CN109091676A - A kind of preparation method of pharmaceutical carrier of the modified with folic acid fluorinated graphene with target function - Google Patents
A kind of preparation method of pharmaceutical carrier of the modified with folic acid fluorinated graphene with target function Download PDFInfo
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- CN109091676A CN109091676A CN201810969441.0A CN201810969441A CN109091676A CN 109091676 A CN109091676 A CN 109091676A CN 201810969441 A CN201810969441 A CN 201810969441A CN 109091676 A CN109091676 A CN 109091676A
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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
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
Abstract
The present invention relates to field of medicaments, disclose a kind of preparation method of pharmaceutical carrier of the modified with folic acid fluorinated graphene with target function.Graphene oxide is prepared by raw material of crystalline flake graphite first in the present invention, then partially fluorinated graphene is prepared for by fluorization agent of diethylaminosulfurtrifluoride by solwution method, a large amount of oxygen containing hydrophilic functional groups that its surface is possessed, this facilitates it and is loaded and improved biocompatibility to drug by hydrogen bond.The partially fluorinated graphene aqueous solution of nano-scale is then obtained by ultrasonication.It is modified using folic acid afterwards, obtains the pharmaceutical carrier that modified with folic acid fluorinated graphene has target function.The nanoparticle of this method preparation will be expected to become a kind of up-and-coming pharmaceutical carrier, this method will not make a significant impact cell in the experimentation in later period simultaneously, the science of experimental result is not influenced, and experiment flow is simple and convenient to operate, does not need harsh reaction condition and special reaction unit.
Description
Technical field
The present invention relates to the drug loads that field of medicaments more particularly to a kind of modified with folic acid fluorinated graphene have target function
The preparation method of body.
Background technique
Fluorinated graphene just spreads out as the novel of graphene after 2010 are successfully prepared for the first time by Geim seminar
Biology, by people's extensive concern, it is similar with its, still has good mechanical property, while fluorine original is introduced on the basis of it
Son, to obtain many uniquenesses and excellent performance.It possesses outstanding electronics, optically and mechanically performance, while also
The effect of interface energy is reduced, and thermal stability and inoxidizability well.This allows the main research hotspot of fluorinated graphene
In fields such as optics, electronics and theoretical calculations.
Fluorinated graphene not only inherits the excellent properties of grapheme material, but also has not available for other carbon materials
Significant advantage (such as: stable paramagnetism, stable luminescence generated by light, fluorine medically special effect), has as novel swollen
The potential value of the carrier of tumor medicine.But poor biocompatibility caused by hydrophobicity, harsh preparation condition and cumbersome conjunction
Fluorinated graphene is seriously limited in the application of biological field at factors such as steps.So how probing by fluorinated graphene application
It is very significant in biological field.
Summary of the invention
In order to solve the above-mentioned technical problems, the present invention provides a kind of modified with folic acid fluorinated graphenes to have target function
The preparation method of pharmaceutical carrier.The present invention is first using crystalline flake graphite as raw material, by improving hummers method and a series of rear places
Graphene oxide is prepared in reason, then by solwution method using diethylaminosulfurtrifluoride as fluorization agent, by graphene oxide portion
Point oxygen-containing group is converted into fluoro-containing group, is prepared for hydrophilic partially fluorinated graphene, and can be stable be dispersed in water
In.A large amount of oxygen containing hydrophilic functional groups that oxidation fluorinated graphene sheet surfaces are possessed, this helps to make it through hydrogen bond pair
Drug is loaded and is improved biocompatibility.Then in deionized water by obtained partially fluorinated graphene dispersion, pass through
Ultrasonic treatment obtains the partially fluorinated graphene aqueous solution of evenly dispersed nano-scale.Be added in backward solution sodium hydroxide and
- OH is converted-COOH by sodium hypochlorite, obtains partially fluorinated graphene-COOH.Pass it through again after certain processing with folic acid
Reaction, while 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride and the p- COOH of n-hydroxysuccinimide is added
It is activated, reacts to obtain a kind of pharmaceutical carrier of the modified with folic acid fluorinated graphene with target function by acyl ammonia.This method
The nanoparticle of preparation will be expected to become a kind of up-and-coming pharmaceutical carrier, while this method will not be in the experimentation in later period
In cell is made a significant impact, do not influence the science of experimental result, experiment flow is simple and convenient to operate, does not need harshness
Reaction condition and special reaction unit.
