CN106139144B - A kind of hyaluronic acid decorated gold-Nano carbon balls and the preparation method and application thereof with synergistic antitumor characteristic - Google Patents
A kind of hyaluronic acid decorated gold-Nano carbon balls and the preparation method and application thereof with synergistic antitumor characteristic Download PDFInfo
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
Abstract
A kind of hyaluronic acid decorated gold-Nano carbon balls with synergistic antitumor characteristic are made by laxative remedy: preparing solid silica nanosphere first；Poly-dopamine is wrapped on silica template, poly-dopamine-silicon dioxide nanocomposite is formed；Poly-dopamine-silicon dioxide nanocomposite gold point is sewed in reduction potassium chloroaurate realization.By under oxygen-free environment calcined product realize the carbonization of poly-dopamine.Then dissolution removes silica template, then is stirred in a solvent with drug, obtains the hollow Nano carbon balls of carrying medicament；By the amine-modified hyaluronic acid of DOPA with load chemotherapeutics hollow Nano carbon balls reacted in phosphate buffer to get.The present invention has the characteristics that high photothermal conversion efficiency, high drug load, good biocompatibility, can targeting inhibit tumour cell, especially have excellent killing rejection ability to resistant tumors with photo-thermal/photodynamics/chemistry combination therapy.
Description
Technical field
The present invention relates to field of biomedical materials, and in particular to a kind of preparation of hollow gold-Nano carbon balls, surface are repaired
Decorations carry anti-tumor drug and the application in oncotherapy.
Background technique
In recent years, Cancer Mortality constantly increases, it has also become one of maximum harm of human health.Based on nanometer medicine
The tumor thermal therapy and photodynamic therapy of object are proved to have the effect of under study for action splendid, are a kind of the swollen of great potential
Tumor treatment method.Photo-thermal therapy is by will have the Nano medication of photothermal conversion efficiency to be enriched to tumor locus, in specific light
Source irradiation is lower to generate the method that heat melts neoplasm necrosis.Photodynamic therapy is to be shone using photosensitizer in specific wavelength light source
Penetrate the lower method for generating active oxygen lethality tumour cell.Nano carbon balls are as a kind of novel nano material that biological safety is splendid
Material has optical and thermal conversion capability, photo-catalysis capability, great specific surface area and extremely strong adsorption capacity.It is as a kind of outstanding
Photosensitizer, heat and active oxygen can be generated in the case where near infrared light, effectively tumour cell can be killed.Cause
This, Nano carbon balls are very suitable for the photo-thermal and photodynamic therapy of tumour.However the photothermal conversion efficiency of Nano carbon balls is limited,
The efficiency of photo-thermal therapy is limited, how to improve its photothermal conversion efficiency is current one of research emphasis.
Jenner's grain of rice is nanoscale simple substance gold particle, is readily synthesized, and has very high chemical stability, surface is easy to
Modification, and cytotoxicity is low, biocompatibility is high, is widely used in biomedicine field.Gold nanoparticle is to 700-
The near infrared light of 1100 nm has high absorption, can convert thermal energy for the luminous energy of absorption.Therefore, on Nano carbon balls surface
Gold nanoparticle is interspersed, the nanoparticle that two kinds of nano material preparations have higher photothermal conversion efficiency can be organically combined
Son.Currently, being combined without any article and patent using gold nanoparticle and Nano carbon balls to prepare with bloom thermal conversion efficiency
The Nano medication of energy, and carry the combination therapy that chemotherapeutics is applied to tumour.
Targeted therapy is a kind of new treatment means, and drug specificity can be infused in tumour cell, is reduced just
The often accumulation in tissue reduces side effect to heighten the effect of a treatment.Cell surface trans-membrane glycoprotein C D44 is a kind of important tumour
Marker, and the invasion of tumour are related with transfer, and the high expression in kinds of tumor cells.Hyaluronic acid is that have with CD44
The ligands specific of high affinity can be entered in tumour cell by the cell endocytic that CD44 is mediated.Therefore, by hyaluronic acid
Or derivatives thereof be introduced into Nano medication, it can be achieved that the Clinics and Practices of tumor-targeting act on.
The present invention synthesizes Nano carbon balls as carbon source using poly-dopamine, and obtains using poly-dopamine reduction potassium chloroaurate
It is interspersed to simple substance gold nano grain and obtains gold-Nano carbon balls in Nano carbon balls surface, received later by hyaluronic acid decorated in gold-carbon
Rice ball surface, is successfully prepared for good biocompatibility, high drug load, has both the multiple responses such as pH, enzyme and near-infrared
The targeting multifunctional intellectual therapy system of property, can be effectively used for oncotherapy, and also have splendid killing energy to resistant tumors
Power.
