CN103301465A - 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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- 229910052709 silver Inorganic materials 0.000 title claims abstract description 82
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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 the near infrared light controlled drug delivery system take silver/graphene oxide composite nano-granule as carrier.
Background technology
Graphene oxide (GO) is the derivant of Graphene, its structure is substantially identical with Graphene, the unlimited basal plane that extends of two-dimensional space that just consists of at one deck carbon atom is connected with carbonyl, hydroxyl, the hydrophilic functional group that carboxyl etc. are a large amount of, in biotic environment, has good dispersive property, the characteristics such as the obvious raising of high drug loading and certain slow release characteristic and drug effect, the problems such as the easy reunion in the time of can overcoming independent use medicine and drug action time are short are mainly used in medicine-carried system at biomedicine field, biological detection, bio-imaging, the aspects such as oncotherapy.
Biosystem has the height permeability to the near infrared light of 700～1,100nm scope, and GO has the high characteristic that absorbs in this scope, can utilize the photo-thermal transfer characteristic of GO in this scope that tumor is carried out laserthermia.GO Tumor Targeting Drug Delivery System and laserthermia use in conjunction can be reached more effective antitumour effect.
Under the 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 the medicine that weak chemical bond such as ester bond, amido link link to each other under near infrared light, thereby can reduce the prominent toxic and side effects that causes of releasing because of medicine.
The at present preparation of the near infrared light controlled drug delivery system take silver/graphene oxide composite nano-granule as carrier and the application in oncotherapy thereof yet there are no report.Therefore, meaning and the actual clinical meaning that has statistically of succeeding in developing of the present invention.
Summary of the invention
For above-mentioned situation, for overcoming the defective of prior art, the present invention's purpose just provides a kind of preparation and application thereof of the near infrared light controlled drug delivery system take silver/graphene oxide composite nano-granule as 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, near infrared light controlled drug delivery system take silver/graphene oxide composite nano-granule as carrier, at first that graphene oxide is (on sale on the market, as: the nano grain of silver that Nanjing Ji Cang nanosecond science and technology company limited) has the SPR effect on the area load obtains silver/graphene oxide composite nano-granule, existing hydroxyl and p-nitrophenyl chloroformate ester reaction on the recycling graphene oxide, generate nanometer silver/graphene oxide-p-nitrophenyl chloroformate ester derivant, then with the antitumor drug reaction that contains carbonyl, obtain the near infrared light controlled drug delivery system take silver/graphene oxide composite nano-granule as carrier, step is as follows:
1) will form suspension among the water-soluble 20-60ml of graphene oxide 40-60mg, then dripping concentration is the silver nitrate (AgNO of 10mmol/L
3) solution 40-60ml, ultrasonic mixing 30min, get mixed solution, mixed solution is inserted in 70 ℃ of water-baths, under the 600-800r/min mechanical agitation, be the A solution 15-25ml of 4mol/L to mixed solution and dripping concentration, behind the reaction 11min, the centrifugal fixture that gets, solids is washed to neutrality, then 20-60 ℃ of vacuum drying 24-56h gets 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 ultrasonic 1h formation suspension among the solvent B, adds p-nitrophenyl chloroformate ester 200-500mg, solvent C 1.5-2.5ml and catalyst n, N-dimethylamino naphthyridine 15-25mg, 0 ℃ of lower N
2Protection is reacted 12-48h, the ultrasonic 1h of every 8h under 200～300r/min stirs; Reacted product adds the liquid D precipitation, repeatedly use successively again liquid D, dichloromethane, washed with isopropyl alcohol 2-3 time after, 20-60 ℃ of vacuum drying 24-56h gets nanometer silver/graphene oxide-Nitrodracylic acid ester derivant;
Described solvent B is a kind of in anhydrous DMF, the dimethyl sulfoxide (DMSO); Solvent C is a kind of in pyridine, the triethylamine; Described liquid D is a kind of in dehydrated alcohol, the absolute ether;
3) nanometer silver/graphene oxide-Nitrodracylic acid ester derivant 20-25mg is dissolved among the solvent B N
2Protect ultrasonic 30min, then add antitumor drug E20-60mg and the solvent F8-12ml that contains carbonyl, stir 10min and make its mix homogeneously, room temperature N
2The gas protection, under stirring, 200-300r/min reacts 10-40h, every the ultrasonic 1h of 8h, reacted product adds the liquid D precipitation, then with twice of the washed with dichloromethane that splashes into 1-2 and drip solution G, be dissolved at last in the deionized water and dialysed 1-3 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 (nanometer silver/graphene oxide/medicine);
The described antitumor drug E that contains 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, the triethylamine; Described solution G is one or more the compositions in methanol, ethanol, the acetone.
