CN102397563B - Preparation method for nanometer graphene carrier used for magnetic resonance imaging (MRI) contrast agent - Google Patents
Preparation method for nanometer graphene carrier used for magnetic resonance imaging (MRI) contrast agent Download PDFInfo
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- CN102397563B CN102397563B CN 201010283987 CN201010283987A CN102397563B CN 102397563 B CN102397563 B CN 102397563B CN 201010283987 CN201010283987 CN 201010283987 CN 201010283987 A CN201010283987 A CN 201010283987A CN 102397563 B CN102397563 B CN 102397563B
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Abstract
The invention relates to a preparation method for a nanometer graphene carrier used for an MRI contrast agent. According to the method, nanometer graphene oxide and hydrophilic high polymers are used as raw materials; the hydrophilic high polymers are grafted onto the surface of nanometer graphene oxide, and a contrast agent is loaded wherein. Compared to the prior art, the invention has the following advantages: by utilizing good hydrophilicity and biocompatibility of some hydrophilic high polymers and the characteristic that the system of nanometer graphene oxide and hydrophilic high polymers can enter into biological cells at a nanometer level, the contrast agent is enabled to have long in-vivo retention time, good histocompatibility and low cytotoxicity; the system shows a good application prospect in the aspect of MRI radiography.
Description
Technical field
The present invention relates to a kind of preparation method of functional Graphene, especially relate to the preparation method of a kind of magnetic resonance imaging contrast with the graphene nano carrier.
Background technology
Nuclear magnetic resonance resonance image-forming (MRI) is one of important means of current diagnosing tumor, particularly the application of various contrast agent.But clinical MRI checks that contrast agent used mostly is containing gadolinium micromolecular contrast agent at present, there is specificity low, the short shortcomings of retention time in body, structure has tissue-specific MRI contrast agent of new generation becomes one of study hotspot of material circle, medical circle.
Nano graphene oxide is a kind of water dispersible Two-dimensional Carbon nano material preferably, and preparation cost is cheap.After the chemical modification of the hydrophilic polymer of good biocompatibility, can improve its biocompatibility and reduce cytotoxicity, reach certain slow releasing function and there is good bio-medical application prospect.
Summary of the invention
Purpose of the present invention is exactly to provide a kind of in order to overcome the defect that above-mentioned prior art exists and can be used as multiple inhomogeneity contrast agent carrier, solve the contrast agent preparation method of graphene nano carrier for magnetic resonance imaging contrast of the short and problem that cytotoxicity is large of retention time in vivo.
Purpose of the present invention can be achieved through the following technical solutions:
The preparation method of graphene nano carrier for a kind of magnetic resonance imaging contrast, it is characterized in that, it is raw material that the method be take nano graphene oxide and hydrophilic macromolecule, at the surface grafting hydrophilic macromolecule of nano graphene oxide, then contrast agent is loaded wherein.
The method specifically comprises the following steps:
(1) add hydrophilic macromolecule in graphene oxide solution, by the ultrasonic dispersion 4～6min of mixture, utilizing dichloroethanes and N-hydroxy-succinamide to regulate pH is 5.6, continue at room temperature to stir 20～30h, then the product obtained is transferred in 10000 molecular weight bag filters, in deionized water, dialysis obtains pure graphene nano carrier;
(2) graphene nano carrier contrast agent and step (1) obtained is soluble in water, at room temperature lucifuge stirs 3～5h, to obtain again mixture and be transferred in 100000 molecular weight bag filters the 20～30h that dialysed, remove the contrast agent on chelating not, stop dialysis and obtain magnetic resonance imaging contrast graphene nano carrier.
The concentration of described graphene oxide solution is 0.8～1.5mg/ml.
The weight ratio of described graphene oxide and hydrophilic macromolecule is 1: (8～12).
Described hydrophilic macromolecule comprises Polyethylene Glycol (PEG), hydrophilic polypeptide or hydrophilic natural macromolecule.
Described hydrophilic polypeptide comprises polyserine, poly-cysteine, polyglutamic acid, poly-aspartate, polylysine or poly arginine.
Described hydrophilic natural macromolecule comprises starch, functional fiber element, chitosan, pectin or alginic acid.
The weight ratio of described contrast agent and graphene nano carrier is 2: 1.