Summary of the invention
The present invention is directed to the surface points for using biomass carbon source to provide a kind of hyaluronic acid package to be embroidered with the sky of Jenner's grain of rice
Heart Nano carbon balls pharmaceutical carrier and its preparation method and application.Intersperse gold nano in the surface of the hyaluronic acid package of this method preparation
The Nano carbon balls of grain have good biocompatibility, and high drug load has both the multiple responses such as pH, hyaluronidase and near-infrared
Property the characteristics of, and can specificity the highly expressed tumour cell of targeting CD44, and utilize photo-thermal therapy, photodynamic therapy and change
The effective killing tumor cell of the combination therapy for the treatment of, and the toxic side effect of anti-tumor drug is effectively reduced.
Technical proposal that the invention solves the above-mentioned problems is, a kind of surface point of hyaluronic acid package is embroidered with Jenner's grain of rice
Hollow Nano carbon balls pharmaceutical carrier and its preparation method and application.The surface point of hyaluronic acid package is embroidered with the sky of Jenner's grain of rice
Heart Nano carbon balls pharmaceutical carrier is made of tumor targeted molecular, gold-Nano carbon balls and drug three parts.Wherein, cancer target point
Son is hyaluronic acid；Gold-Nano carbon balls are the hollow Nano carbon balls that surface point is embroidered with Jenner's grain of rice；Drug can be hormone or anti-
Raw element or anticancer drug etc..
The hollow Nano carbon balls pharmaceutical carrier that the surface point of the hyaluronic acid package is embroidered with Jenner's grain of rice is made by laxative remedy:
(1) the solid titanium dioxide for being 80-450 nm using hydrolysis diameter of the tetraethyl orthosilicate in alkaline environment
Silicon nanosphere；
(2) it disperses obtained silica nanosphere in step (1) in alkaline solution, dopamine hydrochloric acid is added
Salt obtains poly-dopamine using polymerization of the dopamine in alkaline solution and is wrapped on silica template, forms poly- DOPA
Amine-silicon dioxide nanocomposite；
(3) it disperses poly-dopamine-silicon dioxide nanocomposite obtained in step (2) in distilled water, is added
Gold in gold potassium chloride can be reduced to 0 valence state and on its surface since poly-dopamine has strong reducing property by appropriate potassium chloroaurate
Original crystallization is nanoparticle, obtains poly-dopamine-silicon dioxide nanocomposite that surface point is embroidered with gold nanoparticle；
(4) surface point obtained in step (3) is embroidered with poly-dopamine-silicon dioxide nanocomposite of gold in anaerobic item
It is calcined under part, poly-dopamine is made to be carbonized, obtain carbon-silica composite that surface point is embroidered with gold nanoparticle；
(5) hydrogen fluorine is dispersed by carbon-silica composite that surface point obtained in step (4) is embroidered with gold nanoparticle
In acid solution, dissolution removes silica template, obtains the hollow Nano carbon balls that surface point is embroidered with Jenner's grain of rice, referred to as gold-
Nano carbon balls；
(6) it is reacted using the carboxyl of hyaluronic acid with the amido of dopamine, synthesis obtains the amine-modified hyaluronic acid of DOPA；
(7) gold-Nano carbon balls in step (5) are stirred in a solvent with drug, carrying medicament can be obtained
Surface point is embroidered with the hollow Nano carbon balls of Jenner's grain of rice；
(8) surface point of the DOPA that step (6) obtains amine-modified hyaluronic acid and carrying medicament is embroidered with Jenner's grain of rice
Hollow Nano carbon balls reaction in the phosphate buffer (PBS), the gold-carbon that can obtain the carrying medicament of hyaluronic acid package receives
Rice ball.
Solid ball-type silica template in the step (1) is the ammonium hydroxide using tetraethyl orthosilicate as organosilicon precursor
For obtained by catalyst.Specifically, measure 100-1000 ml ethyl alcohol be placed in flask, be added 1.5-15 mL distilled water and
5-50 mL ammonium hydroxide (25 ~ 28%), stirs evenly；1.5-15 mL tetraethyl orthosilicate is added dropwise later, reaction 4 is stirred at room temperature
Hour.After completion of the reaction, 10000 revs/min of centrifugations, 15 minutes collection silica spheres, and washed using dehydrated alcohol to supernatant
It is in neutrality.Poly-dopamine-silicon dioxide nanocomposite in the step (2) is three hydroxyls using DOPA amine monomers in alkalinity
Aminomethane buffer occurs to polymerize and be wrapped on silica template obtained.Specifically, step (1) is obtained
Silica spheres be scattered in the 10 mM TRIS buffers of pH 8.5 (mass volume ratio be 1 g: 300
ML), Dopamine hydrochloride (the 90% of silica template quality) is added to be stirred to react 48 hours, obtains the poly-dopamine-two of brown
Silica nano-complex suspension, vacuum filtration are collected product and are washed with distilled water, and pure gather is obtained after freeze-drying
Dopamine-silicon dioxide nanocomposite.
