CN101642579A - Chitosan modified paramagnetic metal ion magnetic resonance imaging contrast agent preparation method - Google Patents
Chitosan modified paramagnetic metal ion magnetic resonance imaging contrast agent preparation method Download PDFInfo
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Abstract
The invention provides a chitosan modified paramagnetic metal ion magnetic resonance imaging contrast agent preparation method, belonging to the technical field of magnetic resonance imaging contrastagent. The method comprises the following steps: firstly preparing acid anhydride with polyamine and polycarboxylic acid, adopting the acid anhydride to react with water soluble chitosan or chitosan with narrow molecular weight distribution in the presence of catalyst, using absolute alcohol to precipitate and obtain solids, purifying the solids with a Sephadex G-25 type gel column to obtain chitosan ligand, adopting the ligand to react with paramagnetic metal inorganic salt, using absolute alcohol to precipitate and finally dying the sediment to obtain the magnetic resonance imaging contrastagent solid powder. The invention combines the acid anhydride with polyamine and polycarboxylic acid with the amino of chitosan through covalent bond and adopts paramagnetic rare earth or transition metal ions for complexing so as to ensure the obtained product to be a new magnetic resonance imaging contrast agent with a certain targeting effect, proper drug duration in vivo, higher relaxivity than magnevist and low toxicity. The invention has simple processing and producing technology and low facility request, thus being easy for processing and producing.
Description
Technical field
The present invention relates to the mr imaging technique field, relate in particular to a kind of preparation method of novel nuclear magnetic resonance contrast medium.
Background technology
(Magnetic Resonance Imaging is that a kind of the utilization under the influence of organism different tissues outside magnetic field produces the medical image technology that different magnetic resonance signals come imaging MRI) in nuclear magnetic resonance.MRI has no ionizing radiation, can realize multinuclear and multiparameter imaging, need not to change the scanning of the just practicable arbitrary orientation aspect of position, higher spatial resolution and contrast and do not have the pseudo-shadow of sclerotin, can reflect tested tissue water proton surrounding and obtain advantage such as relevant physiological Biochemical Information, becomes one of clinical effective diagnosis means.For guaranteeing the accuracy of clinical diagnosis, MRI more than 30% needs nuclear magnetic resonance contrast medium (be called for short contrast medium or claim contrast agent) to improve picture contrast, the whole world contains gadolinium metal ion contrast medium (being called for short the gadolinio contrast medium) year sales volume more than 30 tons, is the high added value medical product.Good contrast medium should have: i) enough structural stability; Ii) self hypotoxicity; Iii) relaxation usefulness height; Iv) to histoorgan selective (targeting); Suitable retention time is v) arranged in vivo and be easy in body, discharge.In occupation of consequence, corresponding part has the gadolinio contrast medium: diethylenetriamine pentaacetic acid (DTPA) in the nuclear magnetic resonance contrast medium; 1,4,7, the 10-tetraazacyclododecanand; 1,4,7,10-tetraacethyl (DOTA) and ethylenediaminetetraacetic acid (EDTA) and their derivant.Entered clinical practice have Gd-DTPA (magnevist, Magnevist), Gd-DTPA-BMA, Gd-DO3A-HP (gadolinium for alcohol, Prohance), Gd-DOTA (Dotarem).Yet,, confirm that in recent years traditional gadolinio imaging contrast can cause the nephrocyte fibrosis from finding over 1987 that the gadolinio contrast medium can cause direct infringement to renal tubules.Therefore, how avoiding additional toxic and side effects is the R﹠D direction of following gadolinio contrast medium.Present international development trend still ensure that the contrast medium molecule is stable, on the basis of low toxicity, high relaxation rate, pursuit is at particular organization and organ design synthesis of selective height, contrast medium molecule that targeting is strong, comprises the chemical constitution of gadolinio nuclear magnetic resonance contrast medium is modified and explored novel superparamagnetism (based on Fe
3O
4) contrast medium and water solublity paramagnetism contrast medium.These chemical compounds can pass through the further Chemical Physics of albumin, glucosan, polystyrene, monoclonal antibody etc. and modify the intensifier target tropism.But owing to be in development mostly, do not have last final conclusion, notice that simultaneously the contrast medium of seeking to have lower toxic and side effects also is the direction of studying from now on.
