CN107551275A - A kind of preparation of magnetic nano drug and its method for load doxorubicin hydrochloride - Google Patents
A kind of preparation of magnetic nano drug and its method for load doxorubicin hydrochloride Download PDFInfo
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Abstract
The present invention relates to a kind of preparation of magnetic nano drug and its method for load doxorubicin hydrochloride, it belongs to magnetic Nano material medicament transport technical field.Present invention mainly solves the technical problem that toxicity existing for prior art is high, therapeutic effect is poor.The technical scheme is that：A kind of preparation method of magnetic nano drug, comprises the following steps：1) preparation of cyclodextrin hyaluronic acid supermolecule polymer；2) preparation of magnetic oxygenated graphene；3) preparation of the magnetic nano drug of cyclodextrin hyaluronic acid polymer functionalization.Compared with prior art, bio-compatibility of the present invention is strong, toxic side effect is low, has cancer cell targeting positioning action and medicine controlled release characteristic, there is important application value in terms of bio-pharmaceutical carrier.
Description
Technical field
The invention belongs to magnetic Nano material medicament transport technical field, and in particular to a kind of magnetic nano drug
The method for preparing and its loading doxorubicin hydrochloride.
Background technology
The shortcomings of traditional anti-tumor medicine has whole body distribution, and cytotoxicity is big.Anthraquinone is as broad-spectrum anti-tumor
Medicine, it will be blocked to replicate and reach antitumor purpose in drug molecule intercalation of DNA chain.Doxorubicin hydrochloride (DOX) is as new
Generation Anthraquinone, Cardiac depression lower than other Anthraquinone toxicity effect is weak, but liver function can be produced certain
Influence.In order that DOX reaches safe and efficient therapeutic effect, the pharmaceutical carrier with targeting delivery function is studied to improve curative effect
It is particularly important with security.
Graphite alkenyl nanometer materials synthesis is simple, specific surface area is big, can be used as carrier high-efficiency cross-film delivering medicine, and swollen
Drug molecule is discharged in oncocyte.Due to lacking the target function at specific tumors position, therapeutic effect is limited.In addition, GO parent
Water base group easily by loss on heating, influence nano composite material further disperse and load capacity, and beta-schardinger dextrin (β-CD)
There is loop configuration, there is hydrophily exocoel and lipophile inner chamber, inclusion compound can be formed with many medicines, improve the life of drug molecule
Thing availability, solubility and stability.However, when medicine/β-CD compounds dilute in physiological solution, unwind compound
And medicine controls and release becomes unavailable.
The content of the invention
The shortcomings that it is an object of the invention to overcome prior art, there is provided a kind of preparation of magnetic nano drug and its
The method for loading doxorubicin hydrochloride, the technical problem that toxicity is high, therapeutic effect is poor is solved existing for prior art.
The present invention is achieved by the following technical solutions：A kind of preparation method of magnetic nano drug, wherein：Bag
Include following steps：
1) cyclodextrin -- the preparation of hyaluronic acid supermolecule polymer：
17-19g beta-schardinger dextrins and 11-12g paratoluensulfonyl chlorides are slowly added to 100-150mL pyridine solvents successively first
In and be stirred, react 5-8h at room temperature；Pyridine solvent is removed by rotary evaporation, then passes through recrystallization, cold acetone in water
Sediment list -6- deoxidations -6- (p-toluenesulfonyl)-beta-schardinger dextrin is made in washing purifying；
Then mono- -6- deoxidations -6- (the p-toluenesulfonyl)-beta-schardinger dextrins of 4-6g and 10-12g ethylenediamines are dissolved in 20-
In 30mL N-N- dimethylformamides, and magnetic agitation is reacted 18-24 hours in nitrogen environment, at 80 DEG C, and question response is completed
Afterwards, mixture is cooled to room temperature, then washs 3-5 removal residue ethylenediamine with cold acetone and done under vacuo
It is dry, white powder is made；
Finally by 22-24mg 1- ethyls (3- dimethylaminopropyls) carbodiimide hydrochloride and 13-15mgN- hydroxyls
Succinimide solution activates 40-42mg hyaluronic acids, and continuously stirs 2 hours obtained dispersion liquids, and white powder is added to
In above-mentioned dispersion liquid, mixed liquor is reacted 18-24 hours at room temperature, in deionized water dialysis purification, made after freeze-drying
Obtain cyclodextrin -- hyaluronic acid supermolecule polymer；
2) preparation of magnetic oxygenated graphene：
180-220mg graphene oxides are peeled off into 1 hour obtained graphene oxide in deionized water by being ultrasonically treated
Dispersion liquid, then it is placed in three-neck flask and is heated to 60-80 DEG C；
Nitrogen is passed through graphene oxide solution 10-15 minutes and removes air therein, in nitrogen environment, with 800r/
Min speed carries out mechanical agitation, by 2.7g FeCl3·6H2O and 1.0g FeCl2·4H2O is dissolved in graphene oxide solution
In, reaction solution is made；
Then concentrated ammonia liquor is added dropwise until the pH of reaction solution is adjusted to 9-12；Reactant is stirred into 1-3 hours at 80 DEG C, obtained
Magnetic black precipitate；After being cooled to room temperature, magnetic hysteresis separation, after black precipitate is washed repeatedly with deionized water and absolute ethyl alcohol
20-30h is freeze-dried, obtains magnetic oxygenated graphene powder；
3) preparation of the magnetic nano drug of cyclodextrin-hyaluronic acid polymer functionalization：
First by the magnetic oxygenated graphene powder ultrasonic disperse obtained in 180-220mg steps 2) in 180-220mL
Ethanol in 30-40 minutes to ensure that it is completely dissolved (concentration is 1mg/mL), add 200-400 μ L 3- under nitrogen protection
Aminopropyl triethoxysilane, at room temperature mechanical agitation 6-8 hours；After the completion of reaction, abandoning supernatant is separated by magnetic hysteresis, will
Sediment is washed more than 3 times with ethanol and deionized water respectively, and amidized magnetic oxygenated graphene is obtained after freeze-drying and is received
Rice compound；
By the cyclodextrin obtained in 48-52mg steps 1) -- hyaluronic acid supermolecule polymer is ultrasonic in deionized water
1-3 hours are handled, after it is completely dissolved, add 22-24mg 1- ethyls (3- dimethylaminopropyls) carbodiimide hydrochloride
With 13-15mg n-hydroxysuccinimides, 2-4 hours are continuously stirred, to activate cyclodextrin -- hyaluronic acid supermolecule polymerize
The carboxyl of thing；Amidized magnetic oxygenated graphene nanometer composite is added to cyclodextrin -- the hyaluronic acid oversubscription after activation
In sub- polymer solution, after 24-48 hours are stirred at room temperature in reactant, it are freeze-dried and are gathered so that cyclodextrin-hyaluronic acid is made
The magnetic nano drug of compound functionalization.
