CN109266349B - Preparation method and application of water-soluble rare earth up-conversion nanoparticles - Google Patents
Preparation method and application of water-soluble rare earth up-conversion nanoparticles Download PDFInfo
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- XWFVFZQEDMDSET-UHFFFAOYSA-N gadolinium(3+);trinitrate;hexahydrate Chemical compound O.O.O.O.O.O.[Gd+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XWFVFZQEDMDSET-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a preparation method of water-soluble rare earth up-conversion nanoparticles, which is characterized in that the surface of the nanoparticles is modified in a biocompatible manner while the nanoparticles are formed, so that the operation steps can be simplified, the production efficiency can be accelerated, and the production cost can be reduced; the prepared rare earth up-conversion nanoparticles have excellent water solubility and biocompatibility, and can be applied to magnetic resonance imaging as a contrast agent and fluorescence imaging.
Description
Technical Field
The invention relates to a preparation method and application of nanoparticles, in particular to a preparation method and application of water-soluble rare earth up-conversion nanoparticles, belonging to the technical field of inorganic nano materials
Background
In recent years, with the rapid development of nanotechnology, rare earth ion doped up-conversion nanomaterials have important research and application prospects in the fields of biological imaging, photodynamic therapy and the like due to the excellent optical and magnetic properties of the rare earth ion doped up-conversion nanomaterials. The rare earth doped up-conversion luminescent nano material can convert low-frequency photons into high-frequency photons, and near infrared light positioned in a light transmission window of a biological tissue can be converted into visible light or high-frequency near infrared light by regulating sensitizer ions and luminescence center ions in the material. The biological tissue has very weak light absorption in the wave band, so that the generation of autofluorescence can be avoided, and a higher signal-to-noise ratio of a fluorescence signal is obtained. Wherein, Gd-doped NaYF4Nanoparticles, and Yb3+And Er3+、Tm3+Or Ho3+Co-doped NaGdF4The nano-particles have more excellent T due to the existence of Gd1Magnetic resonance imaging performance can be realized simultaneouslyFluorescence imaging is converted to magnetic resonance imaging. NaYF4Rare earth based up-conversion nanoparticles and NaGdF4There are several methods for synthesizing rare earth-based up-conversion nanoparticles, which can be selected according to different needs. At present, the preparation method of rare earth up-conversion nanoparticles mainly comprises a hydrothermal method, a solvothermal method and a thermal decomposition method. However, the hydrothermal method is difficult to control the particle size and the dispersibility of the nanoparticles, the rare earth upconversion nanoparticles prepared by the solvothermal method and the thermal decomposition method have hydrophobicity, the further biological application needs to convert the hydrophobic material into the hydrophilic material, the experimental process is relatively complex and tedious, the efficiency is low, and the practical application is not facilitated. Furthermore, the upconversion nanoparticles need to have not only water solubility but also good biocompatibility in biological applications.
At present, no preparation method of rare earth upconversion nanoparticles in the prior art can realize simple steps and high yield, and the prepared rare earth upconversion nanoparticles have excellent water solubility and biocompatibility.
Therefore, it is an urgent problem to be solved by those skilled in the art to provide a simple method for preparing water-soluble biocompatible upconversion nanoparticles.
Disclosure of Invention
In view of the above, the invention provides a preparation method and application of water-soluble rare earth up-conversion nanoparticles, the method has simple steps, and the surface of the nanoparticles is modified in a biocompatible manner while the nanoparticles are formed; and the prepared rare earth up-conversion nanoparticles have excellent water solubility and biocompatibility, and can be applied to magnetic resonance imaging.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of water-soluble rare earth up-conversion nanoparticles is characterized by comprising the following steps:
a. respectively weighing a rare earth element precursor, biocompatible molecules and sodium fluoride, and measuring a high-boiling-point solvent for later use;
b. adding the raw materials into a reaction container, introducing inert gas for protection, heating the reaction container to 100-; continuously heating to boil under stirring and keeping for 0.1-24 h;
c. and after the reaction system is cooled to 15-25 ℃, adding a solvent for washing, centrifuging and drying to obtain the water-soluble biocompatible upconversion nanoparticles.
The beneficial effects of the preferred technical scheme are as follows: the method disclosed by the invention has a simple preparation process, and the surface of the nano-particles is subjected to biocompatible modification while the nano-particles are formed, so that the operation steps are simplified, and the production cost can be reduced; and the rare earth up-conversion nanoparticles with excellent water solubility and biocompatibility are prepared, and the effect of optical/magnetic resonance dual-mode imaging is achieved.
