CN102631682B - Graphene oxide and sanguinarine compound and preparation method thereof - Google Patents
Graphene oxide and sanguinarine compound and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a graphene oxide and sanguinarine compound and a preparation method thereof. The compound includes a graphene oxide carrier and sanguinarine loaded on the surface of the carrier via a non-covalent pi-pi action, the radial size of the graphene oxide carrier is smaller than or equal to 200nm, the thickness of the graphene oxide carrier is smaller than or equal to 1nm, and a six-arm PEG (polyethylene glycol) is further preferably decorated on the surface of the graphene oxide carrier. The preparation method includes steps of treating the surface of graphene oxide; accordingly forming an active linker on the surface of the graphene oxide; connecting the surface of the graphene oxide with high-polymer materials with hydrophobic groups via the active linker to form the graphene oxide carrier; steeping the graphene oxide carrier into organic solvent with the sanguinarine until the graphene oxide carrier absorbs the sanguinarine in a saturation manner; and then obtaining an objective product by means of separation. The graphene oxide and sanguinarine compound has the advantages that solubility and stability of the sanguinarine can be greatly improved, the sanguinarine has targeting property, and the graphene oxide and sanguinarine compound is expectably widely applied as an anticancer preparation with a huge potential.
Description
Technical field
The present invention is specifically related to a kind of GO-SAN complex and preparation method thereof.
Background technology
Malignant tumor is that current serious affects human health, threatens one of principal disease of human life, and its diagnosis and treatment are focus and the difficult point of numerous biologists and medical worker always.At present, the Therapeutic Method of cancer mainly contains operative treatment, radiotherapy, chemotherapy and Biotherapeutics etc.These Therapeutic Method all have obvious toxic and side effects to human body.Therefore filtering out the cancer therapy drug that therapeutic effect is good, toxic and side effects is low, is a human common science difficult problem of being concerned about.
Take Chinese herbal medicine as raw material, extracting the novel drugs with anti-tumor activity is one of focus of anticancer medical research.By modern extractive technique, from Chinese herbal medicine, extract the effective antitumor composition, carry by selecting suitable pharmaceutical carrier, can greatly improve the therapeutic effect of malignant tumor.Sanguinarine mainly is present in the rhizome of the fruit of Herba Macleayae Cordatae and Eomecon chionantha Hance.Studies show that in recent years, Sanguinarine (SAN) is for human epithelium's cancer (A431), Human Prostate Cancer Cells (LNCaP, DU-145, PC3), human hela (HeLa cell), human ovarian carcinoma (SKOV-3 cell), Humanmachine tumour (M4Beu), human colon adenocarcinoma (DLD-1), nonsmall-cell lung cancer (A549), people's uveal (OCM-1), tissue lymph lymphoma (U937), marrow leukaemia cell (ML-1a), human erythroleukemia (K562, JM1) cell line, the kinds of tumors such as people's immortality horn cell (HaCaT) all have extraordinary anti-tumor activity.But because the Sanguinarine poorly water-soluble is difficult to be absorbed by body, cause bioavailability relatively poor, limited its use clinically.Therefore, how to develop the study hotspot that a kind of high-performance carrier systems that can effectively improve Sanguinarine dissolubility and stability has become industry.
Summary of the invention
The object of the invention is to propose a kind of GO-SAN complex that can effectively promote the dissolubility of Sanguinarine in water-based system and stability and preparation method thereof, thereby overcome deficiency of the prior art.
For achieving the above object, the present invention has adopted following technical scheme:
A kind of GO-SAN complex comprises the graphene oxide carrier and passes through non-covalent π-π used load in the Sanguinarine (SAN) of carrier surface that the radial dimension of described graphene oxide carrier is below 200nm, and thickness is more than 1 nm.
Preferably, the mass ratio of SAN and carrier more than 25:100, especially preferred 25:100-29:100.
Preferably, described graphene oxide carrier surface also is modified with peg molecule (PEG), to improve the biocompatibility of graphene oxide.Certainly, also can adopt other material to replace, but PEG toxicity is lower, safe.
More preferred, the radial dimension of described graphene oxide carrier is preferably 100nm～200nm, and thickness is preferably 1 nm～2nm.
