One has T
1, T
2the preparation method of the mix type contrast agent of radiography function
Technical field
The invention belongs to contrast agent material field, be specifically related to one and there is T
1, T
2the preparation method of the mix type contrast agent of radiography function.
Background technology
In order to realize targeting efficiency to tumor tissues of gene or pharmaceutical carrier and the dynamic monitoring of therapeutic effect, people introduce carrier by contrast agent conventionally.Because tumor tissues compared with normal structure, has abundant blood vessel network structure, contrast agent can be by the abundant blood vessel network of tumor tissues and vessel wall permeability in the more enrichment of tumor locus.Utilize contrast agent can change the contrast between normal structure and tumor tissues, reach the effect of better observation tumor tissues.
Strengthen type according to developing and divide, the MRI contrast agent using is at present divided into two classes: opaque contrast medium T
1with negative contrast medium T
2.They are respectively by strengthening the 1/T of regional area
1or 1/T
2relaxivity reaches picture signal and strengthens the effect that picture brightens or picture is dimmed.But under different scanning pulse train, for same contrast agent, the picture signal that can not simultaneously reach strengthens picture and brightens and the dimmed effect of picture.Although for example opaque contrast medium Gd-DTPA has T simultaneously
1and T
2radiography effect, but T
1radiography effect is better than T
2radiography effect, negative contrast medium SPIO is contrary.The T simultaneously having had in order to realize a kind of contrast agent
1and T
2radiography effect, the unpredictable danger of avoiding the dissimilar contrast agent of multiple injection to bring to patient.The present invention has developed a kind of method of preparing mix type contrast agent material by hydro-thermal reaction.The method has the advantages that preparation is simple, reaction condition is gentle, be easy to control.The mix type contrast agent material of preparing can reach good T simultaneously
1and T
2radiography effect is the novel contrast agent material of a class.
Summary of the invention
The object of the present invention is to provide one to there is T
1, T
2the preparation method of the mix type contrast agent of radiography function, the method is to do template with double end parents organic molecule, under the condition existing at aromatic acid, a kind of mix type contrast agent that blending rare earth ion and VI B~VIII B family ion are being prepared in steam pressure system.Mix type contrast agent material prepared by the present invention has Nano Particle and good T
1, T
2radiography effect.
The invention provides one and there is T
1, T
2the preparation method of the mix type contrast agent of radiography function, the method comprises the steps:
(1) by a kind of double end parents' organic formwork molecular melting in solvent, ultrasonic at 30~50 DEG C it is fully dissolved;
(2) aromatic acid, rare earth chloride and VI B~VIII B family chloride are slowly added in above-mentioned (1) solution, continue ultrasonic until obtain the solution of homogeneous transparent;
(3) clear solution obtaining in (2) is added in hydrothermal reaction kettle, at 70~150 DEG C of reaction 24~72h, obtain granule precipitate;
(4) granule precipitate organic solvent washing step (3) being obtained is removed unreacting material;
(5) solid obtaining in (4) is put into 60~80 DEG C of backflow 24h of organic solvent to remove double end parents organic formwork molecule;
(6), finally by the product organic solvent washing in (5), in 40 DEG C~200 DEG C vacuum dryings, obtain mix type contrast agent.
Provided by the invention have a T
1, T
2the preparation method of the mix type contrast agent of radiography function, in step (1), described double end parents' organic formwork molecule is polyether surfactant; Described polyether surfactant is one or more in polyoxyethylene and polyoxypropylene block copolymers Pluronic F127, Pluronic F108, Pluronic P123, Pluronic P103, Pluronic P104, Pluronic P105, Pluronic P85, Pluronic P65.
Provided by the invention have a T
1, T
2the preparation method of the mix type contrast agent of radiography function, in step (1), described solvent is one or both in secondary deionized water, ethanol.
Provided by the invention have a T
1, T
2the preparation method of the mix type contrast agent of radiography function, in step (2), described aromatic acid is one or more in p-phthalic acid, diaminourea p-phthalic acid, Trimesic acid, M-phthalic acid; Cation in described rare earth chloride can be one or more in praseodymium (Pr), neodymium (Nd), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), lutecium (Lu); Cation in described VI B~VIII B chloride can be one or more in ferrum (Fe), cobalt (Co), nickel (Ni), manganese (Mn).
Provided by the invention have a T
1, T
2the preparation method of the mix type contrast agent of radiography function, in step (4), described organic solvent is ethanol water miscible agent (mixed proportion is 4:1~1:1), N, N-diethylformamide, N, dinethylformamide, N,N-dimethylacetamide, N, N-dimethyl propylene amide, N, N-diethyl acetamide, N, one or more in N-diethyl propionic acid amide..
Provided by the invention have a T
1, T
2the preparation method of the mix type contrast agent of radiography function, in step (5), described organic solvent is the one in methanol, ethanol, methanol-water miscible agent (mixed proportion is 5:1~1:5), ethanol water miscible agent (mixed proportion is 5:1~1:5).