The specific technical proposal of the invention is: a kind of modified with folic acid fluorinated graphene has the pharmaceutical carrier of target function
Preparation method, in terms of g and mL, comprising the following steps:
1) container is cooled to 0 DEG C in ice-water bath, the 20-25 mL concentrated sulfuric acid is added；Then 0.5-2 g crystalline graphite powder is added
With 0.2-1 g sodium nitrate；It is ultrasonically treated 20-30 min.
The present invention is cheap using crystalline flake graphite as raw material.
2) it is stirred to react, keeps reaction temperature to be lower than 10 DEG C, 2-4 g potassium permanganate is then weighed, in 25-30 min
It is slowly added in batches；Elementary reaction 1.5-2.5 h.
The present invention increases potassium manganate in batches can make reaction more mild, convenient for control temperature of reaction system, prevent anti-
Should be excessively fierce, generate unnecessary impurity.Simultaneously graphite-sulfuric acid single order can be generated under its oxidation by sulfuric acid intercalation
Intercalation object.
3) it is warming up to 35-40 DEG C, reacts 25-30 min；
4) 70-120 mL deionized water is measured, is slowly added to after ice-water bath is cooled to 0 DEG C；Then temperature adjustment is to 90-95
DEG C, continue to be stirred to react 25-30 min.
The present invention is by graphite oxide obtained in step 3), by being reacted with water, while water enter interlayer substitution it is therein
Acid obtains graphene oxide to removing.
5) 50-70 mL distilled water stopped reaction is added, adds the H that 20-30 mL volume fraction is 25-35%2O2, continue
It is stirred to react 15-20 min；
6) HCl solution that 30-50 mL volume fraction is 8-12% is added, stands 4-5 days.
Product is stood 4-5 days in step 6) by the present invention, is that the separation of the impurity such as the acid in lower sediment penetrates into supernatant
In liquid, to reduce centrifugation time.
7) supernatant of solution, Zai Qu lower layer viscous fluid centrifugal treating are first removed with dropper, until viscous fluid is in neutrality, it will
Viscous fluid in centrifuge tube pours into evaporating dish, is freeze-dried 24-48 h, obtains graphene oxide sheet；
8) graphene oxide sheet is ground into graphene oxide powder；
9) 0.5-1.5 g graphene oxide powder and 20-40 mL methylene chloride or 1,2- dichloroethanes, stirring is added in another extracting container
10-14 h keeps its evenly dispersed.
For the present invention with methylene chloride or 1 in step 9), 2- dichloroethanes is solvent, enables graphene oxide powder at it
In it is evenly dispersed.
10) 0.5-1 mL fluorization agent diethylaminosulfurtrifluoride is added dropwise, is then ultrasonically treated 4-6 h, stirring at room temperature
React 24-72 h.
The present invention, using diethylaminosulfurtrifluoride as fluorization agent, has very strong fluorination in step 10), can be normal
The oxygen-containing functional group in graphene oxide is partially converted into fluorine-containing functional group under normal temperature and pressure.It is prepared for hydrophilic partially fluorinated
Graphene, and can be stable be dispersed in water.Oxidation fluorinated graphene sheet surfaces are possessed a large amount of oxygen containing hydrophilic
Functional group, this, which helps to make it through hydrogen bond, is loaded to drug and is improved biocompatibility.
11) after the termination reaction of 15-30 mL methanol is added, partially fluorinated graphite ene product is obtained by filtration, and with ethyl alcohol and go
Ionized water sufficiently washs, dry at 50-70 DEG C；
12) the partially fluorinated graphene dispersion of 25-30 mg is weighed in 45-60 mL deionized water, is ultrasonically treated, is obtained part fluorine
Graphite alkene solution.
The present invention obtains the portion of nano-scale evenly dispersed in water in step 12) using ultrasonic cell disruptor
Divide fluorinated graphene solution, is brought conveniently for the modification of folic acid below.
13) take 1-1.5 g sodium hydroxide and 1.2-1.5 g sodium hypochlorite that partially fluorinated graphene solution, ultrasonic 3-4 is added
h。
Sodium hydroxide and sodium hypochlorite is added in the present invention in step 13), and-the OH in partially fluorinated graphene is converted
For-COOH, partially fluorinated graphene-COOH is obtained.