A kind of as natural polysaccharide, chitosan belongs to amino straight-chain polysaccharide, belongs to the pure natural renewable green resource of getting bumper crops.Selecting chitosan to modify contrast medium is because it has a lot of good characteristics, as: i) self zero toxicity, good water-solubility and with the affinity characteristic of heavy metal ion; Ii) with polyamines polyacid contrast medium compounds easily by covalent bonds, in conjunction with after utilize chitosan long-chain winding characteristic the paramagnetic metal ion of chelating is wrapped in core, increase relaxation efficient simultaneously; Chitosan can be degraded after iii) entering in the body, but needs certain hour, and the metal ion of assurance contrast medium is in package status when retaining in vivo and does not leak; Iv) the chitosan degree of polymerization waits with Albumin (human blood serum). at 12～6 o'clock that to transport proteic binding ability the strongest, can imaging measure will be not after finishing fully the contrast medium metabolism of degraded excrete; V) saccharide compound has different affinities to Different Organs or focus organ, improves the targeting of contrast medium with this; Vi) chitosan self can also improve the immunity of life entity, and has certain antitumaous effect, is expected to strengthen synergism; Therefore vii) chitosan is easy to be processed into microcapsule, advantage is also arranged in dosage form aspect preparing.These characteristics meet the prerequisite as the MRI contrast medium very much.In addition from present the radiography contrast properties of glucosan and other saccharide compounds being studied, chitosan extremely is expected to become a kind of MRI contrast medium of novel, function admirable.
This method will be got up by covalent bonds by the anhydride and the amino of chitosan of polyamines polyacid compound, paramagnetic ion such as complex rare-earth or transition metal again, as gadolinium, ferrum, manganese etc., make it to become and have holdup time, relaxation efficient in certain targeting and the suitable body and be higher than magnevist, novel nuclear magnetic resonance contrast medium that toxicity is little.Its advantage also is: the i) chitosan of amido link binding self avirulence, can reduce medicine application procedures link, easily listing; Ii) carbohydrate molecule has recognition reaction to Different Organs tissue and focus, improves corresponding selectivity; Iii) the gadolinium amount that contains with magnevist 1/4 to 2/3 just can reach same imaging contrast effect, can further reduce metal ion and may cause toxic risk in vivo; Iv) processing and preparing technology is simple, and equipment requirements is low, is easy to processing.
Summary of the invention
The objective of the invention is in order to reduce the toxic and side effects that traditional gadolinio contrast medium produces organ, a kind of potential new function NMR (Nuclear Magnetic Resonance)-imaging contrast medium and preparation method thereof is provided, in improving relaxation efficient, extension body, improve selectivity in the relaxation time, and reduce toxic and side effects Different Organs tissue or focus.
The preparation method of chitosan modified paramagnetic metal ion magnetic resonance imaging contrast medium of the present invention is as follows:
(1) in reaction vessel; the polyamines polycarboxylic acid solid that adds certain mass; and then add the anhydrous acetic acid acid anhydride of certain volume respectively; wherein said polyamines polycarboxylic acid can be diethylenetriamine pentaacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA); the ratio of polyamines polycarboxylic acid and anhydrous acetic acid acid anhydride (quality: be 1: 1～3 volume) wherein; the anhydrous pyridine that adds certain volume again is as catalyst; logical drying nitrogen protection; sucking filtration behind 55～60 ℃ of following stirring reaction 24h; use the anhydrous acetic acid acid anhydride respectively; anhydrous N; N '-dimethyl formamide (DMF) and absolute ether washing; obtain the polycarboxylic corresponding anhydride of polyamines, the polycarboxylic anhydride of resulting polyamines is diethylenetriamine pentaacetic acid anhydride (DTPAA) or ethylenediaminetetraacetic acid anhydride (EDTAA).
(2) at anhydrous N, add water-soluble chitosan or Narrow Molecular Weight Distribution water-soluble chitosan in N '-dimethyl formamide (DMF) or the dimethyl sulfoxide (DMSO), add 4-dimethylamino naphthyridine or triethylamine or pyridine again as catalyst, add the polyamines polycarboxylic acid anhydride for preparing in the step (1) under the stirring at normal temperature, wherein the mol ratio of chitosan and polyamines polycarboxylic acid anhydride is 1: 1～5, stir 36～72h under room temperature, ice bath cooling back adds distilled water and continues to stir 12～120h.Vacuum concentration adds dehydrated alcohol and separates out faint yellow solid, vacuum drying to small size.