Preferably, the method further comprises a step d, specifically:
dissolving the water-soluble biocompatible upconversion nanoparticles obtained in the step c in deionized water, and purifying by dialysis or centrifugal ultrafiltration to obtain a water-soluble biocompatible upconversion nanoparticle solution; and then precipitating, washing and drying the water-soluble biocompatible upconversion nanoparticle solution to obtain the water-soluble biocompatible upconversion nanoparticle dry powder.
Preferably, the rare earth element precursor in step a includes a mixture of one or more of gadolinium precursor, ytterbium precursor, erbium precursor, thulium precursor, holmium precursor, or yttrium precursor.
The beneficial effects of the preferred technical scheme are as follows: according to the invention, a gadolinium precursor, an ytterbium precursor, an erbium precursor, a thulium precursor, a holmium precursor or a yttrium precursor is used as a rare earth element precursor to prepare the water-soluble rare earth upconversion nanoparticles containing rare earth elements such as gadolinium, ytterbium, erbium, thulium, holmium or yttrium, and upconversion luminescence can be realized; wherein NaYF4And NaGdF4The material is a matrix material with highest upconversion luminous efficiency at present; in addition, the mixture of ytterbium precursor and erbium precursor is used as the rare earth element precursor to obtain ytterbium-erbium double-doped water-soluble rare earth upconversion nanoparticles, and ytterbium is used as a sensitizer and erbium is used as a sensitizerThe up-conversion effect can be improved by the activator; the mixture of ytterbium precursor and thulium precursor is used as rare earth element precursor, so that ytterbium and thulium double-doped water-soluble rare earth upconversion nanoparticles can be obtained, and ytterbium is used as sensitizer and thulium is used as activator, so that upconversion effect can be improved; the mixture of ytterbium precursor and holmium precursor is used as rare earth element precursor to obtain ytterbium-holmium double-doped water-soluble rare earth up-conversion nanoparticles, ytterbium is used as sensitizer, holmium is used as activator, and up-conversion effect can be improved.
Preferably, the rare earth element precursor in step a comprises rare earth oleate, rare earth nitrate or rare earth hydrochloride.
Preferably, the biocompatible molecule in the step a is polyethylene glycol or a polyethylene glycol derivative, and the number average molecular weight of the biocompatible molecule is 300-50000.
The beneficial effects of the preferred technical scheme are as follows: the polyethylene glycol (PEG) and the derivatives thereof adopted by the invention are water-soluble high molecular materials, have very low interfacial free energy in water, and have good molecular chain flexibility and high mobility, so the polyethylene glycol (PEG) and the derivatives thereof have good biocompatibility; in addition, because polyethylene glycol has smaller surface energy and is easily wetted by an aqueous medium, the adhesion amount of platelets on the surface of the hydrophilic material containing the PEG structure is less, and thus the polyethylene glycol and the derivatives thereof can help nanoparticles to avoid the identification and removal of reticuloendothelial tissues. The invention occasionally discovers that polyethylene glycol and derivatives thereof can form a layer of film on the surface of the nano-particles while the nano-particles are formed, so that mutual aggregation among the particles is prevented, and the obtained nano-particles have good dispersibility, water solubility and biocompatibility. Meanwhile, the surface of the nano particles is coated with biocompatible molecules with the number average molecular weight of 300-50000, so that the nano particles can be endowed with water solubility, colloidal stability and biocompatibility.
Preferably, the high boiling point solvent in step a comprises phenyl ether, benzyl ether or octadecene.
Preferably, the molar ratio of the rare earth element precursor, the biocompatible molecule and the sodium fluoride in step a is 1: 0.5-20: 2 to 16; then, according to the molar volume ratio of the rare earth element precursor to the high-boiling-point solvent of 1 mmol: 5-40mL of high boiling point solvent was added.
Preferably, the rare earth oleate used in step a is prepared by a chemical reaction, and specifically comprises the following steps:
firstly, respectively weighing sodium oleate and rare earth salt, and then respectively weighing deionized water, ethanol and n-hexane for later use;
uniformly mixing the raw materials for chemical reaction;
after the chemical reaction is finished, separating and purifying the reaction product to obtain rare earth oleate;
preferably, the rare earth salt in the step (i) comprises rare earth nitrate or rare earth hydrochloride.