Further, the course of reaction of the beta-schardinger dextrin in the step 1) and paratoluensulfonyl chloride is entered under anhydrous conditions
OK；And the reaction time is 5 hours.
Further, the magnetic agitation reaction time is 18 hours in nitrogen environment, at 80 DEG C in the step 1)；It is cooled to
Washing times of the mixture of room temperature in cold acetone are 3 times；The reaction time of mixed liquor at room temperature is 24 hours.
Further, graphene oxide dispersion is heated to 80 DEG C after being placed in three-neck flask in the step 2)；Nitrogen is passed through
The time of graphene oxide solution is 10 minutes；Be added dropwise concentrated ammonia liquor to reaction solution pH be 10；During stirring of the reactant at 80 DEG C
Between be 2 hours；Black precipitate is freeze-dried 24h after being washed repeatedly with deionized water and absolute ethyl alcohol.
Further, magnetic oxygenated graphene powder ultrasonic disperse 30 minutes in ethanol in the step 3)；3- aminopropyls
The addition of triethoxysilane is 300 μ L；The mechanical agitation time is 7 small at room temperature after addition 3- aminopropyl triethoxysilanes
When.
Further, 1- ethyls (3- dimethylaminopropyls) carbodiimide hydrochloride and N- hydroxyls are added in the step 3)
Continuously stirred after succinimide 2 hours；Amidized magnetic oxygenated graphene nanometer composite is added to the ring paste after activation
Essence -- mixing time in hyaluronic acid supermolecule polymer solution and at room temperature is 48 hours.
A kind of method that doxorubicin hydrochloride is loaded using magnetic nano drug, wherein：Comprise the following steps：
0.5mg cyclodextrin-hyaluronic acid is added into the doxorubicin hydrochloride solution that 4mL concentration ranges are 1-300mg/L
Functionalized magnetic nano drug, after vibrating 7 hours under normal temperature, magnetic hysteresis separation.
The present invention introduces magnetic Fe on the big ratio surface of graphene oxide (GO)3O4It is (strong superparamagnetism, hypotoxicity, excellent
Different biocompatibility and easily prepare), by guiding magnetic field that pharmaceutical carrier rapid aggregation is carried into specific tumor tissues,
The killing-efficiency of medicine is improved, the graphene oxide (RGO) of reduction is used as a kind of photothermal deformation nano material, can absorb near red
Outer light, free electronic heating is produced, so as to locally cause high temperature, finally kill tumour cell；Hyaluronic acid (HA) is a kind of
Good biocompatibility, biodegradable, non-immune linear polysaccharide, and it has been proved that HA can be with tumor cell surface
The acceptor of overexpression combines, and effectively strengthens combination and the internalization capability of itself and tumour cell, is rapidly introduced into tumour cell,
Huge potentiality are shown in a variety of biomedical applications, using hyaluronic acid as targeting vector, assign medicinal inclusion compound cancer cell
Positioning function is targetted, the targeting of medicine can be realized, reduces toxic side effect.By bio-compatible and hydrophilic cyclodextrin -- thoroughly
Bright matter acid supermolecule polymer (β-CD-HA) is assembled into magnetic oxygenated graphene (MGO) nanometer sheet, synthesis cyclodextrin-transparent
The magnetic nanometer composite material (MGO- β-CD-HA) of matter acid polymer functionalization.Using MGO- β-CD-HA as targeting delivery function
Pharmaceutical carrier, transport DOX to tumour cell, produce safe and efficient therapeutic effect.
Compared with prior art, bio-compatibility of the present invention is strong, toxic side effect is low, have cancer cell targeting positioning action and
Medicine controlled release characteristic, there is important application value in terms of bio-pharmaceutical carrier.
