CN104368003B - 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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- CN104368003B CN104368003B CN201410652133.7A CN201410652133A CN104368003B CN 104368003 B CN104368003 B CN 104368003B CN 201410652133 A CN201410652133 A CN 201410652133A CN 104368003 B CN104368003 B CN 104368003B
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- hyaluronic acid
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- titanic oxide
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- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 title claims abstract description 223
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- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 109
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 101
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 99
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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 400 kd, 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 medical, particularly a kind of preparation method of hyaluronic acid decorated Au doped titanic oxide nano tubes
And its application.
Background technology
Malignant tumor has exceeded cardiovascular disease, becomes the primary lethal cause of disease of urbanite, seriously threatens the life of the mankind
Life and health.At present, medically universal Bian chemotherapy, actinotherapy and surgical operation is come treating cancer.Chemotherapy
Cancerous cell is destroyed by medicine, but there is a problem of targeting difference and dose limiting toxicity；Actinotherapy is using electricity
Shoot to death from linchpin and hinder cancerous cell and make tumor wife contract, but in clinical treatment, normal structure also can be penetrated damage by corresponding good fortune；
Surgical operation is the purpose that treating cancer is reached by tumor resection tissue, but it is larger to human body wound, and Chang Yin
Cause curative effect poor for cancerous cell has spread.Therefore, with the continuous development of photoactive substance and laser technology, photodynamics
Therapy provides a kind of minimally invasive and effective therapy approach for treatment of cancer.
Titanium dioxide (Ti02) it is a kind of conventional photocatalyst, with wet sensitive, air-sensitive, dielectric effect, opto-electronic conversion, light
The performance such as mutagens color and superior photocatalysis, thus it is widely used in the fields such as sensor, dielectric material, self-cleaning material.And phase
Close research to find, Ti02Chemistry and good light stability, less to the toxicity of organism, is a kind of quite safe in cellular level
Material, thus Ti0 in the last few years2In terms of biological photodynamic therapy basic research in vivo is carried out as pharmaceutical carrier achieved with
A series of progress, are potential photodynamic therapy materials.And titania nanotube (TiNTs) has compared with nano-powder
Bigger specific surface area and the hollow structure of specificity, therefore have more tempting application prospect in terms of pharmaceutical carrier.
However, although titania nanotube (TiNTs) is a kind of photodynamic therapy carrier material of great potential,
Its application in oncotherapy is realized, lot of challenges is still faced, such as：Titanium dioxide is used as a kind of n-type semiconductor, band gap
Wider, photo-generate electron-hole recombination probability is higher and relatively low to sun light utilization efficiency；It is bad in water stability, surface energy
Height, easy coagulation under physiological condition；The compatibility in vivo awaits further improvement etc..It is essential that, dioxy
Change titanium nanotube itself and do not have tumor cell targeting, it is difficult to realize the targeting transhipment of medicine and the efficient, photodynamics of low toxicity
Combined chemotherapy.Therefore, if its biocompatibility can be improved suitably by functionalization, while solving its targeting defect, it will significantly
Improve its application in field of medicaments.But so far there are no useful hyaluronic acid decorated Au doped titanic oxide nano tubes and its should
Open report.
The content of the invention
For above-mentioned situation, to overcome the defect of prior art, the purpose of the present invention to be just to provide a kind of hyaluronic acid and repair
The preparation method and applications of the Au doped titanic oxide nano tubes of decorations, can effectively solving with hyaluronic acid decorated Au doping two
The preparation of titanium oxide nanotubes, and the application problem in tumor is prepared.
The present invention solve technical scheme be, the preparation side of the hyaluronic acid decorated Au doped titanic oxide nano tubes
Method, is to prepare titania nanotube by hydrothermal synthesis method, then with titania nanotube as predecessor, using illumination also
Former calcination method prepares the titania nanotube of surface modification Au；TGA is connected to by mercapto gold key for the dioxy of Au doping
Change on titanium nanotube, hyaluronic acid is linking arm and the mercapto of Au doped titanic oxide nano tube surface modifications by Alkylenediamine
Guanidine-acetic acid is covalently attached, and nanometer layer is formed in aqueous medium；The hyaluronic acid is that molecular weight is equal to or less than 400kd, and is waited
In or higher than the low-molecular-weight hyaluronic acid of 600 dalton；The linking arm is the Alkylenediamine structure of carbon number 2-12,
Specifically include following steps：
