WO2021134786A1 - 生物体内可降解上转换无机纳米材料及制备方法和应用 - Google Patents

生物体内可降解上转换无机纳米材料及制备方法和应用 Download PDF

Info

Publication number
WO2021134786A1
WO2021134786A1 PCT/CN2020/070277 CN2020070277W WO2021134786A1 WO 2021134786 A1 WO2021134786 A1 WO 2021134786A1 CN 2020070277 W CN2020070277 W CN 2020070277W WO 2021134786 A1 WO2021134786 A1 WO 2021134786A1
Authority
WO
WIPO (PCT)
Prior art keywords
hafnium
zirconium
rare earth
zrf
doped
Prior art date
Application number
PCT/CN2020/070277
Other languages
English (en)
French (fr)
Inventor
洪茂椿
彭鹏飞
刘永升
付虎辉
Original Assignee
中国科学院福建物质结构研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国科学院福建物质结构研究所 filed Critical 中国科学院福建物质结构研究所
Priority to PCT/CN2020/070277 priority Critical patent/WO2021134786A1/zh
Priority to EP20910945.3A priority patent/EP4086324A4/en
Publication of WO2021134786A1 publication Critical patent/WO2021134786A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/08—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials
    • C09K11/77—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing rare earth metals
    • C09K11/7766—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing rare earth metals containing two or more rare earth metals
    • C09K11/7772—Halogenides
    • C09K11/7773—Halogenides with alkali or alkaline earth metal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0065—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle
    • A61K49/0067—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle quantum dots, fluorescent nanocrystals

