CN102321604A - Application of oxidized graphene modified by polyethylene glycol - Google Patents
Application of oxidized graphene modified by polyethylene glycol Download PDFInfo
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- CN102321604A CN102321604A CN 201110227223 CN201110227223A CN102321604A CN 102321604 A CN102321604 A CN 102321604A CN 201110227223 CN201110227223 CN 201110227223 CN 201110227223 A CN201110227223 A CN 201110227223A CN 102321604 A CN102321604 A CN 102321604A
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- graphene oxide
- polyethylene glycol
- oxidized graphene
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Abstract
The invention relates to an application of oxidized graphene modified by polyethylene glycol as a trypsin activator and a stabilizer; the oxidized graphene modified by polyethylene glycol comprises oxidized graphene; the surface of the oxidized graphene is grafted with polyethylene glycol; and the oxidized graphene and polyethylene glycol are connected through amide bonds; wherein the precursor of the polyethylene glycol is polyethylene glycol with six branched chains (with a chain end of an amino group) with a molecular weight of 9000-11000; and the weight percent of the polyethylene glycol is 35-45%; the oxidized graphene modified by polyethylene glycol has a dimension of 10 nm-30 nm, and a height of 1 nm-2 nm. The oxidized graphene modified by polyethylene glycol of the invention is simple in synthesis, and can specifically improve the activity and thermal stability of trypsin; the improvement of the activity and thermal stability of trypsin can meet biomedical requirements.
Description
Technical field
The present invention relates to a kind of polyethyleneglycol modified graphene oxide that can be used as the trypsinase acvator.
Background technology
Trypsin Trypsin) being a kind of of Tryase, is a kind of important digestive ferment in higher animal and the human body.Trypsinase is synthetic with zymogen forms at pancreas, after the composition secretion as pancreatic juice, receives enteropeptidase, or tryptic restricted decomposition and become the trypsinase of biologically active.It is a kind of endopeptidase, can selective hydrolysis protein (polypeptied chain) in by Methionin or the formed peptide chain of arginic carboxyl.
In vivo, trypsinase not only has the effect of digestive ferment, and can act on the precursor (like chymotrypsinogen, proearboxypeptidase, phosphatide proenzyme etc.) of other enzyme, and they are played activation.Clinically; Trypsinase is usually used in treating local edema, hemotoncus and the abscess etc. that pyothorax, hemothorax, ulcer, wound inflammation, traumatic damage, fistula etc. are produced; Can impel decomposition such as blood clot, fester, sputum, be easy to drainage and get rid of, quicken the surface of a wound and purify; Promote granulation tissue newborn, and anti-inflammatory effect is arranged.In addition, it can be used for the treatment of respiratory tract disease, also can be used for the treatment of venom.In life science, trypsinase is a kind of very important toolenzyme.In the zooblast tissue culture, the digestion that is usually used in organizing and the cultivation of zooblast are gone down to posterity.Because the gp on the cytolemma (also being called the sugar quilt); Has adhesion; Can make a plurality of cell adhesions together and formative tissue, trypsinase can be used for the hydrolysis sugar quilt, makes " animal tissues that is used to test " be dispersed into individual cells. and be convenient to process cell suspension and carry out cell cultures and observation.In proteomics research, in biological mass spectrometry identification of protein method, or through 1D or the isolating adhesive tape of 2D glue; The enzymolysis that all needs proteolytic ferment; The most frequently used enzyme is a trypsinase, and it is a kind of sequence-specific proteolytic enzyme, only cuts the C end of l-arginine lysine residue.Because the strong specificity of trypsin digestion is an indispensable toolenzyme in the proteinic determined amino acid sequence.
Trypsinase is external in vivo all to have important function, therefore can significantly improve its bioactive acvator in biomedical research and even undoubtedly important effect will be arranged clinically; And in the mass spectrum qualification process, needing hydrolysis temperature is 56 ℃, has substantially exceeded tryptic optimum temperuture, and too high temperature is prone to make its sex change, loses enzymolysis, and therefore can strengthen its stable stablizer also seems particularly important.But the promoting agent that up to the present, can improve enzymic activity seldom.Recently; The Huang celebrating gold nano grain that teacher studied of Shanghai Chinese Academy of Sciences applied physics can improve tryptic activity about 10%; With respect to other the material that reduces enzymic activity greatly is extraordinary; But still fail to satisfy significantly improving of tryptic activity, fail to satisfy it, yet but almost do not find (except the immobilized enzyme) about tryptic stablizer in the demand of biologically using.
