CN108743948B - Carbon dot-hydroxyapatite nano composite prepared by ultrasonic one-pot method and modification method and application thereof - Google Patents
Carbon dot-hydroxyapatite nano composite prepared by ultrasonic one-pot method and modification method and application thereof Download PDFInfo
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- A—HUMAN NECESSITIES
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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
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- 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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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses a carbon dot-hydroxyapatite nano composite prepared by an ultrasonic one-pot method, and a modification method and application thereof. The carbon dot-hydroxyapatite nano composite is prepared by taking calcium salt, phosphorus salt and folic acid as initial reaction raw materials in one pot under the alkaline and ultrasonic conditions and is modified by hyperbranched polymer, and the composite has the advantages of simple and rapid synthesis reaction method, observable reaction process, good biocompatibility, mass production and the like, and also has good hydrophilic dispersion performance, fluorescence performance and tumor targeting performance. Can be used as a cancer cell targeted imaging probe and a drug targeted delivery carrier, and plays an important role in the fields of cancer diagnosis, treatment and the like.
Description
Technical Field
The invention relates to a method for preparing a carbon dot-hydroxyapatite nano composite by an ultrasonic one-pot method, a modification method and application thereof, belonging to the field of biomedical material science.
Background
Biological nanofluorescent materials play an important role in diagnostic and therapeutic applications because of their small size, large surface area and tunable color. In general, fluorescent nanomaterials include fluorescent nanoparticles, semiconductor quantum dots, photoluminescent carbon dots, and the like. Compared with semiconductor quantum dots and fluorescent nanoparticles, carbon dots have obvious advantages in biological applications, such as good water solubility, excellent biocompatibility, unique optical properties and no toxicity. Interestingly, carbon dots prepared using certain specific carbon sources and synthetic methods will show targeting properties for specific cells. Such as: d-glucose and l-aspartic acid are used as initial raw materials, and a novel carbon dot with a targeting function on brain glioma is successfully prepared by a simple hydrothermal method; the carbon dots prepared by taking folic acid as a carbon source also have targeting performance on cells over-expressed by the folic acid receptor.
Hydroxyapatite is the main inorganic component of human and animal bones. Because of excellent biocompatibility, bioactivity and nontoxicity, the compound can be widely applied to the field of biological medicine and can be used as bone tissue repair materials, drug carriers and the like. However, hydroxyapatite itself does not have targeting functions and fluorescent properties, and thus cannot be "tracked" for imaging within cells and in vivo, nor can it target specific tumor tissues. Therefore, the simple and rapid preparation of the multifunctional carbon dot-hydroxyapatite nano composite with fluorescence and tumor targeting has great significance in the current medical and biological fields.
Disclosure of Invention
The invention aims to provide a preparation method and a modification method of a carbon dot-hydroxyapatite nano composite.
The invention also aims to provide application of the adriamycin-loaded hyperbranched polyglycidyl-carbon dot-hydroxyapatite nano composite.
The technical scheme adopted by the invention is as follows:
an ultrasonic one-pot method for preparing a carbon dot-hydroxyapatite nano composite is characterized by comprising the following steps:
1) dissolving folic acid in a phosphate solution, and adjusting the pH to 9-12 by using a pH adjusting reagent; stirring, dropwise adding into a calcium salt solution, uniformly mixing, adjusting the pH of the obtained mixed solution to 9-12 by using a pH adjusting reagent, stirring, performing ultrasound while stirring, and standing; the molar mass ratio of the calcium salt to the phosphate is (1.66-1.68): 1;
2) and standing, separating to obtain a precipitate and a supernatant, centrifuging and washing the precipitate, and drying to obtain the carbon dot-hydroxyapatite nano composite.
Further, after the folic acid in the step 1) is dissolved in a phosphate solution, the concentration of the folic acid is 0.3-2.6 mg/mL, and the concentration of the phosphate is 0.3-1 mol/L.
Further, the phosphate solution in step 1) is at least one selected from the group consisting of ammonium hydrogen phosphate, diammonium hydrogen phosphate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate.