Described contrast agent, for the micromolecule contrast agent chelate containing gadolinium, manganese or ferroso-ferric oxide, comprises DTPA-Gd (Gd-DTPA) or Mn-meso (Mn-meso).
Compared with prior art, the present invention utilizes some hydrophilic macromolecules to have good hydrophilic and biocompatibility, utilize this individual system can enter the characteristic of biological cell inside at nanoscale simultaneously, showing good application prospect aspect the MRI radiography, have the following advantages:
(1) by using this carrier can realize the purpose extended in human body people retention time of all kinds contrast agent;
(2) by using this kind of system can realize the purpose that the contrast agent biocompatibility improves;
(3) by using this system can realize reducing the purpose of contrast agent toxicity.
The accompanying drawing explanation
Fig. 1 is the AFM figure that embodiment 1 obtains product;
Fig. 2 be embodiment 1 obtain product particle size distribution figure;
The cell survival rate figure of graphene nano carrier in people's cell for the magnetic resonance imaging contrast that Fig. 3 is variable concentrations.
The specific embodiment
Below in conjunction with the drawings and specific embodiments, the present invention is described in detail.
The preparation method of graphene nano carrier for a kind of magnetic resonance imaging contrast, the method specifically comprises the following steps:
The preparation of graphene oxide
(1) 1g flake graphite, 0.75g Chile saltpeter and 75mL 98% concentrated sulphuric acid are positioned in ice-water bath and stir, then in one hour, slowly add during 4.5g potassium permanganate solid and guarantee that temperature is below 20 ℃, these mixture at room temperature stir 5 days;
(2) under the ice-water bath condition, in mixture, slowly add the 2.25g solid potassium permanganate, keep the ice-water bath condition to continue reaction 2h, mixture continues at room temperature to stir 5 days;
(3) repeating step (2) obtains the Graphene of abundant oxidation for twice;
(4) Graphene of abundant oxidation step (3) obtained adds the dilute sulfuric acid that the 140ml mass fraction is 5%, under 98 ℃, stirs 2h, cools the temperature to 60 ℃ and adds the aqueous hydrogen peroxide solution that the 3mL mass fraction is 30%, cessation reaction after reaction 2h;
(5) product step (4) obtained is removed the supernatant through centrifugal, in lower floor's solid, adds 200mL to contain 3wt%H
2sO
4and 0.5wt%H
2o
2aqueous solution, utilize ultrasonic it to be disperseed, repeat above step 15 time and remove oxidant ion and the impurity in system;
(6) make its dispersion to the dilute hydrochloric acid that adds the 200mL mass fraction to be 3% in step (5) products therefrom is ultrasonic, centrifugation, repeat above step 3 time;
(7) step (6) gained mixture is removed to the impurity such as HCL as for the 48h that dialyses in deionized water in 3500 molecular weight bag filters;
(8) getting 1.2g sodium hydroxide, 1.0g monoxone, to add 10mL concentration be 2mgmL
-1the graphite oxide aqueous solution in, under the 400w ultra sonic bath, reaction obtains the carboxylated Graphene in surface in 3 hours, the centrifugal supernatant that goes, add isopyknic deionized water again to disperse under ultrasonic, the 3500 molecular weight bag filters of after repeating 1 time, solution being packed into are dialysed 48 hours in deionized water, obtain carboxylic graphene aqueous solution soluble in water;
MPEG-NH
2preparation
(1) at room temperature 4g terminal hydroxy group Polyethylene Glycol (mPEG4000-OH) and 2.8mL triethylamine are dissolved in the 40mL oxolane, mixed liquor are added drop-wise in the mixed liquor of 2mL thionyl chloride and 40mL oxolane, system is warming up to 60 ℃ of reaction 8h; Organic facies is concentrated in to precipitation in ether and obtains yellow mPEG-Cl three times;
(2) get 2gmPEG-Cl and 2g Hydrazoic acid,sodium salt and be dissolved in 50mL dimethyl formamide (DMF), temperature is risen to 60 ℃ of reaction 24h, organic facies is concentrated in to precipitation in ether and obtains glassy yellow powder mPEG4000-N for three times
3;
(3) get 1.3g mPEG4000-N
3be dissolved in 10mL dimethyl formamide (DMF) with the 0.075g triphenylphosphine, under room temperature, stir 2h, add the 1mL deionized water that temperature is risen to 90 ℃ and keep 3h, the gained material is obtained to whiteness three times with ether sedimentation and be mPEG4000-NH
2;
The finishing of graphene oxide hydrophilic macromolecule
Add 100mg mPEG4000-NH in (1mg/mL) in the carboxylic graphene solution of 10ml
2by the ultrasonic dispersion of mixture 5min, 10mg EDC, 8mg N-hydroxy-succinamide (NHS) are added in mixture, regulating pH is 5.6, at room temperature stir 24h, product is dialysed in deionized water (10000 bag filter) obtains pure NGO-mPEG;
The structure of imaging complex
Will containing the micromolecule contrast agent chelate of gadolinium and NGO-mPEG in water under room temperature lucifuge stir 4h, obtain mixture and be transferred in 100000 molecular weight bag filters the 24h that dialysed and remove the contrast agent on chelating not, stop dialysis and obtain the NGO-mPEG that contains the MRI image probe.
