CN108524940A - A kind of graphene oxide of modification carries medicine delivery system and its preparation method and application - Google Patents

A kind of graphene oxide of modification carries medicine delivery system and its preparation method and application Download PDF

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CN108524940A
CN108524940A CN201810412533.9A CN201810412533A CN108524940A CN 108524940 A CN108524940 A CN 108524940A CN 201810412533 A CN201810412533 A CN 201810412533A CN 108524940 A CN108524940 A CN 108524940A
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graphene oxide
pil
drug
dox
paa
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CN108524940B (en
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吴浩天
刘宇
韩佳婧
郭忠秋
潘春娇
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Liaoning University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to a kind of graphene oxides of modification to carry medicine delivery system and its preparation method and application.Including：The drug loading of graphene oxide GO prepares GO X, and positively charged polymeric ionic liquid PIL and negatively charged polyacrylic acid PAA are wrapped in the surfaces GO X layer by layer using the principle of charge attraction forms two layers of protective layer.The load medicine compound system favorable solubility in water of the present invention, can be such that drug is protected in strong acidic environment, increase the stability of drug after carrying medicine, the release characteristics with PH sensitivities.Drug can be made to stablize under one's belt, be discharged in enteron aisle, increase the assimilation effect of drug, bioavilability be improved, to enhance its antitumor curative effect.Present invention can apply to antitumor researchs, have good clinical research application value.

Description

A kind of graphene oxide of modification carries medicine delivery system and its preparation method and application
Technical field
The invention belongs to field of pharmaceutical preparations, more particularly to a kind of polymeric ionic liquid (PIL) and polyelectrolyte (PAA) packet The graphene oxide (GO) for wrapping up in modification carries medicine and preparation method thereof.
Background technology
Graphene oxide (GO) be by single layer of carbon atom in the form of sp2 hydridization existing for two-dimentional (2D) honeycomb crystal lattice structure Mouthful, surface has hydroxyl, carboxyl and epoxy group and a large amount of oxygen-containing polar group, is hydrophilic material, and surface is modified GO can stablize in high level salt solution and physiological solution.Carbon atom in GO structures forms stable chemical bond with medicines structure, So a large amount of bioactive molecule can be adsorbed with hydrophobic interaction by the way that π-is pi-conjugated.GO and its derivative are as carrier Transhipment such as enzyme, albumen and drug are in research hotspot.However, GO is easy to flocculate and gather in salting liquid and physiological solution Collection.Therefore, there is an urgent need to by functional modification, obtain the graphene oxide that can be stabilized in physiological solution to carry medicine body System.
Invention content
The object of the present invention is to provide the graphene oxide medicine-carried systems that a kind of polymeric ionic liquid and polyelectrolyte are modified And preparation method thereof, this method is easy to operate, and reaction condition is mild.Composite drug-loaded material drug carrier amount is high, and stability is good, has slow Release the release characteristics with PH sensitivities.
The present invention adopts the following technical scheme that：A kind of graphene oxide load medicine delivery system of modification, the oxygen of the modification Graphite alkene carries medicine delivery system, is to obtain graphene oxide compound GO-X with graphene oxide for carrier loaded drug X, The surface layer of graphene oxide compound GO-X wraps up positively charged polymeric ionic liquid PIL and negatively charged polypropylene PAA-PIL/GO-X made from sour PAA.
Preferably, the drug X includes but not limited to adriamycin (DOX) or taxol (PTX) or rcumenol (CUR).
Preferably, the polymeric ionic liquid PIL is poly- 1- vinyl -3- ethyl imidazol(e)s bromide, poly- 1- allyls -3- Ethyl imidazol(e) bromide, poly- 1- vinyl -3- butyl imidazoles bromide or poly- 1- vinyl -3- ethyl imidazol(e) villaumites.It is furthermore preferred that institute The polymeric ionic liquid PIL stated is poly- 1- vinyl -3- ethyl imidazol(e) bromides.
A kind of graphene oxide of modification carries the preparation method of medicine delivery system, includes the following steps：
1) under stirring, drug X is dissolved in solvent, and is slowly dropped in the aqueous solution of graphene oxide GO, by super Sound loads to drug X on graphene oxide GO；Centrifugation, sediment are washed with solvent, are lyophilized, are obtained graphene oxide compound GO-X。
Preferably, in mass ratio, drug X:GO=1:0.2~1:5；It is furthermore preferred that drug X:GO=1:0.5.