Further, the pH adjusting reagent in the step 1) is at least one selected from ammonia water and ethylenediamine.
Further, the calcium salt solution in the step 1) is at least one selected from calcium nitrate, calcium nitrate tetrahydrate, calcium chloride and calcium carbonate.
Further, the molar mass ratio of the calcium salt to the phosphate in the step 1) is (1.66-1.68): 1.
Further, the ultrasonic temperature in the step 1) is 25-60 ℃, the time is 3-5 hours, and the power is 100-500W.
Further, the washing in step 2) is performed by using water and/or absolute ethyl alcohol for alternate washing.
A preparation method of a drug-loaded hyperbranched polymer-carbon dot-hydroxyapatite nano-composite is characterized by comprising the following steps:
1) adding the prepared carbon dot-hydroxyapatite nano compound into glycidol, uniformly mixing, heating, stirring and reacting, adding water, and ultrasonically dissolving to obtain a hyperbranched polymer modified carbon dot-hydroxyapatite nano compound;
2) adding the antineoplastic agent into the hyperbranched polymer modified carbon-hydroxyapatite nano-composite, stirring for complete reaction, and centrifugally washing the obtained precipitate to obtain the drug-loaded hyperbranched polymer-carbon-hydroxyapatite nano-composite.
Further, the dosage ratio of the carbon dot-hydroxyapatite nano composite in the step 1) to the glycidol is (3 mg-10 mg): 1 mL.
Further, the stirring condition in the step 1) is that the magnetic stirring is carried out for 36-48 hours under the conditions of room temperature and dark.
Further, the dosage ratio of the antitumor drug to the hyperbranched polymer-modified carbon dot-hydroxyapatite nano-composite in the step 2) is (1 mg-2.5 mg): 1 mL.
Furthermore, the hyperbranched polymer is hyperbranched polyglycidyl glycerin.
The drug-loaded hyperbranched polymer-carbon dot-hydroxyapatite nano-composite prepared by any one of the methods.
The drug-loaded hyperbranched polymer-carbon dot-hydroxyapatite nano compound is applied to the preparation of a reagent for target recognition or/and inhibition of cancer cells.
Further, the cancer cell is a cancer cell with over-expression of folic acid.
The invention has the beneficial effects that:
in the invention, the carbon dot-hydroxyapatite nano compound is prepared by one pot under mechanical stirring with the assistance of ultrasound. The synthesis method is simple, convenient and rapid, the synthesis raw materials are cheap, and the obtained product has good fluorescence performance and biocompatibility. The hyperbranched polyglycidyl is adopted to carry out water-soluble modification on the prepared carbon dot-hydroxyapatite, and the obtained product has good hydrophilic dispersion performance, stability, non-toxicity performance and targeting performance; but also has better fluorescence property. The prepared drug-loaded hyperbranched polymer-carbon dot-hydroxyapatite nano compound can also be used as a targeted cancer cell imaging probe and a targeted drug delivery carrier; opens up a new way for the development of multifunctional fluorescence targeting composite biological materials integrating diagnosis and treatment.
Drawings
FIG. 1 is a transmission electron microscope image of a carbon dot-hydroxyapatite nanocomposite, wherein the hydroxyapatite has a length of 20 to 150nm and a diameter of 4 to 8 nm; the diameter of the carbon dots is 1-3 nm.
FIG. 2 is an XRD spectrum comparing the carbon dot-hydroxyapatite nanocomposite with a hydroxyapatite standard card, and JCDPS NO.009 and 0432 are hydroxyapatite standard cards.
FIG. 3 is a fluorescence emission spectrum of the carbon dot-hydroxyapatite nanocomposite under excitation of 360 nm.
FIG. 4 is a fluorescence emission spectrum of the hyperbranched polyglycidyl modified carbon dot-hydroxyapatite nanocomposite under excitation of 360 nm.
