CN104368003A - Preparation method and application of hyaluronic acid modified Au-doped titanium dioxide nano-tube - Google Patents
Preparation method and application of hyaluronic acid modified Au-doped titanium dioxide nano-tube Download PDFInfo
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- CN104368003A CN104368003A CN201410652133.7A CN201410652133A CN104368003A CN 104368003 A CN104368003 A CN 104368003A CN 201410652133 A CN201410652133 A CN 201410652133A CN 104368003 A CN104368003 A CN 104368003A
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Abstract
The invention relates to a preparation method and an application of a hyaluronic acid modified Au-doped titanium dioxide nano-tube, and is used for effectively solving the problems of the preparation of the hyaluronic acid modified Au-doped titanium dioxide nano-tube and the application in preparing medicaments for treating tumors. The preparation method comprises the following steps: preparing a titanium dioxide nano-tube by virtue of a hydrothermal synthesis process, then preparing a titanium dioxide nano-tube with Au modified on the surface by using the titanium dioxide nano-tube as a precursor by virtue of an illumination reductive calcination process, connecting mercaptoacetic acid to the Au-doped titanium dioxide nano-tube by virtue of thiol gold bonds, and performing covalent linkage on hyaluronic acid and mercaptoacetic acid modified on the surface of Au-doped titanium dioxide nano-tube by using alkylene diamine as a connecting arm to form a nano layer in an aqueous medium, wherein the molecular weight of hyaluronic acid is more than or equal to 600 daltons and less than or equal to 400kd, and the connecting arm is an alkylene diamine structure with 2-12 carbon atoms. The hyaluronic acid modified Au-doped titanium dioxide nano-tube is strong in targeting performance, and can be used for achieving comprehensive therapies of cancers more effectively by combining photodynamic therapy, photothermal therapy and chemotherapy together.
Description
Technical field
The present invention relates to medicine, particularly a kind of preparation method of hyaluronic acid decorated Au doped titanic oxide nano tube and application thereof.
Background technology
Malignant tumor exceedes cardiovascular disease, becomes the primary lethal cause of disease of urbanite, and serious threat the life of the mankind with healthy.At present, medically general Bian chemotherapy, actinotherapy and surgical operation carry out Therapeutic cancer.Chemotherapy carrys out destroy cancer cells by medicine, but there is the problem of targeting difference and dose limiting toxicity; Actinotherapy uses ionization linchpin to shoot to death and hinder cancerous cell and tumor wife is contracted, but normal structure also can be subject to corresponding good fortune and penetrates damage when clinical treatment; Surgical operation organizes by tumor resection the object reaching Therapeutic cancer, but it is comparatively large to human body wound, and Chang Yinwei cancerous cell spreads and causes curative effect poor.Therefore, along with the development of photoactive substance and laser technology, photodynamic therapy is that treatment of cancer provides a kind of Wicresoft and effective therapy approach.
Titanium dioxide (Ti0
2) be a kind of conventional photocatalyst, there is the performances such as wet sensitive, air-sensitive, dielectric effect, opto-electronic conversion, photochromic and superior photocatalysis, be thus widely used in the fields such as sensor, dielectric material, self-cleaning material.And correlational study finds, Ti0
2chemistry and good light stability, less to the toxicity of organism is a kind of quite safe material at cellular level, thus Ti0 in the last few years
2carrying out as pharmaceutical carrier having obtained a series of progress in photodynamic therapy basic research in organism, it is potential photodynamic therapy material.And titania nanotube (TiNTs) has larger specific surface area and specific hollow structure compared with nano-powder, therefore in pharmaceutical carrier, there is more tempting application prospect.
But, although titania nanotube (TiNTs) is a kind of photodynamic therapy carrier material of great potential, but realize its application in oncotherapy, still face lot of challenges, as: titanium dioxide is as a kind of n-type semiconductor, band gap is wider, and photo-generate electron-hole recombination probability is higher and lower to sunlight utilization rate; Bad at water stability, surface energy is high, easy coagulation under physiological condition; The compatibility in vivo awaits improving further.It is essential, titania nanotube itself does not have a tumor cell targeting, is difficult to realize the targeting transhipment of medicine and photodynamics combined chemotherapy that is efficient, low toxicity.Therefore, if suitably by functionalization, its biocompatibility can be improved, solve its targeting defect simultaneously, greatly will improve its application at field of medicaments.But the open report of so far there are no useful hyaluronic acid decorated Au doped titanic oxide nano tube and application thereof.
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 preparation method and application thereof of hyaluronic acid decorated Au doped titanic oxide nano tube, effectively can solve the preparation with hyaluronic acid decorated Au doped titanic oxide nano tube, and the application problem in preparation tumor.