Definitions

  • the invention belongs to the technical field of luminescent materials, and specifically relates to a kind of rare earth-doped zirconium/hafnium-based alkali metal fluoride upconversion nano luminescent materials that can be degraded in vivo, and a preparation method and application thereof.
  • Rare earth-doped up-conversion inorganic nanomaterials are a promising fluorescent contrast agent due to their low toxicity, good photobleaching resistance, no background fluorescence, and deep light penetration depth. And various in vivo applications such as disease diagnosis and treatment have shown excellent application prospects.
  • all existing rare earth upconversion inorganic nanomaterials represented by the most representative ⁇ -NaYF4 cannot be biodegraded in the body, and aggregate in a large amount in the organism, and cannot be removed from the organism in a harmless manner. Effective elimination in the body makes their clinical application transformation almost impossible.
  • the invention aims to provide a rare earth-doped zirconium/hafnium-based alkali metal fluoride up-conversion nano luminescent material that is degradable in vivo, and a preparation method and application thereof.
  • a biodegradable upconversion inorganic nanomaterial which is obtained from a rare earth-doped matrix material zirconium/hafnium-based alkali metal fluoride, wherein the general formula of the matrix material is M x T y F x+4y , the general formula of the nanocrystalline structure after rare earth doping is M x T y F x+4y :z%Ln, where M is one or more of Li, Na and K; T Zr and/or Hf; Ln is selected from one or more of Yb, Er, Tm, Ho, Gd, Eu, Tb, Sm, Dy, Ce and Nd; 1 ⁇ x ⁇ 7; 1 ⁇ y ⁇ 6 ; 0 ⁇ z ⁇ 50.
  • the general formula of the rare earth-doped nanocrystalline structure of the present invention is M x T y F x+4y : in z% Ln, 1 ⁇ x ⁇ 3; 1 ⁇ y ⁇ 2; 10.5 ⁇ z ⁇ 22 . Preferably, 21 ⁇ z ⁇ 22.
  • the general formula of the doped nanocrystalline structure is K 3 ZrF 7 :z%Ln.
  • the crystal structure formula is K 3 ZrF 7 :z1%Yb/z2%Er, where 5 ⁇ z1 ⁇ 30 and 0.5 ⁇ z2 ⁇ 5.
  • the structural formula of the doped nanocrystal is K x Zr y F x+4y : 20% Yb/2% Er, K x Zr y F x+4y : 20% Yb/1% Tm, K x Hf y F x+4y : 20%Yb/2%Er, K x Zr y1 Hf y2 F x+4(y1+y2) : 20%Yb/2%Er, Na x Zr y F x+4y : 20%Yb/2 %Er, Na x Hf y F x+4y : 20%Yb/2%Er, Na x Zr y1 Hf y2 F x+4(y1+y2) : 20%Yb/2%Er, Li x Zr y F x +4y : 20%Yb/2%Er; where 1 ⁇ y1+y2 ⁇ 6.
  • the rare earth doped nanocrystals are K 3 ZrF 7 : 20% Yb/2% Er, K 2 ZrF 6 : 20% Yb/2% Er, KZrF 5 : 20% Yb/2% Er, K 3 HfF 7 : 20% Yb/2% Er, K 2 HfF 6 : 20% Yb/2% Er, K 3 Zr 0.5 Hf 0.5 F 7 : 20% Yb/2% Er, Na 3 ZrF 7 : 20% Yb/2% Er, Na 2 ZrF 6 : 20% Yb/2% Er, Na 5 Zr 2 F 13 : 20% Yb/2% Er, Na 7 Zr 6 F 31 : 20% Yb/2% Er, Na 3 HfF 7 : 20% Yb/2% Er, Na 5 Hf 2 F 13 : 20% Yb/2% Er, Na 3 Zr 0.5 Hf 0.5 F7: 20% Yb/2% Er, Li 4 ZrF 8 : 20% Yb/ 2% Er, Li
  • a method for preparing biodegradable up-conversion inorganic nanomaterials which adopts zirconium/hafnium ion salts, rare earth acetates, ammonium fluoride and alkali metal hydroxides
  • a high-temperature solvent co-precipitation method is used to obtain rare earth-doped zirconium/hafnium-based alkali metal fluoride upconversion nanomaterials.
  • the high-temperature solvent co-precipitation method includes the following steps: S1, weigh zirconium/hafnium acetylacetonate and rare earth acetate, mix, and add a solvent to obtain a solid mixture; S2, heat and keep the solid mixture to make the solid mixture Dissolve the reactants in step S2 to obtain a mixed solution; S3, add a methanol solution in which ammonium fluoride and alkali metal hydroxide are dissolved to the mixed solution obtained in step S2, and heat and keep it warm to remove methanol and water; S4, continue heating and Heat preservation, cooling to room temperature, precipitation, separation, washing, and drying to obtain the rare earth-doped zirconium/hafnium-based alkali metal fluoride upconversion nanomaterial.
  • the zirconium/hafnium ion-containing salt is selected from one or more of zirconium/hafnium acetylacetonate, zirconium/hafnium acetate, zirconium chloride/hafnium, zirconium nitrate/hafnium, zirconium oxychloride/hafnium; rare earth acetate
  • the salt ion in is selected from one or more of Yb, Er, Tm, Ho, Gd, Eu, Tb, Sm, Dy, Ce and Nd; preferably, the molar ratio of zirconium/hafnium ion to rare earth metal salt (1 ⁇ 10):1; preferably (2 ⁇ 5):1; more preferably, the rare earth acetate is a mixture of ytterbium acetate and erbium acetate, the molar ratio of the rare earth acetate and the zirconium acetylacetonate/hafnium The ratio is 1:4.
  • the solvent is a mixed solvent of oleic acid and octadecene.
  • the volume ratio of oleic acid and octadecene is 1:(0.5-3); more preferably, the volume ratio of oleic acid and octadecene is 1:2.
  • the molar ratio of the ammonium fluoride to the alkali metal hydroxide is 7:(6-12); preferably, the molar ratio of the ammonium fluoride to the potassium hydroxide is 7:6.
  • step S2 the solid mixture is heated to 120-160° C. under the protection of inert gas, and kept for 30-40 minutes. More preferably, it is heated to 140°C under an inert atmosphere to completely dissolve the above-mentioned solid and then naturally cooled to room temperature to obtain a clear solution.
  • step S3 under the protection of an inert gas, heating to 50-70°C and holding for 30 minutes to remove methanol, and heating to 100-110°C and holding for 10 to 20 minutes to remove water.
  • step S4 under the protection of inert gas, continue to heat to 300-310°C and keep the temperature for 40-60 minutes. More preferably, in step S4, the temperature is increased to 305° C. under an inert atmosphere, and the temperature is kept for 40 minutes and then naturally cooled to room temperature.
  • the separation is centrifugal separation.
  • biodegradable up-conversion inorganic nanomaterials in the field of biotechnology. It is preferably used for safe biodegradable fluorescent labels.
  • biodegradable up-conversion inorganic nanomaterials in the pH-dependent water degradation is preferably used for the specific labeling of weakly acidic tumor tissues.
  • the present invention uses an inorganic zirconium/hafnium-based alkali metal fluoride system as a matrix material, and uses a solvothermal synthesis method to incorporate up-conversion rare earth ions into its crystal lattice, that is, a high-temperature co-precipitation method is used to prepare a type of biological Up-conversion inorganic nano-luminescent materials that can be effectively degraded and removed in the body have the following advantages:
  • the conditions of the synthesis method are easy to control, and the repeatability is good.
  • the prepared nanocrystalline material has good dispersibility, uniformity and repeatability, and the rare earth ion doping realizes up-conversion luminescence under near-infrared light excitation.
  • Nanocrystalline materials can be decomposed into water-soluble zirconium fluoride/hafnium ions ([T y F x+4y ] x- , T is Zr or Hf), providing a unique pH-dependent water degradation ability, and can also While decomposing in the water environment, it can provide up-conversion luminescence, benefiting from the hydrolysis characteristics of the matrix material in the special water environment, it can be hydrolyzed and removed quickly in the organism, which provides the possibility of application in the organism.
  • the nanocrystalline material prepared by the present invention will be inhibited to a certain extent from decomposition under the weak acidity (pH 5-6) in the tumor environment. Benefit from the material's ability to delay hydrolysis in the weakly acidic environment. The existence time in the tumor environment is longer than other in vivo environments, and can be applied to specific fluorescent labeling of weakly acidic tumors.
  • the nanocrystalline material prepared by the present invention benefits from its lower cytotoxicity and biological toxicity, exhibits good biological safety, can be used safely in the body, and is not easy to aggregate in large amounts in the body. Therefore, it can be used as an up-conversion fluorescent labeling material in organisms, and has potential application prospects in the fields of biological imaging and fluorescent labeling.
  • Fig. 1 is an X-ray powder diffraction pattern of K 3 ZrF 7 :20%Yb/2%Er upconversion nanocrystals in Example 1 of the present invention.
  • Figure 2a is a transmission electron microscope image of K 3 ZrF 7 :20%Yb/2%Er up-conversion nanocrystals with different resolutions in Example 1 of the present invention
  • Figure 2b is a statistical diagram of the particle size of K 3 ZrF 7 :20%Yb/2%Er up-conversion nanocrystalline nanoparticles in Example 1 of the present invention.
  • Fig. 3 is an up-conversion emission spectrum diagram of K 3 ZrF 7 :20%Yb/2%Er up-conversion nanocrystals excited by a low-power density 980nm continuous semiconductor laser in Example 1 of the present invention.
  • Fig. 4 is an X-ray powder diffraction pattern of K 3 HfF 7 :20%Yb/2%Er upconversion nanocrystals in Example 2 of the present invention.
  • Fig. 5a is a transmission electron microscope image of K 3 HfF 7 :20%Yb/2%Er up-conversion nanocrystals with different resolutions in Example 2 of the present invention
  • Fig. 5b is a statistical diagram of the particle size of K 3 HfF 7 :20%Yb/2%Er up-conversion nanocrystalline nanoparticles in Example 2 of the present invention.
  • Fig. 6 is an upconversion emission spectrum diagram of K 3 HfF 7 :20%Yb/2%Er upconversion nanocrystals excited by a low-power density 980nm continuous semiconductor laser in embodiment 2 of the present invention.
  • Figure 7 is a graph showing the change of up-conversion luminescence intensity with time under the excitation of 980nm laser after adding the cyclohexane solution of K 3 ZrF 7 :20%Yb/2%Er upconversion nanocrystals to deionized water in Example 1 of the present invention And the corresponding luminous photos.
  • Figure 8 is the K 3 ZrF 7 :20%Yb/2%Er upconversion nanocrystal powder in Example 1 of the present invention after adding deionized water, the upconversion luminescence intensity under 980nm laser excitation changes with time and the corresponding curve Glowing photos.
  • Figure 9 is the K 3 ZrF 7 :20%Yb/2%Er upconversion nanocrystal powder in Example 1 of the present invention after adding strong acid and strong base, the upconversion luminous intensity under 980nm laser excitation changes with time and the corresponding curve Glowing photo.
  • Figure 10 is the K 3 ZrF 7 :20%Yb/2%Er upconversion nanocrystal powder in Example 1 of the present invention after adding a weak alkaline aqueous solution, the upconversion luminescence intensity under 980nm laser excitation changes with time and the corresponding curve Glowing photo.
  • Fig. 11 is a graph showing the change curve of the up-conversion luminescence intensity of K 3 ZrF 7 : 20% Yb/2% Er up-conversion nanocrystals in Example 1 of the present invention after adding a weakly acidic aqueous solution under 980nm laser excitation and the corresponding Glowing photos.
  • Figure 12 is the CCD imaging system used in the test of the present invention.
  • Fig. 13 is a schematic diagram showing the effect of subcutaneous imaging of K 3 ZrF 7 :20%Yb/2%Er upconversion nanocrystals in nude mice in Example 1 of the present invention.
  • Fig. 14 is a graph showing the cytotoxicity results of K 3 ZrF 7 :20%Yb/2%Er upconversion nanocrystals in Example 1 of the present invention.
  • Fig. 15 is a graph showing the weight change of mice in the acute toxicity test of K 3 ZrF 7 :20% Yb/2% Er upconversion nanocrystals in Example 1 of the present invention.
  • Fig. 16 is a tissue section of main organs of mice after acute toxicity test of K 3 ZrF 7 :20%Yb/2%Er upconversion nanocrystals in Example 1 of the present invention.
  • Fig. 17 is a sectional view of muscle tissue after a muscle irritation test of K 3 ZrF 7 :20%Yb/2%Er upconversion nanocrystals in Example 1 of the present invention.
  • Figure 18 is a diagram showing the distribution of elements in various organs within a short period of time after the K 3 ZrF 7 :20%Yb/2%Er upconversion nanocrystals are injected into the mouse body through the tail vein in Example 1 of the present invention.
  • Fig. 19 is a schematic diagram of the conversion principle of K 3 ZrF 7 :20%Yb/2%Er nanocrystals in Example 1 of the present invention.
  • a biodegradable up-conversion inorganic nanomaterial obtained from a rare earth-doped matrix material zirconium/hafnium-based alkali metal fluoride.
  • the general formula of the matrix material is M x T y F x+4y
  • the general formula of the nanocrystalline structure after rare earth doping is M x T y F x+4y :z% Ln, where M is one or more of Li, Na and K; T is Zr and/or Hf; Ln One or more selected from Yb, Er, Tm, Ho, Gd, Eu, Tb, Sm, Dy, Ce and Nd, 1 ⁇ x ⁇ 7; 1 ⁇ y ⁇ 6; 0 ⁇ z ⁇ 50.
  • the present invention adopts rare earth doped zirconium/hafnium-based alkali metal fluoride, the fluorozirconium/hafnium ion in the matrix material provides a unique pH-dependent water degradation ability, and the rare earth ion doping realizes the uptake under near-infrared light excitation.