The described application of near infrared light controlled drug delivery system in the medicine for treating tumor thing take silver/graphene oxide composite nano-granule as carrier, described cancerous cell are 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 the 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 the 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 can be realized by following steps in implementation:
1), the 50mg graphene oxide be dissolved in the 40ml water form suspension, then drip the AgNO that 50ml concentration is 10mmol/l
3Solution, ultrasonic mixing 30min, get mixed solution, mixed solution is inserted in 70 ℃ of water-baths, under the 600-800r/min mechanical agitation, be the NaOH solution 20ml of 4mol/L to mixed solution and dripping concentration, behind the reaction 11min, the centrifugal fixture that gets, solids is washed to neutrality, then 20-60 ℃ of vacuum drying 24-56h gets silver-colored/graphene oxide composite nano-granule;
2), silver/graphene oxide composite nano-granule 60mg is dissolved in the anhydrous N of 30ml, ultrasonic 1h forms suspension in the N dimethyl formamide (DMF), add p-nitrophenyl chloroformate ester 400mg, pyridine 2ml and catalyst n, N-dimethylamino naphthyridine 20mg, 0 ℃ of lower N2 protection 200～300r/min stirs lower reaction 48h, the ultrasonic 1h of every 8h; Reacted product adds the 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 gets nanometer silver/graphene oxide-Nitrodracylic acid ester derivant;
3), nanometer silver/graphene oxide-Nitrodracylic acid ester derivant 30mg is dissolved among the anhydrous DMF 20ml N
2Protect ultrasonic 30min; then add DOXHCl30mg and 10ml N; the 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 the absolute ether precipitation, then washes twice with splashing into the dichloromethane that 1-2 drips methanol, is dissolved at last in the deionized water dialysis 2 days; 8000rpm is centrifugal, and 10min removes bulky grain, and it is the controlled drug delivery system of carrier that lyophilization is able to silver/graphene oxide composite nano-granule.
Embodiment 2
The present invention also can be realized by following steps in implementation:
1), will form suspension among the water-soluble 20ml of graphene oxide 40mg, then dripping concentration is the silver nitrate (AgNO of 10mmol/L
3) solution 40ml, ultrasonic mixing 30min, get mixed solution, mixed solution is inserted in 70 ℃ of water-baths, under the 600-800r/min mechanical agitation, be the KOH solution 15ml of 4mol/L to mixed solution and dripping concentration, behind the reaction 11min, the centrifugal fixture that gets, solids is washed to neutrality, then 20-60 ℃ of vacuum drying 24-56h gets silver-colored/graphene oxide composite nano-granule;
2), above-mentioned silver/graphene oxide composite nano-granule 30mg is dissolved in ultrasonic 1h formation suspension in the dimethyl sulfoxide (DMSO), adding p-nitrophenyl chloroformate ester 200mg, triethylamine 1.5ml and N, N-dimethylamino naphthyridine 15mg, 0 ℃ of lower N
2Protection is reacted 12-48h, the ultrasonic 1h of every 8h under 200～300r/min stirs; Reacted product adds the dehydrated alcohol precipitation, repeatedly use successively again dehydrated alcohol, dichloromethane, washed with isopropyl alcohol 2-3 time after, 20-60 ℃ of vacuum drying 24-56h gets nanometer silver/graphene oxide-Nitrodracylic acid ester derivant;
3), nanometer silver/graphene oxide-Nitrodracylic acid ester derivant 20mg is dissolved in the dimethyl sulfoxide (DMSO) N
2Protect ultrasonic 30min, then add Docetaxel 20mg and triethylamine 8ml, stir 10min and make its mix homogeneously, room temperature N
2The gas protection; under stirring, 200-300r/min reacts 10-40h; every the ultrasonic 1h of 8h; reacted product adds the dehydrated alcohol precipitation; then with twice of the washed with dichloromethane that splashes into 1-2 and drip ethanol; be dissolved at last in the deionized water and dialysed 1-3 days, 8000rpm is centrifugal, and 10min removes bulky grain, and it is the controlled drug delivery system of carrier that lyophilization is able to silver/graphene oxide composite nano-granule.