Preferably, solvent is water, methanol, ethyl alcohol or DMSO.
Preferably, ultrasonic time 5-60min, it is furthermore preferred that ultrasonic time is 30min.
2) it after redissolving GO-X, is added drop-wise in 45 DEG C of polymeric ionic liquid PIL solution, is uniformly mixed under slow stirring Afterwards, it is stirred to react, in mass ratio, obtains PIL/GO-X.
Preferably, GO:PIL=1:1~1:20.It is furthermore preferred that GO:PIL=1:16.
Preferably, it is described be stirred to react for：Shading, 100rpm stir 0.1~5h.
3) under stirring, polyacrylic acid PAA solution is added drop-wise in PIL/GO-X solution, at 45-70 DEG C, heating stirring is anti- 1h is answered, reacts at room temperature 12h later, obtains PAA-PIL/GO-X.
Preferably, GO:PAA=1:1~1:20.It is furthermore preferred that GO:PAA=1:16
A kind of graphene oxide of above-mentioned modification carries medicine delivery system PAA-PIL/GO-X in the preparation of antitumor drugs Application.
The beneficial effects of the invention are as follows：
1, polymeric ionic liquid (Polymeric ionic liquid, PIL) is polymerized by ionic liquid monomer, is one Class has both the new function polymer substance of the advantages of ionic liquid and polymer, has heat more higher than general ionic liquid steady Qualitative and more adsorption sites.The present invention, polymeric ionic liquid is compound with graphene, it increases the hydrophily of graphene and divides Property is dissipated, obtains the higher compound of stability, while being avoided that graphene due to π-pi-electron sedimentation and van der Waals interaction And the phenomenon that reuniting.Graphene is combined with polymeric ionic liquid, and it is good to impart graphene, is increased in physiological solution Solubility and stability.
Polyelectrolyte (PAA) is a kind of highly effective intestinal permeation enhancers.Its mechanism of action may be its cation Part and the glycoprotein anion part of cell surface interact, or internal negative charge region phase interaction is connect with epithelial tight With leading to the structural rearrangement of tight junction protein and open close connection.Polyelectrolyte has small toxicity, inhibition of enzyme activity strong Mucosa adhesion ability is not easy to be absorbed by alimentary canal after taking orally, can play the features such as absorption enhancement effect for a long time.
2, of the invention, it is by the pi-conjugated suction-operateds of π-, anticancer drug is non-with graphene oxide (GO) for pharmaceutical carrier Covalent bond is adsorbed in the surfaces GO, does not change its original physical chemistry and biological property, and the huge specific surface areas of GO can be carried significantly The carrying drug ratio of high drug.
3, of the invention, utilization independently fills technology layer by layer, and positively charged PIL and negatively charged is wrapped up respectively on the surfaces GO PAA finally obtains PAA-PIL/GO-X.Drug can be protected to be degraded and destroy in the digestive tract, stability is good.It can prolong The rate of release of slow drug, sustained release improve the bioavilability of drug.
4, the double wrapped of the present invention, release characteristics of the drug with PH sensitivities, PAA and PIL make drug stablize under one's belt, It is discharged in enteron aisle, the acid-fast ability of drug is made to be improved, be conducive to the absorption of drug, improve the targeting of drug, To enhance its bioavilability.
Therefore, the graphene oxide medicine-carried system modified in such a way that PIL and PAA are wrapped up layer by layer has good water solubility, Stability is strong, there is the release characteristics of PH sensitivities.Drug can be made to stablize under one's belt, be discharged in enteron aisle, increase the absorption of drug Effect improves bioavilability, to enhance its antitumor curative effect.
Description of the drawings
Fig. 1 is DOX ultraviolet scanning atlases in embodiment 1.
Fig. 2 is DOX standard curves in embodiment 1.
Fig. 3 is the grain size distribution of PAA-PIL/GO-DOX in embodiment 1.
Fig. 4 is the zeta potential diagrams of PAA-PIL/GO-DOX in embodiment 1.
Fig. 5 is the transmission electron microscope picture of PAA-PIL/GO-DOX in embodiment 1.
