CN105348410B - One kind polysaccharide containing iodine and its synthetic method and application - Google Patents
One kind polysaccharide containing iodine and its synthetic method and application Download PDFInfo
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- CN105348410B CN105348410B CN201510929052.1A CN201510929052A CN105348410B CN 105348410 B CN105348410 B CN 105348410B CN 201510929052 A CN201510929052 A CN 201510929052A CN 105348410 B CN105348410 B CN 105348410B
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B31/00—Preparation of derivatives of starch
- C08B31/02—Esters
- C08B31/04—Esters of organic acids, e.g. alkenyl-succinated starch
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0018—Pullulan, i.e. (alpha-1,4)(alpha-1,6)-D-glucan; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
- C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
- C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
Abstract
The invention discloses a kind of polysaccharide containing iodine, which is characterized in that for its molecular structure using hydrophilic natural polysaccharide as skeleton, general structure is as follows:Wherein, R base is selected from the triiodo benzoyl of hydrogen or derivatization, and R is not all hydrogen；The structural formula of the triiodo benzoyl of derivatization are as follows:Wherein, R ' base is selected from one or both of hydrogen, methyl, methylamino, acetylamino, N '-methylcarbamoyl, methoxyacetamido, N- methylacetamido or alkyl.High substitution polysaccharide containing iodine in the present invention is relative to small molecule containing iodine, and outstanding advantages are small molecules containing iodine by after producing high-molecular, and cytotoxicity substantially reduces, and there is no the small molecule leakage problems caused by spreading；In addition, CT contrast agent content of iodine of the invention is high, contrasting effects are good, cytotoxicity is low, clinical CT examination and diagnosis can be used for as a kind of blood pool contrast agent.
Description
Technical field
The invention belongs to high molecular material and CT contrast preparation fields, and in particular, to a kind of polysaccharide containing iodine and its synthesis
Method, and its application in preparation nanometer CT contrast agent.
Background technique
X-ray tomography (CT) is one of current clinically most widely used noninvasive test method, application range
Extensively, high-efficient, speed is fast, expense is relatively low, can provide high-precision non-overlapping three-dimensional tissue's density image；In addition,
The appearance (PET/CT, SPECT/CT) of some Combining diagnosis methods in recent years make CT technology have broader practice/liter
Grade space.However, the similar density of human body soft tissue, there is similar X-ray absorption coefficient；For certain soft tissue inspections,
The contrast effect between tissue must be improved using CT contrast agent.Currently, clinical use is most widely the small molecule containing iodine
Contrast agent.Some contrast agent, such as amidotrizoic acidTM, it is the ionic benzoic acid derivative containing triiodo-benzene, after being injected into vivo
Very high osmotic pressure can be generated, and the probability for generating serious side effects is higher, in some instances it may even be possible to adverse reaction is caused even to suffer a shock,
It is dead；Some improved small molecule contrast preparations, such as Ultravist (Ultravist)TM, Omnipaque (Omnipaque)TM,
It is non-ionic by changing into ionic compound, or small molecule coupling can be reduced into toxicity at dimer, reduce infiltration
Pressure improves patient's tolerance.But this micromolecular CT contrast agent because molecular weight it is low, in vivo recycle when can be rapidly by kidney
Remove exclude it is external, so as to cause can developing time it is short, interval, which checks, takes duplicate injection to be needed；Furthermore small molecule is made containing iodine
Shadow agent can be all distributed with extravascular tissue in the blood vessels, without tissue selectivity, CT radiography precision be caused to be deteriorated.
The particle CT contrast agent of nanosizing containing iodine exists in the form of micella, nanoparticle or nano-emulsion mostly, ruler
It is very little to be removed in blood by kidney between 20-200 nanometers, specificity is distributed in vivo, can be used for blood pool radiography and
Liver, spleen, lymphography.The nanoparticle contrast agent of commercialization such as Fenestra LCTMWith Fenestra VCTM, it is to use macromolecule
The liquid lotion of glyceryl ester containing iodine of surfactant package, Fenestra LCTMIt can be used as liver cancer passive target contrast agent,
Fenestra VCTMIt can be used as long circulating contrast agent.Patent US20050036946 A1 discloses a kind of using common biology
The method that medical material PEG, PEO-PPO-PEO, amphipathic degradable poly ester molecule etc. modify triiodo benzoyl in chain end group,
Its nanoparticle containing iodine that can be formed in aqueous solution self assembly, but its theoretical highest content of iodine is low；Patent US8258190
B2 will contain iodine small molecule and contain as CT contrast agent in nanoparticle, and method is easy, but theoretical content of iodine is low, and exists
The shortcomings that small molecule containing iodine leaks.It is had been reported that in the document that can be consulted by Triiodobenzoic acid methacrylate and other
The microballoon containing iodine or nanoparticle that monomer is formed by emulsion copolymerization are as CT contrast agent, and reaction is controllable, and preparation is received
Rice corpuscles size uniformity, but such material is not biodegradable；Also have using phosphatide, amphiphilic polymer and artificial synthesized
The nano-emulsion containing iodine of lipiodol preparation is as CT contrast agent, and content of iodine is very high, but such emulsion intercalation method is insufficient.By containing
The natural polysaccharide self assembly preparation CT of nanoparticle containing the iodine contrast agent that iodine group replaces only has an example report
(Biomaterials2009, 30(29), 5667), the document is in 2,3,5- triiodo benzoyl of cellulose acetate side chain graft
Base prepares the CT of nanoparticle containing iodine contrast agent by the method precipitated in Tween 80 aqueous solution；Polysaccharide main chain is in this method
It is hydrophobic, it can not be self-assembled into nanoparticle in aqueous solution after the 2 of grafted hydrophobic, 3,5- triiodo benzoyls, it can only
Nanoparticle is formed with the help of surfactant；In addition, 2,3, the 5- triiodo benzoyl acetate fibers that the method obtains
The content of iodine of element is lower, and the nanoparticle stability of preparation is poor, and practical application value is low.Therefore, it needs to prepare a kind of amount of iodine
Nanoparticle CT contrast agent high, stability is good.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of polysaccharide containing iodine.Polysaccharide containing iodine of the invention has higher
Content of iodine, cytotoxicity substantially reduces, and there is no the small molecule leakage problems caused by spreading.