(3) take by weighing Sephadex G-25 type gel, activation back dress post.Resulting solid in the step (2) is dissolved in a small amount of distilled water, solid and distilled water ratio (quality: be 1: 2～100 volume) wherein, upper prop, with the distilled water is eluting solvent, the colour developing of 0.1% 1,2,3-indantrione monohydrate butanol solution, detect (the detection wavelength is 254nm) with uv analyzer, two eluting peaks appear in the process of eluting, the eluting peak of part at first goes out post, it is collected final vacuum be concentrated into small size, the cooling back adds dehydrated alcohol and gets faint yellow precipitation, filters, and vacuum drying gets the part powder.
(4) take by weighing in the step (3) resulting part powder dissolution in distilled water, part powder and distilled water ratio (quality: be 1: 5～20 volume) wherein, stir and add metal inorganic salt down, the mol ratio of part and metal inorganic salt is 1: 1～5, continue to stir 2～24h under room temperature, with solution for vacuum concentration, the cooling back adds the dehydrated alcohol precipitation, washing and filtering obtains the pressed powder 0.3～3.0g of nuclear magnetic resonance contrast medium after the drying.Wherein said metal inorganic salt is the salt of all paramagnetic rare-earths and transition metal ions, comprises the hydrochlorate, nitrate, acetate, sulfate or the perchlorate that contain different water of crystallization, preferred Gd
3+Salt, Mn
2+Salt, Fe
3+Salt.
The present invention compared with prior art has following remarkable advantage:
1) reaction at normal temperatures, operation and equipment needed thereby are simple, and be with low cost, is easy to accomplish scale production; 2) product good water solubility, relaxation rate are 10～14Lmmol
-1S
-1, be 1～3 times of Gd-DTPA relaxation rate; 3) liver and renal tissue there are the selection of targeting, can effectively improve the correlated definition of radiography of liver and kidney; 4) contrast correlated mice in vivo test result with magnevist and show that 30 days gadolinium ions reduce by 2/5～2/3 the residual of liver and kidney after the drug withdrawal; 5) chitosan is the renewable green resource of natural high yield, has excellent biological compatibility and degradability, and self is nontoxic.
Concrete embodiment:
Example 1
The preparation method of water-soluble chitosan is as follows: the high molecular weight chitosan that takes by weighing certain mass is in there-necked flask, the volume fraction that adds certain volume is 0.5% acetic acid solution, the ratio of chitosan and acetic acid (quality: volume) be 1: 50 wherein, under agitation, the mass fraction that adds certain volume is 10% hydrogen peroxide, the ratio of chitosan and hydrogen peroxide (quality: volume) be 1: 1, stir about 10min wherein.Resulting solution is carried out microwave treatment, microwave parameters (microwave time: 30min, microwave temperature: 60 ℃) is set, microwave leaves standstill cooling after finishing, and regulates pH to neutral.Again with resulting solution for vacuum concentration to certain volume, add ethanol and separate out solid, the washing of reuse ether, vacuum drying, (degree of polymerization is 11, molecular weight distributing index (DPI or M promptly to obtain mean molecule quantity and be 1980
w/ M
n)=1.9) water-soluble chitosan.
(1) in three-neck flask; diethylenetriamine pentaacetic acid (DTPA) solid that adds certain mass; the anhydrous acetic acid acid anhydride that adds certain volume then; the ratio of DTPA and anhydrous acetic acid acid anhydride (quality: volume) be 1: 1 wherein; the anhydrous pyridine that adds certain volume again is as catalyst; logical drying nitrogen protection; sucking filtration behind 55～60 ℃ of following stirring reaction 24h; use anhydrous acetic acid acid anhydride, anhydrous N respectively; N '-dimethyl formamide (DMF) and absolute ether wash, and obtain the white solid powder of the polycarboxylic anhydride DTPAA of polyamines.(2) at anhydrous N, add the chitosan for preparing in the step (1) among the N '-dimethyl formamide (DMF), add the 4-dimethylamino naphthyridine again as catalyst, add the polyamines polycarboxylic acid anhydride for preparing in the step (1) under the stirring at normal temperature, wherein the mol ratio of chitosan and polyamines polyacid anhydride is 1: 1, stir 36h under room temperature, ice bath cooling back adds distilled water and continues to stir 12h.Vacuum concentration adds dehydrated alcohol and separates out faint yellow solid, vacuum drying to small size.(3) take by weighing Sephadex G-25 type gel, activation back dress post.Resulting solid in the step (2) is dissolved in a small amount of distilled water, solid and distilled water ratio (quality: volume) be 1: 2 wherein, upper prop, with the distilled water is eluting solvent, the colour developing of 0.1% 1,2,3-indantrione monohydrate butanol solution, detect (wavelength is 254nm) with uv analyzer, two eluting peaks appear in the process of eluting, the eluting peak of part at first goes out post, it is collected final vacuum be concentrated into small size, the cooling back adds dehydrated alcohol and gets faint yellow precipitation, filters, and vacuum drying gets the part powder.(4) take by weighing in the step (3) resulting part powder dissolution in distilled water, wherein part powder and distilled water ratio (quality: volume) be 1: 5, stir and add metal inorganic salt GdCl down
36H
2O, wherein part and GdCl
36H
2The mol ratio of O is 1: 1, continues to stir 2h under room temperature, and with solution for vacuum concentration, the cooling back adds the dehydrated alcohol precipitation, and washing and filtering obtains after the drying about the pressed powder 1.0g of nuclear magnetic resonance contrast medium.