Therefore,, satisfy its extensive utilization on biomedicine, very be necessary to invent a kind of trypsinase acvator in order to significantly improve tryptic activity and stability.
In the prior art; Polyethyleneglycol modified graphene oxide is generally as pharmaceutical carrier, for example: Dai Hongjie seminar reported first in 2008 utilize PEG (polyoxyethylene glycol) to modify graphene oxide contain the anti-cancer medicament carrier of aromatic structure as insoluble.They are at first with graphite oxidation, and (Nanoscale Grapheneoxide, NGO), the side chain PEG with biocompatible 10k is grafted on the NGO again less than the nano graphene oxide of 50nm to have obtained size.This grapheme material is included under physiological condition has excellent biological compatibility and stability in the serum.Through π-physical actions such as π stacking that the NGO that cancer therapy drug SN38 (camptothecin derivative) is adsorbed on PEGization is surperficial then, form Graphene-medicinal composition.Graphene has monoatomic layer thickness, and its two basal planes can adsorb medicine, so the unrivaled superelevation carrying drug ratio of other nano materials of tool.Simultaneously, the NGO-SN38 mixture has good water-solubility, shows that it can be used for the solubilising of insoluble drug as pharmaceutical carrier.And medicine wherein has high activity, and simultaneously, this pharmaceutical carrier does not have significant cytotoxicity, has good biological safety.(referring to: LIU Z, ROBINSON J, SUN X M, et al. J Am Chem Soc, 2008,130:10876-10877).
Summary of the invention
Goal of the invention of the present invention provides a kind of new application of polyethyleneglycol modified graphene oxide, promptly improves tryptic activity and thermostability specifically as trypsinase acvator and stablizer.
For reaching the foregoing invention purpose; The technical scheme that the present invention adopts is: a kind of polyethyleneglycol modified graphene oxide; Said polyethyleneglycol modified graphene oxide comprises graphene oxide; Said graphene oxide surface grafting base polyoxyethylene glycol, and be connected through amido linkage with polyoxyethylene glycol in the said graphene oxide; Wherein, the precursor of said polyoxyethylene glycol is six branched chair polymacrogols (end of the chain is for amino) of molecular weight (weight-average molecular weight) 9000～11000; Be preferably molecular weight and be 9500～10500 six branched chair polymacrogols (end of the chain is for amino); And the weight percent of said polyoxyethylene glycol is 35～45%, is preferably 38～40%.
In the technique scheme, polyethyleneglycol modified graphene oxide size is 10nm～30nm, highly is 1nm～2nm.
The document YANG K that the preparation method of above-mentioned polyethyleneglycol modified graphene oxide can deliver with reference to Liu Zhuan seminar, ZHANG S, et al. ACS NANO, 2010.
Above-mentioned polyethyleneglycol modified graphene oxide can improve tryptic activity and thermostability specifically; Therefore, the present invention requires to protect the application of above-mentioned polyethyleneglycol modified graphene oxide as tryptic activity specific agent; Require of the application of the above-mentioned polyethyleneglycol modified graphene oxide of protection simultaneously as tryptic stablizer.
Because the technique scheme utilization, the present invention compared with prior art has advantage:
1. polyethyleneglycol modified graphene oxide according to the invention is synthetic simple, and can specificity improve tryptic activity, thermally-stabilised; Tryptic activity can satisfy its demand on biomedicine with the enhancing of stability.