Poly-dopamine-silicon dioxide nanocomposite gold point is sewed using potassium chloroaurate realization in the step (3).Tool
Body, disperses poly-dopamine-silicon dioxide nanocomposite obtained in step (2) in distilled water that (mass/volume ratio is
1 g: 300 mL), it is added potassium chloroaurate (poly-dopamine-silicon dioxide nanocomposite compound quality 25%), in ice bath
In be stirred to react 30 minutes；After the reaction was completed, collected by suction reaction product is lyophilized after being washed using distilled water, table can be obtained
Millet cake is embroidered with poly-dopamine-silicon dioxide nanocomposite of gold nanoparticle.
The step (4) be by under oxygen-free environment calcined product realize the carbonization of poly-dopamine.Specifically, by table
Millet cake is embroidered with poly-dopamine-silicon dioxide nanocomposite of gold under protection of argon gas, and 500 DEG C are calcined 3 hours.
Hydrofluoric acid dissolution is selected to remove silica template in the step (5).Specifically, two will be contained after carbonization
The product of silica template is placed in 100 mL4% hydrofluoric acid, is stirred to react 1 hour to dissolve silica template, is finally obtained
Gold-Nano carbon balls.
Hyaluronic acid is selected to react to obtain the amine-modified hyaluronic acid of DOPA with Dopamine hydrochloride in the step (6).Tool
Body, it weighs 100 ~ 1000 mg hyaluronis and is dissolved in the PBS of 50 ~ 500 mL deoxygenations.Carbodiimide is added later
With n-hydroxysuccinimide and stir to being completely dissolved.Wherein, hyaluronic acid unit: carbodiimide: N- hydroxysuccinimidyl acyl is sub-
The molar ratio of amine is 1: 1: 1.50 ~ 500 mg Dopamine hydrochlorides are weighed, are added in above-mentioned mixed liquor, it is complete to dopamine
The pH of solution is adjusted to 4 ~ 6 and is stirred to react 9 hours after dissolution.During the reaction, primary first-order equation liquid is detected per hour
PH value simultaneously adjusts in real time, and pH value is made to remain at 4 ~ 6.After completion of the reaction, by reaction solution be transferred to molecular cut off be 8000 ~
It in the bag filter of 14000 dalton, dialyses in the PBS of 20 mM 24 hours (changing the liquid once within every six hours), is changed to double steamings later
Water 24 hours (changing the liquid once for every six hours) of dialysis.The amine-modified hyaluronic acid of DOPA can be obtained after freeze-drying.
In the step (7) selected drug can be tumor Drugs (such as doxorubicin hydrochloride, cis-platinum, taxol,
Camptothecine etc.) one or more.Further, the drug (such as hormone, antibiotic etc.) of other effects is equally applicable to this hair
It is bright.Preferably, appropriate hydrochloric acid adriamycin is dissolved in PBS(pH 7.4 by this step) in, then Jia Jin-Nano carbon balls, room temperature are protected from light
Stirring 24 hours, can be obtained gold-Nano carbon balls of carrying medicament.
It is gold-Nano carbon balls using the amine-modified hyaluronic acid package carrying medicament of DOPA in the step (8).Specifically
Ground disperses the gold-Nano carbon balls for containing drug in PBS, be then added the amine-modified hyaluronic acid of DOPA (mass ratio 1:
1), continue to be protected from light and be stirred to react 24 hours；After the reaction was completed, 12000 revs/min of centrifugation collection in 15 minutes precipitatings, and using double
It steams water washing three times, gold-Nano carbon balls of the carrying medicament of hyaluronic acid package can be obtained.
The beneficial effects of the present invention are:
(1) this method is easy to operate, and raw material acquisition pattern is easy, low in cost, is generally applicable in, and is not necessarily to Special complex equipment
Deng.
(2) nano composite system prepared using this method, while possessing outer layer hyaluronic acid and internal layer gold-Nano carbon balls
Characteristic, have the characteristics that high photothermal conversion efficiency, high drug load, high-biocompatibility.It has pH/ hyaluronidase/close
The drug release characteristics of infrared multiple response, can targeting inhibit tumour cell, especially with photo-thermal/photodynamics/chemistry
Combination therapy have excellent killing rejection ability to resistant tumors, tumour diagnosis and treatment field be especially solve tumour it is more
Has wide application prospect in terms of weight drug resistance.
Detailed description of the invention
Fig. 1 is representative prepared gold-Nano carbon balls transmission electron microscope figure.
Fig. 2 is the uv-visible absorption spectra of the amine-modified hyaluronic acid of representative prepared DOPA.
Fig. 3 wraps up for the amine-modified hyaluronic acid of representative prepared gold-Nano carbon balls, DOPA, hyaluronic acid
Gold-Nano carbon balls thermogravimetric weight loss figure.