  • the converted luminescence can be better applied to the detection in the body.
  • the rare earth-doped zirconium/hafnium-based alkali metal fluoride nano material powder prepared by the present invention is immersed in a water environment, and can be hydrolyzed quickly without other conditions. After the hydrolysis occurs, the steam-dried product of the supernatant is still the original Matrix material.
  • the nano material can also be dispersed in solvents such as cyclohexane, olive oil and peanut oil, can diffuse into the external water environment and undergo hydrolysis, and the hydrolyzed product does not emit light.
  • the rare-earth-doped zirconium/hafnium-based alkali metal fluoride nanomaterials hydrolyze faster in a strong acid and alkali environment, while the decomposition in a weak acid (pH 5-6) environment will be inhibited to a certain extent. So the rate of hydrolysis slows down. Utilizing its slow hydrolysis in acidic environment, it can be used for in vivo fluorescent labeling of weakly acidic tumor environment.
  • the host material is K 3 ZrF 7
  • the nanocrystalline structure after rare earth doping The general formula is K 3 ZrF 7 : z% Ln.
  • the matrix material is K 3 ZrF 7
  • the structural formula of the rare-earth-doped nanocrystalline material is K 3 ZrF 7 : z1%Yb/z2%Er, where 5 ⁇ z1 ⁇ 30, 0.5 ⁇ z2 ⁇ 5.
  • the structural formula of the nanocrystalline doped with rare earth is K x Zr y F x+4y : 20% Yb/2% Er, K x Zr y F x+4y : 20% Yb/1 %Tm, K x Hf y F x+4y : 20%Yb/2%Er, K x Zr y1 Hf y2 F x+4(y1+y2) : 20%Yb/2%Er, Na x Zr y F x +4y : 20%Yb/2%Er, Na x Hf y F x+4y : 20%Yb/2%Er, Na x Zr y1 Hf y2 F x+4(y1+y2) : 20%Yb/2% Er, Li x Zr y F x+4y : 20% Yb/2% Er, where 1 ⁇ y1+y2 ⁇ 6.
  • the nanocrystalline structural formula may be K 3 ZrF 7 : 20% Yb/2% Er, K 2 ZrF 6 : 20% Yb/2% Er, KZrF 5 : 20% Yb/2% Er, K 3 HfF 7 : 20%Yb/2%Er, K 2 HfF 6 : 20%Yb/2%Er, K 3 Zr 0.5 Hf 0.5 F 7 : 20%Yb/2%Er, Na 3 ZrF 7 : 20%Yb/2%Er , Na 2 ZrF 6 : 20% Yb/2% Er, Na 5 Zr 2 F 13 : 20% Yb/2% Er, Na 7 Zr 6 F 31 : 20% Yb/2% Er, Na 3 HfF 7 : 20 %Yb/2%Er, Na 5 Hf 2 F 13 : 20% Yb/2% Er, Na 3 Zr 0.5 Hf 0.5 F 7 : 20% Yb/2% Er, Li 4 ZrF 8 : 20% Yb/2% Er, Li 2 ZrF 6 : 20% Y
  • a method for preparing biodegradable up-conversion inorganic nanomaterials which adopts zirconium/hafnium ion salts, rare earth acetates, ammonium fluoride and alkali metal hydroxides
  • a high-temperature solvent co-precipitation method is used to obtain rare earth-doped zirconium/hafnium-based alkali metal fluoride upconversion nanomaterials.
  • the high-temperature solvent co-precipitation method includes the following steps: S1, weigh zirconium/hafnium acetylacetonate and rare earth acetate, mix, and add a solvent to obtain a solid mixture; S2, heat and keep the solid mixture to make the solid mixture Dissolve the reactants in step S2 to obtain a mixed solution; S3, add a methanol solution in which ammonium fluoride and alkali metal hydroxide are dissolved to the mixed solution obtained in step S2, and heat and keep it warm to remove methanol and water; S4, continue heating and Heat preservation, cooling to room temperature, precipitation, separation, washing, and drying to obtain rare earth-doped zirconium/hafnium-based alkali metal fluoride upconversion nanomaterials.
  • the zirconium/hafnium ion salt is selected from one or more of zirconium/hafnium acetylacetonate, zirconium/hafnium acetate, zirconium chloride/hafnium, zirconium nitrate/hafnium, and zirconium oxychloride/hafnium.
  • the above-mentioned zirconium/hafnium ion-containing salt is preferred, but it is not limited to this, and only water-soluble zirconium/hafnium ion can be formed.
  • the salt ion in the rare earth acetate is selected from ytterbium (Yb), erbium (Er), thulium (Tm), holmium (Ho), gadolinium (Gd), europium (Eu), terbium (Tb), samarium (Sm) )
  • ytterbium (Yb) and erbium (Er) are co-doped.
  • the molar ratio of zirconium/hafnium ion to rare earth metal salt is (1-10):1; preferably (2-5):1.
  • the rare earth acetate is a mixture of ytterbium acetate and erbium acetate, wherein the molar ratio of the rare earth acetate to zirconium acetylacetonate/hafnium is 1:4.
  • the solvent is a mixed solvent of oleic acid and octadecene.
  • the volume ratio of oleic acid and octadecene is 1:(0.5-3); more preferably, it is 1:2.
  • the molar ratio of ammonium fluoride to alkali metal hydroxide is 7:(6-12); preferably, the molar ratio of ammonium fluoride to potassium hydroxide is 7:6.
  • step S2 the solid mixture is heated to 120-160°C under the protection of inert gas, and kept for 30-40 minutes. By heating and keeping warm, the solid can be completely dissolved to obtain a clear solution. More preferably, it is heated to 140°C under an inert atmosphere to completely dissolve the above-mentioned solid and then naturally cooled to room temperature to obtain a clear solution.
  • step S3 under the protection of an inert gas, heating to 50-70°C and holding for 30 minutes to remove methanol, and heating to 100-110°C and holding for 10 to 20 minutes to remove water.
  • step S4 under the protection of inert gas, continue to heat to 300-310°C and keep the temperature for 40-60 minutes. More preferably, in step S4, the temperature is increased to 305° C. under an inert atmosphere, and the temperature is kept for 40 minutes and then naturally cooled to room temperature. In the present invention, centrifugal separation is preferred.
  • the invention also provides the application of a class of biodegradable rare earth-doped zirconium/hafnium-based alkali metal fluoride upconversion inorganic nano materials in the field of biotechnology; it is preferably used for safe biodegradable fluorescent labels.
  • the application of the biodegradable rare earth-doped zirconium/hafnium-based alkali metal fluoride upconversion inorganic nanomaterial in the aspect of pH-dependent water degradation is preferably used for the specific labeling of weakly acidic tumor tissues.
  • the ray diffraction pattern analysis was performed on the nanocrystals obtained in Example 1.
  • Figures 2a and 2b are TEM images and particle size statistics of nanocrystals with different resolutions in Example 1.
  • the instrument model used is TECNAI G2 F20, and the manufacturer is FEI). It can be seen from Figure 2 that the nanocrystals have good dispersibility, uniform morphology, and a particle size of about 27.5 nm.
  • a steady-state transient fluorescence spectrometer was used to analyze the nanocrystals in Example 1.
  • the instrument model used was FLS980, and the manufacturer was Edinburgh.
  • the oil-soluble nanocrystals emit red upconversion luminescence with the main peak at 656nm, which corresponds to the electric dipole transition of the Er 3+ ion 4F9/2-4I15/2.
  • the nanocrystal has good crystallinity, and its diffraction peak position and relative intensity are consistent with the PDF standard card of K3HfF7 (JCPDS No. 78-1827), which belongs to the cubic crystal system.
  • Figures 5a and 5b are TEM images and particle size statistics of nanocrystals with different resolutions in Example 2. (The instrument model used is TECNAI G2 F20, and the manufacturer is FEI). It can be seen from Figure 5 that the nanocrystalline grain size is about 28.4 nm.
  • a steady-state transient fluorescence spectrum analyzer was used to analyze the nanocrystals in Example 2.
  • the instrument model used was FLS980, and the manufacturer was Edinburgh.
  • the oil-soluble nanocrystals emit red upconversion luminescence with a main peak at 656nm, which corresponds to the electric dipole transition of the Er 3+ ion 4F9/2-4I15/2.
  • K 3 ZrF 7 The hydrolysis performance test of 20%Yb/2%Er nanocrystals.
  • a steady-state transient fluorescence spectrum analyzer was used to analyze the nanocrystals in Example 1, the instrument model was FLS980, and the manufacturer was Edinburgh.
  • the camera model is EOS 5D and the manufacturer is Canon.
  • the nanocrystals prepared in Example 1 were dissolved in cyclohexane, and an equal volume of deionized water was added.
  • the upper cyclohexane solution became red
  • the luminescence gradually weakens, and the lower layer never emits light; measure the luminescence intensity of the upper layer at intervals and extract the deionized water from the lower layer to detect the ions in it.
  • the relative luminescence intensity of the upper cyclohexane solution changes as the material goes away. The dissolution in ionized water gradually weakened. It can be seen that the K 3 ZrF 7 :20%Yb/2%Er nanocrystals prepared in Example 1 have good hydrolysis performance.
  • the nanocrystals prepared in Example 1 were dried into powder and immersed in a certain amount of deionized water. Under the excitation of a 980nm laser, the red luminescence of the solid powder gradually weakened with time, and the upper layer The clear liquid never emits light; measure the luminescence intensity of the solid and the ion content in the supernatant liquid at intervals, and record the luminescence photo, as shown in Figure 8 (b), the relative luminescence intensity of the solid powder soaked in deionized water It weakens rapidly until it basically no longer emits light, and almost all the lower layer ions are dissolved in the upper layer of deionized water.
  • Figure 8(c) is the powder diffraction spectrum of the solid after soaking for a certain period of time after the supernatant is evaporated to dryness.
  • the diffraction peak position is still consistent with the PDF standard card of K 3 ZrF 7 (JCPDS No. 73-1530). It shows that the nanocrystals prepared in Example 1 are well decomposed in deionized water.
  • the nanocrystals prepared in Example 1 were dried into powder, and soaked in a certain amount of strong acid (HCl 1mol/L) and strong alkali (NaOH 3mol/L). /L), under the excitation of 980nm laser, it can be seen that the solid powder immersed in strong acid in Figure 9(a) and the red luminescence of solid powder immersed in strong alkali in Figure 9(b) disappear rapidly. The supernatant liquid never emits light.
  • Figure 9 (d) is a transmission electron micrograph of the supernatant liquid, and the residual particles are KYb 3 F 10 crystals of about 5 nm. It shows that the nanocrystals prepared in Example 1 can be decomposed in strong acid and strong alkali solutions.
  • the nanocrystals prepared in Example 1 were dried into powder, and immersed in a certain amount of Tris-HCl (pH 8.8 1M) and NaHCO3 (pH 8.3). Under the excitation of a 980nm laser, the red luminescence of the solid powder gradually weakened over time , The supernatant liquid never emits light; measure the luminescence intensity of the solid in time and record the luminescence photos. As shown in Figure 10, the relative luminescence intensity of the solid powder in a weakly alkaline environment rapidly weakens until it basically no longer emits light.
  • the nanocrystal prepared in Example 1 was dried into powder, and immersed in a certain amount of NaAc-HAc (pH 5.2). Under the excitation of 980nm laser, the rate of weakening of the red luminescence of the solid powder slowed down, and it remained for a long time. Luminescence, the supernatant liquid never emits light; measure the luminescence intensity of the solid in time and record the luminescence photos. As shown in Figure 11, the relative luminescence intensity of the solid powder in a weakly acidic environment decreases slowly, and the luminescence can exist for a longer time.
  • K 3 ZrF 7 Biological imaging of 20%Yb/2%Er nanocrystals
  • Subcutaneous 4T1 tumor tissue imaging in nude mice As shown in Figure 13(c), a small amount of peanut oil solution (50mg/mL) of nanocrystals in Example 1 was injected into the subcutaneous 4T1 tumor tissue of nude mice, and the CCD imaging system Next, use 980nm excitation light to excite imaging. Fluorescence can be observed at the injection site of the nanocrystal, and the luminescence of the injection site decreases with time, and basically no longer emits light in about 4 hours.
  • K 3 ZrF 7 Biosafety detection of 20%Yb/2%Er nanocrystals
  • the nanocrystals prepared in Example 1 can maintain normal cell viability of human cervical tumor HeLa cells within the concentration range of 0 ⁇ 0.25mg/mL, indicating that the nanocrystals have very low cytotoxicity. .
  • mice As shown in Figure 15, within the concentration range of 0-100mg/kg, the weight change of male and female mice was not significantly different from that of the control group. They developed normally to maturity. During the observation period, the appearance, nervous system, respiratory and circulatory system, and urogenital There were no abnormal reactions in the system, behavioral activities, food and water intake. As shown in Figure 16, no macroscopic lesions were found during anatomy, and no abnormal lesions were found in the histopathological examination of the heart, liver, lung, kidney, and intestinal tissues of all animals.
  • K 3 ZrF 7 20%Yb/2%Er nanocrystals can be degraded in vivo