Aforesaid GO-SAN complex prepares by the following method: get radial dimension below 200nm, the graphene oxide of thickness more than 1 nm carries out surface treatment, thereby form active linking group on the graphene oxide surface, via described active linking group on graphene oxide surface connect macromolecular material with hydrophobic group and form the graphene oxide carrier thereafter, again with the graphene oxide carrier impregnation in the organic solvent that is dissolved with Sanguinarine, behind the saturated adsorption Sanguinarine, separate obtaining target product to the graphene oxide carrier;
Described organic solvent to the solvability of Sanguinarine greater than water.
As one of preferred scheme, by to the carboxylated processing in graphene oxide surface in the preceding method, thereby form carboxyl on the graphene oxide surface, thereafter the described carboxyl of mat is connected to the graphene oxide surface with hydrophobic group, thereby form the graphene oxide carrier, described hydrophobic group comprises poly-six arm peg molecules.
A kind of preparation method of GO-SAN complex:
Get radial dimension below 200nm, the graphene oxide of thickness more than 1 nm carries out surface treatment, thereby form active linking group on the graphene oxide surface, via described active linking group on graphene oxide surface connect macromolecular material with hydrophobic group and form the graphene oxide carrier thereafter, again with the graphene oxide carrier impregnation in the organic solvent that is dissolved with Sanguinarine, behind the saturated adsorption Sanguinarine, separate obtaining target product to the graphene oxide carrier.
Further, the method is specially:
To radially size is below 200nm, carboxylated processing is carried out on the graphene oxide surface of thickness more than 1 nm;
With carboxylated graphene oxide pH value be in the water-based system of 8.0-9.0 with at room temperature fully reaction of the macromolecular material with active amine and hydrophobic group, dialysis treatment then, thus make the graphene oxide carrier,
With the graphene oxide carrier impregnation in the organic solvent that is dissolved with Sanguinarine, to the graphene oxide carrier behind the saturated adsorption Sanguinarine, again through separate, washing, obtain target product;
Described macromolecular material preferably adopts Polyethylene Glycol, and described organic solvent preferably adopts DMSO.
More specifically, as a kind of preferred scheme, the method comprises the steps:
(1) the preparation radial dimension is at 100nm～200nm, and thickness is at the graphene oxide of 1 nm～2nm;
(2) graphene oxide is added under room temperature, react in the aqueous solution contain highly basic and oxidant to reactant mixture and change black into by brownish red, centrifugalize goes out the solids in the reactant mixture again, then solids is scattered in and forms dispersion liquid in the water, and the pH value of regulating this dispersion liquid is extremely neutral, thereafter centrifugalize is out from this dispersion liquid with solids again, and again be scattered in the water, after the bag filter dialysis treatment with 8000-14000 Da, make carboxylated graphene oxide again;
Described oxidant comprises sodium chloroacetate, and described highly basic is selected from sodium hydroxide and potassium hydroxide at least, and the condition of described centrifugalize is: rotating speed is more than 13000 rpm, and the time is more than 15 min;
(3) carboxylated graphene oxide is scattered in the water, and the pH value of regulating dispersion liquid is 8.0-9.0, adds again more than Polyethylene Glycol and the EDAC reaction 12h, then dialyse more than 72 h with 50 kDa bag filters, obtain the graphene oxide carrier;
(4) the graphene oxide carrier is well-dispersed in the water, and adding contains the solution of SAN, the concentration of DMSO is more than 50% in the mixed reactant that extremely forms, stirring is spent the night, and the SAN that is not adsorbed is removed in then ultrafiltration, ultrafiltrate is no longer changed with 25% DMSO solution and water cyclic washing to color again, then with after the aqueous dispersion, and with more than centrifugal 30 min of the speed of 4000 rpm, keep supernatant, obtain target product.
Compared with prior art, advantage of the present invention is at least: a kind of high-performance SAN carrier systems based on graphene oxide is provided, it can significantly improve dissolubility and the stability of Sanguinarine, also can make it have targeting, thus be expected to as a kind of liquid preparation that has a high potential particularly injection in the treatment of cancer, be widely used.
Description of drawings
Fig. 1 a is the AFM photo of obtained nano graphene oxide (NGO) in one embodiment of the present invention;
Fig. 1 b is the thickness distribution test pattern of obtained nano graphene oxide (NGO) in one embodiment of the present invention;
Fig. 2 is the infrared spectrogram of obtained graphene oxide carrier (GO-PEG) in one embodiment of the present invention;
Fig. 3 a is the ultraviolet-visible light spectrogram of GO-SAN complex in one embodiment of the present invention;
Fig. 3 b is the fluorescence spectrum figure of GO-SAN complex in one embodiment of the present invention;
Fig. 4 a is Sanguinarine concentration-absorbance canonical plotting;
Fig. 4 b be in one embodiment of the present invention the graphene oxide carrier to the adsorption curve figure of Sanguinarine complex;
Fig. 5 is at the releasing curve diagram of SAN under the different pH value from the graphene oxide carrier in one embodiment of the present invention.
