CN103301465B - Preparation and applications of near-infrared light drug controlled release system taking silver/oxidized graphene composite nanoparticle as carrier - Google Patents
Preparation and applications of near-infrared light drug controlled release system taking silver/oxidized graphene composite nanoparticle as carrier Download PDFInfo
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Abstract
The invention relates to preparation and applications of near-infrared light drug controlled release system taking a silver/oxidized graphene composite nanoparticle as a carrier, which aim at solving the problems that the drug for treating tumor is low in curative effect and large in side effect. The method comprises the steps of dissolving oxidized graphene into water, dropwise adding silver nitrate solution, dropwise adding A solution under ultrasonic mixing, reacting, centrifuging, washing solid to be neutral, carrying out vacuum drying, dissolving in a solvent B, adding nitrophenyl chloroformate, solvent C and N,N-dimethylaminopyridine, carrying out N2 protection at 0 DEG C, stirring to conduct ultrasonic reaction, then adding liquid D for precipitating, washing with the liquid D, dichloromethane and isopropyl alcohol, carrying out vacuum drying, then dissolving in the solvent B, carrying out N2 protection and ultrasonic, adding antitumor drug E and solvent F, carrying out N2 protection and ultrasonic reaction, adding the liquid D for precipitating, washing with dichloromethane, dialyzing, centrifuging to remove large particles, freezing and drying. The preparation method is simple, the near-infrared light drug controlled release system is obvious in near-infrared light controlled release effect, good in effect and high in curative effect, and the side effect can be greatly reduced.
Description
Technical field
The present invention relates to chemical field, particularly a kind of preparation and application thereof of take the near infrared light controlled drug delivery system that silver/graphene oxide composite nano-granule is carrier.
Background technology
Graphene oxide (GO) is the derivant of Graphene, its structure is substantially identical with Graphene, on the unlimited basal plane extending of two-dimensional space just forming at one deck carbon atom, be connected with carbonyl, hydroxyl, the hydrophilic functional group that carboxyl etc. are a large amount of, in biotic environment, there is good dispersive property, high drug loading and certain slow release characteristic and drug effect are obviously carried high, the problems such as the easy reunion in the time of can overcoming independent use medicine and drug action time are short, at biomedicine field, be mainly used in medicine-carried system, biological detection, bio-imaging, the aspects such as oncotherapy.
Biosystem has height permeability to the near infrared light of 700～1,100nm scope, and GO has the high characteristic absorbing within the scope of this, can utilize the photo-thermal transfer characteristic of GO within the scope of this to carry out laserthermia to tumor.GO Tumor Targeting Drug Delivery System and laserthermia use in conjunction can be reached to effective antitumour effect more.
Under nanometer state, small-size effect and the skin effect of silver significantly strengthen, and have very strong penetrating power and antibacterial activity.Nanometer silver tool SPR(surface plasmon resonance) effect can be controlled the release of weak chemical bond medicine as connected in ester bond, amido link, thereby can reduce the prominent toxic and side effects causing of releasing because of medicine under near infrared light.
The preparation of the near infrared light controlled drug delivery system that silver/graphene oxide composite nano-granule of take is at present carrier and the application in oncotherapy thereof have not been reported.Therefore, the meaning that has statistically and the actual clinical meaning succeeded in developing of the present invention.
Summary of the invention
For above-mentioned situation, for overcoming the defect of prior art, the present invention's object is just to provide a kind of preparation and application thereof of take the near infrared light controlled drug delivery system that silver/graphene oxide composite nano-granule is carrier, the curative effect of medication that can effectively solve prior art treatment tumor is low, the problem that side effect is large.