Preferably, the stoichiometric ratio of the sodium oleate, the rare earth salt, the deionized water, the ethanol and the n-ethane in the step (i) is 1 mmol: 2-6 mmol: 2-20 mL: 2-20 mL: 2-40 mL.
Preferably, the reaction temperature in the step (II) is 15-35 ℃, and the reaction time is 6-24 h.
Preferably, the stirring speed in the step b is 400-1000 r/min.
Preferably, the solvent used in step c comprises a mixture of one or more of ethanol, diethyl ether, acetone, petroleum ether, ethyl acetate or hexane.
The beneficial effects of the preferred technical scheme are as follows: the inventors have discovered that the water-soluble nanoparticles prepared by the present invention are not dissolved in solvents such as ethyl ether, acetone, petroleum ether, ethyl acetate, hexane, etc., and thus the present invention can remove the high-boiling solvent by washing the reaction product with the above solvents to dissolve only the high-boiling solvent in the above solvents, thereby achieving the purpose of purifying the water-soluble nanoparticles.
Preferably, the particle size of the water-soluble rare earth upconversion nanoparticles prepared in step c is 2-100 nm.
The application of the water-soluble rare earth up-conversion nanoparticles prepared by the preparation method in magnetic resonance imaging and fluorescence imaging.
The beneficial effects of the preferred technical scheme are as follows: the water-soluble rare earth up-conversion nanoparticles prepared by the method can be applied to magnetic resonance imaging as a contrast agent and fluorescence imaging, and have excellent use effect.
According to the technical scheme, compared with the prior art, the invention discloses the preparation method of the water-soluble rare earth up-conversion nanoparticles, the surface of the nanoparticles is modified in a biocompatible manner while the nanoparticles are formed, the operation steps are simplified, the production efficiency can be accelerated, and the production cost can be reduced; the prepared rare earth up-conversion nanoparticles have excellent water solubility and biocompatibility, and can be applied to magnetic resonance imaging as a contrast agent and fluorescence imaging.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
FIG. 1 accompanying drawing is a 25nm water-soluble biocompatible upconversion nanoparticle NaGdF prepared in example 14:Yb3 +,Er3+(20/2 mol%), 15nm water-soluble biocompatible upconversion nanoparticles NaGdF prepared in example 24:Yb3 +,Er3+(30/1.5 mol%) and 9nm water-soluble biocompatible upconversion nanoparticles NaGdF prepared in example 34:Yb3+,Er3+(30/1 mol%) XRD pattern;
FIG. 2 accompanying drawing shows 25nm water-soluble biocompatible upconversion nanoparticles NaGdF prepared in example 14:Yb3 +,Er3+(20/2 mol%) TEM image and HR-TEM image;
FIG. 3 is the 25nm water-soluble biocompatible upconversion nanoparticle NaGdF prepared in example 14:Yb3 +,Er3+(20/2 mol%) stability analysis in salt solutions of different concentrations;
FIG. 4 accompanying drawing shows 25nm water-soluble biocompatible upconversion nanoparticles NaGdF prepared in example 14:Yb3 +,Er3+(20/2 mol%) of T1Weighting the imaging map;
FIG. 5 accompanying drawing shows the 15nm water-soluble biocompatible upconversion nanoparticle NaGdF prepared in example 24:Yb3 +,Er3+(30/1.5 mol%) TEM image and HR-TEM image;
FIG. 6 is a drawing of 15nm water-soluble biocompatible upconversion nanoparticle NaGdF prepared in example 24:Yb3 +,Er3+(30/1.5 mol%) cytotoxicity assay;
FIG. 7 accompanying drawing shows 9nm water-soluble biocompatible upconversion nanoparticles NaGdF prepared in example 34:Yb3 +,Er3+(30/1 mol%) TEM image;
FIG. 8 accompanying drawing is a 25nm water soluble biocompatible upconversion nanoparticle NaGdF4:Yb3+,Er3+(20/2 mol%), 15nm water-soluble biocompatible up-conversion nano-particle NaGdF4:Yb3+,Er3+(30/1.5 mol%) and 9nm water-soluble biocompatible upconversion nanoparticles NaGdF4:Yb3+,Er3+(30/1 mol%) of fluorescence spectrum;
FIG. 9 is the 30nm water-soluble biocompatible upconversion nanoparticle NaGdF prepared in example 44:Yb3 +,Tm3+(20/5 mol%) XRD pattern;
FIG. 10 shows the 30nm water-soluble biocompatible upconversion nanoparticle NaGdF prepared in example 44:Yb3+,Tm3+(20/5 mol%) TEM image;
FIG. 11 is the 30nm water-soluble biocompatible upconversion nanoparticle NaGdF prepared in example 44:Yb3+,Tm3+(20/5 mol%) of fluorescence spectrum;