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Inorganic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Nanotechnology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Luminescent Compositions (AREA)

Abstract

提供一种生物体内可降解上转换纳米材料及制备方法和应用。该材料为稀土掺杂的锆/铪基碱金属氟化物，其中基质材料氟化物通式为M xT yF x+4y，掺杂后纳米材料结构通式为M xT yF x+4y:z％Ln，M为Li、Na和K中的一种或多种；T为Zr和/或Hf；Ln选自Yb、Er、Tm、Ho、Gd、Eu、Tb、Sm、Dy、Ce和Nd中的一种或多种；且1≤x≤7；1≤y≤6；0≤z≤50。该材料可在生物体内较快的水解并清除，不容易大量聚集，具有较低的细胞毒性和生物毒性，展现了良好的生物安全性，并且在肿瘤环境中的弱酸性下分解会受到一定程度的抑制，能够延缓水解，在弱酸性的肿瘤环境中存在时间长于其他体内环境，可用于肿瘤的特异性荧光标记。

Description

生物体内可降解上转换无机纳米材料及制备方法和应用 技术领域
本发明属于发光材料技术领域，具体而言，涉及一类可在生物体内降解的稀土掺杂锆/铪基碱金属氟化物上转换纳米发光材料及其制备方法和应用。
背景技术
稀土掺杂上转换无机纳米材料由于具有低毒、良好的抗光漂白性、无背景荧光、较深的光穿透深度等特点，是一种很有前途的荧光造影剂，在生物检测、成像以及疾病诊断治疗等各种体内应用领域都展示出极好的应用前景。然而，以最具代表性的β-NaYF4为代表的所有现有的稀土上转换无机纳米材料都不能在体内进行生物降解，并在生物体内大量的聚集，而不能以无害的方式从生物体体内进行有效的清除，这使得它们的临床应用转化几乎不可能。
因此，目前亟需出现一种可在生物体内降解的稀土掺杂上转换纳米发光材料。
发明内容
本发明旨在提供一种生物体内可降解的稀土掺杂锆/铪基碱金属氟化物上转换纳米发光材料及其制备方法和应用。
为了实现上述目的，根据本发明的一个方面，提供了一种生物体内可降解上转换无机纳米材料，由稀土掺杂基质材料锆/铪基碱金属氟化物得到，其中基质材料的通式为M xT yF x+4y，稀土掺杂后的纳米晶结构通式为M xT yF x+4y:z％Ln，其中，M为Li、Na和K中的一种或多种；T为Zr和/或Hf；Ln选自Yb、Er、Tm、Ho、Gd、Eu、Tb、Sm、Dy、Ce和Nd中的一种或多种；1≤x≤7；1≤y≤6；0≤z≤50。
进一步地，本发明所述的稀土掺杂后的纳米晶结构通式为M xT yF x+4y:z％Ln中，1≤x≤3；1≤y≤2；10.5≤z≤22。优选地，21≤z≤22。
进一步地，本发明所述的稀土掺杂后的纳米晶结构通式为M xT yF x+4y:z％Ln中，x＝3，y＝1，基质材料为K 3ZrF 7，稀土掺杂后的纳米晶结构通式为K 3ZrF 7:z％Ln。
进一步地，稀土掺杂后的纳米晶结构通式为M xT yF x+4y:z％Ln中，x＝3，y＝1，基质材料为K 3ZrF 7，稀土掺杂后的纳米晶结构式为K 3ZrF 7:z1％Yb/z2％Er，其中5≤z1≤30，0.5≤z2≤5。优选地，10≤z1≤20，0.5≤z2≤2。
进一步地，掺杂后的纳米晶结构式为K xZr yF x+4y:20％Yb/2％Er、K xZr yF x+4y:20％Yb/1％Tm、K xHf yF x+4y:20％Yb/2％Er、K xZr y1Hf y2F x+4(y1+y2):20％Yb/2％Er、Na xZr yF x+4y:20％Yb/2％Er、 Na xHf yF x+4y:20％Yb/2％Er、Na xZr y1Hf y2F x+4(y1+y2):20％Yb/2％Er、Li xZr yF x+4y:20％Yb/2％Er；其中，1≤y1+y2≤6。
优选地，稀土掺杂后的纳米晶为K 3ZrF 7:20％Yb/2％Er、K 2ZrF 6:20％Yb/2％Er、KZrF 5:20％Yb/2％Er、K 3HfF 7:20％Yb/2％Er、K 2HfF 6:20％Yb/2％Er、K 3Zr 0.5Hf 0.5F 7:20％Yb/2％Er、Na 3ZrF 7:20％Yb/2％Er、Na 2ZrF 6:20％Yb/2％Er、Na 5Zr 2F 13:20％Yb/2％Er、Na 7Zr 6F 31:20％Yb/2％Er、Na 3HfF 7:20％Yb/2％Er、Na 5Hf 2F 13:20％Yb/2％Er、Na 3Zr 0.5Hf 0.5F7:20％Yb/2％Er、Li 4ZrF 8:20％Yb/2％Er、Li 2ZrF 6:20％Yb/2％Er。
根据本发明的另一方面，还提供了一种生物体内可降解上转换无机纳米材料的制备方法，其采用含锆/铪离子盐和稀土乙酸盐、氟化铵和碱金属的氢氧化物作为原料，并利用高温溶剂共沉淀法，从而获得稀土掺杂锆/铪基碱金属氟化物上转换纳米材料。
进一步地，高温溶剂共沉淀法包括以下步骤：S1、称取乙酰丙酮锆/铪和稀土乙酸盐，混合，并加入溶剂，得到固体混合物；S2、将固体混合物加热并保温，以使固体混合物中的反应物溶解，得到混合液；S3、向步骤S2中得到的混合液中加入溶有氟化铵和碱金属氢氧化物的甲醇溶液，加热保温以去除甲醇和水；S4、继续加热并保温，冷却至室温，沉淀，分离，洗涤，干燥，得到所述稀土掺杂锆/铪基碱金属氟化物上转换纳米材料。
进一步地，含锆/铪离子盐选自乙酰丙酮锆/铪、乙酸锆/铪、氯化锆/铪、硝酸锆/铪、氯氧化锆/铪中的一种或多种；稀土乙酸盐中的盐离子是选自Yb、Er、Tm、Ho、Gd、Eu、Tb、Sm、Dy、Ce和Nd中的一种或多种；优选地，锆/铪离子与稀土金属盐的摩尔比为(1～10):1；优选为(2～5):1；更优选地，稀土乙酸盐为醋酸镱和醋酸铒的混合物，稀土乙酸盐和所述乙酰丙酮锆/铪的摩尔比为1:4。
优选地，溶剂为油酸和十八烯的混合溶剂。优选所述油酸和十八烯的体积比为1:(0.5～3)；更优选所述油酸和十八烯的体积比为1:2。
所述氟化铵与碱金属氢氧化物的摩尔比为7:(6～12)；优选地，所述氟化铵与氢氧化钾的摩尔比为7:6。
进一步地，步骤S2中，在惰性气体保护下将固体混合物加热升温至120～160℃，并保温30～40分钟。更优选地，在惰性气氛下加热升温至140℃将上述固体完全溶解后自然冷却到室温，得到澄清溶液。
优选地，在步骤S3中，在惰性气体保护下，加热至50～70℃并保温30分钟去除甲醇，加热至100～110℃并保温10～20分钟去除水。
优选地，在步骤S4中，在惰性气体保护下继续加热至300～310℃并保温40～60分钟。更优选地，在步骤S4中，在惰性气氛下升温至305℃，保温40分钟后自然冷却到室温。优选分离为离心分离。
根据本发明的又一方面，还提供了一种生物体内可降解上转换无机纳米材料在生物技术领域中的应用。优选用于安全的生物体内可降解的荧光标记。
进一步地，生物体内可降解上转换无机纳米材料在酸碱度依赖的水降解方面的应用，优选用于弱酸性肿瘤组织的特异性标记。
本发明的有益效果：
本发明采用使用无机锆/铪基碱金属氟化物体系作为基质材料，利用溶剂热的合成方法将上转换稀土离子掺入其晶格中，即采用高温共沉淀法制备出了一类可在生物体内有效降解和清除的上转换无机纳米发光材料，具有以下优点：
1)该合成方法条件容易控制，重复性好，制备出的纳米晶材料分散性、均一性和重复性都很好，且稀土离子掺杂实现了在近红外光激发下的上转换发光。
2)纳米晶材料可以分解为水溶性的氟锆/铪酸根离子([T yF x+4y] x-，T为Zr或Hf)，提供了独特的酸碱度依赖的水降解能力，并且还能够在水环境分解的同时，可以提供上转换发光，受益于该基质材料特殊的水环境下的水解特性，可以在生物体内较快的水解并清除，为生物体内的应用提供了可能。
3)本发明制备的纳米晶材料在肿瘤环境中的弱酸性(pH 5～6)下分解会受到一定程度的抑制，受益于这种材料在弱酸性的环境下能够延缓水解，其在弱酸性的肿瘤环境中的存在时间长于其他体内环境，可以应用于弱酸性肿瘤的特异性荧光标记。