Fig. 4 is gold-Nano carbon balls cytocompatibility of representative prepared gold-Nano carbon balls and hyaluronic acid package
Property figure.
Fig. 5 is gold-Nano carbon balls hemolytic experiment of representative prepared gold-Nano carbon balls and hyaluronic acid package
Figure.
Fig. 6 is temperature variation of the representative prepared gold-Nano carbon balls under near-infrared laser irradiation.
Fig. 7 be gold-Nano carbon balls of the hyaluronic acid package of representative prepared load adriamycin in different pH and
Drug release profiles in enzyme environment.
Fig. 8 is that gold-Nano carbon balls of the hyaluronic acid package of representative prepared load adriamycin swash in near-infrared
Drug release profiles under light irradiation.
Fig. 9 is gold-Nano carbon balls of the hyaluronic acid package of representative prepared load adriamycin to tumour cell
Cytotoxicity figure.
Figure 10 is gold-Nano carbon balls of the hyaluronic acid package of representative prepared load adriamycin to drug resistant
Photo-thermal, photodynamics, the chemotherapy combined therapeutic effect figure of MCF-7/ADR cell.
Figure 11 is gold-Nano carbon balls of the hyaluronic acid package of representative prepared load adriamycin to tumor-bearing mice
Tumor inhibitory effect figure.
Specific embodiment
Embodiment 1: it intersperses on the surface provided by the invention for using dopamine to wrap up as hyaluronic acid prepared by carbon source
There is the hollow Nano carbon balls pharmaceutical carrier of Jenner's grain of rice
(1) synthesis for the silica spheres (template) that diameter is about 80 nm
100 mL dehydrated alcohols are measured, are placed in 150 mL beakers, 1.5 mL distilled waters and 5 mL 25-28% are added
Ammonium hydroxide, while using magnetic stirrer；Later, 1.5 mL tetraethyl orthosilicates are added dropwise, are stirred at room temperature 4 hours.Reaction
After the completion, 12000 revs/min of centrifugations, 15 minutes precipitated silica silicon balls, dehydrated alcohol wash three times, the titanium dioxide purified
Silicon ball.
(2) silica nanosphere of synthesis poly-dopamine package
200 mg step (1) resulting silica spheres are weighed, the 10 mM trihydroxy methyls of 60 mL pH 8.5 are distributed to
In aminomethane buffer solution；Later, 180 mg Dopamine hydrochlorides are weighed, are added in above-mentioned reaction system, then at room temperature
It is stirred to react 48 hours；After the reaction was completed, collected by suction product and washed using distilled water, be placed in freeze drier and freeze
It is dry, obtain the silica nanosphere of poly-dopamine package.
(3) synthetic surface point is embroidered with the silica nanosphere of the poly-dopamine package of gold
Product obtained in 200 mg steps (2) is weighed, is dispersed in 50 mL distilled waters, weighs 50 mg chlorinations later
Golden potassium is added in above-mentioned dispersion liquid, quick stir about 30 minutes in ice bath；After the reaction was completed, collected by suction reaction produces
Object, and be lyophilized after being washed using distilled water, obtain the silica nanosphere that surface point is embroidered with the poly-dopamine package of gold.
(4) gold-Nano carbon balls are synthesized
The silica nanosphere for the poly-dopamine package for being dotted with golden by step (3) resulting surface is in 500 DEG C, argon gas
The lower carbonization of protection.The carbon ball containing silica template of acquisition is placed in a plastics reaction cup after carbonization, concentration is added
About 4% hydrofluoric acid is stirred to react 1 hour dissolution silica template, obtains the gold-Nano carbon balls for being a little embroidered with gold nano grain.
It is as shown in Figure 1: 100 nm or so by gold-Nano carbon balls diameter that this method synthesizes, surface uniformly puts and is embroidered with gold particle.
(5) synthesis of the amine-modified hyaluronic acid of DOPA
It weighs 100 mg hyaluronis to be placed in one 100 mL round-bottomed flasks, the PBS after 50 mL deoxygenations are added is simultaneously
Stirring is completely dissolved until hyaluronic acid.Later, 50 mg carbodiimides are weighed respectively and 30 mg n-hydroxysuccinimides add
Enter into hyaluronic acid solution, is completely dissolved carbodiimide and n-hydroxysuccinimide within stir about 30 minutes.Then, it weighs
50 mg Dopamine hydrochlorides, are added in above-mentioned mixed liquor, adjust the pH of solution to 4-6 after dopamine is completely dissolved, stir
Mix reaction 9 hours.Primary first-order equation liquid pH is detected per hour during reaction and is adjusted in real time, and pH value is made to be maintained at 4-6.Later
Reaction solution is transferred in the bag filter that molecular cut off is 8000-14000 dalton, is dialysed 24 hours in the PBS of 20 mM
(changing the liquid once within every six hours) is placed in distilled water again later and dialyses 24 hours (changing the liquid once within every six hours), obtain after freeze-drying
The amine-modified hyaluronic acid of DOPA.It is as shown in Figure 2: UV absorption of the detection dopamine at 280 nm, and with dopamine standard
The absorption value of product solution is compared, and calculates to be averaged every 100 hyaluronic acid units and is connected to 9.4 dopamine residues.