(1) synthesis of titania nanotube：NaOH is placed in beaker, deionized water is added, stirring under ice bath makes it
Dissolving, is cooled to room temperature, is the solution of 40g/100ml into mass concentration, adds TiO2Powder of nanometric particles, NaOH and TiO2
The weight ratio of powder of nanometric particles is 2000 ︰ 1, ultrasonic disperse 15min, and 140-160 DEG C of heating 24-35h is cooled to room temperature, then according to
Secondary 0.1mol/L HCl solutions and deionized water are cleaned to the neutrality that pH value is 7, sucking filtration, remove liquid, obtain solidss, solid
60 DEG C of vacuum drying of thing, obtain dried object, grind, and into titania nanotube (TiNTs), keep in dark place；
(2) preparation of Au doped titanic oxide nano tubes：By gold chloride (AuCl4H) solid is added in distilled water and stirred, will
It is completely dissolved, and is 1 ︰ 50-100 according still further to Au in gold chloride and titania nanotube mass ratio into the solution of 200mg/ml
Titania nanotube is added, by its lucifuge sonic oscillation 1h so as to be uniformly dispersed, then lucifuge stirring 12h so as to fully inhale
It is attached, by dispersion liquid ultraviolet light 3h, 6-8h is stood, filter, filtrate is discarded, fixed body is obtained, 80 DEG C of solidss are dried 18h,
Again 500 DEG C are warming up to by 2 DEG C/min of speed, keep 3h, be cooled to room temperature, it is finely ground, obtain the nano titania of Au doping
Pipe (Au@TiNTs)；
(3) TGA is TiO 2 nanotubes modified：The titania nanotube that Au is adulterated adds ultrapure water dissolution
Into the solution of 1mg/ml, TGA is added in solution, made by the titania nanotube per 150-200mg Au doping
TGA 10-15mg, lucifuge stirring 24h, dialysis, sucking filtration, 50 DEG C of vacuum drying is added to obtain TGA modification in solution
The titania nanotube of Au doping；
(4) synthesis of ammonification hyaluronic acid：180-220mg hyaluronic acids (HA) are dissolved in 10-15ml organic solvents,
2-3h is dissolved in 45-55 DEG C of oil bath, adds 400-500mg 1- ethyls-(3- dimethylaminopropyls) carbodiimide, 260-320mg
N-Hydroxysuccinimide, room temperature activation 30min, in being then added to the Alkylenediamine solution that 8-12ml concentration is 0.5M, room
Temperature reaction 12-48h, the acetone for adding pre-cooling is precipitated, and sucking filtration obtains precipitate；Precipitate adds water redissolution, and dialysis, freezing is dry
Dry hyaluronic acid (the NH for obtaining ammonification2-HA)；
Described organic solvent is Methanamide, N,N-dimethylformamide, one kind of dimethyl sulfoxide；
(5) synthesis of hyaluronic acid decorated Au doped titanic oxide nano tubes：The Au doping that TGA is modified
Titania nanotube and ammonification hyaluronic acid are according to 1:The mass ratio of 1.5-2 is dissolved in reaction dissolvent, according to 1:1.4-1.8
(ammonification hyaluronic acid:EDC mass ratio) add 1- ethyls-(3- dimethylaminopropyls) carbodiimide (EDC), 1:1.5-
2.0 (ammonification hyaluronic acids:NHS mass ratio) adds N-Hydroxysuccinimide (NHS) to be activated, room temperature reaction 12-36h；
Add acetone to be precipitated, sucking filtration obtains precipitate, add water redissolution precipitate, dialyse, lyophilization obtains final product hyaluronic acid decorated
Au doped titanic oxide nano tubes (HA-Au@TiNTs)；Described reaction dissolvent is water or Methanamide or N, N- dimethyl
The mixed solvent of Methanamide and water or Methanamide and water or DMF and Methanamide, or other similar solvents with
And the mixture of other similar solvents.
The present invention adopts noble metal (Au, Pt, Pd etc.) modified titanic oxide, is distributed by the electronics in change system, shadow
The surface nature of titanium dioxide is rung, and then expands its absorption spectrum to visible ray, so as to improve its photocatalytic activity.In noble metal
In, Au is cheap and easy to get than Pt, Pd, small toxicity and with bactericidal action, and in addition Jenner's grain of rice has the photothermal deformation of brilliance special
Property, the heat production better performances under the irradiation of near infrared light, the combination drug carrier for so being formed just becomes a kind of great potential
Photodynamics and photo-thermal therapy carrier material；Simultaneously using with good biocompatibility, tumor cell targeting it is natural many
Sugar --- hyaluronic acid, it is linking arm that its carboxyl is passed through into simple Alkylenediamine, the Au doping two with TGA modification
Titanium oxide nanotubes are covalently attached, and construct the nano-carrier that a kind of photo-thermal treats joint photodynamic therapy.The carrier
Synthesis technique is simple, and by the remarkable photocatalysis performance of titania nanotube and powerful drug loading characteristic, Jenner's grain of rice
Significant light and heat-sensitive, the unique tumor cell targeting of hyaluronic acid, anti-tumor activity, the good bio-compatible of auxiliary
Property be organically integrated in one, the medicine that can have anti-tumor activity with physical load in addition, can both overcome traditional tumour to treat
A non-target tropism difficult problem, reduce the damage of normal tissue in therapeutic process, with efficient, controllable advantage, also, it is by light
Photodynamic therapy, photo-thermal therapy, chemotherapy combine well, more effectively realize the Comprehensive Treatment of cancer, are treating cancers
Innovation on medicine, economic and social benefit is huge.
Specific embodiment
The specific embodiment of the present invention is elaborated with reference to embodiments.
