CN110724517B - Rare earth/chlorophyll composite probe and preparation method and application thereof - Google Patents
Rare earth/chlorophyll composite probe and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a rare earth/chlorophyll composite probe, a preparation method and an application thereof, wherein the rare earth/chlorophyll composite probe is formed by coating lanthanide oxyfluoride with up-conversion fluorescent elements by chlorophyll, and has a general structural formula as follows: ReOF is Ln @ chl, wherein Re and Ln are lanthanide elements, and chl is chlorophyll. The nano material in the rare earth/chlorophyll composite probe has better fluorescence property, is a better up-conversion fluorescent material, and has good luminous effect, so that the rare earth/chlorophyll composite probe can carry out targeted marking and positioning on tumor tissues and cancer tissues for guiding surgical resection of the tumor tissues and the cancer tissues, and the composite probe has better photodynamic effect by compounding chlorophyll on the surface of the nano material, so that the tumor can be subjected to photodynamic treatment.
Description
Technical Field
The invention belongs to the technical field of biological materials, and particularly relates to a rare earth/chlorophyll composite probe and a preparation method and application thereof.
Background
Photodynamic therapy (PDT) has evolved with the development of photochemistry and photophysics since phototoxicity was discovered in some dyes. PDT can be defined as an oxygen-dependent reaction with a non-toxic dye called a photosensitizer that is activated by an appropriate light source to produce the cytotoxic Reactive Oxygen Species (ROS) for a particular application. PDT has its own advantages such as negligible side effects, minimal cumulative toxicity, excellent functional and cosmetic effects, precise targeted therapy without damaging adjacent normal tissues, and optimal long-term tumor regression. More importantly, unlike chemotherapeutic drugs and ionizing radiation therapies that tend to be immunosuppressive, PDT can elicit anti-tumor immune responses, relieve pain and prolong survival beyond what is expected in end-stage cancer patients. PDT may therefore be an ideal anti-cancer strategy that is not only effective in destroying tumors, but also sensitizes the immune system to seek and destroy metastases.
Optical bioimaging based on rare earth doped up-converting nanoparticles (UCNPs) has attracted a great deal of attention in recent years in basic biological research and clinical diagnostics, mainly due to its very excellent photochemical properties, including low autofluorescence background, excellent optical stability, high penetration depth under Near Infrared (NIR) excitation, and weak light damage to tissues. Due to the strong tissue absorption capability of short wavelength light (<650nm) and the shallow tissue penetration depth, upconversion nanoparticles with emission bands in the bio-transparent window (650 + 950nm) become key parameters for the development of optical imaging of deep tissues in vivo, and furthermore, there are a large number of available light sources/detectors in the 650 + 950nm range. Therefore, the use of 650-950nm excitation/emission schemes is a good choice in terms of biological and technical compatibility, penetration depth (between one and several centimeters) and cost-effectiveness.
Chlorophyll (chlorophyllil) is the most important pigment involved in photosynthesis, and is present in all organisms capable of photosynthesis, especially in green plants. The chlorophyll is taken from natural plants, so that the chlorophyll has good biocompatibility, and experiments prove that the chlorophyll can stably exist in certain solvents, so that the chlorophyll has good stability and compatibility when being used for preparing the cancer treatment nano probe, and does not generate harmful side effects on human bodies. The maximum absorption light band of the chlorophyll can be well combined with the emission of the red light region of the nano probe in the red light and blue-violet light regions, which is favorable for the photodynamic effect of the composite nano probe to a great extent.
There are many limitations to having only one function as a fluorescent rare earth compound for photodynamic therapy. In order to realize the deep application of the medical application of the. How to apply the synthesized fluorescent probe to real clinical treatment still needs further research and study.