(6) gold-Nano carbon balls of synthesis hyaluronic acid package
It disperses gold-Nano carbon balls (100 mg) that step (4) obtains in the PBS of 10 mM, 100 mg DOPA is added
Amine-modified hyaluronic acid is protected from light and is stirred to react 24 hours；After the reaction was completed, 12000 revs/min of mixed liquor are centrifuged 15 minutes
And three times using distilled water washing precipitating, gold-Nano carbon balls of hyaluronic acid package are obtained.It is as shown in Figure 3: when temperature is increased to
At 790 DEG C, the weight loss of the amine-modified hyaluronic acid of gold-Nano carbon balls, the DOPA that carbon-gold nanosphere, hyaluronic acid wrap up
Respectively 13.5%, 35.0%, 73.4% illustrate that hyaluronic acid is successfully modified on carbon-gold nanosphere, and mass percent is about
It is 34.6%.
Experimental example 1: research gold-Nano carbon balls biocompatibility
1, gold-Nano carbon balls of unloaded carbon-gold nanosphere and hyaluronic acid package and kinds of tumor cells are incubated for altogether
After 48 hours, CCK8 method detects cell viability, as shown in Figure 4: the work when compound system does not carry any drug, to cell
Power does not influence significantly.
2, gold-Nano carbon balls of unloaded gold-Nano carbon balls and hyaluronic acid package and human red blood cells are total at 37 DEG C
With being incubated for 2 hours, to simulate intracorporal haemolysis situation.As shown in Figure 5A: red blood cell and gold-Nano carbon balls or hyaluronic acid wrap up
Gold-Nano carbon balls be incubated for and be centrifuged altogether after supernatant clarify substantially, show that obvious haemolysis does not occur.By detecting hemoglobin
Absorption peak at 585 nm, and compared with positive control 1% Triton X-100 and negative control PBS, it can calculate molten
Blood ratio.It is as shown in Figure 5 B: compared with gold-Nano carbon balls, gold-Nano carbon balls hemolysis rate at various concentrations of hyaluronic acid package
It is less than 0.5%, this shows the modification of hyaluronic acid so that influence of the gold-Nano carbon balls to red blood cell is minimum.In conclusion
Gold-Nano carbon balls of gold-Nano carbon balls and hyaluronic acid package have extraordinary red blood cell compatibility, in vivo in circulation not
It will cause apparent haemolysis.
Experimental example 2: research gold-Nano carbon balls optical and thermal transformation efficiency
Using the near-infrared laser of 808 nm in 2 W/cm2Power under irradiate gold-Nano carbon balls dispersion liquid, and using heat
Imager observes the temperature of dispersion liquid.As shown in fig. 6, under the irradiation of near-infrared laser, gold-Nano carbon balls dispersion liquid
Temperature rapid increase, reaches about 73 DEG C ten minutes later.Should the result shows that, the gold-Nano carbon balls have good light- heat transfer
Efficiency, this excellent photothermal conversion efficiency can not only be effectively by overheating come killing tumor cell, it is also possible to promote institute
The release of the drug contained.Further, since photothermal conversion efficiency is higher, gold-Nano carbon balls can be in the laser irradiation of lower-wattage
Under reach higher temperature, so as to avoid the damage for using non-lesion position caused by high power laser light.
Experimental example 3: gold-Nano carbon balls medicine-carried system pH/ hyaluronidase/near-infrared of research hyaluronic acid package swashs
Light multiple response drug release behavior
1, pH/ hyaluronidase/near-infrared laser multiple response controlled drug delivery systems of preparation load anti-tumor drug
(1) this research uses broad-spectrum anti-cancer drug adriamycin.100 mg adriamycins are dissolved in 200 mL PBS(pH
7.4) in, 100 mg gold-Nano carbon balls are added, room temperature is protected from light stirring 24 hours.
(2) the amine-modified hyaluronic acid of 100 mg DOPA is added in the mixed liquor of step (1), room temperature is protected from light 24
After hour, product is collected by centrifugation, it is colourless to supernatant using distilled water washed product, products therefrom freeze-drying be can be obtained into powder later
Gold-Nano carbon balls drug-loading nanoparticles of the hyaluronic acid package of last shape can be surveyed by calculating DOX content in the supernatant of load medicine front and back
Obtaining drugloading rate is about 35.5%.