Description of drawings
Fig. 1 is gained GO-2k-among the embodiment one
l-NH
2The AFM figure of-PEG;
Fig. 2 is gained GO-10k-among the embodiment one
Br-PEG-NH
2TGA figure;
Fig. 3 is GO-10k-among the embodiment two
Br-PEG-NH
2Influence to the trypsinase vigor;
Fig. 4 is GO-10k-among the embodiment two
Br-PEG-NH
2Influence to the chymotrypsin protein enzyme activity;
Fig. 5 is GO-10k-when casein is as substrate among the embodiment three
Br-PEG-NH
2To tryptic thermostability influence;
Fig. 6 is GO-10k-when oxyphorase is as substrate among the embodiment three
Br-PEG-NH
2To tryptic thermostability influence.
Embodiment
Below in conjunction with accompanying drawing and embodiment the present invention is further described:
Embodiment one: specific, activated dose of GO-10k-of preparation trypsinase
Br-PEG-NH
2
Do the most initial raw material with the 1g expanded graphite, the solid sodium chloride that adds about 30 times of weight is ground to no obvious visible particle shape thing, adds the water suction filtration, and flush away sodium-chlor is with the graphite dry for standby of porphyrize.In flask, add about 30mL vitriol oil (98.3%), put into the porphyrize graphite of having dried, stirred 8 hours under the room temperature; Then mixture is placed ice bath, add about 3g potassium permanganate, slowly be warming up to 115 ℃; Slowly add about 150mL water; Add about 10mL30% hydrogen peroxide and stirring afterwards, the centrifugal upper water solution of removing, repeated water washing to solution no longer occur till the deposition.With 5mL concentration is that the ultrasonic 30min of graphene oxide suspension liquid of 3mg/mL obtains the clarifying graphene oxide water-sol; Pressing final concentration 0.12 g/mL then adds the NaOH solid and 50 ℃ of stirred in water bath 4 hours, adds concentrated hydrochloric acid adjustment pH value of solution value afterwards near 1.Wash repeatedly and centrifugal purification with zero(ppm) water then, obtain water-soluble good alkalization graphene aqueous solution.Add six branched chair polymacrogols (end of the chain is for amino) (10k-by final concentration 3mg/mL
Br-PEG-NH
2) to the graphene aqueous solution that alkalizes (concentration is 0.5mg/ml), ultrasonic making it mixes, and continues ultrasonic half a hour then, and added about 1mg EDC at the 5th minute, in the time of the 30th minute, add about 2.5mgEDC.The mixture stirred overnight is got final product.Remove six branched chair polymacrogols (end of the chain is for the amino) (10k-that does not combine through the ultrafiltration post washing of 100kDa then
Br-PEG-NH
2), the Graphene (GO-10k-that six branched chair polymacrogols that can obtain (end of the chain is for amino) are modified
Br-PEG-NH
2).
Above-mentioned polyethyleneglycol modified graphene oxide is carried out AFM (AFM) analysis, get Fig. 1, can know from figure: polyethyleneglycol modified graphene oxide size is 10nm-30nm, highly is 1nm-2nm.
Above-mentioned polyethyleneglycol modified graphene oxide is carried out thermogravimetric analysis, Fig. 2, can know from figure: the weight percentage of PEG is about 40% (to account for whole GO-10k-
Br-PEG-NH
2Ratio).
Embodiment two: study the influence of the polyethyleneglycol modified graphene oxide of embodiment one gained to tryptic activity.
The graphene oxide GO-10k-that embodiment one gained is polyethyleneglycol modified
Br-PEG-NH
2Interact with trypsinase, mix 16min under the room temperature, measure the activity of enzyme then, concrete grammar is: the trypsinase of the 0.1mg/ml of 20 μ l respectively with the sterilized water of 20 μ l, the GO-10k-of 0.15mg/mL, 0.2mg/mL
Br-PEG-NH
2Mix 16min at 25 ℃, add 10 μ l, 5 * PBS again and add to 50 μ l, the substrate casein that adds the 5mg/ml of 50 μ l again carries out 40 ℃ of enzyme digestion reactions; 10min; With TCA (0.4M) termination reaction of 100 μ l, centrifugal, get 100 μ l supernatants and 100 μ l forint phenol (1:1) Na to 500 μ l
2CO
3(0.4M) 40 ℃, the 20min coupling reaction is surveyed OD
680
The result is as shown in Figure 3: the enhancing of tryptic activity demonstrates concentration dependent, works as GO-10k-
Br-PEG-NH
2When final concentration is respectively 30,40 μ g/mL, increased about 94%, 126% respectively; Therefore, above-mentioned polyethyleneglycol modified graphene oxide GO-10k-
Br-PEG-NH
2Can strengthen tryptic activity.
