CN105194679A - Preparation method and application of titanium dioxide-graphene oxide composite material modified by hyaluronic acid of antitumor drug nanometer layer - Google Patents

Preparation method and application of titanium dioxide-graphene oxide composite material modified by hyaluronic acid of antitumor drug nanometer layer Download PDF

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CN105194679A
CN105194679A CN201510551231.6A CN201510551231A CN105194679A CN 105194679 A CN105194679 A CN 105194679A CN 201510551231 A CN201510551231 A CN 201510551231A CN 105194679 A CN105194679 A CN 105194679A
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hyaluronic acid
titanium dioxide
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room temperature
nano composite
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张红岭
张慧娟
张振中
陈倩倩
张晓戈
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Zhengzhou University
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Zhengzhou University
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Abstract

The invention relates to a preparation method and application of a titanium dioxide-graphene oxide composite material modified by hyaluronic acid of an antitumor drug nanometer layer and effectively solves the problem of preparing the Ti-GO nanometer composite material which has thermal therapy and photodynamic therapy activity, tumor cell targeting property and good biocompatibility and is modified by HA and the problem of achieving pharmacy of anti-tumor treatment. The method includes the steps that the titanium dioxide-graphene oxide composite material is synthesized through a hydrothermal method, then the hyaluronic acid is in chemical connection with the titanium dioxide-graphene oxide composite material through an amido bond with thionyldialkylamine as a connection arm, and the titanium dioxide-graphene oxide composite material modified by the hyaluronic acid of the nanometer layer is formed in a water medium. The titanium dioxide-graphene oxide composite material modified by the hyaluronic acid of the antitumor drug nanometer layer can be used for tumor near infrared imaging diagnosis and tumor treatment at the same time, and application of the titanium dioxide-graphene oxide composite material to preparation of drugs for tumor near infrared imaging diagnosis and tumor treatment is achieved.

Description

There are hyaluronic acid decorated titanium dioxide-graphene oxide composite material preparation method and the application of antitumor drug nanometer layer
Technical field
The present invention relates to medicine, particularly a kind of hyaluronic acid decorated titanium dioxide-graphene oxide composite material (Ti-GO-HA) preparation method and application having antitumor drug nanometer layer.
Background technology
At present, general Bian chemotherapy, radiotherapy and operation carry out Therapeutic cancer clinically.The distribution of amic therapy method medicine whole body is wide, toxic and side effects greatly and easily recur.Radiotherapy utilizes cancerous cell to the characteristic of lonizing radiation sensitivity, use high-energy electromagnetic radiation line kill and wound cancerous cell and make Tumor shrank, but normal structure also can be subject to corresponding radiation damage when clinical treatment.Though surgical operation can tumor resection focus, large to human body wound, and Chang Yinwei cancerous cell spreads and causes curative effect poor.Therefore, the treatment of cancer new technology and method further developing high-efficiency low-toxicity has become the problem paid close attention to the most in world-wide medical field.
In the last few years, along with the development of photoactive substance and laser technology, as a kind of novel minimally-invasive treatment, optical therapeutic received the extensive concern of researcher.Phototherapy comprises photo-thermal therapy and photodynamic therapy.Photodynamic therapy (PDT) is a kind of new method being effective to treat malignant tumor, its treatment principle is that to utilize tumor tissues to compare its surrounding tissue selectivity low, can take in some dyestuffs of retention or medicine as photosensitizer, laser etc. is utilized to produce a large amount of reactive oxygen species (ROS) as light source irradiation photosensitizer, thus effective killing tumor cell, reach therapeutic purposes.Photo-thermal therapy (PTT) is the new method of another kind for the treatment of tumor, and because its treatment time is short, therapeutic effect is obvious, and material non-toxic is harmless, little to human body side effect, therefore has very large development potentiality.Its treatment principle utilizes the material with high photo-thermal conversion efficiency, be injected into inside of human body, utilize targeting recognition technology to be gathered near tumor tissues, and be that heat energy is to kill cancerous cell by light energy conversion under the irradiation of external light source (being generally near infrared light).
And location in tumor of photosensitizer and photothermal deformation agent and accumulation are the key factors determining optical therapeutic effect.Therefore, attempt the specific region these therapeutants being positioned tumor tissues, can killing tumor cell specifically, avoid the infringement to health tissues or organ, optimize phototherapy effect, reduce toxic and side effects.In addition, determine that the time that photosensitizer or photothermal deformation agent arrive tumor target site is also the key factor affecting therapeutic effect.Only such material arrive target site and accumulate a certain amount of after give the effect that illumination farthest could play phototherapy.Therefore the treatment developed under picture monitoring pattern is imperative.
Due to less to the toxicity of organism, photocatalysis effect is lasting, and titanium dioxide is expected to become a kind of safer novel photosensitive agent for oncotherapy.Existing lot of experiments confirms that titanium dioxide is under irradiation under ultraviolet ray, and having certain lethal effect to kinds of tumors such as cervical cancer, wing wrist cancer, leukemia, gastric cancer, intestinal cancer, breast carcinoma, is potential photodynamic therapy material.But its clinical practice will be realized, still face lot of challenges, as: band gap is wider, can only absorb ultraviolet light, to visible and near infrared light utilization rate is low; The easy compound of light induced electron and hole; Smooth surface, absorption property is poor, and carrying drug ratio is extremely low.And graphene oxide (GO) has excellent electronic conduction ability, effective separation of photo-generate electron-hole can be realized, improve photodynamic therapy efficiency; After the two compound, as sensitizer, absorption spectrum can be extended to visible and near-infrared region.In addition, GO is monoatomic layer structure, has larger specific surface area, and its two sides all by stronger physisorption and fragrant lopps medicine Non-covalent binding, thus has the drug load amount of superelevation.Meanwhile, the photothermal deformation characteristic of GO under near infrared light is utilized can to carry out the photo-thermal therapy of tumor.