Brief description of the drawings
Fig. 1 is GO, MGO, MGO-APTES and MGO- β-CD-HA infrared spectrogram；
Fig. 2 is MNPs, MGO and MGO- β-CD-HA thermogravimetric analysis figure；
Fig. 3 is MGO and MGO- β-CD-HA x-ray diffraction pattern；
Fig. 4 is MGO hysteresis curve figure；
Fig. 5 is 0.0025mg/mL DOX, DOX+MGO supernatant and DOX+MGO- β-CD-HA fluorogram；
Fig. 6 is pH value to the influence schematic diagram of the net fluorescence intensities of MGO- β-CD-HA+DOX, wherein F0：0.03mg/mL DOX
Fluorescence intensity, F：The fluorescence intensity of supernatant after MGO-CD-HA absorption DOX；
Fig. 7 is MGO- β-CD-HA to DOX adsorption isotherm curves；
Fig. 8 is cumulative release behavior of the MGO- β-CD-HA nano composite materials under different temperatures and different pH condition
Figure；
Fig. 9 is MGO- β-CD-HA, MGO (0.4mg/mL) and the cushioning liquid PBS of various concentrations (0.4 and 0.8mg/mL),
By 2Wcm-2Near infrared light after, the rise of its temperature and the functional arrangement of time；
Figure 10 is photo-thermal curves of the MGO- β-CD-HA (1.2mg/mL) under different capacity intensity；
Figure 11 is that timing laser ON/OFF (irradiate/does not irradiate) shape after DOX loads to MGO- β-CD-HA nano-material surfaces
State DOX release profiles；For wherein both of which at pH=5.3,37 DEG C, laser illumination wavelength is 808nm, intensity 2Wcm-2；
Figure 12 is after DOX inclusion bodies are incubated different time with human liver cancer cell BEL-7402, to be seen with fluorescence inverted microscope
The cytological map observed；
Figure 13 is cytotoxicity figure of the medicinal inclusion compound under various concentrations.
Embodiment
With reference to embodiment, the invention will be further described, but embodiment is not limit the scope of the invention.
Embodiment 1：
A kind of preparation method of magnetic nano drug, comprises the following steps in the present embodiment：
1) preparation of cyclodextrin -- hyaluronic acid supermolecule polymer (β-CD-HA)：
18g beta-schardinger dextrins (β-CD) and 11.06g paratoluensulfonyl chlorides (TsCl) are slowly added to 120mL pyrroles successively first
In pyridine solvent and it is stirred, reacts 6h at room temperature；By rotary evaporation remove pyridine solvent, then by water recrystallize, it is cold
Sediment list -6- deoxidations -6- (p-toluenesulfonyl)-beta-schardinger dextrin (M-6-O-Ts- β-CD) is made in acetone washing purifying；
Then mono- -6- deoxidations -6- (the p-toluenesulfonyl)-beta-schardinger dextrins of 5g and 10.55g ethylenediamines (EDA) are dissolved in
In 25mL N-N- dimethylformamides (DMF), and magnetic agitation is reacted 18 hours in nitrogen environment, at 80 DEG C, and question response is complete
Cheng Hou, mixture is cooled to room temperature, then washs 3 removal residue ethylenediamines with cold acetone and done under vacuo
It is dry, white powder (β-CD-EDA) is made；
Finally by 23.23mg1- ethyls (3- dimethylaminopropyls) carbodiimide hydrochloride (EDCI) and 13.8mgN-
HOSu NHS (NHS) solution activation 40.85mg hyaluronic acids (HA), and 2 hours obtained dispersion liquids are continuously stirred, will be white
Color powder is added in above-mentioned dispersion liquid, mixed liquor is reacted at room temperature 24 hours, dialysis purification, is freezed in deionized water
Cyclodextrin -- hyaluronic acid supermolecule polymer (β-CD-HA) is made after drying；
2) preparation of magnetic oxygenated graphene (MGO)：
200mg graphene oxides (GO) are peeled off into 1 hour obtained graphene oxide in deionized water by being ultrasonically treated
Dispersion liquid, then it is placed in three-neck flask and is heated to 80 DEG C；
Nitrogen is passed through graphene oxide solution and removes air therein within 10 minutes, in nitrogen environment, with 800r/min
Speed carry out mechanical agitation, by 2.7gFeCl3·6H2O and 1.0g FeCl2·4H2O is dissolved in above-mentioned graphene oxide solution
In, reaction solution is made；
Then concentrated ammonia liquor is added dropwise until the pH of reaction solution is adjusted to 10；Reactant is stirred 2 hours at 80 DEG C, obtains magnetic
Black precipitate；After being cooled to room temperature, magnetic hysteresis separation, freezed after black precipitate is washed repeatedly with deionized water and absolute ethyl alcohol
24h is dried, obtains magnetic oxygenated graphene (MGO) powder；
3) preparation of the magnetic nano drug (MGO- β-CD-HA) of cyclodextrin-hyaluronic acid polymer functionalization：
First by the magnetic oxygenated graphene powder ultrasonic disperse obtained in 200mg steps 2) in 200mL ethanol
To ensure that it is completely dissolved (MGO concentration is 1mg/mL), the ethoxy of 300 μ L 3- aminopropyls three is added under nitrogen protection within 30 minutes
Base silane (APTES), at room temperature mechanical agitation 7 hours；After the completion of reaction, abandoning supernatant is separated by magnetic hysteresis, by sediment
Washed more than 3 times with ethanol and deionized water respectively, amidized magnetic oxygenated graphene (MGO) nanometer is obtained after freeze-drying
Compound；
By the cyclodextrin obtained in 50mg steps 1) -- hyaluronic acid supermolecule polymer is in deionized water at ultrasound
Reason 2 hours, after it is completely dissolved, add 23.23mg 1- ethyls (3- dimethylaminopropyls) carbodiimide hydrochloride
(EDCI) and 13.8mg n-hydroxysuccinimides (NHS), continuously stir 2 hours, to activate cyclodextrin -- hyaluronic acid surpasses
The carboxyl of Molecularly Imprinted Polymer；Amidized magnetic oxygenated graphene nanometer composite is added to the cyclodextrin after activation -- it is transparent
In matter acid supermolecule polymer solution, after reactant is stirred at room temperature 48 hours, it is freeze-dried so that cyclodextrin-hyalomitome is made
The magnetic nano drug (MGO- β-CD-HA) of acid polymer functionalization.