Fig. 6 is the vitro Drug cumulative release curve of PAA-PIL/GO-DOX and GO-DOX in embodiment 2.
Specific implementation mode
The present invention is expanded on further below by specific embodiment, it is to be noted that protection scope of the present invention It should not be by any restrictions of these embodiments.
A kind of graphene oxide of 1 modification of embodiment carries medicine delivery system PAA-PIL/GO-DOX
(1) graphene oxide compound GO-DOX is prepared
1, method is as follows：
1) the graphene oxide GO of 50mg is weighed in beaker, 100mL pure water is added, and keeps it fully molten by ultrasound Solution.
2) 10mg DOX are weighed and are added in the beaker for filling 10mL distilled water and are dissolved.
3) under conditions of magnetic agitation, the aqueous solution of DOX is slowly dropped in the aqueous solution of GO, by ultrasound by medicine Object loads on graphene oxide GO.
4) supercentrifuge high speed centrifugation 20min at 10000rpm is used, free DOX is removed.Repeatedly with pure washing After washing precipitation, centrifuge again.Lower sediment thing is collected, sediment adds water to redissolve, obtains GO-DOX.
2, the calculating of encapsulation rate
The encapsulation rate of GO-DOX medicine-carried systems measures medicament contg using ultraviolet spectroscopy.
1) determination of DOX Detection wavelengths
It weighs DOX reference substances in right amount and is dissolved in distilled water, ultraviolet specrophotometer pair is used in the sections 300nm-800nm It carries out full wavelength scanner, and record ultra-violet absorption spectrum is as shown in Figure 1.By ultraviolet spectrogram it is found that DOX has most in 480nm It is big to absorb, it is contemplated that blank material selects Detection wavelengths of the wavelength 480nm as DOX here without absorption.
2) foundation of DOX standard curves
Precision weighs DOX reference substances 25mg in right amount in 500mL volumetric flasks, and the PBS buffer solution that pH7.4 is added is settled to quarter Line is spent, the mother liquor of a concentration of 50 μ g/mL is prepared into.With the gradual diluted concentrations of PBS it is respectively 5 μ g/mL, 10 μ g/ by above-mentioned mother liquor ML, 15 μ g/mL, 20 μ g/mL, 25 μ g/mL, the series standard solution of 50 μ g/mL are measured using PBS as blank control at 480nm Light absorption value.The regression equation of DOX standard curves is：(x is concentration to y=0.0159x+0.0191, and y is absorbance, correlation coefficient r =0.9996), standard curve is shown in Fig. 2.Within the scope of 5-50 μ g/mL, DOX concentration has good linear relationship with absorbance.
3) entrapment efficiency determination：It takes the supernatant of known volume to be placed in 25mL volumetric flasks, adds water to graduation mark, and take 1mL It is placed in be determined in the EP pipes of 10mL.It is measured under ultraviolet chromatographic condition 1), records data, and substitute into 2) standard curve The drug concentration of formula, calculated supernatant is C1, total dose is then C0.Encapsulation rate is calculated according to following formula.
Encapsulation rate (EE)=(C0-C1)/C0× 100%
3, the formulation and technology of GO-DOX is investigated
Using encapsulation rate as inspection target, the preparation process of GO-DOX is optimized into screening.Pass through single factor exploration (ultrasound Time and medicine matter ratio) come determine carry medicine experiment best prescription technique.
1) influence of the ultrasonic time to encapsulation rate
If table 1 changes the ultrasonic time of step 3) in preparation method, and 4 batches are done respectively.In the ultrasonic link of experiment, lead to It crosses and selects different ultrasonic times, respectively (5min, 15min, 30min and 60min).After ultrasound by each solution with 10000rpm centrifuges 20min, takes supernatant and measures its medicament contg to calculate experiment encapsulation rate.Its encapsulation rate result such as table 1.
Influence of 1 ultrasonic time of table to entrapment efficiency
As shown in Table 1, ultrasonic time has significant impact to reach when ultrasonic time is 30min for carrying the encapsulation rate of medicine Maximum encapsulation rate, therefore it is 30min to select ultrasonic time.
