentrifugation is with the precipitate lyophilization that obtains.Sample carries Gd-DTPA amount 17%, mean diameter 850nm.
Embodiment 2
Take by weighing the mesoporous cavity spherical structure of 45mg hydroxyapatite (HAP), add 10ml 45mg/ml to, pH is in 7.0 the Gd-DTPA aqueous solution, supersound process 10min.Stirring condition soaks 24h down, and lyophilization is handled.Compound concentration is the sodium alginate soln of 3mg/ml, then the Gd-DTPA/HAP lyophilized powder is joined 15ml sodium alginate soln ultrasound condition and disperses, and electromagnetic agitation reaction 20min obtains the suspension system.The suspension ultracentrifugation is with the precipitate lyophilization that obtains.Sample carries Gd-DTPA amount 19%, mean diameter 760nm.
Claims (6)
1. one kind contains the gadolinium magnetic resonance contrast agent, it is characterized in that mainly being made up of gadolinium chelate compound, hydroxyapatite and sodium alginate, and its weight ratio is as follows:
1 part of gadolinium chelate compound
Hydroxyapatite 1-10 part
Sodium alginate 1-10 part
2. according to the described gadolinium magnetic resonance contrast agent that contains of claim 1, it is characterized in that the weight ratio of each component is as follows:
1 part of gadolinium chelate compound
Hydroxyapatite 3-5 part
Sodium alginate 1-2 part
3. according to the described gadolinium magnetic resonance contrast agent that contains of claim 1, it is characterized in that: described gadolinium chelate compound is Gd-DTPA (Magnevist Solution), Gd-DTPA-BMA (gadodiamide), Gd-DO3A-HP (gadolinium is for alcohol) or Gd-DOTA (Dotarem), preferred Gd-DTPA.
4. according to the described gadolinium magnetic resonance contrast agent that contains of claim 1, it is characterized in that: described hydroxyapatite has mesoporous cavity spherical structure, and grain diameter is 100～2000nm, and shell thickness is 10～100nm, and specific surface area is 130～230m
2/ g, surface mesoporous aperture is 10～50nm.
5. according to claim 1 or the 2 described gadolinium magnetic resonance contrast agents that contain, it is characterized in that: its 1% viscosity in aqueous solution of described sodium alginate 〉=20cp.
6. according to each described preparation method that contains the gadolinium magnetic resonance contrast agent of claim 1～5, it is characterized in that comprising the steps:
(1) hydroxyapatite is added in the sodium hydrate aqueous solution that pH is 6～8 gadolinium chelate compound, behind the ultrasonic 3～10min of place, soaks 15～24h again under stirring condition, the solution lyophilization obtains the hydroxyapatite powder of load gadolinium chelate compound;
(2) hydroxyapatite powder with the load gadolinium chelate compound is added in 1～7mg/mL sodium alginate soln, reaction 20～30min, and high speed centrifugation takes out the precipitate lyophilization, can make to contain gadolinium magnetic resonance contrast agent lyophilized powder.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109437139A (en) * | 2018-12-12 | 2019-03-08 | 中国人民解放军南京军区南京总医院 | A kind of rodlike nano hydroxyapatite material of magnetism and preparation method thereof |
| CN112587673A (en) * | 2020-12-08 | 2021-04-02 | 天津医科大学第二医院 | Preparation of sodium alginate nano-microspheres containing gadolinium mesoporous silica and application of sodium alginate nano-microspheres in ultrasound-magnetic resonance image registration fusion navigation |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101549161A (en) * | 2009-05-13 | 2009-10-07 | 中南大学 | Liver, spleen specific positive magnetic nuclear resonance contrast agent and method of preparing the same |
| CN101773112A (en) * | 2010-01-28 | 2010-07-14 | 武汉理工大学 | Preparation method of pesticide diuron slow controlled release nanometer composite material |
-
2010
- 2010-10-20 CN CN 201010512605 patent/CN101979097A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101549161A (en) * | 2009-05-13 | 2009-10-07 | 中南大学 | Liver, spleen specific positive magnetic nuclear resonance contrast agent and method of preparing the same |
| CN101773112A (en) * | 2010-01-28 | 2010-07-14 | 武汉理工大学 | Preparation method of pesticide diuron slow controlled release nanometer composite material |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109437139A (en) * | 2018-12-12 | 2019-03-08 | 中国人民解放军南京军区南京总医院 | A kind of rodlike nano hydroxyapatite material of magnetism and preparation method thereof |
| CN112587673A (en) * | 2020-12-08 | 2021-04-02 | 天津医科大学第二医院 | Preparation of sodium alginate nano-microspheres containing gadolinium mesoporous silica and application of sodium alginate nano-microspheres in ultrasound-magnetic resonance image registration fusion navigation |
| CN112587673B (en) * | 2020-12-08 | 2022-10-11 | 天津医科大学第二医院 | Preparation of sodium alginate nano microspheres containing gadolinium mesoporous silica and application of sodium alginate nano microspheres in ultrasound-magnetic resonance image registration fusion navigation |
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Application publication date: 20110223 |