A kind of method of magnetic nano drug load doxorubicin hydrochloride (DOX), comprises the following steps：
0.5mg cyclodextrin-hyaluronic acid is added into the doxorubicin hydrochloride solution that 4mL concentration ranges are 1-300mg/L
Functionalized magnetic nano drug (MGO- β-CD-HA), 7h is vibrated under normal temperature, after magnetic hysteresis separation.
Embodiment 2：
A kind of preparation method of magnetic nano drug, comprises the following steps in the present embodiment：
1) preparation of cyclodextrin -- hyaluronic acid supermolecule polymer (β-CD-HA)：
It is molten that 17g beta-schardinger dextrins (β-CD) and 11g paratoluensulfonyl chlorides (TsCl) are slowly added to 100mL pyridines successively first
In agent and it is stirred, reacts 5h at room temperature；Pyridine solvent is removed by rotary evaporation, then passes through recrystallization, cold acetone in water
Sediment list -6- deoxidations -6- (p-toluenesulfonyl)-beta-schardinger dextrin (M-6-O-Ts- β-CD) is made in washing purifying；
Then mono- -6- deoxidations -6- (the p-toluenesulfonyl)-beta-schardinger dextrins of 4g and 10g ethylenediamines (EDA) are dissolved in 20mL
In N-N- dimethylformamides (DMF), and magnetic agitation is reacted 18 hours in nitrogen environment, at 80 DEG C, after the completion of question response,
Mixture is cooled to room temperature, then 3 removal residue ethylenediamines is washed with cold acetone and is dried under vacuum, be made
White powder (β-CD-EDA)；
Finally by 22mg 1- ethyls (3- dimethylaminopropyls) carbodiimide hydrochloride (EDCI) and 13mg N- hydroxyls
Base succinimide (NHS) solution activation 40mg hyaluronic acids (HA), and 2 hours obtained dispersion liquids are continuously stirred, by white powder
Last (β-CD-EDA) is added in above-mentioned dispersion liquid, mixed liquor is reacted at room temperature 18 hours, is dialysed in deionized water pure
Change, cyclodextrin -- hyaluronic acid supermolecule polymer (β-CD-HA) is made after freeze-drying；
2) preparation of magnetic oxygenated graphene (MGO)：
180mg graphene oxides (GO) are peeled off into 1 hour obtained graphene oxide in deionized water by being ultrasonically treated
Dispersion liquid, then it is placed in three-neck flask and is heated to 60 DEG C；
Nitrogen is passed through graphene oxide solution and removes air therein within 10 minutes, in nitrogen environment, with 800r/min
Speed carry out mechanical agitation, by 2.7gFeCl3·6H2O and 1.0g FeCl2·4H2O is dissolved in above-mentioned graphene oxide solution
In, reaction solution is made；
Then concentrated ammonia liquor is added dropwise until the pH of reaction solution is adjusted to 9；Reactant is stirred 1 hour at 80 DEG C, obtains magnetic
Black precipitate；After being cooled to room temperature, magnetic hysteresis separation, freezed after black precipitate is washed repeatedly with deionized water and absolute ethyl alcohol
20h is dried, obtains magnetic oxygenated graphene (MGO) powder；
3) preparation of the magnetic nano drug (MGO- β-CD-HA) of cyclodextrin-hyaluronic acid polymer functionalization：
Magnetic oxygenated graphene (MGO) powder ultrasonic obtained in 180mg steps 2) is dispersed in 180mL second first
In alcohol 30 minutes to ensure that it is completely dissolved (MGO concentration is 1mg/mL), add 200 μ L 3- aminopropyls three under nitrogen protection
Ethoxysilane (APTES), at room temperature mechanical agitation 6 hours；After the completion of reaction, abandoning supernatant is separated by magnetic hysteresis, will be heavy
Starch is washed more than 3 times with ethanol and deionized water respectively, and amidized magnetic oxygenated graphene (MGO) is obtained after freeze-drying
Nano-complex；
By the cyclodextrin obtained in 48mg steps 1) -- hyaluronic acid supermolecule polymer (β-CD-HA) is in deionized water
It is middle to be ultrasonically treated 1 hour, after it is completely dissolved, add 22mg 1- ethyls (3- dimethylaminopropyls) carbodiimide hydrochloride
Salt (EDCI) and 13mgN- HOSu NHSs (NHS), are continuously stirred 2 hours, to activate cyclodextrin -- and hyaluronic acid surpasses
The carboxyl of Molecularly Imprinted Polymer (β-CD-HA)；After amidized magnetic oxygenated graphene (MGO) nano-complex is added into activation
Cyclodextrin -- in hyaluronic acid supermolecule polymer (β-CD-HA) solution, after reactant is stirred at room temperature 24 hours, freezing
Dry so that the magnetic nano drug (MGO- β-CD-HA) of cyclodextrin-hyaluronic acid polymer functionalization is made.
A kind of method of magnetic nano drug load doxorubicin hydrochloride (DOX), comprises the following steps：
0.5mg cyclodextrin-hyaluronic acid is added into the doxorubicin hydrochloride solution that 4mL concentration ranges are 1-300mg/L
Functionalized magnetic nano drug (MGO- β-CD-HA), 7h is vibrated under normal temperature, after magnetic hysteresis separation.