The technical scheme that the present invention solves is, the near infrared light controlled drug delivery system that silver/graphene oxide composite nano-granule of take is carrier, first graphene oxide is (on sale on market, as: nano grain of silver Nanjing Ji Cang nanosecond science and technology company limited) on area load with SPR effect obtains silver/graphene oxide composite nano-granule, on recycling graphene oxide, existing hydroxyl reacts with p-nitrophenyl chloroformate ester, generate nanometer silver/graphene oxide-p-nitrophenyl chloroformate ester derivant, then react with the antitumor drug containing carbonyl, the near infrared light controlled drug delivery system that to obtain take silver/graphene oxide composite nano-granule be carrier, step is as follows:
1) will in the water-soluble 20-60ml of graphene oxide 40-60mg, form suspension, then dripping concentration is the silver nitrate (AgNO of 10mmol/L
3) solution 40-60ml, ultrasonic mixing 30min, obtain mixed solution, mixed solution is inserted in 70 ℃ of water-baths, under 600-800r/min mechanical agitation, the A solution 15-25ml that is 4mol/L to mixed solution and dripping concentration, after reaction 11min, the centrifugal fixture that obtains, solids is washed to neutrality, then 20-60 ℃ of vacuum drying 24-56h, obtains silver-colored/graphene oxide composite nano-granule; Described A solution is NaOH, KOH, NaBH
4in one or more;
2) above-mentioned silver/graphene oxide composite nano-granule 30-80mg is dissolved in to ultrasonic 1h in solvent B and forms suspension, add p-nitrophenyl chloroformate ester 200-500mg, solvent C 1.5-2.5ml and catalyst n, N-dimethylamino naphthyridine 15-25mg, N at 0 ℃
2protection is reacted 12-48h, the ultrasonic 1h of every 8h under 200～300r/min stirs; Reacted product adds liquid D precipitation, more repeatedly uses successively after liquid D, dichloromethane, washed with isopropyl alcohol 2-3 time, and 20-60 ℃ of vacuum drying 24-56h, obtains nanometer silver/graphene oxide-Nitrodracylic acid ester derivant;
Described solvent B is a kind of in anhydrous DMF, dimethyl sulfoxide (DMSO); Solvent C is a kind of in pyridine, triethylamine; Described liquid D is a kind of in dehydrated alcohol, absolute ether;
3) nanometer silver/graphene oxide-Nitrodracylic acid ester derivant 20-25mg is dissolved in solvent B to N
2protect ultrasonic 30min, then add antitumor drug E20-60mg and solvent F8-12ml containing carbonyl, stir 10min and make its mix homogeneously, room temperature N
2gas protection, under stirring, 200-300r/min reacts 10-40h, every the ultrasonic 1h of 8h, reacted product adds liquid D precipitation, then by twice of the washed with dichloromethane that splashes into 1-2 and drip solution G, finally be dissolved in the 1-3 days that dialyses in deionized water, 8000rpm is centrifugal, and 10min removes bulky grain, and lyophilization is able to the controlled drug delivery system (nanometer silver/graphene oxide/medicine) that silver/graphene oxide composite nano-granule is carrier;
The described antitumor drug E containing carbonyl is one or more the compositions in the medicines such as Docetaxel, paclitaxel, amycin, NSC 654509, daunorubicin; Described solvent F is one or more the compositions in DIPEA, pyridine, triethylamine; Described solution G is one or more the compositions in methanol, ethanol, acetone.
Described take the application in medicine for treating tumor thing of near infrared light controlled drug delivery system that silver/graphene oxide composite nano-granule is carrier, described cancerous cell is organ surface or the inner various solid tumors that occur, pulmonary carcinoma, nasopharyngeal carcinoma, esophageal carcinoma, gastric cancer, hepatocarcinoma, colorectal cancer, breast carcinoma, ovarian cancer, bladder cancer, leukemia, cancer of pancreas, cervical cancer, laryngeal carcinoma, thyroid carcinoma, carcinoma of tongue, cerebroma (intracranial tumor), intestinal tumor, carcinoma of gallbladder, cancer of biliary duct, renal carcinoma, carcinoma of prostate, carcinoma of penis, tumor of testis, carcinoma of endometrium, choriocarcinoma, For Primary Vaginal Carcinoma, Vulvar, Hodgkin, non-Hodgkin lymphoma, skin carcinoma, a kind of in malignant melanoma.
Preparation method of the present invention is simple, and prepared product has obvious near infrared light controlled-release effect, can be effective to the treatment to tumor, and result of use is good, and curative effect is high, has greatly alleviated the side effect for the treatment of tumor Chinese medicine, is the innovation on medicine for treating tumor thing.
The specific embodiment
Below in conjunction with embodiment, the specific embodiment of the present invention is elaborated.