14) it is centrifuged and removes supernatant, add deionized water and obtain uniform dispersion, be added during dilute hydrochloric acid to pH is
Property, it is placed in dialysis 48-72 h in deionized water；
15) 0.1-0.12 g folic acid is added, 25-30 mg 1- (3- dimethylamino third is added in ultrasonic 0.5-1 min while stirring
Base) -3- ethyl-carbodiimide hydrochloride and 25-30 mg n-hydroxysuccinimide, ultrasonic 2-2.5 h.
The present invention is sub- by the way that 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride and N- hydroxysuccinimidyl acyl is added
Amine activates the-COOH in partially fluorinated graphene-COOH, reacts to carry out amide with the amino in folic acid.Together
When in conjunction with folic acid after have target function.
16) using the sodium bicarbonate solution of pH=8 to acquired solution dialysis treatment in step 15), every 3-4 h changes a water,
It is transferred them to after 48-60 h in deionized water and continues the 24-36 h that dialyses；
17) using the moisture in rotary evaporation removal solution, it is placed in drying at 35-45 DEG C, obtains modified with folic acid fluorographite
Alkene has the pharmaceutical carrier of target function.
Preferably, stirring rate is 400-800 rpm in step 2,20-40 min is stirred.
Preferably, during standing, every 1-2 d removes supernatant in step 6), aliquots of deionized water is added.
Preferably, in step 7), centrifugal process specifically: supercentrifuge is used, respectively in 4000 rpm, 6000
Respectively be centrifuged 10 min under rpm, 8000 rpm, 10000 rpm, 12000 rpm, every time centrifugation after remove centrifuge tube in supernatant simultaneously
Aliquots of deionized water is added.
Preferably, each reaction that step 9), step 10), step 11) carry out carries out at room temperature.
Preferably, in step 12), ultrasonic treatment specifically: utilize ultrasound under 630 W power of ultrasonic cell disruptor
Wave processing 2.5-3 h obtains the partially fluorinated graphene solution of evenly dispersed nano-scale.
Preferably, in step 13), ultrasound specifically: using ultrasonic cleaning instrument, the ultrasound 3-4 under 550-600 W power
h。
Preferably, in step 14), dialysis specifically: be fitted into dispersion liquid in the bag filter that specification is 8000-14000D
It is placed in dialysis 48-72 h in deionized water.
Preferably, in step 16, dialysis specifically: it is 8000- that acquired solution in step 15), which is packed into specification,
Dialysis treatment in the sodium bicarbonate solution of pH=8 is placed in the bag filter of 14000D, every 3-4 h changes a water, will after 48-60 h
It, which is transferred in deionized water, continues the 24-36 h that dialyses.
Preferably, the revolving speed of rotary evaporation is 2.5 rpm/s in step 17, temperature is 40 DEG C.
It is compared with the prior art, the beneficial effects of the present invention are: the present invention passes through improvement first using crystalline flake graphite as raw material
Graphene oxide is prepared in hummers method and a series of post-processings, then passes through fluorization agent diethylaminosulfurtrifluoride
Fluorination converts fluoro-containing group for graphene oxide part oxygen-containing group, is prepared for hydrophilic partially fluorinated graphene,
And can be stable be dispersed in water.Fluorinated graphene preparation process is simple and convenient to operate, does not need harsh reaction simultaneously
Condition and special reaction unit.A large amount of oxygen containing hydrophilic functional groups that partially fluorinated graphene film layer surface is possessed, this has
Help to make it through hydrogen bond and biocompatibility is loaded and improved to drug.The partially fluorinated graphene dispersion that will then obtain
In deionized water, the partially fluorinated graphene by the evenly dispersed nano-scale of ultrasonic cell disruptor ultrasonic wave is water-soluble
Liquid.Sodium hydroxide and sodium hypochlorite is added in backward solution, converts-COOH for-OH, obtains partially fluorinated graphene-COOH.
It is reacted after passing it through certain processing again with folic acid, while 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide hydrochloride is added
Salt and the p- COOH of n-hydroxysuccinimide are activated, and react to obtain a kind of modified with folic acid fluorinated graphene tool by acyl ammonia
There is the pharmaceutical carrier of target function.The nanoparticle of this method preparation will be expected to become a kind of up-and-coming pharmaceutical carrier, together
When this method cell will not be made a significant impact in the experimentation in later period, do not influence the science of experimental result, test
Process is simple and convenient to operate, does not need harsh reaction condition and special reaction unit.