Embodiment 3：
A kind of preparation method of magnetic nano drug, comprises the following steps in the present embodiment：
1) preparation of cyclodextrin -- hyaluronic acid supermolecule polymer (β-CD-HA)：
It is molten that 19g beta-schardinger dextrins (β-CD) and 12g paratoluensulfonyl chlorides (TsCl) are slowly added to 150mL pyridines successively first
In agent and it is stirred, reacts 8h at room temperature；Pyridine solvent is removed by rotary evaporation, then passes through recrystallization, cold acetone in water
Sediment list -6- deoxidations -6- (p-toluenesulfonyl)-beta-schardinger dextrin (M-6-O-Ts- β-CD) is made in washing purifying；
Then by mono- -6- deoxidations -6- (the p-toluenesulfonyl)-beta-schardinger dextrins of 6g (M-6-O-Ts- β-CD) and 12g ethylenediamines
(EDA) be dissolved in 30mL N-N- dimethylformamides (DMF), and in nitrogen environment, at 80 DEG C magnetic agitation reaction it is 24 small
When, after the completion of question response, mixture is cooled to room temperature, then washing 5 times with cold acetone removes residue ethylenediamines (EDA) simultaneously
It is dried under vacuum, white powder (β-CD-EDA) is made；
Finally by 24mg 1- ethyls (3- dimethylaminopropyls) carbodiimide hydrochloride (EDCI) 15mgN- hydroxyl ambers
Amber acid imide (NHS) solution activation 42mg hyaluronic acids (HA), and continuously stir 2 hours obtained dispersion liquids, by white powder (β-
CD-EDA) it is added in above-mentioned dispersion liquid, mixed liquor is reacted at room temperature 24 hours, dialysis purification, cold in deionized water
Lyophilized dry rear obtained cyclodextrin -- hyaluronic acid supermolecule polymer (β-CD-HA)；
2) preparation of magnetic oxygenated graphene (MGO)：
220mg graphene oxides (GO) are peeled off into 1 hour obtained graphene oxide in deionized water by being ultrasonically treated
Dispersion liquid, then it is placed in three-neck flask and is heated to 80 DEG C；
Nitrogen is passed through graphene oxide solution and removes air therein within 15 minutes, in nitrogen environment, with 800r/min
Speed carry out mechanical agitation, by 2.7g FeCl3·6H2O and 1.0g FeCl2·4H2It is molten that O is dissolved in above-mentioned graphene oxide
In liquid, reaction solution is made；
Then concentrated ammonia liquor is added dropwise until the pH of reaction solution is adjusted to 12；Reactant is stirred 3 hours at 80 DEG C, obtains magnetic
Black precipitate；After being cooled to room temperature, magnetic hysteresis separation, freezed after black precipitate is washed repeatedly with deionized water and absolute ethyl alcohol
30h is dried, obtains magnetic oxygenated graphene (MGO) powder；
3) preparation of the magnetic nano drug (MGO- β-CD-HA) of cyclodextrin-hyaluronic acid polymer functionalization：
Magnetic oxygenated graphene (MGO) powder ultrasonic obtained in 220mg steps 2) is dispersed in 220mL second first
In alcohol 40 minutes to ensure that it is completely dissolved (MGO concentration is 1mg/mL), add the second of 400 μ L3- aminopropyls three under nitrogen protection
TMOS (APTES), at room temperature mechanical agitation 8 hours；After the completion of reaction, abandoning supernatant is separated by magnetic hysteresis, will be precipitated
Thing is washed more than 3 times with ethanol and deionized water respectively, and amidized magnetic oxygenated graphene (MGO) is obtained after freeze-drying and is received
Rice compound；
By the cyclodextrin obtained in 52mg steps 1) -- hyaluronic acid supermolecule polymer (β-CD-HA) is in deionized water
It is middle to be ultrasonically treated 3 hours, after it is completely dissolved, add 24mg 1- ethyls (3- dimethylaminopropyls) carbodiimide hydrochloride
Salt (EDCI) and 15mg n-hydroxysuccinimides (NHS), are continuously stirred 4 hours, to activate cyclodextrin -- and hyaluronic acid surpasses
The carboxyl of Molecularly Imprinted Polymer (β-CD-HA)；After amidized magnetic oxygenated graphene (MGO) nano-complex is added into activation
Cyclodextrin -- in hyaluronic acid supermolecule polymer (β-CD-HA) solution, after reactant is stirred at room temperature 48 hours, freezing
Dry so that the magnetic nano drug (MGO- β-CD-HA) of cyclodextrin-hyaluronic acid polymer functionalization is made.
A kind of method of magnetic nano drug load doxorubicin hydrochloride (DOX), comprises the following steps：
0.5mg cyclodextrin-hyaluronic acid is added into the doxorubicin hydrochloride solution that 4mL concentration ranges are 1-300mg/L
Functionalized magnetic nano drug (MGO- β-CD-HA), 7h is vibrated under normal temperature, after magnetic hysteresis separation.
Magnetic nano drug (MGO- β-the CD- of cyclodextrin-hyaluronic acid polymer functionalization after research absorption property
HA anhydrous ethanol elution) is used, sonic oscillation 10min, magnetic hysteresis separation, is washed three times respectively with secondary water and absolute ethyl alcohol again,
The magnetic nano complex of Dissociative is obtained after vacuum drying, cycling and reutilization can be carried out.
As shown in figure 1, curve a represents GO infrared spectrum, 3424cm- in figure1Locate corresponding the flexible of-OH of strong broad peak to shake
It is dynamic, 1737cm-1Neighbouring peak corresponds to the carboxyl-C=O-O, 1250cm on GO surfaces-1And 1052cm-1Neighbouring peak corresponds to epoxy respectively
The stretching vibration of base and alkoxy, and 1650cm-1Peak then correspond to aromatic series C=C stretching vibration；Curve b represents that MGO's is red
External spectrum, wherein 584cm-1Neighbouring characteristic peak corresponds to the stretching vibration of Fe-O keys, although with naked Fe3O4Compared to peak value
It is mobile, but still Fe can be illustrated3O4It has been successfully incorporated on GO surfaces；Curve c represents MGO-APTEs infrared spectrum, wherein
1565cm-1And 1184cm-1Neighbouring spectral peak corresponds to N-H flexural vibrations and C-N stretching vibration respectively；Curve d represents MGO-
β-CD-HA infrared spectrum, the characteristic absorption peak (1200- that MGO nano-particles are still had β-CD after β-CD further modification in figure
900cm-1), and in 1157cm-1The C-O-C stretching vibrations of the corresponding coupling of the spectral peak at place and O-H in-plane bending vibrations, in 1040cm-1And 1079cm-1The C-O of the corresponding coupling of the characteristic peak at place, C-C stretching vibrations, and O-H flexural vibrations, have shown β-CD-HA
Through being successfully combined on MGO surface.