The technical scheme that the present invention solves is, the preparation method of this hyaluronic acid decorated Au doped titanic oxide nano tube, prepare titania nanotube by hydrothermal synthesis method, then be predecessor with titania nanotube, utilize photoreduction calcination method to prepare the titania nanotube of finishing Au; To be connected to by TGA on the titania nanotube of Au doping by mercapto gold key, hyaluronic acid is that the TGA of linking arm and the finishing of Au doped titanic oxide nano tube is covalently bound by Alkylenediamine, in aqueous medium, form nanometer layer; Described hyaluronic acid is that molecular weight is equal to or less than 400kd, and is equal to or higher than 600 daltonian low-molecular-weight hyaluronic acids; Described linking arm is the Alkylenediamine structure of carbon number 2-12, specifically comprises the following steps:
(1) synthesis of titania nanotube: NaOH is placed in beaker, adds deionized water, stirs under ice bath and makes it dissolve, be cooled to room temperature, become mass concentration to be the solution of 40g/100ml, then add TiO
2powder of nanometric particles, NaOH and TiO
2the weight ratio of powder of nanometric particles is 2000 ︰ 1, ultrasonic disperse 15min, 140-160 DEG C of heating 24-35h, be chilled to room temperature, be the neutrality of 7 with 0.1mol/L HCl solution and washed with de-ionized water to pH value successively again, sucking filtration, removing liquid, obtain solids, solids 60 DEG C of vacuum dryings, obtain dry thing, grinding, become titania nanotube (TiNTs), keep in Dark Place;
(2) preparation of Au doped titanic oxide nano tube: by gold chloride (AuCl
4h) solid adds in distilled water and stirs, it is dissolved completely, become the solution of 200mg/ml, be that 1 ︰ 50-100 adds titania nanotube according to Au in gold chloride and titania nanotube mass ratio again, by its lucifuge sonic oscillation 1h, make it be uniformly dispersed, lucifuge stirs 12h again, it is made fully to adsorb, dispersion liquid is used irradiation under ultraviolet ray 3h, leave standstill 6-8h, filter, discard filtrate, obtain fixed body, solids 80 DEG C of dry 18h, be that 2 DEG C/min is warming up to 500 DEG C with speed again, keep 3h, to be cooled to room temperature, porphyrize, obtain the titania nanotube (Au@TiNTs) of Au doping,
(3) TGA is TiO 2 nanotubes modified: the titania nanotube that Au adulterates is added the solution that ultra-pure water is dissolved into 1mg/ml, TGA is added in solution, TGA 10-15mg is added in the solution that the titania nanotube that every 150-200mg Au adulterates is made, lucifuge stirs 24h, dialysis, sucking filtration, 50 DEG C of vacuum dryings, obtain the titania nanotube of the Au doping that TGA is modified;
(4) the hyaluronic synthesis of ammonification: 180-220mg hyaluronic acid (HA) is dissolved in 10-15ml organic solvent, 2-3h is dissolved in 45-55 DEG C of oil bath, add 400-500mg 1-ethyl-(3-dimethylaminopropyl) carbodiimide, 260-320mg N-Hydroxysuccinimide, room temperature activation 30min, then joining 8-12ml concentration is in the Alkylenediamine solution of 0.5M, room temperature reaction 12-48h, then the acetone adding pre-cooling precipitates, sucking filtration obtains precipitate; Precipitate adds water redissolution, and dialysis, lyophilization obtains the hyaluronic acid (NH of ammonification
2-HA);
Described organic solvent is the one of Methanamide, DMF, dimethyl sulfoxide;
(5) synthesis of hyaluronic acid decorated Au doped titanic oxide nano tube: titania nanotube and the ammonification hyaluronic acid of the Au doping of being modified by TGA are dissolved in reaction dissolvent according to the mass ratio of 1:1.5-2, add 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) according to the mass ratio of 1:1.4-1.8 (ammonification hyaluronic acid: EDC), the mass ratio of 1:1.5-2.0 (ammonification hyaluronic acid: NHS) adds N-Hydroxysuccinimide (NHS) and activate, room temperature reaction 12-36h; Add acetone again to precipitate, sucking filtration obtains precipitate, and add water redissolution precipitate, dialysis, and namely lyophilization obtains hyaluronic acid decorated Au doped titanic oxide nano tube (HA-Au@TiNTs); Described reaction dissolvent is the mixed solvent of water or Methanamide or DMF and water or Methanamide and water or DMF and Methanamide, or the mixture of other similar solvent and other similar solvent.
