CN106139144A - A kind of hyaluronic acid decorated golden Nano carbon balls with synergistic antitumor characteristic and preparation method and application - Google Patents
A kind of hyaluronic acid decorated golden Nano carbon balls with synergistic antitumor characteristic and preparation method and application Download PDFInfo
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- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0042—Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- B82Y40/00—Manufacture or treatment of nanostructures
Abstract
A kind of hyaluronic acid decorated golden Nano carbon balls with synergistic antitumor characteristic is prepared by purgation: first prepare solid silica nanosphere；Poly-dopamine is wrapped on silica template, forms poly-dopamine silicon dioxide nanocomposite；Reduction potassium chloroaurate realizes sewing the gold point of poly-dopamine silicon dioxide nanocomposite.The carbonization of poly-dopamine is realized by calcined product under oxygen-free environment.Then dissolve and remove silica template, then stir in a solvent with medicine and mix, obtain the hollow Nano carbon balls of carrying medicament；The hyaluronic acid modified by dopamine reacts in phosphate buffer with the hollow Nano carbon balls of load chemotherapeutics, to obtain final product.The present invention has the features such as high photo-thermal conversion efficiency, high drug load, good biocompatibility, can targeting suppression tumor cell, especially with the therapeutic alliance of photo-thermal/photodynamics/chemistry, resistant tumors had excellent killing rejection ability.
Description
Technical field
The present invention relates to field of biomedical materials, be specifically related to the preparation of a kind of hollow gold-Nano carbon balls, surface is repaiied
Decorations, lift-launch antitumor drug and the application in oncotherapy.
Background technology
In recent years, Cancer Mortality constantly raises, it has also become one of maximum harm of human health.Based on nanometer medicine
The tumor photo-thermal treatment of thing and photodynamic therapy are proved to have splendid effect under study for action, are the swollen of a kind of great potential
Tumor Therapeutic Method.Photo-thermal therapy is by the Nano medication with photothermal conversion usefulness is enriched to tumor locus, in specific light
The method that lower generation heat makes neoplasm necrosis melt is irradiated in source.Photodynamic therapy is to utilize photosensitizer to shine at specific wavelength light source
The method penetrating lower generation active oxygen lethality tumor cell.Nano carbon balls is as the splendid novel nano material of a kind of biological safety
Material, has optical and thermal conversion capability, photo-catalysis capability, great specific surface area and extremely strong absorbability.It is outstanding as one
Photosensitizer, heat and active oxygen can be produced in the case of near infrared light, can effectively tumor cell be killed.Cause
This, Nano carbon balls is very suitable for photo-thermal and the photodynamic therapy of tumor.But the photothermal conversion limited efficacy of Nano carbon balls,
Limiting the efficiency of photo-thermal therapy, how improving its photothermal conversion efficiency is one of current research emphasis.
Jenner's grain of rice is nano level elemental gold particle, and it is readily synthesized, and has the highest chemical stability, and surface is prone to
Modify, and cytotoxicity is low, biocompatibility is high, is widely used in biomedicine field.Golden nanometer particle is to 700-
The near infrared light of 1100 nm has high absorption, the luminous energy of absorption can be converted into heat energy.Therefore, on Nano carbon balls surface
Intersperse golden nanometer particle, two kinds of nano material preparations can be organically combined there is the nanoparticle of higher photothermal conversion efficiency
Son.At present, do not have any article and patent to use golden nanometer particle to prepare with Nano carbon balls combination and there is high photothermal conversion effect
Can Nano medication, and carry chemotherapeutics and be applied to the therapeutic alliance of tumor.
Targeted therapy is a kind of new treatment means, and drug specificity can be infused in tumor cell by it, reduces just
The often accumulation in tissue, thus heighten the effect of a treatment, reduce side effect.Cell surface trans-membrane gC D44 is a kind of important tumor
Mark, it is relevant with transfer with the invasion and attack of tumor, and high expressed in kinds of tumor cells.Hyaluronic acid is to have with CD44
The ligands specific of high affinity, can be entered in tumor cell by the cell endocytic that CD44 mediates.Therefore, by hyaluronic acid
Or derivatives thereof is incorporated in Nano medication, can realize the Clinics and Practices effect of tumor-targeting.
The present invention uses poly-dopamine to synthesize Nano carbon balls as carbon source, and is utilizing poly-dopamine reduction potassium chloroaurate to obtain
Intersperse to elemental gold nano-particle and obtain gold-Nano carbon balls in Nano carbon balls surface, receive hyaluronic acid decorated in gold-carbon afterwards
Rice ball surface, is successfully prepared for having good biocompatibility, high drug load, have the multiple responses such as pH, enzyme and near-infrared concurrently
The targeting multifunctional intellectual therapy system of property, can be effectively used for oncotherapy, and also has splendid killing energy to resistant tumors
Power.