FIG. 5 is a fluorescence image of a confocal laser scanning microscope; wherein HeLa represents HeLa cells with over-expressed folic acid, and MCF-7 represents human MCF-7 cells with low expressed folic acid; specifically, each of the images is a combined and overlapped image (E) of a bright field image (A) of a HeLa cell, a DAPI staining fluorescence image (B) of a nucleus of the HeLa cell, a green fluorescence image (C) of HAp-CDs-PG in the HeLa cell, a red fluorescence image (D) of doxorubicin in the HeLa cell, a bright field image (E) of the HeLa cell, a DAPI staining nucleus, HAp-CDs-PG and doxorubicin; FIG. 5 shows, from left to right, a bright field image (F) of MCF-7 cells, a DAPI-stained fluorescence image (G) of the MCF-7 cell nucleus, a fluorescence image (H) of HAp-CDs-PG of MCF-7 cells, a fluorescence image (I) of doxorubicin of MCF-7 cells, and a merged overlap image (J) of the bright field image, the DAPI-stained nucleus, the HAp-CDs-PG, and the doxorubicin of MCF-7 cells.
FIG. 6 shows the cell viability of HAp-CDs-PG-Dox (HAp-CDs-PG-Dox is a drug-loaded hyperbranched polymer-carbon dot-hydroxyapatite nano-composite, wherein HAp represents hydroxyapatite, CDs represents carbon dots, PG represents hyperbranched polyglycidyl glycerol, and Dox represents an antitumor drug adriamycin) after co-culturing with HeLa cells for 24 hours at different concentrations of Dox.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1 ultrasonic one-pot method of carbon dot-hydroxyapatite nanocomposite
(1) Dissolving 20mg folic acid in 30ml 0.3mol/l diammonium hydrogen phosphate water solution by ultrasonic wave, and adjusting the pH value to 10 by ammonia water;
(2) and (2) dropwise adding the solution obtained in the step (1) into 30ml of calcium nitrate tetrahydrate under stirring (the rotating speed is 400 rpm), wherein the molar mass ratio of calcium to phosphorus is 1.67: 1, and adjusting the pH to 10 with ammonia water. Stirring for 30min, performing ultrasonic treatment (300W) on the mixed solution at 40 ℃, stirring all the time, performing ultrasonic treatment for 3 hours, and standing overnight;
(3) and (3) separating the precipitate after standing overnight from the supernatant, centrifuging the yellow precipitate at the rotation speed of 4000 rpm, alternately washing with water and absolute ethyl alcohol, washing for 6 times, and drying the yellow precipitate at 60 ℃ for 12 hours to obtain the carbon dot-hydroxyapatite nano compound.
EXAMPLE 2 Synthesis of HAp-CDs-PG-Dox
(1) 50mg of the carbon-hydroxyapatite nanocomposite obtained in example 1 was weighed, ultrasonically dispersed in 10ml of glycidol, heated at 140 ℃ and magnetically stirred, reacted for 24 hours, cooled to room temperature, and then added with 5ml of deionized water to be ultrasonically dissolved to obtain a dispersion. The dispersion was washed 6 times centrifugally in a 100kD ultrafiltration tube with deionized water to remove free hyperbranched polyglycidyl glycerol. And finally, adding deionized water to dilute to 5ml to obtain the hyperbranched polyglycidyl glycerol modified carbon dot-hydroxyapatite nano composite, storing the hyperbranched polyglycidyl glycerol modified carbon dot-hydroxyapatite nano composite in a refrigerator at 4 ℃, and using the hyperbranched polyglycidyl glycerol modified carbon dot-hydroxyapatite nano composite in the next step.
(2) And (3) weighing 2mg of adriamycin, and ultrasonically dispersing the adriamycin into 2ml of the carbon dot-hydroxyapatite nano composite modified by the hyperbranched polyglycidyl prepared in the step (1). The mixture was magnetically stirred at room temperature in a dark environment for 48 hours. Then pouring into an ultrafiltration tube with 10KD, using deionized water to centrifugally wash for 4 times to remove the unloaded adriamycin to obtain the adriamycin-loaded hyperbranched polyglycidyl-carbon dot-hydroxyapatite nano composite (HAp-CDs-PG-Dox, wherein HAp represents hydroxyapatite, CDs represents carbon dots, PG represents hyperbranched polyglycidyl, and Dox represents antitumor drug adriamycin). The doxorubicin concentration was calculated using an ultraviolet spectrophotometer with the carrier absorbance subtracted.