Embodiment 3
The present invention also can be realized by following steps in implementation:
1) will form suspension among the water-soluble 60ml of graphene oxide 60mg, then dripping concentration is the silver nitrate (AgNO of 10mmol/L
3) solution 60ml, ultrasonic mixing 30min, get mixed solution, mixed solution is inserted in 70 ℃ of water-baths, under the 600-800r/min mechanical agitation, be the NaBH4 solution 15-25ml of 4mol/L to mixed solution and dripping concentration, behind the reaction 11min, the centrifugal fixture that gets, solids is washed to neutrality, then 20-60 ℃ of vacuum drying 24-56h gets silver-colored/graphene oxide composite nano-granule;
2) above-mentioned silver/graphene oxide composite nano-granule 80mg is dissolved in ultrasonic 1h formation suspension in the anhydrous DMF, adds p-nitrophenyl chloroformate ester 500mg, pyridine 2.5ml and N, N-dimethylamino naphthyridine 25mg, 0 ℃ of lower N
2Protection is reacted 12-48h, the ultrasonic 1h of every 8h under 200～300r/min stirs; Reacted product adds the dehydrated alcohol precipitation, repeatedly use successively again dehydrated alcohol, dichloromethane, washed with isopropyl alcohol 2-3 time after, 20-60 ℃ of vacuum drying 24-56h gets nanometer silver/graphene oxide-Nitrodracylic acid ester derivant;
3) nanometer silver/graphene oxide-Nitrodracylic acid ester derivant 25mg is dissolved in the anhydrous DMF N
2Protect ultrasonic 30min, then add paclitaxel 60mg and pyridine 12ml, stir 10min and make its mix homogeneously, room temperature N
2The gas protection; under stirring, 200-300r/min reacts 10-40h; every the ultrasonic 1h of 8h; reacted product adds the dehydrated alcohol precipitation; then with twice of the washed with dichloromethane that splashes into 1-2 and drip acetone; be dissolved at last in the deionized water and dialysed 1-3 days, 8000rpm is centrifugal, and 10min removes bulky grain, and it is the controlled drug delivery system of carrier that lyophilization is able to silver/graphene oxide composite nano-granule.
The present invention has obtained good useful technique effect through test, and the related tests data is as follows:
The application of near infrared light controlled drug delivery system in anti-tumor medicine take silver/graphene oxide composite nano-granule as carrier is divided into two parts in the external and body:
1) outer body is the nanometer silver/graphene oxide that will make/DOX solution of making soluble in water, join in the cancerous cell and cultivate, after the administration behind the 3h with light source B illumination, 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 the malignant melanoma;
Light source B is: a kind of in the wide wavelength light source of 780-1100nm wavelength or the laser, preferred 808nm laser;
2) part is the nanometer silver/graphene oxide that will make/DOX solution of making soluble in water in the body, intravenous injection in the tumor-bearing mice body, after the administration behind the 3h with light source D illumination, 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 the malignant melanoma;
Light source D is: a kind of in the wide wavelength light source of 780-1100nm wavelength or the laser, preferred 808nm laser.