Summary of the invention
It is contemplated that use biomass carbon source to provide the surface point of a kind of hyaluronic acid parcel to be embroidered with the sky of Jenner's grain of rice
Heart Nano carbon balls pharmaceutical carrier and its preparation method and application.Gold nano is interspersed on the surface of hyaluronic acid parcel prepared by the method
The Nano carbon balls of grain has good biocompatibility, high drug load, has the multiple responses such as pH, hyaluronidase and near-infrared concurrently
The feature of property, and can the tumor cell of specific targeting CD44 high expressed, and utilize photo-thermal therapy, photodynamic therapy and change
The effective killing tumor cell of therapeutic alliance treated, and effectively reduce the toxic and side effects of antitumor drug.
The present invention solves the technical scheme of the problems referred to above, and the surface point of a kind of hyaluronic acid parcel is embroidered with Jenner's grain of rice
Hollow Nano carbon balls pharmaceutical carrier and its preparation method and application.The surface point of this hyaluronic acid parcel is embroidered with the sky of Jenner's grain of rice
Heart Nano carbon balls pharmaceutical carrier is made up of tumor targeted molecular, gold-Nano carbon balls and medicine three part.Wherein, cancer target divides
Son is hyaluronic acid；Gold-Nano carbon balls is the hollow Nano carbon balls that surface point is embroidered with Jenner's grain of rice；Medicine can be hormone or anti-
Raw element or cancer therapy drug etc..
The surface point of described hyaluronic acid parcel is embroidered with the hollow Nano carbon balls pharmaceutical carrier of Jenner's grain of rice and is prepared by purgation:
(1) the solid silicon dioxide utilizing tetraethyl orthosilicate hydrolysis in alkaline environment a diameter of 80-450 nm is received
Rice ball；
(2) silica nanosphere obtained in step (1) is scattered in alkaline solution, adds dopamine hydrochloride, profit
Obtain poly-dopamine with dopamine polymerization in alkaline solution and be wrapped on silica template, forming poly-dopamine-two
Silicon oxide nano-complex；
(3) poly-dopamine-silicon dioxide nanocomposite obtained in step (2) is scattered in distilled water, adds appropriate
Potassium chloroaurate, owing to poly-dopamine has strong reducing property, can be reduced to 0 valence state and at the former knot in its surface by the gold in gold potassium chloride
Crystalline substance is nanoparticle, obtains surface point and is embroidered with the poly-dopamine-silicon dioxide nanocomposite of golden nanometer particle；
(4) surface point obtained in step (3) is embroidered with the poly-dopamine-silicon dioxide nanocomposite of gold under anaerobic
Calcine, make poly-dopamine carbonization, obtain surface point and be embroidered with the carbon-silica composite of golden nanometer particle；
(5) surface point obtained in step (4) is embroidered with golden nanometer particle that carbon-silica composite is scattered in Fluohydric acid. is molten
In liquid, dissolve and remove silica template, obtain surface point and be embroidered with the hollow Nano carbon balls of Jenner's grain of rice, referred to as gold-carbon and receive
Rice ball；
(6) using the carboxyl of hyaluronic acid to react with the amido of dopamine, synthesis obtains the hyaluronic acid that dopamine is modified；
(7) gold-Nano carbon balls in step (5) is stirred in a solvent with medicine mix, i.e. can get the surface of carrying medicament
Point is embroidered with the hollow Nano carbon balls of gold nano grain；
(8) hyaluronic acid of dopamine modification step (6) obtained and the surface point of carrying medicament are embroidered with the sky of Jenner's grain of rice
Heart Nano carbon balls is reaction in the phosphate buffer (PBS), the gold-carbon nanometer of carrying medicament of hyaluronic acid parcel
Ball.
Solid ball-type silica template in described step (1) is with tetraethyl orthosilicate as organosilicon precursor, ammonia
Obtained by catalyst.Specifically, measure 100-1000 ml ethanol and be placed in flask, add 1.5-15 mL distilled water and
5-50 mL ammonia (25 ~ 28%), stirs；It is added dropwise over 1.5-15 mL tetraethyl orthosilicate afterwards, reaction 4 is stirred at room temperature
Hour.After completion of the reaction, within centrifugal 15 minutes, collect silica spheres, and use absolute ethanol washing to supernatant for 10000 revs/min
In neutrality.Poly-dopamine-silicon dioxide nanocomposite in described step (2) is to utilize dopamine monomer at three hydroxyls of alkalescence
There is polymerization and be wrapped on silica template obtained in aminomethane buffer.Specifically, step (1) is obtained
Silica spheres be scattered in the 10 mM TRIS buffer of pH 8.5 that (mass volume ratio is 1 g: 300
ML), add dopamine hydrochloride (the 90% of silica template quality) stirring reaction 48 hours, obtain the poly-dopamine-two of brown
Silicon oxide nano-complex suspension, vacuum filtration is collected product and washs with distilled water, obtains pure gathering after lyophilizing
Dopamine-silicon dioxide nanocomposite.