Another object of the present invention is to provide the synthetic methods of the above-mentioned polysaccharide containing iodine.
Another object of the present invention is to provide above-mentioned polysaccharide containing iodine answering in the preparation CT of nanoparticle containing iodine contrast agent
With.
Above-mentioned purpose of the invention is achieved by the following technical programs.
A kind of polysaccharide containing iodine, for molecular structure using hydrophilic natural polysaccharide as skeleton, general structure is as follows:
Wherein, R is independently chosen from the triiodo benzoyl of hydrogen or derivatization, and R is not all hydrogen；The triiodo benzoyl of derivatization
The structural formula of base (TIB) are as follows:
Wherein, R ' base is selected from hydrogen (- H), methyl (- CH3), methylamino (- NHCH3), acetylamino (- NHCOCH3), N '-
Methylcarbamoyl (- CONHCH3), methoxyacetamido (- NHCOCH2OCH3), N- methylacetamido (- N (CH3)
COCH3) or alkyl (- (CH2)nCH3One or both of).It is the most common situation when wherein R ' is two hydrogen, structure is most
To be simple, at this time in the triiodo benzoyl of derivatization iodine mass fraction highest；Work as R ' to be hydrogen and other substituent groups or be
When one or both of other substituent groups, because the molecular weight of the molecular weight of substituent group and three base benzoyls is compared to smaller,
So derivative group content of iodine still with higher at this time, the polysaccharide containing iodine of the structure with this triiodo benzoyl is also still
So there is considerable content of iodine；And all possible R ' group chemical property is all very stable, can be used of the present invention
It is prepared by all synthetic schemes.
Wherein long-chain molecule is the schematic diagram of natural polysaccharide, passes through glycosidic bond links, different natural polysaccharides between saccharide ring
Have different chemical structures, conformation saccharide ring unit (L, D), the connection type of different sugar interannular (α-Isosorbide-5-Nitrae glycosidic bond, α -1,
6 glycosidic bonds, α -2,6 glycosidic bonds, β-(1,3) glycosidic bond) and different branching regimes.
Heretofore described natural polysaccharide is from a wealth of sources, good biocompatibility, can be with degradation in vivo, and polysaccharide divides
Unit mass number of functional groups on son is more, and each saccharide ring unit contains can be used to be grafted to guarantee containing iodine group there are three hydroxyl
Final polysaccharide containing iodine also content of iodine with higher.
Polysaccharide containing iodine in the present invention, its main feature is that having at high grafting degree (the every 100 saccharide ring units in DS=160 ~ 300)
There is high content of iodine, but is hydrophobic molecule；When low grafting degree (DS=20 ~ 150) it is amphipathic molecule in, has higher
Content of iodine, stable nanoparticle containing iodine can be self-assembled into aqueous solution, and still stable under very high concentration；Compared with
The polysaccharide containing iodine of low grafting degree is water-soluble (DS=1 ~ 19).
Preferably, the natural polysaccharide is glucan, Pulan polysaccharide, starch, chitosan or schizophyllum abamectin.
Preferably, the triiodo benzoyl of the derivatization is 2,3,5- triiodo benzoyls, 4- methyl -6- acetyl ammonia
Base -2,3,5- triiodo benzoyl, 4- methylamino -6- methoxyacetamido -2,3,5- triiodo benzoyl, 2,4,6- triiodo
Benzoyl, 3,5- dimethylamino -2,4,6- triiodo benzoyl, 3- (N '-methylcarbamoyl) -5- (N- methyl vinyl ammonia
Base) -2,4,6- triiodo benzoyl or 3- methyl -5- alkyl -2,4,6- triiodo benzoyl.The derivatization of above structure
Triiodo benzoyl can be prepared by existing general chemical synthesis process.It is highly preferred that the triiodo of the derivatization
Benzoyl is 2,3,5- triiodo benzoyl or 2,4,6- triiodo benzoyl.The triiodo benzoyl of above two derivatization
Structure it is simple, cost of material is low.
Preferably, the grafting degree of the triiodo benzoyl of derivatization is 8 ~ 300 on the polysaccharide molecule, and above-mentioned grafting degree is pressed
Every 100 saccharide rings unit meter.It is highly preferred that the grafting degree of the triiodo benzoyl of derivatization is 20 ~ 150 on the polysaccharide molecule
(based on every 100 saccharide ring units), polysaccharide containing iodine within the scope of this grafting degree not only content of iodine with higher, but also can be with
It is self-assembled into nanoparticle in aqueous solution.
A kind of synthetic method of the polysaccharide containing iodine, using acyl chloride esterification method, specifically: by the natural polysaccharide in nitrogen
It is heated to 90 DEG C under protective condition, makes it completely dissolved in solvent, it is cooling, the triiodo chlorobenzoyl chloride of derivatization is added at room temperature
And acid binding agent, after reacting a period of time, purifying obtains polysaccharide containing iodine；The dosage of the triiodo chlorobenzoyl chloride of the derivatization is natural
0.1 ~ 4 times of polysaccharide saccharide ring unit (AGU) mole.