2) influence of the drug/vehicle ratio to encapsulation rate
If table 2 changes the mass ratio of DOX and GO, and 4 batches are done respectively.It is different by selecting in the link that feeds intake of experiment Drug/vehicle ratio be respectively (1:2,1:1,1:0.5,1:0.2).Ultrasonic 30min centrifuges each solution with 10000rpm 20min takes supernatant and measures its medicament contg, and computational envelope rate.Its encapsulation rate result such as table 2.
2 medicine matter of table compares the influence of the encapsulation rate and drugloading rate of drug
As can be seen from Table 2, in mass ratio, drug:Carrier=1:When 0.5, encapsulation rate 87.58% reaches good load medicine Effect, therefore it is 1 to select the mass ratio of drug and carrier:0.5 is best prescription technique.
(2) PIL/GO-DOX is prepared
Preparation method includes the following steps：After GO-DOX plus water are redissolved, it is molten that it is added drop-wise to 45 DEG C of PIL under slow stirring In liquid, after mixing, ultrasonic reaction attracts each other PIL and GO combination by charge.It centrifuges, wash after reaction, is dry It is dry, obtain PIL/GO-DOX.
Differential responses condition is investigated to preparing the influence of PIL/GO-DOX, screens optimal formulation and technology.
1, the influence of PIL and GO mass ratioes
It is as a filter, under volume same case, GO-DOX solution concentrations 1mg/ml, PIL (poly- 1- vinyl -3- ethyls Imidazoles bromide solution) concentration is respectively 1mg/ml, 5mg/ml, 16mg/ml.Compare different PIL with GO mass ratioes to composite wood The influence of material, such as table 3.
Influence of 3 mass ratio of table to PIL/GO-DOX
By table 3 as it can be seen that most preferred, PIL and GO mass ratioes are PIL:GO(m:M)=16:1.
2, influence of polymeric ionic liquid (PIL) type to PIL/GO-DOX
(1) 100ml GO-DOX solution (1mg/ml) is taken, under 100rpm stirrings, is added drop-wise to 45 DEG C of the poly- 1- second of 100ml In alkenyl -3- ethyl imidazol(e) bromide solution (16mg/ml), shading, ultrasonic reaction 20min and 100rpm are stirred to react 3h；Reaction After the completion, repeated centrifugation, dry the acquisition PIL/GO-DOX after 10000 centrifugation 5min, pure water.
(2) 100ml GO-DOX solution (1mg/ml) is taken, under 100rpm stirrings, is added drop-wise to 45 DEG C of the poly- 1- alkene of 100ml In propyl -3- ethyl imidazol(e) bromide solution (16mg/ml), shading, ultrasonic reaction 20min and 100rpm are stirred to react 3h；Reaction After the completion, repeated centrifugation, dry the acquisition PIL/GO-DOX after 10000 centrifugation 5min, pure water.
(3) 100ml GO-DOX solution (1mg/ml) is taken, under 100rpm stirrings, is added drop-wise to 45 DEG C of the poly- 1- second of 100ml In alkenyl -3- butyl imidazoles bromide (16mg/ml), shading, ultrasonic reaction 20min and 100rpm are stirred to react 3h；Reaction is completed Afterwards, repeated centrifugation, dry the acquisition PIL/GO-DOX after 10000 centrifugation 5min, pure water.
(4) 100ml GO-DOX solution (1mg/ml) is taken, under 100rpm stirrings, is added drop-wise to 45 DEG C of the poly- 1- second of 100ml In alkenyl -3- ethyl imidazol(e)s villaumite (16mg/ml), shading, ultrasonic reaction 20min and 100rpm are stirred to react 3h；Reaction is completed Afterwards, repeated centrifugation, dry the acquisition PIL/GO-DOX after 10000 centrifugation 5min, pure water.
The influence of 4 different ionic liquid of table
By table 4 as it can be seen that in Integrated comparative (1)~(4) PIL/GO-DOX character, most preferably (1) poly- 1- ethylene PIL/GO-DOX prepared by base -3- ethyl imidazol(e) bromide solution.
(3) PAA-PIL/GO-DOX is prepared
1, preparation method includes the following steps：
1) the graphene oxide GO of 5mg is weighed in beaker, and 100mL pure water is added, so that it is fully dissolved by ultrasound.
2) 10mg DOX are weighed and are added in the beaker for filling 10mL distilled water and are dissolved.
3) under conditions of magnetic agitation, the aqueous solution of DOX is slowly dropped in the aqueous solution of GO, ultrasonic 30min, it will On drug loading to graphene oxide GO.
