NL2026426B1 - Fluorine-containing graphene quantum dots, preparation method and application thereof as photosensitiser for photodanamic therapy - Google Patents
Fluorine-containing graphene quantum dots, preparation method and application thereof as photosensitiser for photodanamic therapy Download PDFInfo
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Abstract
Fluorine-containing graphene quantum dots, a preparation method and use of them as a photodynamic therapy photosensitizer are disclosed. The new quantum dots are prepared by using a fluorinated graphite as a raw material and a Hummers method to obtain an oxidized fluorine-containing graphene. Next, a chemical oxidative cleavage reaction is performed to obtain the fluorine-containing graphene quantum dots. The new fluorinecontaining graphene quantum dots have an average thickness of 1.0-3.0 nm, a size of 2.0-3.0 nm, a fluorine content of l%-2%, an oxygen content of 20%-30%, and a carbon content of 60%- 70%. They are smaller and more uniform in size and morphology, stable in structure, high in singlet oxygen quantum yield under visible light irradiation, very low cytotoxicity, and good water solubility, which makes them an ideal photosensitizer for photodynamic therapy useful for the early treatment of esophageal cancer, skin cancer, lung cancer and other diseases.
Description
-1- FLUORINE-CONTAINING GRAPHENE QUANTUM DOTS, PREPARATION
TECHNICAL FIELD The present invention belongs to the technical field of nano-medical materials, and more particularly, to fluorine-containing graphene quantum dots, a preparation method and an application thereof as a photodynamic therapy photosensitizer.
BACKGROUND Graphene quantum dots (GQDs) represent a new type of carbon quantum dots with unique properties. It is a zero-dimensional material with characteristics derived from both graphene and carbon dots, which is essentially a small piece of graphene smaller than 10 nanometers. GQDs are slated to substitute traditional semiconductor quantum dots and organic dyes in life sciences applications. Because of their excellent biocompatibility, superior resistance against photobleaching, good fluorescence performance, and easy surface modification, graphene quantum dots have gained tremendous attention for their potential in biomarking, bioimaging, and photodynamic therapy applications.
Photosensitizers (PSs) play a vital role in photodynamic therapy (PDT), a triggering strategy typically used in the treatment of superficial tumors. During PDT, the photosensitizer absorbs the photon energy having a suitable wavelength and transitions to an excited state. Reactive oxygen species (ROS), such as singlet oxygen, are produced by energy transfer from an excited photosensitizer, and eventually, cancer cells are killed by the produced cytotoxic ROS. PDT has been used to treat a variety of cancers such as esophageal cancer, skin cancer, and early stage lung cancer. Compared with traditional tumor therapies, the advantage of PDT is the ability to treat tumors accurately and effectively, with fewer side effects.
Current reported works involving GQDs utilized as PDT photosensitizers indicate a fluorescence emission peak at 700 nm and a singlet oxygen (102) quantum yield of 1.3 (relative yield). However, the as-reported synthesis process is complicated. They are
-2- prepared by changing the terminal group structure of the thiophene monomer, which has poorer hydrophilicity and greater cytotoxicity. There is current work involving fluorinated graphene quantum dots. These are fluorine- containing graphene quantum dots with sizes of 2.5 nm to 3.5 nm synthesized by a solvothermal method using fluorinated graphite as a raw material, but their fluorine content is as high as 17%-25%. In the synthesis process, the procedures are complicated and cumbersome, which is not conducive to practical applications. Unfortunately, the aforementioned fluorinated graphene quantum dots have not been used in the study of PDT photosensitizers. Another source reporting synthesis of fluorinated graphene quantum dots indicates production by a microwave-assisted hydrothermal method using fluorinated graphite as a raw material. Although the fluorinated graphene quantum dots have a fluorine content aslow as 1.2%, their size is slightly larger (3.0 nm to 10.0 nm), and the synthesis process is relatively complex. In addition, these fluorinated graphene quantum dots have not been used in the study of PDT photosensitizers. Chinese patent (CN201610935474.4) discloses a method of synthesizing fluorinated graphene quantum dots, but due to the different raw materials and synthesis of the patented methods, the subject fluorinated GQDs are not uniform in size, and the fluorine content is inconsistent and unclear. Moreover, they also have not been used in the study of PDT photosensitizers.