Example 2
(1) in three-neck flask; diethylenetriamine pentaacetic acid (DTPA) solid that adds certain mass; the anhydrous acetic acid acid anhydride that adds certain volume then; the ratio of DTPA and anhydrous acetic acid acid anhydride (quality: volume) be 1: 3 wherein; add the certain volume anhydrous pyridine again as catalyst; logical drying nitrogen protection; sucking filtration behind 55～60 ℃ of following stirring reaction 24h; use anhydrous acetic acid acid anhydride, anhydrous N respectively; N '-dimethyl formamide (DMF) and absolute ether wash, and obtain the white solid powder of the polycarboxylic anhydride DTPAA of polyamines.(2) at anhydrous N, (degree of polymerization is 8, molecular weight distributing index (DPI or M to add mean molecule quantity among the N '-dimethyl formamide (DMF) and be 1460
w/ M
n)=1.06) (this raw material is provided by Hainan Province's fine chemistry industry key lab water-soluble chitosan, preparation method is with example 1), add the 4-dimethylamino naphthyridine again as catalyst, add the polyamines polycarboxylic acid anhydride for preparing in the step (1) under the stirring at normal temperature, wherein the mol ratio of chitosan and polyamines polyacid anhydride DTPAA is 1: 5, stir 72h under room temperature, ice bath cooling back adds distilled water and continues to stir 120h.Vacuum concentration adds dehydrated alcohol and separates out faint yellow solid, vacuum drying to small size.(3) take by weighing Sephadex G-25 type gel, activation back dress post.Resulting solid in the step (2) is dissolved in a small amount of distilled water, solid and distilled water ratio (quality: volume) be 1: 100 wherein, upper prop, with the distilled water is eluting solvent, the colour developing of 0.1% 1,2,3-indantrione monohydrate butanol solution, detect (wavelength is 254nm) with uv analyzer, two eluting peaks appear in the process of eluting, the eluting peak of part at first goes out post, it is collected final vacuum be concentrated into small size, the cooling back adds dehydrated alcohol and gets faint yellow precipitation, filters, and vacuum drying gets the part powder.(4) take by weighing in the step (3) resulting part powder dissolution in distilled water, wherein part powder and distilled water ratio (quality: volume) be 1: 20, stir and add metal inorganic salt MnCl down
24H
2O, wherein part and MnCl
24H
2The mol ratio of O is 1: 5, continue to stir 24h under room temperature, and with solution for vacuum concentration, the cooling back adds the dehydrated alcohol precipitation, and washing and filtering obtains the pressed powder 1.0g of nuclear magnetic resonance contrast medium after the drying.