When the drug system take silver/graphene oxide composite nano-granule as carrier of the present invention carried out in the 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.
Drug system take silver/graphene oxide composite nano-granule as carrier of the present invention can be made arbitrarily medicament form of pharmaceutical preparation 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 that needs.Administering mode can for: intravenous injection, intramuscular injection, intratumor injection and subcutaneous injection, transdermal administration, body are implanted into mode etc.
One, use rayed nanometer silver/graphene oxide/DOX to the mensuration of the inhibition activity of growth of tumour cell:
By rayed nanometer silver/graphene oxide/DOX at anti tumor activity in vitro: with MCF-7 breast cancer cell (being provided by the Shanghai cell bank) as cancerous cell to be investigated.The MCF-7 cell culture is being contained hyclone (FBS) 10%, and in the RPMI1640 culture medium of mycillin mixed liquor 1%, the incubator condition is 37 ℃, 5%CO
2, went down to posterity once in per 2～3 days.Collect the logarithmic (log) phase cell, adjust concentration of cell suspension, the every hole of 96 orifice plates adds 200 μ l, and bed board makes cell to be measured transfer density to 6 * 10
3Individual/hole, (edge hole is filled with aseptic PBS).Place 5%CO
2, hatch 24h for 37 ℃, be paved with the hole to cell monolayer at the bottom of (96 hole flat underside), add nanometer silver/graphene oxide in the example 1 of Concentraton gradient (12.5,25,50,100 μ g/ml)/DOX, it is 4～6 that multiple hole is set.Light group is placed on 2min among the 808nm near infrared light 2W, and temperature places CO with aluminium foil parcel cell plates at 37 ℃ after illumination finishes in the maintenance During Illumination
2Hatch 24h in the incubator, for light group not, then directly place CO with aluminium foil parcel cell plates
2Hatch 24h in the incubator, 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, leaves standstill to place 10min, does not wash 5 times air drying with 1% acetic acid with protein bound SRB.In conjunction with SRB with the non-buffering of 150 μ l10mmol/L Tris alkali dissolution.Measure the OD value in every hole at the 808nm place.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 the deduction blank group.
Verified when using rayed 2min, nanometer silver/graphene oxide of the present invention/DOX is higher than simple DOX group to the successful of MCF-7 cell.
Two, during rayed, the anti-tumor in vivo determination of activity of nanometer silver/graphene oxide of the present invention/DOX:
Get the mouse S180 ascites sarcoma cell, with the injection normal saline with 3 ︰, 1 dilution proportion after, every mice is in lumbar injection 0.3ml, mice was fed after 7 days, extracted the mouse S180 ascites sarcoma cell, became concentration as 2 * 10 take the injection normal saline dilution behind the counting
6The cell suspension of individual/ml, subcutaneous vaccination and mice right fore top.Behind the 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, wherein the light source that uses of light group is the 808nm near-infrared light source, power is 2W, laser irradiation tumor locus behind the 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.Observe the mice animation every day in the whole experimentation, and every 2d claims its body weight and uses the major diameter (A) and minor axis (B), by formula gross tumor volume of vernier caliper measurement murine sarcoma
Calculate gross tumor volume.
When administration nanometer silver/graphene oxide of the present invention/DOX merged laser irradiation, the increase of the gross tumor volume of mice had obtained obvious inhibition.