In conclusion, it is of great significance to synthesize a composite probe which has universal applicability, can be produced in large scale, has good biocompatibility from nature, and has a high photodynamic therapy effect.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a rare earth/chlorophyll composite probe and a preparation method and application thereof. The technical problem to be solved by the invention is realized by the following technical scheme:
the invention provides a rare earth/chlorophyll composite probe, wherein the rare earth/chlorophyll composite probe is formed by coating lanthanide oxyfluoride with up-conversion fluorescent elements by chlorophyll to form a core-shell structure, and the general structural formula of the rare earth/chlorophyll composite probe is as follows: ReOF is Ln @ chl, wherein Re and Ln are lanthanide elements, and chl is chlorophyll.
In one embodiment of the invention, Re is one or more of La, Gd, Y.
In one embodiment of the present invention, Ln is Yb and Er.
The invention also provides a preparation method of the rare earth/chlorophyll composite probe, which comprises the following steps:
s1: 1.5-3 g of urea is weighed and dissolved in 30-50 ml of deionized water, and Re (NO) is added at the same time3)3、Yb(NO3)3And Er (NO)3)3Adding 0.08-0.12 g of KF, stirring until the solution is uniform, packaging the solution, placing the solution in a water bath at 70-95 ℃ for coprecipitation reaction for 2-4 h, and after the reaction is finished, performing centrifugal separation and drying on a reaction product to obtain a nuclear precursor ReOHCO3F:Ln；
S2: subjecting the nuclear precursor ReOHCO3Calcining F, Ln in air at the temperature of 400-600 ℃ for 3-5 h to generate a nano material ReOF, Ln, wherein Re and Ln are lanthanide elements;
s3: shearing the green leaves, immersing the sheared green leaves in an organic solvent to obtain chlorophyll liquid, adding the nano material ReOF: Ln into the chlorophyll liquid, and stirring at room temperature to obtain the rare earth/chlorophyll composite probe ReOF: Ln @ chl.
In one embodiment of the invention, Re is at least one of La, Gd, Y, and Ln is Yb and Er.
In one embodiment of the present invention, the organic solvent is one of ethanol, acetone, diethyl ether and chloroform.
In an embodiment of the present invention, the S1 includes:
1.5g of urea are weighed out and dissolved in 50ml of deionized water and 0.5mmol of Gd (NO) is added simultaneously3)30.5mmol of Yb (NO)3)3And 0.5mmol of Er (NO)3)3Then adding 0.1g of KF, stirring until the solution is uniform, packaging the solution, placing the solution in a water bath at 90 ℃ for coprecipitation reaction, wherein the reaction time is 3h, and after the reaction is finished, performing centrifugal separation and drying on a reaction product to obtain a nuclear precursor GdOHCO3F:Yb/Er。
In an embodiment of the present invention, the S2 includes:
subjecting the nuclear precursor GdOHCO3F, Yb/Er is calcined in air at 500 ℃ for 3 hours to generate a nano material GdOF, Yb/Er.
The invention also provides a rare earth/chlorophyll composite probe as described in any one of the above embodiments, application of the rare earth/chlorophyll composite probe as a marker for marking and positioning tumor tissues and cancer tissues, application of a navigator for navigating and surgically resecting the tumor tissues and the cancer tissues, and application of the rare earth/chlorophyll composite probe as a photodynamic therapy medicament.
Compared with the prior art, the invention has the beneficial effects that:
1. the nano material in the rare earth/chlorophyll composite probe has better fluorescence property, is a better up-conversion fluorescent material, and has good luminous effect, so that the rare earth/chlorophyll composite probe can carry out targeted marking and positioning on tumor tissues and cancer tissues for guiding surgical resection of the tumor tissues and the cancer tissues, and the composite probe has better photodynamic effect by compounding chlorophyll on the surface of the nano material, so that the tumor can be subjected to photodynamic treatment.
2. The nano material in the rare earth/chlorophyll composite probe is prepared by adopting a coprecipitation method, the product of the coprecipitation method has high purity, uniform particle size, simple and easy operation and green and environment-friendly preparation process, and the generated nano material has good dispersibility.
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical means of the present invention more clearly understood, the present invention may be implemented in accordance with the content of the description, and in order to make the above and other objects, features, and advantages of the present invention more clearly understood, the following preferred embodiments are described in detail with reference to the accompanying drawings.
