CN101979096B - Gold and iodine element-supported arborescent macromolecular computed tomography (CT) targeted contrast medium and preparation thereof - Google Patents
Gold and iodine element-supported arborescent macromolecular computed tomography (CT) targeted contrast medium and preparation thereof Download PDFInfo
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Abstract
The invention relates to a gold and iodine element-supported arborescent macromolecular computed tomography (CT) targeted contrast medium and preparation thereof. The CT targeted contrast medium comprises the following components of arborescent macromolecules, targeted molecules, a gold nanoparticle and iodine-containing micromolecules. The preparation method comprises the following steps of: (1) connecting the targeted molecules and amino groups on the surfaces of the PAMAM arborescent macromolecules in a chemical bonding way to prepare a target arborescent macromolecule carrier; (2) dissolving the carrier into water, adding dropwise the aqueous solution of chloroauric acid and adding sodium borohydride to form a gold nanoparticle-supported targeted arborescent macromolecular material; and (3) dissolving the material into the solution of dimethyl sulfoxide, and connecting the iodine-containing micromolecules and the amino groups on the surfaces of the arborescent macromolecules to obtain the CT targeted contrast medium. The contrast medium of the invention has the advantages of high contrast ratio, high biocompatibility, long in-vivo circulation time, high stability and the like, and can be applied to X-ray computed tomography examination.
Description
Technical field
The invention belongs to CT targeted contrast agent and preparation field thereof, particularly relate to dendrimer CT targeted contrast agent and the preparation thereof of a kind of gold-supported and I.
Background technology
X-ray computer tomo photography (CT) is the large-scale medical imaging method that develops rapidly nearly decades.Because it has image definition, tissue density shows the characteristics such as superior and zero lap structure, and CT examination has been widely used in each clinical medicine domains such as central nervous system, respiratory system, digestive system, genitourinary system, osteoarthrosis system at present.Clinically, the early diagnosis of the diagnosis of some disease, especially tumor, need to do enhanced ct scans can be qualitative, and this just must use contrast agent.The contrast agent that uses at present mainly is the micromolecule contrast agent that contains iodine.But because the micromolecule iodide are easy to cause human vas wall or other histiocytic anaphylaxiss, therefore this class contrast agent in use may cause untoward reaction such as gastrointestinal reaction, vomiting, shock even death, circulation time is short in vivo for this class contrast agent simultaneously, and inconvenience is observed.Therefore, medical worker and material scholar strive to find always have good biocompatibility, the new CT contrast agent of high-contrast, long body-internal-circulation time and targeting.
Summary of the invention
Technical problem to be solved by this invention provides dendrimer CT targeted contrast agent and the preparation thereof of a kind of gold-supported and I, and the toxicity that overcomes existing CT contrast agent is large, imaging effect is poor, the body-internal-circulation time is short and without defectives such as targetings.
The dendrimer CT targeted contrast agent of a kind of while gold-supported element of the present invention and I comprises following component:
Dendrimer, targeted molecular, nanogold particle and contain the micromolecule of iodine, wherein targeted molecular is 3: 1～10: 1 with the ratio of the amount of substance of dendrimer, gold atom is 25: 1～200: 1 with the ratio of the amount of substance of dendrimer, the iodine atom is 5: 1～200: 1 with the ratio of the amount of substance of dendrimer, and the diameter of this CT targeted contrast agent is 1～20nm.
Described dendrimer is polyamide amine PAMAM dendrimer.
Described targeted molecular is folic acid, lactobionic acid, polypeptide or antibody.
The described micromolecule that contains iodine is amidotrizoic acid, 2,3,5-Triiodobenzoic acid or iodate wet goods.
The preparation method of the dendrimer CT targeted contrast agent of a kind of while gold-supported element of the present invention and I comprises:
(1) mode by chemical bonding is connected targeted molecular with PAMAM dendrimer surface amino groups, makes the targeting dendrimer supports; Wherein targeted molecular is 3: 1～10: 1 with the ratio of the amount of substance of dendrimer;
(2) with soluble in water after the purified processing of above-mentioned carrier, drip again 0.5～1wt% gold chloride (HAuCl
4) aqueous solution and stirring, then add the borane reducing agent sodium hydride gold chloride is reduced, obtain the targeting dendrimer material of loaded with nano gold grain; Wherein, gold chloride is 25: 1～200: 1 with the ratio of the amount of substance of polyamide-amine dendrimer; Sodium borohydride is 5: 1 with the ratio of the amount of substance of chloroaurate;
(3) be dissolved in the dimethyl sulfoxide solution after the purified processing of targeting dendrimer material with above-mentioned loaded with nano gold grain, the molecule that mode by chemical bonding will contain iodine is connected with the dendrimer surface amino groups, simultaneously (perhaps) molecule of adopting solvent evaporation method will contain iodine by physical action load to dendrimer inner and (or) surface, obtain the simultaneously targeting dendrimer material of gold-supported and two kinds of elements of iodine, the molecule that wherein contains iodine is 5: 1～200: 1 with the ratio of the amount of substance of dendrimer.