Curve a is naked MNPs thermogravimetric curve in Fig. 2, and curve b is MGO thermogravimetric curve, and curve c is MGO- β-CD-HA
Thermogravimetric curve；As illustrated, in curve a, MNPs occurs weightless first during less than 125 DEG C, and this, which can be attributed in sample, adsorbs
The volatilization of water and surface-OH loss, then occurs a weak weightening process at 150-250 DEG C, reason is that MNPs is adding
It is oxidized during thermal weight loss, the weight-loss ratio in so whole temperature range is about 3.5%；Curve b low temperature (<100 DEG C) under
Have weightless first, this can be attributed to the loss of residual solvent and water, and then the weightlessness in the range of 120-220 DEG C shows to eliminate
GO and Fe3O4Upper unstable oxygen-containing functional group；Equally, also showed that in curve c it is weightless twice, in the range of about 180-500 DEG C
Weightlessness can be attributed to β-CD-HA decomposition, and the skeleton that the notable weightlessness of high-temperature area (about 600-800 DEG C) is due to GO is broken
Bad, the total mass loss in so whole temperature ranges is about just 36.5%, and it is about 200mgg to calculate-1, illustrate β-CD- again
HA has successfully modified MGO surfaces.
Fig. 3 a are MGO x-ray diffraction pattern, wherein the diffraction maximum at 2 θ=11.8 corresponds to GO (001) crystal face, and 2
It is respectively Fe that θ, which is located at 30.31,35.58,43.19,53.58,57.18,62.87 corresponding diffraction maximums,3O4It is face-centred cubic
(220), (311), (400), (422), (511) and (440) diffraction surfaces, result and the JCPDS (No.85-1436) of this collection of illustrative plates are marked
Bloodstone is consistent in quasi- card, shows that GO surfaces have been arrived in MNPs modifications, and the MGO synthesized has cubic spinel structure；Figure
3b is MGO- β-CD-HA diffracting spectrum, and contrast finds that MGO- β-CD-HA intensity is weaker than MGO, this be probably because β-
CD-HA absorption causes the relative amount of MGO in composite to reduce.Drawn in addition, can be estimated by Scherrer formula
MGO- β-CD-HA particle size is 14.9512nm.
D=0.94 λ/Bcos θ (1)
To sum up, MGO and MGO- β-CD-HA XRD spectrum proves that GO and β-CD-HA modification does not cause Fe3O4Structure
Change.
Fig. 4 is MGO hysteresis curve figure, it can be seen that when externally-applied magnetic field is 0, MGO magnetic induction intensity is
0, but curve passes through origin, meets the concept of superparamagnetic, and this explanation MGO is superparamagnetism, available for target administration, according to magnetic
Torque experimental result：MGO magnetization value is 32.46emu/g.
In Fig. 5, curve a is 0.0025mg/mL DOX fluorogram, and curve b is the spectrogram of DOX+MGO supernatants, bent
Line c is DOX+MGO- β-CD-HA spectrogram.It can be seen that different magnetic Nano material MGO and MGO- β-CD-HA are
There is certain load effect to medicine DOX, being computed MGO- β-CD-HA reduces 99% to DOX net fluorescence intensity, and
MGO but reduces 80% to DOX, this explanation MGO- β-CD-HA than MGO have preferably carry drug effect fruit, can be attributed to MGO- β-
Ratio surface larger CD-HA and hydrophobic cavity, make it have excellent load capacity.
Fig. 6 is that pH value is to the net fluorescence of MGO- β-CD-HA+DOX after MGO- β-CD-HA and 0.03mg/mL DOX interact
The influence schematic diagram of intensity, it can be seen from the figure that, MGO- β-CD-HA to DOX load capacity from pH 3.0 to 7.0 gradually on
Rise, and when pH is more than 8.0, load capacity substantially reduces.It is a homeostasis process to carry medicine experiment, in acid or alkaline ring
In border, relatively low or higher pH can cause DOX height to protonate, and cause the part of hydrogen bond to be dissociated, and load capacity shows
It is bad, and in pH7.0, MGO- β-CD-HA-OH ,-COOH and-OH ,-NH in medicine2Between multiple strong hydrogen bondings it is mutual
Effect is advantageous to the combination of MGO- β-CD-HA and medicine, causes load capacity quickly to increase.
As shown in fig. 7, it is MGO- β-CD-HA to DOX adsorption isotherm, it can be seen that removing independent DOX's
After influence, MGO- β-CD-HA increase (wherein initial DOX concentration to DOX load capacity with the increase of initial DOX concentration
For 0.5mg/mL), and when adsorbance reaches 450mgg-1It is still unsaturated, it is fitted, is found by Langmuir adsorption isothermal curves
MGO- β-CD-HA are 485.43mgg to DOX maximal absorptive capacity-1。
Fig. 8 is cumulative release behavior of the GO- β-CD-HA nano composite materials under different temperatures and different pH condition
Figure；When pH value is 7.4, in cushioning liquid PBS, DOX is discharged with very slow speed from MGO- β-CD-HA nano-complexes
Out, after 10h, 15% insoluble drug release only less than total amount comes out；However, in acid condition (pH 5.3), preceding 5 is small
When it is interior, DOX from MGO- β-the CD-HA speed discharged are sharply increased, and 5-10 is gradually reduced in hour, and estimated preceding 8 is small
When interior, pH value be 5.3 when, DOX cumulative maximum burst size is about 50%, because acid lyase in tumour cell be present
Body；In addition, it can also be seen that the higher insoluble drug release of temperature is more in figure, this explanation MGO- β-CD-HA/DOX are temperature sensitive
Carrier.Therefore, the scattered MGO- β-CD-HA of moisture can target DOX and be transported to target site as preferable delivery vehicles,
Then by endocytosis by medicament transport to cancer cell.