FIG. 12 is a drawing showing the results obtained in example 525nm water-soluble biocompatible upconversion nanoparticles NaGdF4:Yb3+,Ho3+(20/2 mol%) XRD pattern;
FIG. 13 shows 25nm water-soluble biocompatible upconversion nanoparticles NaGdF prepared in example 54:Yb3+,Ho3+(20/2 mol%) TEM image;
FIG. 14 shows 25nm water-soluble biocompatible upconversion nanoparticles NaGdF prepared in example 54:Yb3+,Ho3+(20/2 mol%) of an infrared spectrum;
FIG. 15 shows 25nm water-soluble biocompatible upconversion nanoparticles NaGdF prepared in example 54:Yb3+,Ho3+(20/2 mol%) stability analysis.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The embodiment of the invention discloses a preparation method of water-soluble rare earth up-conversion nanoparticles, which specifically comprises the following steps:
a. respectively weighing a rare earth element precursor, biocompatible molecules and sodium fluoride, and measuring a high-boiling-point solvent for later use;
b. adding the raw materials into a reaction container, introducing inert gas for protection, heating the reaction container to 100-; then removing water in the reaction system; continuously heating to reflux under stirring, and continuously refluxing for 0.1-24 h;
c. after the reaction system is cooled to 15-25 ℃, adding a solvent for washing, centrifuging and drying to obtain the water-soluble biocompatible up-conversion nanoparticles;
d. dissolving the water-soluble biocompatible upconversion nanoparticles obtained in the step c in deionized water, and purifying by dialysis or centrifugal ultrafiltration to obtain a water-soluble biocompatible upconversion nanoparticle solution; and then precipitating, washing and drying the water-soluble biocompatible upconversion nanoparticle solution to obtain the water-soluble biocompatible upconversion nanoparticle dry powder.
In order to further optimize the technical scheme, the rare earth element precursor comprises one or more of a gadolinium precursor, an ytterbium precursor, an erbium precursor, a thulium precursor, a holmium precursor or a yttrium precursor.
In order to further optimize the technical scheme, the rare earth element precursor comprises rare earth oleate, rare earth nitrate or rare earth hydrochloride.
In order to further optimize the technical scheme, the biocompatible molecules are polyethylene glycol or polyethylene glycol derivatives, and the number average molecular weight of the biocompatible molecules is 300-50000.
In order to further optimize the technical scheme, the high boiling point solvent comprises phenyl ether, benzyl ether or octadecene.
In order to further optimize the technical scheme, the stoichiometric ratio of the rare earth element precursor, the biocompatible molecule and the sodium fluoride is 1: 0.5-20: 2-16, and then, according to the molar volume ratio of the rare earth element precursor to the high-boiling-point solvent of 1 mmol: 5-40mL of high boiling point solvent was added.
In order to further optimize the technical scheme, the rare earth oleate used in the step a is prepared by chemical reaction, and the method specifically comprises the following steps:
firstly, respectively weighing sodium oleate and rare earth salt, and then respectively weighing deionized water, ethanol and n-hexane for later use;
uniformly mixing the raw materials for chemical reaction;
after the chemical reaction is finished, separating and purifying the reaction product to obtain rare earth oleate;
in order to further optimize the technical scheme, the rare earth salt in the step (i) comprises rare earth nitrate or rare earth hydrochloride.
In order to further optimize the technical scheme, the stoichiometric ratio of sodium oleate, rare earth salt, deionized water, ethanol and n-ethane in the step I is 1 mmol: 2-6 mmol: 2-20 mL: 2-20 mL: 2-40 mL.
In order to further optimize the technical scheme, the reaction temperature in the step II is 15-35 ℃, and the reaction time is 6-24 h.
For further optimization of the technical scheme, the rotation speed of stirring in the step b is 400-2000 rpm.
In order to further optimize the technical scheme, the solvent used in the step c comprises one or more of ethanol, diethyl ether, acetone, petroleum ether, ethyl acetate or hexane.
In order to further optimize the technical scheme, the particle size of the water-soluble rare earth up-conversion nanoparticles prepared in the step c is 2-100 nm.