But untreated GO also has certain shortcoming, as biocompatibility is bad; Easily reunite under physiological environment; Do not have a tumor cell targeting, be difficult to realize the targeting transhipment of medicine and phototherapy that is efficient, low toxicity.So often carry out functional modification to it before application.And hyaluronic acid (HA) is a kind of natural acidic mucopolysaccharide, various active group is there is in structure, there is good biocompatibility and tumor-targeting, the biocompatibility of GO and the dispersion stabilization in water can be improved, by receptor-mediated effect, increase the drug level of focal zone, thus realize the targeted therapy of tumor.But so far there are no the open report of the hyaluronic acid decorated titanium dioxide-graphene oxide composite material and application that have antitumor drug nanometer layer.
Summary of the invention
For above-mentioned situation, for overcoming the defect of prior art, the object of the present invention is just to provide a kind of hyaluronic acid decorated titanium dioxide-graphene oxide composite material (Ti-GO-HA) preparation method and the application that have antitumor drug nanometer layer, effectively can solve the preparation of the Ti-GO nano composite material (Ti-GO-HA) of the HA modification having thermotherapy and optical dynamic therapy activity, tumor cell targeting and good biocompatibility concurrently and realize antineoplastic medicine for treatment problem.
The technical scheme that the present invention solves is, by water heat transfer titanium dioxide-graphene oxide (Ti-GO) nano material, then hyaluronic acid is that linking arm is connected by amide bond chemistry with titanium dioxide-graphene oxide (Ti-GO) nano composite material with Alkylenediamine, in aqueous medium, form the hyaluronic acid decorated titanium dioxide-graphene oxide composite material (Ti-GO-HA) of nanometer layer, specifically realized by following steps:
(1) synthesis of titanium dioxide-graphene oxide (Ti-GO) nano composite material: take 0.25-0.75g titanium sulfate, be dissolved in 10-30ml water, add 80-240mg graphene oxide, stir 4h, add 0.262-0.786g cetyl trimethyl ammonium bromide (CTAB) again, stir 12h, then be transferred in reactor, 120-150 DEG C of water-bath 48-96h, centrifugalize, removing moisture, obtain crude product, crude product deionized water and dehydrated alcohol are respectively washed 5 times, sucking filtration after ion exchange, obtain filter cake, filter cake is put into vacuum drying oven 60-80 DEG C of dry 12-24h, 350-450 DEG C of calcining 2-4h, obtain titanium dioxide-graphene oxide (Ti-GO) nano composite material,
(2) ammonification hyaluronic acid (HA) is synthesized: take 100-200mg hyaluronic acid (HA) and add in 5-20ml solvent, 50 DEG C of oil baths are dissolved, be cooled to room temperature, add 200-500mg1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC), 150-310mg N-Hydroxysuccinimide (NHS) again, stirring at room temperature 30min carries out activated carboxylic, obtains hyaluronic acid (HA) solution of activated carboxylic; Under ice bath, 0.5-2ml ethylenediamine is slowly instilled in hyaluronic acid (HA) solution of activated carboxylic, room temperature reaction 2-6h, be added beyond the pre-cold acetone of hyaluronic acid (HA) amount of solution of activated carboxylic again, ice bath cools, crystallize, the precipitating crystalline of separating out is the hyaluronic acid (HA) of ammonification, and sucking filtration must precipitate; Add water to redissolve and precipitate, dialysis, namely lyophilization obtains ammonification hyaluronic acid (HA);
Described solvent is water or ethanol;
(3) titanium dioxide-graphene oxide (Ti-GO) nano composite material (Ti-GO-HA) that hyaluronic acid (HA) is modified is synthesized, method is: titanium dioxide-graphene oxide (Ti-GO) nano composite material taking 45-120mg, add 30-50ml solvent dispersion and become dispersion liquid, take 346-841mg1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) respectively, 206-610mg N-Hydroxysuccinimide (NHS) joins in dispersion liquid, stir, room temperature priming reaction 10-18h (spending the night), obtains priming reaction liquid; Take the ammonification hyaluronic acid (HA) of 50-150mg, add 10ml dissolution with solvents, be added drop-wise in priming reaction liquid, stirring at room temperature reaction 8-24h, become reactant liquor, be added beyond the pre-cold acetone of load responsive fluid again, ice bath cools, crystallize, sucking filtration, obtain crystal, crystal dialysis lyophilizing, obtains titanium dioxide-graphene oxide (Ti-GO) nano composite material (Ti-GO-HA) that hyaluronic acid (HA) is modified;
(4), the formation of nanometer layer in aqueous medium: titanium dioxide-graphene oxide (Ti-GO) nano composite material (Ti-GO-HA) of being modified by hyaluronic acid (HA) and water are by weight 1-20 ︰ 100 ultrasonic dissolution, mix with the antitumor drug of dissolve with ethanol, through ultrasonic or high pressure homogenize, stirring at room temperature 24h, dialysis or ultrafiltration or post partition method is adopted to remove ethanol and free drug, lyophilizing, antitumor drug particle diameter must be had to be the hyaluronic acid decorated titanium dioxide-graphene oxide composite material (Ti-GO-HA) of 10 ~ 1000 nanometers (nm) layer,
Described hyaluronic molecular weight is 600d-400kd;
Described antitumor drug is the one of doxorubicin hydrochloride, paclitaxel, Docetaxel, hydroxy camptothecin, mitoxantrone and indocyanine green.
Prepared by the inventive method has the hyaluronic acid decorated titanium dioxide-graphene oxide composite material of antitumor drug nanometer layer simultaneously for the diagnosis of tumor near infrared imaging and oncotherapy, can realize the application in the near infrared imaging diagnosis of preparation tumor and anti-tumor medicine.
Accompanying drawing explanation
Fig. 1 is hyaluronic acid decorated titanium dioxide-stannic oxide/graphene nano composite of the present invention photo-thermal effect figure under 808nm laser irradiates.