Example 3 ultrasonic one-pot method of carbon dot-hydroxyapatite nanocomposite
(1) Dissolving folic acid 80mg in 30ml of 1mol/l disodium hydrogen phosphate aqueous solution by ultrasonic treatment, and adjusting the pH to 12 by using ethylenediamine;
(2) adding 30ml of calcium chloride dropwise into the solution obtained in the step (1) under stirring (the rotating speed is 500 rpm), wherein the molar mass ratio of calcium to phosphorus is 1.66: 1 and adjusting the pH to 12 with ethylenediamine. After stirring for 10min, the mixture was sonicated (400W) at 60 ℃ for 5 hours with stirring. After the reaction is finished, standing overnight;
(3) the yellow precipitate after standing overnight was separated from the supernatant, washed centrifugally in a centrifuge at 8000 rpm, washed alternately with water and absolute ethanol. After 8 washes, the pale yellow precipitate was dried at 80 ℃ for 12 hours. Obtaining the carbon dot-hydroxyapatite nano compound;
EXAMPLE 4 Synthesis of HAp-CDs-PG-Dox
(1) 100mg of the carbon dot-hydroxyapatite nanocomposite obtained in example 3 was weighed and dispersed in 10ml of glycidol by ultrasonic dispersion. Heat at 120 ℃ and magnetically stir. After 24 hours of reaction, the mixture was cooled to room temperature and dissolved by adding 10ml of deionized water with ultrasound. Free hyperbranched polyglycidyl alcohol was removed by centrifugation in deionized water 7 times in a 100kD ultrafiltration tube. And finally, adding deionized water into the residual dispersion liquid to dilute to 5ml to obtain the hyperbranched polyglycidyl glycerol modified carbon dot-hydroxyapatite nano compound, and storing the hyperbranched polyglycidyl glycerol modified carbon dot-hydroxyapatite nano compound in a refrigerator at 4 ℃ for next use.
(2) And (3) weighing 5mg of adriamycin, and ultrasonically dispersing the adriamycin into 2ml of the carbon dot-hydroxyapatite nano composite modified by the hyperbranched polyglycidyl prepared in the step (1). The mixture was magnetically stirred at room temperature in a dark environment for 36 hours. Then pouring the mixture into an ultrafiltration tube with 10KD, centrifugally washing the mixture for 7 times by using deionized water, and removing the unloaded adriamycin to obtain the adriamycin-loaded hyperbranched polyglycidyl-carbon dot-hydroxyapatite nano compound (HAp-CDs-PG-Dox). The doxorubicin concentration was calculated using an ultraviolet spectrophotometer with the carrier absorbance subtracted.
Example 5 ultrasonic one-pot method of carbon dot-hydroxyapatite nanocomposite
(1) Dissolving 10mg folic acid in 30ml 0.05mol/l dipotassium hydrogen phosphate-containing water solution by ultrasonic wave, and adjusting the pH value to 9 by ammonia water;
(2) adding the solution obtained in the step (1) into 30ml of calcium carbonate dropwise under stirring (the rotating speed is 100 revolutions per minute), wherein the molar mass ratio of calcium to phosphorus is 1.68: 1, and adjusting the pH to 9 with ammonia water. After stirring for 30min, the mixture was sonicated (100W) at 25 ℃ and the sonication was maintained for 5 hours. After the reaction was completed, the mixture was allowed to stand overnight.
(3) The yellow precipitate after standing overnight was separated from the supernatant, washed centrifugally in a centrifuge at 4000 rpm, washed alternately with water and absolute ethanol. After washing for 8 times, drying the light yellow precipitate for 12 hours at 50 ℃ to obtain the carbon dot-hydroxyapatite nano compound.