The specific embodiment
Below in conjunction with a preferred embodiment technical scheme of the present invention is further described.
Preparation technology, characterizing method and the performance test methods of the GO-SAN complex that this preferred embodiment is addressed are specific as follows described:
One, the preparation of graphene oxide carrier (GO-PEG)
1.1 preparation graphene oxide (GO)
1.1.1 native graphite pre-oxidation
Pre-oxidation graphite: get 1g natural graphite flake (commercially available, such as the natural graphite flake that can adopt Alfa Aesar company to produce), 1.5ml concentrated sulphuric acid, 0.5g potassium peroxydisulfate and 0.5g phosphorus pentoxide and be mixed and heated to 80 ℃, hatch 6h.
The graphite oxide that obtains is filtered repeatedly with distilled water, until filtrate is neutral, at room temperature dry.
1.1.2 the preparation of graphite oxide
The graphite of 1 g pre-oxidation is mixed with 23 ml concentrated sulphuric acids, slowly adding 3 g potassium permanganate (the control temperature is below 20 ℃ in this process) under the mixture of ice and water stirring condition.Then temperature is risen to 35 ℃, insulated and stirred 2 h.Add 46 ml distilled water, continue to stir 15 min, add at last 140 ml distilled water.Then, add 30% hydrogen peroxide, 2 ml in reactant liquor, at this moment, the color of the solution has become obvious bright green.With mixture with 10% hydrochloric acid, 250 ml eccentric cleaning to remove unnecessary metal ion.The precipitation that obtains with distilled water repeatedly eccentric cleaning to solution be neutral.
1.1.3 peeling off and purification of graphite oxide
To obtain lamellar GO in order peeling off, in the centrifuge tube that graphite oxide is housed, to add 40 ml distilled water, ultrasonic 30 min of cell pulverization instrument 400 W.With centrifugal 15 min of its 13000 rpm, collect supernatant, after precipitation adds distilled water again, ultrasonic peeling off repeatedly, be 8000-14000 Da with the GO that obtains with the ultra-pure water 48 h(bag filters of dialysing at last), to remove remaining inorganic ions, finally obtain the GO dispersion liquid.
1.2 the preparation of nanoscale graphene oxide (NGO)
With ultrasonic 1 h of the GO dispersion liquid that has prepared, making its further dispersion, then is that 0.22 μ m filter membrane filters with the GO diameter that disperses, and gets filtrate, with the bag filter of 8000 to 14000 Da, 24 h that dialyse, further remove inorganic ions a small amount of in the dispersion liquid and obtain NGO.Utilize atomic force microscope (AFM) and transmission electron microscope (TEM) that the pattern of NGO is observed, referring to Fig. 1 a, the size of NGO is substantially below 200 nm, and this case inventor is through studying discovery for a long period of time, the size of drug delivery vehicle the best is conducive to the picked-up of cell normally at 100 ~ 200 nm.If system too little (＜30 nm) is discharged from kidney easily, be unfavorable for that system is in the gathering of target site; System is too large, is unfavorable for the picked-up of cell.Consult Fig. 1 b, the thickness of the GO of preparation is 1 ~ 2 nm, because the thickness of known single-layer graphene is about 1 nm, inferring accordingly its number of plies is 1 ~ 2 layer, and the number of plies is fewer, and specific surface area is larger, and then absorbability is stronger, is conducive to carrying out of follow-up work.Therefore, the NGO of present embodiment preparation should can be used as a kind of desirable SAN delivery vector.
1.3 the preparation of carboxylated graphene oxide (GO-COOH)
A large amount of hydroxyls and epoxy radicals are contained in the Graphene surface, in order to increase the carboxyl-content on NGO surface, adopt under the highly basic condition, make itself and sodium chloroacetate generation nucleophilic substitution, and the hydroxyl on NGO surface and epoxide group are transformed into carboxymethoxyl the most at last.