Drawings
FIG. 1 is an SEM image of a GdOF: Yb/Er nano-material provided by an embodiment of the invention;
FIG. 2 is a UV-vis diagram of chlorophyll provided in the examples of the present invention after and before three days in ethanol;
FIG. 3 is a spectrum diagram of UCL of GdOF: Yb/Er nano-material provided by the embodiment of the invention when the wavelength of exciting light is 980 nm;
FIG. 4 is a spectrum diagram of UCL of a GdOF Yb/Er @ chl rare earth/chlorophyll composite probe provided by an embodiment of the invention when the wavelength of excitation light is 980 nm;
FIG. 5 is a DPBF absorption graph of the nano-material provided by the embodiment of the invention when the wavelength of the excitation light is 980 nm;
FIG. 6 is a DPBF absorption graph of a GdOF/Er @ chl rare earth/chlorophyll composite probe provided by an embodiment of the invention when the wavelength of excitation light is 980 nm;
FIG. 7 is a diagram of the subcutaneous luminescence imaging of mice using a GdOF Yb/Er @ chl rare earth/chlorophyll composite probe according to an embodiment of the present invention;
FIG. 8 is a graph showing the comparison of body weight after photodynamic therapy with a GdOF Yb/Er @ chl rare earth/chlorophyll composite probe according to an embodiment of the present invention;
FIG. 9 is a comparison graph of tumor diameters after photodynamic therapy with a GdOF: Yb/Er @ chl rare earth/chlorophyll composite probe according to an embodiment of the present invention.
Detailed Description
In order to further illustrate the technical means and effects of the present invention adopted to achieve the predetermined objects, the following detailed description will be made on a rare earth/chlorophyll composite probe and its preparation method and application in accordance with the present invention with reference to the accompanying drawings and the detailed description.
The foregoing and other technical matters, features and effects of the present invention will be apparent from the following detailed description of the embodiments, which is to be read in connection with the accompanying drawings. The technical means and effects of the present invention adopted to achieve the predetermined purpose can be more deeply and specifically understood through the description of the specific embodiments, however, the attached drawings are provided for reference and description only and are not used for limiting the technical scheme of the present invention.
Example one
The embodiment provides a rare earth/chlorophyll composite probe, the rare earth/chlorophyll composite probe is formed by coating lanthanide oxyfluoride with up-conversion fluorescent elements by chlorophyll, and the general structural formula of the rare earth/chlorophyll composite probe is as follows: ReOF is Ln @ chl, wherein Re and Ln are lanthanide elements, and chl is chlorophyll.
The rare earth/chlorophyll composite probe comprises a nano material and chlorophyll coated outside the nano material, wherein the nano material has good fluorescence performance and is a good up-conversion fluorescent material, and the chlorophyll is taken from natural plants, has good stability and compatibility and does not produce harmful side effects on human bodies. The nanometer material is formed by three parts of a host element, a sensitizer and an activator, wherein the host element mainly influences the appearance of the nanometer material and has small influence on the luminescence of the nanometer material. The activator is an up-conversion luminescent element, which is mainly used for up-conversion luminescence, so that the up-conversion luminescence is different colors.
In this embodiment, in the general structural formula of the rare earth/chlorophyll composite probe, Re is a matrix element, and may be one or more of La, Gd, and Y. Ln includes a sensitizer element which may be Yb and an upconverted light emitting element which may be Er, and thus, Ln may be Yb/Er, where "/" means "and".
The nano material in the rare earth/chlorophyll composite probe has good fluorescence performance, is a good up-conversion fluorescent material, and has a good luminous effect, so that the rare earth/chlorophyll composite probe can be used for carrying out targeted marking and positioning on tumor tissues and cancer tissues and guiding surgical resection of the tumor tissues and the cancer tissues, and the composite probe has good photodynamic effect by compounding chlorophyll on the surface of the nano material, so that the tumor can be subjected to photodynamic treatment.