The present invention adopts noble metal (Au, Pt, Pd etc.) modified titanic oxide, by the electron distributions in change system, affects the surface nature of titanium dioxide, and then expands its absorption spectrum to visible ray, thus improves its photocatalytic activity.In noble metal, Au is cheap and easy to get than Pt, Pd, toxicity is little and have bactericidal action, Jenner's grain of rice has remarkable photothermal deformation characteristic in addition, heat production better performances under the irradiation of near infrared light, the combination drug carrier formed like this to be held concurrently photo-thermal therapy carrier material with regard to the photodynamics becoming a kind of great potential; Adopt natural polysaccharide---the hyaluronic acid with good biocompatibility, tumor cell targeting simultaneously, be linking arm by its carboxyl by simple Alkylenediamine, the Au doped titanic oxide nano tube modified with TGA is covalently bound, constructs the nano-carrier of a kind of photo-thermal treatment associating photodynamic therapy.This carrier synthesis technique is simple, and by the photocatalysis performance of titania nanotube brilliance and powerful drug loading characteristic, the significant photo-thermal sensitivity of Jenner's grain of rice, the tumor cell targeting of hyaluronic acid uniqueness, auxiliary anti-tumor activity, good biocompatibility is organically integrated in one, in addition physical load the medicine of anti-tumor activity can be had, , both a non-target tropism difficult problem for traditional tumour treatment can have been overcome, reduce the damage of normal tissue in therapeutic process, have efficient, controlled advantage, and, it is by photodynamic therapy, photo-thermal therapy, chemotherapy well combines, the more effective Comprehensive Treatment realizing cancer, it is the innovation on Therapeutic cancer medicine, economic and social benefit is huge.
Detailed description of the invention
Below in conjunction with embodiment, the specific embodiment of the present invention is elaborated.
The present invention, in concrete enforcement, also can be realized by following steps:
(1) synthesis of titania nanotube: take 40g NaOH and be placed in beaker, add deionized water, ice bath stirs and makes it dissolve, and is cooled to room temperature, then adds deionized water and be settled to 100ml, add 200mg TiO
2powder of nanometric particles, ultrasonic disperse 15min, insert in the reactor of polytetrafluoroethylliner liner, in Muffle furnace, 150 DEG C of heating 24-35h, are chilled to room temperature, be 7 by 0.1mol/L HCl solution and washed with de-ionized water to pH successively, with microporous filter membrane (moisture film) sucking filtration of diameter 0.22 μm, 60 DEG C of oven dry in vacuum drying oven, grinding, obtain titania nanotube (TiNTs), keep in Dark Place;
(2) preparation of Au doped titanic oxide nano tube: the gold chloride solid taking 200mg is placed in beaker, add the solution that distilled water is made into 200mg/ml, stirring and dissolving is even, be that 1 ︰ 50-100 adds titania nanotube according to Au in gold chloride and titania nanotube mass ratio in beaker again, lucifuge is placed in ultrasonic oscillator and vibrates 1h, make it be uniformly dispersed, lucifuge stirs 12h again, it is made fully to adsorb, irradiate 3h under ultraviolet light, leave standstill 6-8h, filter, dry 18h at 80 DEG C, proceed in temperature programmed control Muffle furnace again, be that 2 DEG C/min is warming up to 500 DEG C with speed, and keep 3h, porphyrize is taken out after being cooled to room temperature, obtain the titania nanotube (Au@TiNTs) of Au doping,
(3) TGA is TiO 2 nanotubes modified: take the titania nanotube that 175mg Au adulterates, add the ultra-pure water wiring solution-forming of 175ml, the TGA of 13mg is added in solution, lucifuge stirs 24h, dialyse with the bag filter of MW=3500, use microporous filter membrane (moisture film) sucking filtration of diameter 0.22 μm again, 50 DEG C of dryings in vacuum drying oven, obtain the titania nanotube of the Au doping that TGA is modified;
(4) the hyaluronic synthesis of ammonification: get 200mg hyaluronic acid (HA) in 10-15ml organic solvent, 2-3h is dissolved in 50 DEG C of oil baths, add 450mg 1-ethyl-(3-dimethylaminopropyl) carbodiimide and 290mg N-Hydroxysuccinimide activates, room temperature activation 30min; Then joining 10ml concentration is in the Alkylenediamine solution of 0.5M, room temperature reaction 12-48h; The acetone adding pre-cooling after reaction terminates precipitates, and sucking filtration obtains precipitate; Add water redissolution precipitate, and dialysis, lyophilization, obtains the hyaluronic acid (NH of ammonification
2-HA);
(5) synthesis of hyaluronic acid decorated Au doped titanic oxide nano tube: titania nanotube and the ammonification hyaluronic acid of the Au doping of being modified by TGA are dissolved in reaction dissolvent according to the mass concentration ratio of 1:1.5-2, 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) is added according to the mass ratio of 1:1.4-1.8 (ammonification hyaluronic acid: EDC), the mass ratio of 1:1.5-2.0 (ammonification hyaluronic acid: NHS) adds N-Hydroxysuccinimide (NHS) and activates, room temperature reaction 12-36h, add acetone precipitation, sucking filtration obtains precipitate, add water redissolution precipitate, dialysis, namely lyophilization obtains hyaluronic acid decorated Au doped titanic oxide nano tube (HA-Au@TiNTs).