Take by weighing 5.0 g sodium hydroxide, fully dissolve and be cooled to room temperature with 5 ml water, toward wherein adding sodium chloroacetate 5.0 g, fully be settled to 10 ml after the dissolving again, this solution is joined 40 ml(50 mg) the NGO aqueous dispersions, fully mix ultrasonic 3 h of room temperature.React complete after, the reactant liquor color changes black into by brownish red, with reactant liquor centrifugal 15 min under 13000 rpm, abandoning supernatant, precipitation adds 50 ml distilled water and disperses, and extremely neutral with the hydrochloric acid adjust pH, recentrifuge, and abandoning supernatant, precipitation is used aqueous dispersion again, and with the dialysis of 8000-14000 Da bag filter, to remove remaining inorganic ions.
But, need to prove, the preparation technology of aforementioned graphene oxide (GO), nanoscale graphene oxide (NGO) and carboxylated graphene oxide (GO-COOH) only is that this case inventor puts into practice a kind of most preferred scheme of finding out through studying for a long period of time with a large amount of, but those skilled in the art should also can adopt other technique of commonly seeing to reach identical target easily.
1.4GO-PEG preparation
Although GO-COOH has good water solublity, biocompatibility is relatively poor.In order to improve its biocompatibility, the further macromolecular material with hydrophobic group that uses of the NGO of preparation is modified.Preferably adopted six arm PEG to modify in the present embodiment.
Get GO-COOH 9ml(0.9mg/ml), the ultrasonic 30min of water-bath, after fully disperseing, use triethylamine to transfer pH to 8.0-9.0, add the PEG aqueous solution and get 0.5ml(50mg/ml), under the stirring at room, add EDAC 0.15ml(80mg/ml), continue to stir 30min, again add EDAC 0.35ml(80mg/ml), continue to stir and spend the night.Use 50kDa bag filter dialysis 72h behind the 12h, obtain 10ml GO-PEG(0.8mg/ml).
In this step, this case inventor carries out the EDC cross-linking reaction in order further to improve the stability of NGO by the carboxyl with the amino on the PEG and NGO-COOH surface, makes GO-PEG, is dispersed in the physiological solution so that NGO can be stable.Referring to Fig. 2, GO-COOH and GO-PEG are respectively at ~ 1600cm
-1Absworption peak occurs, belong to the C=O stretching vibration of carboxyl; Behind the grafting PEG, at ~ 2850cm
-1With ~ 1100cm
-1Two obvious absworption peaks have appearred in the place, correspond respectively to c h bond and C-O key on the PEG.In addition, at 1635cm
-1The new peak that occurs is the absworption peak of amido link, proves being grafted on the GO of PEG success.
But, need to prove equally, to those skilled in the art, under the enlightenment of previous embodiment, also can expect easily adopting other safety, nontoxic macromolecular material replacement PEG to realize the modification to NGO, thereby improve its biocompatibility.
Two, the preparation of GO-SAN complex (GO-SAN), sign and performance measurement 2.1GO-PEG load SAN
The SAN solution of variable concentrations (solvent is DMSO) joins in the NGO-PEG dispersion liquid, and final DMSO concentration is 50%, and stirring is spent the night, and with the super filter tube ultrafiltration of 100kDa, removes the SAN that is not adsorbed.With the 25%DMSO solution washing for several times, use again the distilled water cyclic washing, until the ultrafiltrate color no longer changes, hold back the most at last part distilled water ultra-sonic dispersion, the centrifugal 30min of 4000rpm removes insoluble part, and supernatant is the complex of GO-PEG and SAN, will use determined by ultraviolet spectrophotometry after its dilution, take SAN, GO-PEG as contrast, observe the variation of uv-spectrogram; Excite the mensuration fluorescence spectrum at the 326nm place,, take SAN as contrast, observe the variation of fluorescence spectrum, thereby confirm that SAN successfully is adsorbed onto on the GO-PEG.
In this step, by physical absorption SAN is adsorbed onto on the GO-PEG, and by ultraviolet spectra and fluorescence spectrum, determines that GO-PEG is to the active adsorption of Sanguinarine.
Consult Fig. 3 a, compare with GO-PEG, the GO-PEG of absorption behind the SAN ~ 326 nm and ~ there is obvious absworption peak at 273 nm places, this shows being adsorbed on the GO-PEG of SAN success corresponding to the uv absorption of SAN.Same, consult Fig. 3 b, the compound system of GO-SAN causes the fluorescence of SAN by quencher, when in compound system, adding ethanol, can be so that fluorescence recover, this mainly is to cause SAN to split away off from the Graphene surface because ethanol adds, and therefore also further confirms the successful absorption of SAN.