The structural formula of the triiodo chlorobenzoyl chloride (TIBC) of above-mentioned derivatization are as follows:
Wherein, R ' is independently chosen from hydrogen (- H), methyl (- CH3), methylamino (- NHCH3), acetylamino (- NHCOCH3),
N '-methylcarbamoyl (- CONHCH3), methoxyacetamido (- NHCOCH2OCH3), N- methylacetamido (- N (CH3)
COCH3) or alkyl (- (CH2)nCH3One or both of).
Preferably, the triiodo chlorobenzoyl chloride of the derivatization is 2,3,5- triiodo chlorobenzoyl chlorides, 2,4,6- triiodo benzoyls
Chlorine.
Using acyl chloride esterification method, it is preferable that the natural polysaccharide is glucan, Pulan polysaccharide or starch.
Using acyl chloride esterification method, it is preferable that the dosage of the triiodo chlorobenzoyl chloride of the derivatization is natural polysaccharide saccharide ring list
0.25 ~ 2 times of first (AGU) mole, the degree of polysaccharide graft containing iodine obtained under this feed ratio is between 20 ~ 150 (by every 100
A saccharide ring unit meter), polysaccharide containing iodine within the scope of this grafting degree not only content of iodine with higher, but also can be in aqueous solution
It is self-assembled into nanoparticle.
Using acyl chloride esterification method, according to the difference of natural polysaccharide type, it is preferable that the solvent is water, sodium hydroxide is molten
Liquid, n,N-Dimethylformamide (DMF), dimethyl acetamide (DMAc), formamide (formamide) or N-Methyl pyrrolidone
(NMP) mixing of one or more of solvent.
Using acyl chloride esterification method, according to the difference of natural polysaccharide type, it is preferable that be dissolved completely in the natural polysaccharide
Cosolvent is also added into during solvent, the cosolvent is anhydrous lithium chloride (LiCl) or anhydrous lithium bromide (LiBr).
Using acyl chloride esterification method, according to the difference of natural polysaccharide type, it is preferable that in the triiodo benzoyl that derivatization is added
Catalyst is also added into while the solution of chlorine, the catalyst is triethylamine (TEA), 4-dimethylaminopyridine (DMAP) or 4-
Pyrrolidines pyridine (PP).
Using acyl chloride esterification method, according to the difference of natural polysaccharide type and solvent for use, it is preferable that the acid binding agent is three
Ethamine, DMAP, pyridine (Py) or Anhydrous potassium carbonate (K2CO3).
Using acyl chloride esterification method, the triiodo chlorobenzoyl chloride of the derivatization can by conventional chemical synthesis method, for example, by
The Triiodobenzoic acid and thionyl chloride of corresponding derivatization react to obtain.
Using acyl chloride esterification method, it is preferable that the temperature of the reaction is 0 ~ 100 DEG C；The time of reaction is 1 ~ 24 hour.
Using acyl chloride esterification method, it is preferable that the specific steps of the purifying are as follows: in organic solvent by product dissolution,
It is precipitated in methanol or ethyl alcohol to remove remaining small molecule, repeatedly several times, last time precipitates in water, dialyses, and removes residual
Remaining hydrochloride, freeze-drying, obtains white powder product, as polysaccharide containing iodine.
A kind of synthetic method of the polysaccharide containing iodine, is condensed esterification process using DCC, specifically: the natural polysaccharide is molten
Solution adds N, bis- hexamethylene of N'- after the Triiodobenzoic acid of 4-dimethylaminopyridine (DMAP), derivatization is added into organic solvent
Base carbodiimide (DCC), is stirred at room temperature reaction, obtains polysaccharide containing iodine after purification；Triiodobenzoic acid, the N of the derivatization, N'-
The dosage of dicyclohexylcarbodiimide is 0.1 ~ 4 times of natural polysaccharide saccharide ring unit mole.
The structural formula of the Triiodobenzoic acid (TIBA) of above-mentioned derivatization are as follows:
Wherein, R ' is independently chosen from hydrogen (- H), methyl (- CH3), methylamino (- NHCH3), acetylamino (- NHCOCH3),
N '-methylcarbamoyl (- CONHCH3), methoxyacetamido (- NHCOCH2OCH3), N- methylacetamido (- N (CH3)
COCH3) or alkyl (- (CH2)nCH3) one or two.
Preferably, the Triiodobenzoic acid of the derivatization is 2,3,5- Triiodobenzoic acids, 2,4,6- Triiodobenzoic acids.
Esterification process is condensed using DCC, it is preferable that the natural polysaccharide is glucan, Pulan polysaccharide or starch.
Esterification process is condensed using DCC, it is preferable that the dosage of the Triiodobenzoic acid of the derivatization is natural polysaccharide saccharide ring list
0.25 ~ 2 times of first (AGU) mole.The degree of polysaccharide graft containing iodine obtained under such feed ratio is between 20 ~ 150 (by every
100 saccharide ring unit meters), polysaccharide containing iodine within the scope of this grafting degree not only content of iodine with higher, but also can be water-soluble
Nanoparticle is self-assembled into liquid.
Esterification process is condensed using DCC, it is preferable that the time of the reaction is 12 ~ 48 hours.