Dendrimer in the described step (1) is polyamide amine PAMAM dendrimer.
Targeted molecular in the described step (1) is folic acid, lactobionic acid, polypeptide or antibody.
The mode of the chemical bonding in the described step (1) is specially: get targeted molecular and be dissolved in the dimethyl sulfoxine (DMSO), form solution A; Get again 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloric acid (EDC) is dissolved among the DMSO, forms solution B; Solution A is added drop-wise to reacts 4h in the solution B, more reacted solution slowly is added drop-wise in the DMSO solution (2mg/mL) of PAMAM dendrimer, reaction is 2 days under the stirring condition; Through dialysis and lyophilization, obtain to have modified the dendrimer supports of targeted molecular folic acid.
The micromolecule that contains iodine in the described step (3) is amidotrizoic acid, 2,3,5-Triiodobenzoic acid or iodate wet goods.
The mode of the chemical bonding in the described step (3) is specially: take by weighing the micromolecule that contains iodine and be dissolved in dimethyl sulfoxine/dimethyl formamide (1: 1) mixed solution, then add EDC solution (110.0mg is dissolved in 10mL DMSO) priming reaction 4h, reacted solution slowly is added drop-wise in the solution of the targeting dendrimer material that is dissolved with the loaded with nano gold grain, reaction is 2 days under the stirring condition again.
The dendrimer CT targeted contrast agent of a kind of while gold-supported element of the present invention and I is applied to prepare the CT contrast agent material.
Polyamide amine dendrimer is a kind of highly branched single macromole that disperses with good biocompatibility, it not only has a large amount of functional groups that are positioned at the surface, can be used for chemistry and connect or adsorb some targeting groups, antibody or drug molecule etc., also has inner hydrophobicity cavity, can provide the place for the load of hydrophobic molecule and inorganic functional material, therefore, the present invention selects polyamide amine dendrimer as CT contrast agent nano carrier material, by the mode of chemical bonding targeted molecular being carried out on its surface modifies, preparation has the carrier material of target function, the internal cavities of recycling dendrimer and gold element and the I that the load of exhibiting high surface group has strong X-ray attenuation characteristic, the dendrimer contrast agent of gold-supported element and I when finally obtaining having target function.(application number: 200910198801.2.), the inventor has successfully prepared the dendrimer targeted contrast agent of load gold nano grain, and proves that it is a kind of potential Medical contrast reinforcing material in patent before.In the present invention, in order further to improve the imaging effect of contrast agent, the micromolecule contrast agent that contains iodine of clinical use will by chemical bonding and (or) mode of physical absorption add to the loaded with nano gold grain the targeting dendrimer inside and (or) surface.Compare with the dendrimer supports material of simple load gold nano grain, the contrast agent of the present invention's preparation has not only kept the advantage of dendrimer as the contrast agent carrier, can when CT examination, realize the long body-internal-circulation time, more effectively identify diseased region, and have higher contrast and the imaging effect of Geng Jia, can effectively reduce the consumption of contrast agent and to the injury of human body.
Beneficial effect
(1) the present invention is a kind of targeted contrast agent for CT, because dendrimer gold-supported and two kinds of elements of iodine of adopting targeted molecular to modify, therefore have the following advantages: good biocompatibility can not cause the untoward reaction of human body; Have strong X-attenuation coefficient, can be applied to the inspection of X-ray computer tomo photography; Has good stability, the long body-internal-circulation time; The targeting group of material surface can be positioned specific tissue, reaches the purpose of targeting diagnosis;
(2) CT targeted contrast agent of the present invention is compared with the dendrimer supports material of simple load gold nano grain, not only kept the advantage of dendrimer as the contrast agent carrier, can when CT examination, realize the long body-internal-circulation time, more effectively identify diseased region, and have higher contrast and the imaging effect of Geng Jia, can effectively reduce the consumption of contrast agent and to the injury of human body.