Embodiment 1
The present invention, in concrete enforcement, can be realized by following steps:
1), 50mg graphene oxide is dissolved in 40ml water and forms suspension, then drip the AgNO that 50ml concentration is 10mmol/l
3solution, ultrasonic mixing 30min, obtain mixed solution, mixed solution is inserted in 70 ℃ of water-baths, under 600-800r/min mechanical agitation, the NaOH solution 20ml that is 4mol/L to mixed solution and dripping concentration, after reaction 11min, the centrifugal fixture that obtains, solids is washed to neutrality, then 20-60 ℃ of vacuum drying 24-56h, obtains silver-colored/graphene oxide composite nano-granule;
2), silver/graphene oxide composite nano-granule 60mg is dissolved in to the anhydrous N of 30ml, in N dimethyl formamide (DMF), ultrasonic 1h forms suspension, add p-nitrophenyl chloroformate ester 400mg, pyridine 2ml and catalyst n, N-dimethylamino naphthyridine 20mg, at 0 ℃, N2 protection 200～300r/min stirs lower reaction 48h, the ultrasonic 1h of every 8h; Reacted product adds absolute ether precipitation, and repeatedly uses absolute ether, dichloromethane and washed with isopropyl alcohol 2-3 time, and 20-60 ℃ of vacuum drying 24-56h, obtains nanometer silver/graphene oxide-Nitrodracylic acid ester derivant;
3), nanometer silver/graphene oxide-Nitrodracylic acid ester derivant 30mg is dissolved in anhydrous DMF 20ml to N
2protect ultrasonic 30min; then add DOXHCl30mg and 10ml N; N-diisopropylethylamine, stirs 10min and makes its mix homogeneously, the lower 30h that stirs of room temperature N2 gas protection; every the ultrasonic 1h of 8h; reacted product adds absolute ether precipitation, then with splashing into the dichloromethane that 1-2 drips methanol, washes twice, is finally dissolved in deionized water and dialyses 2 days; 8000rpm is centrifugal, and 10min removes bulky grain, and lyophilization is able to the controlled drug delivery system that silver/graphene oxide composite nano-granule is carrier.
Embodiment 2
The present invention, in concrete enforcement, also can be realized by following steps:
1), will in the water-soluble 20ml of graphene oxide 40mg, form suspension, then dripping concentration is the silver nitrate (AgNO of 10mmol/L
3) solution 40ml, ultrasonic mixing 30min, obtain mixed solution, mixed solution is inserted in 70 ℃ of water-baths, under 600-800r/min mechanical agitation, the KOH solution 15ml that is 4mol/L to mixed solution and dripping concentration, after reaction 11min, the centrifugal fixture that obtains, solids is washed to neutrality, then 20-60 ℃ of vacuum drying 24-56h, obtains silver-colored/graphene oxide composite nano-granule;
2), above-mentioned silver/graphene oxide composite nano-granule 30mg be dissolved in to ultrasonic 1h in dimethyl sulfoxide (DMSO) form suspension, add p-nitrophenyl chloroformate ester 200mg, triethylamine 1.5ml and N, N-dimethylamino naphthyridine 15mg, N at 0 ℃
2protection is reacted 12-48h, the ultrasonic 1h of every 8h under 200～300r/min stirs; Reacted product adds dehydrated alcohol precipitation, more repeatedly uses successively after dehydrated alcohol, dichloromethane, washed with isopropyl alcohol 2-3 time, and 20-60 ℃ of vacuum drying 24-56h, obtains nanometer silver/graphene oxide-Nitrodracylic acid ester derivant;
3), nanometer silver/graphene oxide-Nitrodracylic acid ester derivant 20mg is dissolved in dimethyl sulfoxide (DMSO) to N
2protect ultrasonic 30min, then add Docetaxel 20mg and triethylamine 8ml, stir 10min and make its mix homogeneously, room temperature N
2gas protection; under stirring, 200-300r/min reacts 10-40h; every the ultrasonic 1h of 8h; reacted product adds dehydrated alcohol precipitation; then by twice of the washed with dichloromethane that splashes into 1-2 and drip ethanol; finally be dissolved in the 1-3 days that dialyses in deionized water, 8000rpm is centrifugal, and 10min removes bulky grain, and lyophilization is able to the controlled drug delivery system that silver/graphene oxide composite nano-granule is carrier.