The AFM figure of the product obtained and particle size distribution figure are as Fig. 1, shown in 2, as seen from the figure, the particle diameter of graphene nano carrier is near 200nm, just in time can meet the purpose of contrast agent passive target, by Before and after dialysis contrast agent complex MRI imaging effect relatively, confirm the feasibility of graphene oxide radiography system construction method, known by deployment conditions in DMEM, graphene oxide radiography system can reach good dispersion effect in human body, the graphene nano carrier is carried out to cell toxicity test, its result as shown in Figure 3, result shows that the graphene nano carrier does not have obvious cytotoxicity, meet the requirement of biologic applications fully.
The preparation method of graphene nano carrier for a kind of magnetic resonance imaging contrast, it is raw material that the method be take nano graphene oxide and hydrophilic macromolecule, at the surface grafting hydrophilic macromolecule of nano graphene oxide, then contrast agent is loaded wherein.
The method specifically comprises the following steps:
(1) in the graphene oxide solution that is 0.8mg/ml to concentration, add polylysine, the weight ratio of graphene oxide and polylysine is 1: 8, by the ultrasonic dispersion of mixture 4min, EDC and NHS catalyzing and condensing, regulating pH is 5.6, continue at room temperature to stir 20h, then the product obtained is transferred in 10000 molecular weight bag filters, in deionized water, dialysis obtains pure graphene nano carrier;
(2) the graphene nano carrier that will obtain containing micromolecule contrast agent chelate Mn-meso (Mn-meso) and the step (1) of manganese is soluble in water by weight 2: 1, at room temperature lucifuge stirs 3h, to obtain again mixture and be transferred in 100000 molecular weight bag filters the 20h that dialysed, remove the contrast agent on chelating not, stop dialysis and obtain magnetic resonance imaging contrast graphene nano carrier.
The preparation method of graphene nano carrier for a kind of magnetic resonance imaging contrast, it is raw material that the method be take nano graphene oxide and hydrophilic macromolecule, at the surface grafting hydrophilic macromolecule of nano graphene oxide, then contrast agent is loaded wherein.
The method specifically comprises the following steps:
(1) in the graphene oxide solution that is 1.2mg/ml to concentration, add chitosan, the weight ratio of graphene oxide and chitosan is 1: 12, by the ultrasonic dispersion of mixture 6min, EDC and NHS catalyzing and condensing, regulating pH is 5.6, continue at room temperature to stir 30h, then the product obtained is transferred in 10000 molecular weight bag filters, in deionized water, dialysis obtains pure graphene nano carrier;
(2) the graphene nano carrier that will obtain containing micromolecule contrast agent chelate DTPA-Gd (Gd-DTPA) and the step (1) of gadolinium be by weight 2: 1 soluble in water, at room temperature lucifuge stirs 5h, to obtain again mixture and be transferred in 100000 molecular weight bag filters the 30h that dialysed, remove the contrast agent on chelating not, stop dialysis and obtain magnetic resonance imaging contrast graphene nano carrier.