4)本发明制备的纳米晶材料受益于其较低的细胞毒性和生物毒性，展现了良好的生物安全性，在生物体内能够安全使用，并且在生物体内不容易大量聚集。因此，可以用作生物体内的上转换荧光标记材料，在生物成像和荧光标记等领域具有潜在的应用前景。
附图说明
图1是本发明实施例1中K 3ZrF 7:20％Yb/2％Er上转换纳米晶的X射线粉末衍射图。
图2a是本发明实施例1中K 3ZrF 7:20％Yb/2％Er上转换纳米晶不同分辨率的透射电镜图；
图2b是本发明实施例1中K 3ZrF 7:20％Yb/2％Er上转换纳米晶纳米颗粒的粒径统计图。
图3是本发明实施例1中K 3ZrF 7:20％Yb/2％Er上转换纳米晶在低功率密度980nm连续半导体激光器激发下的上转换发射光谱图。
图4是本发明实施例2中K 3HfF 7:20％Yb/2％Er上转换纳米晶的X射线粉末衍射图。
图5a是本发明实施例2中K 3HfF 7:20％Yb/2％Er上转换纳米晶不同分辨率的透射电镜图；
图5b是本发明实施例2中K 3HfF 7:20％Yb/2％Er上转换纳米晶纳米颗粒的粒径统计图。
图6是本发明实施例2中K 3HfF 7:20％Yb/2％Er上转换纳米晶在低功率密度980nm连续半导体激光器激发下的上转换发射光谱图。
图7是本发明实施例1中K 3ZrF 7:20％Yb/2％Er上转换纳米晶的环己烷溶液加入去离子水后， 在980nm激光激发下上转换发光强度随时间的变化曲线以及相应的发光照片。
图8是本发明实施例1中K 3ZrF 7:20％Yb/2％Er上转换纳米晶的粉末加入去离子水后，在980nm激光激发下上转换发光强度随时间的变化曲线以及相应的发光照片。
图9是本发明实施例1中K 3ZrF 7:20％Yb/2％Er上转换纳米晶的粉末加入强酸和强碱后，在980nm激光激发下上转换发光强度随时间的变化曲线以及相应的发光照片。
图10是本发明实施例1中K 3ZrF 7:20％Yb/2％Er上转换纳米晶的粉末加入弱碱性水溶液后，在980nm激光激发下上转换发光强度随时间的变化曲线以及相应的发光照片。
图11是本发明实施例1中K 3ZrF 7:20％Yb/2％Er上转换纳米晶的粉末加入弱酸性水溶液后，在980nm激光激发下上转换发光强度随时间的变化曲线以及相应的发光照片。
图12是本发明测试使用的CCD成像系统。
图13是本发明实施例1中K 3ZrF 7:20％Yb/2％Er上转换纳米晶在裸鼠皮下成像的效果示意图。
图14是本发明实施例1中K 3ZrF 7:20％Yb/2％Er上转换纳米晶的细胞毒性结果图。
图15是本发明实施例1中K 3ZrF 7:20％Yb/2％Er上转换纳米晶的小鼠急毒测试中小鼠的体重变化曲线图。
图16是本发明实施例1中K 3ZrF 7:20％Yb/2％Er上转换纳米晶的小鼠急毒测试后小鼠主要脏器的组织切片图。
图17是本发明实施例1中K 3ZrF 7:20％Yb/2％Er上转换纳米晶的大鼠肌肉刺激性试验后的肌肉组织切片图。
图18是本发明实施例1中K 3ZrF 7:20％Yb/2％Er上转换纳米晶尾静脉注射入小鼠体内后短时间内元素在各个器官的分布图。
图19是本发明实施例1中K 3ZrF 7:20％Yb/2％Er纳米晶的转换原理示意图。
具体实施方式
下文将结合具体实施例对本发明的制备方法做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
根据本发明，提供了一种生物体内可降解上转换无机纳米材料，由稀土掺杂基质材料锆/铪基碱金属氟化物得到，该基质材料的通式为M xT yF x+4y，稀土掺杂后的纳米晶结构通式为M xT yF x+4y:z％Ln，其中，M为Li、Na和K中的一种或多种；T为Zr和/或Hf；Ln选自Yb、Er、Tm、Ho、Gd、Eu、Tb、Sm、Dy、Ce和Nd中的一种或多种，1≤x≤7；1≤y≤6；0≤z≤50。
优选地，纳米晶结构通式中，1≤x≤3；1≤y≤2；10.5≤z≤22。更优选21≤z≤22。
本发明采用稀土掺杂锆/铪基碱金属氟化物，基质材料中的氟锆/铪酸根离子提供了独特 的酸碱度依赖的水降解能力，稀土离子掺杂实现了在近红外光激发下的上转换发光，能够更好的应用于生物体内的检测。
本发明制备的稀土掺杂锆/铪基碱金属氟化物纳米材料的粉末浸泡在水环境中，无需其他条件就能迅速发生水解，水解发生后上清液的蒸干产物经检测仍是原来的基质材料。该纳米材料还可以分散在环己烷、橄榄油和花生油等溶剂中，可以扩散至外界水环境中并发生水解，水解产物不发光。
根据本发明，稀土掺杂锆/铪基碱金属氟化物纳米材料在强酸和强碱的环境下水解更快，而在弱酸性(pH 5～6)的环境下分解会受到一定程度的抑制，所以水解速率减慢。利用其在偏酸性环境中水解缓慢，可以用于弱酸性肿瘤环境的体内荧光标记。
根据本发明，稀土掺杂锆/铪基碱金属氟化物上转换无机纳米材料的结构式中，x＝3，y＝1，所述基质材料为K 3ZrF 7，稀土掺杂后的纳米晶结构通式为K 3ZrF 7:z％Ln。
根据本发明，稀土掺杂锆/铪基碱金属氟化物上转换无机纳米材料的结构式中，x＝3，y＝1，基质材料为K 3ZrF 7，稀土掺杂后的纳米晶结构式为K 3ZrF 7:z1％Yb/z2％Er，其中5≤z1≤30，0.5≤z2≤5。优选地，10≤z1≤20，0.5≤z2≤2。
在本发明的一个具体实施例中，稀土掺杂后的纳米晶结构式为K xZr yF x+4y:20％Yb/2％Er、K xZr yF x+4y:20％Yb/1％Tm、K xHf yF x+4y:20％Yb/2％Er、K xZr y1Hf y2F x+4(y1+y2):20％Yb/2％Er、Na xZr yF x+4y:20％Yb/2％Er、Na xHf yF x+4y:20％Yb/2％Er、Na xZr y1Hf y2F x+4(y1+y2):20％Yb/2％Er、Li xZr yF x+4y:20％Yb/2％Er，其中，1≤y1+y2≤6。
具体地，纳米晶结构式可以为K 3ZrF 7:20％Yb/2％Er、K 2ZrF 6:20％Yb/2％Er、KZrF 5:20％Yb/2％Er、K 3HfF 7:20％Yb/2％Er、K 2HfF 6:20％Yb/2％Er、K 3Zr 0.5Hf 0.5F 7:20％Yb/2％Er、Na 3ZrF 7:20％Yb/2％Er、Na 2ZrF 6:20％Yb/2％Er、Na 5Zr 2F 13:20％Yb/2％Er、Na 7Zr 6F 31:20％Yb/2％Er、Na 3HfF 7:20％Yb/2％Er、Na 5Hf 2F 13:20％Yb/2％Er、Na 3Zr 0.5Hf 0.5F 7:20％Yb/2％Er、Li 4ZrF 8:20％Yb/2％Er、Li 2ZrF 6:20％Yb/2％Er。
根据本发明的另一方面，还提供了一种生物体内可降解上转换无机纳米材料的制备方法，其采用含锆/铪离子盐和稀土乙酸盐、氟化铵和碱金属的氢氧化物作为原料，并利用高温溶剂共沉淀法，从而获得稀土掺杂锆/铪基碱金属氟化物上转换纳米材料。
优选地，高温溶剂共沉淀法包括以下步骤：S1、称取乙酰丙酮锆/铪和稀土乙酸盐，混合，并加入溶剂，得到固体混合物；S2、将固体混合物加热并保温，以使固体混合物中的反应物溶解，得到混合液；S3、向步骤S2中得到的混合液中加入溶有氟化铵和碱金属氢氧化物的甲醇溶液，加热保温以去除甲醇和水；S4、继续加热并保温，冷却至室温，沉淀，分离，洗涤，干燥，得到稀土掺杂锆/铪基碱金属氟化物上转换纳米材料。
在本发明中，含锆/铪离子盐选自乙酰丙酮锆/铪、乙酸锆/铪、氯化锆/铪、硝酸锆/铪、氯 氧化锆/铪中的一种或多种。本发明优选上述含锆/铪离子的盐，但并不局限于此，只有能够在形成水溶性的锆/铪离子即可。
优选稀土乙酸盐中的盐离子是选自镱(Yb)、铒(Er)、铥(Tm)、钬(Ho)、钆(Gd)、铕(Eu)、铽(Tb)、钐(Sm)镝(Dy)、铈(Ce)和钕(Nd)中的一种或多种。优选是镱(Yb)和铒(Er)共掺。优选地，锆/铪离子与稀土金属盐的摩尔比为(1～10):1；优选为(2～5):1。
更优选地，稀土乙酸盐为醋酸镱和醋酸铒的混合物，其中稀土乙酸盐和乙酰丙酮锆/铪的摩尔比为1:4。
优选地，溶剂为油酸和十八烯的混合溶剂。优选油酸和十八烯的体积比为1:(0.5～3)；更优选为1:2。根据本发明，氟化铵与碱金属氢氧化物的摩尔比为7:(6～12)；优选地，氟化铵与氢氧化钾的摩尔比为7:6。