Described step (3) uses potassium chloroaurate realize the gold point of poly-dopamine-silicon dioxide nanocomposite to sew.Tool
Body ground, is scattered in the poly-dopamine-silicon dioxide nanocomposite obtained in step (2) in distilled water that (mass/volume ratio is
1 g: 300 mL), add potassium chloroaurate (the 25% of poly-dopamine-silicon dioxide nanocomposite complex quality), at ice bath
Middle stirring reaction 30 minutes；After having reacted, collected by suction product, use lyophilizing after distilled water washing, i.e. can get table
Cake is embroidered with the poly-dopamine-silicon dioxide nanocomposite of golden nanometer particle.
Described step (4) is to realize the carbonization of poly-dopamine by calcined product under oxygen-free environment.Specifically, by table
Cake be embroidered with gold poly-dopamine-silicon dioxide nanocomposite under argon shield, 500 DEG C calcine 3 hours.
Described step (5) is selected hydrofluoric acid dissolution remove silica template.Specifically, by after carbonization containing two
The product of silicon oxide template is placed in 100 mL4% Fluohydric acid .s, and stirring reaction finally gives for 1 hour to dissolve silica template
Gold-Nano carbon balls.
Described step (6) is selected hyaluronic acid react with dopamine hydrochloride and obtain the hyaluronic acid that dopamine is modified.Tool
Body ground, weighs in the PBS that 100 ~ 1000 mg hyaluronis are dissolved in 50 ~ 500 mL deoxygenations.Add carbodiimide afterwards
With N-hydroxy-succinamide and stir to being completely dissolved.Wherein, hyaluronic acid unit: carbodiimide: N-hydroxysuccinimidyl acyl is sub-
The mol ratio of amine is 1: 1: 1.Weigh 50 ~ 500 mg dopamine hydrochlorides, join in above-mentioned mixed liquor, treat that dopamine is complete
After dissolving, the pH of solution adjusted to 4 ~ 6 and stir reaction 9 hours.In course of reaction, detect primary first-order equation liquid per hour
PH value also adjusts in real time, makes pH value remain at 4 ~ 6.After completion of the reaction, reactant liquor is transferred to molecular cut off be 8000 ~
In 14000 daltonian bag filters, 24 hours (changing liquid once in every six hours) of dialysing in the PBS of 20 mM, it is changed to double steaming afterwards
Water 24 hours (changing liquid once in every six hours) of dialysis.The hyaluronic acid that dopamine is modified i.e. is can get after lyophilizing.
Medicine selected in described step (7) can be tumor Drugs (example hydrochloric acid amycin, cisplatin, paclitaxel,
Camptothecine etc.) one or more.Further, the medicine (such as hormone, antibiotic etc.) of other effects is equally applicable to this
Bright.Preferably, appropriate hydrochloric acid amycin is dissolved in PBS(pH 7.4 by this step) in, then Jia Jin-Nano carbon balls, room temperature lucifuge
Stir 24 hours, i.e. can get the gold-Nano carbon balls of carrying medicament.
It described step (8) is the gold-Nano carbon balls of the hyaluronic acid parcel carrying medicament using dopamine to modify.Specifically
Ground, the gold-Nano carbon balls of bag medicine carrying thing is scattered in PBS, then add dopamine modify hyaluronic acid (mass ratio 1:
1) lucifuge stirring reaction 24 hours, is continued；After having reacted, within centrifugal 15 minutes, collect precipitation, and use double for 12000 revs/min
Steam water to wash three times, i.e. can get the gold-Nano carbon balls of the carrying medicament of hyaluronic acid parcel.
The beneficial effects of the present invention is:
(1) the method is simple to operate, and raw material acquisition pattern is easy, with low cost, is generally suitable for, it is not necessary to Special complex equipment etc..
(2) nano composite system using the method to prepare, has outer layer hyaluronic acid and internal layer gold-Nano carbon balls simultaneously
Characteristic, there is the features such as high photo-thermal conversion efficiency, high drug load, high-biocompatibility.It possesses pH/ hyaluronidase/near
The drug release characteristics of infrared multiple response, targeting can suppress tumor cell, especially with photo-thermal/photodynamics/chemistry
Therapeutic alliance resistant tumors is had excellence killing rejection ability, in tumor diagnosis and treatment field particularly solve tumor many
Weight drug resistance aspect possesses wide application prospect.
Accompanying drawing explanation
Fig. 1 is the transmission electron microscope figure of representational prepared gold-Nano carbon balls.
Fig. 2 is the uv-visible absorption spectra of the hyaluronic acid that representational prepared dopamine is modified.