Detailed description of the invention
Fig. 1 is the infrared spectrum comparison diagram of product and commercially available graphene oxide made from embodiment 1-3.
Specific embodiment
The present invention will be further described with reference to the examples below.
Embodiment 1:
1) beaker is cooled to 0 DEG C in ice-water bath, magneton is added, 250 mL is added to the concentrated sulfuric acid that graduated cylinder measures 20 mL and burns
In cup；Then it weighs 0.5 crystalline graphite powder and beaker is added in 0.2 sodium nitrate；Then ultrasound is carried out, 20 min are continued；
2) beaker in step 1) is placed in magnetic agitation water-bath and stirs 20 min under the revolving speed of 400 rpm, keep reaction
Temperature is lower than 10 DEG C, then weighs 2g potassium permanganate on an electronic balance, is slowly added in batches in 25min；The stage is anti-
Answer 1.5 h；
3) water bath temperature in step 2 is risen to 35 DEG C, reacts 25 min；
4) 70mL deionized water is measured slowly to be added in step 3) in beaker after ice-water bath is cooled to 0 DEG C；Then it adjusts
Step 3) water bath temperature is to after 90 DEG C or so, the reaction was continued under stirring auxiliary 25 min；
5) into step 4) beaker be added 50mL distilled water stopped reaction, add 25 mL volume fractions be 30% H2O2,
Continue to be stirred to react 15 min；
6) HCl solution that 40 mL volume fractions are 10% is measured with graduated cylinder, is then added into beaker in step 5).Product is existed
4-5 d is stood in beaker, every 1-2 d removes supernatant, and aliquots of deionized water is added；
7) supernatant in step 6) in beaker first is removed with dropper, Zai Qu lower layer viscous fluid uses supercentrifuge, exists respectively
10 min are centrifuged under 4000 rpm, 6000 rpm, 8000 rpm, 10000 rpm, 12000 rpm, remove centrifugation after centrifugation every time
Supernatant and aliquots of deionized water is added in pipe, until graphene oxide viscous fluid is in neutrality, the viscous fluid in centrifuge tube is poured into
In evaporating dish, 24 h of freeze-drying obtain graphene oxide sheet；
8) by graphene oxide sheet grind into powder in step 7)；
9) methylene chloride or 1 of graphene oxide and 20 mL in 0.5 g step 8), bis- chloroethene of 2- are added into 100 mL flasks
Alkane, and it is put into magneton；Stirring 10 h keeps its evenly dispersed；
10) into step 9) flask be added dropwise 0.5 mL fluorization agent diethylaminosulfurtrifluoride, be then ultrasonically treated 4 at room temperature
H is stirred to react 24 h；
11) after the termination reaction of 15 mL methanol is added in flask into step 10), partially fluorinated graphite ene product is obtained by filtration, is used in combination
Ethyl alcohol and deionized water are sufficiently washed, and are put into drying over night in 60 DEG C of baking ovens；
12) the partially fluorinated graphene dispersion in 25 mg step 11) is weighed in 45 mL deionized waters, it is thin using ultrasonic wave
2.5 h of ultrasonication obtains the partially fluorinated graphene solution of evenly dispersed nano-scale under 630 W power of born of the same parents' pulverizer；
13) sodium hypochlorite of the sodium hydroxide and 1.2 g that take 1 g is added to filling fluorinated graphene solution in part in step 12),
Using ultrasonic cleaning instrument, 3 h of ultrasound under 550 W power；
14) be centrifuged and removed supernatant to solution after ultrasound in step 13), add deionized water obtain it is evenly dispersed
Liquid, it is neutrality that dilute hydrochloric acid, which is added, to pH, and dispersion liquid is fitted into the bag filter that specification is 8000-14000D and is placed in deionized water
Dialyse 48 h；
15) be added 0.1 g folic acid in the solution after dialysing in step 14), 0.5 min of ultrasound, after while stirring to mixture
Middle addition 25 mg 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride and 2 mg:N- HOSu NHSs surpass
After 2 h of sound；
16) by acquired solution in step 15) be fitted into specification be 8000-14000D bag filter in be placed in sodium bicarbonate solution (pH=
8) dialysis treatment is carried out, every 3 h changes a water, transfers them in deionized water after 48 h and continues 24 h that dialyse；
17) Rotary Evaporators are used, the moisture in solution is removed under 40 DEG C, 2.5 rpm/s revolving speeds, is placed on 40 DEG C of baking ovens
Middle drying obtains the pharmaceutical carrier that modified with folic acid fluorinated graphene has target function.