Esterification process is condensed using DCC, according to the difference of natural polysaccharide type, it is preferable that the organic solvent is N, N- bis-
Methylformamide (DMF), dimethyl acetamide (DMAc), formamide (formamide) or N-Methyl pyrrolidone (NMP) or two
The mixing of one or more of chloromethanes.
Esterification process is condensed using DCC, according to the difference of natural polysaccharide type, it is preferable that be dissolved in the natural polysaccharide
Cosolvent is also added into while organic solvent, the cosolvent is anhydrous lithium chloride (LiCl) or or anhydrous lithium bromide
(LiBr).
Esterification process is condensed using DCC, it is preferable that the specific steps of the purifying are as follows: be dissolved in product a small amount of organic molten
DCU and the unreacted small molecule precipitated in methanol to generate except dereaction is added drop-wise in agent, after cold filtration, it is repeatedly several
It is secondary, it is dried in vacuo to get polysaccharide containing iodine.
A kind of synthetic method of the polysaccharide containing iodine, is condensed esterification process using CDI, specifically: by the triiodo-benzene of derivatization
Formic acid is dissolved into organic solvent, addition N, N '-carbonyl dimidazoles (Carbonyldiimidazole, CDI), and 60 DEG C of reactions 4 are small
When after room temperature the reaction was continued 20 hours, obtain Orazamide intermediate；The natural polysaccharide is dissolved into organic solvent again, is added
Enter into Orazamide midbody solution, reaction 24 hours is stirred at room temperature, obtains polysaccharide containing iodine after purification；The three of the derivatization
The dosage of iodo-benzoic acid, N, N '-carbonyl dimidazoles (CDI) is equal, and is 0.1 ~ 4 times of polysaccharide saccharide ring mole.
The structural formula of the Triiodobenzoic acid (TIBA) of above-mentioned derivatization are as follows:
Wherein, R ' is independently chosen from hydrogen (- H), methyl (- CH3), methylamino (- NHCH3), acetylamino (- NHCOCH3),
N '-methylcarbamoyl (- CONHCH3), methoxyacetamido (- NHCOCH2OCH3), N- methylacetamido (- N (CH3)
COCH3) or alkyl (- (CH2)nCH3One or both of).
Preferably, the Triiodobenzoic acid is 2,3,5- Triiodobenzoic acids, 2,4,6- Triiodobenzoic acids.
Esterification process is condensed using CDI, it is preferable that the natural polysaccharide is glucan, Pulan polysaccharide or starch.
Esterification process is condensed using CDI, it is preferable that the dosage of the Triiodobenzoic acid of the derivatization is natural polysaccharide saccharide ring list
0.25 ~ 2 times of first (AGU) mole.The degree of polysaccharide graft containing iodine obtained under such feed ratio is between 20 ~ 150 (by every
100 saccharide ring unit meters), polysaccharide containing iodine within the scope of this grafting degree not only content of iodine with higher, but also can be water-soluble
Nanoparticle is self-assembled into liquid.
Esterification process is condensed using CDI, according to the difference of natural polysaccharide type, it is preferable that the organic solvent is dimethyl
In sulfoxide (DMSO), n,N-Dimethylformamide (DMF), dimethyl acetamide (DMAc) or N-Methyl pyrrolidone (NMP)
One or more of mixing.
Esterification process is condensed using CDI, according to the difference of natural polysaccharide type, it is preferable that be dissolved in the natural polysaccharide
Be also added into cosolvent while organic solvent, the cosolvent is anhydrous lithium chloride (LiCl), anhydrous lithium bromide (LiBr) or
Tetrabutyl ammonium fluoride (TBAF).
Esterification process is condensed using CDI, it is preferable that the specific steps of the purifying are as follows: in organic solvent by product dissolution,
It is added drop-wise in methanol and precipitates to remove unreacted small molecule, repeatedly several times, be dried in vacuo to get polysaccharide containing iodine.
Application of the polysaccharide containing iodine in the preparation CT of nanoparticle containing iodine contrast agent.
Preferably, the polysaccharide containing iodine is dissolved into organic solvent with the concentration of 2 ~ 50 mg/mL, is delayed under stirring condition
Slowly it is added drop-wise in water, dialysis removing organic solvent, up to the CT contrast agent after centrifugal concentrating.
Preferably, the grafting degree of the polysaccharide containing iodine is 20 ~ 150, and above-mentioned grafting degree is based on every 100 saccharide ring units.
Preferably, the organic solvent is dimethyl sulfoxide (DMSO) or dimethyl acetamide (DMAc).
Compared with prior art, the beneficial effects of the invention are that: the polysaccharide containing iodine in the present invention, content of iodine substantially exceeds
The polyurethane replaced containing iodine group in document report, with the polylactic acid of chain extender containing iodine chain extension or it is reported other
Class high molecular material containing iodine.High in the present invention to replace polysaccharide containing iodine relative to the small molecule containing iodine, outstanding advantages are small containing iodine
Molecule is very low to the toxicity of cell by after producing high-molecular, and there is no the small molecule leakage problems caused by spreading；In addition,
High content of iodine in nanoparticle and the stability under high concentration ensure that this nanoparticle CT contrast agent has good radiography
Effect.
CT contrast agent of the invention, highest content of iodine can achieve 150 mgI/mL, and external CT experiment shows to have non-
Often good contrast ability.
Detailed description of the invention
Fig. 1 is that the nuclear-magnetism of the product of polysaccharide containing iodine for the different grafting degrees for being is total using different feed ratios in embodiment 1
Vibration hydrogen spectrum (1H-NMR).(a) glucan;(b) feed ratio 0.3, the DS=0.26 of polysaccharide containing iodine;(c) feed ratio 1.0 contain iodine
Polysaccharide DS=0.9;(d) feed ratio 3.0, the DS=2.8 of polysaccharide containing iodine.