Fig. 9 is MGO- β-CD-HA, MGO (0.4mg/mL) and the cushioning liquid PBS of various concentrations (0.4 and 0.8mg/mL),
By 2Wcm-2Near infrared light after, the rise of its temperature and the functional arrangement of time；Wherein curve a is that near-infrared laser shines
Function of the temperature to time when penetrating cushioning liquid PBS；Function of the temperature to time when curve b is near-infrared laser irradiation MGO；And
C and d be respectively when near-infrared laser irradiation concentration is 0.4mg/mL and 0.8mg/mL MGO- β-CD-HA temperature to the letter of time
Number, it can be seen that under the irradiation of identical near-infrared laser, MGO- β-CD-HA concentration is that 0.8mg/mL temperature compares 0.4mg/
ML temperature is high, and temperature adds 19 DEG C and 17 DEG C respectively, so as to show that 0.8mg/mL MGO- β-CD-HA photothermal conversions are imitated
Rate is higher.In addition, in NIR region, MGO- β-CD-HA temperature is higher than MGO, illustrates that MGO- β-CD-HA light absorbs are strong, photo-thermal
Transformation efficiency is high.The above results show, are irradiated for near-infrared laser, and MGO- β-CD-HA have excellent photothermal conversion ability.
Curve a, curve b and curve c represent that MGO- β-CD-HA (1.2mg/mL) are respectively in laser intensity respectively in Figure 10
1.5th, 2.0 and 2.5W/cm-2Under photo-thermal curve；It can be seen that under near-infrared laser irradiation, with laser intensity
Increase, MGO- β-CD-HA photothermal conversion efficiency gradually steps up.
To sum up, Fig. 9 and Figure 10 respectively illustrates MGO- β-CD-HA concentration dependent and laser power intensity dependence.
Figure 11 is that timing laser ON/OFF (irradiate/does not irradiate) shape after DOX loads to MGO- β-CD-HA nano-material surfaces
State DOX release profiles；Wherein, curve a is the release profiles that timing laser closes (not irradiating) state DOX, and curve b swashs for timing
Light opens (irradiation) state DOX release profiles, and for both of which at pH=5.3,37 DEG C, laser illumination wavelength is 808nm, and intensity is
2Wcm-2；As seen from the figure, apparently higher than what is do not irradiated, this explanation near-infrared swashs the release amount of medicine of timing near-infrared laser irradiation
Light irradiation is advantageous to insoluble drug release.
To sum up, MGO- β-CD-HA nano composite materials can realize pH and near-infrared laser double stimuli reactivity medicine
Release, it is excellent medicament transport carrier to illustrate the composite.
Figure 12 is after DOX inclusion bodies are incubated different time with human liver cancer cell BEL-7402, to be seen with fluorescence inverted microscope
The cytological map observed, wherein a, b, c and d be respectively DOX inclusion bodies and human liver cancer cell BEL-7402 be incubated 0.5h, 1h, 2h and
During 4h, with fluorescence inverted microscope it was observed that its distribution in cell.As seen from the figure：Growth over time, gradually exists
Fluorescence is observed in the cytoplasm of liver cancer cells, and is constantly increased, it was demonstrated that inclusion body successfully enters cell and constantly discharges medicine
Thing.This shows that MGO- β-CD-HA nano composite materials are good pharmaceutical carriers.
Figure 13 is cytotoxicity figure of the medicinal inclusion compound under various concentrations, wherein a posts (not having near infrared light) and b
Post (near infrared light) be MGO- β-CD-HA under the complex various concentrations versus cell activity figure, then c posts (without
Near infrared light) and d posts (through near infrared light) be MGO- β-CD-HA+DOX it is relative under the inclusion compound various concentrations
Cytoactive figure.It can be seen that complex does not have cytotoxicity, illustrate that the carrier has superior biocompatibility；When
Load DOX inclusion compound enters BEL-7402 liver cancer cells, and with the increase of DOX inclusion compound concentration, cytoactive is significantly dropping
Low, the inclusion compound that this external application near infrared light is crossed is to the kill rate of cell apparently higher than non-irradiated, this explanation near infrared light
Be advantageous to insoluble drug release and kill cell.Result above show MGO- β-CD-HA be a kind of nontoxic, good biocompatibility, it is near red
Outer controllable, effective DOX drug-carriers.
The above-described embodiments are merely illustrative of preferred embodiments of the present invention, not to the structure of the present invention
Think and protection domain is defined, on the premise of design concept of the present invention is not departed from, ordinary skill technical staff in this area
Various variations and modifications are made to the technical scheme of present aspect, protection scope of the present invention all should be fallen into.