Embodiment 2:
1) beaker is cooled to 0 DEG C in ice-water bath, magneton is added, 250 mL is added to the concentrated sulfuric acid that graduated cylinder measures 23 mL and burns
In cup；Then it weighs 0.1 g crystalline graphite powder and beaker is added in 0.5 g sodium nitrate；Then ultrasound is carried out, 5min is continued；
2) beaker in step 1) is placed in magnetic agitation water-bath, 30 min is stirred under the revolving speed of 600 rpm, keep reaction
Temperature is lower than 10 DEG C, then weighs 3 g potassium permanganate on an electronic balance, is slowly added in batches in 28 min；The stage
React 2 h；
3) water bath temperature in step 2 is risen to 38 DEG C, reacts 30 min；
4) 100 mL deionized waters are measured slowly to be added in step 3) in beaker after ice-water bath is cooled to 0 DEG C；Then it adjusts
Step 3) water bath temperature is saved to after 93 DEG C or so, the reaction was continued under stirring auxiliary 27 min；
5) into step 4) beaker be added 60 mL distilled water stopped reaction, add 25 mL volume fractions be 30% H2O2,
Continue to be stirred to react 18 min；
6) HCl solution that 40 mL volume fractions are 10% is measured with graduated cylinder, is then added into beaker in step 5).Product is existed
4.5 d are stood in beaker, every 1.5 d removes supernatant, and aliquots of deionized water is added；
7) supernatant in step 6) in beaker first is removed with dropper, Zai Qu lower layer viscous fluid uses supercentrifuge, exists respectively
10 min are centrifuged under 4000 rpm, 6000 rpm, 8000 rpm, 10000 rpm, 12000 rpm, remove centrifugation after centrifugation every time
Supernatant and aliquots of deionized water is added in pipe, until graphene oxide viscous fluid is in neutrality, the viscous fluid in centrifuge tube is poured into
In evaporating dish, freeze-drying 24-48 h obtains graphene oxide sheet；
8) by graphene oxide sheet grind into powder in step 7)；
9) it is added the methylene chloride or 1 of graphene oxide and 30 mL in 1 g step 8) into 100 mL flasks, 2- dichloroethanes,
And it is put into magneton；Stirring 12 h keeps its evenly dispersed；
10) into step 9) flask be added dropwise 0.8 mL fluorization agent diethylaminosulfurtrifluoride, be then ultrasonically treated 5 at room temperature
H is stirred to react 36 h；
11) after the termination reaction of 25 mL methanol is added in flask into step 10), partially fluorinated graphite ene product is obtained by filtration, is used in combination
Ethyl alcohol and deionized water are sufficiently washed, and are put into drying over night in 60 DEG C of baking ovens；
12) the partially fluorinated graphene dispersion in 28 mg step 11) is weighed in 50 mL deionized waters, it is thin using ultrasonic wave
2.5 h of ultrasonication obtains the partially fluorinated graphene solution of evenly dispersed nano-scale under 630 W power of born of the same parents' pulverizer；
13) sodium hypochlorite of the sodium hydroxide and 1.3 g that take 1.2 g is added molten to part fluorinated graphene in step 12) is filled
Liquid, using ultrasonic cleaning instrument, 3.5 h of ultrasound under 570 W power；
14) be centrifuged and removed supernatant to solution after ultrasound in step 13), add deionized water obtain it is evenly dispersed
Liquid, be added dilute hydrochloric acid to pH be neutrality, after by dispersion liquid is fitted into specification for 8000-14000D bag filter in be placed in deionized water
60 h of middle dialysis；
15) be added 0.11 g folic acid in the solution after dialysing in step 14), 0.7 min of ultrasound, after while stirring to mixture
Middle addition 28 mg 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride and 28 mg:N- HOSu NHSs,
After 2 h of ultrasound；
16) by acquired solution in step 15) be fitted into specification be 8000-14000D bag filter in be placed in sodium bicarbonate solution (pH=
8) dialysis treatment is carried out, every 3.5 h changes a water, transfers them in deionized water after 55 h and continues 30 h that dialyse；
17) Rotary Evaporators are used, revolving speed is 2.5 rpm/s, and water bath temperature is 40 DEG C, except the moisture in solution.It is placed on
It is dry in 40 DEG C of baking ovens, obtain the pharmaceutical carrier that modified with folic acid fluorinated graphene has target function.