Description of drawings
Fig. 1 is the structural representation of X-ray computer tomo photography of the present invention (CT) targeted contrast agent.(1) is targeted molecular among the above-mentioned figure, and (2) are the dendrimer material, and (3) are nanogold particle, and (4) are for containing the molecule of iodine;
Fig. 2 is that the ratio of gold atom/the 5th generation dendrimer amount of substance is 100: 1, and the ratio of iodine atom/the 5th generation dendrimer amount of substance is the ultraviolet spectrogram of 60: 1 nano-particle;
The ratio of Fig. 3 gold atom/the 5th generation dendrimer amount of substance is 100: 1, and the ratio of iodine atom/the 5th generation dendrimer amount of substance is the X-ray attenuation graph of a relation that 60: 1 nano-particle and conventional contrast agent Omnipaque change with the iodine atomic concentration;
The ratio of Fig. 4 gold atom/the 5th generation dendrimer amount of substance is 100: 1, and the ratio of iodine atom/the 5th generation dendrimer amount of substance is that the dendrimer CT contrast agent (Au DENPs) of 60: 1 nano-particle and loaded with nano gold grain is with the X-ray attenuation graph of a relation of gold atom concentration change.
The specific embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims limited range equally.
(1) takes by weighing in the dimethyl sulfoxine (DMSO) that folic acid (FA) 1.70mg is dissolved in 3mL, take by weighing again 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloric acid (EDC) 7.38mg is dissolved among the DMSO of 3mL, the FA solution of 3mL is added drop-wise in the EDC solution reacts 4h, mentioned solution slowly is added drop-wise in the DMSO solution (2mg/mL) of PAMAM dendrimer of 10mL, reaction is 2 days under the stirring condition again.Through dialysis and lyophilization, obtain to have modified the dendrimer supports of targeted molecular folic acid.
(2) the 1wt% chloroaurate aqueous solution that takes by weighing 3.96ml slowly is added drop-wise in the aqueous solution of (1) and stirs, the sodium borohydride aqueous solution that adds the 1wt% of Reducing agent 1.85ml in the mixed solution, with chloroaurate fully reduction under the dendrimer protection, form the dendrimer that load has nanogold particle; And the targeting dendrimer material that can obtain load gold nano grain is processed in lyophilization.
(3) taking by weighing 70.81mg amidotrizoic acid (DTA) is dissolved in dimethyl sulfoxine/dimethyl formamide (1: 1) mixed solution, then add EDC solution (110.55mg is dissolved in 10mL DMSO) priming reaction 4h, mentioned solution slowly is added drop-wise in the aqueous solution of (2), reaction is 2 days under the stirring condition again.Through dialysis and lyophilization, the dendrimer CT contrast agent (Au DENP-DTA) of gold-supported element and I when obtaining to have target function.
(1) takes by weighing in the water that lactobionic acid 2.75mg is dissolved in 3mL, take by weighing again 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloric acid (EDC) 11.80mg and N-hydroxy-succinamide (NHS) 7.08mg be dissolved in the water of 5mL, and the lactobionic acid solution of 3mL is added drop-wise to reacts 4h in the mentioned solution.Lactobionic acid solution after will activating again slowly is added drop-wise in the aqueous solution (2mg/mL) of PAMAM dendrimer of 20mL, and reaction is 2 days under the stirring condition.Through dialysis and lyophilization, obtain to have modified the dendrimer supports with liver targeting function.
(2) the 1wt% chloroaurate aqueous solution of getting 7.92ml slowly is added drop-wise in the dendrimer aqueous solution of (1) and stirs; the sodium borohydride aqueous solution that adds the 1wt% of Reducing agent 3.70ml in the mixed solution; with chloroaurate fully reduction under the dendrimer protection; process through lyophilization, obtain the targeting dendrimer material of load gold nano grain.
(3) take by weighing 2,3 of 115.30mg, the 5-Triiodobenzoic acid is dissolved in dimethyl sulfoxine/dimethyl formamide (1: 1) mixed solution, then adds EDC solution (221.22mg is dissolved in the 15mL dimethyl sulfoxine) priming reaction 4h.Mentioned solution slowly is added drop-wise in the aqueous solution of (2), reaction is 2 days under the stirring condition again.Through dialysis and lyophilization, the dendrimer CT contrast agent of gold-supported element and I when obtaining to have target function.