Example 3
(1) in three-neck flask; add diethylenetriamine pentaacetic acid (DTPA) solid; the anhydrous acetic acid acid anhydride that adds certain volume then; the ratio of DTPA and anhydrous acetic acid acid anhydride (quality: volume) be 1: 1 wherein; the anhydrous pyridine that adds certain volume again is as catalyst; logical drying nitrogen protection; sucking filtration behind 55～60 ℃ of following stirring reaction 24h; use anhydrous acetic acid acid anhydride, anhydrous N respectively; N '-dimethyl formamide (DMF) and absolute ether wash, and obtain the white solid powder of the polycarboxylic anhydride DTPAA of polyamines.(2) adding mean molecule quantity in anhydrous dimethyl sulphoxide (DMSO) is that 1080 (degree of polymerization is 6, molecular weight distributing index (DPI or M
w/ M
n)=1.03) (this raw material is provided by Hainan Province's fine chemistry industry key lab water-soluble chitosan, preparation method is with example 1), add triethylamine again as catalyst, add the polyamines polycarboxylic acid anhydride for preparing in the step (1) under the stirring at normal temperature, wherein the mol ratio of chitosan and polyamines polyacid anhydride DTPAA is 1: 1, stir 36h under room temperature, ice bath cooling back adds distilled water and continues to stir 12h.Vacuum concentration adds dehydrated alcohol and separates out faint yellow solid, vacuum drying to small size.(3) take by weighing Sephadex G-25 type gel, activation back dress post.Resulting solid in the step (2) is dissolved in a small amount of distilled water, solid and distilled water ratio (quality: volume) be 1: 2 wherein, upper prop, with the distilled water is eluting solvent, the colour developing of 0.1% 1,2,3-indantrione monohydrate butanol solution, detect (wavelength is 254nm) with uv analyzer, two eluting peaks appear in the process of eluting, the eluting peak of part at first goes out post, it is collected final vacuum be concentrated into small size, the cooling back adds dehydrated alcohol and gets faint yellow precipitation, filters, and vacuum drying gets the part powder.(4) take by weighing in the step (3) resulting part powder dissolution in distilled water, wherein part powder and distilled water ratio (quality: volume) be 1: 5, stir and add metal inorganic salt GdCl down
36H
2O, wherein part and GdCl
36H
2The mol ratio of O is 1: 1, continues to stir 2h under room temperature, and with solution for vacuum concentration, the cooling back adds the dehydrated alcohol precipitation, and washing and filtering obtains after the drying about the pressed powder 0.5g of nuclear magnetic resonance contrast medium.
Example 4
(1) in three-neck flask; add ethylenediaminetetraacetic acid (EDTA) solid; the anhydrous acetic acid acid anhydride that adds certain volume then; the ratio of EDTA and anhydrous acetic acid acid anhydride (quality: volume) be 1: 3 wherein; the anhydrous pyridine that adds certain volume again is as catalyst; logical drying nitrogen protection; sucking filtration behind 55～60 ℃ of following stirring reaction 24h; use anhydrous acetic acid acid anhydride, anhydrous N respectively; N '-dimethyl formamide (DMF) and absolute ether wash, and obtain the white solid powder of the polycarboxylic anhydride EDTAA of polyamines.(2) at anhydrous N, (degree of polymerization is 6, molecular weight distributing index (DPI or M to add mean molecule quantity among the N '-dimethyl formamide (DMF) and be 1080
w/ M
n)=1.03) (this raw material is provided by Hainan Province's fine chemistry industry key lab water-soluble chitosan, preparation method is with example 1), add the 4-dimethylamino naphthyridine again as catalyst, add the polyamines polycarboxylic acid anhydride for preparing in the step (1) under the stirring at normal temperature, wherein the mol ratio of chitosan and polyamines polyacid anhydride EDTAA is 1: 5, stir 72h under room temperature, ice bath cooling back adds distilled water and continues to stir 120h.Vacuum concentration adds dehydrated alcohol and separates out faint yellow solid, vacuum drying to small size.(3) take by weighing Sephadex G-25 type gel, activation back dress post.With a small amount of dissolved in distilled water of resulting solid in the step (2), wherein (quality: volume) be 1: 2, upper prop is an eluting solvent with the distilled water for solid and distilled water ratio, the colour developing of 0.1% 1,2,3-indantrione monohydrate butanol solution, detect (wavelength is 254nm) with uv analyzer, two eluting peaks occur in the process of eluting, the eluting peak of part at first goes out post, it is collected final vacuum be concentrated into small size, the cooling back adds dehydrated alcohol and gets faint yellow precipitation, filters, and vacuum drying gets the part powder.(4) take by weighing in the step (3) resulting part powder dissolution in distilled water, wherein part powder and distilled water ratio (quality: volume) be 1: 20, stir and add metal inorganic salt GdCl down
36H
2O, wherein part and GdCl
36H
2The mol ratio of O is 1: 5, continues to stir 24h under room temperature, and with solution for vacuum concentration, the cooling back adds the dehydrated alcohol precipitation, and washing and filtering obtains after the drying about the pressed powder 1.5g of nuclear magnetic resonance contrast medium.