Fig. 3 is representational prepared gold-Nano carbon balls, the hyaluronic acid of dopamine modification, hyaluronic acid parcel
The thermogravimetric weight loss figure of gold-Nano carbon balls.
Fig. 4 is the cytocompatibility of the gold-Nano carbon balls of representational prepared gold-Nano carbon balls and hyaluronic acid parcel
Property figure.
Fig. 5 is the hemolytic experiment of the gold-Nano carbon balls of representational prepared gold-Nano carbon balls and hyaluronic acid parcel
Figure.
Fig. 6 is representational prepared gold-Nano carbon balls temperature variation under near-infrared laser irradiates.
Fig. 7 be the gold-Nano carbon balls of the hyaluronic acid parcel of representational prepared load amycin at different pH and
Drug release profiles in enzyme environment.
Fig. 8 is that the gold-Nano carbon balls of the hyaluronic acid parcel of representational prepared load amycin swashs at near-infrared
Drug release profiles under light irradiation.
Fig. 9 is that the gold-Nano carbon balls of the hyaluronic acid parcel of representational prepared load amycin is to tumor cell
Cytotoxicity figure.
Figure 10 is that the gold-Nano carbon balls of the hyaluronic acid parcel of representational prepared load amycin is to drug resistance
The photo-thermal of MCF-7/ADR cell, photodynamics, chemotherapy combined therapeutic effect figure.
Figure 11 is that the gold-Nano carbon balls of the hyaluronic acid parcel of representational prepared load amycin is to tumor-bearing mice
Tumor inhibitory effect figure.
Detailed description of the invention
Embodiment 1: the surface using dopamine to wrap up as the hyaluronic acid prepared by carbon source that the present invention provides is interspersed
There is the hollow Nano carbon balls pharmaceutical carrier of Jenner's grain of rice
(1) diameter is about the synthesis of silica spheres (template) of 80 nm
Measure 100 mL dehydrated alcohol, be placed in 150 mL beakers, add 1.5 mL distilled waters and the ammonia of 5 mL 25-28%,
Use magnetic stirrer simultaneously；Afterwards, it is added dropwise over 1.5 mL tetraethyl orthosilicates, is stirred at room temperature 4 hours.Reaction completes
After, 12000 revs/min of centrifugal 15 minutes precipitated silica balls, absolute ethanol washing three times, obtain the silicon dioxide of purification
Ball.
(2) silica nanosphere of poly-dopamine parcel is synthesized
Weigh the silica spheres of 200 mg step (1) gained, be distributed to the 10 mM trihydroxy methyl amino of 60 mL pH 8.5
In aminomethane buffer；Afterwards, weigh 180 mg dopamine hydrochlorides, join in above-mentioned reaction system, be then stirred at room temperature
React 48 hours；After having reacted, collected by suction product also uses distilled water to wash, be placed on lyophilizing in freezer dryer,
Obtain the silica nanosphere of poly-dopamine parcel.
(3) synthetic surface point is embroidered with the silica nanosphere that the poly-dopamine of gold wraps up
Weigh the product of gained in 200 mg steps (2), be dispersed in 50 mL distilled waters, weigh 50 mg auric chlorides afterwards
Potassium, joins in above-mentioned dispersion liquid, quick stir about 30 minutes in ice bath；After having reacted, collected by suction product,
And use lyophilizing after distilled water washing, obtain the silica nanosphere that surface point is embroidered with the poly-dopamine parcel of gold.
(4) synthesis gold-Nano carbon balls
The silica nanosphere of the poly-dopamine parcel being dotted with on the surface of step (3) gained golden is 500 DEG C, argon shield
Lower carbonization.After carbonization, the carbon ball containing silica template obtained is placed in a plastics reaction cup, adds concentration and be about
The Fluohydric acid. of 4%, stirring reaction is dissolved silica template in 1 hour, is obtained a little being embroidered with the gold-Nano carbon balls of gold nano grain.Such as figure
Shown in 1: a diameter of about 100 nm of gold-Nano carbon balls synthesized by the method, its surface is uniformly put and is embroidered with gold grain.