Example two
The embodiment provides a preparation method for preparing the rare earth/chlorophyll composite probe in the first embodiment, wherein the rare earth/chlorophyll composite probe is prepared by adopting a coprecipitation method.
The main synthesis methods of the nano material include a solid phase method and a liquid phase method, wherein the liquid phase method is widely used due to safe operation, simple equipment and uniform product. Liquid phase methods include coprecipitation, hydrothermal/solvothermal, sol-gel, and high temperature pyrolysis methods. The product prepared by the coprecipitation method has the advantages of high crystallinity, narrow particle size distribution, good dispersibility, high yield and simple and feasible device. In this embodiment, the coprecipitation method of the rare earth oxide mainly adopts rare earth trivalent nitrate and urea to perform coprecipitation, and a uniform micro-nanocrystalline material is generated after high-temperature calcination.
Specifically, the rare earth/chlorophyll composite probe is prepared by taking deionized water as a solvent and rare earth nitrate as a precursor, generating a monodisperse rare earth oxyfluoride precursor under the participation of urea and potassium fluoride, then calcining to generate a nano material, and further coating the nano material with chlorophyll to obtain the rare earth/chlorophyll composite probe. The method specifically comprises the following steps:
firstly, Ln is mixed2O3(lanthanide oxide, 99.99%) (Ln ═ Gd/Yb/Er) was dissolved in nitric acid, heated to remove excess nitric acid and diluted with deionized water.
Secondly, preparing a nuclear precursor ReOHCO by adopting a coprecipitation method3F is Ln. 1.5-3 g of urea is weighed and dissolved in 30-50 ml of deionized water, and Re (NO) is added at the same time3)3、Yb(NO3)3And Er (NO)3)3Adding 0.08-0.12 g of KF, stirring until the solution is uniform, packaging the solution, placing the solution in a water bath at 70-95 ℃ for coprecipitation reaction for 2-4 h, and after the reaction is finished, performing centrifugal separation and drying on a reaction product to obtain a nuclear precursor ReOHCO3F:Ln；
Thirdly, the nuclear precursor ReOHCO3F, calcining Ln in air at the temperature of 400-600 ℃ for 3-5 h to generate a nano material ReOF;
and finally, shearing the green leaves, immersing the sheared green leaves in an organic solvent to obtain chlorophyll liquid, adding the nano material ReOF: Ln into the chlorophyll liquid, and stirring at room temperature to obtain the rare earth/chlorophyll composite probe ReOF: Ln @ chl.
In the above preparation method, both Re and Ln are lanthanoid elements. Specifically, Re is at least one of La, Gd and Y, and Ln is Yb and Er. The organic solvent is one of ethanol, acetone, diethyl ether and chloroform.
When the rare earth probe is prepared, factors such as the proportion of reactants, the reaction time, the reaction temperature and the like need to be controlled. The reaction time and the reaction temperature are main factors influencing the particle size and the particle size uniformity of the nano-material. In addition, the yield and production of the nanomaterial can be controlled by the amount of the lanthanide nitrate reactant, and the more the amount of the lanthanide nitrate reactant is, the higher the product yield and the greater the production.
In the embodiment, the rare earth/chlorophyll composite probe prepared by a coprecipitation method has good dispersibility and high purity. In addition, the operation steps of the coprecipitation method are simple and easy to implement, the preparation process is green and environment-friendly, and the preparation of the rare earth/chlorophyll composite probe has high yield and can be produced in large batch.
EXAMPLE III
In this embodiment, the preparation of the rare earth/chlorophyll composite probe is described by taking GdOF: Yb/Er @ chl as an example, and the specific steps are as follows:
s1: 1.5g of urea are weighed out and dissolved in 50ml of deionized water and 0.5mmol of Gd (NO) is added simultaneously3)30.5mmol of Yb (NO)3)3And 0.5mmol of Er (NO)3)3Then adding 0.1g of KF, stirring until the solution is uniform, packaging the solution, placing the solution in a water bath at 90 ℃ for coprecipitation reaction, wherein the reaction time is 3h, and after the reaction is finished, performing centrifugal separation and drying on a reaction product to obtain a nuclear precursor GdOHCO3F:Yb/Er。
S2: subjecting the nuclear precursor GdOHCO3F, Yb/Er is calcined in air at 500 ℃ for 3 hours to generate a nano material GdOF, Yb/Er.