Example 1
A preparation method of water-soluble rare earth up-conversion nanoparticles specifically comprises the following steps:
a. 19.26g (0.78mmol) gadolinium oleate, 2.98g (0.2mmol) ytterbium oleate and 0.03g (0.02mmol) erbium oleate are weighed into a 50mL dry three-necked flask, 20mL octadecene is added into the flask, and then 0.34g (4mmol) NaF and 12g (20mmol) polyethylene glycol dicarboxylic acid (M)n600), standby;
b. introducing nitrogen into the three-neck flask for protection, heating to 100 ℃ while stirring, and keeping the temperature at 100 ℃ for 1 h; then, continuously heating to 310 ℃ under the stirring condition, starting refluxing, and reacting for 1h under the refluxing condition;
c. after the reaction system is cooled to 15-25 ℃, adding a mixed solvent of 10mL of hexane, 30mL of acetone and 3mL of diethyl ether for washing and centrifugal separation, repeating the washing and the centrifugal separation for three times, and drying to obtain 25nm water-soluble biocompatible upconversion nanoparticle NaGdF4:Yb3+,Er3+(20/2mol％)。
Example 2
A preparation method of water-soluble rare earth up-conversion nanoparticles specifically comprises the following steps:
a. 16.92g (0.685mmol) gadolinium oleate, 4.47g (0.3mmol) ytterbium oleate and 0.02g (0.015mmol) oil are weighed out respectivelyErbium acid was added to a 50mL dry three-necked flask, then 10mL benzyl ether was added to the flask, followed by the addition of 0.085g (2mmol) NaF and 2.4g (4mmol) polyethylene glycol dicarboxylic acid (M)n600), standby;
b. introducing nitrogen into the three-neck flask for protection, heating to 105 ℃ while stirring, and keeping the temperature at 105 ℃ for 0.5 h; then, continuously heating to 298 ℃ under the stirring condition, starting refluxing, and reacting for 1h under the refluxing condition;
c. after the reaction system is cooled to 15-25 ℃, 10mL ethyl acetate is added for washing and centrifugal separation, the washing and the centrifugal separation are repeated for three times, and then the 15nm water-soluble biocompatible upconversion nanoparticle NaGdF can be obtained after drying4:Yb3+,Er3+(30/1.5mol％)。
Example 3
A preparation method of water-soluble rare earth up-conversion nanoparticles specifically comprises the following steps:
a. 17.04g (0.69mmol) gadolinium oleate, 4.47g (0.3mmol) ytterbium oleate and 0.01g (0.01mmol) erbium oleate are weighed into a 50mL dry three-neck flask, 35mL phenyl ether is added into the flask, 1.36g (16mmol) NaF and 1.2g (2mmol) single-end carboxylated polyethylene glycol (M)n600), standby;
b. introducing nitrogen into the three-neck flask for protection, heating to 130 ℃ while stirring, and keeping the temperature at 130 ℃ for 0.5 h; then, continuously heating to 260 ℃ under the stirring condition, starting refluxing, and reacting for 0.5h under the refluxing condition;
c. after the reaction system is cooled to 15-25 ℃, adding 10mL petroleum ether for washing and centrifugal separation, repeating the washing and centrifugal separation for three times, and drying to obtain 9nm water-soluble biocompatible upconversion nanoparticle NaGdF4:Yb3+,Er3+(30/1mol％)。
Example 4
A preparation method of water-soluble rare earth up-conversion nanoparticles specifically comprises the following steps:
a. 18.52g (0.75mmol) gadolinium oleate, 2.98g (0.2mmol) ytterbium oleate and 0.0 mmol ytterbium oleate are weighed respectively6g (0.05mmol) of thulium oleate is added to a 50mL dry three-necked flask, then 20mL of octadecene is added to the flask, and then 0.34g (4mmol) of NaF and 9.2g (2mmol) of polyethylene glycol dicarboxylic acid (M) are added sequentiallyn4600), for standby;
b. introducing nitrogen into a three-neck flask for protection, heating to 135 ℃ while stirring, and keeping the temperature at 135 ℃ for 1 h; then, continuously heating to 310 ℃ under the stirring condition, starting refluxing, and reacting for 10 hours under the refluxing condition;
c. after the reaction system is cooled to 15-25 ℃, adding a mixed solvent consisting of 10mL of ethanol, 30mL of acetone and 3mL of diethyl ether for washing and centrifugal separation, repeating the washing and the centrifugal separation for three times, and drying to obtain the 30nm water-soluble biocompatible upconversion nanoparticle NaGdF4:Yb3+,Tm3+(20/5mol％)。
Example 5
A preparation method of water-soluble rare earth up-conversion nanoparticles specifically comprises the following steps:
a. 18.52g (0.75mmol) gadolinium oleate, 2.98g (0.2mmol) ytterbium oleate and 0.06g (0.05mmol) holmium oleate are weighed into a 50mL dry three-neck flask, then 20mL octadecene is added into the flask, and then 0.34g (4mmol) NaF and 6g (10mmol) polyethylene glycol (M) are added in turnn600), standby;
b. introducing nitrogen into the three-neck flask for protection, heating to 100 ℃ while stirring, and keeping the temperature at 100 ℃ for 1 h; then, continuously heating to 310 ℃ under the stirring condition, starting refluxing, and reacting for 1h under the refluxing condition;
c. after the reaction system is cooled to 15-25 ℃, adding a mixed solvent of 10mL of hexane, 30mL of acetone and 3mL of diethyl ether for washing and centrifugal separation, repeating the washing and the centrifugal separation for three times, and drying to obtain 25nm water-soluble biocompatible upconversion nanoparticle NaGdF4:Yb3+,Ho3+(20/2mol％)。
Example 6
The gadolinium oleate precursor in the embodiments 1-5 is prepared by the following method, which specifically comprises the following steps:
weighing 1mmol gadolinium nitrate hexahydrate (Gd (NO)3)3·6H2O) and 3mmol of sodium oleate (C)17H33COONa), then respectively measuring 3mL of deionized water, 4mL of anhydrous ethanol and 7mL of normal hexane for later use;
adjusting, and continuously stirring at room temperature. Uniformly mixing the raw materials under magnetic stirring at 600rpm, and continuously reacting for 12h at room temperature under the stirring condition;
③ after the completion of the chemical reaction, the aqueous layer was removed by using a separatory funnel, and the organic layer was washed three times with 10mL of a mixture of distilled water and ethanol (V/V ═ 1:1), and the solvent was removed to obtain a gadolinium oleate precursor.
The upconverting nanoparticles prepared in examples 1-5 above were characterized.
1. 25nm water-soluble biocompatible upconversion nanoparticles NaGdF prepared in example 14:Yb3+,Er3+(20/2 mol%), 15nm water-soluble biocompatible upconversion nanoparticles NaGdF prepared in example 24:Yb3+,Er3+(30/1.5 mol%) and 9nm water-soluble biocompatible upconversion nanoparticles NaGdF prepared in example 34:Yb3 +,Er3+(30/1 mol%) was subjected to X-ray diffraction, and the results are shown in FIG. 1.
The results in FIG. 1 show that: XRD patterns and NaGdF of the products prepared in example 1, example 2 and example 34Standard card (JCPDS No.27-0699) one-to-one correspondence, and peak intensity and the ratio between the peak intensities are also generally consistent with the standard card, which shows that the matrix material NaGdF4The crystal is successfully synthesized, has good crystal growth and is a hexagonal crystal form, and shows that the Yb and Er doping has no obvious influence on the main body structure. In addition, the position of the diffraction peak is shifted to a large angle integrally compared with the position of the peak on the standard card, and the Yb and Er ions have smaller radius than the Gd ions, so that the successful doping of the Yb and the Er into NaGdF is further shown according to the Bragg formula4In a matrix.
2. The 25nm water-soluble biocompatible upconversion nanoparticle NaGdF prepared in example 1 is used4:Yb3+,Er3+(20/2 mol%) in transmissionThe photographs were taken under an electron microscope (TEM) and a high-resolution transmission electron microscope (HR-TEM), and the results are shown in FIG. 2.
Figure 2 results show that: the average particle size of the nano particles is 25nm, and the nano particles do not have obvious agglomeration phenomenon, which shows that the nano particles have good dispersibility in water. The (101) plane with a lattice spacing of 0.297nm in the HR-TEM image shows NaGdF4: Yb3+,Er3+(20/2 mol%) the crystalline state of the nanoparticles was good.
3. The 25nm water-soluble biocompatible upconversion nanoparticle NaGdF prepared in example 1 is used4:Yb3+,Er3+(20/2 mol%) were placed in NaCl salt solutions of various concentrations ranging from 0.08 to 2.5mmol/L and their hydrated diameters were measured, the results are shown in FIG. 3.
Figure 3 the results show: the hydration diameter of the nano-particles has not changed obviously, which shows that the nano-particles have no obvious agglomeration behavior in 0.08-2.5mmol/L NaCl solution and have good colloidal stability.