4) supercentrifuge high speed centrifugation 20min at 10000rpm is used, free DOX is removed.Repeatedly with pure washing After washing precipitation, centrifuge again.Lower sediment thing is collected, adds water to redissolve, obtains GO-DOX.
5) 100ml GO-DOX solution (1mg/ml) is taken, under 100rpm stirrings, is slowly dropped to the poly- of 45 DEG C of 100ml In 1- vinyl -3- butyl imidazoles bromides (16mg/ml), shading, ultrasonic reaction 20min and 100rpm are stirred to react 3h, obtain PIL/GO-DOX solution.
6) under stiring, 100ml PAA solution (16mg/ml) is added drop-wise in PIL/GO-X solution, is heated at 60 DEG C It is stirred to react 1h, reacts at room temperature 12h later, the graphene oxide carrying medicine PAA-PIL/GO-DOX modified.
2, the investigation of PAA-PIL/GO-DOX
1) grain size and Zeta potential
PAA-PIL-GO/DOX is dissolved in distilled water, mixing is shaken.Measure grain size and Zeta potential and PDI values. As a result shown in following Fig. 3, Fig. 4.As seen from the figure, the grain size of PAA-PIL/GO-DOX is in 750nm or so, and PDI values are about 0.23, Less than 0.3, uniform particle sizes, distribution is well.Zeta potential is -34.1mV, illustrates that surface carries negative electrical charge energy side illustration preparation Outer layer is that PAA shows elecrtonegativity.And its absolute value is more than 20mV, since with larger electrostatic repulsion, drug particle is not easy to gather It is heavy, therefore have good stability.
2) transmission electron microscope is tested
Sample preparation：About 1mL PAA-PIL/GO-DOX solution is taken, is diluted 20 times, 100 μ L is drawn with pipette tips, drips to 200 On purpose copper mesh；And the phosphotungstic acid of configuration 2%, pH to 6.4-7.0 is adjusted with sodium hydroxide, then draws 100 μ L phosphotungstic acids, is delayed Slow drips on copper mesh, airing, measures.The results are shown in Figure 5.It can be seen from the figure that GO-DOX exists with black flaky, outside The black lamella of layer wrappage is PAA and PIL lamellas, and grain size about in 750nm or so, does not occur clustering phenomena.
The release in vitro research of 2 PAA-PIL/GO-DOX of embodiment
(1) prepared by PAA-PIL/GO-DOX
1) the graphene oxide GO of 5mg is weighed in beaker, and 100mL pure water is added, so that it is fully dissolved by ultrasound.
2) 10mg DOX are weighed and are added in the beaker for filling 10mL distilled water and are dissolved.
3) under conditions of magnetic agitation, the aqueous solution of DOX is slowly dropped in the aqueous solution of GO, ultrasonic 30min, it will Drug DOX is loaded on graphene oxide GO.
4) supercentrifuge high speed centrifugation 20min at 10000rpm is used, free DOX is removed.Repeatedly with pure washing After washing precipitation, centrifuge again.Lower sediment thing is collected, adds water to redissolve, obtains GO-DOX.
5) 100ml GO-DOX solution (1mg/ml) is taken, under 100rpm stirrings, is slowly dropped to the poly- of 45 DEG C of 100ml In 1- vinyl -3- butyl imidazoles bromides (16mg/ml), shading, ultrasonic reaction 20min and 100rpm are stirred to react 3h, obtain PIL/GO-DOX solution.
6) under stiring, 100ml PAA solution (16mg/ml) is added drop-wise in PIL/GO-X solution, is heated at 60 DEG C It is stirred to react 1h, reacts at room temperature 12h later, the graphene oxide carrying medicine PAA-PIL/GO-DOX modified.