The present invention can also be realized in being embodied as by following steps：
(1) synthesis of titania nanotube：Weigh 40g NaOH to be placed in beaker, add deionized water, ice bath stirring
It is dissolved, room temperature is cooled to, then adds deionized water to be settled to 100ml, add 200mg TiO2Powder of nanometric particles, ultrasound point
Scattered 15min, in inserting the reactor of polytetrafluoroethylliner liner, 150 DEG C of heating 24-35h, are cooled to room temperature, successively in Muffle furnace
It is 7 to be cleaned with 0.1mol/L HCl solutions and deionized water to pH, with 0.22 μm of microporous filter membrane (moisture film) sucking filtration of diameter, vacuum
60 DEG C of drying in drying baker, grinding obtains titania nanotube (TiNTs), keeps in dark place；
(2) preparation of Au doped titanic oxide nano tubes：The gold chloride solid for weighing 200mg is placed in beaker, is added and is steamed
Distilled water is made into the solution of 200mg/ml, and stirring and dissolving is uniform, then in beaker according to Au in gold chloride and titania nanotube
Mass ratio is that 1 ︰ 50-100 add titania nanotube, lucifuge to be placed in ultrasonic oscillator and vibrate 1h so as to be uniformly dispersed,
Again lucifuge stirs 12h so as to fully absorption, and 3h is irradiated under ultraviolet light, stands 6-8h, filters, and 18h is dried at 80 DEG C, then turns
In entering temperature programmed control Muffle furnace, 500 DEG C are warming up to by 2 DEG C/min of speed, and keep 3h, be cooled to after room temperature and take out finely ground,
Obtain final product the titania nanotube (Au@TiNTs) of Au doping；
(3) TGA is TiO 2 nanotubes modified：The titania nanotube of 175mg Au doping is weighed, is added
The ultra-pure water wiring solution-forming of 175ml, the TGA of 13mg, lucifuge stirring 24h, with the dialysis of MW=3500 are added in solution
Bag dialysis, then with microporous filter membrane (moisture film) sucking filtration of 0.22 μm of diameter, 50 DEG C of dryings in vacuum drying oven, obtain TGA modification
Au doping titania nanotube；
(4) synthesis of ammonification hyaluronic acid：200mg hyaluronic acids (HA) are taken in 10-15ml organic solvents, 50 DEG C of oil baths
Dissolving 2-3h, adds 450mg 1- ethyls-(3- dimethylaminopropyls) carbodiimide and 290mg N-Hydroxysuccinimide to carry out
Activation, room temperature activation 30min；In being then added to the Alkylenediamine solution that 10ml concentration is 0.5M, room temperature reaction 12-48h；
Reaction adds the acetone of pre-cooling to be precipitated after terminating, and sucking filtration obtains precipitate；Add water redissolution precipitate, and dialysis, lyophilization is obtained
Hyaluronic acid (the NH of ammonification2-HA)；
(5) synthesis of hyaluronic acid decorated Au doped titanic oxide nano tubes：The Au doping that TGA is modified
Titania nanotube and ammonification hyaluronic acid are according to 1:The mass concentration ratio of 1.5-2 is dissolved in reaction dissolvent, according to 1:1.4-
1.8 (ammonification hyaluronic acids:EDC mass ratio) add 1- ethyls-(3- dimethylaminopropyls) carbodiimide (EDC), 1:
1.5-2.0 (ammonification hyaluronic acid:NHS mass ratio) adds N-Hydroxysuccinimide (NHS) to be activated, room temperature reaction 12-
36h, adds acetone precipitation, sucking filtration to obtain precipitate, and add water redissolution precipitate, dialysis, and lyophilization obtains final product hyaluronic acid decorated
Au doped titanic oxide nano tubes (HA-Au@TiNTs).
Hyaluronic acid decorated Au doped titanic oxide nano tubes prepared by said method, can be used to prepare antitumor drug
Compositionss, realize the answering in antineoplastic pharmaceutical compositions are prepared with hyaluronic acid decorated Au doped titanic oxide nano tubes
With described pharmaceutical composition is hyaluronic acid decorated Au doped titanic oxide nano tube and pharmaceutical active or pharmacologically active point
Son makes medicament-carried nano layer, described pharmaceutical active or pharmacologically active molecule be insoluble anti-tumor medicament, water soluble drug and
Nucleic acid drug；
Described hyaluronic acid decorated Au doped titanic oxide nano tubes answering in antineoplastic pharmaceutical compositions are prepared
With described medicament-carried nano layer is hyaluronic acid decorated Au doped titanic oxide nano tubes and water 1～50 ︰ 100 by weight
Proportioning probe ultrasonic dissolution, with Jing solvents dissolving antitumor drug mix, Jing ultrasound or high pressure homogenize process, be stirred at room temperature
Organic solvent and free drug are removed using dialysis or ultrafiltration or post separation method after 24 hours, lyophilizing be obtained particle diameter be 10～
The nanometer layer of 1000nm；
Described antineoplastic pharmaceutical compositions can be used as photo-thermal therapy, photodynamic therapy, combined chemotherapy cancer drug, real
Application in photo-thermal therapy, photodynamic therapy, combined chemotherapy cancer drug now.
From the foregoing, it is an object of the invention to provide one kind has antitumor optical dynamic therapy activity, photo-thermal therapy work concurrently
The hyaluronic acid decorated Au doped titanic oxide nano tubes of property, tumor cell targeting and good biocompatibility.This is saturating
The Au doped titanic oxide nano tubes synthesis technique and chemical constitution of bright matter acid modification be relatively simple, it is to avoid biological to improve
The compatibility, stability and targeting and introduce different kinds of molecules group, and remain the photocatalysis characteristic that titanium dioxide has, gold
The Photothermal characterisation that nanoparticle has；Additionally, can physical load antitumor drug, the effect for the treatment of cancer is reached jointly.
It is a further object to provide comprising above-mentioned hyaluronic acid decorated Au doped titanic oxide nano tubes
Pharmaceutical composition.
It is a further object to provide above-mentioned hyaluronic acid decorated Au doped titanic oxide nano tubes and including
The preparation method of above-mentioned hyaluronic acid decorated Au doped titanic oxide nano tube pharmaceutical compositions.
The present invention's it is also an object that provide above-mentioned hyaluronic acid decorated Au doped titanic oxide nano tubes and its
Application of the pharmaceutical composition in field of medicaments.
