CN115465853A - Orange light carbon dot based on citric acid and chiral 2-amino-1, 2-diphenylethanol and preparation method and application thereof - Google Patents
Orange light carbon dot based on citric acid and chiral 2-amino-1, 2-diphenylethanol and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of fluorescent nano materials, and particularly relates to orange fluorescent carbon dots based on citric acid and chiral 2-amino-1, 2-diphenylethanol, and a preparation method and application thereof. Citric acid and chiral 2-amino-1, 2-diphenylethanol are used as raw materials, no solvent is added, high-temperature solid-phase reaction is carried out, and then column chromatography is carried out to separate and purify the target fluorescent carbon dots, wherein the carbon dots prepared from (1R, 2S) -2-amino-1, 2-diphenylethanol are named RCDs, and the carbon dots prepared from (1S, 2R) -2-amino-1, 2-diphenylethanol are named SCDs. Both RCDs and SCDs have two-photon fluorescence property and have excellent single-photon and two-photon cell imaging effects. Because RCDs have better ability of generating hydroxyl radicals and photothermal conversion ability, the inventor uses the RCDs for photodynamic and photothermal combined therapy, successfully inhibits the growth of tumors in a mouse tumor-bearing model, embodies good combined therapy effect, and is a potential photodynamic and photothermal combined therapeutic agent.
Description
Technical Field
The invention belongs to the field of fluorescent nano materials, and particularly relates to orange fluorescent carbon dots based on citric acid and chiral 2-amino-1, 2-diphenylethanol, and a preparation method and application thereof.
Background
Cancer treatment is always a difficult problem to overcome in the medical field, patients usually receive chemotherapy, radiotherapy and surgery, but the conventional therapies have serious side effects and bring great burden to the bodies of the patients. Photodynamic and photothermal therapy is the brilliant sword which is ground by human beings in continuous struggle with cancers, and has accurate treatment and low toxic and side effects. In photodynamic therapy (PDT), photosensitizers generate high concentrations of ROS under light to oxidatively damage malignant cells; in photothermal therapy (PTT), a photothermal agent rapidly accumulates heat under laser irradiation to increase the local temperature at the tumor site to kill cancer cells. However, due to hypoxic microenvironment or thermotolerance of tumor cells, limited efficacy of PDT or PTT alone, rendering tumor cells indedicable, combining PDT and PTT is a necessary option, but it may involve cumbersome design steps and high cost investment, and thus development of a simple therapeutic agent capable of achieving both PDT and PTT is urgent.
Carbon Dots (CDs) are a new type of Carbon nanomaterials. In 2004, the luminescent carbon nano material appears in the visual field of researchers for the first time, in 2006, the material is reported by the name of carbon dots for the first time, the excellent Photoluminescence (PL) property of CDs enables the material to gain the attention of numerous scholars, more superior performances of CDs are mined along with the further understanding and research of CDs, the material has shown huge application advantages in the fields of sensing, biology, photoelectric devices, anti-counterfeiting and the like, and the CDs are a large research hotspot in the field of nano materials. Recent research finds that the carbon dots can realize PDT and PTT synergistic treatment, has the advantages of low cost, simple preparation, photobleaching resistance, low toxicity and the like, can realize in-vivo tumor imaging-guided PDT/PTT combined treatment, and in addition, multi-photon fluorescence excitation has deeper penetration depth and smaller toxic and side effects, which is more beneficial to the biological application of the carbon dots. The carbon dots have great application potential in clinic, so that the development of more carbon dots with excellent photodynamic and photothermal properties is significant for proving and supporting the carbon dots as a phototherapeutic agent for treating tumors.
Disclosure of Invention
In view of the above problems, it is an object of the present invention to provide a carbon dot based on citric acid and chiral 2-amino-1, 2-diphenylethanol, which has a single or two-photon fluorescence property and an excellent PDT/PTT combined treatment effect in vitro and in vivo, and can be used as a safe and low-toxic phototherapy agent for cancer treatment, and a preparation and use thereof.