Example 5
(1) in three-neck flask; add ethylenediaminetetraacetic acid (EDTA) solid; the anhydrous acetic acid acid anhydride that adds certain volume then; the ratio of EDTA and anhydrous acetic acid acid anhydride (quality: volume) be 1: 3 wherein; the anhydrous pyridine that adds certain volume again is as catalyst; logical drying nitrogen protection; sucking filtration behind 55～60 ℃ of following stirring reaction 24h; use anhydrous acetic acid acid anhydride, anhydrous N respectively; N '-dimethyl formamide (DMF) and absolute ether wash, and obtain the white solid powder of the polycarboxylic anhydride EDTAA of polyamines.(2) at anhydrous N, (degree of polymerization is 8, molecular weight distributing index (DPI or M to add mean molecule quantity among the N '-dimethyl formamide (DMF) and be 1460
w/ M
n)=1.06) (this raw material is provided by Hainan Province's fine chemistry industry key lab water-soluble chitosan, preparation method is with example 1), add pyridine again as catalyst, add the polyamines polycarboxylic acid anhydride for preparing in the step (1) under the stirring at normal temperature, wherein the mol ratio of chitosan and polyamines polyacid anhydride EDTAA is 1: 5, stir 72h under room temperature, ice bath cooling back adds distilled water and continues to stir 120h.Vacuum concentration adds dehydrated alcohol and separates out faint yellow solid, vacuum drying to small size.(3) take by weighing SephadexG-25 type gel, activation back dress post.Resulting solid in the step (2) is dissolved in a small amount of distilled water, solid and distilled water ratio (quality: volume) be 1: 100 wherein, upper prop, with the distilled water is eluting solvent, the colour developing of 0.1% 1,2,3-indantrione monohydrate butanol solution, detect (wavelength is 254nm) with uv analyzer, two eluting peaks appear in the process of eluting, the eluting peak of part at first goes out post, it is collected final vacuum be concentrated into small size, the cooling back adds dehydrated alcohol and gets faint yellow precipitation, filters, and vacuum drying gets the part powder.(4) take by weighing in the step (3) resulting part powder dissolution in distilled water, wherein part powder and distilled water ratio (quality: volume) be 1: 20, stir and add metal inorganic salt MnCl down
24H
2O, wherein part and MnCl
24H
2The mol ratio of O is 1: 5, continues to stir 24h under room temperature, and with solution for vacuum concentration, the cooling back adds the dehydrated alcohol precipitation, and washing and filtering obtains after the drying about the pressed powder 1.5g of nuclear magnetic resonance contrast medium.
Example 6
(1) in three-neck flask; add diethylenetriamine pentaacetic acid (DTPA) solid; the anhydrous acetic acid acid anhydride that adds certain volume then; the ratio of DTPA and anhydrous acetic acid acid anhydride (quality: volume) be 1: 1 wherein; the anhydrous pyridine that adds certain volume again is as catalyst; logical drying nitrogen protection; sucking filtration behind 55～60 ℃ of following stirring reaction 24h; use anhydrous acetic acid acid anhydride, anhydrous N respectively; N '-dimethyl formamide (DMF) and absolute ether wash, and obtain the white solid powder of the polycarboxylic anhydride DTPAA of polyamines.(2) adding mean molecule quantity in anhydrous dimethyl sulphoxide (DMSO) is that 1980 (degree of polymerization is 11, molecular weight distributing index (DPI or M
w/ M
n)=1.08) (this raw material is provided by Hainan Province's fine chemistry industry key lab water-soluble chitosan, preparation method is with example 1), add the 4-dimethylamino naphthyridine again as catalyst, add the polyamines polycarboxylic acid anhydride for preparing in the step (1) under the stirring at normal temperature, wherein the mol ratio of chitosan and polyamines polyacid anhydride DTPAA is 1: 1, stir 36h under room temperature, ice bath cooling back adds distilled water and continues to stir 12h.Vacuum concentration adds dehydrated alcohol and separates out faint yellow solid, vacuum drying to small size.(3) take by weighing Sephadex G-25 type gel, activation back dress post.Resulting solid in the step (2) is dissolved in a small amount of distilled water, solid and distilled water ratio (quality: volume) be 1: 2 wherein, upper prop, with the distilled water is eluting solvent, the colour developing of 0.1% 1,2,3-indantrione monohydrate butanol solution, detect (wavelength is 254nm) with uv analyzer, two eluting peaks appear in the process of eluting, the eluting peak of part at first goes out post, it is collected final vacuum be concentrated into small size, the cooling back adds dehydrated alcohol and gets faint yellow precipitation, filters, and vacuum drying gets the part powder.(4) take by weighing in the step (3) resulting part powder dissolution in distilled water, wherein part powder and distilled water ratio (quality: volume) be 1: 5, stir and add metal inorganic salt GdCl down
36H
2O, wherein part and GdCl
36H
2The mol ratio of O is 1: 1, continues to stir 2h under room temperature, and with solution for vacuum concentration, the cooling back adds the dehydrated alcohol precipitation, and washing and filtering obtains after the drying about the pressed powder 1.2g of nuclear magnetic resonance contrast medium.