Detailed description of the invention
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) synthesis of titanium dioxide-graphene oxide (Ti-GO) nano composite material: take 0.5g titanium sulfate, be dissolved in 20ml water, add 160mg graphene oxide, stir 4h, add 0.524g cetyl trimethyl ammonium bromide (CTAB) again, stir 12h, then be transferred in reactor, 120-150 DEG C of water-bath 48-96h, centrifugalize, removing moisture, obtain crude product, crude product deionized water and dehydrated alcohol are respectively washed 5 times, sucking filtration after ion exchange, obtain filter cake, filter cake is put into vacuum drying oven 60-80 DEG C of dry 12-24h, 350-450 DEG C of calcining 2-4h, obtain titanium dioxide-graphene oxide (Ti-GO) nano composite material,
(2) ammonification hyaluronic acid (HA) is synthesized: take 150mg hyaluronic acid (HA) and add in 12.5ml solvent, 50 DEG C of oil baths are dissolved, be cooled to room temperature, add 350mg1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC), 230mg N-Hydroxysuccinimide (NHS) again, stirring at room temperature 30min carries out activated carboxylic, obtains hyaluronic acid (HA) solution of activated carboxylic; Under ice bath, 1.25ml ethylenediamine is slowly instilled in hyaluronic acid (HA) solution of activated carboxylic, room temperature reaction 2-6h, be added beyond the pre-cold acetone of hyaluronic acid (HA) amount of solution of activated carboxylic again, ice bath cools, crystallize, the precipitating crystalline of separating out is the hyaluronic acid (HA) of ammonification, and sucking filtration must precipitate; Add water to redissolve and precipitate, dialysis, namely lyophilization obtains ammonification hyaluronic acid (HA);
(3) titanium dioxide-graphene oxide (Ti-GO) nano composite material (Ti-GO-HA) that hyaluronic acid (HA) is modified is synthesized, method is: titanium dioxide-graphene oxide (Ti-GO) nano composite material taking 83mg, add 40ml solvent dispersion and become dispersion liquid, take 594mg1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) respectively, 408mg N-Hydroxysuccinimide (NHS) joins in dispersion liquid, stir, room temperature priming reaction 10-18h (spending the night), obtains priming reaction liquid; Take the ammonification hyaluronic acid (HA) of 100mg, add 10ml dissolution with solvents, be added drop-wise in priming reaction liquid, stirring at room temperature reaction 8-24h, become reactant liquor, be added beyond the pre-cold acetone of load responsive fluid again, ice bath cools, crystallize, sucking filtration, obtain crystal, crystal dialysis lyophilizing, obtains titanium dioxide-graphene oxide (Ti-GO) nano composite material (Ti-GO-HA) that hyaluronic acid (HA) is modified;
(4), the formation of nanometer layer in aqueous medium: titanium dioxide-graphene oxide (Ti-GO) nano composite material (Ti-GO-HA) of being modified by hyaluronic acid (HA) and water are by weight 10 ︰ 100 ultrasonic dissolutions, mix with the antitumor drug of dissolve with ethanol, through ultrasonic or high pressure homogenize, stirring at room temperature 24h, dialysis or ultrafiltration or post partition method is adopted to remove ethanol and free drug, lyophilizing, antitumor drug particle diameter must be had to be the hyaluronic acid decorated titanium dioxide-graphene oxide composite material (Ti-GO-HA) of 10 ~ 1000 nanometers (nm) layer.
Embodiment 2
The present invention, in concrete enforcement, also can be realized by following steps:
(1) synthesis of titanium dioxide-graphene oxide (Ti-GO) nano composite material: take 0.25g titanium sulfate, be dissolved in 10ml water, add 80mg graphene oxide, stir 4h, add 0.262g cetyl trimethyl ammonium bromide (CTAB) again, stir 12h, then be transferred in reactor, 120-150 DEG C of water-bath 48-96h, centrifugalize, removing moisture, obtain crude product, crude product deionized water and dehydrated alcohol are respectively washed 5 times, sucking filtration after ion exchange, obtain filter cake, filter cake is put into vacuum drying oven 60-80 DEG C of dry 12-24h, 350-450 DEG C of calcining 2-4h, obtain titanium dioxide-graphene oxide (Ti-GO) nano composite material,
(2) ammonification hyaluronic acid (HA) is synthesized: take 100mg hyaluronic acid (HA) and add in 5ml solvent, 50 DEG C of oil baths are dissolved, be cooled to room temperature, add 200mg1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC), 150mg N-Hydroxysuccinimide (NHS) again, stirring at room temperature 30min carries out activated carboxylic, obtains hyaluronic acid (HA) solution of activated carboxylic; Under ice bath, 0.5ml ethylenediamine is slowly instilled in hyaluronic acid (HA) solution of activated carboxylic, room temperature reaction 2-6h, be added beyond the pre-cold acetone of hyaluronic acid (HA) amount of solution of activated carboxylic again, ice bath cools, crystallize, the precipitating crystalline of separating out is the hyaluronic acid (HA) of ammonification, and sucking filtration must precipitate; Add water to redissolve and precipitate, dialysis, namely lyophilization obtains ammonification hyaluronic acid (HA);
(3) titanium dioxide-graphene oxide (Ti-GO) nano composite material (Ti-GO-HA) that hyaluronic acid (HA) is modified is synthesized, method is: titanium dioxide-graphene oxide (Ti-GO) nano composite material taking 45mg, add 30ml solvent dispersion and become dispersion liquid, take 346mg1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) respectively, 206mg N-Hydroxysuccinimide (NHS) joins in dispersion liquid, stir, room temperature priming reaction 10-18h (spending the night), obtains priming reaction liquid; Take the ammonification hyaluronic acid (HA) of 50mg, add 10ml dissolution with solvents, be added drop-wise in priming reaction liquid, stirring at room temperature reaction 8-24h, become reactant liquor, be added beyond the pre-cold acetone of load responsive fluid again, ice bath cools, crystallize, sucking filtration, obtain crystal, crystal dialysis lyophilizing, obtains titanium dioxide-graphene oxide (Ti-GO) nano composite material (Ti-GO-HA) that hyaluronic acid (HA) is modified;
(4), the formation of nanometer layer in aqueous medium: titanium dioxide-graphene oxide (Ti-GO) nano composite material (Ti-GO-HA) of being modified by hyaluronic acid (HA) and water are by weight 2 ︰ 100 ultrasonic dissolutions, mix with the antitumor drug of dissolve with ethanol, through ultrasonic or high pressure homogenize, stirring at room temperature 24h, dialysis or ultrafiltration or post partition method is adopted to remove ethanol and free drug, lyophilizing, antitumor drug particle diameter must be had to be the hyaluronic acid decorated titanium dioxide-graphene oxide composite material (Ti-GO-HA) of 10 ~ 1000 nanometers (nm) layer.