SUMMARY In view of the above-mentioned problems in the prior art, the present invention provides fluorine-containing graphene quantum dots that are small in size, have good water solubility, high singlet oxygen generation efficiency and a stable structure, which can be optimally used in PDT.
The fluorine-containing graphene quantum dots of the present invention are prepared by using a fluorinated graphite as a raw material and a Hummers method to obtain an oxidized fluorine-containing graphene, and then performing a chemical oxidative
-3- cleavage reaction to obtain the fluorine-containing graphene quantum dots, with an average thickness of 1.0 nm to 3.0 nm, a size of 2.0 nm to 3.0 nm, a fluorine content of 1%-2%, an oxygen content of 20%-30%, a carbon content of 60%-70%, and a 'O: quantum yield of 0.4-0.5 under visible light irradiation.
A preparation method of the fluorine-containing graphene quantum dots of the present invention includes the following steps: 1) performing an ultrasonic peeling treatment of the fluorinated graphite with a strong alkaline substance and then using a Hummers method to prepare the oxidized fluorinated graphene; 2) weighing and dissolving the oxidized fluorine-containing graphene in ultrapure water, performing an ultrasonic treatment to disperse sufficiently to obtain a solution; adding a strong oxidizer to the solution, followed by adding lye, refluxing for 5-9 hours at 60-100°C, to fully carry out the chemical oxidative cleavage reaction; and 3) after the refluxing is completed, filtration, purification, and drying to obtain the fluorine-containing graphene quantum dots. In the preparation method of the fluorine-containing graphene quantum dots described above, the strong alkaline substance in step 1) can be sodium hydroxide, potassium hydroxide, and the like, which can be prepared into an alkaline solution for better soaking graphite. There is no special requirement for a concentration of the alkali solution, a mass concentration of the alkali solution can generally be between 10%-80%, and more preferably between 20%-50%, soaking and peeling at high concentration takes a short time, and soaking and peeling at low concentration takes slightly longer.
The oxidized fluorinated graphene obtained in step 1) has a fluorine content of 6%-8%, an oxygen content of 6%-8%, and a carbon content of 80%-90%. In this step, the fluorinated graphite can be soaked in a strong alkaline solution to achieve peeling. The step of using the Hummers method to prepare the oxidized fluorinated graphene is disclosed in the following publication: ACS Nano, 2010, 4 (8), 4806-4814, the contents of which is incorporated herein by reference. In the preparation method of the fluorine-containing graphene quantum dots described
-4- above, the strong oxidizer in step 2) may be a mixture of one or more of hydrogen peroxide, concentrated sulfuric acid, concentrated nitric acid, and potassium persulfate.
In the preparation method of the fluorine-containing graphene quantum dots described above, a mass ratio of the oxidized fluorine-containing graphene and the strong oxidizer in step 2) may be (1-3):(1000-3000), preferably (1-3):1000; and a mass ratio of the oxidized fluorine-containing graphene to the ultrapure water may be (1-3):(1000-3000), preferably 1:(1000-3000).
As an improvement, for the preparation method of the fluorine-containing graphene quantum dots described above, an ultrasonic power in step 2) may be 500-800 watts; the strong oxidizer may be a mixture of one or more of hydrogen peroxide, concentrated sulfuric acid, and concentrated nitric acid; and the lye can be potassium hydroxide solution, sodium hydroxide solution, ammonia water, and the like, which mainly promotes the chemical oxidative cleavage reaction and has a catalytic effect, and its concentration can generally be 0.5-2 mol/L.
As an improvement, for the preparation method of the fluorine-containing graphene quantum dots described above, the purification in step 3) may be performed by suction filtration, chromatography, dialysis, filtration, extraction, distillation and fractionation, and the like; and the drying can be vacuum drying, freeze drying, high temperature drying, and the like.
The fluorine-containing graphene quantum dots of the present invention can be used as a photosensitizer for photodynamic therapy.