(5) synthesis of the hyaluronic acid that dopamine is modified
Weigh 100 mg hyaluronis to be placed in one 100 mL round-bottomed flasks, add the PBS after 50 mL deoxygenations and stir
Until hyaluronic acid is completely dissolved.Afterwards, weigh 50 mg carbodiimides respectively and 30 mg N-hydroxy-succinamides join
In hyaluronic acid solution, stir about makes carbodiimide and N-hydroxy-succinamide be completely dissolved for 30 minutes.Then, 50 are weighed
Mg dopamine hydrochloride, joins in above-mentioned mixed liquor, is adjusted by the pH of solution to 4-6, stirring after dopamine is completely dissolved
React 9 hours.Detect primary first-order equation liquid pH during reaction per hour and adjust in real time, making pH value be maintained at 4-6.Afterwards will
It is in the daltonian bag filter of 8000-14000 that reactant liquor is transferred to molecular cut off, dialyses 24 hours in the PBS of 20 mM
(within every six hours, changing liquid once), is placed in distilled water 24 hours (changing liquid once in every six hours) of dialysis the most again, obtains after lyophilizing
The hyaluronic acid that dopamine is modified.As shown in Figure 2: detection dopamine uv absorption at 280 nm, and with dopamine standard
The absorption value of product solution is compared, calculate the most every 100 hyaluronic acid unit are connected to 9.4 dopamine residues.
(6) gold-Nano carbon balls of synthesis hyaluronic acid parcel
Gold-the Nano carbon balls (100 mg) step (4) obtained is scattered in the PBS of 10 mM, adds 100 mg dopamine and repaiies
The hyaluronic acid of decorations, lucifuge stirring reaction 24 hours；After having reacted, mixed liquor 12000 revs/min is centrifuged 15 minutes and makes
Precipitate three times with distilled water washing, obtain the gold-Nano carbon balls of hyaluronic acid parcel.As shown in Figure 3: when temperature brings up to 790
DEG C time, the weight loss of the hyaluronic acid that the gold-Nano carbon balls of carbon-gold nanosphere, hyaluronic acid parcel, dopamine are modified is respectively
Being 13.5%, 35.0%, 73.4%, illustrate that hyaluronic acid is successfully modified on carbon-gold nanosphere, its mass percent is about
34.6%。
Experimental example 1: the biocompatibility of research gold-Nano carbon balls
1, the gold-Nano carbon balls of unloaded carbon-gold nanosphere and hyaluronic acid parcel is hatched altogether 48 little with kinds of tumor cells
Shi Hou, CCK8 method detection cell viability, as shown in Figure 4: when compound system does not carry any medicine, does not has the vigor of cell
There is significantly impact.
2, the gold-Nano carbon balls of unloaded gold-Nano carbon balls and hyaluronic acid parcel is total at 37 DEG C with human red blood cell
With hatching 2 hours, carry out the haemolysis situation in analogue body.As shown in Figure 5A: erythrocyte and gold-Nano carbon balls or hyaluronic acid parcel
Gold-Nano carbon balls hatch altogether and be centrifugal after supernatant the most substantially clarify, show obvious haemolysis.By detection hemoglobin
Absworption peak at 585 nm, and compared with positive control 1% Triton X-100 and negative control PBS, can calculate molten
Blood ratio.As shown in Figure 5 B: compared with gold-Nano carbon balls, gold-Nano carbon balls hemolysis rate at various concentrations of hyaluronic acid parcel
All not less than 0.5%, this shows that the modification of hyaluronic acid makes gold-Nano carbon balls minimum on erythrocytic impact.In sum,
Gold-the Nano carbon balls of gold-Nano carbon balls and hyaluronic acid parcel has the extraordinary erythrocyte compatibility, in vivo in circulation not
Obvious haemolysis can be caused.
Experimental example 2: the optical and thermal transformation efficiency of research gold-Nano carbon balls
Use the near-infrared laser of 808 nm at 2 W/cm2Power under irradiate gold-Nano carbon balls dispersion liquid, and use thermal imaging
The temperature of dispersion liquid is observed by instrument.As shown in Figure 6, under the irradiation of near-infrared laser, the temperature of gold-Nano carbon balls dispersion liquid
Degree rapid increase, reaches about 73 DEG C after ten minutes.This result shows, this gold-Nano carbon balls has good light-heat transfer effect
Rate, the photo-thermal conversion efficiency of this excellence can not only effectively by overheated come killing tumor cell, it is also possible to promote wrapped
The release of the medicine carried.Additionally, due to photo-thermal conversion efficiency is higher, gold-Nano carbon balls can be under the laser of lower-wattage irradiates
Reach higher temperature, thus avoid the damage at the non lesion position using high power laser light to be caused.
Experimental example 3: the pH/ hyaluronidase/near-infrared laser of the gold-Nano carbon balls medicine-carried system of research hyaluronic acid parcel is many
Weight response drug release behavior
1, the controlled drug delivery systems of the pH/ hyaluronidase/near-infrared laser multiple response of preparation load antitumor drug
(1) this research uses broad-spectrum anti-cancer drug amycin.100 mg amycin are dissolved in 200 mL PBS(pH 7.4) in,
Adding 100 mg gold-Nano carbon balls, room temperature lucifuge stirs 24 hours.