Embodiment 3
The present invention, in concrete enforcement, also can be realized by following steps:
(1) synthesis of titanium dioxide-graphene oxide (Ti-GO) nano composite material: take 0.75g titanium sulfate, be dissolved in 30ml water, add 80-240mg graphene oxide, stir 4h, add 0.262-0.786g cetyl trimethyl ammonium bromide (CTAB) again, stir 12h, then be transferred in reactor, 120-150 DEG C of water-bath 48-96h, centrifugalize, removing moisture, obtain crude product, crude product deionized water and dehydrated alcohol are respectively washed 5 times, sucking filtration after ion exchange, obtain filter cake, filter cake is put into vacuum drying oven 60-80 DEG C of dry 12-24h, 350-450 DEG C of calcining 2-4h, obtain titanium dioxide-graphene oxide (Ti-GO) nano composite material,
(2) ammonification hyaluronic acid (HA) is synthesized: take 200mg hyaluronic acid (HA) and add in 20ml solvent, 50 DEG C of oil baths are dissolved, be cooled to room temperature, add 500mg1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC), 310mg N-Hydroxysuccinimide (NHS) again, stirring at room temperature 30min carries out activated carboxylic, obtains hyaluronic acid (HA) solution of activated carboxylic; Under ice bath, 2ml ethylenediamine is slowly instilled in hyaluronic acid (HA) solution of activated carboxylic, room temperature reaction 2-6h, be added beyond the pre-cold acetone of hyaluronic acid (HA) amount of solution of activated carboxylic again, ice bath cools, crystallize, the precipitating crystalline of separating out is the hyaluronic acid (HA) of ammonification, and sucking filtration must precipitate; Add water to redissolve and precipitate, dialysis, namely lyophilization obtains ammonification hyaluronic acid (HA);
(3) titanium dioxide-graphene oxide (Ti-GO) nano composite material (Ti-GO-HA) that hyaluronic acid (HA) is modified is synthesized, method is: titanium dioxide-graphene oxide (Ti-GO) nano composite material taking 120mg, add 50ml solvent dispersion and become dispersion liquid, take 841mg1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) respectively, 610mg N-Hydroxysuccinimide (NHS) joins in dispersion liquid, stir, room temperature priming reaction 10-18h (spending the night), obtains priming reaction liquid; Take the ammonification hyaluronic acid (HA) of 150mg, add 10ml dissolution with solvents, be added drop-wise in priming reaction liquid, stirring at room temperature reaction 8-24h, become reactant liquor, be added beyond the pre-cold acetone of load responsive fluid again, ice bath cools, crystallize, sucking filtration, obtain crystal, crystal dialysis lyophilizing, obtains titanium dioxide-graphene oxide (Ti-GO) nano composite material (Ti-GO-HA) that hyaluronic acid (HA) is modified;
(4), the formation of nanometer layer in aqueous medium: titanium dioxide-graphene oxide (Ti-GO) nano composite material (Ti-GO-HA) of being modified by hyaluronic acid (HA) and water are by weight 18 ︰ 100 ultrasonic dissolutions, mix with the antitumor drug of dissolve with ethanol, through ultrasonic or high pressure homogenize, stirring at room temperature 24h, dialysis or ultrafiltration or post partition method is adopted to remove ethanol and free drug, lyophilizing, antitumor drug particle diameter must be had to be the hyaluronic acid decorated titanium dioxide-graphene oxide composite material (Ti-GO-HA) of 10 ~ 1000 nanometers (nm) layer.
The inventive method is easy to operate, reliable and stable, and its product can be effective to the medicine preparing treatment tumor, and achieves very satisfied Advantageous Effects through test, and interrelated data is as follows:
1, the photo-thermal effect of the Ti-GO nano composite material (Ti-GO-HA) of HA modification
Prepare the Ti-GO-HA aqueous solution of a series of concentration, adopt 808nmNIR laser device with 2W/cm 2energy density irradiate, and in 0,1,2,3,4,5min measures the temperature of solution, obtain Fig. 1, known from figure: the Ti-GO nano composite material (Ti-GO-HA) that HA modifies has excellent photothermal conversion effect near-infrared laser irradiates, can be used as photo-thermal agent and treats for tumor photo-thermal.
2, the photodynamic effect of the Ti-GO nano composite material (Ti-GO-HA) of HA modification
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 hyclone (FBS) 10%, and in the RPMI1640 culture medium of mycillin mixed liquor 1%, incubator condition is 37 DEG C, 5%CO 2, within every 2 ~ 3 days, go down to posterity once.Collect logarithmic (log) phase cell, adjustment concentration of cell suspension, the 6 every holes of orifice plate add 1ml, and bed board makes cell to be measured adjust density to 3 × 10 4individual/hole.Be placed in 5%CO 2, hatch 24h for 37 DEG C, be paved with at the bottom of hole to cell monolayer, add the Ti-GO-HA of 10 μ g/ml, arranging multiple hole is 2 ~ 4.After dosing 4h, light group is placed on 2min in 808nm laser 1.5W, keeps temperature in During Illumination at 37 DEG C, to add active oxygen probe after illumination terminates, and is placed in CO by aluminium foil parcel cell version 2hatch 0.5h in incubator, stop cultivating, sucking-off pastille culture medium, every hole 3mlPBS washes 2 times, fixes 0.5h with 70% ice ethanol, is then placed in fluorescence microscopy Microscopic observation active oxygen production.