To reach above-mentioned purpose, the technical solution used in the present invention is to prepare nano titania by hydrothermal synthesis method
Pipe, then with homemade titania nanotube as predecessor, using photoreduction calcination method the two of surface modification Au is prepared for
Titanium oxide nanotubes；Afterwards TGA is connected on the titania nanotube of Au doping by mercapto gold key, hyaluronic acid
By the TGA covalent attachment that Alkylenediamine is linking arm and Au doped titanic oxide nano tube surface modifications, the medicine
Carrier can spontaneously form nanometer layer in aqueous medium, then by the stronger drug carrying capacity of titania nanotube, physics is born
Carrying anti-tumor medicine, constitutes the titania nanotube pharmaceutical composition of hyaluronic acid decorated Au doping.Due to titanium dioxide
The powerful photothermal deformation characteristic of the remarkable photocatalysis performance of nanotube and Jenner's grain of rice, therefore the achievable photo-thermal therapy of the system,
Photodynamic therapy combined chemotherapy, Comprehensive Treatment of the significantly more efficient realization to cancer.
Described antineoplastic pharmaceutical compositions, receive comprising hyaluronic acid decorated Au of the present invention is titania-doped
Mitron 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：Docetaxel, paclitaxel, amycin, cisplatin, carboplatin, daunorubicin, few justice antinucleus
One or more in thuja acid, siRNA and enzyme drug.
Described antineoplastic pharmaceutical compositions, can be used for injection, oral or drug delivery implant.Wherein drug administration by injection is preferably noted
Agent, freeze-dried powder are penetrated, oral administration preferred tablet, capsule, pill, syrup, granule, drug delivery implant preferably is selected from gel
Agent, solution.
And the relevant experiments of Jing have obtained fully proving that relevant experimental data is as follows：
1st, carry out ultraviolet spectrophotometry to the titania nanotube in the present invention, Au doped titanic oxide nano tubes to sweep
Analysis of spectrum, it was demonstrated that the absorption spectrum of titanium dioxide effectively can be expanded to visible ray by the doping of Jenner's grain of rice by ultraviolet region
Area；It is titania-doped to homemade titania nanotube, Au doped titanic oxide nano tubes and hyaluronic acid decorated Au
Nanotube carries out transmission electron microscope morphologic observation and the test of the dispersibility in water understands that titania nanotube form is homogeneous, internal diameter
Greatly, can successfully be loaded on titanium dioxide tube with efficient loading medicine, Au, hyaluronic acid to Au doped titanic oxide nano tubes into
After work(modification, its dispersibility in water is obviously improved.
The photo-thermal effect experiment of the 2nd, hyaluronic acid decorated Au doped titanic oxide nano tubes
A series of titania nanotube and hyaluronic acid decorated Au doped titanic oxide nano tubes for preparing concentration is molten
Liquid, adopts 808nm NIR laser device with 2 W/cm2Energy density be irradiated, and in 0,1,2,3,4,5,6,7,8,9,
10min measures the temperature of solution, and the titania nanotube after Au doping has excellent photothermal conversion effect, and hyalomitome
Modification of the acid to Au doped titanic oxide nano tubes does not have an impact its Photothermal characterisation.
3rd, hyaluronic acid decorated Au doped titanic oxide nano tubes produce the determination experiment of active oxygen to tumor cell
MCF-7 breast cancer cells (being provided by Shanghai cell bank) are used as into cancerous cell to be investigated.By MCF-7 cell culture
Containing hyclone (FBS) 10%, in the culture medium of RPMI 1640 of mycillin mixed liquor 1%, incubator condition is 37 DEG C,
5%CO2, passed on once per 2～3 days.Logarithmic (log) phase cell is collected, concentration of cell suspension is adjusted, 6 orifice plates add 1ml, bed board per hole
Cell to be measured is set to adjust density to 3 × 104Individual/hole.It is placed in 5%CO2, 37 DEG C are incubated 24h, and to cell monolayer bottom hole is paved with, and add 20
Hyaluronic acid decorated Au doped titanic oxide nano tubes in the embodiment 1 of μ g/ml, it is 2～4 to arrange multiple holes.Dosing 4h
Afterwards, light group is placed on 2min in 532nm laser 2W, and, at 37 DEG C, illumination adds activity after terminating to keep temperature in During Illumination
Oxygen probe, with aluminium foil parcel cell version CO is placed in20.5h is incubated in incubator, terminates culture, suction out pastille culture medium, used per hole
3ml PBS are washed 2 times, and with 70% ice ethanol 0.5h is fixed, and are subsequently placed in fluorescence microscopy Microscopic observation active oxygen production.
Fluorescence microscope result is recorded, it is known that hyaluronic acid decorated Au doped titanic oxide nano tubes are visible
A large amount of active oxygens can be produced under light irradiation in tumor cell, can be used to carry out photodynamic therapy to tumor as photosensitizer.
4th, using the hyaluronic acid decorated Au doped titanic oxide nano tubes of the light irradiation present invention to growth of tumour cell
Inhibitory activity measure.