Claims (7)
- A kind of 1. preparation method of magnetic nano drug, it is characterised in that：Comprise the following steps：1) cyclodextrin -- the preparation of hyaluronic acid supermolecule polymer：17-19g beta-schardinger dextrins and 11-12g paratoluensulfonyl chlorides are slowly added in 100-150mL pyridine solvents simultaneously successively first It is stirred, reacts 5-8h at room temperature；Pyridine solvent is removed by rotary evaporation, then washed by recrystallization, cold acetone in water Sediment list -6- deoxidations -6- (p-toluenesulfonyl)-beta-schardinger dextrin is made in purifying；Then mono- -6- deoxidations -6- (the p-toluenesulfonyl)-beta-schardinger dextrins of 4-6g and 10-12g ethylenediamines are dissolved in 20-30mL N- In dinethylformamide, and magnetic agitation is reacted 18-24 hours in nitrogen environment, at 80 DEG C, will be mixed after the completion of question response Compound is cooled to room temperature, then washs 3-5 removal residue ethylenediamine with cold acetone and is dried under vacuum, is made white Color powder；Finally by 22-24mg 1- ethyls (3- dimethylaminopropyls) carbodiimide hydrochloride and 13-15mg N- hydroxyl ambers Amber imide solution activates 40-42mg hyaluronic acids, and continuously stirs 2 hours obtained dispersion liquids, and white powder is added to State in dispersion liquid, mixed liquor is reacted 18-24 hours at room temperature, in deionized water dialysis purification, be made after freeze-drying Cyclodextrin -- hyaluronic acid supermolecule polymer；2) preparation of magnetic oxygenated graphene：180-220mg graphene oxides are peeled off into 1 hour obtained graphene oxide in deionized water by supersound process to disperse Liquid, then it is placed in three-neck flask and is heated to 60-80 DEG C；Nitrogen is passed through graphene oxide solution 10-15 minutes and removes air therein, in nitrogen environment, with 800r/min's Speed carries out mechanical agitation, by 2.7g FeCl3·6H2O and 1.0g FeCl2·4H2O is dissolved in graphene oxide solution, system Obtain reaction solution；Then concentrated ammonia liquor is added dropwise until the pH of reaction solution is adjusted to 9-12；Reactant is stirred into 1-3 hours at 80 DEG C, obtains magnetic Black precipitate；After being cooled to room temperature, magnetic hysteresis separation, freezed after black precipitate is washed repeatedly with deionized water and absolute ethyl alcohol 20-30h is dried, obtains magnetic oxygenated graphene powder；3) preparation of the magnetic nano drug of cyclodextrin-hyaluronic acid polymer functionalization：First by the magnetic oxygenated graphene powder ultrasonic disperse obtained in 180-220mg steps 2) 180-220mL second 30-40 minutes to ensure that it is completely dissolved, add 200-400 μ L 3- aminopropyl triethoxysilanes under nitrogen protection in alcohol, Mechanical agitation 6-8 hours at room temperature；After the completion of reaction, abandoning supernatant is separated by magnetic hysteresis, by sediment respectively with ethanol and Deionized water is washed more than 3 times, and amidized magnetic oxygenated graphene nanometer composite is obtained after freeze-drying；By the cyclodextrin obtained in 48-52mg steps 1) -- hyaluronic acid supermolecule polymer is ultrasonically treated in deionized water 1-3 hours, after it is completely dissolved, add 22-24mg 1- ethyls (3- dimethylaminopropyls) carbodiimide hydrochloride and 13-15mg n-hydroxysuccinimides, 2-4 hours are continuously stirred, to activate cyclodextrin-hyaluronic acid supermolecule polymer Carboxyl；Amidized magnetic oxygenated graphene nanometer composite is added to cyclodextrin -- the hyaluronic acid supermolecule after activation In polymer solution, after 24-48 hours are stirred at room temperature in reactant, it is freeze-dried so that cyclodextrin-hyaluronic acid polymerization is made The magnetic nano drug of thing functionalization.
- 2. the preparation method of magnetic nano drug according to claim 1, it is characterised in that：In the step 1) The course of reaction of beta-schardinger dextrin and paratoluensulfonyl chloride is carried out under anhydrous conditions, and the reaction time is 5 hours.
- 3. the preparation method of magnetic nano drug according to claim 1, it is characterised in that：In the step 1) In nitrogen environment, at 80 DEG C the magnetic agitation reaction time be 18 hours；It is cooled to washing of the mixture of room temperature in cold acetone Number is 3 times；The reaction time of mixed liquor at room temperature is 24 hours.
- 4. the preparation method of magnetic nano drug according to claim 1, it is characterised in that：Oxygen in the step 2) Graphite alkene dispersion liquid is heated to 80 DEG C after being placed in three-neck flask；The time that nitrogen is passed through graphene oxide solution is 10 minutes； Be added dropwise concentrated ammonia liquor to reaction solution pH be 10；Mixing time of the reactant at 80 DEG C is 2 hours；Black precipitate deionized water 24h is freeze-dried after being washed repeatedly with absolute ethyl alcohol.
- 5. the preparation method of magnetic nano drug according to claim 1, it is characterised in that：Magnetic in the step 3) Property graphene oxide powder ultrasonic disperse 30 minutes in ethanol；The addition of 3- aminopropyl triethoxysilanes is 300 μ L；Add Enter after 3- aminopropyl triethoxysilanes that the mechanical agitation time is 7 hours at room temperature.
- 6. the preparation method of magnetic nano drug according to claim 1, it is characterised in that：Add in the step 3) Continuously stirred 2 hours after entering 1- ethyls (3- dimethylaminopropyls) carbodiimide hydrochloride and n-hydroxysuccinimide；Ammonia The magnetic oxygenated graphene nanometer composite of base is added to cyclodextrin -- the hyaluronic acid supermolecule polymer solution after activation In and mixing time at room temperature be 48 hours.
- 7. utilize the method for the magnetic nano drug load doxorubicin hydrochloride described in claim 1, it is characterised in that：Including Following steps：0.5mg cyclodextrin-hyaluronic acid polymerization is added into the doxorubicin hydrochloride solution that 4mL concentration ranges are 1-300mg/L The magnetic nano drug of thing functionalization, after vibrating 7 hours under normal temperature, magnetic hysteresis separation.
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