The surface of the fluorine-containing graphene quantum dots of the present invention is rich in hydroxyl and carboxyl groups, and the interior is mainly composed of sp? hybridized carbon atoms, which has a good water-solubility (see FIG. 1 and FIG. 3). In the ultraviolet-visible light region, the fluorine-containing graphene quantum dots have superior absorption (see FIG. 2) and excitation-independent luminescence properties; and under visible light irradiation, the !O2 quantum yield can reach 0.4-0.5. The fluorine- containing graphene quantum dots of the present invention have stable structure, high
-5- efficiency in producing singlet oxygen, low cytotoxicity, good water solubility and excellent biocompatibility. They are ideal photosensitizers for PDT, and can be better applied in PDT. However, the prior art GQDs have poor cytotoxicity and lack biocompatibility. Additionally, prior GQDs are difficult to be used as a PDT photosensitizer. Compared with the prior art, the present invention has the following advantages.
1) The fluorine-containing graphene quantum dots prepared by the present invention are biomedical nanomaterials with hydrophilic groups such as hydroxyl, carboxyl, and amino groups on the surface. The material is smaller and more uniform in size and morphology, has stable optical performance and easy surface modification, and can be well dispersed in water, phosphate buffer solution, biological culture medium and other aqueous solution systems.
2) The cytotoxicity of the fluorine-containing graphene quantum dots prepared by the present invention was tested by the MTT method (tetramethylazolium salt). The test results show that after co-cultivating esophageal cancer cells with different concentrations of fluorinated graphene quantum dots in 1640 medium solution for 12 hours, the survival rate of the esophageal cancer cells is still maintained at more than 90%, indicating that the fluorine-containing graphene quantum dots prepared by the present invention have very low toxicity (see FIG. 6).
3) The fluorine-containing graphene quantum dots prepared by the present invention have good absorption in the ultraviolet-visible light region. When the fluorine- containing graphene quantum dots prepared by the present invention are irradiated with visible light, singlet oxygen can be generated (see FIG. 5), and the O2 quantum yield is as high as 0.4-0.5. Compared with the ideal photosensitizer Rose Bengal (RB) currently used for photodynamic therapy, the +02 quantum yield of Rose Bengal (RB) is 0.75. In addition, compared with the reported use of existing graphene quantum dots as a photosensitizer for PDT, the 102 quantum yield of the fluorine-containing graphene quantum dots of the present invention reaches 0.4-0.5. Based on this, the fluorine- containing graphene quantum dots of the present invention can effectively kill tumor cells under visible light irradiation, and can be used as photosensitizers for PDT (see FIG. 7).
4) When the fluorine-containing graphene quantum dots prepared by the present
-6- invention are used in photodynamic therapy, they can also be used for biological imaging, and the operation process is simple, which is conducive to practical applications.
BRIEF DESCRIPTION OF THE DRAWINGS FIG. Lis a transmission electron microscope spectrum of fluorine-containing graphene quantum dots of the present invention. FIG. 2 is a diagram showing an ultraviolet-visible absorption spectrum and a fluorescence emission spectrum of the fluorine-containing graphene quantum dots in ultrapure water (with an excitation wavelength of 320 nm). FIG. 3 is an X-ray photoelectron spectrogram of the fluorine-containing graphene quantum dots of the present invention. FIG. 4 is a scanning electron microscope spectrum of an oxidized fluorine-containing graphene of the present invention. FIG. 5 is an electron paramagnetic resonance spectroscopy (EPR) spectrum of 2,2,6,6- tetramethylpiperidine (TEMP) as a capturing agent of the fluorine-containing graphene quantum dots under the conditions of LED laser irradiation and without LED laser irradiation, respectively. FIG. 6 shows the results of the cytotoxicity test by MTT method after co-cultivation of the fluorine-containing graphene quantum dots of the present invention at different concentrations with esophageal cancer cells for 12 hours. FIG. 7 shows the results of the cytotoxicity test by MTT method after co-cultivation of the fluorine-containing graphene quantum dots of the present invention at different concentrations with esophageal cancer cells for 12 hours and then illumination for 12 minutes.
DETAILED DESCRIPTION OF THE EMBODIMENTS The following embodiments are further descriptions of the content of the present invention as an explanation of the technical content of the present invention, but the essential content of the present invention is not limited to the following embodiments. Those skilled in the art can and should know that any simple changes or substitutions
-7- based on the essential spirit of the present invention shall fall within the protective scope required by the present invention.