Example 7
(1) takes by weighing the high molecular weight chitosan of certain mass in there-necked flask, the volume fraction that adds certain volume is 0.5% acetic acid solution, the ratio of chitosan and acetic acid (quality: volume) be 1: 50 wherein, under agitation, 10% hydrogen peroxide that adds certain volume, the ratio of chitosan and hydrogen peroxide (quality: volume) be 1: 1, stir about 10min wherein.Resulting solution is carried out microwave treatment, microwave parameters (microwave time: 30min, microwave temperature: 60 ℃) is set, microwave leaves standstill cooling after finishing, and regulates pH to neutral.Again with resulting solution for vacuum concentration to small size, add ethanol and separate out solid, the washing of reuse ether, vacuum drying, (degree of polymerization is 11, molecular weight distributing index (DPI or M promptly to obtain mean molecule quantity and be 1980
w/ M
n)=1.9) water-soluble chitosan.(2) in three-neck flask; add ethylenediaminetetraacetic acid (EDTA) solid; the anhydrous acetic acid acid anhydride that adds certain volume then; the ratio of EDTA and anhydrous acetic acid acid anhydride (quality: volume) be 1: 1 wherein; the anhydrous pyridine that adds certain volume again is as catalyst; logical drying nitrogen protection; sucking filtration behind 55～60 ℃ of following stirring reaction 24h; use anhydrous acetic acid acid anhydride, anhydrous N respectively; N '-dimethyl formamide (DMF) and absolute ether wash, and obtain the white solid powder of the polycarboxylic anhydride EDTAA of polyamines.(3) at anhydrous N, add the chitosan for preparing in the step (1) among the N '-dimethyl formamide (DMF), add the 4-dimethylamino naphthyridine again as catalyst, add the polyamines polycarboxylic acid anhydride for preparing in the step (2) under the stirring at normal temperature, wherein the mol ratio of chitosan and polyamines polyacid anhydride EDTAA is 1: 1, stir 36h under room temperature, ice bath cooling back adds distilled water and continues to stir 12h.Vacuum concentration adds dehydrated alcohol and separates out faint yellow solid, vacuum drying to small size.(4) take by weighing Sephadex G-25 type gel, activation back dress post.Resulting solid in the step (3) is dissolved in a small amount of distilled water, solid and distilled water ratio (quality: volume) be 1: 100 wherein, upper prop, with the distilled water is eluting solvent, the colour developing of 0.1% 1,2,3-indantrione monohydrate butanol solution, detect (wavelength is 254nm) with uv analyzer, two eluting peaks appear in the process of eluting, the eluting peak of part at first goes out post, it is collected final vacuum be concentrated into small size, the cooling back adds dehydrated alcohol and gets faint yellow precipitation, filters, and vacuum drying gets the part powder.(5) take by weighing in the step (4) resulting part powder dissolution in distilled water, wherein part powder and distilled water ratio (quality: volume) be 1: 5, stir and add metal inorganic salt GdCl down
36H
2O, wherein part and GdCl
36H
2The mol ratio of O is 1: 1, continues to stir 2h under room temperature, and with solution for vacuum concentration, the cooling back adds the dehydrated alcohol precipitation, and washing and filtering obtains after the drying about the pressed powder 1.0g of nuclear magnetic resonance contrast medium.