2, extracorporeal releasing test method includes the following steps：The case where release in vitro of GO-DOX is probed into using dialysis. Using DOX concentration in determined by ultraviolet spectrophotometry dissolution medium.1mL is taken to prepare GO-DOX and PAA-PIL/GO- respectively The DOX, (MWCO in bag filter:8000Da is put into (pH2.3, pH7.4) under condition of different pH fills 10mL (0.1% respectively (w/v) PBS buffer solution of SDS is as dialysis medium) beaker in, rotating speed is set as 100r/min, respectively in 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, for 24 hours, 48h sample 1mL, while supplementing same fresh dissolution medium 1mL.0.45 μm of filter is used in combination It is filtered, is measured according to the chromatographic condition sample introduction in embodiment 1, measure the content of DOX, and calculate the tired of corresponding time point Product burst size.M- cumulative release amount curve such as Fig. 6 when making.By release profiles it is found that by the cumulative release amount of condition of different pH As a comparison, wherein burst size is higher than neutrallty condition to drug in acid condition, shows certain pH sensibility.Its reason May be mainly：DOX has hydroxyl, the functional groups such as amino, and GO has hydroxyl, carboxyl, in acid condition, makes drug and GO shapes At hydrogen bond fracture, so release amount of medicine be more than other environment.PH7.4 neutrallty conditions, hydroxyl, amino on DOX can be with GO Upper hydroxyl, carboxyl form hydrogen bond, in conjunction with stabilization.And after DOX is wrapped upper polyelectrolyte in PAA-PIL/GO-DOX so that its It is suitable with the Cumulative release amount of pH 7.4 under conditions of pH 2.3.Release situation of change under condition of different pH is consistent, explanation Under double-deck package, the DOX in preparation group has obtained good protection.Under acid environment, double wrapped obviously makes medicine The acid resistance of object is improved, to improve the oral administration biaavailability of drug.

Claims (10)

1. a kind of graphene oxide of modification carries medicine delivery system, which is characterized in that the graphene oxide of the modification carries medicine and passs System is sent, be with graphene oxide is that carrier loaded drug X obtains graphene oxide compound GO-X, it is compound in graphene oxide The surface layer of object GO-X wraps up made from positively charged polymeric ionic liquid PIL and negatively charged polyacrylic acid PAA PAA-PIL/GO-X。
2. a kind of graphene oxide of modification according to claim 1 carries medicine delivery system, which is characterized in that the medicine Object X includes adriamycin (DOX) or taxol (PTX) or rcumenol (CUR).
3. a kind of graphene oxide of modification according to claim 1 carries medicine delivery system, which is characterized in that described is poly- It is poly- 1- vinyl -3- ethyl imidazol(e)s bromide, poly- 1- allyls -3- ethyl imidazol(e)s bromide, poly- 1- ethylene to close ionic liquid PIL Base -3- butyl imidazoles bromide or poly- 1- vinyl -3- ethyl imidazol(e) villaumites.
4. a kind of graphene oxide of modification as claimed in claim 1,2 or 3 carries the preparation method of medicine delivery system, feature exists In including the following steps：
1) under stirring, drug X is dissolved in solvent, and is slowly dropped in the aqueous solution of graphene oxide GO, it will by ultrasound Drug X is loaded on graphene oxide GO；Centrifugation, sediment are washed with solvent, are lyophilized, are obtained graphene oxide compound GO-X；
2) it after redissolving GO-X, is added drop-wise under slow stirring in 45 DEG C of polymeric ionic liquid PIL solution, after mixing, It is stirred to react, obtains PIL/GO-X；
3) under stirring, polyacrylic acid PAA solution is added drop-wise in PIL/GO-X solution, at 45-70 DEG C, heating stirring reaction 1h reacts at room temperature 12h later, obtains PAA-PIL/GO-X.
5. preparation method according to claim 4, which is characterized in that in step 1), in mass ratio, drug X:GO=1: 0.2~1:5；The solvent is water, methanol, ethyl alcohol or DMSO.
6. preparation method according to claim 4, which is characterized in that in step 1), ultrasonic time 5-60min.
7. preparation method according to claim 4, which is characterized in that in mass ratio, GO:PIL=1:1~1:20.
8. preparation method according to claim 4, which is characterized in that in mass ratio, GO:PAA=1:1~1:20.
9. preparation method according to claim 4, which is characterized in that in step 2), it is described be stirred to react for：Shading, 100rpm stirs 0.1~5h.
10. a kind of graphene oxide of modification described in claim 1 carries medicine delivery system PAA-PIL/GO-X and is preparing anti-swell Application in tumor medicine.
CN201810412533.9A 2018-05-03 2018-05-03 Modified graphene oxide drug-loaded delivery system and preparation method and application thereof Active CN108524940B (en)

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