Fig. 2 is transmission electron microscope (TEM) photo of the nanoparticle containing iodine in embodiment 9.
Fig. 3 is the external contrasting effects that nanoparticle CT contrast agent is tested on Micro-CT machine in embodiment 10.
Specific embodiment
The present invention is described in further details with specific embodiment with reference to the accompanying drawings of the specification, but embodiment is not right
The present invention limits in any form.Unless stated otherwise, the present invention uses reagent, method and apparatus are normal for the art
Advise reagent, method and apparatus.
Embodiment 1 ~ 6 is the specific embodiment of different types of polysaccharide containing iodine and its synthetic method.Specific embodiment
The degree of polysaccharide graft containing iodine of middle synthesis by nuclear magnetic resonance spectroscopy (1H-NMR it) tests, content of iodine is used by Sch niger method
Chemistry titration is tested after oxygen combustion resolution.
Embodiment 7 ~ 9 is the specific reality applied in the CT contrast agent of nanoparticle containing iodine prepared using the polysaccharide containing iodine of synthesis
Apply mode.Nanoparticle containing iodine can test hydrodynamic radius by dynamic light scattering method, pass through transmission electron microscope observing nanoparticle
Sub- pattern；The external contrast ability of nanoparticle suspension is measured by Micro-CT.
Embodiment 10 is the specific implementation that the CT contrast agent of nanoparticle containing iodine uses Micro-CT testing in vitro contrast ability
Method.
Embodiment 1(glucan 2,3,5 triiodobenzoic acid ester-acyl chloride esterification method)
Glucan 2,3,5- Triiodobenzoic acid ester, general formula of molecular structure are as follows:
Wherein, R is selected from hydrogen or 2,3,5- triiodo benzoyls, and R is not all hydrogen, the grafting of 2,3,5- triiodo benzoyls
Degree is 8 ~ 300(in terms of every 100 saccharide ring units).
Above-mentioned polysaccharide containing iodine synthesizes as follows: by glucan (Dextran, 2 g, 12.3 mmol AGU) and
Lithium chloride (2 g) is added in 50 mL DMAc under the conditions of nitrogen protection, is heated to 90 DEG C, is made it completely dissolved, cooling；Room
Temperature is lower to be added catalytic amount DMAP, acid binding agent triethylamine (with 2,3,5- triiodo chlorobenzoyl chloride equivalent) and different amounts of 2, and 3,5- tri-
Iodobenzoyl chloride (ratio of 1.23 ~ 49.2 mmol, i.e., 2,3,5- triiodo chlorobenzoyl chlorides and glucan AGU mole is 0.1 ~ 4)
50 mL of DMF solution reacts 1 hour at 70 DEG C, and methanol extraction is dissolved with DMSO repeatedly, precipitates repeatedly in methanol, finally exists
It dissolves in DMSO, precipitates in water, dialyse, white powder polysaccharide containing iodine is lyophilized.After tested, glucan 2,3,5- triiodo-benzene first
The grafting degree of 2,3,5- triiodo benzoyls increases as the inventory of 2,3,5- triiodo chlorobenzoyl chlorides increases in acid esters, for 8 ~
300, based on every 100 saccharide ring.When feed ratio is 0.1, the degree of polysaccharide graft containing iodine is 8(based on every 100 saccharide ring), content of iodine is most
It is low, it is 15%；When feed ratio is 4, the degree of polysaccharide graft containing iodine is 300(based on every 100 saccharide ring), content of iodine highest is 71%；From
And this content of iodine of polysaccharide containing iodine is 15 ~ 71%.
Nuclear magnetic resonance spectroscopy such as Fig. 1 institute of the glucan 2,3,5 triiodobenzoic acid ester of raw material glucan and three kinds of grafting degrees
Show, (a) glucan;(b) feed ratio 0.3, the DS=0.26 of polysaccharide containing iodine;(c) feed ratio 1.0, the DS=0.9 of polysaccharide containing iodine;
(d) feed ratio 3.0, the DS=2.8 of polysaccharide containing iodine.
Embodiment 2 (glucan 2,4,6- Triiodobenzoic acid ester DCC method)
Glucan 2,4,6- Triiodobenzoic acid ester, general formula of molecular structure are as follows:
Wherein, R is selected from hydrogen or 2,4,6- triiodo benzoyls, and R is not all hydrogen, the grafting of 2,3,5- triiodo benzoyls
Degree is 8 ~ 300(in terms of every 100 saccharide ring units).
Above-mentioned polysaccharide containing iodine synthesizes as follows: by glucan (Dextran, 2 g, 12.3 mmol AGU) and
Lithium bromide (2 g) is added in 50 mL DMAc under the conditions of nitrogen protection, is heated to 90 DEG C, is made it completely dissolved, cooling；Add
Enter catalytic amount DMAP and different amounts of 2,4,6- Triiodobenzoic acid (1.23 ~ 49.2 mmol, i.e., 2,4,6- Triiodobenzoic acids and Portugal
The ratio of glycan AGU mole be 0.1 ~ 4) after add DCC(and 2,4,6- Triiodobenzoic acid equivalent), reaction, mistake is stirred at room temperature
Methanol extraction after filter obtains polysaccharide containing iodine after purification.After tested, glucan 2,2,4,6- triiodo-benzenes in 4,6- Triiodobenzoic acid esters
The grafting degree of formoxyl increases as the inventory of 2,4,6- Triiodobenzoic acids increases, and is 8 ~ 300(based on every 100 saccharide ring).