In order to achieve the above object, the present invention provides the following technical solutions:
an orange fluorescent carbon dot based on citric acid and chiral 2-amino-1, 2-diphenylethanol, the raw material consists of citric acid and (1R, 2S) -2-amino-1, 2-diphenylethanol or (1S, 2R) -2-amino-1, 2-diphenylethanol, and the molar ratio of the citric acid to the chiral 2-amino-1, 2-diphenylethanol is 1-5.
In the invention, the particle size range of fluorescent carbon dots (hereinafter referred to as RCDs) of the citric acid and the (1R, 2S) -2-amino-1, 2-diphenylethanol is 0.8-6.3nm; further, the average particle diameter was 2.7nm.
In the invention, the particle size range of fluorescent carbon dots (hereinafter referred to as SCDs) of the citric acid and the (1S, 2R) -2-amino-1, 2-diphenylethanol is 1.3-5.6nm; further, the average particle diameter was 3.0nm.
The invention also provides a preparation method of the fluorescent carbon dots (RCDs or SCDs), which comprises the following steps:
(1) Mixing citric acid and (1R, 2S) -2-amino-1, 2-diphenylethanol or (1S, 2R) -2-amino-1, 2-diphenylethanol, and performing high temperature solid phase reaction;
(2) And (2) cooling, dissolving and carrying out column chromatography purification treatment on the reactant obtained in the step (1) to obtain the carbon dots.
In the invention, the temperature for preparing the high-temperature solid phase in the step (1) is 180-220 ℃, and the preparation time is 6-10h.
In the invention, in the step (2), a solvent is added to fully dissolve the reactant obtained in the step (1), and then separation and purification are carried out in a column chromatography mode;
further, the solvent in step (2) is selected from organic solvents such as ethyl acetate, dichloromethane and the like.
The research results of the inventors show that the orange fluorescent carbon dots, RCDs and SCDs in the invention all show single-photon or two-photon fluorescence characteristics. For the two-photon fluorescence characteristics, under different powers and long-wavelength excitation lights (excitation lights in an infrared region), the RCDs and the SCDs have logarithmic relations between laser powers and emission light intensities, which shows that the RCDs and the SCDs both have the two-photon fluorescence characteristics.
The invention also uses the orange fluorescent carbon dots in fluorescence imaging.
Furthermore, the orange fluorescent carbon dots are used as single-photon and/or two-photon cell imaging probes or dyes.
In some embodiments of the present invention, the orange fluorescent carbon dots are used for fluorescence imaging, specifically, the fluorescent carbon dots are added into a culture solution, incubated with cells, washed off carbon dots which do not enter the cells with PBS, and observed under a confocal fluorescence microscope, so that orange fluorescence is present inside the cells;
in the invention, for citric acid and (1R, 2S) -2-amino-1, 2-diphenylethanol fluorescent carbon dots, the wavelength of excitation light during single photon fluorescence imaging is 380 nm-540 nm, preferably 488nm; the excitation wavelength of the two-photon fluorescence imaging is 800nm to 1000nm, preferably 900nm.
In the invention, for citric acid and (1S, 2R) -2-amino-1, 2-diphenylethanol fluorescent carbon dots, the wavelength of excitation light during single photon imaging is 380nm to 540nm, preferably 490nm; the excitation wavelength in two-photon fluorescence imaging is 800nm to 1000nm, preferably 850nm.
The invention also provides a fluorescent imaging probe or dye, which comprises RCDs and/or SCDs.
The inventor researches and discovers that RCDs and SCDs have good photodynamic and photothermal performance, can generate ROS under light irradiation, and can convert light energy into heat energy.
Based on the above, the orange fluorescent carbon dots are also used for preparing anti-cancer drugs;
further, the orange fluorescent carbon dots are used for preparing anti-adenocarcinoma drugs;
furthermore, the orange fluorescent carbon dots are used for preparing anti-breast cancer drugs.
The adenocarcinoma is formed by glandular epithelial cells, such as breast cancer, colon cancer, prostate cancer and the like.
In some embodiments of the invention, the orange fluorescent carbon dots are used for preparing photodynamic and/or photothermal therapeutic agents for cancer treatment.
The present invention also provides a photodynamic and/or photothermal therapeutic agent comprising RCDs and/or SCDs.