Embodiment 1 A method for preparing fluorine-containing graphene quantum dots that can be used for photodynamic therapy, specifically includes the following steps.
1) A fluorinated graphite is soaked in 30% sodium hydroxide solution, followed by stirring and dispersing ultrasonically for 12 hours to fully peel off, filtering, and drying. 2) The fluorinated graphite treated in step (1) is prepared into an oxidized fluorine- containing graphene by Hummers method; the oxidized fluorine-containing graphene has a fluorine content of 6%-8%, an oxygen content of 6%-8%, and a carbon content of 80%-90%, and it can be regarded as a two-dimensional nano film (see FIG. 4).
3) 60 mg of the above-mentioned oxidized fluorine-containing graphene is weighed and dissolved in 60 mL of ultrapure water, and treated with an ultrasonic power of 500 watts, and then 60 mL of hydrogen peroxide is added to fully dissolve the oxidized fluorine- containing graphene.
4) 400 pL of potassium hydroxide solution with a concentration of 1 mol/L is added to the above solution, and then the above solution is transferred to a round-bottom flask and refluxed in an oil bath at 60°C for 6 hours.
5) After the reflux, the above solution is purified by vacuum filtration with an organic microporous filter membrane with a pore diameter of 0.22 um to remove bulk impurities, and then dried to obtain fluorine-containing graphene quantum dots, which are characterized by smaller size (approximately 2.0-3.0 nm in lateral size), uniform morphology, excitation-independent luminescence, and, as set out below, other desirable biochemical properties.
6) The solution after the above reaction 1s put into a dialysis bag with a molecular weight cut-off (MWCO) of 500-1000 for dialysis, followed by rotary steaming, and freeze- drying to prepare fluorine-containing graphene quantum dots with an average thickness of 1.0-3.0 nm, a size of 2.0-3.0 nm, and a fluorine content of 1 %-2%.
FIG. 1 is a transmission electron microscope spectrum of the fluorine-containing graphene quantum dots. It can be seen that the fluorine-containing graphene quantum dots have good mono-dispersity and are flat round particles with a size of about 2 nm. FIG. 2 is a diagram showing an ultraviolet-visible absorption spectrum and a
-8- fluorescence emission spectrum of the fluorine-containing graphene quantum dots prepared by the present invention in ultrapure water (with an excitation wavelength of 320 nm). According to the analysis, the aqueous solution of fluorine-containing graphene quantum dots shows bright green fluorescence under the ultraviolet lamp of 365 nm, and has a fluorescence emission peak at 510 nm under 320 nm light excitation. FIG. 6 shows the cytotoxicity of the prepared fluorine-containing graphene quantum dots under dark conditions detected by the MTT method. After co-cultivation of esophageal cancer cells (provided by Anhui Medical University) with the fluorine- containing graphene quantum dots for 12 hours, the survival rate of the esophageal cancer cells remained above 90%, indicating that the prepared fluorine-containing graphene quantum dots have very low toxicity. Finally, the singlet oxygen generated by the prepared fluorine-containing graphene quantum dots in the aqueous solution is detected, and the steps are as follows.
(a) The synthesized fluorine-containing graphene quantum dots are weighed and mixed with ultrapure water to form a fluorine-containing graphene quantum dot solution with a concentration of 0.2 mg/mL.
(b) 1 mL of the 0.2 mg/mL fluorine-containing graphene quantum dot solution prepared above is added into a 2 mL centrifuge tube A, then 10 uL 2,2,6,6- tetramethylpiperidine (TEMP) is added to the centrifuge tube A, and then the centrifuge tube A is illuminated with LED light (with an excitation wavelength of 400-700 nm) for 12 minutes.
(c) 30-50 pL of the sample to be measured are extracted with a capillary tube with a diameter of 0.55 mm. Subsequently, the capillary tube is placed at a bottom of a test tube, the sample is adjusted to a center of the test tube, and then the test tube is placed in the electron paramagnetic resonance spectrometer (EPR), and the EPR tube is placed in a center position of the resonator cavity. EPR measurement parameters are as follows: central magnetic field, 3430.00 Gauss; sweep field width, 60.00 Gauss; scan times, 10; and time constant, 10.49 milliseconds.