When feed ratio is 0.1, the degree of polysaccharide graft containing iodine is 8(based on every 100 saccharide ring), content of iodine is minimum, is 15%；When feed ratio is 4
When, the degree of polysaccharide graft containing iodine is 300 based on every 100 saccharide ring, and content of iodine highest is 71%；To which this content of iodine of polysaccharide containing iodine is 15
~71%。
Embodiment 3 (Pulan polysaccharide 2,3,5 triiodobenzoic acid ester DCC method)
2,3,5- Triiodobenzoic acid ester of Pulan polysaccharide, general formula of molecular structure are as follows:
Wherein, R is selected from hydrogen or 2,3,5- triiodo benzoyls, and R is not all hydrogen, the grafting of 2,3,5- triiodo benzoyls
Degree is 8 ~ 300(in terms of every 100 saccharide ring units).
Above-mentioned polysaccharide containing iodine synthesizes as follows: by Pulan polysaccharide (Pullulan, 2 g, 12.3 mmol AGU)
It is added under the conditions of nitrogen protection in 50 mL DMF with lithium chloride (2 g), is heated to 90 DEG C, makes it completely dissolved, it is cooling；
Be added catalytic amount DMAP, different amounts of 2,3,5- Triiodobenzoic acids (1.23 ~ 49.2 mmol, i.e., 2,3,5- Triiodobenzoic acids with it is general
The ratio of blue Polysaccharide A GU mole be 0.1 ~ 4) after add DCC(and 2,3,5- Triiodobenzoic acid equivalent), reaction is stirred at room temperature,
Methanol extraction after filtering obtains polysaccharide containing iodine after purification.After tested, Pulan polysaccharide 2,2,3,5- tri- in 3,5- Triiodobenzoic acid esters
The grafting degree of iodobenzoyl increases as the inventory of 2,3,5- triiodo benzoylacrylic acids increases, and is 8 ~ 300(by every 100 sugar
Ring meter).When feed ratio is 0.1, the degree of polysaccharide graft containing iodine is 8(based on every 100 saccharide ring), content of iodine is minimum, is 15%；Work as throwing
When material is than being 4, the degree of polysaccharide graft containing iodine is 300 based on every 100 saccharide ring, and content of iodine highest is 71%；To this iodine of polysaccharide containing iodine
Content is 15 ~ 71%.
Embodiment 4 (Pulan polysaccharide 2,4,6- Triiodobenzoic acid ester CDI method)
2,4,6- Triiodobenzoic acid ester of Pulan polysaccharide, general formula of molecular structure are as follows:
Wherein, R is selected from hydrogen or 2,3,5- triiodo benzoyls, and R is not all hydrogen, the grafting of 2,3,5- triiodo benzoyls
Degree is 8 ~ 300(in terms of every 100 saccharide ring units).
Above-mentioned polysaccharide containing iodine synthesizes as follows: by different amounts of 2,4,6- Triiodobenzoic acid (1.23 ~ 49.2
The ratio of mmol, i.e., 2,4,6- Triiodobenzoic acids and Pulan Polysaccharide A GU mole is 0.1 ~ 4) it is dissolved into DMSO, equivalent is added
CDI(and 2,4,6- Triiodobenzoic acid equivalent), 60 DEG C reaction 4 hours after room temperature the reaction was continued 20 hours, obtain in Orazamide
Mesosome；After Pulan polysaccharide (2 g, 12.3 mmol AGU) is dissolved directly into DMSO, it is added to Orazamide midbody solution
In, reaction 24 hours is stirred at room temperature, methanol extraction obtains polysaccharide containing iodine after purification.After tested, Pulan polysaccharide 2,4,6- triiodo-benzenes
The grafting degree of 2,4,6- triiodo benzoyls increases as the inventory of 2,4,6- Triiodobenzoic acids increases in formic acid esters, for 8 ~
300, based on every 100 saccharide ring.When feed ratio is 0.1, the degree of polysaccharide graft containing iodine is 8(based on every 100 saccharide ring), content of iodine is most
It is low, it is 15%；When feed ratio is 4, the degree of polysaccharide graft containing iodine is 300(based on every 100 saccharide ring), content of iodine highest is 71%；From
And this content of iodine of polysaccharide containing iodine is 15 ~ 71%.
Embodiment 5 (starch 2,3,5 triiodobenzoic acid ester CDI method)
Starch 2,3,5- Triiodobenzoic acid ester, general formula of molecular structure are as follows:
Wherein, R is selected from hydrogen or 2,3,5- triiodo benzoyls, and R is not all hydrogen, the grafting of 2,3,5- triiodo benzoyls
Degree is 8 ~ 300(in terms of every 100 saccharide ring units).