Claims (5)
1. the preparation method of graphene nano carrier for a magnetic resonance imaging contrast, it is characterized in that, it is raw material that the method be take nano graphene oxide and hydrophilic macromolecule, at the surface grafting hydrophilic macromolecule of nano graphene oxide, then contrast agent is loaded wherein; The method specifically comprises the following steps:
(1) add hydrophilic macromolecule in graphene oxide solution, by the ultrasonic dispersion 4～6min of mixture, utilizing dichloroethanes and N-hydroxy-succinamide to regulate pH is 5.6, continue at room temperature to stir 20～30h, then the product obtained is transferred in 10000 molecular weight bag filters, in deionized water, dialysis obtains pure graphene nano carrier;
(2) graphene nano carrier contrast agent and step (1) obtained is soluble in water, at room temperature lucifuge stirs 3～5h, to obtain again mixture and be transferred in 100000 molecular weight bag filters the 20～30h that dialysed, and stop dialysis and obtain magnetic resonance imaging contrast graphene nano carrier;
Described contrast agent is the micromolecule contrast agent chelate containing gadolinium, manganese or ferroso-ferric oxide, the concentration of described graphene oxide solution is 0.8～1.5mg/ml, the weight ratio of described graphene oxide and hydrophilic macromolecule is 1:(8～12), the weight ratio of described contrast agent and graphene nano carrier is 2:1.
2. the preparation method of graphene nano carrier for a kind of magnetic resonance imaging contrast according to claim 1, is characterized in that, contrast agent comprises DTPA-Gd (Gd-DTPA) or Mn-meso (Mn-meso).
3. the preparation method of graphene nano carrier for a kind of magnetic resonance imaging contrast according to claim 1, is characterized in that, described hydrophilic macromolecule comprises Polyethylene Glycol (PEG), hydrophilic polypeptide or hydrophilic natural macromolecule.
4. the preparation method of graphene nano carrier for a kind of magnetic resonance imaging contrast according to claim 3, it is characterized in that, described hydrophilic polypeptide comprises polyserine, poly-cysteine, polyglutamic acid, poly-aspartate, polylysine or poly arginine.
5. the preparation method of graphene nano carrier for a kind of magnetic resonance imaging contrast according to claim 3, is characterized in that, described hydrophilic natural macromolecule comprises starch, functional fiber element, chitosan, pectin or alginic acid.
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| CN104436221B (en) * | 2013-09-23 | 2018-03-20 | 中国科学院苏州纳米技术与纳米仿生研究所 | Contrast agent based on graphene oxide composite material and preparation method thereof |
| CN103866605A (en) * | 2014-02-28 | 2014-06-18 | 苏州恒康新材料有限公司 | Magnetic composition and preparation method thereof |
| CN103923090B (en) * | 2014-04-18 | 2016-05-11 | 湖南科技大学 | The preparation method of Isosorbide-5-Nitrae-porphyrin-dihydropyridine-graphene oxide compound |
| CN104777117B (en) * | 2015-04-16 | 2017-10-20 | 福建医科大学 | The method that cysteine is determined based on stannic oxide/graphene nano platinum composite |
| CN105797174B (en) * | 2016-01-22 | 2019-01-11 | 复旦大学附属肿瘤医院 | A kind of magnetic resonance imaging contrast and preparation method thereof based on nano graphene oxide |
| CN105801914A (en) * | 2016-03-17 | 2016-07-27 | 四川大学 | Functional graphene composite material modified with polypeptide and preparing method thereof |
| CN107343963A (en) * | 2016-05-04 | 2017-11-14 | 复旦大学附属肿瘤医院 | It is a kind of to be used for what SPECT was imaged99mTc marking nano probes and preparation method thereof |
| CN108295255A (en) * | 2018-01-31 | 2018-07-20 | 武汉大学 | A kind of drug loaded magnetic graphene multifunctional composite and preparation method thereof |
| CN111494649B (en) * | 2019-01-31 | 2021-11-12 | 安徽大学 | Graphene quantum dot and gadolinium ion chelate magnetic resonance contrast agent and preparation method thereof |
| CN115252878B (en) * | 2022-07-26 | 2024-03-29 | 北京石墨烯技术研究院有限公司 | Graphene microsphere and preparation method and application thereof |
| CN116477619B (en) * | 2023-04-22 | 2024-07-12 | 青岛华腾石墨科技有限公司 | Phase modification method of natural graphite |
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