EXAMPLE 6 Synthesis of HAp-CDs-PG-Dox
(1) 30mg of the carbon-hydroxyapatite nanocomposite of example 5 was weighed, ultrasonically dispersed in 10ml of glycidol, heated at 90 ℃ and magnetically stirred. After 24 hours of reaction, the mixture is cooled to room temperature, and 5ml of deionized water is added for ultrasonic dissolution to obtain dispersion liquid. Free hyperbranched polyglycidyl alcohol was removed by centrifugation in deionized water 8 times in 100kD ultrafiltration tubes. And finally, adding deionized water to dilute to 5ml to obtain the hyperbranched polyglycidyl glycerol modified carbon dot-hydroxyapatite nano composite, and storing the hyperbranched polyglycidyl glycerol modified carbon dot-hydroxyapatite nano composite in a refrigerator at 4 ℃ for next use.
(2) And (3) weighing 5mg of adriamycin, and ultrasonically dispersing the adriamycin into 2ml of the carbon dot-hydroxyapatite nano composite modified by the hyperbranched polyglycidyl prepared in the step (1). The mixture was magnetically stirred at room temperature for 46 hours in a dark environment. Then pouring into an ultrafiltration tube with 10KD, centrifugally washing for 5 times by using deionized water, and removing the unloaded adriamycin to obtain the adriamycin-loaded hyperbranched polyglycidyl-carbon dot-hydroxyapatite nano compound (HAp-CDs-PG-Dox). The doxorubicin concentration was calculated using an ultraviolet spectrophotometer with the carrier absorbance subtracted.
Example 7 ultrasonic one-pot method of carbon dot-hydroxyapatite nanocomposite
(1) Dissolving 10mg folic acid in 30ml 0.05mol/l ammonium hydrogen phosphate-containing aqueous solution by ultrasonic wave, and adjusting the pH value to 9 by using ammonia water;
(2) adding the solution obtained in the step (1) into 30ml of calcium nitrate dropwise under stirring (the rotating speed is 100 revolutions per minute), wherein the molar mass ratio of calcium to phosphorus is 1.68: 1, and adjusting the pH to 9 with ammonia water. After stirring for 30min, the mixture was sonicated (500W) at 25 ℃ and the sonication was maintained for 5 hours. After the reaction was completed, the mixture was allowed to stand overnight.
(3) The yellow precipitate after standing overnight was separated from the supernatant, washed centrifugally in a centrifuge at 4000 rpm, washed alternately with water and absolute ethanol. After washing for 8 times, drying the light yellow precipitate for 12 hours at 50 ℃ to obtain the carbon dot-hydroxyapatite nano compound.
EXAMPLE 8 Synthesis of HAp-CDs-PG-Dox
(1) 30mg of the carbon-hydroxyapatite nanocomposite of example 7 was weighed, ultrasonically dispersed in 10ml of glycidol, heated at 90 ℃ and magnetically stirred. After 24 hours of reaction, the mixture is cooled to room temperature, and 5ml of deionized water is added for ultrasonic dissolution to obtain dispersion liquid. Free hyperbranched polyglycidyl alcohol was removed by centrifugation in deionized water 8 times in 100kD ultrafiltration tubes. And finally, adding deionized water to dilute to 5ml to obtain the hyperbranched polyglycidyl glycerol modified carbon dot-hydroxyapatite nano composite, and storing the hyperbranched polyglycidyl glycerol modified carbon dot-hydroxyapatite nano composite in a refrigerator at 4 ℃ for next use.
(2) And (3) weighing 5mg of adriamycin, and ultrasonically dispersing the adriamycin into 2ml of the carbon dot-hydroxyapatite nano composite modified by the hyperbranched polyglycidyl prepared in the step (1). The mixture was magnetically stirred at room temperature for 46 hours in a dark environment. Then pouring into an ultrafiltration tube with 10KD, centrifugally washing for 5 times by using deionized water, and removing the unloaded adriamycin to obtain the adriamycin-loaded hyperbranched polyglycidyl-carbon dot-hydroxyapatite nano compound (HAp-CDs-PG-Dox). The doxorubicin concentration was calculated using an ultraviolet spectrophotometer with the carrier absorbance subtracted.