(2) hyaluronic acid that 100 mg dopamine are modified is joined in the mixed liquor of step (1), room temperature lucifuge reaction 24
After hour, centrifugal product of collecting, use distilled water washed product is colourless to supernatant, afterwards products therefrom lyophilizing can be obtained powder
Gold-Nano carbon balls the drug-loading nanoparticles of the hyaluronic acid parcel of powder, can be surveyed by DOX content in supernatant before and after calculating medicine carrying
Obtain drug loading and be about 35.5%.
3, the gold-Nano carbon balls medicine-carried system of detection hyaluronic acid parcel drug release profiles under the conditions of different pH and enzyme
Gold-the Nano carbon balls of the hyaluronic acid parcel of 2 mg load amycin is divided in (0.5 mg in 42 mL centrifuge tubes
Often pipe), it is separately added into 1.5 mL pH 5.0, the 7.4 and PBS of the pH 5.0 and 7.4 containing hyaluronidase, lucifuge is placed in
37 DEG C of concussions, collect supernatant at the time point set, measure the light absorption value at 480 nm with ultraviolet spectrophotometer, according to mark
Directrix curve calculates amycin amount and the ratio of release, draws release profiles.As shown in Figure 7: at the environment of pH 5.0 after 24 hours
Under have the drug release of 44% out, after adding hyaluronidase, have the medicine of 70% to discharge from system, it was demonstrated that this is released
Medicine system is to pH and hyaluronidase Dual Sensitive.
3, the gold-Nano carbon balls medicine-carried system of detection hyaluronic acid parcel drug release profiles under near-infrared irradiates
Gold-the Nano carbon balls of the hyaluronic acid parcel of 2 mg load amycin is divided in (0.5 mg in 42 mL centrifuge tubes
Often pipe), it is separately added into the buffer of 1.5 mL pH 7.4, lucifuge is placed in 37 DEG C of concussions, uses 808 nm at the time point set
Near-infrared laser is with 2 W/cm2Power illumination 5 minutes, and collect supernatant at future time point, use ultraviolet spectrophotometer
Measure the light absorption value at 480 nm, calculate amycin amount and the ratio of release according to standard curve, draw release profiles.Such as Fig. 8
Shown in: in the environment of pH 7.4, there is the drug release of 34% after 24 hours out, far above without near-infrared laser irradiation group, demonstrate,prove
Near-infrared laser is irradiated sensitivity by this medicine-releasing system real.
Experimental example 4: the gold-Nano carbon balls medicine-carried system of the hyaluronic acid parcel of research load amycin is for drug susceptibility-types
Tumor cell and the chemotherapy lethal effect of multidrug resistant type tumor cell
By gold-Nano carbon balls and the drug susceptibility-types human liver cancer cell (HepG2 cell) of the hyaluronic acid parcel of load amycin,
Human cervical carcinoma cell (HeLa cell), human breast cancer cell (MCF-7 cell), and multidrug resistant type human breast cancer cell
(MCF-7/ADR cell) hatches 48 hours altogether, detects cell viability by CCK8 method.As shown in Figure 9: by thin for drug susceptibility-types tumor
After born of the same parents process with free doxorubicin hydrochloride, most tumor cell occurs in that death；Similarly, hyaluronic acid wraps up
Gold-Nano carbon balls also can inducing death of neoplastic cells effectively, but when low concentration, the lethal effect of tumor cell is weaker than trip
From amycin, because amycin is micromolecular water soluble drug, is easily absorbed by tumor cell by diffusion way and play in time
Graft Versus Tumor.And on the contrary, after being processed with free amycin by multidrug resistant type breast cancer cell, cell viability is the highest
Tumor cell after the gold wrapped up with hyaluronic acid-Nano carbon balls processes, because multidrug resistant type tumor cell exists a large amount of
Drug efflux pump, be pumped out extracellular soon when free amycin enters after Cytoplasm through cell membrane, thus tumor killed
Overstrain is decreased obviously；And the cell endocytic that the gold-Nano carbon balls of hyaluronic acid parcel is mediated by CD44 enters intracellular, can keep away
Writing a prescription thing pumping action, meanwhile, lysosomal acidity and the environment rich in hyaluronidase make medicine be released in a large amount in an early stage out and expand
It is dissipated to nucleus, thus in multidrug resistant type tumor cell, plays stronger cell killing effect.
Experimental example 5: the gold-Nano carbon balls medicine-carried system of the hyaluronic acid parcel of research load amycin swells for multidrug resistant type
Chemotherapy-the photo-thermal therapy of oncocyte-photodynamic therapy associating lethal effect
By gold-Nano carbon balls and the multidrug resistant type human breast cancer cell (MCF-7/ADR of the hyaluronic acid parcel of load amycin
Cell) hatch 4 hours (doxorubicin concentration is 10 μ g/mL) altogether, use 1.5 W/cm afterwards2808 nm near-infrared lasers irradiate
0-5 minute, after continuing to hatch 24 hours, use CCK8 method detection cell viability.As shown in Figure 10: irradiate at identical near-infrared
Under time, load amycin group cytotoxicity is noticeably greater than unsupported amycin group, shows that amycin plays with gold-Nano carbon balls
The effect of therapeutic alliance, causes significantly killing to the MCF-7/ADR cell of drug resistance.