Embodiment 3
The present invention, in concrete enforcement, also can be realized by following steps:
1) will in the water-soluble 60ml of graphene oxide 60mg, form suspension, then dripping concentration is the silver nitrate (AgNO of 10mmol/L
3) solution 60ml, ultrasonic mixing 30min, obtain mixed solution, mixed solution is inserted in 70 ℃ of water-baths, under 600-800r/min mechanical agitation, the NaBH4 solution 15-25ml that is 4mol/L to mixed solution and dripping concentration, after reaction 11min, the centrifugal fixture that obtains, solids is washed to neutrality, then 20-60 ℃ of vacuum drying 24-56h, obtains silver-colored/graphene oxide composite nano-granule;
2) above-mentioned silver/graphene oxide composite nano-granule 80mg is dissolved in to ultrasonic 1h in anhydrous DMF and forms suspension, add p-nitrophenyl chloroformate ester 500mg, pyridine 2.5ml and N, N-dimethylamino naphthyridine 25mg, N at 0 ℃
2protection is reacted 12-48h, the ultrasonic 1h of every 8h under 200～300r/min stirs; Reacted product adds dehydrated alcohol precipitation, more repeatedly uses successively after dehydrated alcohol, dichloromethane, washed with isopropyl alcohol 2-3 time, and 20-60 ℃ of vacuum drying 24-56h, obtains nanometer silver/graphene oxide-Nitrodracylic acid ester derivant;
3) nanometer silver/graphene oxide-Nitrodracylic acid ester derivant 25mg is dissolved in anhydrous DMF to N
2protect ultrasonic 30min, then add paclitaxel 60mg and pyridine 12ml, stir 10min and make its mix homogeneously, room temperature N
2gas protection; under stirring, 200-300r/min reacts 10-40h; every the ultrasonic 1h of 8h; reacted product adds dehydrated alcohol precipitation; then by twice of the washed with dichloromethane that splashes into 1-2 and drip acetone; finally be dissolved in the 1-3 days that dialyses in deionized water, 8000rpm is centrifugal, and 10min removes bulky grain, and lyophilization is able to the controlled drug delivery system that silver/graphene oxide composite nano-granule is carrier.
The present invention has obtained good useful technique effect through test, and related tests data is as follows:
The application of the near infrared light controlled drug delivery system that silver/graphene oxide composite nano-granule of take is carrier in anti-tumor medicine is divided in vitro and in vivo two parts:
1) outer body is by the nanometer silver/graphene oxide/DOX the making solution of making soluble in water, joins in cancerous cell and cultivates, and uses light source B illumination after administration after 3h, and illumination 1-5min, continues to cultivate 24 hours, measures the survival rate of cancerous cell;
Cancerous cell is: organ surface or the inner various solid tumors that occur, pulmonary carcinoma, nasopharyngeal carcinoma, esophageal carcinoma, gastric cancer, hepatocarcinoma, colorectal cancer, breast carcinoma, ovarian cancer, bladder cancer, leukemia, cancer of pancreas, cervical cancer, laryngeal carcinoma, thyroid carcinoma, carcinoma of tongue, cerebroma (intracranial tumor), intestinal tumor, carcinoma of gallbladder, cancer of biliary duct, renal carcinoma, carcinoma of prostate, carcinoma of penis, tumor of testis, carcinoma of endometrium, choriocarcinoma, For Primary Vaginal Carcinoma, Vulvar, Hodgkin, non-Hodgkin lymphoma, skin carcinoma, a kind of in malignant melanoma;
Light source B is: a kind of in the wide wavelength light source of 780-1100nm wavelength or laser, preferably 808nm laser;
2) in body, part is by the nanometer silver/graphene oxide/DOX the making solution of making soluble in water, and intravenous injection, in tumor-bearing mice body, is used light source D illumination after 3h after administration, and light application time is 1-5min, measures the gross tumor volume size of tumor-bearing mice C.
Tumor-bearing mice is: organ surface or the inner various solid tumors that occur, pulmonary carcinoma, nasopharyngeal carcinoma, esophageal carcinoma, gastric cancer, hepatocarcinoma, colorectal cancer, breast carcinoma, ovarian cancer, bladder cancer, leukemia, cancer of pancreas, cervical cancer, laryngeal carcinoma, thyroid carcinoma, carcinoma of tongue, cerebroma (intracranial tumor), intestinal tumor, carcinoma of gallbladder, cancer of biliary duct, renal carcinoma, carcinoma of prostate, carcinoma of penis, tumor of testis, carcinoma of endometrium, choriocarcinoma, For Primary Vaginal Carcinoma, Vulvar, Hodgkin, non-Hodgkin lymphoma, skin carcinoma, a kind of in malignant melanoma;
Light source D is: a kind of in the wide wavelength light source of 780-1100nm wavelength or laser, preferably 808nm laser.
Of the present inventionly using drug system that silver/graphene oxide composite nano-granule is carrier while carrying out in temperature-sensitive treatment body degree of depth tumor as heat sensitizer, 808nm laser can the degree of depth penetrate organism, can be used for the treatment of biological tumor.