4. The 25nm water-soluble biocompatible upconversion nanoparticle NaGdF prepared in example 1 is used4:Yb3+,Er3+(20/2 mol%) for T1The imaging was weighted and the results are shown in figure 4.
Figure 4 results show that: t as the concentration of nanoparticles increases1The weighted imaging gradually brightens, the pseudo-color image gradually turns red, the in vitro imaging change rule is obvious, and the r of the nano particles1A value of 4.6956mM-1s-1And is larger than the clinical contrast agent Magnevist.
5. The 15nm water-soluble biocompatible upconversion nanoparticle NaGdF prepared in example 2 is used4:Yb3+,Er3+(30/1.5 mol%) photographs were taken under a Transmission Electron Microscope (TEM) and a high-resolution transmission electron microscope (HR-TEM), and the results are shown in FIG. 5.
FIG. 5 shows the results: the nano particles have no obvious agglomeration phenomenon, the average particle size is 15nm, and the crystallization state of the nano particles is good.
6. For the 15nm water-soluble biocompatible upconversion nanoparticle NaGdF prepared in example 24:Yb3+,Er3+(30/1.5 mol%) is notCytotoxicity was measured at the same concentration, and the results are shown in FIG. 6.
The results in FIG. 6 show that: the survival rate of the HeLa cells is still kept above 90% under the condition of high concentration (100mg/L Gd), and the nano particle freeze-dried powder has no obvious cytotoxicity, so that the upconversion nano particles prepared by the method have good biocompatibility.
7. The 9nm water-soluble biocompatible upconversion nanoparticle NaGdF prepared in example 3 is used4:Yb3+,Er3+(30/1 mol%) A photograph was taken under a Transmission Electron Microscope (TEM) and the results are shown in FIG. 7.
The results in FIG. 7 show that: the nano particles have no obvious agglomeration phenomenon, the average particle size is 9nm, and the crystallization state of the nano particles is good.
8. Up-conversion nano-particle NaGdF with 25nm water-soluble biocompatibility4:Yb3+,Er3+(20/2 mol%), 15nm water-soluble biocompatible up-conversion nano-particle NaGdF4:Yb3+,Er3+(30/1.5 mol%) and 9nm water-soluble biocompatible upconversion nanoparticles NaGdF4:Yb3+,Er3+(30/1 mol%) was subjected to fluorescence spectroscopy, and the results are shown in FIG. 8.
The results in FIG. 8 show that: the strong emission peak at about 526nm is due to Er3+Is/are as follows2H11/2→4I15/2、4S3/2→4I15/2Transition, corresponding to green emission. The result shows that the Yb and Er doping ratio in the matrix can be regulated and controlled by changing the ratio of the rare earth precursor in the reactant, so that the emission wavelength and the luminous intensity of the nano-particles can be regulated.
9. 30nm water-soluble biocompatible upconversion nanoparticles NaGdF prepared in example 44:Yb3+,Tm3+(20/5 mol%) was subjected to X-ray diffraction, the results are shown in FIG. 9;
the results in FIG. 9 show that: with NaGdF4The number and distribution of peaks in the Standard card (JCPDS No.27-0699) correspond to each other, indicating that the host Material NaGdF4Good growth condition and hexagonal crystal form. In addition, the position of the diffraction peak is shifted to a large angle integrally compared with the position of the peak in the standard card, and the Yb and Tm ions have smaller radius than the Gd ions, so that the successful doping of the Yb and Tm into NaGdF is further shown according to the Bragg formula4In a matrix.
10. FIG. 10 shows the 30nm water-soluble biocompatible upconversion nanoparticle NaGdF prepared in example 44:Yb3 +,Tm3+(20/5 mol%) A photograph was taken under a Transmission Electron Microscope (TEM) and the result is shown in FIG. 10.
The results in FIG. 10 show that the nanoparticles do not significantly agglomerate, with an average particle size of 30 nm.
11. The 30nm water-soluble biocompatible upconversion nanoparticle NaGdF prepared in example 4 is used4:Yb3+,Tm3+(20/5 mol%) and detecting by fluorescence spectrum;
FIG. 11 shows that the emission peak at 474nm is stronger than the peak at 696nm, corresponding to each other1D2→3F4Transition process and1G4→3H6and (4) transition process. In addition, the sample emitted significant blue-violet light after 980nm excitation due to1D2→3F4Violet light emitted during the transition and1G4→3H6and (4) superposing blue light emitted in the transition process to generate a result.