Provided by the invention have a T
1, T
2the preparation method of the mix type contrast agent of radiography function, in step (6), described organic solvent is the one in methanol, ethanol, methanol-water miscible agent (mixed proportion is 5:1~1:5), ethanol water miscible agent (mixed proportion is 5:1~1:5).
The present invention compared with prior art has following excellent beneficial effect:
Mix type contrast agent material prepared by the present invention has Nano Particle and good T
1, T
2radiography effect.
Brief description of the drawings
Fig. 1 is by the rare-earth cation Gd of regulation and control different proportion in the embodiment of the present invention 1
3+with VIII B cation Fe
3+, the mix type contrast agent Gd of preparation
80fe
20transmission electron microscope picture;
Fig. 2 is by the rare-earth cation Gd of regulation and control different proportion in the embodiment of the present invention 2
3+with VIII B cation Fe
3+, the mix type contrast agent Gd of preparation
20fe
80transmission electron microscope picture;
Fig. 3 is by the rare-earth cation Gd of regulation and control different proportion in the embodiment of the present invention 1
3+with VIII B cation Fe
3+, the mix type contrast agent Gd of preparation
80fe
20mR image;
Fig. 4 is by the rare-earth cation Gd of regulation and control different proportion in the embodiment of the present invention 2
3+with VIII B cation Fe
3+, the mix type contrast agent Gd of preparation
20fe
80mR image.
Detailed description of the invention
The following examples will be further described the present invention, but not thereby limiting the invention.
Embodiment 1
1,0.718g F127 is dissolved in 25mL secondary deionized water, the ultrasonic 30min of 50 degree fully dissolves it.
2,0.189g p-phthalic acid, 0.160g gadolinium trichloride and 0.041g Iron(III) chloride hexahydrate are slowly added in above-mentioned solution,, continue ultrasonic until obtain the solution of homogeneous transparent.
3, the clear solution obtaining in 2 is added in hydrothermal reaction kettle, at 150 DEG C of reaction 24h.
4, after reaction finishes, by the centrifugal reactant liquor secondary deionized water reactant liquor that goes.
5, then crude product is washed to twice with DMF again, to remove unreacting material.
6, the solid obtaining in 5 is put into ethanol 80 degree 1d to remove F127.
7, finally product washing with alcohol 3 times of F127 will be removed in 6.After 60 DEG C of vacuum drying 24h, obtain target product Gd
80fe
20.Embodiment 2
1,0.718g F127 is dissolved in 25mL secondary deionized water, the ultrasonic 30min of 50 degree fully dissolves it.
2,0.189g p-phthalic acid, 0.04g gadolinium trichloride and 0.164g Iron(III) chloride hexahydrate are slowly added in above-mentioned solution,, continue ultrasonic until obtain the solution of homogeneous transparent.
3, the clear solution obtaining in 2 is added in hydrothermal reaction kettle, at 150 DEG C of reaction 24h.
4, after reaction finishes, by the centrifugal reactant liquor secondary deionized water reactant liquor that goes.
5, then crude product is washed to twice with DMF again, to remove unreacting material.
6, the solid obtaining in 5 is put into ethanol 80 degree 1d to remove F127.
7, finally product washing with alcohol 3 times of F127 will be removed in 6.After 60 DEG C of vacuum drying 24h, obtain target product Gd
20fe
80.
Embodiment 3-6
Embodiment 3-6 and embodiment 1~2 difference see the following form:
T
1, T
2contrast agent structure and MR property representation
The mix type contrast agent Gd that adopts MinMR-60 that JEM-2000EX transmission electron microscope that Japanese JEOL Electronics Co., Ltd produces and Shanghai Niumai Electronic Technology Co., Ltd. produce and NMI20 magnetic resonance device to prepare the present invention
80fe
20and Gd
20fe
80particle diameter pattern and contrast agent imaging characterize, result is as shown in Fig. 1~4.
The mix type contrast agent Gd of the preparation of the embodiment of the present invention 1~2 shown in Fig. 1~4
80fe
20and Gd
20fe
80dispersion of materials is all very even, and the similar acicular texture of the former similar Fructus Mori structure the latter, size is respectively in 70nm(short end), 150nm(long end) and 140nm(short end), 890nm(long end).In addition compared with matched group ferroso-ferric oxide, along with the increase of contrast concentration, the T of two kinds of mix type contrast agent
1weighted imaging, brightness increases gradually, T
2weighted imaging, brightness reduces gradually.And matched group ferroso-ferric oxide, along with the increase of contrast concentration, T
1weighted imaging brightness there is not variation, T substantially
2weighted imaging brightness reduces gradually, and this explanation mix type contrast agent has T simultaneously
1and T
2radiography effect.