Of the present inventionly using the drug system that silver/graphene oxide composite nano-granule is carrier and can make medicament form of pharmaceutical preparation arbitrarily as heat sensitizer, such as: injection, aseptic powder needle for injection, dispersant, patch, gel, implant etc.Drug system of the present invention can add the additive of various preparations, such as: normal saline, glucose, buffer solution and antiseptic etc. are so that be prepared into the dosage form needing.Administering mode can be: intravenous injection, intramuscular injection, intratumor injection and subcutaneous injection, transdermal administration, body are implanted into mode etc.
One, use the mensuration of rayed nanometer silver/graphene oxide/DOX to the inhibition activity of growth of tumour cell:
By rayed nanometer silver/graphene oxide/DOX anti-tumor activity in vitro: by MCF-7 breast cancer cell (being provided by Shanghai cell bank) as cancerous cell to be investigated.MCF-7 cell culture is being contained to hyclone (FBS) 10%, and in the RPMI1640 culture medium of mycillin mixed liquor 1%, incubator condition is 37 ℃, 5%CO
2, within every 2～3 days, go down to posterity once.Collect logarithmic (log) phase cell, adjust concentration of cell suspension, the 96 every holes of orifice plate add 200 μ l, and bed board makes cell to be measured adjust density to 6 * 10
3individual/hole, (edge hole is filled with aseptic PBS).Be placed in 5%CO
2, hatch 24h for 37 ℃, at the bottom of being paved with hole to cell monolayer (96 hole flat underside), add the nanometer silver/graphene oxide/DOX in the example 1 of Concentraton gradient (12.5,25,50,100 μ g/ml), it is 4～6 that multiple hole is set.Light group is placed on 2min in 808nm near infrared light 2W, keeps in During Illumination temperature at 37 ℃, and illumination finishes with aluminium foil parcel cell plates, to be placed in CO afterwards
2in incubator, hatch 24h, for light group not, directly with aluminium foil parcel cell plates, be placed in CO
2in incubator, hatch 24h, stop cultivating, sucking-off pastille culture medium, every hole is washed 2 times with 150 μ l PBS, adds the 10%TCA200 μ l of pre-cooling, places 1h for 4 ℃.Outwell fixative, every hole is washed 5 times with deionized water, dries air drying.Every hole adds the SRB solution of 100 μ l, and standing placement 10min does not wash 5 times air drying with 1% acetic acid with protein bound SRB.In conjunction with the non-buffering of 150 μ l10mmol/L Tris alkali dissolution for SRB.At 808nm place, measure the OD value in every hole.The computing formula of survival rate: survival rate=experimental group OD value/matched group OD value, wherein experimental group and matched group are the value after deduction blank group.
Verified when use rayed 2min, nanometer silver/graphene oxide/DOX of the present invention to the successful of MCF-7 cell higher than DOX group merely.
Two, during rayed, the anti-tumor in vivo determination of activity of nanometer silver/graphene oxide/DOX of the present invention:
Get mouse S180 ascites sarcoma cell, after using injection normal saline with 3 ︰ 1 dilution proportion, every mice is in lumbar injection 0.3ml, and mice was fed after 7 days, extracted mouse S180 ascites sarcoma cell, and the injection normal saline dilution of take after counting becomes concentration as 2 * 10
6the cell suspension of individual/ml, subcutaneous vaccination and mice right fore top.After mouse inoculation tumor 7d, get wherein 24 gross tumor volume>=100mm
3kunming mice, is divided into 4 groups at random, 6 every group.Specifically be grouped as follows: (1) matched group (NS group): normal saline; (2) normal saline laser group; (3) nanometer silver/graphene oxide/DOX group; (4) nanometer silver/graphene oxide/DOX laser group.4 groups of modes that all adopt intravenously administrable, the light source that wherein light group is used is 808nm near-infrared light source, power is 2W, laser irradiation tumor locus after administration 3h, the once irradiating time is 2min.Every 2d is administered once, nanometer silver/graphene oxide of per injection normal saline or 2mg/ml/DOX100 μ l, and administration is 7 times altogether.In whole experimentation, observe mice animation every day, and every 2d claims its body weight and uses the major diameter (A) and minor axis (B) of vernier caliper measurement murine sarcoma, by formula gross tumor volume
calculate gross tumor volume.
When administration nanometer silver/graphene oxide of the present invention/DOX merges laser irradiation, the increase of the gross tumor volume of mice has obtained obvious inhibition.