The invention has the beneficial effects that:
(1) Citric acid is used as a carbon source, chiral 2-amino-1, 2-diphenylethanol is used as a nitrogen source, the used nitrogen source is not reported, and the raw materials have novelty;
(2) The preparation process of the carbon dots is simple and the cost is low;
(3) The RCDs and the SCDs both have two-photon fluorescence properties, can be used as two-photon fluorescence imaging probes or dyes, and have the advantages of small tissue autofluorescence background, large penetration depth and slight damage to biological tissues;
(4) The RCDs provided by the invention also have better capability of generating hydroxyl radicals and photo-thermal conversion capability, and the laser (1 w/cm) at 808nm 2 ) Under irradiation, the temperature of the RCDs solutionThe temperature can be raised to about 46 ℃, indicating that RCDs have potential for photodynamic, photothermal combination therapy. Experimental results prove that the combined treatment effect of in vitro and in vivo photodynamic and photothermal of RCDs is excellent, the tumor growth is successfully inhibited in a mouse tumor-bearing model, and the blood biochemical detection and the tissue H&The E staining results demonstrate that RCDs have no significant toxicity to mice and have potential as drug candidates for tumor phototherapy.
Drawings
FIG. 1 is a transmission electron/high resolution transmission electron (TEM/HRTEM) image of RCDs prepared according to the present invention.
FIG. 2 is (a) the fluorescence spectrum of RCDs solid at 490nm, 900nm excitation; (b) Two-photon fluorescence spectra of RCDs under the excitation of different powers of 900nm and (c) a relationship graph between laser power and fluorescence intensity of the RCDs.
FIG. 3 shows the fluorescence spectra of RCDs solution (containing DCFH) under different illumination time.
FIG. 4 is an Electron Paramagnetic Resonance (EPR) spectrum of the RCDs solution after light irradiation.
FIG. 5 is a graph showing the temperature changes of RCDs solution and blank solution under 808nm laser irradiation.
FIG. 6 is a graph of single-photon and two-photon fluorescence images of 4T1 cells after co-incubation with RCDs.
FIG. 7 is a fluorescent image of Calcein-AM/PI stained 4T1 cells.
FIG. 8 is (a) tumor growth in mice during treatment; (b) tumor tissue size after 14 days; (c) a body weight trend graph of the mice.
FIG. 9 is a transmission electron/high resolution transmission electron (TEM/HRTEM) image of SCDs prepared according to the present invention.
FIG. 10 is the fluorescence spectrum of (a) SCDs solid at 490nm, 850nm excitation; (b) Two-photon fluorescence spectra of SCDs under different power of 850nm excitation and (c) a relationship graph between laser power and SCDs fluorescence intensity.
FIG. 11 is a single photon and two photon fluorescence image of 4T1 cells after co-incubation with SCDs.
Detailed Description
The technical solutions provided in the present invention are described in detail by the following specific examples, but the scope of protection claimed is not limited to the description.
Example 1
The preparation method of the RCDs comprises the following steps:
(1) Uniformly mixing 0.384g of ground citric acid and 0.640g of (1R, 2S) -2-amino-1, 2-diphenylethanol (the molar ratio is 1: 1.5), adding into a high-pressure reaction kettle, placing into an air-blast drying oven, and keeping for 6 hours after the temperature is raised to 180 ℃;
(2) After the reaction is finished, opening the reaction kettle after the reaction kettle is naturally cooled to room temperature, and adding ethyl acetate into the reaction kettle to stir and dissolve; separating and purifying the orange fluorescent carbon dots RCDs in a column chromatography mode.
FIG. 1 is a Transmission Electron Microscope (TEM) image of the RCDs prepared in this example, from which it can be seen that the prepared RCDs are approximately circular and have good dispersibility; the particle size range is 0.8-6.3nm, and the average particle size is 2.7nm. High Resolution Transmission Electron Microscopy (HRTEM) images of RCDs show that carbon dots have obvious lattice fringes and interplanar spacing of 0.23nm.
FIG. 2 (a) is a fluorescence spectrum of RCDs with excitation at 490nm and 900nm, and emission peak positions at about 590 nm; FIG. 2 (b) is a two-photon fluorescence spectrum of the RCDs solid under the excitation of different powers of 900nm, wherein the higher the output power is, the stronger the fluorescence of the RCDs is; FIG. 2 (c) shows the relationship between laser power and logarithm of the emission fluorescence intensity of RCDs, with a slope of 1.83, indicating that RCDs have two-photon fluorescence characteristics.