Carry out record to fluorescence microscope result, result shows, Ti-GO-HA can produce a large amount of active oxygen in tumor cell under near-infrared laser irradiates, and can be used as photosensitizer for carrying out photodynamic therapy to tumor.
3, the preparation and characterization of the Ti-GO-HA antineoplastic pharmaceutical compositions of load indocyanine-green
By Ti-GO-HA composite 5mg, be dissolved in 5ml water and stir 30min, Probe Ultrasonic Searching 30min under condition of ice bath.5mg indocyanine-green is dissolved in water, then the two mixing, Probe Ultrasonic Searching 30min under condition of ice bath, stirred overnight at room temperature, ultra-pure water dialysis 1d, centrifugal (5000rpm) 10min, lyophilization.
The mensuration of indocyanine-green content in Ti-GO-HA antineoplastic pharmaceutical compositions
Adopt ultraviolet spectrophotometry, measure the content of indocyanine-green in 777nm wavelength place.The drug loading of (1) calculation sample with the formula.Drug loading reaches 75%.
4, the phototherapy determination of activity of the Ti-GO-HA antineoplastic pharmaceutical compositions of load indocyanine-green
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 hyclone (FBS) 10%, and in the RPMI1640 culture medium of mycillin mixed liquor 1%, incubator condition is 37 DEG C, 5%CO 2, within every 2 ~ 3 days, go down to posterity once.Collect logarithmic (log) phase cell, adjustment 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 5 × 10 3individual/hole, (the aseptic PBS of edge hole fills).Be placed in 5%CO 2hatch 24h for 37 DEG C, (96 hole flat underside) at the bottom of hole is paved with to cell monolayer, add the Ti-GO-HA pharmaceutical composition that Concentraton gradient is the load indocyanine-green of 0,0.1,0.2,0.5,1,2 μ g/ml, free indocyanine-green is matched group, arranging multiple hole is 4 ~ 6, is divided into 6 groups, is specifically grouped as follows: (1) indocyanine-green group; (2) indocyanine-green-808nm laser group; (3) Ti-GO-HA group; (4) Ti-GO-HA-808nm laser group; (5) the Ti-GO-HA pharmaceutical composition group of load indocyanine-green; (6) the Ti-GO-HA pharmaceutical composition-808nm laser group of load indocyanine-green; Wherein laser group is placed on 2min in 808nm laser 1.5W, and in maintenance During Illumination, temperature is at 37 DEG C, and illumination terminates rear aluminium foil parcel cell version and is placed in CO 2hatch 24h in incubator, for not light group, then direct aluminium foil parcel cell version is placed in CO 2hatch 24h in incubator, stop cultivating, srb assay measures suppression ratio.
Experiment proves that the Ti-GO-HA in the present invention can enter inside tumor cells by mediate drug as during pharmaceutical carrier, and itself is little to the growth effect of tumor cell, but can the propagation of inhibition tumor cell preferably under the irradiation of near-infrared laser; After its load indocyanine-green, associating 808nm laser, has synergistic antitumor effect to occur.
Anti-tumor in vivo is active: get mouse S180 ascites sarcoma cell, with injection normal saline with after 3:1 dilution proportion, every mice in lumbar injection 0.3ml, after mice feeds 7 days, extract mouse S180 ascites sarcoma cell, after counting, become concentration for 2 × 10 with injection normal saline dilution 6the cell suspension of individual/ml, subcutaneous vaccination is in mice right fore top.After mouse inoculation tumor 7d, get wherein 36 gross tumor volume>=100mm 3kunming mice, is divided into 7 groups at random, often organizes 6.Specifically be grouped as follows: (1) matched group (NS group): normal saline; (2) indocyanine-green group; (3) indocyanine-green-808nm laser group; (4) Ti-GO-HA group; (5) Ti-GO-HA-808nm laser group; (6) the Ti-GO-HA pharmaceutical composition group of load indocyanine-green; (7) the Ti-GO-HA pharmaceutical composition-808nm laser group of load indocyanine-green.In each group indocyanine-green and Ti-GO-HA dosage equal, indocyanine-green is 5mg/kg, Ti-GO-HA is 10mg/kg.7 groups of modes all adopting intravenously administrable, wherein laser group power is 1.5W, and after administration 3h, laser irradiates tumor locus, and the once irradiating time is 2min.Every 2d is administered once, altogether administration 7 times.In whole experimentation, every day observes mice animation, and every 2d claims its body weight and uses the major diameter (A) of vernier caliper measurement murine sarcoma and minor axis (B), calculates gross tumor volume by formula gross tumor volume V=.
As administration Ti-GO-HA, gross tumor volume is there was no significant difference compared with saline control group, but in conjunction with after near-infrared laser, the growth of gross tumor volume is obviously slack-off; When the Ti-GO-HA pharmaceutical composition of load indocyanine-green irradiates in conjunction with laser, the increase of the gross tumor volume of mice adds laser irradiation compared with indocyanine-green injection and obtains obvious suppression; In all groups, the effect of the Ti-GO-HA pharmaceutical composition-808nm laser group Tumor suppression growth of load indocyanine-green is the most obvious.