By the hyaluronic acid decorated Au doped titanic oxide nano tubes anti-tumor activity in vitro of the light irradiation present invention：
MCF-7 breast cancer cells (being provided by Shanghai cell bank) are used as into cancerous cell to be investigated.By MCF-7 cell culture in cattle containing tire
Serum (FBS) 10%, in the culture medium of RPMI 1640 of mycillin mixed liquor 1%, incubator condition is 37 DEG C, 5%CO2, often
Pass on once within 2～3 days.Logarithmic (log) phase cell is collected, concentration of cell suspension is adjusted, 96 orifice plates add 200 μ l per hole, and bed board makes to be measured
Cell adjusts density to 5 × 103Individual/hole, (edge hole is filled with aseptic PBS).It is placed in 5%CO2, 37 DEG C of incubation 24h, to cell list
Layer is paved with bottom hole (96 hole flat underside), adds the hyaluronic acid in the embodiment 1 of Concentraton gradient (12.5,25,50,100 μ g/ml)
The Au doped titanic oxide nano tubes of modification, it is 4～6 to arrange multiple holes, is divided into 4 groups, is specifically grouped as follows：(1) hyalomitome
The Au doped titanic oxide nano tube groups of acid modification；(2) hyaluronic acid decorated Au doped titanic oxide nano tubes -808nm swashs
Light group；(3) hyaluronic acid decorated Au doped titanic oxide nano tube -532nm laser groups；(4) hyaluronic acid decorated Au mixes
Miscellaneous titania nanotube -808nm-532nm combines laser group；Wherein laser group is placed in 532nm or 808nm laser 2W
2min, at 37 DEG C, illumination is placed in CO after terminating with aluminium foil parcel cell version to keep temperature in During Illumination2It is incubated in incubator
24h, for not light group, then directly wraps up cell version and is placed in CO with aluminium foil224h is incubated in incubator, terminates culture, inhaled
Go out pastille culture medium, washed 2 times with 150 μ l PBS per hole, add the 10%TCA200 μ l of pre-cooling, 4 DEG C of placement 1h.Outwell fixation
Liquid.It is washed with deionized water 5 times per hole, dries, is air-dried.The SRB solution of 100 μ l is added per hole, is stood and is placed 10min, not
Washed 5 times with 1% acetic acid with protein bound SRB, be air-dried.With reference to SRB with 150 μ l 10mmol/L non-buffered Tris alkali
Dissolving.The OD values per hole are determined at 515nm.The computing formula of survival rate：Survival rate=experimental group OD values/matched group OD values,
Wherein experimental group and matched group are the value deducted after empty bag matched group.
Have confirmed when with 808nm laser or 532nm laser irradiating cells, can all affect the increasing of MCF-7 tumor cells
Grow, wherein joint laser group suppresses the effect of tumour growth most obvious.
During light irradiation, the anti-tumor in vivo activity of the hyaluronic acid decorated Au doped titanic oxide nano tubes of the present invention is surveyed
It is fixed：Mouse S180 ascites sarcoma cell is taken, with injection normal saline with 3:After 1 dilution proportion, every mice is in lumbar injection
0.3ml, after mice is fed 7 days, extracts mouse S180 ascites sarcoma cell, is into concentration with injection normal saline dilution after counting
2×106The cell suspension of individual/ml, subcutaneous vaccination is in mice right fore top.After mouse inoculation tumor 7d, take wherein 30 and swell
Tumor volume >=100mm3Kunming mice, is randomly divided into 5 groups, 6 per group.Specifically it is grouped as follows：(1) matched group (NS groups)：Physiology
Saline；(2) hyaluronic acid decorated Au doped titanic oxide nano tube groups；(3) hyaluronic acid decorated Au is titania-doped
Nanotube -808nm laser groups；(4) hyaluronic acid decorated Au doped titanic oxide nano tube -532nm laser groups；(5) it is transparent
Au doped titanic oxide nano tubes -808nm-532nm joint the laser groups of matter acid modification.5 groups by the way of intravenously administrable,
Wherein laser group (532nm or 808nm laser), power is 2W, laser irradiation tumor locus, once irradiating time after administration 3h
For 2min.It is administered once per 2d, the hyaluronic acid decorated Au of per injection normal saline or 10mg/ml is titania-doped
The μ l of nanotube 100, are administered 7 times altogether.Daily observation mice animation, its body weight is claimed per 2d and using trip in whole experiment process
The major diameter (A) and minor axis (B) of mark kind of calliper murine sarcoma, by formula gross tumor volumeCalculate gross tumor volume.
When the hyaluronic acid decorated Au doped titanic oxide nano tubes of the administration present invention merge laser to be irradiated, mice
The increase of gross tumor volume has obtained obvious suppression, wherein joint laser group suppresses the effect of tumour growth most obvious.
6th, the anti-tumor activity of hyaluronic acid decorated Au doped titanic oxide nano tubes-amycin drug-supplying system
Anti tumor activity in vitro：MCF-7 breast cancer cells (being provided by Shanghai cell bank) are used as into cancerous cell to be investigated.