FIG. 3 is a fluorescence spectrum of RCDs solution (containing DCFH) under different illumination time, wherein the peak at about 525nm is gradually increased with the increase of the illumination time, because the RCDs solution can generate Reactive Oxygen Species (ROS) under the illumination condition, and the DCFH is oxidized after reacting with the ROS to generate DCF with strong green fluorescence.
FIG. 4 is an Electron Paramagnetic Resonance (EPR) spectrum of the RCDs solution after light irradiation. And (3) performing Electron Paramagnetic Resonance (EPR) test on the RCDs solution subjected to the illumination treatment by using DMPO as a free radical trapping agent, wherein the test result shows that the RCDs solution has a stronger hydroxyl free radical signal. The results of the photodynamic performance tests show that RCDs have the potential to be used for type I photodynamic therapy by combining with figures 3 and 4.
FIG. 5 shows the temperature variation trend of the RCDs solution under 808nm laser irradiation, the initial temperature of the RCDs solution is 21.7 ℃, the temperature can rise to 42.4 ℃ when 10min, the temperature approaches 46 ℃ when 20min, and the temperature of the RCDs solution is only 29.3 ℃ when the blank control solution is irradiated for 10min, the temperature is about 32 ℃ when 20min, the temperature rise rate of the RCDs solution is significantly higher than that of the blank control solution, and the temperature can reach 46 ℃, which indicates that the RCDs have better photothermal conversion capability and potential application in photothermal therapy.
Example 2:
the preparation method of the SCDs comprises the following steps:
(1) Uniformly mixing 0.384g of ground citric acid and 0.640g of (1S, 2R) -2-amino-1, 2-diphenylethanol (the molar ratio is 1.5), adding into a high-pressure reaction kettle, placing into a forced air drying oven, and keeping for 6 hours after the temperature is raised to 180 ℃;
(2) After the reaction is finished, opening the reaction kettle after the reaction kettle is naturally cooled to room temperature, adding ethyl acetate, and stirring for dissolving; and separating and purifying the orange fluorescent carbon point SCDs in a column chromatography mode.
FIG. 9 is a Transmission Electron Microscope (TEM) image of the SCDs prepared in this example, from which it can be seen that the prepared SCDs are approximately circular and have good dispersibility; the particle size range is 1.3-5.6nm, and the average particle size is 3.0nm. High Resolution Transmission Electron Microscopy (HRTEM) images of SCDs showed significant lattice fringes at carbon points with interplanar spacing of 0.21nm.
FIG. 10 (a) is a fluorescence spectrum of SCDs with excitation at 490nm and 850nm, with emission peak positions at about 590 nm; FIG. 10 (b) is the two-photon fluorescence spectrum of SCDs solid under the excitation of different powers at 850nm, the higher the output power, the stronger the SCDs fluorescence; FIG. 10 (c) shows the relationship between laser power and logarithm of the fluorescence intensity emitted from SCDs, with a slope of 1.77, indicating that SCDs have two-photon fluorescence characteristics.
Application example 1
The RCDs obtained in the embodiment 1 of the invention are used for fluorescence imaging of mouse breast cancer cells (4T 1), and the specific steps are as follows:
(1) Inoculating 4T1 cells into laser confocal culture dish with diameter of 20mm, adding CO at 37 deg.C and 5% 2 Incubating in a cell incubator;
(2) Taking out the confocal dish in step (1), aspirating the old medium, rinsing the cells with PBS, adding the medium containing RCDs (RCDs concentration of 20. Mu.g/mL), adding CO at 37 deg.C and 5% 2 Continuously incubating for 4h in the cell incubator;
(3) After the incubation was completed, the old medium was aspirated, and the cells were rinsed 3 times with PBS solution to remove excess RCDs that did not enter the cells, and then observed under a confocal fluorescence microscope.