The doxorubicin-loaded hyperbranched polyglycidyl-carbon dot-hydroxyapatite nanocomposites (HAp-CDs-PG-Dox) prepared in the examples were further verified below.
Example 9 characterization and fluorescence Properties of HAp-CDs nanocomposites
A carbon dot-hydroxyapatite nano composite is subjected to hyperbranched water-soluble modification and drug loading, and the expression is as follows: HAp-CDs-PG-Dox. Wherein HAp represents hydroxyapatite; CDs represent carbon points; PG represents hyperbranched polyglycidyl glycerol; dox stands for the antitumor drug doxorubicin. HAp-CDs-PG-Dox also has a targeting recognition function and a fluorescence imaging function on cancer cells with over-expressed folic acid.
Taking the carbon dot-hydroxyapatite nano composite as an experimental intermediate product to perform electron microscope development, and finding that the carbon dot-hydroxyapatite nano composite is rod-shaped, the length is about 20-150nm, and the diameter is 4-8 nm; the carbon dots on the surface of the carbon fiber are spherical and have a diameter of about 1 to 3 nm. Calcium nitrate tetrahydrate is used as a calcium source, diammonium hydrogen phosphate is used as a phosphorus source, and folic acid molecules are used as a carbon source. See fig. 1, transmission electron microscopy images show that carbon dots are successfully bound to the hydroxyapatite surface. In the XRD spectrum of fig. 2, it is found that the prepared carbon dot-hydroxyapatite nanocomposite is identical to a hydroxyapatite standard card and has better crystallinity, and furthermore, the absorption peak of the carbon dot is masked compared to the strong crystallization peak of the hydroxyapatite. The carbon dot-hydroxyapatite nano-composite in fig. 3 has good fluorescence performance, the maximum excitation wavelength is 360nm, and the maximum emission wavelength is 452 nm. FIG. 4 shows that the carbon dot-hydroxyapatite nanocomposite modified by hyperbranched polyglycidyl still has good fluorescence performance; the maximum excitation wavelength is 360nm and the maximum emission wavelength is red-shifted to 460 nm.
Example 10 cellular uptake and imaging assays of HAp-CDs-PG-Dox
The method comprises the following steps: inoculating HeLa cells with over-expression of folic acid and MCF-7 cells with low expression of folic acid into a 6-well plate, culturing overnight, and adding the prepared adriamycin-loaded hyperbranched polyglycidyl-carbon dot-hydroxyapatite nano compound (HAp-CDs-PG-Dox) into the well plate respectively according to the final adriamycin concentration of 3mg/ml in a culture system; after 3 hours of co-culture with the cells, the cells were washed 3 times with PBS, and then fixed with 4% paraformaldehyde in PBS for 10 min. Finally, the cells were washed twice with PBS and the nuclei were labeled with DAPI and observed under confocal fluorescence microscopy. Wherein the blue fluorescence belongs to DAPI stained nuclei, the green fluorescence belongs to HAp-CDs-PG, and the red fluorescence belongs to Dox.
The results show that: HAp-CDs-PG-Dox emits strong green fluorescence belonging to HAp-CDs-PG in HeLa cells (FIG. 5 (C)), and strong red fluorescence belonging to Dox (FIG. 5 (D)). However, both green and red fluorescence were very weak in MCF-7 cells ((H) (I) of FIG. 5). Therefore, HAp-CDs-PG-Dox showed stronger cellular uptake ability in HeLa cells over-expressed with folic acid. FIG. 5 (A) (F) is a bright field, (B) (G) is a DAPI-stained nucleus, and (E) (J) is a merged image. The result shows that HAp-CDs-PG can selectively image HeLa cells with over-expressed folic acid and can carry out targeted delivery of anti-cancer drugs for treating tumors.