2.2 the SAN load-carry duty is measured
2.2.1 the preparation of SAN standard curve
Accurately take by weighing SAN standard substance 1mg, be dissolved in the 100ml volumetric flask, obtain the standard substance storing solution of 10ug/ml.The accurate Sanguinarine standard solution of drawing different volumes complements to 1ml respectively, makes concentration be respectively 1,2,4,6,8,10 g/ml.Measure its OD value at the 326nm place, do standard curve.
2.2.2 measure SAN concentration among the GO-SAN
Get 10mlGO-PEG(1mg/ml), add subsequently 5mlDMSO, add again 5ml and be dissolved in the SAN(2.3mg/ml of DMSO), stirring is spent the night, remove free SAN with super filter tube, use the ultraviolet spectra of determined by ultraviolet spectrophotometry GO-SAN, measure the concentration of SAN by the absorbance of deduction GO-PEG.
2.2.3 measure the SAN load-carry duty
Get respectively 100 ul GO-PEG(400 ug/ml), add 400 ul water, add subsequently 20,30,40,60,80 ul and be dissolved in the Sanguinarine (1 mg/ml) of DMSO, complement to 1 ml with DMSO, stirring is spent the night, remove free SAN with super filter tube, use ultraviolet spectrophotometry to calculate final SAN load-carry duty.
This case inventor uses ultraviolet spectroscopy that GO-SAN is measured, and by the absorbance of GO-PEG, then (consults Fig. 4 a), calculates final SAN load-carry duty (consulting Fig. 4 b) according to the standard curve of SAN.Found that in certain SAN concentration range, GO-PEG rises along with the concentration of SAN to the absorbance of SAN and increases, and presents linear correlation, until carrier reaches capacity to the absorption of SAN.Therefore just can control carrier GO-PEG to the adsorbance of SAN by the concentration of control input SAN.
Postscript, the dissolubility of medicine is one of key factor that affects drug bioavailability, SAN is difficult to be absorbed by body because of the dissolubility in water little (＜0.3 mg/ml), causes bioavailability relatively poor, gives full play to clinically curative effect thereby limited it.This case inventor has also measured the dissolubility of NGO-SAN complex, finds that it has good water solublity, and equivalent SAN concentration is as follows up to ~ 2.0 mg/ml(computational methods), greatly improved the water solublity of SAN.
Example: GO-PEG(8 ug/ml) the GO-SAN(dilution is 100 times)
326nm 0.408（A1） 0.708（A3）
700nm 0.074（A2） 0.111（A4）
△=A3-A1*A4/A2=0.096 substitution standard curve:
0.096=0.0611x-0.0203
X=1.7398 ug/ml multiply by extension rate
Get c=1000x=1903.4 ug/ml=1.9 mg/ml
2.3 GO-SAN release in vitro
In general, medicine is the antitumor drug necessary condition that plays a role from the release on the nano-carrier, and desirable Nano medication should realize that the control of medicine discharges.And those skilled in the art are known, and the environment of general tumor tissues is faintly acid, and pH is about 6.75, is starkly lower than 7.23 of normal structure.In addition, after nano-carrier enters tumor cell inside, can run into the lower lysosome of pH value and endosome (pH=5.0-5.5).Therefore, this case inventor has measured the release of SAN under neutral and acid condition among this GO-SAN, concrete operations are as follows: discharge under (1) acid condition: get 2 ml SAN-GO solution and be dissolved in the PBS buffer of 8 ml pH=5, with its bag filter of packing into (8000-14000 Da), then bag filter is placed in the beaker of dialysis, the PBS buffer 80ml that adds pH=5, from beaker, draw 1 ml dialysis solution respectively at 12 h, 24 h, 36 h, 48 h, and in beaker, replenish immediately the fresh PBS of 1ml, make its cumulative volume keep 80ml constant.Adopt determined by ultraviolet spectrophotometry in the OD value of 326 nm excitation wave strong points the 1ml dialysis solution that takes out, and calculate its burst size.(2) discharge under the neutrallty condition: get 2 ml SAN-GO solution and be dissolved in the PBS buffer of 8 ml pH=7, with its bag filter of packing into (8000-14000 Da), then bag filter is placed in the beaker of dialysis, the PBS buffer 80ml that adds pH=7, from beaker, draw 1 ml dialysis solution respectively at 12 h, 24 h, 36 h, 48 h, and in beaker, replenish immediately the fresh PBS of 1ml, make its cumulative volume keep 80ml constant.Adopt determined by ultraviolet spectrophotometry in the OD value of 326 nm excitation wave strong points the 1ml dialysis solution that takes out, and calculate its burst size.