5, the near infrared imaging test of the Ti-GO-HA antineoplastic pharmaceutical compositions of load indocyanine-green
When the gross tumor volume of mice reaches 100mm 3time, by the Ti-GO-HA pharmaceutical composition aqueous solution 200 μ L of indocyanine-green solution and load indocyanine-green respectively tail vein injection enter in tumor-bearing mice body and (often organize 3 mices), make the indocyanine-green metering in Mice Body be 2mg/kg.The PBS of 200 μ L to be expelled in other three Mice Bodies as a control group with same operation.The bio distribution analysis of indocyanine-green can special time small animal living body imaging system (Maestro, the U.S.) after injection obtain, and collects fluorescence, carry out near infrared imaging test in 704nm excitation wavelength and 735nm filter.
Result display is compared with indocyanine-green solution group, and the Ti-GO-HA antineoplastic pharmaceutical compositions group of load indocyanine-green obviously strengthens at the fluorescence signal of tumor region, illustrates that Ti-GO-HA has significant tumor-targeting, can realize the targeted delivery of antitumor drug.
While doing above-mentioned experiment, other near-infrared light source and antitumor drug doxorubicin hydrochloride, paclitaxel, Docetaxel, hydroxy camptothecin and mitoxantrone is also adopted to do identical or similar experiment, all achieve identical and similar result, other experiment will not enumerate.Experiment shows, the present invention is easy to operate, and method is reliable and stable, has very strong practicality, has tangible clinical meaning, compared with prior art, has following outstanding Advantageous Effects:
(1) Ti-GO nano material provided by the invention, by by titanium dioxide and graphene oxide compound, can the absorption spectrum of titanium dioxide be expanded to visible and near-infrared region, and the electronic conduction ability of GO excellence can avoid electron-hole compound in titanium dioxide, simultaneously the conjugated structure of GO uniqueness and larger specific surface area can the payload of realize target transmitter, its photothermal deformation characteristic under near infrared light makes Ti-GO nano material while as carrier in addition, itself can be used as again the effect of photosensitizer and photo-thermal therapy agent performance multimachine Synergistic treatment.
(2) the present invention select have good biocompatibility, tumor cell targeting natural polysaccharide---hyaluronic acid is decorating molecule, take Alkylenediamine as linking arm, carry out chemical modification by a kind of simple economy and the method that easily realizes suitability for industrialized production to Ti-GO composite, mild condition, reaction is simple, productive rate is high;
(3) the Ti-GO nano composite material structure of HA modification provided by the invention is comparatively simple, there is excellent biocompatibility, water solublity and stability, tumour-specific targeting can also be realized, and the efficiency light thermal therapeutical remaining graphene oxide is active and titanium dioxide in near-infrared region efficient photocatalytic activity, achieve cancer target photo-thermal therapy associating optical dynamic therapy;
(4) the Ti-GO nano composite material of HA modification provided by the invention, physical load antitumor drug indocyanine-green (ICG), not only can realize the tumor phototherapy under near-infrared irradiation, also can realize the oncotherapy in body under near infrared imaging monitoring pattern.
(5) adopt near infrared light as light source, not only penetration into tissue is strong, and little to harm, and can be used for the optical therapeutic of human body deep tumor, be that one in tumor is innovated greatly, economic and social benefit is huge.

Claims (7)

1. one kind has the hyaluronic acid decorated titanium dioxide-graphene oxide composite material preparation method of antitumor drug nanometer layer, it is characterized in that, by water heat transfer titanium dioxide-stannic oxide/graphene nano material, then hyaluronic acid is that linking arm is connected by amide bond chemistry with titanium dioxide-stannic oxide/graphene nano composite with Alkylenediamine, in aqueous medium, form the hyaluronic acid decorated titanium dioxide-graphene oxide composite material of nanometer layer, specifically realized by following steps:
(1) synthesis of titanium dioxide-stannic oxide/graphene nano composite: take 0.25-0.75g titanium sulfate, be dissolved in 10-30ml water, add 80-240mg graphene oxide, stir 4h, add 0.262-0.786g cetyl trimethyl ammonium bromide again, stir 12h, then be transferred in reactor, 120-150 DEG C of water-bath 48-96h, centrifugalize, removing moisture, obtain crude product, crude product deionized water and dehydrated alcohol are respectively washed 5 times, sucking filtration after ion exchange, obtain filter cake, filter cake is put into vacuum drying oven 60-80 DEG C of dry 12-24h, 350-450 DEG C of calcining 2-4h, obtain titanium dioxide-stannic oxide/graphene nano composite,
(2) ammonification hyaluronic acid is synthesized: take 100-200mg hyaluronic acid and add in 5-20ml solvent, 50 DEG C of oil baths are dissolved, be cooled to room temperature, add 200-500mg1-ethyl-(3-dimethylaminopropyl) carbodiimide, 150-310mg N-Hydroxysuccinimide again, stirring at room temperature 30min carries out activated carboxylic, obtains the hyaluronic acid solution of activated carboxylic; Under ice bath, 0.5-2ml ethylenediamine is slowly instilled in the hyaluronic acid solution of activated carboxylic, room temperature reaction 2-6h, then be added beyond the pre-cold acetone of hyaluronic acid solution amount of activated carboxylic, ice bath cools, crystallize, the precipitating crystalline of precipitation is the hyaluronic acid of ammonification, and sucking filtration must precipitate; Add water to redissolve and precipitate, dialysis, namely lyophilization obtains ammonification hyaluronic acid;
Described solvent is water or ethanol;
(3) hyaluronic acid decorated titanium dioxide-stannic oxide/graphene nano composite is synthesized, method is: the titanium dioxide-stannic oxide/graphene nano composite taking 45-120mg, add 30-50ml solvent dispersion and become dispersion liquid, take 346-841mg1-ethyl-(3-dimethylaminopropyl) carbodiimide respectively, 206-610mg N-Hydroxysuccinimide joins in dispersion liquid, stir, room temperature priming reaction 10-18h, obtains priming reaction liquid; Take the ammonification hyaluronic acid of 50-150mg, add 10ml dissolution with solvents, be added drop-wise in priming reaction liquid, stirring at room temperature reaction 8-24h, become reactant liquor, be added beyond the pre-cold acetone of load responsive fluid again, ice bath cools, crystallize, sucking filtration, obtain crystal, crystal dialysis lyophilizing, obtains hyaluronic acid decorated titanium dioxide-stannic oxide/graphene nano composite;
(4), the formation of nanometer layer in aqueous medium: by hyaluronic acid decorated titanium dioxide-stannic oxide/graphene nano composite and water by weight 1-20 ︰ 100 ultrasonic dissolution, mix with the antitumor drug of dissolve with ethanol, through ultrasonic or high pressure homogenize, stirring at room temperature 24h, dialysis or ultrafiltration or post partition method is adopted to remove ethanol and free drug, lyophilizing, must have antitumor drug particle diameter to be the hyaluronic acid decorated titanium dioxide-graphene oxide composite material of 10 ~ 1000 nanometer layer.