Three, the particle size of the near infrared light controlled drug delivery system that silver/graphene oxide composite nano-granule is carrier and determining of surface band electric weight are take in the present invention:
Use Nano-ZS90 type laser particle size analyzer to measure, refractive index is set to 1.590, and absorptance is set to 0.010, and temperature setting is set to 25 ℃, and measurement pattern is set to automatically, usings Z average statistics value as measurement result.Each horizontal nanometer silver/graphene oxide/DOX all prepares 3 parts, and every part of measurement once, is got the meansigma methods of three measured values as measurement result.Dielectric constant is set to 79, and coefficient of viscosity is set to 0.8872, and temperature setting is set to 25 ℃, and measurement pattern is set to automatically.Each horizontal nanometer silver/graphene oxide/DOX all prepares 3 parts, and every part of measurement once, is got the meansigma methods of three measured values as measurement result, and acquired results is that particle diameter is 100～200nm, and current potential is-35mV.
The invention provides a kind of near infrared light controlled drug delivery system that silver/graphene oxide composite nano-granule is carrier of take, its preparation method is usingd and as the application of heat sensitizer.New nanometer silver/graphene oxide/DOX of the present invention can not destroy the characteristic of graphene oxide itself, test result shows, new nanometer silver/graphene oxide/DOX derivant of the present invention, water dispersible is strong, very low to the toxicity of organism, and physics and chemical stability are good, quality is good, the condition of preparation easily meets, and raw material sources are abundant, and cost is low.
New nanometer silver/graphene oxide/DOX of the present invention release under near infrared light obviously increases, and has obvious near infrared light controlled-release effect.
Nanometer silver/graphene oxide/DOX provided by the invention can be used as a kind of good heat sensitizer of antitumor temperature-sensitive treatment, test shows no matter be external or body in well generation and the development of inhibition tumor cell and tissue in the situation that of illumination, and the in the situation that of not illumination new nanometer silver/graphene oxide/DOX provided by the invention to normal cell and organize toxic and side effects very little.
Nanometer silver/graphene oxide/DOX provided by the invention, itself has minimum toxicity, stronger water solublity, and good biocompatibility, specific surface area is large, chemical inertness advantages of higher.Test result shows, nanometer silver/graphene oxide/DOX provided by the invention, particle diameter is even, can improve the water solublity of water-insoluble antitumor drug, under near infrared light, the release of medicine obviously increases, but also can more arrive the effect of playing target administration in tumor tissues, in conjunction with illumination, can also give play to more outstanding anti-tumor activity.This nanometer silver/graphene oxide/DOX is expected to fully develop talents in the treatment of tumor.
Expection can be used for the treatment of a kind of good heat sensitizer of tumor, can be used as the transport vehicle of chemicals, protein, nucleic acid, is the innovation greatly in medicine preparation.
The present invention compared with prior art has following outstanding useful technique effect:
1) new nanometer silver/graphene oxide/DOX of the present invention can not destroy the characteristic of graphene oxide itself, and water dispersible is strong, very low to the toxicity of organism, physics and chemical stability are good, and quality is good, and the condition of preparation easily meets, raw material sources are abundant, and cost is low.
2) new nanometer silver/graphene oxide/DOX of the present invention under near infrared light, be blank group 2-3 doubly, there is obvious near infrared light controlled-release effect.
3) nanometer silver/graphene oxide/DOX provided by the invention can be used as a kind of good heat sensitizer of antitumor temperature-sensitive treatment, during illumination, produce heat energy and enough bring into play anti-tumor activity, during not illumination, malicious secondary side effect is very little, can come optionally killing tumor cells tissue and cell according to the means such as focusing of light.
4) provided by the inventionly take the drug-supplying system that silver/graphene oxide composite nano-granule is carrier, can effectively prevent that the prominent of DOX release, thereby alleviate the toxicity of medicine, and there is near infrared light controlled capability and targeting, can give play to more outstanding antitumous effect.