Three, determining of the particle size of the near infrared light controlled drug delivery system of the present invention take silver/graphene oxide composite nano-granule as carrier and surface band electric weight:
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, with Z average statistics value as measurement result.Each horizontal nanometer silver/graphene oxide/DOX all prepares 3 parts, and every part of measurement is once 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 is once 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 take silver/graphene oxide composite nano-granule as carrier, its preparation method with and as the application of heat sensitizer.New nanometer silver/graphene oxide of the present invention/DOX can not destroy the characteristic of graphene oxide itself, test result shows, new nanometer silver/graphene oxide of the present invention/DOX derivant, water dispersible is strong, and very low to the toxicity of organism, physics and chemical stability are good, quality is good, the condition of preparation easily satisfies, and raw material sources are abundant, and cost is low.
New nanometer silver/graphene oxide of the present invention/DOX release under near infrared light obviously increases, and has obvious near infrared light controlled-release effect.
Nanometer silver/graphene oxide provided by the invention/DOX can be used as a kind of good heat sensitizer of antitumor temperature-sensitive treatment, test shows no matter be external or body in the situation that well generation and the development of inhibition tumor cell and tissue of illumination, and in the situation that not illumination new nanometer silver/graphene oxide provided by the invention/DOX is to normal cell and organize toxic and side effects very little.
Nanometer silver/graphene oxide provided by the invention/DOX itself has minimum toxicity, stronger water solublity, and good biocompatibility, specific surface area is large, the chemical inertness advantages of higher.Test result shows, nanometer silver/graphene oxide provided by the invention/DOX, particle diameter is even, can improve the water solublity of water-insoluble antitumor drug, the release of medicine obviously increases under near infrared light, but also can more arrive the effect of playing target administration in the tumor tissues, can also give play to more outstanding anti-tumor activity in conjunction with illumination.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 greatly innovation in the medicine preparation.
The present invention compared with prior art has following outstanding useful technique effect:
1) new nanometer silver/graphene oxide of the present invention/DOX can not destroy the characteristic of graphene oxide itself, and water dispersible is strong, and is very low to the toxicity of organism, physics and chemical stability are good, and quality is good, and the condition of preparation easily satisfies, raw material sources are abundant, and cost is low.
2) new nanometer silver/graphene oxide of the present invention/DOX is 2-3 times of blank group under near infrared light, has obvious near infrared light controlled-release effect.
3) nanometer silver/graphene oxide provided by the invention/DOX can be used as a kind of good heat sensitizer of antitumor temperature-sensitive treatment, produce heat energy during illumination and enough bring into play anti-tumor activity, then malicious secondary side effect is very little during not illumination, can come optionally killing tumor cells tissue and cell according to the means such as focusing of light.
4) drug-supplying system take silver/graphene oxide composite nano-granule as carrier provided by the invention, can prevent effectively that the prominent of DOX release, thereby alleviate the toxicity of medicine, and have near infrared light controlled capability and targeting, can give play to more outstanding antitumous effect.
Claims (5)
1. the preparation of the near infrared light controlled drug delivery system take silver/graphene oxide composite nano-granule as carrier is characterized in that, step is as follows:
1) will form suspension among the water-soluble 20-60ml of graphene oxide 40-60mg, then dripping concentration is the silver nitrate solution 40-60ml of 10mmol/L, ultrasonic mixing 30min, get mixed solution, mixed solution is inserted in 70 ℃ of water-baths, under the 600-800r/min mechanical agitation, be the A solution 15-25ml of 4mol/L to mixed solution and dripping concentration, behind the reaction 11min, the centrifugal fixture that gets, solids is washed to neutrality, and then 20-60 ℃ of vacuum drying 24-56h gets 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 ultrasonic 1h formation suspension among the solvent B, adds p-nitrophenyl chloroformate ester 200-500mg, solvent C 1.5-2.5ml and catalyst n, N-dimethylamino naphthyridine 15-25mg, 0 ℃ of lower N
2Protection is reacted 12-48h, the ultrasonic 1h of every 8h under 200～300r/min stirs; Reacted product adds the liquid D precipitation, repeatedly use successively again liquid D, dichloromethane, washed with isopropyl alcohol 2-3 time after, 20-60 ℃ of vacuum drying 24-56h gets nanometer silver/graphene oxide-Nitrodracylic acid ester derivant;
Described solvent B is a kind of in anhydrous DMF, the dimethyl sulfoxide; Solvent C is a kind of in pyridine, the triethylamine; Described liquid D is a kind of in dehydrated alcohol, the absolute ether;
3) nanometer silver/graphene oxide-Nitrodracylic acid ester derivant 20-25mg is dissolved among the solvent B N
2Protect ultrasonic 30min, then add antitumor drug E 20-60mg and the solvent F 8-12ml that contains carbonyl, stir 10min and make its mix homogeneously, room temperature N
2The gas protection, under stirring, 200-300r/min reacts 10-40h, every the ultrasonic 1h of 8h, reacted product adds the liquid D precipitation, then with twice of the washed with dichloromethane that splashes into 1-2 and drip solution G, be dissolved at last in the deionized water and dialysed 1-3 days, 8000rpm is centrifugal, and 10min removes bulky grain, and it is the controlled drug delivery system of carrier that lyophilization is able to silver/graphene oxide composite nano-granule;
The described antitumor drug E that contains 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, the triethylamine; Described solution G is one or more the compositions in methanol, ethanol, the acetone.
2. the preparation of the near infrared light controlled drug delivery system take silver/graphene oxide composite nano-granule as carrier according to claim 1 is characterized in that, is realized by following steps:
1), the 50mg graphene oxide be dissolved in the 40ml water form suspension, then drip the AgNO that 50ml concentration is 10mmol/l
3Solution, ultrasonic mixing 30min, get mixed solution, mixed solution is inserted in 70 ℃ of water-baths, under the 600-800r/min mechanical agitation, be the NaOH solution 20ml of 4mol/L to mixed solution and dripping concentration, behind the reaction 11min, the centrifugal fixture that gets, solids is washed to neutrality, then 20-60 ℃ of vacuum drying 24-56h gets silver-colored/graphene oxide composite nano-granule;
2), silver/graphene oxide composite nano-granule 60mg is dissolved in the anhydrous N of 30ml, ultrasonic 1h forms suspension in the N dimethyl formamide, add p-nitrophenyl chloroformate ester 400mg, pyridine 2ml and catalyst n, N-dimethylamino naphthyridine 20mg, 0 ℃ of lower N2 protection 200～300r/min stirs lower reaction 48h, the ultrasonic 1h of every 8h; Reacted product adds the 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 gets nanometer silver/graphene oxide-Nitrodracylic acid ester derivant;
3), nanometer silver/graphene oxide-Nitrodracylic acid ester derivant 30mg is dissolved among the anhydrous DMF 20ml N
2Protect ultrasonic 30min; then add DOX HCl30mg and 10ml N; the 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 the absolute ether precipitation, then washes twice with splashing into the dichloromethane that 1-2 drips methanol, is dissolved at last in the deionized water dialysis 2 days; 8000rpm is centrifugal, and 10min removes bulky grain, and it is the controlled drug delivery system of carrier that lyophilization is able to silver/graphene oxide composite nano-granule.