根据本发明，在步骤S2中，在惰性气体保护下将固体混合物加热升温至120～160℃，并保温30～40分钟。通过升温和保温，可将固体完全溶解得到澄清溶液。更优选地，在惰性气氛下加热升温至140℃将上述固体完全溶解后自然冷却到室温，得到澄清溶液。
优选地，在步骤S3中，在惰性气体保护下，加热至50～70℃并保温30分钟去除甲醇，加热至100～110℃并保温10～20分钟去除水。
优选地，在步骤S4中，在惰性气体保护下继续加热至300～310℃并保温40～60分钟。更优选地，在步骤S4中，在惰性气氛下升温至305℃，保温40分钟后自然冷却到室温。本发明优选离心分离。
本发明还提供了一类生物体内可降解稀土掺杂锆/铪基碱金属氟化物上转换无机纳米材料在生物技术领域中的应用；优选用于安全的生物体内可降解的荧光标记。
进一步优选，生物体内可降解稀土掺杂锆/铪基碱金属氟化物上转换无机纳米材料在酸碱度依赖的水降解方面的应用，优选用于弱酸性肿瘤组织的特异性标记。
对比例1
β-NaYF 4:20％Yb/2％Er上转换纳米晶的制备：
室温下称取0.2075g醋酸钇和0.07g醋酸镱、0.007g醋酸铒至两颈烧瓶，加入6mL油酸和15mL十八烯作为溶剂，在惰性气氛下加热升温至140℃将上述固体完全溶解后自然冷却到室温，得到澄清溶液；将溶有0.1482g氟化铵和0.10g氢氧化钠的8mL甲醇溶液加到上述溶液中，在惰性气氛下升温至50℃，保温至甲醇除净，升温至100～110℃，保温至水除净，然后在惰性气氛下升温至300℃，保温60分钟后自然冷却到室温，沉淀并洗涤，得到β-NaYF 4:20％Yb/2％Er纳米晶。
实施例1
利用高温溶剂共沉淀法制备无毒的生体内可降解的K 3ZrF 7:20％Yb/2％Er上转换纳米晶：
室温下称取0.1961g乙酰丙酮锆和0.034g醋酸镱、0.0034g醋酸铒至两颈烧瓶(其中醋酸镱、醋酸铒与乙酰丙酮锆的摩尔比为1:4)，加入8.5mL油酸和17mL十八烯作为溶剂，在惰性气氛下加热升温至140℃并保温30分钟，将上述固体完全溶解后自然冷却到室温，得到澄清溶液。
将溶有0.1296g氟化铵的9mL甲醇溶液和溶有0.1683g氢氧化钾的3mL甲醇溶液分别加到上述溶液中，在惰性气氛下升温至50℃，保温30分钟，甲醇除净，升温至100～110℃，保温10～20分钟至水除净。然后在惰性气氛下升温至305℃，保温40分钟后自然冷却到室温，沉淀并洗涤，得到立方相的K 3ZrF 7:20％Yb/2％Er纳米晶。
对实施例1中得到的纳米晶进行射线衍射图谱分析，仪器型号为MiniFlex2，厂家为Rigaku，铜靶辐射波长为λ＝0.154187nm。从图1中可以看出，该纳米晶具有良好的结晶性，其衍射峰位置和相对强度与K3ZrF7的PDF标准卡片(JCPDS No.73-1530)一致，属于立方晶系。
图2a和2b是实施例1中纳米晶不同分辨率的透射电镜图和粒径统计图，(所采用的仪器型号为TECNAI G2 F20，产家为FEI)。从图2可以看出，该纳米晶分散性好、形貌均一，粒径约为27.5nm。
采用稳态瞬态荧光光谱分析仪对实施例1中的纳米晶分析，所采用的仪器型号为FLS980，产家为Edinburgh。如图3所示，在980nm光源激发下，油溶性纳米晶发射出主峰位于656nm处的红色上转换发光，对应于Er 3+离子4F9/2-4I15/2电偶极跃迁。
实施例2
利用高温溶剂共沉淀法制备无毒的生体内可降解的K 3HfF 7:20％Yb/2％Er上转换纳米晶：
室温下称取0.2311g乙酰丙酮铪和0.034g醋酸镱、0.0034g醋酸铒至两颈烧瓶，加入8.5mL油酸和17mL十八烯作为溶剂，在惰性气氛下加热升温至160℃并保温30分钟，将上述固体完全溶解后自然冷却到室温，得到澄清溶液。
将溶有0.1296g氟化铵的9mL甲醇溶液和溶有0.1683g氢氧化钾的3mL甲醇溶液分别加到上述溶液中，在惰性气氛下升温至50℃，保温30分钟，甲醇除净，升温至100～110℃，保温10～20分钟至水除净。然后在惰性气氛下升温至310℃，保温40分钟后自然冷却到室温，沉淀并洗涤，得到立方相的K 3HfF 7:20％Yb/2％Er纳米晶。
从图4中可以看出，该纳米晶具有良好的结晶性，其衍射峰位置和相对强度与K3HfF7的PDF标准卡片(JCPDS No.78-1827)一致，属于立方晶系。
图5a和5b是实施例2中纳米晶不同分辨率的透射电镜图和粒径统计图，(所采用的仪器型号为TECNAI G2 F20，产家为FEI)。从图5可以看出，该纳米晶粒径约为28.4nm。
采用稳态瞬态荧光光谱分析仪对实施例2中的纳米晶分析，所采用的仪器型号为FLS980， 产家为Edinburgh。如图6所示，在980nm光源激发下，油溶性纳米晶发射出主峰位于656nm处的红色上转换发光，对应于Er 3+离子4F9/2-4I15/2电偶极跃迁。
实施例3
K 3ZrF 7:20％Yb/2％Er纳米晶的水解性能检测。采用稳态瞬态荧光光谱分析仪对实施例1中的纳米晶分析，仪器型号为FLS980，产家为Edinburgh。相机型号为EOS 5D，厂家为Canon。
(1)纳米晶在环己烷溶液中的水解
如图7中(a)和(c)所示，实施例1中制备的纳米晶溶解在环己烷中，加入等体积的去离子水，在980nm激光激发下，上层环己烷溶液的红色发光逐渐减弱，下层始终不发光；分时段测定上层发光强度并提取下层去离子水检测其中的离子，如图7中(b)所示，上层环己烷溶液的相对发光强度随着材料在去离子水中溶解逐渐减弱。可知，实施例1中制备的K 3ZrF 7:20％Yb/2％Er纳米晶的水解性能良好。
(2)纳米晶固体粉末在去离子水中的分解
如图8中(a)所示，将实施例1中制备的纳米晶干燥成粉末，浸泡在一定量的去离子水中，在980nm激光激发下，固体粉末的红色发光随着时间逐渐减弱，上层清液始终不发光；分时段测定固体的发光强度以及上层清液中的离子含量，并记录发光照片，如图8中(b)所示，固体粉末在去离子水的浸泡下，相对发光强度迅速减弱直至基本不再发光，下层离子几乎都溶解在上层去离子水中。图8(c)为浸泡一定时间后上层清液蒸干后固体的粉末衍射谱图，其衍射峰位置仍与K 3ZrF 7的PDF标准卡片(JCPDS No.73-1530)一致。说明实施例1中制备的纳米晶较好地分解在了去离子水中。
(3)纳米晶固体粉末在强酸强碱中的分解
如图9中(a)、(b)和(c)所示，将实施例1中制备的纳米晶干燥成粉末，分别浸泡在一定量的强酸(HCl 1mol/L)和强碱(NaOH 3mol/L)中，在980nm激光激发下，可以看到图9(a)中浸泡在强酸中的固体粉末，以及图9(b)中浸泡在强碱中的固体粉末的红色发光均迅速消失，上层清液始终不发光。图9中(d)为上层清液的透射电镜照片，残余颗粒为5nm左右的KYb 3F 10晶体。说明实施例1中制备的纳米晶能够在强酸和强碱溶液中分解。
(4)固体粉末在弱碱性环境下的分解
将实施例1中制备的纳米晶干燥成粉末，浸泡在一定量的Tris-HCl(pH 8.8 1M)和NaHCO3(pH 8.3)中，在980nm激光激发下，固体粉末的红色发光随着时间逐渐减弱，上层清液始终不发光；分时段测定固体的发光强度并记录发光照片，如图10所示，固体粉末在弱碱性环境下，相对发光强度迅速减弱直至基本不再发光。
(5)固体粉末在弱酸性环境下的分解
将实施例1中制备的纳米晶干燥成粉末，浸泡在一定量的NaAc-HAc(pH 5.2)，在980nm 激光激发下，固体粉末的红色发光减弱的速率有所减慢，较长时间仍有发光，上层清液始终不发光；分时段测定固体的发光强度并记录发光照片，如图11所示，固体粉末在弱酸性环境下，相对发光强度减弱速率较慢，发光能存在更长时间。
实施例4
K 3ZrF 7:20％Yb/2％Er纳米晶的生物成像
使用如图12所示的一套CCD成像系统(厂家为ANDOR)进行裸鼠皮下成像的测试：
(1)裸鼠皮下成像：如图13中(a)所示，皮下注射微量实施例1中纳米晶的花生油溶液(50mg/mL)，在CCD成像系统下，使用980nm激发光激发成像。在注射纳米晶的位置可以观察到荧光，并且注射位置的发光随着时间逐渐减弱，在40分钟左右就基本不再发光。
(2)裸鼠皮下成像(对比例1中的NaYF4对照组)：如图13中(b)所示，皮下注射微量对比例1中NaYF4纳米晶的花生油溶液(50mg/mL)，在CCD成像系统下，使用980nm激发光激发成像。在注射纳米晶的位置可以观察到荧光，并且注射位置的发光随着时间无明显变化，保持2小时以上仍有明显发光。