2. the hyaluronic acid decorated titanium dioxide-graphene oxide composite material preparation method having antitumor drug nanometer layer according to claim 1, it is characterized in that, described hyaluronic molecular weight is 600d-400kd.
3. the hyaluronic acid decorated titanium dioxide-graphene oxide composite material preparation method having antitumor drug nanometer layer according to claim 1, it is characterized in that, described antitumor drug is the one of doxorubicin hydrochloride, paclitaxel, Docetaxel, hydroxy camptothecin, mitoxantrone and indocyanine green.
4. the hyaluronic acid decorated titanium dioxide-graphene oxide composite material preparation method having antitumor drug nanometer layer according to claim 1, is characterized in that, realized by following steps:
(1) synthesis of titanium dioxide-stannic oxide/graphene nano composite: take 0.5g titanium sulfate, be dissolved in 20ml water, add 160mg graphene oxide, stir 4h, add 0.524g cetyl trimethyl ammonium bromide again, stir 12h, then be transferred in reactor, 120-150 DEG C of water-bath 48-96h, centrifugalize, removing moisture, obtain crude product, crude product deionized water and dehydrated alcohol are respectively washed 5 times, sucking filtration after ion exchange, obtain filter cake, filter cake is put into vacuum drying oven 60-80 DEG C of dry 12-24h, 350-450 DEG C of calcining 2-4h, obtain titanium dioxide-stannic oxide/graphene nano composite,
(2) ammonification hyaluronic acid is synthesized: take 150mg hyaluronic acid and add in 12.5ml solvent, 50 DEG C of oil baths are dissolved, be cooled to room temperature, add 350mg1-ethyl-(3-dimethylaminopropyl) carbodiimide, 230mg N-Hydroxysuccinimide again, stirring at room temperature 30min carries out activated carboxylic, obtains the hyaluronic acid solution of activated carboxylic; Under ice bath, 1.25ml ethylenediamine is slowly instilled in the hyaluronic acid solution of activated carboxylic, room temperature reaction 2-6h, then be added beyond the pre-cold acetone of hyaluronic acid solution amount of activated carboxylic, ice bath cools, crystallize, the precipitating crystalline of precipitation is the hyaluronic acid of ammonification, and sucking filtration must precipitate; Add water to redissolve and precipitate, dialysis, namely lyophilization obtains ammonification hyaluronic acid;
(3) hyaluronic acid decorated titanium dioxide-stannic oxide/graphene nano composite is synthesized, method is: the titanium dioxide-stannic oxide/graphene nano composite taking 83mg, add 40ml solvent dispersion and become dispersion liquid, take 594mg1-ethyl-(3-dimethylaminopropyl) carbodiimide respectively, 408mg N-Hydroxysuccinimide joins in dispersion liquid, stir, room temperature priming reaction 10-18h, obtains priming reaction liquid; Take the ammonification hyaluronic acid of 100mg, add 10ml dissolution with solvents, be added drop-wise in priming reaction liquid, stirring at room temperature reaction 8-24h, become reactant liquor, be added beyond the pre-cold acetone of load responsive fluid again, ice bath cools, crystallize, sucking filtration, obtain crystal, crystal dialysis lyophilizing, obtains hyaluronic acid decorated titanium dioxide-stannic oxide/graphene nano composite;
(4), the formation of nanometer layer in aqueous medium: by hyaluronic acid decorated titanium dioxide-stannic oxide/graphene nano composite and water by weight 10 ︰ 100 ultrasonic dissolutions, mix with the antitumor drug of dissolve with ethanol, through ultrasonic or high pressure homogenize, stirring at room temperature 24h, dialysis or ultrafiltration or post partition method is adopted to remove ethanol and free drug, lyophilizing, must have antitumor drug particle diameter to be the hyaluronic acid decorated titanium dioxide-graphene oxide composite material of 10 ~ 1000 nanometer layer.