Hyaluronic acid decorated Au doped titanic oxide nano tube prepared by said method, can be used for preparing antineoplastic pharmaceutical compositions, realize preparing the application in antineoplastic pharmaceutical compositions with hyaluronic acid decorated Au doped titanic oxide nano tube, described pharmaceutical composition is that hyaluronic acid decorated Au doped titanic oxide nano tube and pharmaceutical active or pharmacologically active molecule make medicament-carried nano layer, and described pharmaceutical active or pharmacologically active molecule are insoluble anti-tumor medicament, water soluble drug and nucleic acid drug;
Described hyaluronic acid decorated Au doped titanic oxide nano tube is preparing the application in antineoplastic pharmaceutical compositions, described medicament-carried nano layer is hyaluronic acid decorated Au doped titanic oxide nano tube and the water Proportioning probe ultrasonic dissolution by weight 1 ~ 50 ︰ 100, mix with the antitumor drug through dissolution with solvents, through ultrasonic or high pressure homogenize process, stirring at room temperature adopts dialysis or ultrafiltration or post partition method to remove organic solvent and free drug after 24 hours, lyophilizing obtains the nanometer layer that particle diameter is 10 ~ 1000nm;
Described antineoplastic pharmaceutical compositions can be used as photo-thermal therapy, photodynamic therapy, combined chemotherapy cancer drug, realizes the application in photo-thermal therapy, photodynamic therapy, combined chemotherapy cancer drug.
From the above, the object of this invention is to provide a kind ofly have that antitumor optical dynamic therapy is active, photo-thermal therapy is active concurrently, the hyaluronic acid decorated Au doped titanic oxide nano tube of tumor cell targeting and good biocompatibility.This hyaluronic acid decorated Au doped titanic oxide nano tube synthesis technique and chemical constitution all comparatively simple, avoid and introduce different kinds of molecules group for improving biocompatibility, stability and targeting, and remain the photocatalysis characteristic that titanium dioxide has, the Photothermal characterisation that Jenner's grain of rice has; In addition, can physical load antitumor drug, jointly reach the effect of Therapeutic cancer.
Another object of the present invention is to provide the pharmaceutical composition comprising above-mentioned hyaluronic acid decorated Au doped titanic oxide nano tube.
Another object of the present invention is to provide above-mentioned hyaluronic acid decorated Au doped titanic oxide nano tube and comprises the preparation method of above-mentioned hyaluronic acid decorated Au doped titanic oxide nano tube pharmaceutical composition.
Of the present invention also have an object to be to provide above-mentioned hyaluronic acid decorated Au doped titanic oxide nano tube and the application of pharmaceutical composition in field of medicaments thereof.
For achieving the above object, the technical solution used in the present invention prepares titania nanotube by hydrothermal synthesis method, then with homemade titania nanotube for predecessor, utilize photoreduction calcination method to prepare the titania nanotube of finishing Au; By mercapto gold key, TGA is connected on the titania nanotube of Au doping afterwards, hyaluronic acid is that the TGA of linking arm and the finishing of Au doped titanic oxide nano tube is covalently bound by Alkylenediamine, this pharmaceutical carrier can spontaneous formation nanometer layer in aqueous medium, relend the drug carrying capacity that assisting titanium dioxide nanotube is stronger, physical load antitumor drug, forms the titania nanotube pharmaceutical composition of hyaluronic acid decorated Au doping.Due to the photocatalysis performance of titania nanotube brilliance and the powerful photothermal deformation characteristic of Jenner's grain of rice, therefore this system can realize photo-thermal therapy, photodynamic therapy combined chemotherapy, more effectively realizes the Comprehensive Treatment to cancer.
Described antineoplastic pharmaceutical compositions, comprises hyaluronic acid decorated Au doped titanic oxide nano tube of the present invention and pharmaceutical active or pharmacologically active molecule.Wherein pharmaceutical active or pharmacologically active molecule are: insoluble anti-tumor medicament, water soluble drug and nucleic acid drug, such as: one or more in Docetaxel, paclitaxel, amycin, cisplatin, carboplatin, daunorubicin, few adopted antinucleus thuja acid, siRNA and enzyme drug.
Described antineoplastic pharmaceutical compositions, may be used for injection, oral or drug delivery implant.Wherein drug administration by injection optimizing injection, freeze-dried powder, oral administration preferred tablet, capsule, pill, syrup, granule, drug delivery implant preferably from gel, solution.
And obtain sufficient proof through regarding assay, regarding assay data is as follows:
1, the titania nanotube in the present invention, Au doped titanic oxide nano tube are carried out to ultraviolet spectrophotometry and sweep analysis of spectrum, prove that the absorption spectrum of titanium dioxide effectively can be expanded to visible region by ultraviolet region by the doping of Jenner's grain of rice; The dispersibility test carried out in transmission electron microscope morphologic observation and water homemade titania nanotube, Au doped titanic oxide nano tube and hyaluronic acid decorated Au doped titanic oxide nano tube is known, titania nanotube form is homogeneous, internal diameter is large, can efficient loading medicine, Au is successful load on titanium dioxide tube, after hyaluronic acid is successfully modified Au doped titanic oxide nano tube, its dispersibility in water obviously improves.