12. 25nm water-soluble biocompatible upconversion nanoparticles NaGdF prepared in example 54:Yb3+,Ho3+(20/2 mol%) was subjected to X-ray diffraction measurement, and the results are shown in FIG. 12.
The results in FIG. 12 show that: XRD pattern and NaGdF of the product prepared in example 54The number and distribution of peaks in the Standard card (JCPDS No.27-0699) correspond to each other, indicating that the host Material NaGdF4The growth condition is good, and the crystal form is a hexagonal crystal form. Compared with the peak position in the standard card, the position of the diffraction peak shifts towards a large angle integrally because the radius of Yb and Ho ions is smaller than that of Gd ions, and further shows that the Yb and Ho are successfully doped with NaGdF according to the Bragg formula4In a matrix.
13. The 25nm water-soluble biocompatible upconversion nanoparticle NaGdF prepared in example 5 is used4:Yb3+,Ho3+(20/2 mol%) A photograph was taken under a Transmission Electron Microscope (TEM) and the result is shown in FIG. 13.
The results in FIG. 13 show that the nanoparticles do not significantly agglomerate, with an average particle size of 25 nm.
14. 25nm water-soluble biocompatible upconversion nanoparticles NaGdF prepared in example 54:Yb3+,Ho3+(20/2 mol%) was subjected to infrared spectroscopic examination, and the results are shown in FIG. 14;
the results in FIG. 14 show that: wherein the length of the groove is 3400cm-1Is a characteristic absorption peak of-OH in polyethylene glycol dicarboxylic acid, 2922cm-1And 2873cm-1At 1110cm of stretching vibration of alkyl C-H-1Is the absorption peak of C-O-C of polyethylene glycol dicarboxylic acid at 1740cm-1And 908cm-1The absorption peak is from the characteristic absorption peak of-COO-group, which shows that the surface of the nano-particle is successfully modified with polyethylene glycol and has carboxyl functional group on the surface.
15. 25nm water-soluble biocompatible upconversion nanoparticles NaGdF prepared in example 54:Yb3+,Ho3+(20/2 mol%) stability was examined, and the results are shown in FIG. 15
Figure 15 results show that: the nano particles are narrow in distribution, have no obvious agglomeration behavior and have good colloidal stability.
The embodiments in the present description are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments are referred to each other. The device disclosed by the embodiment corresponds to the method disclosed by the embodiment, so that the description is simple, and the relevant points can be referred to the method part for description.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (4)
1. A preparation method of water-soluble rare earth up-conversion nanoparticles is characterized by comprising the following steps:
a. respectively weighing a rare earth element precursor, biocompatible molecules and sodium fluoride, and measuring a high-boiling-point solvent for later use; the rare earth element precursor is rare earth oleate; the high boiling point solvent is phenyl ether, benzyl ether or octadecene;
b. adding the raw materials into a reaction container, introducing inert gas for protection, heating the reaction container to 100-; continuously heating to boil under stirring and keeping for 0.1-24 h;
c. after the reaction system is cooled to 15-25 ℃, adding a solvent, washing, centrifuging and drying to obtain the water-soluble biocompatible up-conversion nanoparticles;
the rare earth element precursor comprises one or a mixture of gadolinium precursors, ytterbium precursors, erbium precursors, thulium precursors, holmium precursors or yttrium precursors;
the biocompatible molecule is polyethylene glycol or a polyethylene glycol derivative, and the number average molecular weight of the biocompatible molecule is 600-4600;
the molar ratio of the rare earth element precursor to the biocompatible molecule to the sodium fluoride is 1: 0.5-20: 2 to 16; according to the molar volume ratio of the rare earth element precursor to the high-boiling-point solvent of 1 mmol: 5-40mL of high boiling point solvent was added.
2. The method for preparing water-soluble rare earth upconversion nanoparticles according to claim 1, further comprising a step d of:
dissolving the water-soluble biocompatible upconversion nanoparticles obtained in the step c in deionized water, and purifying by dialysis or centrifugal ultrafiltration to obtain a water-soluble biocompatible upconversion nanoparticle solution; and then precipitating, washing and drying the water-soluble biocompatible upconversion nanoparticle solution to obtain the water-soluble biocompatible upconversion nanoparticle dry powder.
3. The method as claimed in claim 1, wherein the stirring speed in step b is 400-1000 r/min.
4. The method as claimed in claim 1, wherein the solvent used in step c comprises one or more of ethanol, diethyl ether, acetone, petroleum ether, ethyl acetate, and hexane.
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