FIG. 6 is a 4T1 cell fluorescence imaging image after co-incubation with RCDs, which shows that RCDs have bright fluorescence under 488nm and 900nm excitation, and have excellent single photon and two-photon imaging effects, and RCDs are mainly enriched in lysosome parts and show lysosome targeting.
Application example 2
The RCDs obtained in the embodiment 1 of the invention are used for phototherapy of mouse breast cancer cells (4T 1), and the specific steps are as follows:
(1) 4T1 cells in the logarithmic growth phase were seeded into 4 confocal dishes and charged at 37 ℃ with 5% CO 2 Incubating for 24 hours in a cell incubator;
(2) Marking the 4 confocal small dishes in the step (1) as a blank group, an only illumination group (white light +808nm laser), an only administration group (RCDs) and an administration + illumination group respectively, and then performing corresponding experimental treatment: after the cells of the light-only group were added to the new medium, xenon lamp (200 mw/cm) was used 2 ) And 808nm laser (1 w/cm) 2 ) After the cells are irradiated for 10min, the cells are incubated for 12h; incubation continued after only the administration group cells replaced the old medium with a medium containing RCDs (20. Mu.g/mL); administration + light group cells after replacing the old medium with the medium containing RCDs (20. Mu.g/mL), xenon lamp (200 mw/cm) 2 ) And 808nm laser (1 w/cm) 2 ) Irradiating the cells for 10min, and placing the cells into an incubator for continuous incubation; the blank group was incubated without any treatment after addition of new medium.
(3) After the incubation is finished, the old culture medium is removed, calcein-AM/PI buffer solution is added for incubation for 30min, and finally the cells are rinsed by PBS and observed under a confocal fluorescence microscope.
FIG. 7 shows that the cells in both the light-only group and the drug-only group were labeled with Calcein-AM, and strongly fluoresced green at 488nm, and no red fluorescence was observed in PI-stained dead cells at 552nm, indicating that there was little toxicity of light or RCDs to the cells; the cells of the administration and illumination group show large-area red fluorescence signals under the excitation of 552nm, and almost all cell nuclei are stained by PI, which shows that ROS generated by RCDs under the irradiation of white light and heat generated under the irradiation of 808nm laser have better killing effect on 4T 1. RCDs successfully realize photodynamic/photothermal cooperative therapy at the cellular level. Based on the method, a mouse subcutaneous tumor model is further constructed to study the in-vivo phototherapy effect.
Application example 3
The RCDs obtained in the embodiment 1 of the invention are used for phototherapy of subcutaneous tumors of mice, and the specific steps are as follows:
(1) Constructing a mouse tumor model: BALB/C mice (female, 4-week-old) were used as subjects, and 100. Mu.L of 4T1 cells in PBS suspension (approx.2X 10) 6 ) Injecting the mixture into the tail side of a mouse by subcutaneous injection, and then placing the mixture into a mouse feeding room for normal feeding, so that the mouse can eat food freely;
(2) Five days after cancer cell inoculation, mice were equally divided into four groups, namely a blank control group, a drug-only group, a light-only group, and a drug-plus-light group, and then were subjected to different treatments. The experimental steps are as follows: the blank control group was not subjected to any treatment; tumors from the light-only group mice were injected in situ with 100. Mu.L of PBS solution and xenon lamp (200 mw/cm) 2 2 min) and 808nm laser (1 w/cm) 2 10 min) irradiating the tumor site of the mouse; tumors of mice of the administration group alone were injected in situ with 100. Mu.L of RCDs solution (100. Mu.g/mL) without light; tumors of mice in the administration + illumination group were injected with 100. Mu.L of RCDs solution (100. Mu.g/mL) in situ with xenon lamp (200 mw/cm) 2 2 min) and 808nm laser (1 w/cm) 2 10 min) the tumor site of the mice was irradiated.