The photo-thermal effect experiment of 2, hyaluronic acid decorated Au doped titanic oxide nano tube
Prepare the titania nanotube of a series of concentration and hyaluronic acid decorated Au doped titanic oxide nano tube solution, adopt 808nm NIR laser device with 2 W/cm
2energy density irradiate, and in 0,1,2,3,4,5,6,7,8,9,10min measures the temperature of solution, titania nanotube after Au doping has excellent photothermal conversion effect, and hyaluronic acid does not affect its Photothermal characterisation to the modification of Au doped titanic oxide nano tube.
3, hyaluronic acid decorated Au doped titanic oxide nano tube produces the determination experiment of active oxygen to tumor cell
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 RPMI 1640 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 hyaluronic acid decorated Au doped titanic oxide nano tube in the embodiment 1 of 20 μ g/ml, arranging multiple hole is 2 ~ 4.After dosing 4h, light group is placed on 2min in 532nm laser 2W, 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 3ml PBS 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, known hyaluronic acid decorated Au doped titanic oxide nano tube can produce a large amount of active oxygen in tumor cell under visible light illumination, can be used as photosensitizer for carrying out photodynamic therapy to tumor.
4, illumination is used to penetrate hyaluronic acid decorated Au doped titanic oxide nano tube of the present invention to the mensuration of the inhibit activities of growth of tumour cell.
Hyaluronic acid decorated Au doped titanic oxide nano tube anti-tumor activity in vitro of the present invention is penetrated: by MCF-7 breast cancer cell (being provided by Shanghai cell bank) as cancerous cell to be investigated by illumination.MCF-7 cell culture is being contained hyclone (FBS) 10%, and in RPMI 1640 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 hyaluronic acid decorated Au doped titanic oxide nano tube in the embodiment 1 of Concentraton gradient (12.5,25,50,100 μ g/ml), arranging multiple hole is 4 ~ 6, be divided into 4 groups, be specifically grouped as follows: the Au doped titanic oxide nano tube group that (1) is hyaluronic acid decorated; (2) hyaluronic acid decorated Au doped titanic oxide nano tube-808nm laser group; (3) hyaluronic acid decorated Au doped titanic oxide nano tube-532nm laser group; (4) hyaluronic acid decorated Au doped titanic oxide nano tube-808nm-532nm combines laser group; Wherein laser group is placed on 2min in 532nm or 808nm laser 2W, 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, sucking-off pastille culture medium, every hole 150 μ l PBS wash 2 times, add the 10%TCA200 μ l of pre-cooling, place 1h for 4 DEG C.Outwell fixative.Every hole deionized water washes 5 times, dries, air drying.Every hole adds the SRB solution of 100 μ l, leaves standstill and places 10min, do not wash 5 times, air drying with protein bound SRB 1% acetic acid.In conjunction with SRB 150 μ l 10mmol/L non-buffered Tris alkali dissolutions.The OD value in every hole is measured at 515nm 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 deducting empty bag matched group.
Verifiedly when with 808nm laser or 532nm laser irradiating cell, all can affect the propagation of MCF-7 tumor cell, the effect of wherein combining the growth of laser group Tumor suppression is the most obvious.
When illumination is penetrated, the anti-tumor in vivo determination of activity of hyaluronic acid decorated Au doped titanic oxide nano tube of the present invention: get mouse S180 ascites sarcoma cell, with injection normal saline with after 3:1 dilution proportion, every mice is 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 30 gross tumor volume>=100mm
3kunming mice, is divided into 5 groups at random, often organizes 6.Specifically be grouped as follows: (1) matched group (NS group): normal saline; (2) hyaluronic acid decorated Au doped titanic oxide nano tube group; (3) hyaluronic acid decorated Au doped titanic oxide nano tube-808nm laser group; (4) hyaluronic acid decorated Au doped titanic oxide nano tube-532nm laser group; (5) hyaluronic acid decorated Au doped titanic oxide nano tube-808nm-532nm combines laser group.5 groups of modes all adopting intravenously administrable, wherein laser group (532nm or 808nm laser), power is 2W, and after administration 3h, laser irradiates tumor locus, and the once irradiating time is 2min.Every 2d is administered once, the hyaluronic acid decorated Au doped titanic oxide nano tube 100 μ l of per injection normal saline or 10mg/ml, 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), by formula gross tumor volume
calculate gross tumor volume.
When administration hyaluronic acid decorated Au doped titanic oxide nano tube of the present invention merges laser irradiation, the increase of the gross tumor volume of mice obtains obvious suppression, and the effect of wherein combining the growth of laser group Tumor suppression is the most obvious.