(3)裸鼠皮下4T1肿瘤组织成像：如图13中(c)所示，在裸鼠皮下4T1肿瘤组织位置注射微量实施例1中纳米晶的花生油溶液(50mg/mL)，在CCD成像系统下，使用980nm激发光激发成像。在注射纳米晶的位置可以观察到荧光，并且注射位置的发光随着时间减弱，在4小时左右就基本不再发光。
以上，说明该K 3ZrF 7:20％Yb/2％Er纳米晶在生物体内的发光会随时间减弱，但在弱酸性肿瘤环境下能够保持更长时间的发光。
实施例5
K 3ZrF 7:20％Yb/2％Er纳米晶的生物安全性检测
(1)细胞毒性测试：(采用MTT比色法和人宫颈肿瘤HeLa细胞)
如图14所示，实施例1所制备的纳米晶，在0～0.25mg/mL浓度范围内，都能使人宫颈肿瘤HeLa细胞保持正常的细胞活性，说明该纳米晶具有很低的细胞毒性。
(2)小鼠单次静脉给药毒性试验
如图15所示，在0-100mg/kg给药浓度范围内，雌雄小鼠体重变化与对照组没有明显差异，正常发育直至成熟，在观察时间内外观、神经系统、呼吸循环系统、泌尿生殖系统、行为活动、摄食饮水情况未见异常反应。如图16所示，解剖未见肉眼可见病变，所有动物心、肝、肺、肾、肠组织行病理组织学检查均未见异常病变。
(3)大鼠肌肉刺激性试验
如图17所示，分别于给药后1、6、24、72小时对动物安乐死，在四个观察时间段，纳米 晶给药侧与对照侧比较无明显差异，局部未见明显充血、红肿等刺激现象。
以上测试均说明了本发明的K3ZrF7:20％Yb/2％Er纳米晶具有生物安全性。
实施例6
K 3ZrF 7:20％Yb/2％Er纳米晶可在生物体内降解
体内元素分布：如图18(a)所示，裸鼠尾静脉注射微量纳米晶的5％DMSO水溶液，分别于给药后0.5、2、4、8小时后对动物安乐死，在四个时间段分别测定裸鼠主要脏器中的锆元素含量，可以观察到，在注射入裸鼠体内很短的时间内，有很大一部分锆离子随着排泄物排出体外，而在体内其他主要脏器中很少聚集。相对的，如图18(b)所示，对比例1中的NaYF4在注射入裸鼠体内较长时间内会在主要的脏器内聚集。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种生物体内可降解上转换无机纳米材料，由稀土掺杂基质材料锆/铪基碱金属氟化物得到，其中，基质材料的通式为M xT yF x+4y，稀土掺杂后的纳米晶结构通式为M xT yF x+4y:z％Ln，其中，M为Li、Na和K中的一种或多种；T为Zr和/或Hf；Ln选自Yb、Er、Tm、Ho、Gd、Eu、Tb、Sm、Dy、Ce和Nd中的一种或多种；1≤x≤7；1≤y≤6；0≤z≤50。
  2. 根据权利要求1所述的生物体内可降解上转换无机纳米材料，其中，1≤x≤3；1≤y≤2；10.5≤z≤22。优选地，21≤z≤22。
  3. 根据权利要求1所述的生物体内可降解上转换无机纳米材料，其中，x＝3，y＝1，所述基质材料为K 3ZrF 7，所述稀土掺杂后的纳米晶结构通式为K 3ZrF 7:z％Ln。
  4. 根据权利要求1所述的生物体内可降解上转换无机纳米材料，其中，x＝3，y＝1，所述基质材料为K 3ZrF 7，稀土掺杂后的纳米晶结构式为K 3ZrF 7:z1％Yb/z2％Er，其中5≤z1≤30，0.5≤z2≤5。优选地，10≤z1≤20，0.5≤z2≤2。
  5. 根据权利要求1所述的生物体内可降解上转换无机纳米材料，其中，掺杂后的纳米晶结构式为K xZr yF x+4y:20％Yb/2％Er、K xZr yF x+4y:20％Yb/1％Tm、K xHf yF x+4y:20％Yb/2％Er、K xZr y1Hf y2F x+4(y1+y2):20％Yb/2％Er、Na xZr yF x+4y:20％Yb/2％Er、Na xHf yF x+4y:20％Yb/2％Er、Na xZr y1Hf y2F x+4(y1+y2):20％Yb/2％Er、Li xZr yF x+4y:20％Yb/2％Er；其中，1≤y1+y2≤6。
    优选地，稀土掺杂后的纳米晶为K 3ZrF 7:20％Yb/2％Er、K 2ZrF 6:20％Yb/2％Er、KZrF 5:20％Yb/2％Er、K 3HfF 7:20％Yb/2％Er、K 2HfF 6:20％Yb/2％Er、K 3Zr 0.5Hf 0.5F 7:20％Yb/2％Er、Na 3ZrF 7:20％Yb/2％Er、Na 2ZrF 6:20％Yb/2％Er、Na 5Zr 2F 13:20％Yb/2％Er、Na 7Zr 6F 31:20％Yb/2％Er、Na 3HfF 7:20％Yb/2％Er、Na 5Hf 2F 13:20％Yb/2％Er、Na 3Zr 0.5Hf 0.5F 7:20％Yb/2％Er、Li 4ZrF 8:20％Yb/2％Er、Li 2ZrF 6:20％Yb/2％Er。
  6. 权利要求1至5中任一项所述生物体内可降解上转换无机纳米材料的制备方法，其采用含锆/铪离子盐和稀土乙酸盐、氟化铵和碱金属的氢氧化物作为原料，并利用高温溶剂共沉淀法，从而获得稀土掺杂锆/铪基碱金属氟化物上转换纳米材料。
  7. 根据权利要求6所述的制备方法，其中，所述高温溶剂共沉淀法包括以下步骤：
    S1、称取乙酰丙酮锆/铪和稀土乙酸盐，混合，并加入溶剂，得到固体混合物；
    S2、将固体混合物加热并保温，以使固体混合物中的反应物溶解，得到混合液；
    S3、向步骤S2中得到的混合液中加入溶有氟化铵和碱金属氢氧化物的甲醇溶液，加热保温以去除甲醇和水；
    S4、继续加热并保温，冷却至室温，沉淀，分离，洗涤，干燥，得到所述稀土掺杂锆/铪基碱金属氟化物上转换纳米材料。
  8. 根据权利要求5或6所述的制备方法，其中，所述含锆/铪离子盐选自乙酰丙酮锆/铪、乙酸锆/铪、氯化锆/铪、硝酸锆/铪、氯氧化锆/铪中的一种或多种；所述稀土乙酸盐中的盐离子是选自Yb、Er、Tm、 Ho、Gd、Eu、Tb、Sm、Dy、Ce和Nd中的一种或多种。
    优选地，锆/铪离子与稀土金属盐的摩尔比为(1～10):1；优选为(2～5):1。
    更优选地，所述稀土乙酸盐为醋酸镱和醋酸铒的混合物，所述稀土乙酸盐和所述乙酰丙酮锆/铪的摩尔比为1:4。
    优选地，所述溶剂为油酸和十八烯的混合溶剂；优选所述油酸和十八烯的体积比为1:(0.5～3)；更优选所述油酸和十八烯的体积比为1:2。
    所述氟化铵与碱金属氢氧化物的摩尔比为7:(6～12)；优选地，所述氟化铵与氢氧化钾的摩尔比为7:6。
  9. 根据权利要求7所述的制备方法，其中，所述步骤S2中，在惰性气体保护下将固体混合物加热升温至120～160℃，并保温30～40分钟。
    更优选地，在惰性气氛下加热升温至140℃将上述固体完全溶解后自然冷却到室温，得到澄清溶液。
    优选地，在所述步骤S3中，在惰性气体保护下，加热至50～70℃并保温30分钟去除甲醇，加热至100～110℃并保温10～20分钟去除水。
    优选地，在所述步骤S4中，在惰性气体保护下继续加热至300～310℃并保温40～60分钟。
    更优选地，在所述步骤S4中，在惰性气氛下升温至305℃，保温40分钟后自然冷却到室温。优选分离为离心分离。
  10. 权利要求1-5中任一项所述的生物体内可降解上转换无机纳米材料在生物技术领域中的应用；优选用于安全的生物体内可降解的荧光标记。
    进一步优选，生物体内可降解上转换无机纳米材料在酸碱度依赖的水降解方面的应用，优选用于弱酸性肿瘤组织的特异性标记。
PCT/CN2020/070277 2020-01-03 2020-01-03 生物体内可降解上转换无机纳米材料及制备方法和应用 WO2021134786A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2020/070277 WO2021134786A1 (zh) 2020-01-03 2020-01-03 生物体内可降解上转换无机纳米材料及制备方法和应用
EP20910945.3A EP4086324A4 (en) 2020-01-03 2020-01-03 IN VIVO DEGRADABLE UPCONVERSION NANOMATERIAL, METHOD FOR PREPARATION AND USE