3, drug release profiles of the gold-Nano carbon balls medicine-carried system of detection hyaluronic acid package under the conditions of different pH and enzyme
Gold-Nano carbon balls of the hyaluronic acid package of 2 mg load adriamycin are divided in (0.5 in 42 mL centrifuge tubes
The every pipe of mg), it is separately added into the PBS of 1.5 mL pH 5.0,7.4 and the pH 5.0 and 7.4 containing hyaluronidase, is protected from light and sets
It is shaken in 37 DEG C, collects supernatant at the time point of setting, measure the light absorption value at 480 nm with ultraviolet specrophotometer, according to
Standard curve calculates the adriamycin amount and ratio of release, draws release profiles.It is as shown in Figure 7: in the ring of pH 5.0 after 24 hours
There is 44% drug release to come out under border, after hyaluronidase is added, there is 70% drug to release from system, it was demonstrated that should
Medicine-releasing system is to pH and hyaluronidase Dual Sensitive.
3, drug release profiles of the gold-Nano carbon balls medicine-carried system of detection hyaluronic acid package under near-infrared irradiation
Gold-Nano carbon balls of the hyaluronic acid package of 2 mg load adriamycin are divided in (0.5 in 42 mL centrifuge tubes
The every pipe of mg), it is separately added into the buffer of 1.5 mL pH 7.4, is protected from light and is placed in 37 DEG C of concussions, uses 808 at the time point of setting
Nm near-infrared laser is with 2 W/cm2Power illumination 5 minutes, and selected in future time and collect supernatant, use uv-spectrophotometric
Light absorption value at 480 nm of meter measurement, the adriamycin amount and ratio of release are calculated according to standard curve, draws release profiles.Such as figure
Shown in 8: thering is 34% drug release to come out in the environment of 7.4 pH after 24 hours, much higher than no near-infrared laser irradiation group, card
The real medicine-releasing system irradiates near-infrared laser sensitive.
Experimental example 4: gold-Nano carbon balls medicine-carried system of the hyaluronic acid package of research load adriamycin is quick for drug
The chemotherapy lethal effect of sense type tumour cell and multidrug resistant type tumour cell
Will load adriamycin hyaluronic acid package gold-Nano carbon balls (HepG2 is thin with drug susceptibility-types human liver cancer cell
Born of the same parents), 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) is incubated for 48 hours altogether, detects cell viability with CCK8 method.It is as shown in Figure 9: drug susceptibility-types tumour is thin
After the free doxorubicin hydrochloride processing of born of the same parents, there is death in most tumour cell；Similarly, hyaluronic acid wraps up
Gold-Nano carbon balls also can effectively inducing death of neoplastic cells, but trip is weaker than to the lethal effect of tumour cell in low concentration
From adriamycin, because adriamycin is small molecule water soluble drug, easily played in time by diffusion way by tumour cell intake
Anti-tumor effect.And on the contrary, cell viability is obviously high after handling multidrug resistant type breast cancer cell and free adriamycin
In the gold-Nano carbon balls wrapped up with hyaluronic acid treated tumour cell because multidrug resistant type tumour cell exist it is a large amount of
Drug pump, be soon pumped out after free adriamycin enters cytoplasm through cell membrane extracellular, thus tumour is killed
Overstrain is decreased obviously；And gold-Nano carbon balls of hyaluronic acid package are entered into the cell by the cell endocytic that CD44 is mediated, and can be kept away
It writes a prescription object pumping action, meanwhile, the acidity of lysosome and the environment rich in hyaluronidase make drug be released in a large amount in an early stage out and expand
It is dissipated to nucleus, thus has played stronger cell killing effect in multidrug resistant type tumour cell.
Experimental example 5: gold-Nano carbon balls medicine-carried system of the hyaluronic acid package of research load adriamycin is for multidrug resistant
Chemotherapy-photo-thermal therapy of type tumour cell-photodynamic therapy combines lethal effect
Gold-the Nano carbon balls and multidrug resistant type human breast cancer cell (MCF- of the hyaluronic acid package of adriamycin will be loaded
7/ADR cell) it is incubated for altogether 4 hours (doxorubicin concentration is 10 μ g/mL), 1.5 W/cm are used later2808 nm near-infrared lasers
Irradiation 0-5 minutes continues to detect cell viability using CCK8 method after being incubated for 24 hours.It is as shown in Figure 10: in identical near-infrared
Under irradiation time, load adriamycin group cytotoxicity is noticeably greater than unsupported adriamycin group, shows adriamycin and gold-Nano carbon balls
The effect for playing combination therapy causes apparent killing to drug resistant MCF-7/ADR cell.