Claims (4)
1. dendrimer CT targeted contrast agent of gold-supported element and I simultaneously comprises following component:
Dendrimer, targeted molecular, nanogold particle and contain the micromolecule of iodine, wherein targeted molecular is 3:1～10:1 with the ratio of the amount of substance of dendrimer, gold atom is 25:1～200:1 with the ratio of the amount of substance of dendrimer, the iodine atom is 5:1～200:1 with the ratio of the amount of substance of dendrimer, and the diameter of this CT targeted contrast agent is 1～20nm; Wherein, dendrimer is polyamide amine PAMAM dendrimer;
Preparation method comprises:
(1) mode by chemical bonding is connected targeted molecular with PAMAM dendrimer surface amino groups, makes the targeting dendrimer supports; Wherein targeted molecular is 3:1～10:1 with the ratio of the amount of substance of dendrimer;
(2) with soluble in water after the purified processing of above-mentioned carrier, drip again 0.5～1wt% gold chloride HAuCl
4Aqueous solution also stirs, and then adds the borane reducing agent sodium hydride gold chloride is reduced, and obtains the targeting dendrimer material of loaded with nano gold grain; Wherein, gold chloride is 25:1～200:1 with the ratio of the amount of substance of polyamide-amine dendrimer; Sodium borohydride is 5:1 with the ratio of the amount of substance of chloroaurate;
(3) be dissolved in the dimethyl sulfoxide solution after the purified processing of targeting dendrimer material with above-mentioned loaded with nano gold grain, the molecule that mode by chemical bonding will contain iodine is connected with the dendrimer surface amino groups, simultaneously or the molecule that adopts solvent evaporation method will contain iodine by physical action load to dendrimer inner and or the surface, obtain the simultaneously targeting dendrimer material of gold-supported and two kinds of elements of iodine, the molecule that wherein contains iodine is 5:1～200:1 with the ratio of the amount of substance of dendrimer.
2. the dendrimer CT targeted contrast agent of a kind of while gold-supported element according to claim 1 and I, it is characterized in that: described targeted molecular is folic acid, lactobionic acid, polypeptide or antibody.
3. the dendrimer CT targeted contrast agent of a kind of while gold-supported element according to claim 1 and I, it is characterized in that: the described micromolecule that contains iodine is amidotrizoic acid, 2,3,5-Triiodobenzoic acid or iodized oil.
4. preparation method of the dendrimer CT targeted contrast agent of gold-supported element and I simultaneously comprises:
(1) mode by chemical bonding is connected targeted molecular with PAMAM dendrimer surface amino groups, makes the targeting dendrimer supports; Wherein targeted molecular is 3:1～10:1 with the ratio of the amount of substance of dendrimer;
(2) with soluble in water after the purified processing of above-mentioned carrier, drip again 0.5～1wt% gold chloride HAuCl
4Aqueous solution also stirs, and then adds the borane reducing agent sodium hydride gold chloride is reduced, and obtains the targeting dendrimer material of loaded with nano gold grain; Wherein, gold chloride is 25:1～200:1 with the ratio of the amount of substance of polyamide-amine dendrimer; Sodium borohydride is 5:1 with the ratio of the amount of substance of chloroaurate;
(3) be dissolved in the dimethyl sulfoxide solution after the purified processing of targeting dendrimer material with above-mentioned loaded with nano gold grain, the molecule that mode by chemical bonding will contain iodine is connected with the dendrimer surface amino groups, simultaneously or the molecule that adopts solvent evaporation method will contain iodine by physical action load to dendrimer inner and or the surface, obtain the simultaneously targeting dendrimer material of gold-supported and two kinds of elements of iodine, the molecule that wherein contains iodine is 5:1～200:1 with the ratio of the amount of substance of dendrimer.
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| CN102153871B (en) * | 2011-02-25 | 2012-11-07 | 东华大学 | Preparation method for chiral dendrimers/gold nanoparticles modified by mPEG |
| CN102295774B (en) * | 2011-06-08 | 2013-04-17 | 中国科学院上海应用物理研究所 | Detection method of targeting molecule receptor, and polyamide-ammonia derivative and preparation method thereof |
| CN102302782B (en) * | 2011-07-08 | 2013-04-17 | 东华大学 | Preparation method of hepatoma carcinoma cell-targeted polyamido-amine dendrimer support |
| CN102380112B (en) * | 2011-10-27 | 2013-03-06 | 东华大学 | Preparation method for diatrizoic-acid-modified dendrimer gold nanoparticles |
| CN102698295B (en) * | 2012-06-01 | 2014-11-05 | 东华大学 | Preparation of diatrizoic-acid-modified double-element target CT (Computed Tomography) contrast agent containing gold and iodine |
| CN102671217B (en) * | 2012-06-05 | 2014-04-23 | 东华大学 | Preparation of CT/MR bimodal imaging nano contrast medium with folate targeting function |
| CN103212091B (en) * | 2013-04-28 | 2014-11-05 | 东华大学 | Preparation method of hepatocarcinoma target CT (Computed Tomography) contrast medium based on Au DENPs-LA (Dendrimer-entrapped Gold Nanoparticles-Lactobionic acid) |
| CN109663145A (en) * | 2018-12-21 | 2019-04-23 | 太阳雨林（厦门）生物医药有限公司 | A kind of lipiodol targeted drug compound |
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