Claims (4)
1. a preparation for the near infrared light controlled drug delivery system that silver/graphene oxide composite nano-granule of take is carrier, is characterized in that, step is as follows:
1) will in the water-soluble 20-60ml of graphene oxide 40-60mg, form suspension, then dripping concentration is the silver nitrate solution 40-60ml of 10mmol/L, ultrasonic mixing 30min, obtain mixed solution, mixed solution is inserted in 70 ℃ of water-baths, under 600-800r/min mechanical agitation, the A solution 15-25ml that is 4mol/L to mixed solution and dripping concentration, after reaction 11min, the centrifugal fixture that obtains, solids is washed to neutrality, and then 20-60 ℃ of vacuum drying 24-56h, obtains silver-colored/graphene oxide composite nano-granule; Described A solution is NaOH, KOH, NaBH
4in one or more;
2) silver/graphene oxide composite nano-granule 30-80 mg is dissolved in to ultrasonic 1h in solvent B and forms suspension, add p-nitrophenyl chloroformate ester 200-500mg, solvent C 1.5-2.5ml and catalyst n, N-dimethylamino naphthyridine 15-25mg, N at 0 ℃
2protection is reacted 12-48h, the ultrasonic 1h of every 8h under 200～300r/min stirs; Reacted product adds liquid D precipitation, more repeatedly uses successively after liquid D, dichloromethane, washed with isopropyl alcohol 2-3 time, and 20-60 ℃ of vacuum drying 24-56h, obtains nanometer silver/graphene oxide-Nitrodracylic acid ester derivant;
Described solvent B is a kind of in anhydrous DMF, dimethyl sulfoxide; Solvent C is a kind of in pyridine, triethylamine; Described liquid D is a kind of in dehydrated alcohol, absolute ether;
3) nanometer silver/graphene oxide-Nitrodracylic acid ester derivant 20-25mg is dissolved in solvent B to N
2protect ultrasonic 30min, then add antitumor drug E 20-60mg and solvent F 8-12ml containing carbonyl, stir 10min and make its mix homogeneously, room temperature N
2gas protection, under stirring, 200-300r/min reacts 10-40h, every the ultrasonic 1h of 8h, reacted product adds liquid D precipitation, then by twice of the washed with dichloromethane that splashes into 1-2 and drip solution G, finally be dissolved in the 1-3 days that dialyses in deionized water, 8000rpm is centrifugal, and 10min removes bulky grain, and lyophilization is able to the controlled drug delivery system that silver/graphene oxide composite nano-granule is carrier;
The described antitumor drug E containing carbonyl is one or more the compositions in the medicines such as Docetaxel, paclitaxel, amycin, NSC 654509, daunorubicin; Described solvent F is one or more the compositions in DIPEA, pyridine, triethylamine; Described solution G is one or more the compositions in methanol, ethanol, acetone.
2. preparation of take the near infrared light controlled drug delivery system that silver/graphene oxide composite nano-granule is carrier according to claim 1, is characterized in that, by following steps, is realized:
1), will in the water-soluble 20ml of graphene oxide 40mg, form suspension, then dripping concentration is the silver nitrate solution 40ml of 10mmol/L, and ultrasonic mixing 30min, obtains mixed solution, mixed solution is inserted in 70 ℃ of water-baths, under 600-800r/min mechanical agitation, the KOH solution 15ml that is 4mol/L to mixed solution and dripping concentration, after reaction 11min, the centrifugal fixture that obtains, solids is washed to neutrality, and then 20-60 ℃ of vacuum drying 24-56h, obtains silver-colored/graphene oxide composite nano-granule;
2), above-mentioned silver/graphene oxide composite nano-granule 30mg be dissolved in to ultrasonic 1h in dimethyl sulfoxide form suspension, add p-nitrophenyl chloroformate ester 200mg, triethylamine 1.5ml and N, N-dimethylamino naphthyridine 15mg, N at 0 ℃
2protection is reacted 12-48h, the ultrasonic 1h of every 8h under 200～300r/min stirs; Reacted product adds dehydrated alcohol precipitation, more repeatedly uses successively after dehydrated alcohol, dichloromethane, washed with isopropyl alcohol 2-3 time, and 20-60 ℃ of vacuum drying 24-56h, obtains nanometer silver/graphene oxide-Nitrodracylic acid ester derivant;
3), nanometer silver/graphene oxide-Nitrodracylic acid ester derivant 20mg is dissolved in dimethyl sulfoxide to N
2protect ultrasonic 30min, then add Docetaxel 20mg and triethylamine 8ml, stir 10min and make its mix homogeneously, room temperature N
2gas protection; under stirring, 200-300r/min reacts 10-40h; every the ultrasonic 1h of 8h; reacted product adds dehydrated alcohol precipitation; then by twice of the washed with dichloromethane that splashes into 1-2 and drip ethanol; finally be dissolved in the 1-3 days that dialyses in deionized water, 8000rpm is centrifugal, and 10min removes bulky grain, and lyophilization is able to the controlled drug delivery system that silver/graphene oxide composite nano-granule is carrier.