Embodiment 3:
1) beaker is cooled to 0 DEG C in ice-water bath, magneton is added, 250 mL is added to the concentrated sulfuric acid that graduated cylinder measures 25 mL and burns
In cup；Then 2 g crystalline graphite powders are weighed and beaker is added in 1 g sodium nitrate；Then ultrasound is carried out, 30 min are continued；
2) beaker in step 1) is placed in magnetic agitation water-bath, 40 min is stirred under the revolving speed of 800 rpm, keep reaction
Temperature is lower than 10 DEG C, then weighs 4 g potassium permanganate on an electronic balance, is slowly added in batches in 30 min；The stage
React 2.5 h；
3) water bath temperature in step 2 is risen to 40 DEG C, reacts 30 min；
4) 120 mL deionized waters are measured slowly to be added in step 3) in beaker after ice-water bath is cooled to 0 DEG C；Then it adjusts
Step 3) water bath temperature is saved to after 95 DEG C or so, the reaction was continued under stirring auxiliary 30 min；
5) into step 4) beaker be added 70 mL distilled water stopped reaction, add 30 mL volume fractions be 30% H2O2,
Continue to be stirred to react 20 min；
6) HCl solution that 40 mL volume fractions are 10% is measured with graduated cylinder, is then added into beaker in step 5).Product is existed
5 d are stood in beaker, every 2 d removes supernatant, and aliquots of deionized water is added；
7) supernatant in step 6) in beaker first is removed with dropper, Zai Qu lower layer viscous fluid uses supercentrifuge, exists respectively
10 min are centrifuged under 4000 rpm, 6000 rpm, 8000 rpm, 10000 rpm, 12000 rpm, remove centrifugation after centrifugation every time
Supernatant and aliquots of deionized water is added in pipe, until graphene oxide viscous fluid is in neutrality, the viscous fluid in centrifuge tube is poured into
In evaporating dish, 48 h of freeze-drying obtain graphene oxide sheet；
8) by graphene oxide sheet grind into powder in step 7)；
9) methylene chloride or 1 of graphene oxide and 40 mL in 1.5 g step 8), bis- chloroethene of 2- are added into 100 mL flasks
Alkane, and it is put into magneton；Stirring 14 h keeps its evenly dispersed；
10) into step 9) flask be added dropwise 1 mL fluorization agent diethylaminosulfurtrifluoride, be then ultrasonically treated 6 at room temperature
H is stirred to react 72 h；
11) after the termination reaction of 30 mL methanol is added in flask into step 10), partially fluorinated graphite ene product is obtained by filtration, is used in combination
Ethyl alcohol and deionized water are sufficiently washed, and are put into drying over night in 60 DEG C of baking ovens；
12) the partially fluorinated graphene dispersion in 30 mg step 11) is weighed in 60 mL deionized waters: it is thin using ultrasonic wave
3 h of ultrasonication obtains the partially fluorinated graphene solution of evenly dispersed nano-scale under 630 W power of born of the same parents' pulverizer；
13) sodium hypochlorite of the sodium hydroxide and 1.5 g that take 1.5 g is added molten to part fluorinated graphene in step 12) is filled
Liquid, using ultrasonic cleaning instrument, 4 h of ultrasound under 600 W power；
14) be centrifuged and removed supernatant to solution after ultrasound in step 13), add deionized water obtain it is evenly dispersed
Liquid, be added dilute hydrochloric acid to pH be neutrality, after place it in deionized water 2 h that dialyse；
15) be added 0.12 g folic acid in the solution after dialysing in step 14), 1 min of ultrasound, after while stirring into mixture
30 mg 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride and 30 mg:N- HOSu NHSs are added, surpass
After 2.5 h of sound；
16) by acquired solution in step 15) be fitted into specification be 8000-14000D bag filter in be placed in sodium bicarbonate solution (pH=
8) dialysis treatment is carried out, every 4 h changes a water, transfers them in deionized water after 60 h and continues 36 h that dialyse；
17) Rotary Evaporators are used, revolving speed is 2.5 rpm/s, and water bath temperature is 40 DEG C, removes the moisture in solution, postposition
It is dry in 40 DEG C of baking ovens, obtain the pharmaceutical carrier that modified with folic acid fluorinated graphene has target function.