Experimental example 6: the gold-Nano carbon balls medicine-carried system of the hyaluronic acid parcel of research load amycin is for mice multidrug resistant
The chemotherapy of type tumor-thermotherapy lethal effect
Treat that mice multidrug resistant type tumor average volume reaches 70 mm3Time, mice is randomly divided into 6 groups, often group 5, the most quiet
Arteries and veins injection PBS, amycin, amycin/gold-Nano carbon balls, each 200 μ L of amycin/hyaluronic acid/gold-Nano carbon balls.24 is little
Shi Hou, uses 1 W/cm2808 nm near-infrared lasers irradiate each group of 15 minutes, mouse tumor positions (except PBS group), see afterwards
Examine record mouse tumor size.As shown in FIG. Figure 11 A and 11 B: control simple near-infrared and irradiate and cannot suppress tumor growth, free Ah
Mycin group and amycin/gold-Nano carbon balls group the most only demonstrate limited anti-tumor capacity.Amycin/hyaluronic acid/gold-carbon
In nanometer set of balls, tumor size significantly reduces, and only 1 mice is still with the presence of tumor.Hyaluronic acid/gold-Nano carbon balls group
Tumor growth is suppressed, but owing to it is without amycin, it is difficult to effectively remove tumor, still with the presence of 4 mice tumors.This table
Bright, the gold-Nano carbon balls medicine-carried system of the hyaluronic acid parcel of load amycin can effectively be enriched to tumor locus, and leads to
Cross the photo-thermal-photodynamics-chemical combined treatment under near-infrared irradiates tumor is effectively melted and kills.
Claims (10)
1. there is the preparation method of the hyaluronic acid decorated gold-Nano carbon balls of synergistic antitumor characteristic, comprise the following steps:
(1) the solid silicon dioxide utilizing tetraethyl orthosilicate hydrolysis in alkaline environment a diameter of 80-450 nm is received
Rice ball；
(2) silica nanosphere obtained in step (1) is scattered in alkaline solution, adds dopamine hydrochloride, profit
Obtain poly-dopamine with dopamine polymerization in alkaline solution and be wrapped on silica template, forming poly-dopamine-two
Silicon oxide nano-complex；
(3) poly-dopamine-silicon dioxide nanocomposite obtained in step (2) is scattered in distilled water, adds chlorine gold
Acid potassium, obtains surface point and is embroidered with the poly-dopamine-silicon dioxide nanocomposite of golden nanometer particle；
(4) surface point obtained in step (3) is embroidered with the poly-dopamine-silicon dioxide nanocomposite of golden nanometer particle in nothing
Calcine under the conditions of oxygen, make poly-dopamine carbonization, obtain surface point and be embroidered with the carbon-silica composite of golden nanometer particle；
(5) surface point obtained in step (4) is embroidered with golden nanometer particle that carbon-silica composite is scattered in Fluohydric acid. is molten
In liquid, dissolve and remove silica template, obtain surface point and be embroidered with the hollow Nano carbon balls of Jenner's grain of rice；
(6) using the carboxyl of hyaluronic acid to react with the amido of dopamine, synthesis obtains the hyaluronic acid that dopamine is modified；
(7) surface point in step (5) is embroidered with the hollow Nano carbon balls of Jenner's grain of rice stir in a solvent with medicine and mix, i.e.
The surface point obtaining carrying medicament is embroidered with the hollow Nano carbon balls of Jenner's grain of rice；
(8) hyaluronic acid that dopamine step (6) obtained is modified is embroidered with Jenner's grain of rice with the surface point of load chemotherapeutics
Hollow Nano carbon balls react in phosphate buffer, there is the hyaluronic acid decorated of synergistic antitumor characteristic
Gold-Nano carbon balls.
Preparation method the most according to claim 1, is characterized in that: the alkaline environment in described step (1) refers at ammonia
In；Described step (2) neutral and alkali solution is the TRIS buffer of alkalescence.