By MCF-7 cell culture containing hyclone (FBS) 10%, in the culture medium of RPMI 1640 of mycillin mixed liquor 1%, train
Foster case condition is 37 DEG C, 5%CO2, is passed on once per 2～3 days.Logarithmic (log) phase cell is collected, concentration of cell suspension, 96 orifice plates are adjusted
200 μ l, bed board are added to make cell to be measured adjust density to 5 × 10 per hole3Individual/hole, (edge hole is filled with aseptic PBS).It is placed in 5%
CO2, 37 DEG C are incubated 24h, and to cell monolayer bottom hole (96 hole flat underside) is paved with, and add Concentraton gradient (0,0.1,0.5,1,2,4 μ
G/ml the hyaluronic acid decorated Au doped titanic oxide nano tubes-amycin in embodiment 5), dissociates amycin for control
Group, it is 4～6 to arrange multiple holes, is divided into 5 groups, is specifically grouped as follows：(1) amycin group；(2) hyaluronic acid decorated Au mixes
Miscellaneous titania nanotube-amycin group；(3) hyaluronic acid decorated Au doped titanic oxide nano tubes-amycin-
808nm laser groups；(4) hyaluronic acid decorated Au doped titanic oxide nano tubes-amycin -532nm laser groups；(5) it is transparent
The Au doped titanic oxide nano tubes of matter acid modification-amycin -808nm-532nm joint laser groups；Wherein laser group is placed on
2min in 532nm or 808nm laser 2W, at 37 DEG C, illumination wraps up cell version after terminating with aluminium foil to keep temperature in During Illumination
It is placed in CO224h is incubated in incubator, for not light group, then directly cell version is wrapped up with aluminium foil and is placed in CO2In incubator
Incubation 24h, terminates culture, suctions out pastille culture medium, is washed 2 times with 150 μ l PBS per hole, adds the μ l of 10%TCA 200 of pre-cooling,
4 DEG C of placement 1h.Outwell fixative.It is washed with deionized water 5 times per hole, dries, is air-dried.Add the SRB of 100 μ l molten per hole
Liquid, stands and places 10min, is not washed 5 times with 1% acetic acid with protein bound SRB, is air-dried.With reference to SRB with 150 μ l
10mmol/L non-buffered Tris alkali dissolutions.The OD values per hole are determined at 515nm.The computing formula of suppression ratio：Suppression ratio=1-
Experimental group OD values/matched group OD values, wherein experimental group and matched group are the value deducted after empty bag matched group.
Hyaluronic acid decorated Au doped titanic oxide nano tubes in the experiment proof present invention are used as energy during pharmaceutical carrier
Mediate drug enters inside tumor cells, has preferably given play to the curative effect of antitumor drug, and with reference to illumination after, can be brighter
The propagation of aobvious suppression tumor cell, wherein joint laser group suppresses the effect of tumour growth most obvious.
Anti-tumor in vivo activity：Mouse S180 ascites sarcoma cell is taken, with injection normal saline with 3:After 1 dilution proportion,
Every mice after mice is fed 7 days, extracts mouse S180 ascites sarcoma cell in lumbar injection 0.3ml, with injection life after counting
Reason saline is diluted to concentration for 2 × 106The cell suspension of individual/ml, subcutaneous vaccination is in mice right fore top.Mouse inoculation tumor
After 7d, wherein 36 gross tumor volume >=100mm are taken3Kunming mice, is randomly divided into 6 groups, 6 per group.Specifically it is grouped as follows：(1)
Matched group (NS groups)：Normal saline；(2) amycin group；(3) hyaluronic acid decorated Au doped titanic oxide nano tubes-Ah mould
Plain group；(4) hyaluronic acid decorated Au doped titanic oxide nano tubes-amycin -808nm laser groups；(5) hyaluronic acid is repaiied
The Au doped titanic oxide nano tubes of decorations-amycin -532nm laser groups；(6) hyaluronic acid decorated Au is titania-doped
Nanotube-amycin -808nm-532nm joint laser groups.Amycin group, hyaluronic acid decorated Au is titania-doped receives
Mitron-amycin group, hyaluronic acid decorated Au doped titanic oxide nano tubes-amycin -808nm laser groups, hyalomitome
Au doped titanic oxide nano tubes-amycin -532nm the laser groups of acid modification, hyaluronic acid decorated Au are titania-doped
The amycin dosage of nanotube-amycin -808nm-532nm joint laser groups is equal, is all 7.8mg/kg.6 groups are adopted
With the mode of intravenously administrable, wherein laser group (532nm or 808nm laser), power is 2W, laser irradiation tumor after administration 3h
Position, the once irradiating time is 2min.It is administered once per 2d, is administered 7 times altogether.Daily observation mice life in whole experiment process
State, its body weight is claimed per 2d and the major diameter (A) and minor axis (B) of vernier caliper measurement murine sarcoma is used, by formula gross tumor volumeCalculate gross tumor volume.
When to hyaluronic acid decorated Au doped titanic oxide nano tubes-amycin, the increase of the gross tumor volume of mice
Obtained obvious suppression compared with doxorubicin injection, and with reference to illumination after, can more obviously suppress the increasing of tumor cell
Grow, wherein joint laser group suppresses the effect of tumour growth most obvious.
While above-mentioned experiment is done, also similar experiment is done using other light sources and antitumor drug, obtained
Identical and similar result, packet science of the present invention, method is reliable and stable, and other experimental results will not enumerate.
Fully shown by above-mentioned data, preparation method of the present invention is applicant's Jing scientific researches, tests and to practice summary
The creative work crystallization made, compared with prior art, with substantive distinguishing features following prominent and marked improvement：
(1) present invention selects have good biocompatibility, the natural polysaccharide of tumor cell targeting --- hyaluronic acid
For decorating molecule, with Alkylenediamine as linking arm, realize with a kind of simple economy and easily the method for industrialized production to Au
Doped titanic oxide nano tube is modified, and mild condition, reaction are simple, yield is high；
(2) the hyaluronic acid decorated Au doped titanic oxide nano tubes that the present invention is provided have excellent bio-compatible
Property, water solublity and stability, additionally it is possible to realize fluorescent dye with tumour-specific targeting, and remain the efficient photo-thermal therapy activity of Jenner's grain of rice
And titanium dioxide is in the efficient photocatalytic activity in visible region, realize that the photo-thermal therapy to tumor combines the use of optical dynamic therapy
Medicine problem；
(3) the hyaluronic acid decorated Au doped titanic oxide nano tubes that the present invention is provided, being capable of physical load antitumor
Medicine, realizes the Comprehensive Treatment to tumor, is the innovation in tumor, and economic and social benefit is huge.