The anti-tumor activity of 6, hyaluronic acid decorated Au doped titanic oxide nano tube-amycin drug-supplying system
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 RPMI 1640 culture medium of mycillin mixed liquor 1%, incubator condition is 37 DEG C, 5%CO2, within every 2 ~ 3 days, goes 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 hyaluronic acid decorated Au doped titanic oxide nano tube-amycin in the embodiment 5 of Concentraton gradient (0,0.1,0.5,1,2,4 μ g/ml), free amycin is matched group, arranging multiple hole is 4 ~ 6, is divided into 5 groups, is specifically grouped as follows: (1) amycin group; (2) hyaluronic acid decorated Au doped titanic oxide nano tube-amycin group; (3) hyaluronic acid decorated Au doped titanic oxide nano tube-amycin-808nm laser group; (4) hyaluronic acid decorated Au doped titanic oxide nano tube-amycin-532nm laser group; (5) hyaluronic acid decorated Au doped titanic oxide nano tube-amycin-808nm-532nm combines laser group; Wherein laser group is placed on 2min in 532nm or 808nm laser 2W, 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, sucking-off pastille culture medium, every hole 150 μ l PBS wash 2 times, add the 10%TCA 200 μ l of pre-cooling, place 1h for 4 DEG C.Outwell fixative.Every hole deionized water washes 5 times, dries, air drying.Every hole adds the SRB solution of 100 μ l, leaves standstill and places 10min, do not wash 5 times, air drying with protein bound SRB 1% acetic acid.In conjunction with SRB 150 μ l 10mmol/L non-buffered Tris alkali dissolutions.The OD value in every hole is measured at 515nm place.The computing formula of suppression ratio: suppression ratio=1-experimental group OD value/matched group OD value, wherein experimental group and matched group are the value after deducting empty bag matched group.
Experiment proves that the hyaluronic acid decorated Au doped titanic oxide nano tube in the present invention can enter inside tumor cells by mediate drug as during pharmaceutical carrier, better give play to the curative effect of antitumor drug, and in conjunction with after illumination, can the propagation of more obvious inhibition tumor cell, the effect of wherein combining the growth of laser group Tumor suppression is the most obvious.
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 6 groups at random, often organizes 6.Specifically be grouped as follows: (1) matched group (NS group): normal saline; (2) amycin group; (3) hyaluronic acid decorated Au doped titanic oxide nano tube-amycin group; (4) hyaluronic acid decorated Au doped titanic oxide nano tube-amycin-808nm laser group; (5) hyaluronic acid decorated Au doped titanic oxide nano tube-amycin-532nm laser group; (6) hyaluronic acid decorated Au doped titanic oxide nano tube-amycin-808nm-532nm combines laser group.The amycin dosage that amycin group, hyaluronic acid decorated Au doped titanic oxide nano tube-amycin group, hyaluronic acid decorated Au doped titanic oxide nano tube-amycin-808nm laser group, hyaluronic acid decorated Au doped titanic oxide nano tube-amycin-532nm laser group, hyaluronic acid decorated Au doped titanic oxide nano tube-amycin-808nm-532nm combines laser group is equal, is all 7.8mg/kg.6 groups of modes all adopting intravenously administrable, wherein laser group (532nm or 808nm laser), power is 2W, 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), by formula gross tumor volume
calculate gross tumor volume.
When giving hyaluronic acid decorated Au doped titanic oxide nano tube-amycin, the increase of the gross tumor volume of mice obtains obvious suppression compared with doxorubicin injection, and in conjunction with after illumination, can the propagation of more obvious inhibition tumor cell, the effect of wherein combining the growth of laser group Tumor suppression is the most obvious.
While doing above-mentioned experiment, the similar experiment that also adopted other light source and antitumor drug to do, all achieves identical and similar result, and the present invention divides into groups science, and method is reliable and stable, and other experimental result will not enumerate.
Fully shown by above-mentioned data, preparation method of the present invention is applicant through scientific research, experiment and the creative work crystallization made practice summary, compared with prior art, has following outstanding substantive distinguishing features and marked improvement:
(1) the present invention select have good biocompatibility, tumor cell targeting natural polysaccharide---hyaluronic acid is decorating molecule, take Alkylenediamine as linking arm, modify Au doped titanic oxide nano tube by a kind of simple economy and the method that easily realizes suitability for industrialized production, mild condition, reaction is simple, productive rate is high;
(2) hyaluronic acid decorated Au doped titanic oxide nano tube provided by the invention has excellent biocompatibility, water solublity and stability, tumour-specific targeting can also be realized, and the efficiency light thermal therapeutical remaining Jenner's grain of rice is active and titanium dioxide in visible region efficient photocatalytic activity, realize the medication problem of the photo-thermal therapy associating optical dynamic therapy to tumor;
(3) hyaluronic acid decorated Au doped titanic oxide nano tube provided by the invention, can physical load antitumor drug, and realize the Comprehensive Treatment to tumor, be the innovation in tumor, economic and social benefit is huge.