Experimental example 6: gold-Nano carbon balls medicine-carried system of the hyaluronic acid package of research load adriamycin is multiple for mouse
The chemotherapy of drug-resistant type tumour-thermotherapy lethal effect
Reach 70 mm to mouse multidrug resistant type tumor average volume3When, mouse is randomly divided into 6 groups, every group 5, is divided
It Jing Maizhushe not PBS, adriamycin, adriamycin/gold-Nano carbon balls, adriamycin/each 200 μ L of hyaluronic acid/gold-Nano carbon balls.
After 24 hours, 1 W/cm is used2808 nm near-infrared lasers irradiation each group mouse tumor position 15 minutes (removing PBS group), it
After observe and record mouse tumor size.As shown in FIG. Figure 11 A and 11 B: tumour growth can not be inhibited by controlling simple near-infrared irradiation, be swum
Limited anti-tumor capacity is also only shown from adriamycin group and adriamycin/gold-Nano carbon balls group.Adriamycin/hyaluronic acid/
In gold-Nano carbon balls group, tumor size is significantly reduced, and only 1 mouse is still with the presence of tumour.Hyaluronic acid/gold-carbon nanometer
Ball group tumour growth is suppressed, but since it is free of adriamycin, it is difficult to effectively removing tumour, still with the presence of 4 mouse tumours.This
Show that the gold-Nano carbon balls medicine-carried system for loading the hyaluronic acid package of adriamycin can effectively be enriched to tumor locus, and
The chemical combined treatment of photo-thermal-photodynamics-under being irradiated by near-infrared carries out effective ablation and killing to tumour.
Claims (10)
1. hyaluronic acid decorated gold-Nano carbon balls preparation method with synergistic antitumor characteristic, comprising the following steps:
(1) the hydrolysis diameter using tetraethyl orthosilicate in alkaline environment is that the solid silica of 80-450 nm is received
Rice ball；
(2) it disperses obtained silica nanosphere in step (1) in alkaline solution, dopamine hydrochloride, benefit is added
Poly-dopamine is obtained with polymerization of the dopamine in alkaline solution and is wrapped on silica template, and poly-dopamine-two is formed
Silica nano-complex；
(3) it disperses poly-dopamine-silicon dioxide nanocomposite obtained in step (2) in distilled water, chlorine gold is added
Sour potassium obtains poly-dopamine-silicon dioxide nanocomposite that surface point is embroidered with gold nanoparticle；
(4) surface point obtained in step (3) is embroidered with poly-dopamine-silicon dioxide nanocomposite of gold nanoparticle in nothing
It is calcined under the conditions of oxygen, poly-dopamine is made to be carbonized, obtain carbon-silica composite that surface point is embroidered with gold nanoparticle；
(5) surface point obtained in step (4) is embroidered with the carbon-of gold nanoparticle that silica composite is scattered in hydrofluoric acid is molten
In liquid, dissolution removes silica template, obtains the hollow Nano carbon balls that surface point is embroidered with Jenner's grain of rice；
(6) it is reacted using the carboxyl of hyaluronic acid with the amido of dopamine, synthesis obtains the amine-modified hyaluronic acid of DOPA；
(7) hollow Nano carbon balls that the surface point in step (5) is embroidered with Jenner's grain of rice are stirred in a solvent with drug, i.e.,
The surface point for obtaining carrying medicament is embroidered with the hollow Nano carbon balls of Jenner's grain of rice；
(8) surface point of the amine-modified hyaluronic acid of the DOPA that step (6) obtains and load chemotherapeutics is embroidered with Jenner's grain of rice
Hollow Nano carbon balls reacted in phosphate buffer, can must have the hyaluronic acid decorated of synergistic antitumor characteristic
Gold-Nano carbon balls.
2. preparation method according to claim 1, it is characterized in that: the alkaline environment in the step (1) refers in ammonium hydroxide
In；Step (2) the neutral and alkali solution is the TRIS buffer of alkalinity.
3. preparation method according to claim 2, characterized in that the solid silica nanosphere in the step (1)
It is made by laxative remedy: in 100-1000 ml ethyl alcohol, 1.5-15 mL distilled water is added and 5-50 mL concentration is 25 ~ 28% mass
The ammonium hydroxide of percentage, stirs evenly；1.5-15 mL tetraethyl orthosilicate is added later, reaction 4 hours is stirred at room temperature；It has reacted
Bi Hou, 10000 revs/min of centrifugations, 15 minutes collection silica spheres, and washed using dehydrated alcohol to supernatant and be in neutrality to obtain
Solid ball-type silica template；Poly-dopamine-silicon dioxide nanocomposite in the step (2) is made by laxative remedy: will
Step (1) silica spheres obtained are scattered in the 10 mM TRIS buffers of pH 8.5, wherein dioxy
The amount ratio of SiClx ball and TRIS buffer is 1 g silica spheres: 300 mL trihydroxy methyl amino first
Alkane buffer；Dopamine hydrochloride is added in the ratio of silica nanosphere and Dopamine hydrochloride mass ratio 1:0.90, stirring is anti-
It answers 48 hours, obtains poly-dopamine-silicon dioxide nanocomposite suspension of brown, vacuum filtration is collected product and steamed with double
Water is washed, and pure poly-dopamine-silicon dioxide nanocomposite is obtained after freeze-drying.