Claims (5)
1. a kind of preparation method of hyaluronic acid decorated Au doped titanic oxide nano tubes, it is characterised in that closed by hydro-thermal
Titania nanotube is prepared into method, then with titania nanotube as predecessor, using photoreduction calcination method table is prepared
The titania nanotube of Au is modified in face；TGA is connected on the titania nanotube of Au doping by mercapto gold key,
TGA of the hyaluronic acid by Alkylenediamine for linking arm and Au doped titanic oxide nano tube surface modifications covalently connects
Connect, nanometer layer is formed in aqueous medium；The hyaluronic acid is that molecular weight is equal to or less than 400 kd, and equal to or higher than 600
The low-molecular-weight hyaluronic acid of dalton；The linking arm for carbon number 2-12 Alkylenediamine structure, specifically include with
Lower step：
（1）The synthesis of titania nanotube：NaOH is placed in beaker, deionized water is added, stirring under ice bath dissolves it,
Room temperature is cooled to, is the solution of 40g/100ml into mass concentration, add TiO2Powder of nanometric particles, NaOH and TiO2Nanometer
The weight ratio of grain powder is 2000 ︰ 1, ultrasonic disperse 15min, and 140-160 DEG C of heating 24-35h is cooled to room temperature, then uses successively
0.1mol/L HCl solutions and deionized water are cleaned to the neutrality that pH value is 7, sucking filtration, remove liquid, obtain solidss, solidss 60
DEG C vacuum drying, obtain dried object, grind, into titania nanotube, keep in dark place；
（2）The preparation of Au doped titanic oxide nano tubes：Gold chloride solid is added in distilled water and is stirred, be completely dissolved,
It is that 1 ︰ 50-100 add titanium dioxide according still further to Au in gold chloride and titania nanotube mass ratio into the solution of 200mg/ml
Nanotube, by its lucifuge sonic oscillation 1h so as to be uniformly dispersed, then lucifuge stirring 12h so as to fully absorption, dispersion liquid is used
Ultraviolet light 3h, stands 6-8h, filters, and discards filtrate, obtains solidss, and 80 DEG C of solidss are dried 18h, then with speed as 2 DEG C/
Min is warming up to 500 DEG C, keeps 3h, is cooled to room temperature, finely ground, obtains the titania nanotube of Au doping；
（3）TGA is TiO 2 nanotubes modified：The titania nanotube that Au is adulterated adds ultra-pure water to be dissolved into
The solution of 1mg/ml, in solution TGA is added, molten made by the titania nanotube per 150-200mg Au doping
TGA 10-15mg, lucifuge stirring 24h, dialysis, sucking filtration, 50 DEG C of vacuum drying is added to obtain the Au of TGA modification in liquid
The titania nanotube of doping；
（4）The synthesis of ammonification hyaluronic acid：180-220mg hyaluronic acids are dissolved in 10-15ml organic solvents, 45-55 DEG C of oil
Bath dissolving 2-3h, addition 400-500mg 1- ethyls-（3- dimethylaminopropyls）Carbodiimide, 260-320mg hydroxysuccinimidyls
Acid imide, room temperature activation 30min, in being then added to the Alkylenediamine solution that 8-12ml concentration is 0.5M, room temperature reaction 12-
48h, the acetone for adding pre-cooling is precipitated, and sucking filtration obtains precipitate；Precipitate adds water redissolution, and dialysis, lyophilization obtains ammonification
Hyaluronic acid；
Described organic solvent is Methanamide, N,N-dimethylformamide, one kind of dimethyl sulfoxide；
（5）The synthesis of hyaluronic acid decorated Au doped titanic oxide nano tubes：The dioxy of the Au doping that TGA is modified
Change titanium nanotube and ammonification hyaluronic acid is dissolved in reaction dissolvent according to the mass ratio of 1 ︰ 1.5-2, according to ammonification hyaluronic acid:
1- ethyls-（3- dimethylaminopropyls）Carbodiimide be 1 ︰ 1.4-1.8 mass ratio add 1- ethyls-（3- dimethylaminos
Propyl group）Carbodiimide, ammonification hyaluronic acid:N-Hydroxysuccinimide is that the mass ratio of 1 ︰ 1.5-2.0 adds hydroxysuccinimidyl acyl sub-
Amine is activated, room temperature reaction 12-36h；Add acetone to be precipitated, sucking filtration obtains precipitate, add water redissolution precipitate, thoroughly
Analysis, lyophilization obtains final product hyaluronic acid decorated Au doped titanic oxide nano tubes；
Described reaction dissolvent is water or Methanamide or N,N-dimethylformamide and water or Methanamide and water or N, N- bis-
The mixed solvent of methylformamide and Methanamide.