Above-mentioned polysaccharide containing iodine synthesizes as follows: by different amounts of 2,3,5 triiodobenzoic acid (1.23 ~ 49.2
The ratio of mmol, i.e., 2,3,5- Triiodobenzoic acids and starch AGU mole be 0.1 ~ 4) be dissolved into DMAc, be added equivalent CDI(with
2,3,5- Triiodobenzoic acid equivalent), 60 DEG C reaction 4 hours after room temperature the reaction was continued 20 hours, obtain Orazamide intermediate；It will
Starch (Amylose, 2 g, 12.3 mmol AGU) and lithium chloride (2 g) are heated to 90 DEG C and are dissolved into DMAc, add after cooling
Enter into Orazamide midbody solution, reaction 24 hours is stirred at room temperature, methanol extraction obtains polysaccharide containing iodine after purification.Through surveying
Examination, starch 2,3, in 5- Triiodobenzoic acid ester the grafting degree of 2,3,5- triiodo benzoyls with 2,3,5- Triiodobenzoic acids throwing
Doses increases and increases, and is 8 ~ 300, based on every 100 saccharide ring.When feed ratio is 0.1, the degree of polysaccharide graft containing iodine is 8(by every
100 saccharide ring meters), content of iodine is minimum, is 15%；When feed ratio is 4, the degree of polysaccharide graft containing iodine is 300(based on every 100 saccharide ring),
Content of iodine highest is 71%；To which this content of iodine of polysaccharide containing iodine is 15 ~ 71%.
Embodiment 6(starch 2,4,6- Triiodobenzoic acid ester-acyl chloride esterification method)
Starch 2,4,6- Triiodobenzoic acid ester, general formula of molecular structure are as follows:
Wherein, R is selected from hydrogen or 2,4,6- triiodo benzoyls, and R is not all hydrogen, the grafting of 2,4,6- triiodo benzoyls
Degree is 8 ~ 300(in terms of every 100 saccharide ring units).
Above-mentioned polysaccharide containing iodine synthesizes as follows: by starch (Amylose, 2 g, 12.3 mmol AGU) and bromine
Change lithium (2 g) to be added under the conditions of nitrogen protection in 50 mL DMF, is heated to 90 DEG C, makes it completely dissolved, cooling, room temperature
Lower addition DMAP (with 2,4,6- triiodo chlorobenzoyl chloride equivalent) and different amounts of 2,4,6- triiodo chlorobenzoyl chloride (1.23 ~ 49.2
The ratio of mmol, i.e., 2,4,6- triiodo chlorobenzoyl chlorides and starch AGU mole is 0.1 ~ 4) 50 mL of DMF solution, it is anti-at 100 DEG C
5 hours are answered, methanol extraction；Product is dissolved with DMSO repeatedly, is precipitated repeatedly in methanol, is finally being precipitated in water, is dialysed, freeze-drying
Obtain white powder polysaccharide containing iodine.After tested, starch 2, the grafting of 2,4,6- triiodo benzoyls in 4,6- Triiodobenzoic acid esters
Degree increases as the inventory of 2,4,6- triiodo chlorobenzoyl chlorides increases, and is 8 ~ 300, based on every 100 saccharide ring.When feed ratio is
When 0.1, the degree of polysaccharide graft containing iodine is 8(based on every 100 saccharide ring), content of iodine is minimum, is 15%；It is more containing iodine when feed ratio is 4
Sugared grafting degree is 300(based on every 100 saccharide ring), content of iodine highest is 71%；To which this content of iodine of polysaccharide containing iodine is 15 ~ 71%.
Embodiment 7
Starch 2,4,6- Triiodobenzoic acid ester, is prepared by embodiment 6, chooses the grafting of wherein 2,4,6- triiodo benzoyls
Degree be 20(based on every 100 saccharide ring units) product be used to prepare CT contrast agent.This grafting degree polysaccharide containing iodine is to use 3.08
The 2 of mmol, 4,6- triiodo chlorobenzoyl chlorides (feed ratio 0.25) obtain product when reacting, and content of iodine is determined to 34%.
Above-mentioned polysaccharide containing iodine is dissolved in DMSO with the concentration of 2 mg/mL, is then slowly dropped to pure water under stiring
In, dialysis remove organic solvent, high speed centrifugation concentration to get.
After tested, this nanoparticle CT contrast agent iodine concentration is 50 mgI/mL, and nano particle diameter containing iodine is 250 nm.
Embodiment 8
2,4,6- Triiodobenzoic acid ester of Pulan polysaccharide, prepared by embodiment 4, chooses wherein 2,4,6- triiodo benzoyls
Grafting degree be 90(based on every 100 saccharide ring units) product be used to prepare CT contrast agent.This grafting degree polysaccharide containing iodine is to use
The 2 of 12.30 mmol, 4,6- triiodo chlorobenzoyl chlorides (feed ratio 1) obtain product when reacting, and content of iodine is determined to 58%.
Above-mentioned polysaccharide containing iodine is dissolved in DMSO with the concentration of 50 mg/mL, is then slowly dropped to pure water under stiring
In, dialysis remove organic solvent, high speed centrifugation concentration to get.
After tested, this nanoparticle CT contrast agent iodine concentration is 150 mgI/mL, and nano particle diameter containing iodine is 40 nm.
Embodiment 9
Glucan 2,3,5- Triiodobenzoic acid ester, is prepared by embodiment 1, is chosen wherein 2,3,5- triiodo benzoyls and is connect
Branch degree be 150(based on every 100 saccharide ring units) product be used to prepare CT contrast agent.This grafting degree polysaccharide containing iodine is to use
The 2 of 24.60 mmol, 4,6- triiodo chlorobenzoyl chlorides (feed ratio 2) obtain product when reacting, and content of iodine is determined to 65%.
Above-mentioned polysaccharide containing iodine is dissolved in DMAc with the concentration of 10 mg/mL, is then slowly dropped to pure water under stiring
In, dialysis remove organic solvent, high speed centrifugation concentration to get.
After tested, this nanoparticle CT contrast agent iodine concentration is 110 mgI/mL, and nano particle diameter containing iodine is 120 nm.
Fig. 2 is transmission electron microscope (TEM) photo of the present embodiment nanoparticle containing iodine.