3. preparation of take the near infrared light controlled drug delivery system that silver/graphene oxide composite nano-granule is carrier according to claim 1, is characterized in that, by following steps, is realized:
1) will in the water-soluble 60ml of graphene oxide 60mg, form suspension, then dripping concentration is the silver nitrate solution 60ml of 10mmol/L, ultrasonic mixing 30min, obtain mixed solution, mixed solution is inserted in 70 ℃ of water-baths, under 600-800r/min mechanical agitation, the NaBH that is 4mol/L to mixed solution and dripping concentration
4solution 15-25ml, after reaction 11min, the centrifugal fixture that obtains, solids is washed to neutrality, and then 20-60 ℃ of vacuum drying 24-56h, obtains silver-colored/graphene oxide composite nano-granule;
2) above-mentioned silver/graphene oxide composite nano-granule 80 mg are dissolved in to ultrasonic 1h in anhydrous DMF and form suspension, add p-nitrophenyl chloroformate ester 500mg, pyridine 2.5ml and N, N-dimethylamino naphthyridine 25mg, N at 0 ℃
2protection is reacted 12-48h, the ultrasonic 1h of every 8h under 200～300r/min stirs; Reacted product adds dehydrated alcohol precipitation, more repeatedly uses successively after dehydrated alcohol, dichloromethane, washed with isopropyl alcohol 2-3 time, and 20-60 ℃ of vacuum drying 24-56h, obtains nanometer silver/graphene oxide-Nitrodracylic acid ester derivant;
3) nanometer silver/graphene oxide-Nitrodracylic acid ester derivant 25mg is dissolved in anhydrous DMF to N
2protect ultrasonic 30min, then add paclitaxel 60mg and pyridine 12ml, stir 10min and make its mix homogeneously, room temperature N
2gas protection; under stirring, 200-300r/min reacts 10-40h; every the ultrasonic 1h of 8h; reacted product adds dehydrated alcohol precipitation; then by twice of the washed with dichloromethane that splashes into 1-2 and drip acetone; finally be dissolved in the 1-3 days that dialyses in deionized water, 8000rpm is centrifugal, and 10min removes bulky grain, and lyophilization is able to the controlled drug delivery system that silver/graphene oxide composite nano-granule is carrier.
4. a preparation for the near infrared light controlled drug delivery system that silver/graphene oxide composite nano-granule of take is carrier, is characterized in that, by following steps, is realized:
1), 50mg graphene oxide is dissolved in 40ml water and forms suspension, then drip the AgNO that 50ml concentration is 10mmol/l
3solution, ultrasonic mixing 30min, obtain mixed solution, mixed solution is inserted in 70 ℃ of water-baths, under 600-800r/min mechanical agitation, the NaOH solution 20ml that is 4mol/L to mixed solution and dripping concentration, after reaction 11min, the centrifugal fixture that obtains, solids is washed to neutrality, then 20-60 ℃ of vacuum drying 24-56h, obtains silver-colored/graphene oxide composite nano-granule;
2), silver/graphene oxide composite nano-granule 60mg is dissolved in to the anhydrous N of 30ml, in N dimethyl formamide, ultrasonic 1h forms suspension, add p-nitrophenyl chloroformate ester 400mg, pyridine 2ml and catalyst n, N-dimethylamino naphthyridine 20mg, at 0 ℃, N2 protection 200～300r/min stirs lower reaction 48h, the ultrasonic 1h of every 8h; Reacted product adds absolute ether precipitation, and repeatedly uses absolute ether, dichloromethane and washed with isopropyl alcohol 2-3 time, and 20-60 ℃ of vacuum drying 24-56h, obtains nanometer silver/graphene oxide-Nitrodracylic acid ester derivant;
3), nanometer silver/graphene oxide-Nitrodracylic acid ester derivant 30mg is dissolved in anhydrous DMF 20ml to N
2protect ultrasonic 30min; then add DOX HCl30mg and 10ml N; N-diisopropylethylamine, stirs 10min and makes its mix homogeneously, the lower 30h that stirs of room temperature N2 gas protection; every the ultrasonic 1h of 8h; reacted product adds absolute ether precipitation, then with splashing into the dichloromethane that 1-2 drips methanol, washes twice, is finally dissolved in deionized water and dialyses 2 days; 8000rpm is centrifugal, and 10min removes bulky grain, and lyophilization is able to the controlled drug delivery system that silver/graphene oxide composite nano-granule is carrier.
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