Claims (5)
1. the preparation method of a hyaluronic acid decorated Au doped titanic oxide nano tube, it is characterized in that, prepare titania nanotube by hydrothermal synthesis method, be then predecessor with titania nanotube, utilize photoreduction calcination method to prepare the titania nanotube of finishing Au; To be connected to by TGA on the titania nanotube of Au doping by mercapto gold key, hyaluronic acid is that the TGA of linking arm and the finishing of Au doped titanic oxide nano tube is covalently bound by Alkylenediamine, in aqueous medium, form nanometer layer; Described hyaluronic acid is that molecular weight is equal to or less than 400 kd, and is equal to or higher than 600 daltonian low-molecular-weight hyaluronic acids; Described linking arm is the Alkylenediamine structure of carbon number 2-12, specifically comprises the following steps:
(1) synthesis of titania nanotube: NaOH is placed in beaker, adds deionized water, stirs under ice bath and makes it dissolve, be cooled to room temperature, become mass concentration to be the solution of 40g/100ml, then add TiO
2powder of nanometric particles, NaOH and TiO
2the weight ratio of powder of nanometric particles is 2000 ︰ 1, ultrasonic disperse 15min, 140-160 DEG C of heating 24-35h, be chilled to room temperature, be the neutrality of 7 with 0.1mol/L HCl solution and washed with de-ionized water to pH value successively again, sucking filtration, removing liquid, obtain solids, solids 60 DEG C of vacuum dryings, obtain dry thing, grinding, become titania nanotube, keep in Dark Place;
(2) preparation of Au doped titanic oxide nano tube: gold chloride solid is added in distilled water and stirs, it is dissolved completely, become the solution of 200mg/ml, be that 1 ︰ 50-100 adds titania nanotube according to Au in gold chloride and titania nanotube mass ratio again, by its lucifuge sonic oscillation 1h, make it be uniformly dispersed, lucifuge stirs 12h again, it is made fully to adsorb, dispersion liquid is used irradiation under ultraviolet ray 3h, leave standstill 6-8h, filter, discard filtrate, obtain fixed body, solids 80 DEG C of dry 18h, be that 2 DEG C/min is warming up to 500 DEG C with speed again, keep 3h, to be cooled to room temperature, porphyrize, obtain the titania nanotube of Au doping,
(3) TGA is TiO 2 nanotubes modified: the titania nanotube that Au adulterates is added the solution that ultra-pure water is dissolved into 1mg/ml, TGA is added in solution, TGA 10-15mg is added in the solution that the titania nanotube that every 150-200mg Au adulterates is made, lucifuge stirs 24h, dialysis, sucking filtration, 50 DEG C of vacuum dryings, obtain the titania nanotube of the Au doping that TGA is modified;
(4) the hyaluronic synthesis of ammonification: 180-220mg hyaluronic acid is dissolved in 10-15ml organic solvent, 2-3h is dissolved in 45-55 DEG C of oil bath, add 400-500mg 1-ethyl-(3-dimethylaminopropyl) carbodiimide, 260-320mg N-Hydroxysuccinimide, room temperature activation 30min, then joining 8-12ml concentration is in the Alkylenediamine solution of 0.5M, room temperature reaction 12-48h, then the acetone adding pre-cooling precipitates, sucking filtration obtains precipitate; Precipitate adds water redissolution, dialysis, and lyophilization obtains the hyaluronic acid of ammonification;
Described organic solvent is the one of Methanamide, DMF, dimethyl sulfoxide;
(5) synthesis of hyaluronic acid decorated Au doped titanic oxide nano tube: titania nanotube and the ammonification hyaluronic acid of the Au doping of being modified by TGA are dissolved in reaction dissolvent according to the mass ratio of 1 ︰ 1.5-2, according to ammonification hyaluronic acid: 1-ethyl-(3-dimethylaminopropyl) carbodiimide is that the mass ratio of 1 ︰ 1.4-1.8 adds 1-ethyl-(3-dimethylaminopropyl) carbodiimide, ammonification hyaluronic acid: N-Hydroxysuccinimide is that the mass ratio of 1 ︰ 1.5-2.0 adds N-Hydroxysuccinimide and activates, room temperature reaction 12-36h; Add acetone again to precipitate, sucking filtration obtains precipitate, and add water redissolution precipitate, dialysis, and namely lyophilization obtains hyaluronic acid decorated Au doped titanic oxide nano tube;
Described reaction dissolvent is the mixed solvent of water or Methanamide or DMF and water or Methanamide and water or DMF and Methanamide.