Simultaneously, with the polyethyleneglycol modified Graphene GO-10k-of Quimotrase checking
Br-PEG-NH
2Active enhancing is specific to pancreatin.This kind of enzyme and trypsinase belong to Tryase, are again same enzyme families, and structure is quite similar.Under identical situation, change trypsinase into above-mentioned Quimotrase, do identical experiment; Concrete grammar is: the Quimotrase of the 0.06mg/ml of 20 μ l respectively with the GO-10k-of the sterilized water of 20 μ l, 0.15mg/mL, 0.2mg/mL
Br-PEG-NH
2Mix 16min at 25 ℃, add 10 μ l, 5 * PBS again and add to 50ul, the substrate casein that adds the 5mg/ml of 50 μ l again carries out 40 ℃ of enzyme digestion reactions; 10min; With TCA (0.4M) termination reaction of 100 μ l, centrifugal, get 100 μ l supernatants and 100 μ l forint phenol (1:1) Na to 500 μ l
2CO
3(0.4M) 40 ℃, the 20min coupling reaction is surveyed OD
680
The result is as shown in Figure 4, and the result shows GO-10k-
Br-PEG-NH
2Not significantly influence of activity to Quimotrase.
Therefore, The above results shows GO-10k-
Br-PEG-NH
2Fail to improve the activity of Quimotrase, can specificity strengthen tryptic activity, so its raising to tryptic activity is specific, can be used as tryptic special activator.
Embodiment three: study the influence of the polyethyleneglycol modified graphene oxide of embodiment one gained to the trypsinase thermostability.
With trypsinase and GO-10k-
Br-PEG-NH
2Mixing solutions at 70 ℃ and 80 ℃ sex change 5min respectively, measure tryptic activity according to above-mentioned enzyme activity determination method then, be specially:
(1) when casein during as substrate, with trypsinase and GO-10k-
Br-PEG-NH
2According to mass volume ratio (mg/mL) is the mixed of 1:2.In addition, trypsinase and sterilized water, trypsinase and 10k-
Br-PEG-NH
2[mass volume ratio (mg/mL) is 1:10] also mixes each other, then with mixed solution 70 ℃ of placements during with 80 ℃ 5 minutes, and then measure tryptic activity according to above-mentioned measuring method for activity.The result is as shown in Figure 5: do not have GO-10k-
Br-PEG-NH
2Situation under, trypsinase is sex change almost, does not have activity.Yet, at GO-10k-
Br-PEG-NH
2Provide protection under, trypsinase can the higher activity that must keep oneself.In the time of 70 ℃, when reaching 95%, 80 ℃, reach 73%.
(2) when oxyphorase during as substrate, same after the same method ratio is put into 70 ℃ and 80 ℃ with mixed solution, and then measures tryptic activity.The result is as shown in Figure 6: do not have GO-10k-
Br-PEG-NH
2Situation under, when 70 ℃ and 80 ℃, tryptic activity is reduced to 5% and 4% respectively.And GO-10k-
Br-PEG-NH
2Exist under the situation, when 70 ℃ and 80 ℃, trypsinase can be kept active in 73% and 58%.
The above results shows: when making substrate respectively with casein or oxyphorase, and GO-10k-
Br-PEG-NH
2Can both strengthen tryptic stability, this explains GO-10k-
Br-PEG-NH
2Irrelevant to tryptic thermally-stabilised enhancing and substrate.
In sum, GO-10k-
Br-PEG-NH
2This acvator can improve tryptic activity specifically significantly, and under harsh conditions, also can protect tryptic activity, and this enhancing and substrate to tryptic thermostability has nothing to do.This material can make trypsinase on biomedicine, bring into play great use.