3. the preparation of the near infrared light controlled drug delivery system take silver/graphene oxide composite nano-granule as carrier according to claim 1 is characterized in that, is realized by following steps:
1), will form suspension among the water-soluble 20ml of graphene oxide 40mg, then dripping concentration is the silver nitrate solution 40ml of 10mmol/L, and ultrasonic mixing 30min gets mixed solution, mixed solution is inserted in 70 ℃ of water-baths, under the 600-800r/min mechanical agitation, be the KOH solution 15ml of 4mol/L to mixed solution and dripping concentration, behind the reaction 11min, the centrifugal fixture that gets, solids is washed to neutrality, and then 20-60 ℃ of vacuum drying 24-56h gets silver-colored/graphene oxide composite nano-granule;
2), above-mentioned silver/graphene oxide composite nano-granule 30mg is dissolved in ultrasonic 1h formation suspension in the dimethyl sulfoxide, adding p-nitrophenyl chloroformate ester 200mg, triethylamine 1.5ml and N, N-dimethylamino naphthyridine 15mg, 0 ℃ of lower N
2Protection is reacted 12-48h, the ultrasonic 1h of every 8h under 200～300r/min stirs; Reacted product adds the dehydrated alcohol precipitation, repeatedly use successively again dehydrated alcohol, dichloromethane, washed with isopropyl alcohol 2-3 time after, 20-60 ℃ of vacuum drying 24-56h gets nanometer silver/graphene oxide-Nitrodracylic acid ester derivant;
3), nanometer silver/graphene oxide-Nitrodracylic acid ester derivant 20mg is dissolved in the dimethyl sulfoxide N
2Protect ultrasonic 30min, then add Docetaxel 20mg and triethylamine 8ml, stir 10min and make its mix homogeneously, room temperature N
2The gas protection; under stirring, 200-300r/min reacts 10-40h; every the ultrasonic 1h of 8h; reacted product adds the dehydrated alcohol precipitation; then with twice of the washed with dichloromethane that splashes into 1-2 and drip ethanol; be dissolved at last in the deionized water and dialysed 1-3 days, 8000rpm is centrifugal, and 10min removes bulky grain, and it is the controlled drug delivery system of carrier that lyophilization is able to silver/graphene oxide composite nano-granule.
4. the preparation of the near infrared light controlled drug delivery system take silver/graphene oxide composite nano-granule as carrier according to claim 1 is characterized in that, is realized by following steps:
1) will form suspension among the water-soluble 60ml of graphene oxide 60mg, then dripping concentration is the silver nitrate solution 60ml of 10mmol/L, ultrasonic mixing 30min, get mixed solution, mixed solution is inserted in 70 ℃ of water-baths, under the 600-800r/min mechanical agitation, be the NaBH of 4mol/L to mixed solution and dripping concentration
4Solution 15-25ml, behind the reaction 11min, the centrifugal fixture that gets, solids is washed to neutrality, and then 20-60 ℃ of vacuum drying 24-56h gets silver-colored/graphene oxide composite nano-granule;
2) above-mentioned silver/graphene oxide composite nano-granule 80 mg are dissolved in ultrasonic 1h formation suspension in the anhydrous DMF, add p-nitrophenyl chloroformate ester 500mg, pyridine 2.5ml and N, N-dimethylamino naphthyridine 25mg, 0 ℃ of lower N
2Protection is reacted 12-48h, the ultrasonic 1h of every 8h under 200～300r/min stirs; Reacted product adds the dehydrated alcohol precipitation, repeatedly use successively again dehydrated alcohol, dichloromethane, washed with isopropyl alcohol 2-3 time after, 20-60 ℃ of vacuum drying 24-56h gets nanometer silver/graphene oxide-Nitrodracylic acid ester derivant;
3) nanometer silver/graphene oxide-Nitrodracylic acid ester derivant 25mg is dissolved in the anhydrous DMF N
2Protect ultrasonic 30min, then add paclitaxel 60mg and pyridine 12ml, stir 10min and make its mix homogeneously, room temperature N
2The gas protection; under stirring, 200-300r/min reacts 10-40h; every the ultrasonic 1h of 8h; reacted product adds the dehydrated alcohol precipitation; then with twice of the washed with dichloromethane that splashes into 1-2 and drip acetone; be dissolved at last in the deionized water and dialysed 1-3 days, 8000rpm is centrifugal, and 10min removes bulky grain, and it is the controlled drug delivery system of carrier that lyophilization is able to silver/graphene oxide composite nano-granule.
5. the described near infrared light controlled drug delivery system take silver/graphene oxide composite nano-granule as carrier of each among claim 1 or the 2-4 is applied as application in the medicine for treating tumor thing.
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