Infrared detection:
Fluorinated graphene (without modified with folic acid, being denoted as fluorinated graphene 1-3) obtained during embodiment 1-3 is carried out red
The structure of outer detection, fluorinated graphene and graphene oxide pass through ftir analysis result as shown in Figure 1, by
The analysis result, which can see, there are three absorption peaks in raw material graphene oxide, they are respectively with 3430 cm−1And 1730
cm−1With 1630 cm−1Centered on, 3430 cm can be determined by analysis−1The absorption peak at place is the flexible of carboxyl and hydroxyl O-H
Vibration.1730 cm−1The absorption peak at place can be determined that as the stretching vibration of C=O in carboxyl and ketone group.1630 cm−1The suction at place
Receive the stretching vibration that peak is also C=C.This is the result shows that be successful by the conversion of graphene to graphene oxide.
The infrared spectrum of fluorinated graphene and graphene oxide is compared it can be found that they are in 1221 cm−1Occurs one
New absorption peak, it is possible to determine that be the eigen vibration of C-F, while these three samples still have with 3430 cm−1And 1730 cm−1With 1630 cm−1Centered on absorption peak, this illustrates in fluorinated graphene or there are these oxygen-containing groups such as this O-H, C=O
, this also indicates that not all oxygen-containing functional group has been converted to fluorine-containing functional group.
Raw materials used in the present invention, equipment is unless otherwise noted the common raw material, equipment of this field；In the present invention
Method therefor is unless otherwise noted the conventional method of this field.
The above is only presently preferred embodiments of the present invention, is not intended to limit the invention in any way, it is all according to the present invention
Technical spirit any simple modification, change and equivalent transformation to the above embodiments, still fall within the technology of the present invention side
The protection scope of case.
Claims (10)
1. a kind of modified with folic acid fluorinated graphene has the preparation method of the pharmaceutical carrier of target function, in terms of g and mL, feature
Be the following steps are included:
1) container is cooled to 0 DEG C in ice-water bath, the 20-25 mL concentrated sulfuric acid is added；Then 0.5-2 g crystalline graphite powder is added
With 0.2-1 g sodium nitrate；It is ultrasonically treated 20-30 min；
2) it is stirred to react, keeps reaction temperature to be lower than 10 DEG C, then weigh 2-4 g potassium permanganate, in 25-30 min in batches
It is secondary to be slowly added to；Elementary reaction 1.5-2.5 h；
3) it is warming up to 35-40 DEG C, reacts 25-30 min；
4) 70-120 mL deionized water is measured, is slowly added to after ice-water bath is cooled to 0 DEG C；Then temperature adjustment is to 90-95
DEG C, continue to be stirred to react 25-30 min；
5) 50-70 mL distilled water stopped reaction is added, adds the H that 20-30 mL volume fraction is 25-35%2O2, continue to stir
React 15-20 min；
6) HCl solution that 30-50 mL volume fraction is 8-12% is added, stands 4-5 days；
7) supernatant of solution is first removed with dropper, Zai Qu lower layer viscous fluid centrifugal treating will be centrifuged until viscous fluid is in neutrality
Viscous fluid in pipe pours into evaporating dish, is freeze-dried 24-48 h, obtains graphene oxide sheet；
8) graphene oxide sheet is ground into graphene oxide powder；
9) 0.5-1.5 g graphene oxide powder and 20-40 mL methylene chloride or 1,2- dichloroethanes, stirring is added in another extracting container
10-14 h keeps its evenly dispersed；
10) 0.5-1 mL fluorization agent diethylaminosulfurtrifluoride is added dropwise, is then ultrasonically treated 4-6 h at room temperature, is stirred to react
24-72 h；
11) it is added after 15-30 mL methanol terminates reaction, is obtained by filtration partially fluorinated graphite ene product, and with ethyl alcohol and deionization
Water sufficiently washs, dry at 50-70 DEG C；
12) the partially fluorinated graphene dispersion of 25-30 mg is weighed in 45-60 mL deionized water, is ultrasonically treated, is obtained part fluorine
Graphite alkene solution；