2. the preparation method of hyaluronic acid decorated Au doped titanic oxide nano tube according to claim 1, is characterized in that, realized by following steps:
(1) synthesis of titania nanotube: take 40g NaOH and be placed in beaker, add deionized water, ice bath stirs and makes it dissolve, and is cooled to room temperature, then adds deionized water and be settled to 100ml, add 200mg TiO
2powder of nanometric particles, ultrasonic disperse 15min, insert in the reactor of polytetrafluoroethylliner liner, in Muffle furnace, 150 DEG C of heating 24-35h, are chilled to room temperature, be 7 by 0.1mol/L HCl solution and washed with de-ionized water to pH successively, with the microporous filter membrane sucking filtration of diameter 0.22 μm, 60 DEG C of oven dry in vacuum drying oven, grinding, obtain titania nanotube, keep in Dark Place;
(2) preparation of Au doped titanic oxide nano tube: the gold chloride solid taking 200mg is placed in beaker, add the solution that distilled water is made into 200mg/ml, stirring and dissolving is even, be that 1 ︰ 50-100 adds titania nanotube according to Au in gold chloride and titania nanotube mass ratio in beaker again, lucifuge is placed in ultrasonic oscillator and vibrates 1h, make it be uniformly dispersed, lucifuge stirs 12 h again, it is made fully to adsorb, irradiate 3h under ultraviolet light, leave standstill 6-8h, filter, dry 18h at 80 DEG C, proceed in temperature programmed control Muffle furnace again, be that 2 DEG C/min is warming up to 500 DEG C with speed, and keep 3h, porphyrize is taken out after being cooled to room temperature, obtain the titania nanotube of Au doping,
(3) TGA is TiO 2 nanotubes modified: take the titania nanotube that 175mg Au adulterates, add the ultra-pure water wiring solution-forming of 175ml, the TGA of 13mg is added in solution, lucifuge stirs 24h, dialyse with the bag filter of MW=3500, use the microporous filter membrane sucking filtration of diameter 0.22 μm again, 50 DEG C of dryings in vacuum drying oven, obtain the titania nanotube of the Au doping that TGA is modified;
(4) the hyaluronic synthesis of ammonification: get 200mg hyaluronic acid in 10-15ml organic solvent, 2-3h is dissolved in 50 DEG C of oil baths, add 450mg 1-ethyl-(3-dimethylaminopropyl) carbodiimide and 290mg N-Hydroxysuccinimide activates, room temperature activation 30min; Then joining 10ml concentration is in the Alkylenediamine solution of 0.5M, room temperature reaction 12-48h; The acetone adding pre-cooling after reaction terminates precipitates, and sucking filtration obtains precipitate; Add water redissolution precipitate, dialysis, and lyophilization, obtains the hyaluronic acid of ammonification;
(5) synthesis of hyaluronic acid decorated Au doped titanic oxide nano tube: titania nanotube and the ammonification hyaluronic acid of the Au doping of being modified by TGA are dissolved in reaction dissolvent according to the mass concentration ratio of 1:1.5-2, according to ammonification hyaluronic acid: 1-ethyl-(3-dimethylaminopropyl) carbodiimide is that the mass ratio of 1:1.4-1.8 adds 1-ethyl-(3-dimethylaminopropyl) carbodiimide, ammonification hyaluronic acid: N-Hydroxysuccinimide is that the mass ratio of 1:1.5-2.0 adds N-Hydroxysuccinimide and activates, room temperature reaction 12-36h, add acetone precipitation, sucking filtration obtains precipitate, add water redissolution precipitate, dialysis, namely lyophilization obtains hyaluronic acid decorated Au doped titanic oxide nano tube.
3. the hyaluronic acid decorated Au doped titanic oxide nano tube that prepared by method described in claim 1 or 2 is preparing the application in antineoplastic pharmaceutical compositions, described pharmaceutical composition is that hyaluronic acid decorated Au doped titanic oxide nano tube and pharmaceutical active or pharmacologically active molecule make medicament-carried nano layer, and described pharmaceutical active or pharmacologically active molecule are insoluble anti-tumor medicament, water soluble drug and nucleic acid drug.
4. hyaluronic acid decorated Au doped titanic oxide nano tube according to claim 3 is preparing the application in antineoplastic pharmaceutical compositions, it is characterized in that, described medicament-carried nano layer is hyaluronic acid decorated Au doped titanic oxide nano tube and the water Proportioning probe ultrasonic dissolution by weight 1 ~ 50 ︰ 100, mix with the antitumor drug through dissolution with solvents, through ultrasonic or high pressure homogenize process, stirring at room temperature adopts dialysis or ultrafiltration or post partition method to remove organic solvent and free drug after 24 hours, lyophilizing obtains the nanometer layer that particle diameter is 10 ~ 1000 nm.
5. hyaluronic acid decorated Au doped titanic oxide nano tube according to claim 3 is preparing the application in antineoplastic pharmaceutical compositions, it is characterized in that, the application of described antineoplastic pharmaceutical compositions in photo-thermal therapy, photodynamic therapy, combined chemotherapy cancer drug.
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