Claims (3)
1, the preparation method of chitosan modified paramagnetic metal ion magnetic resonance imaging contrast medium is characterized in that carrying out according to the following steps:
(1) in reaction vessel, add the polyamines polycarboxylic acid solid of certain mass and the anhydrous acetic acid acid anhydride of certain volume, add anhydrous pyridine again as catalyst, logical drying nitrogen protection, sucking filtration behind 55～60 ℃ of following stirring reaction 24h is used anhydrous acetic acid acid anhydride, anhydrous N respectively, N '-dimethyl formamide and absolute ether washing, obtain the polycarboxylic corresponding anhydride of polyamines, wherein the ratio of polyamines polycarboxylic acid and anhydrous acetic acid acid anhydride with quality and volume ratio count 1: 1～3;
(2) at anhydrous N, add water-soluble chitosan or Narrow Molecular Weight Distribution water-soluble chitosan in N '-dimethyl formamide or the dimethyl sulfoxide, add 4-dimethylamino naphthyridine or triethylamine or pyridine again as catalyst, add the polyamines polycarboxylic acid anhydride for preparing in the step (1) under the stirring at normal temperature, wherein the mol ratio of chitosan and polyamines polycarboxylic acid anhydride is 1: 1～5, under room temperature, stir 36～72h, ice bath cooling back adds distilled water and continues to stir 12～120h, vacuum concentration is to small size, add dehydrated alcohol and separate out faint yellow solid, vacuum drying;
(3) take by weighing Sephadex G-25 type gel, activation back dress post, resulting solid in the step (2) is dissolved in a small amount of distilled water, wherein solid and distilled water ratio with quality and volume ratio count 1: 2～100, upper prop, with the distilled water is eluting solvent, the colour developing of 0.1% 1,2,3-indantrione monohydrate butanol solution detects with uv analyzer, and the detection wavelength is 254nm, two eluting peaks appear in the process of eluting, the eluting peak of part at first goes out post, it is collected final vacuum be concentrated into small size, and the cooling back adds dehydrated alcohol and gets faint yellow precipitation, filter, vacuum drying gets the part powder;
(4) take by weighing in the step (3) resulting part powder dissolution in distilled water, wherein part powder and distilled water ratio with quality and volume ratio count 1: 5～20, stir and add metal inorganic salt down, the mol ratio of part and metal inorganic salt is 1: 1～5, continue to stir 2～24h under room temperature, with solution for vacuum concentration, the cooling back adds the dehydrated alcohol precipitation, washing and filtering obtains the pressed powder 0.3～3.0g of nuclear magnetic resonance contrast medium after the drying.
2, the preparation method of chitosan modified paramagnetic metal ion magnetic resonance imaging contrast medium according to claim 1 is characterized in that the polyamines polycarboxylic acid can be diethylenetriamine pentaacetic acid or ethylenediaminetetraacetic acid.
3, the preparation method of chitosan modified paramagnetic metal ion magnetic resonance imaging contrast medium according to claim 1, it is characterized in that wherein said metal inorganic salt can be the salt of all paramagnetic rare-earths and transition metal ions, comprise the hydrochlorate, nitrate, acetate, sulfate or the perchlorate that contain different water of crystallization, the salt of preferred Gd3+, the salt of Mn2+, the salt of Fe3+.
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| CN102274529A (en) * | 2011-05-06 | 2011-12-14 | 宁波大学 | Magnetic resonance imaging contrast agent and preparation method thereof |
| CN102329438A (en) * | 2011-10-24 | 2012-01-25 | 武汉大学 | Magnetic chitosan/doped rare earth compound particles and preparation method thereof |
| CN102358786A (en) * | 2011-08-29 | 2012-02-22 | 武汉大学 | Magnetic carboxylation chitosan/mixing rare earth composite particle and method for preparing same |
| CN103304686A (en) * | 2013-06-28 | 2013-09-18 | 江苏大学 | Method for preparing oligomeric narrow-molecular weight distribution chitosan oligosaccharides through ultrasonic-microwave synergetic oxidation |
| CN103316362A (en) * | 2013-06-28 | 2013-09-25 | 江苏大学 | Fluorine-containing potential dual-function probe based on chitosan structure and preparation method thereof |
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| CN102274529A (en) * | 2011-05-06 | 2011-12-14 | 宁波大学 | Magnetic resonance imaging contrast agent and preparation method thereof |
| CN102358786A (en) * | 2011-08-29 | 2012-02-22 | 武汉大学 | Magnetic carboxylation chitosan/mixing rare earth composite particle and method for preparing same |
| CN102329438A (en) * | 2011-10-24 | 2012-01-25 | 武汉大学 | Magnetic chitosan/doped rare earth compound particles and preparation method thereof |
| CN103304686A (en) * | 2013-06-28 | 2013-09-18 | 江苏大学 | Method for preparing oligomeric narrow-molecular weight distribution chitosan oligosaccharides through ultrasonic-microwave synergetic oxidation |
| CN103316362A (en) * | 2013-06-28 | 2013-09-25 | 江苏大学 | Fluorine-containing potential dual-function probe based on chitosan structure and preparation method thereof |
| CN103316362B (en) * | 2013-06-28 | 2015-03-04 | 江苏大学 | Fluorine-containing potential dual-function probe based on chitosan structure and preparation method thereof |
| CN105921134A (en) * | 2016-06-29 | 2016-09-07 | 陕西科技大学 | Preparation method and application of DPTA-chitosan modified magnetic adsorbent |
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