13) take 1-1.5 g sodium hydroxide and 1.2-1.5 g sodium hypochlorite that partially fluorinated graphene solution, ultrasonic 3-4 h is added；
14) it is centrifuged and removes supernatant, add deionized water and obtain uniform dispersion, it is neutrality that dilute hydrochloric acid, which is added, to pH, is set
Dialyse 48-72 h in deionized water；
15) 0.1-0.12 g folic acid is added, 25-30 mg 1- (3- dimethylamino third is added in ultrasonic 0.5-1 min while stirring
Base) -3- ethyl-carbodiimide hydrochloride and 25-30 mg n-hydroxysuccinimide, ultrasonic 2-2.5 h；
16) using the sodium bicarbonate solution of pH=8 to acquired solution dialysis treatment in step 15), every 3-4 h changes a water, 48-
It is transferred them to after 60 h in deionized water and continues the 24-36 h that dialyses；
17) using the moisture in rotary evaporation removal solution, it is placed in drying at 35-45 DEG C, obtains modified with folic acid fluorographite
Alkene has the pharmaceutical carrier of target function.
2. the preparation side that a kind of modified with folic acid fluorinated graphene as described in claim 1 has the pharmaceutical carrier of target function
Method, which is characterized in that in step 2, stirring rate is 400-800 rpm, stirs 20-40 min.
3. the preparation side that a kind of modified with folic acid fluorinated graphene as described in claim 1 has the pharmaceutical carrier of target function
Method, which is characterized in that in step 6), during standing, every 1-2 d removes supernatant, and aliquots of deionized water is added.
4. the preparation side that a kind of modified with folic acid fluorinated graphene as described in claim 1 has the pharmaceutical carrier of target function
Method, which is characterized in that in step 7), centrifugal process specifically: supercentrifuge is used, respectively in 4000 rpm, 6000 rpm,
10 min are respectively centrifuged under 8000 rpm, 10000 rpm, 12000 rpm, remove supernatant in centrifuge tube after centrifugation every time and are added
Aliquots of deionized water.
5. the preparation side that a kind of modified with folic acid fluorinated graphene as described in claim 1 has the pharmaceutical carrier of target function
Method, which is characterized in that each reaction that step 9), step 10), step 11) carry out carries out at room temperature.
6. the preparation side that a kind of modified with folic acid fluorinated graphene as described in claim 1 has the pharmaceutical carrier of target function
Method, which is characterized in that in step 12), ultrasonic treatment specifically: utilize ultrasonic wave under 630 W power of ultrasonic cell disruptor
Processing 2.5-3 h obtains the partially fluorinated graphene solution of evenly dispersed nano-scale.
7. the preparation side that a kind of modified with folic acid fluorinated graphene as described in claim 1 has the pharmaceutical carrier of target function
Method, which is characterized in that in step 13), ultrasound specifically: using ultrasonic cleaning instrument, the ultrasound 3-4 h under 550-600 W power.
8. the preparation side that a kind of modified with folic acid fluorinated graphene as described in claim 1 has the pharmaceutical carrier of target function
Method, which is characterized in that in step 14), dialysis specifically: dispersion liquid is fitted into the bag filter that specification is 8000-14000D and is set
Dialyse 48-72 h in deionized water.
9. the preparation side that a kind of modified with folic acid fluorinated graphene as described in claim 1 has the pharmaceutical carrier of target function
Method, which is characterized in that in step 16, dialysis specifically: it is 8000-14000D's that acquired solution in step 15), which is packed into specification,
Dialysis treatment in the sodium bicarbonate solution of pH=8 is placed in bag filter, every 3-4 h changes a water, transfers them to after 48-60 h
Continue the 24-36 h that dialyses in deionized water.
10. the preparation side that a kind of modified with folic acid fluorinated graphene as described in claim 1 has the pharmaceutical carrier of target function
Method, which is characterized in that in step 17, the revolving speed of rotary evaporation is 2.5 rpm/s, and temperature is 40 DEG C.
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