4. preparation method according to claim 1, it is characterized in that: surface point is embroidered with gold nanoparticle in the step (3)
Poly-dopamine-silicon dioxide nanocomposite be made by laxative remedy: by 1 g poly-dopamine-silicon dioxide nanocomposite: 300
The ratio of mL distilled water disperses poly-dopamine-silicon dioxide nanocomposite obtained in step (2) in distilled water, so
The potassium chloroaurate of 25% poly-dopamine-silicon dioxide nanocomposite quality is added afterwards, is stirred to react in ice bath 30 minutes；Instead
After the completion of answering, collected by suction reaction product is lyophilized after being washed using distilled water and is embroidered with the poly- of gold nanoparticle to get to surface point
Dopamine-silicon dioxide nanocomposite；Step (4) surface point is embroidered with carbon-silica composite of gold nanoparticle
It is obtained by laxative remedy: surface point is embroidered with poly-dopamine-silicon dioxide nanocomposite of gold nanoparticle under protection of argon gas,
500 DEG C are calcined 3 hours to get the carbon-silica composite for being embroidered with gold nanoparticle to surface point.
5. preparation method according to claim 1, it is characterized in that: surface point is embroidered with Jenner's grain of rice in the step (5)
Hollow Nano carbon balls are obtained by laxative remedy: carbon-silica composite that surface point is embroidered with gold nanoparticle is placed in 100 mL matter
It measures in the hydrofluoric acid that percentage is 4%, is stirred to react 1 hour, obtains the hollow Nano carbon balls that surface point is embroidered with Jenner's grain of rice.
6. preparation method according to claim 1, it is characterized in that: the amine-modified hyaluronic acid of the step (6) DOPA by
Laxative remedy obtains: 100 ~ 1000 mg hyaluronis are dissolved in 7.4 phosphate buffer of pH of 50 ~ 500 mL deoxygenations；
Carbodiimide and n-hydroxysuccinimide are added later and stirs to being completely dissolved to obtain mixed liquor；Wherein, hyaluronic acid unit:
Carbodiimide: the molar ratio of n-hydroxysuccinimide is 1: 1: 1；50 ~ 500 mg Dopamine hydrochlorides are weighed, are added to
In above-mentioned mixed liquor, the pH of solution is adjusted to 4 ~ 6 and is stirred to react 9 hours after dopamine is completely dissolved；Then, it will react
Liquid is transferred in the bag filter that molecular cut off is 8000 ~ 14000 dalton, dialyses 24 in the phosphate buffer of 20 mM
Hour, it is changed to distilled water later and dialyses 24 hours, the amine-modified hyaluronic acid of DOPA can be obtained after freeze-drying.
7. preparation method according to claim 1, it is characterized in that: with synergistic antitumor characteristic in the step (8)
Hyaluronic acid decorated gold-Nano carbon balls are obtained by laxative remedy: 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 7.4 phosphate buffer of pH, and the amine-modified hyaluronic acid of DOPA is then added, and is continued to be protected from light and is stirred to react
24 hours；After the reaction was completed, 12000 revs/min of centrifugation collection in 15 minutes precipitatings, and three times using distilled water washing, it can obtain
To 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 and the dosage mass ratio of the amine-modified hyaluronic acid of DOPA are 1:1.
8. preparation method according to claim 1, it is characterized in that: drug selected in the step (7) can be it is sharp
Element or antibiotic or anticancer drug.
9. being obtained by the described in any item preparation methods of claim 1-8 hyaluronic acid decorated with synergistic antitumor characteristic
Gold-Nano carbon balls.
10. hyaluronic acid decorated gold-Nano carbon balls as claimed in claim 9 with synergistic antitumor characteristic are targeted in preparation
Property diagnosis or treatment tumour drug in application.
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| CN116836700A (en) * | 2023-06-29 | 2023-10-03 | 辽宁大学 | Preparation method of hyaluronic acid modified red light carbon dots HA-R-CDs and application of hyaluronic acid modified red light carbon dots HA-R-CDs in lung cancer cell targeted imaging |
| CN117045823B (en) * | 2023-10-11 | 2023-12-19 | 四川美文鑫彩新材料科技有限公司 | Mesoporous hollow copper single-atom carbon sphere, preparation method and application |
| CN117338956B (en) * | 2023-11-08 | 2024-03-05 | 山东第一医科大学附属眼科医院(山东省眼科医院) | Cascade immune regulation nano-drug for treating pseudomonas aeruginosa keratitis and preparation method and application thereof |
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