(d) In addition, 1 mL of the 0.2 mg/mL fluorine-containing graphene quantum dot solution prepared above is added into a 2 mL centrifuge tube B, then 10 pL 2,2,6,6- tetramethylpiperidine (TEMP) is added to the centrifuge tube B, and then the centrifuge
-9- tube B is placed under a dark condition, and the operation step (c) was repeated. The results are shown in FIG. 3. It can be seen from FIG. 3 that the fluorine-containing graphene quantum dots have singlet oxygen generation signal under LED irradiation (with an excitation wavelength 400-700 nm), while in dark conditions there is only a small amount or even no singlet oxygen generation; and the 102 quantum yield of the fluorine-containing graphene quantum dots is 0.4-0.5.
The calculation method of 102 quantum yield is as follows.
The 10: quantum yield is evaluated by a chemical method. The water-soluble 9,10- anthracene diyl-bis(methylene) dimalonic acid (ABDA) is used as 10: capturing agent, and Rose Bengal (RB) is used as a standard photosensitizer. In short, 120 uL of ABDA solution (2.5 mg/mL) is added to 400 pL of fluorine-containing graphene quantum dot solution, and an LED lamp (400-700 nm) set at 40 milliwatts per square centimeter (mW/cm?) are used as the light source. In order to eliminate the inner-filter effect, the absorption maxima of Rose Bengal (RB) and the test sample are adjusted to be less than
0.2. The absorbance of ABDA is recorded at different irradiation times to obtain the decay rate of the photosensitization process. The 0: quantum yield of sample in water is calculated by the following formula: Dem=Pre* (Ksam*Ars) / (Kr* Asam) .
In the formula, Ksam and Krs are the decomposition rate constants of ABDA affected by the test sample and Rose Bengal (RB), respectively. Asam and Ars represent the light absorbed by the sample and Rose Bengal (RB), respectively, which are determined by integration of the optical absorption bands in the wavelength range of 400 to 700 nm. es is the 10: quantum yields of Rose Bengal (RB), ®rp=0.75 in water.
The fluorine-containing graphene quantum dots prepared by the present invention are used as photosensitizers in photodynamic therapy, which can generate a large amount of singlet oxygen under light, with a O2 quantum yield of 0.4-0.5, thereby improving the effect of photodynamic therapy. The fluorine-containing graphene quantum dots can be used in the treatment of various tumors, esophageal cancer, skin cancer, early lung cancer and other diseases.
-10- Culture conditions of esophageal cancer cells.
Esophageal cancer cells are placed in 1640 medium containing 8% fetal bovine serum, and then placed in an incubator at 37°C with 5% CO2. When the cells have proliferated to approximately fill the bottom of the culture flask, the old medium is removed, and 2 mL of phosphate buffer solution (PBS) that has been preheated to 37°C is added to wash the cells.
Subsequently, 1 mL of 0.25% trypsin solution is added to infiltrate cells, followed by centrifugation to remove the trypsin, digestion at 37°C for about 4 minutes, and then placed under an optical microscope to observe the morphological changes of the cells.
Finally, 2 mL of 1640 culture medium is added, the cells are detached by gently pipetting to form a single cell suspension, and 1640 culture medium is added to continue culturing the cells.
The cells are transferred to a 96-well plate at a required concentration to continue the culture.
The cytotoxicity of fluorine-containing graphene quantum dots is detected by the tetramethylazolium salt (MTT) method, which is a common method for the detection of cell survival and growth.
The detection principle is that succinate dehydrogenase in the mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-purple crystalline formazan and then form deposits in the cells, while dead cells have no such function.
Subsequently, the crystalline formazan in the cells is dissolved by dimethyl sulfoxide, and the absorbance is measured using a microplate reader at a test wavelength of 563 nm with a reference wavelength of 630 nm.
The cell viability is standardized to that of cells cultivated in the culture medium.