(3) Mouse body weight and tumor size were recorded every two days for 14 days. Tumor volume calculation formula: 1/2 tumor length x tumor width 2 。
FIG. 8 (a) is the change in tumor volume of mice during treatment, from which it can be seen that the tumors of the blank group and the mice of the administration group alone are growing rapidly and continuously, the tumors of the mice of the illumination group alone are affected by light irradiation and grow slightly slowly, and the tumor growth of the mice of the administration + illumination group is significantly inhibited; fig. 8 (b) is the tumor tissue volume size after 14 days, and it can be seen visually that the tumor volume of the mice in the administration + illumination group was significantly smaller than that of the remaining three groups, even completely ablated, indicating that RCDs had significant phototherapy effect. Fig. 8 (c) reflects the body weight change of the mice, and it can be seen from the figure that the body weights of the four groups of mice did not significantly decrease during the treatment period and all gradually increased, indicating that the treatment means used in the experiment had no major toxic side effects on the bodies of the mice.
The foregoing is a more detailed description of the present invention with reference to specific embodiments thereof, which should not be taken to limit the invention to the specific embodiments thereof. It will be apparent to those skilled in the art that various changes, substitutions and alterations can be made without departing from the spirit and scope of the invention.
Claims (10)
1. An orange fluorescent carbon dot based on citric acid and chiral 2-amino-1, 2-diphenylethanol is characterized in that raw materials consist of citric acid and (1R, 2S) -2-amino-1, 2-diphenylethanol or (1S, 2R) -2-amino-1, 2-diphenylethanol, and the molar ratio of the citric acid to the chiral 2-amino-1, 2-diphenylethanol is 1-5.
2. A fluorescent carbon dot according to claim 1, wherein the citric acid and (1r, 2s) -2-amino-1, 2-diphenylethanol have a fluorescent carbon dot particle size in the range of 0.8-6.3nm; further, the average particle diameter was 2.7nm;
the particle size range of the fluorescent carbon dots of the citric acid and the (1S, 2R) -2-amino-1, 2-diphenylethanol is 1.3-5.6nm; further, the average particle diameter was 3.0nm.
3. A method of making an orange fluorescent carbon dot as claimed in claim 1 or 2, comprising the steps of:
(1) Mixing citric acid and (1R, 2S) -2-amino-1, 2-diphenylethanol or (1S, 2R) -2-amino-1, 2-diphenylethanol, and performing high temperature solid phase reaction;
(2) And (2) cooling, dissolving and carrying out column chromatography purification treatment on the reactant obtained in the step (1) to obtain the carbon dots.
4. The method for preparing an orange fluorescent carbon dot according to claim 3, wherein the temperature for preparing the high-temperature solid phase in the step (1) is 180-220 ℃ and the preparation time is 6-10h.
5. The method for preparing the orange fluorescent carbon dot according to claim 3, wherein in the step (2), a solvent is added to fully dissolve the reactant obtained in the step (1), and then the reactant is separated and purified in a column chromatography manner;
further, the solvent comprises one or two of ethyl acetate and dichloromethane.
6. Use of the orange fluorescent carbon dot of claim 1 or 2 in fluorescence imaging; further, the orange fluorescent carbon dots are used as single-photon and/or two-photon cell imaging probes or dyes.
7. The use of claim 6, wherein the fluorescent carbon dots are added into the culture solution, after the incubation with the cells, the carbon dots which do not enter the cells are washed away by PBS, and then the orange fluorescence is observed in the cells under a confocal fluorescence microscope;
further, for citric acid and (1R, 2S) -2-amino-1, 2-diphenylethanol fluorescent carbon dots, the wavelength of excitation light in single photon fluorescence imaging is 380nm to 540nm, preferably 488nm; the excitation wavelength of the two-photon fluorescence imaging is 800 nm-1000 nm, preferably 900nm;
further, for citric acid and (1S, 2R) -2-amino-1, 2-diphenylethanol fluorescent carbon dots, the wavelength of excitation light in single photon imaging is 380nm to 540nm, preferably 490nm; the excitation wavelength in two-photon fluorescence imaging is 800nm to 1000nm, preferably 850nm.
8. A fluorescent imaging probe or dye comprising a fluorescent carbon dot according to claim 1 or 2.
9. The use of the orange fluorescent carbon dot of claim 1 or 2 in the preparation of an anticancer drug;
further, the orange fluorescent carbon dots are used for preparing anti-adenocarcinoma drugs;
furthermore, the orange fluorescent carbon dots are used for preparing anti-breast cancer drugs.
10. A photodynamic and/or photothermal therapeutic agent comprising the fluorescent carbon dot of claim 1 or 2.
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