2. a kind of preparation method of hyaluronic acid decorated Au doped titanic oxide nano tubes, it is characterised in that by following steps
Realize：
（1）The synthesis of titania nanotube：Weigh 40g NaOH to be placed in beaker, add deionized water, ice bath stirring to make it
Dissolving, is cooled to room temperature, then adds deionized water to be settled to 100ml, adds 200mg TiO2Powder of nanometric particles, ultrasonic disperse
15min, in inserting the reactor of polytetrafluoroethylliner liner, 150 DEG C of heating 24-35h, are cooled to room temperature in Muffle furnace, use successively
It is 7 that 0.1mol/L HCl solutions and deionized water are cleaned to pH, with 0.22 μm of microporous filter membrane sucking filtration of diameter, in vacuum drying oven
60 DEG C of drying, grinding obtains titania nanotube, keeps in dark place；
（2）The preparation of Au doped titanic oxide nano tubes：The gold chloride solid for weighing 200mg is placed in beaker, adds distilled water
The solution of 200mg/ml is made into, stirring and dissolving is uniform, then in beaker according to Au in gold chloride and titania nanotube quality
Than adding titania nanotube, lucifuge to be placed in ultrasonic oscillator and vibrate 1h for 1 ︰ 50-100 so as to be uniformly dispersed, then keep away
Light stirs 12 h so as to fully absorption, and 3h is irradiated under ultraviolet light, stands 6-8h, filters, and 18h is dried at 80 DEG C, then proceeds to journey
In sequence temperature control Muffle furnace, 500 DEG C are warming up to by 2 DEG C/min of speed, and keep 3h, be cooled to after room temperature and take out finely ground, obtained final product
The titania nanotube of Au doping；
（3）TGA is TiO 2 nanotubes modified：The titania nanotube of 175mg Au doping is weighed, 175ml is added
Ultra-pure water wiring solution-forming, add the TGA of 13mg in solution, lucifuge stirring 24h, the bag filter with MW=3500 is saturating
Analysis, then with the microporous filter membrane sucking filtration of 0.22 μm of diameter, 50 DEG C of dryings in vacuum drying oven, obtain the Au doping of TGA modification
Titania nanotube；
（4）The synthesis of ammonification hyaluronic acid：Take 200mg hyaluronic acids to be dissolved in 10-15ml organic solvents, 50 DEG C of oil bath dissolvings
2-3h, addition 450mg 1- ethyls-（3- dimethylaminopropyls）Carbodiimide and 290mg N-Hydroxysuccinimide are lived
Change, room temperature activation 30min；In being then added to the Alkylenediamine solution that 10ml concentration is 0.5M, room temperature reaction 12-48h；Instead
The acetone of pre-cooling is added to be precipitated after should terminating, sucking filtration obtains precipitate；Add water redissolution precipitate, and dialysis, lyophilization obtains ammonia
The hyaluronic acid of change；
（5）The synthesis of hyaluronic acid decorated Au doped titanic oxide nano tubes：The dioxy of the Au doping that TGA is modified
Change titanium nanotube and ammonification hyaluronic acid according to 1:The mass concentration ratio of 1.5-2 is dissolved in reaction dissolvent, according to ammonification hyalomitome
Acid:1- ethyls-（3- dimethylaminopropyls）Carbodiimide is 1:The mass ratio addition 1- ethyls of 1.4-1.8-（3- dimethyl
Aminopropyl）Carbodiimide, ammonification hyaluronic acid:N-Hydroxysuccinimide is 1:The mass ratio of 1.5-2.0 adds hydroxysuccinimidyl
Acid imide is activated, room temperature reaction 12-36h, adds acetone precipitation, sucking filtration to obtain precipitate, and add water redissolution precipitate, dialysis,
Lyophilization obtains final product hyaluronic acid decorated Au doped titanic oxide nano tubes.
3. the hyaluronic acid decorated Au doped titanic oxide nano tubes that prepared by the methods described of claim 1 or 2 are preparing anti-swelling
Application in tumor medicine compositionss, described pharmaceutical composition is hyaluronic acid decorated Au doped titanic oxide nano tube and medicine
Learn bioactive molecule and make medicament-carried nano layer, described pharmaceutically active molecule is insoluble anti-tumor medicament, water soluble drug and core
Sour medicine.
4. hyaluronic acid decorated Au doped titanic oxide nano tubes according to claim 3 are preparing antitumor drug group
Application in compound, it is characterised in that described medicament-carried nano layer is hyaluronic acid decorated Au doped titanic oxide nano tubes
With water by weight the Proportioning probe ultrasonic dissolution of 1 ~ 50 ︰ 100, mix with the antitumor drug of Jing solvents dissolving, Jing it is ultrasonic or
High pressure homogenize process, organic solvent and free medicine are removed after being stirred at room temperature 24 hours using dialysis or ultrafiltration or post separation method
Thing, lyophilizing is obtained nanometer layer of the particle diameter for 10 ~ 1000 nm.
5. hyaluronic acid decorated Au doped titanic oxide nano tubes according to claim 4 are preparing antitumor drug group
Application in compound, it is characterised in that described antineoplastic pharmaceutical compositions are in photo-thermal therapy, photodynamic therapy or amalgamation
Treat and applied in cancer drug.
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| CN105194679A (en) * | 2015-09-01 | 2015-12-30 | 郑州大学 | Preparation method and application of titanium dioxide-graphene oxide composite material modified by hyaluronic acid of antitumor drug nanometer layer |
| CN108479771B (en) * | 2016-05-16 | 2019-07-30 | 南通大学 | Au/TiO2The liquid-phase synthesis process of composite nanometer particle and hetero-junctions |
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| CN103657646A (en) * | 2012-09-07 | 2014-03-26 | 合肥师范学院 | Method for loading gold nanoparticles on titanium dioxide nanotube |
| CN103893777A (en) * | 2014-03-14 | 2014-07-02 | 东华大学 | Preparation method of hyaluronic acid targeted carbon nano-tube loaded anti-cancer medicine |
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| CN103657646A (en) * | 2012-09-07 | 2014-03-26 | 合肥师范学院 | Method for loading gold nanoparticles on titanium dioxide nanotube |
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