Referring to fig. 1, fig. 1 is an SEM (scanning electron microscope) image of a GdOF Yb/Er nanomaterial provided in this embodiment of the present invention, and as shown in the figure, the GdOF Yb/Er nanomaterial prepared by co-precipitation method in this embodiment has a better uniform dispersibility.
S3: shearing the green leaves, immersing the sheared green leaves in ethanol to obtain chlorophyll liquid, adding the nano material GdOF: Yb/Er into the chlorophyll liquid, and stirring at room temperature to obtain the rare earth/chlorophyll composite probe GdOF: Yb/Er @ chl.
In this example, ethanol is used as the organic solvent to extract chlorophyll because ethanol has good volatility, no residue, and no toxicity. Referring to fig. 2, fig. 2 is a UV-vis (ultraviolet-visible absorption spectrum) diagram of chlorophyll provided in the embodiment of the present invention after being dissolved in ethanol for three days, wherein the two chlorophyll solutions after being placed at room temperature, 4 ℃, -20 ℃ for several days are shown in the upper right-hand insert. As can be seen from the figure, the absorption of chlorophyll is kept stable after being placed for several days, and the color of the chlorophyll does not change after being stored for a long time at different temperatures, which indicates that the chlorophyll can be stably stored in ethanol.
Referring to fig. 3 and 4, fig. 3 is a graph showing a UCL (up-conversion luminescence) spectrum of a GdOF Yb/Er nano material provided by an embodiment of the present invention at an excitation wavelength of 980nm, and fig. 4 is a graph showing a UCL spectrum of a GdOF Yb/Er chl rare earth/chlorophyll composite probe provided by an embodiment of the present invention at an excitation wavelength of 980 nm. As shown in the figure, the GdOF: Yb/Er nano material and the GdOF: Yb/Er @ chl rare earth/chlorophyll composite probe have good emission and good stability at 650nm under the excitation of laser with the wavelength of 980nm, and the light emitting performance of the rare earth/chlorophyll composite probe is not greatly influenced.
Referring to fig. 5 and 6, fig. 5 is a DPBF absorption graph of chlorophyll provided by the embodiment of the present invention when the excitation light wavelength is 980 nm; FIG. 6 is a DPBF absorption graph of a GdOF/Er @ chl rare earth/chlorophyll composite probe provided by an embodiment of the invention when the wavelength of excitation light is 980 nm. DPBF (diphenylisobenzofuran) was used to measure the amount of ROS (reactive oxygen species) produced. As shown in the figure, it can be seen that a small amount of ROS is released by the GdOF: Yb/Er nano material under the laser irradiation with the wavelength of 980nm, and a large amount of ROS is released by the GdOF: Yb/Er @ chl rare earth/chlorophyll composite probe formed by compounding the chlorophyll and the GdOF: Yb/Er nano material under the laser irradiation with the wavelength of 980nm, so that the rare earth/chlorophyll composite probe has a good photodynamic effect.
Example four
In this example, the GdOF Yb/Er @ chl rare earth/chlorophyll composite probe prepared in example three is used as a marker to mark and treat subcutaneous tumor tissues of mice, so as to explain the application of the GdOF Yb/Er @ chl rare earth/chlorophyll composite probe
In this example, the subcutaneous tissue of the mouse was labeled with a composite probe and developed. Referring to fig. 7, fig. 7 is a light-emitting imaging diagram of a GdOF: Yb/Er @ chl rare earth/chlorophyll composite probe under mouse skin according to an embodiment of the present invention, as shown in the figure, a solution containing the GdOF: Yb/Er @ chl rare earth/chlorophyll composite probe is injected into tumor tissue under mouse skin by injection, and then irradiated by laser with a wavelength of 980nm, it can be seen that the composite probe has up-conversion imaging under mouse skin, which illustrates the up-conversion fluorescence imaging effect of the composite probe.