Claims (2)
1. a polyethyleneglycol modified graphene oxide is as the application of tryptic activity specific agent; Said polyethyleneglycol modified graphene oxide comprises graphene oxide; Said graphene oxide surface grafting base polyoxyethylene glycol, and be connected through amido linkage with polyoxyethylene glycol in the said graphene oxide; Wherein, the precursor of said polyoxyethylene glycol is six branched chair polymacrogols of molecular weight 9000～11000; And the weight percent of said polyoxyethylene glycol is 35～45%; Said polyethyleneglycol modified graphene oxide size is 10nm～30nm, highly is 1nm～2nm.
2. a polyethyleneglycol modified graphene oxide is as the application of tryptic stablizer; Said polyethyleneglycol modified graphene oxide comprises graphene oxide; Said graphene oxide surface grafting base polyoxyethylene glycol, and be connected through amido linkage with polyoxyethylene glycol in the said graphene oxide; Wherein, the precursor of said polyoxyethylene glycol is six branched chair polymacrogols of molecular weight 9000～11000; And the weight percent of said polyoxyethylene glycol is 35～45%; Said polyethyleneglycol modified graphene oxide size is 10nm～30nm, highly is 1nm～2nm.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103589197A (en) * | 2013-11-25 | 2014-02-19 | 桂林理工大学 | Method for preparing flexibilizer by adopting oxidized graphene and application thereof |
| CN104472538A (en) * | 2014-11-24 | 2015-04-01 | 暨南大学 | Functional graphene oxide loaded nano-silver antibacterial material as well as preparation method and application thereof |
| CN104758240A (en) * | 2014-12-18 | 2015-07-08 | 深圳先进技术研究院 | Nanometer drug complex loaded with paclitaxel and preparation method thereof |
| CN105797174A (en) * | 2016-01-22 | 2016-07-27 | 复旦大学附属肿瘤医院 | Nanometer graphene oxide-based magnetic resonance imaging contrast agent and preparation method thereof |
| CN106543430A (en) * | 2016-11-10 | 2017-03-29 | 无锡市明盛强力风机有限公司 | A kind of synthetic method of the magnetic oxygenated Graphene of Polyethylene Glycol |
| CN107915222A (en) * | 2017-12-29 | 2018-04-17 | 江苏苏博特新材料股份有限公司 | A kind of preparation method of poly ethyldiol modified graphene oxide |
| CN112370530A (en) * | 2020-10-16 | 2021-02-19 | 广州中医药大学(广州中医药研究院) | Lactoferrin-modified pegylated graphene oxide-loaded puerarin nano platform as well as preparation method and application thereof |
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2011
- 2011-08-09 CN CN2011102272238A patent/CN102321604B/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103589197A (en) * | 2013-11-25 | 2014-02-19 | 桂林理工大学 | Method for preparing flexibilizer by adopting oxidized graphene and application thereof |
| CN103589197B (en) * | 2013-11-25 | 2014-11-26 | 桂林理工大学 | Method for preparing flexibilizer by adopting oxidized graphene and application thereof |
| CN104472538A (en) * | 2014-11-24 | 2015-04-01 | 暨南大学 | Functional graphene oxide loaded nano-silver antibacterial material as well as preparation method and application thereof |
| CN104758240A (en) * | 2014-12-18 | 2015-07-08 | 深圳先进技术研究院 | Nanometer drug complex loaded with paclitaxel and preparation method thereof |
| CN105797174A (en) * | 2016-01-22 | 2016-07-27 | 复旦大学附属肿瘤医院 | Nanometer graphene oxide-based magnetic resonance imaging contrast agent and preparation method thereof |
| 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 |
| CN106543430A (en) * | 2016-11-10 | 2017-03-29 | 无锡市明盛强力风机有限公司 | A kind of synthetic method of the magnetic oxygenated Graphene of Polyethylene Glycol |
| CN107915222A (en) * | 2017-12-29 | 2018-04-17 | 江苏苏博特新材料股份有限公司 | A kind of preparation method of poly ethyldiol modified graphene oxide |
| CN112370530A (en) * | 2020-10-16 | 2021-02-19 | 广州中医药大学(广州中医药研究院) | Lactoferrin-modified pegylated graphene oxide-loaded puerarin nano platform as well as preparation method and application thereof |
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