The results of the MTT cytotoxicity assay showed that esophageal cancer cells were co- cultured with different concentrations of fluorine-containing graphene quantum dots for 12 hours, and then illuminated for 12 minutes, as can be seen from FIG. 6 and FIG. 7, after being illuminated by LED lights, the cytotoxicity of different concentrations of fluorine-containing graphene quantum dots is significantly greater than that in the dark, indicating that fluorine-containing graphene quantum dots can be effectively and safely applied in PDT.
Embodiment 2
-11- A method for preparing fluorine-containing graphene quantum dots, specifically includes the following steps.
1) A fluorinated graphite is soaked in 40% sodium hydroxide solution, followed by stirring and dispersing ultrasonically for 12 hours to fully peel off, filtering, and drying. 2) The fluorinated graphite treated in step (1) is prepared into an oxidized fluorine- containing graphene by Hummers method; the oxidized fluorine-containing graphene has a fluorine content of 6%-8%, an oxygen content of 6%-8%, and a carbon content of 80%-90%, and it regarded as a two-dimensional nano film.
3) 60 mg of the above-mentioned oxidized fluorine-containing graphene is weighed and dissolved in 60 mL of ultrapure water, and treated with an ultrasonic power of 800 watts, and then 20 g of concentrated sulfuric acid and concentrated nitric acid are added to fully dissolve the oxidized fluorine-containing graphene.
4) 600 pL of potassium hydroxide solution with a concentration of 1 mol/L is added to the above solution, and then the above solution is transferred to a round-bottom flask and refluxed in an oil bath at 70°C for 6 hours.
5) After the reflux, the above solution is subjected to extraction and purification treatment, and then freeze-drying treatment to obtain fluorine-containing graphene quantum dots with an average thickness of 1.0-3.0 nm, a size of 2.0 nm-3.0 nm, and a fluorine content of 1%-2%.
Embodiment 3 A method for preparing fluorine-containing graphene quantum dots, specifically includes the following steps.
1) A fluorinated graphite is soaked in 30% sodium hydroxide solution, followed by stirring and dispersing ultrasonically for 12 hours to fully peel off, filtering, and drying. 2) The fluorinated graphite treated in step (1) is prepared into an oxidized fluorine- containing graphene by Hummers method; the oxidized fluorine-containing graphene has a fluorine content of 6%-8%, an oxygen content of 6%-8%, and a carbon content of 80%-90%, and it regarded as a two-dimensional nano film.
3) 60 mg of the above-mentioned oxidized fluorine-containing graphene is weighed and dissolved in 60 mL of ultrapure water, and treated with an ultrasonic power of 600 watts, and then 60 mL of hydrogen peroxide is added to fully dissolve the oxidized fluorine- containing graphene.
-12- 4) 400 pL of potassium hydroxide solution with a concentration of 1 mol/L is added to the above solution, and then the above solution is transferred to a round-bottom flask and refluxed in an oil bath at 80°C for 5 hours.
5) After the reflux, the above solution is filtered and purified to remove bulk impurities, and then vacuum dried to obtain fluorine-containing graphene quantum dots with an average thickness of 1.0-3.0 nm, a size of 2.0 nm-3.0 nm, and a fluorine content of 1%- 2%.
The fluorine-containing graphene quantum dots prepared by the present invention have the advantages of simple reaction steps, low cost and environmental protection, are easily dispersed in aqueous systems such as water, phosphate buffer solution, and biological culture medium, and have good biocompatibility and low toxicity.
The fluorine-containing graphene quantum dots prepared by the present invention can generate singlet oxygen under the light irradiation of visible light, which can be used as photosensitizers in photodynamic therapy, applicable to the treatment process of esophageal cancer, skin cancer, early lung cancer, and other diseases, and has a wide application prospect.
The foregoing descriptions are merely preferred embodiments of the present invention, which are not used to limit the present invention. Any modifications, equivalent substitutions, improvements within the spirit and principle of the present invention should be included in the protective scope of the present invention.
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| CN102660270A (en) * | 2012-05-03 | 2012-09-12 | 吉林大学 | Method for preparing fluorescent graphene quantum dots by solvothermal method |
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| Publication number | Publication date |
|---|---|
| CN111518552A (en) | 2020-08-11 |
| CN111518552B (en) | 2021-08-10 |
| WO2021046966A1 (en) | 2021-03-18 |
| NL2026426A (en) | 2021-05-12 |
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