Referring to fig. 8 and 9, fig. 8 is a graph showing the body weight of patients after photodynamic therapy with a GdOF/Er @ chl rare earth/chlorophyll composite probe according to an embodiment of the present invention; FIG. 9 is a comparison graph of tumor diameters after photodynamic therapy with a GdOF: Yb/Er @ chl rare earth/chlorophyll composite probe according to an embodiment of the present invention. Wherein, the figure comprises a control group (no treatment is carried out on the mice), a DOX group (doxycycline is injected into the mice) and a treatment group (GdOF: Yb/Er @ chl rare earth/chlorophyll composite probe is injected into the mice and 980nm laser irradiation is used for treatment). As can be seen from the figure, the body weights of the mice in the 3 groups are not very different after 30 days, but the tumor diameters of the mice in the treatment group are obviously reduced, which shows that the rare earth/chlorophyll composite probe has good treatment effect on the tumor, because the rare earth/chlorophyll composite probe can generate a large amount of active oxygen under 980nm laser irradiation, and the active oxygen can generate oxidation reaction with nearby biological macromolecules to generate cytotoxicity so as to kill tumor cells and achieve the effect of treating the tumor.
The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.
Claims (5)
1. The rare earth/chlorophyll composite probe is characterized in that a lanthanide oxyfluoride with an up-conversion fluorescent element is coated by chlorophyll to form a core-shell structure, and the general structural formula of the rare earth/chlorophyll composite probe is as follows: ReOF is Ln @ chl, wherein chl is chlorophyll, Re is one or more of La, Gd and Y, and Ln is Yb and Er.
2. A preparation method of a rare earth/chlorophyll composite probe is characterized by comprising the following steps:
s1: 1.5-3 g of urea is weighed and dissolved in 30-50 ml of deionized water, and Re (NO) is added at the same time3)3、Yb(NO3)3And Er (NO)3)3Then adding 0.08-0.12 g of KF, stirring until the solution is uniform, packaging the solution, placing the solution in a water bath at 70-95 ℃ for coprecipitation reaction,the reaction time is 2-4 h, and after the reaction is finished, the reaction product is centrifugally separated and dried to obtain a nuclear precursor ReOHCO3F:Ln；
S2: subjecting the nuclear precursor ReOHCO3Calcining the Ln in air at the temperature of 400-600 ℃ for 3-5 h to generate a nano material ReOF;
s3: shearing a green leaf, immersing the sheared green leaf in an organic solvent to obtain a chlorophyll liquid, adding the nano material ReOF: Ln into the chlorophyll liquid, and stirring at room temperature to obtain a rare earth/chlorophyll composite probe ReOF: Ln @ chl;
wherein Re is at least one of La, Gd and Y, and Ln is Yb and Er.
3. The method for preparing the rare earth/chlorophyll composite probe according to claim 2, wherein the organic solvent is one of ethanol, acetone, diethyl ether and chloroform.
4. The method for preparing a rare earth/chlorophyll composite probe according to claim 2, wherein the S1 includes:
1.5g of urea are weighed out and dissolved in 50ml of deionized water and 0.5mmol of Gd (NO) is added simultaneously3)30.5mmol of Yb (NO)3)3And 0.5mmol of Er (NO)3)3Then adding 0.1g of KF, stirring until the solution is uniform, packaging the solution, placing the solution in a water bath at 90 ℃ for coprecipitation reaction, wherein the reaction time is 3h, and after the reaction is finished, performing centrifugal separation and drying on a reaction product to obtain a nuclear precursor GdOHCO3F:Yb/Er。
5. The method for preparing a rare earth/chlorophyll composite probe according to claim 4, wherein the S2 includes:
subjecting the nuclear precursor GdOHCO3And F, calcining Yb/Er in air at 500 ℃ for 3h to generate a nano material GdOF, Yb/Er.
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