Preparation method the most according to claim 2, is characterized in that, the solid silica nanosphere in described step (1)
Prepared by purgation: in 100-1000 ml ethanol, add 1.5-15 mL distilled water and 5-50 mL concentration is 25 ~ 28% mass
The ammonia of percentage ratio, stirs；Add 1.5-15 mL tetraethyl orthosilicate afterwards, reaction 4 hour is stirred at room temperature；React
Bi Hou, collects silica spheres for centrifugal 15 minutes for 10000 revs/min, and to use absolute ethanol washing to supernatant be that neutrality obtains
Solid ball-type silica template；Poly-dopamine-silicon dioxide nanocomposite in described step (2) is prepared by purgation: will
The silica spheres that step (1) is obtained is scattered in the 10 mM TRIS buffer of pH 8.5, wherein dioxy
SiClx ball is 1 g silica spheres with the amount ratio of TRIS buffer: 300 mL trihydroxy methyl amino first
Alkane buffer；Dopamine hydrochloride, stirring reaction is added in the ratio of silica nanosphere and dopamine hydrochloride mass ratio 1:.:0
48 hours, obtaining the poly-dopamine-silicon dioxide nanocomposite suspension of brown, vacuum filtration is collected product and uses distilled water
Wash, after lyophilizing, obtain pure poly-dopamine-silicon dioxide nanocomposite.
Preparation method the most according to claim 1, is characterized in that: in described step (3), surface point is embroidered with golden nanometer particle
Poly-dopamine-silicon dioxide nanocomposite prepared by purgation: by the 1 poly-dopamine-silicon dioxide nanocomposite of g: 300
The ratio of mL distilled water, is scattered in the poly-dopamine-silicon dioxide nanocomposite obtained in step (2) in distilled water, so
The potassium chloroaurate of the poly-dopamine of rear addition 25%-silicon dioxide nanocomposite quality, stirring reaction 30 minutes in ice bath；Instead
After should completing, collected by suction product, use lyophilizing after distilled water washing, i.e. obtain surface point and be embroidered with the poly-of golden nanometer particle
Dopamine-silicon dioxide nanocomposite；Described step (4) surface point is embroidered with the carbon-silica composite of golden nanometer particle
Obtained by purgation: surface point is embroidered with the poly-dopamine-silicon dioxide nanocomposite of golden nanometer particle under argon shield,
Calcine 3 hours, i.e. obtain surface point and be embroidered with the carbon-silica composite of golden nanometer particle for 500 DEG C.
Preparation method the most according to claim 1, is characterized in that: in described step (5), surface point is embroidered with Jenner's grain of rice
Hollow Nano carbon balls is obtained by purgation: carbon-silica composite that surface point is embroidered with golden nanometer particle is placed in 100 mL matter
Amount percent is in the Fluohydric acid. of 4%, and stirring reaction 1 hour obtains surface point and is embroidered with the hollow Nano carbon balls of Jenner's grain of rice.
Preparation method the most according to claim 1, is characterized in that: described step (6) dopamine modify hyaluronic acid by
Purgation obtains: be dissolved in pH 7.4 phosphate buffer of 50 ~ 500 mL deoxygenations by 100 ~ 1000 mg hyaluronis；
Add carbodiimide and N-hydroxy-succinamide afterwards and stir to being completely dissolved to obtain mixed liquor；Wherein, hyaluronic acid unit:
Carbodiimide: the mol ratio of N-hydroxy-succinamide is 1: 1: 1；Weigh 50 ~ 500 mg dopamine hydrochlorides, join
In above-mentioned mixed liquor, after dopamine is completely dissolved, the pH of solution adjusted to 4 ~ 6 and stir reaction 9 hours；Then, will reaction
It is in 8000 ~ 14000 daltonian bag filters that liquid is transferred to molecular cut off, dialysis 24 in the phosphate buffer of 20 mM
Hour, it is changed to distilled water afterwards and dialyses 24 hours, after lyophilizing, i.e. can get the hyaluronic acid that dopamine is modified.
Preparation method the most according to claim 1, is characterized in that: described step has synergistic antitumor characteristic in (8)
Hyaluronic acid decorated gold-Nano carbon balls is obtained by purgation: the hollow carbon that the surface point of carrying medicament is embroidered with Jenner's grain of rice is received
Rice ball is scattered in pH 7.4 phosphate buffer, then adds the hyaluronic acid that dopamine is modified, and continues lucifuge stirring reaction
24 hours；After having reacted, within centrifugal 15 minutes, collect precipitation, and use distilled water to wash three times for 12000 revs/min,
To the hyaluronic acid decorated gold-Nano carbon balls with synergistic antitumor characteristic；Wherein the surface point of carrying medicament is embroidered with Jenner
The hollow Nano carbon balls of the grain of rice is 1:1 with the consumption mass ratio of the hyaluronic acid that dopamine is modified.
Preparation method the most according to claim 1, is characterized in that: medicine selected in described step (7) can be sharp
Element or antibiotic or cancer therapy drug.
9. by what the preparation method described in any one of claim 1-8 obtained, there is the hyaluronic acid decorated of synergistic antitumor characteristic
Gold-Nano carbon balls.
10. the hyaluronic acid decorated gold-Nano carbon balls with synergistic antitumor characteristic described in claim 9 is preparing targeting
Property diagnosis or treatment tumor medicine in application.
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