5. the hyaluronic acid decorated titanium dioxide-graphene oxide composite material preparation method having antitumor drug nanometer layer according to claim 1, is characterized in that, realized by following steps:
(1) synthesis of titanium dioxide-stannic oxide/graphene nano composite: take 0.25g titanium sulfate, be dissolved in 10ml water, add 80mg graphene oxide, stir 4h, add 0.262g cetyl trimethyl ammonium bromide again, stir 12h, then be transferred in reactor, 120-150 DEG C of water-bath 48-96h, centrifugalize, removing moisture, obtain crude product, crude product deionized water and dehydrated alcohol are respectively washed 5 times, sucking filtration after ion exchange, obtain filter cake, filter cake is put into vacuum drying oven 60-80 DEG C of dry 12-24h, 350-450 DEG C of calcining 2-4h, obtain titanium dioxide-stannic oxide/graphene nano composite,
(2) ammonification hyaluronic acid is synthesized: take 100mg hyaluronic acid and add in 5ml solvent, 50 DEG C of oil baths are dissolved, be cooled to room temperature, add 200mg1-ethyl-(3-dimethylaminopropyl) carbodiimide, 150mg N-Hydroxysuccinimide again, stirring at room temperature 30min carries out activated carboxylic, obtains the hyaluronic acid solution of activated carboxylic; Under ice bath, 0.5ml ethylenediamine is slowly instilled in the hyaluronic acid solution of activated carboxylic, room temperature reaction 2-6h, then be added beyond the pre-cold acetone of hyaluronic acid solution amount of activated carboxylic, ice bath cools, crystallize, the precipitating crystalline of precipitation is the hyaluronic acid of ammonification, and sucking filtration must precipitate; Add water to redissolve and precipitate, dialysis, namely lyophilization obtains ammonification hyaluronic acid;
(3) hyaluronic acid decorated titanium dioxide-stannic oxide/graphene nano composite is synthesized, method is: the titanium dioxide-stannic oxide/graphene nano composite taking 45mg, add 30ml solvent dispersion and become dispersion liquid, take 346mg1-ethyl-(3-dimethylaminopropyl) carbodiimide respectively, 206mg N-Hydroxysuccinimide joins in dispersion liquid, stir, room temperature priming reaction 10-18h, obtains priming reaction liquid; Take the ammonification hyaluronic acid of 50mg, add 10ml dissolution with solvents, be added drop-wise in priming reaction liquid, stirring at room temperature reaction 8-24h, become reactant liquor, be added beyond the pre-cold acetone of load responsive fluid again, ice bath cools, crystallize, sucking filtration, obtain crystal, crystal dialysis lyophilizing, obtains hyaluronic acid decorated titanium dioxide-stannic oxide/graphene nano composite;
(4), the formation of nanometer layer in aqueous medium: by hyaluronic acid decorated titanium dioxide-stannic oxide/graphene nano composite and water by weight 2 ︰ 100 ultrasonic dissolutions, mix with the antitumor drug of dissolve with ethanol, through ultrasonic or high pressure homogenize, stirring at room temperature 24h, dialysis or ultrafiltration or post partition method is adopted to remove ethanol and free drug, lyophilizing, must have antitumor drug particle diameter to be the hyaluronic acid decorated titanium dioxide-graphene oxide composite material of 10 ~ 1000 nanometer layer.
6. the hyaluronic acid decorated titanium dioxide-graphene oxide composite material preparation method having antitumor drug nanometer layer according to claim 1, is characterized in that, realized by following steps:
(1) synthesis of titanium dioxide-stannic oxide/graphene nano composite: take 0.75g titanium sulfate, be dissolved in 30ml water, add 80-240mg graphene oxide, stir 4h, add 0.262-0.786g cetyl trimethyl ammonium bromide again, stir 12h, then be transferred in reactor, 120-150 DEG C of water-bath 48-96h, centrifugalize, removing moisture, obtain crude product, crude product deionized water and dehydrated alcohol are respectively washed 5 times, sucking filtration after ion exchange, obtain filter cake, filter cake is put into vacuum drying oven 60-80 DEG C of dry 12-24h, 350-450 DEG C of calcining 2-4h, obtain titanium dioxide-stannic oxide/graphene nano composite,
(2) ammonification hyaluronic acid is synthesized: take 200mg hyaluronic acid and add in 20ml solvent, 50 DEG C of oil baths are dissolved, be cooled to room temperature, add 500mg1-ethyl-(3-dimethylaminopropyl) carbodiimide, 310mg N-Hydroxysuccinimide again, stirring at room temperature 30min carries out activated carboxylic, obtains the hyaluronic acid solution of activated carboxylic; Under ice bath, 2ml ethylenediamine is slowly instilled in the hyaluronic acid solution of activated carboxylic, room temperature reaction 2-6h, then be added beyond the pre-cold acetone of hyaluronic acid solution amount of activated carboxylic, ice bath cools, crystallize, the precipitating crystalline of precipitation is the hyaluronic acid of ammonification, and sucking filtration must precipitate; Add water to redissolve and precipitate, dialysis, namely lyophilization obtains ammonification hyaluronic acid;
(3) hyaluronic acid decorated titanium dioxide-stannic oxide/graphene nano composite is synthesized, method is: the titanium dioxide-stannic oxide/graphene nano composite taking 120mg, add 50ml solvent dispersion and become dispersion liquid, take 841mg1-ethyl-(3-dimethylaminopropyl) carbodiimide respectively, 610mg N-Hydroxysuccinimide joins in dispersion liquid, stir, room temperature priming reaction 10-18h, obtains priming reaction liquid; Take the ammonification hyaluronic acid of 150mg, add 10ml dissolution with solvents, be added drop-wise in priming reaction liquid, stirring at room temperature reaction 8-24h, become reactant liquor, be added beyond the pre-cold acetone of load responsive fluid again, ice bath cools, crystallize, sucking filtration, obtain crystal, crystal dialysis lyophilizing, obtains hyaluronic acid decorated titanium dioxide-stannic oxide/graphene nano composite;
(4), the formation of nanometer layer in aqueous medium: by hyaluronic acid decorated titanium dioxide-stannic oxide/graphene nano composite and water by weight 18 ︰ 100 ultrasonic dissolutions, mix with the antitumor drug of dissolve with ethanol, through ultrasonic or high pressure homogenize, stirring at room temperature 24h, dialysis or ultrafiltration or post partition method is adopted to remove ethanol and free drug, lyophilizing, must have antitumor drug particle diameter to be the hyaluronic acid decorated titanium dioxide-graphene oxide composite material of 10 ~ 1000 nanometer layer.
7. what prepared by method described in claim 1 or any one of 2-6 has the application of the hyaluronic acid decorated titanium dioxide-graphene oxide composite material of antitumor drug nanometer layer in the near infrared imaging diagnosis of preparation tumor and anti-tumor medicine.
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