Embodiment 10
The CT contrast agent of polysaccharide nano particle containing iodine, is prepared by embodiment 9, wherein nano particle diameter containing iodine is 120 nm,
CT contrast agent iodine concentration is 110 mgI/mL.
It takes about 0.5 mL to be put into the gland plastic centrifuge tube of 2 mL the above-mentioned CT of polysaccharide nano particle containing iodine contrast agent, makes
(Nano-X/CT, TriFoil Imaging, USA) is tested with Micro-CT instrument, experiment condition is as follows: bulb electricity
Press 65 kVp, 0.123 mA of tube current, 77 μm of detector size;0.4 mm of screw pitch, preposition aluminium filter thickness are
0.5mm.Test result shows that its CT value is 2991 ± 234 HU with this condition, and its CT value and the iodine contained by it contain
It is corresponding to measure the CT value that should have.
Fig. 3 is the external radiography that the CT contrast agent of polysaccharide nano particle containing iodine is tested on Micro-CT machine in the present embodiment
The comparison diagram of effect and pure water.
Claims (5)
1. a kind of CT contrast agent of nanoparticle containing iodine, which is characterized in that be that will contain iodine polysaccharide to dissolve with the concentration of 2 ~ 50 mg/mL
It into organic solvent, is added drop-wise in pure water under stirring condition, dialysis removing organic solvent, up to the CT radiography after centrifugal concentrating
Agent；For its molecular structure of the polysaccharide containing iodine using hydrophilic natural polysaccharide as skeleton, general structure is as follows:
Wherein, R base is selected from the triiodo benzoyl of hydrogen or derivatization, and R is not all hydrogen；The triiodo benzoyl of the derivatization
Structural formula are as follows:
Wherein, R ' base is selected from hydrogen, methylamino, acetylamino, N '-methylcarbamoyl, methoxyacetamido, N- methyl vinyl
One or both of amino or alkyl；
The natural polysaccharide is glucan, Pulan polysaccharide, chitosan or schizophyllum abamectin；
The grafting degree of derivatization triiodo benzoyl is 20 ~ 150 on the polysaccharide molecule, and above-mentioned grafting degree presses every 100 saccharide rings
Unit meter.
2. the CT of nanoparticle containing iodine contrast agent according to claim 1, which is characterized in that the triiodo-benzene first of the derivatization
Acyl group is 2,3,5- triiodo benzoyl, 4- methyl -6- acetylaminohydroxyphenylarsonic acid 2,3,5- triiodo benzoyl, 4- methylamino -6- methoxy
Base acetylaminohydroxyphenylarsonic acid 2,3,5- triiodo benzoyl, 2,4,6- triiodo benzoyl, 3,5- dimethylamino -2,4,6- triiodo-benzene first
Acyl group, 3- (N '-methylcarbamoyl) -5- (N- methylacetamido) -2,4,6- triiodo benzoyl or 3- methyl -5- are just
Heptyl -2,4,6- triiodo benzoyl.
3. the CT of nanoparticle containing iodine contrast agent according to claim 1 or 2, which is characterized in that the conjunction of the polysaccharide containing iodine
At method be using acyl chloride esterification method, specifically: the natural polysaccharide is heated to 90 DEG C under the conditions of nitrogen protection, keeps its complete
Fully dissolved is cooling in solvent, and the triiodo chlorobenzoyl chloride and acid binding agent of derivatization are added at room temperature, pure after reacting a period of time
Change obtains polysaccharide containing iodine；The dosage of the triiodo chlorobenzoyl chloride of the derivatization is natural polysaccharide saccharide ring unit (AGU) mole
0.25 ~ 2 times.
4. the CT of nanoparticle containing iodine contrast agent according to claim 1 or 2, which is characterized in that the conjunction of the polysaccharide containing iodine
It is that esterification process is condensed using DCC at method, specifically: the natural polysaccharide is dissolved into organic solvent, 4- diformazan ammonia is added
Yl pyridines, derivatization Triiodobenzoic acid after add N, reaction is stirred at room temperature in N'- dicyclohexylcarbodiimide, after purification
To polysaccharide containing iodine；The dosage of the Triiodobenzoic acid of the derivatization is the 0.25 ~ 2 of natural polysaccharide saccharide ring unit (AGU) mole
Times.
5. the CT of nanoparticle containing iodine contrast agent according to claim 1 or 2, which is characterized in that the conjunction of the polysaccharide containing iodine
It is that esterification process is condensed using CDI at method, specifically: the Triiodobenzoic acid of derivatization is dissolved into organic solvent, N is added,
N '-carbonyl dimidazoles, 60 DEG C reaction 4 hours after room temperature the reaction was continued 20 hours, obtain Orazamide intermediate；Again by the day
Right polysaccharide is dissolved into organic solvent, is added in Orazamide midbody solution, and reaction 24 hours is stirred at room temperature, after purification
To polysaccharide containing iodine；The dosage of the Triiodobenzoic acid of the derivatization is the 0.25 ~ 2 of natural polysaccharide saccharide ring unit (AGU) mole
Times.
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| CN101945672A (en) * | 2007-12-21 | 2011-01-12 | 艾奥弗尔玛科技公司 | Biodegradable contrast agents |
| CN102100933A (en) * | 2010-08-10 | 2011-06-22 | 微创医疗器械(上海)有限公司 | Embolic material composition and preparation method thereof |
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| CN101544701A (en) * | 2009-04-28 | 2009-09-30 | 山东省医疗器械研究所 | Developable iodic polymer and embolic material thereof |
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