Test result shows: 48 h under neutrallty condition of the SAN among this GO-SAN can not produce obvious release, and under the slant acidity condition, discharge obviously and accelerate, 48 h release rates are 47%, consult Fig. 5, this proof, this GO-SAN is that the utmost point is hopeful to be used as novel high efficiency anti-tumor medicine extensive use.
Should be understood that the present invention can summarize with other the concrete form without prejudice to spirit of the present invention or principal character.Therefore, no matter from which point, the above embodiment of the present invention can only be thought can not limit the present invention to explanation of the present invention, claims have been pointed out scope of the present invention, and scope of the present invention is not pointed out in above-mentioned explanation, therefore in the implication suitable with claims of the present invention and any change in the scope, all should think to be included in the scope of claims.
Claims (1)
1. the preparation method of a GO-SAN complex is characterized in that the method specifically comprises the steps:
(1) the preparation radial dimension is at l00nm-200nm, and thickness is at the graphene oxide of 1 nm-2nm;
(2) graphene oxide is added under room temperature, react in the aqueous solution contain highly basic and oxidant to reactant mixture and change black into by brownish red, centrifugalize goes out the solids in the reactant mixture again, then solids is scattered in and forms dispersion liquid in the water, and the pH value of regulating this dispersion liquid is extremely neutral, thereafter centrifugalize is out from this dispersion liquid with solids again, and again be scattered in the water, after the bag filter dialysis treatment with 8000-14000 Da, make carboxylated graphene oxide again;
Described oxidant comprises sodium chloroacetate, and described highly basic is selected from sodium hydroxide or potassium hydroxide at least, and the condition of described centrifugalize is: rotating speed is more than 13000 rpm, and the time is more than 15 min;
(3) carboxylated graphene oxide is scattered in the water, and the pH value of regulating dispersion liquid is 8.0-9.0, adds again more than Polyethylene Glycol and the EDAC reaction 12h, then dialyse more than 72 h with 50 kDa bag filters, obtain the graphene oxide carrier;
(4) the graphene oxide carrier is well-dispersed in the water, and adding contains the DMSO solution of Sanguinarine, the concentration of DMSO is more than 50V/V% in the mixed reactant that extremely forms, stirring is spent the night, and the Sanguinarine that is not adsorbed is removed in then ultrafiltration, DMSO solution and water cyclic washing to the color of ultrafiltrate with 25 V/V% is no longer changed again, then with aqueous dispersion, and with more than centrifugal 30 min of the speed more than the 4000rpm, keep supernatant, obtain target product.
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| CN104739921B (en) * | 2015-04-09 | 2019-06-11 | 吉林大学 | A kind of prescription lozenge and preparation method thereof for alleviating visual fatigue |
| CN105641710B (en) * | 2016-01-15 | 2019-01-18 | 武汉理工大学 | The targeted oxidative graphene of HA/RGD modification is double to carry medicine composite material and preparation method thereof |
| CN106474483A (en) * | 2016-12-23 | 2017-03-08 | 中南大学湘雅医院 | The Cetuximab of graphene oxide modification, preparation method and application |
| CN107519534B (en) * | 2017-10-17 | 2020-04-28 | 华南师范大学 | Manufacturing method of 3D drug composite stent with quercetin-loaded polyethylene glycol-modified graphene oxide and acellular dermal matrix |
| CN108635587A (en) * | 2018-04-28 | 2018-10-12 | 孙燕霞 | A kind of graphene Quercetin compound and preparation method and its purposes in antitumor |
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| CN101209043B (en) * | 2006-12-27 | 2011-08-10 | 长沙世唯科技有限公司 | Application of sanguinarine or toddaline in prevention and cure of schistosomiasis |
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| CN101670108A (en) * | 2009-08-13 | 2010-03-17 | 苏州纳米技术与纳米仿生研究所 | Medicine carrying system based on nano graphene oxide |
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