Example 11 cell viability assay after Co-culture of HAp-CDs-PG-Dox and HeLa cells
The method comprises the following steps: inoculating 7000 per hole folic acid over-expressed HeLa cells into a 96-well plate, culturing overnight, and adding different amounts of adriamycin-loaded hyperbranched polyglycidyl-carbon dot-hydroxyapatite nano-complexes (HAp-CDs-PG-Dox) which take adriamycin concentrations of 0.25 mug/ml, 0.5 mug/ml, 1 mug/ml, 2.5 mug/ml and 5 mug/ml in a culture system as calculation; the control group contained cells and medium only; after 24 hours of cell culture, the viability was examined.
The results show that: in FIG. 6, the activity of HeLa cells decreased with the increase of doxorubicin concentration, indicating that HAp-CDs-PG-Dox has a better killing effect on HeLa cells over-expressed with folic acid; at lower concentrations of doxorubicin (5 μ g/ml), cell viability of HeLa decreased to 46%, indicating that HAp-CDs-PG was successfully used to load and deliver anti-tumor drugs and achieve targeted therapy.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. An ultrasonic one-pot method for preparing a carbon dot-hydroxyapatite nano composite is characterized by comprising the following steps:
1) dissolving folic acid in a phosphate solution, and adjusting the pH to 9-12 by using a pH adjusting reagent; stirring, dropwise adding into a calcium salt solution, uniformly mixing, adjusting the pH of the obtained mixed solution to 9-12 by using a pH adjusting reagent, stirring, performing ultrasound while stirring, and standing; the molar mass ratio of the calcium salt to the phosphate is (1.66-1.68): 1;
2) and standing, separating to obtain a precipitate and a supernatant, centrifuging and washing the precipitate, and drying to obtain the carbon dot-hydroxyapatite nano composite.
2. The method according to claim 1, wherein the concentration of folic acid in the step 1) is 0.3-2.6 mg/mL and the concentration of phosphate is 0.3-1 mol/L after the folic acid is dissolved in the phosphate solution.
3. The method according to claim 1, wherein the phosphate solution in step 1) is at least one selected from the group consisting of ammonium hydrogen phosphate, diammonium hydrogen phosphate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate.
4. The method according to claim 1, wherein the calcium salt solution in step 1) is at least one of calcium nitrate, calcium nitrate tetrahydrate, calcium chloride and calcium carbonate.
5. The method according to claim 1, wherein the ultrasonic temperature in the step 1) is 25-60 ℃, the ultrasonic time is 3-5 hours, and the power is 100-500W.
6. A preparation method of a drug-loaded hyperbranched polymer-carbon dot-hydroxyapatite nano-composite is characterized by comprising the following steps:
1) adding the carbon dot-hydroxyapatite nano-composite prepared according to the claim 1 into glycidol, uniformly mixing, heating, stirring and reacting, adding water, and ultrasonically dissolving to obtain a hyperbranched polymer modified carbon dot-hydroxyapatite nano-composite;
2) adding the antineoplastic agent into the hyperbranched polymer modified carbon-hydroxyapatite nano-composite, stirring for complete reaction, and centrifugally washing the obtained precipitate to obtain the drug-loaded hyperbranched polymer-carbon-hydroxyapatite nano-composite.
7. The method according to claim 6, wherein the amount ratio of the carbon dot-hydroxyapatite nanocomposite of step 1) to glycidol is (3mg to 10 mg): 1 mL.
8. The drug-loaded hyperbranched polymer-carbon-site-hydroxyapatite nanocomposite prepared according to the method of claim 6 or 7.
9. Use of the drug-loaded hyperbranched polymer-carbon dot-hydroxyapatite nanocomposite according to claim 8 for preparing a reagent for targeting and recognizing or/and inhibiting cancer cells.
10. The use of claim 9, wherein said cancer cell is a folate-overexpressed cancer cell.
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