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2020/070277 WO2021134786A1 (zh) 2020-01-03 2020-01-03 生物体内可降解上转换无机纳米材料及制备方法和应用

Publications (1)

Publication Number Publication Date
WO2021134786A1 true WO2021134786A1 (zh) 2021-07-08

Family

ID=76686317

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/070277 WO2021134786A1 (zh) 2020-01-03 2020-01-03 生物体内可降解上转换无机纳米材料及制备方法和应用

Country Status (2)

Country Link
EP (1) EP4086324A4 (zh)
WO (1) WO2021134786A1 (zh)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116285949A (zh) * 2023-02-27 2023-06-23 中国科学院福建物质结构研究所 一种核-壳-壳-壳结构的稀土纳米荧光材料及其制备方法和应用
CN116426277A (zh) * 2023-04-19 2023-07-14 浙江大学 一种纯绿色上转换发光纳米材料及其制备方法
CN116445163A (zh) * 2023-04-19 2023-07-18 浙江大学 一种纯红色上转换发光纳米材料及其制备方法
CN116478692A (zh) * 2023-04-19 2023-07-25 浙江大学 一种纯蓝色上转换发光纳米材料及制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107163937A (zh) * 2017-05-04 2017-09-15 中国科学院福建物质结构研究所 一种具有多孔结构的稀土掺杂氟化锆锂纳米发光材料及其制备方法和应用
CN108359458A (zh) * 2018-01-15 2018-08-03 湖州师范学院 一种多孔稀土掺杂Li4ZrF8上转换纳米晶及其制备方法
CN108559511A (zh) * 2018-05-29 2018-09-21 广东工业大学 一种稀土掺杂上转换纳米晶发光材料及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107163937A (zh) * 2017-05-04 2017-09-15 中国科学院福建物质结构研究所 一种具有多孔结构的稀土掺杂氟化锆锂纳米发光材料及其制备方法和应用
CN108359458A (zh) * 2018-01-15 2018-08-03 湖州师范学院 一种多孔稀土掺杂Li4ZrF8上转换纳米晶及其制备方法
CN108559511A (zh) * 2018-05-29 2018-09-21 广东工业大学 一种稀土掺杂上转换纳米晶发光材料及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FU HU-HUI, LIU YONG-SHENG;JIANG FEI-LONG;HONG MAO-CHUN: "Controlled Synthesis and Optical Properties of Lanthanide-doped Na3ZrF7 Nanocrystals", JIEGOU HUAXUE - CHINESE JOURNAL OF STRUCTURAL CHEMISTRY, ZHONGGUO KEXUEYUAN FUJIAN WUZHI JIEGOU YANJIUSUO, CN, vol. 37, no. 11, 1 November 2018 (2018-11-01), CN, pages 1737 - 1748, XP055827829, ISSN: 0254-5861, DOI: 10.14102/j.cnki.0254-5861.2011-2028 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116285949A (zh) * 2023-02-27 2023-06-23 中国科学院福建物质结构研究所 一种核-壳-壳-壳结构的稀土纳米荧光材料及其制备方法和应用
CN116285949B (zh) * 2023-02-27 2023-09-29 中国科学院福建物质结构研究所 一种核-壳-壳-壳结构的稀土纳米荧光材料及其制备方法和应用
CN116426277A (zh) * 2023-04-19 2023-07-14 浙江大学 一种纯绿色上转换发光纳米材料及其制备方法
CN116445163A (zh) * 2023-04-19 2023-07-18 浙江大学 一种纯红色上转换发光纳米材料及其制备方法
CN116478692A (zh) * 2023-04-19 2023-07-25 浙江大学 一种纯蓝色上转换发光纳米材料及制备方法
CN116426277B (zh) * 2023-04-19 2024-01-09 浙江大学 一种纯绿色上转换发光纳米材料及其制备方法
CN116445163B (zh) * 2023-04-19 2024-02-27 浙江大学 一种纯红色上转换发光纳米材料及其制备方法
CN116478692B (zh) * 2023-04-19 2024-02-27 浙江大学 一种纯蓝色上转换发光纳米材料及制备方法

Also Published As

Publication number Publication date
EP4086324A4 (en) 2023-01-11
EP4086324A1 (en) 2022-11-09

Similar Documents

Publication Publication Date Title
WO2021134786A1 (zh) 生物体内可降解上转换无机纳米材料及制备方法和应用
CN113072939B (zh) 生物体内可降解上转换无机纳米材料及制备方法和应用
Xue et al. A 980 nm laser-activated upconverted persistent probe for NIR-to-NIR rechargeable in vivo bioimaging
Zhang et al. Magnetic and optical properties of NaGdF 4: Nd 3+, Yb 3+, Tm 3+ nanocrystals with upconversion/downconversion luminescence from visible to the near-infrared second window
Wang et al. One-pot synthesis and strong near-infrared upconversion luminescence of poly (acrylic acid)-functionalized YF 3: Yb 3+/Er 3+ nanocrystals
CN103589432B (zh) 稀土掺杂氟化镥锂纳米材料及其制备与应用
KR101441485B1 (ko) 녹색 발광 업컨버젼 나노형광체 및 그 합성 방법
Liu et al. Mn-complex modified NaDyF 4: Yb@ NaLuF 4: Yb, Er@ polydopamine core–shell nanocomposites for multifunctional imaging-guided photothermal therapy
Wei et al. Polyol-mediated synthesis and luminescence of lanthanide-doped NaYF4 nanocrystal upconversion phosphors
WO2023070743A1 (zh) 一种放射性医用同位素标记的稀土掺杂纳米材料和pet显像诊疗剂及其制备方法和应用
Yin et al. Structure and dysprosium dopant engineering of gadolinium oxide nanoparticles for enhanced dual-modal magnetic resonance and fluorescence imaging
Chen et al. Multifunctional PVP-Ba2GdF7: Yb3+, Ho3+ coated on Ag nanospheres for bioimaging and tumor photothermal therapy
Godlewski et al. New generation of oxide-based nanoparticles for the applications in early cancer detection and diagnostics
CN113817469A (zh) 一种生物窗口内激发/发射的超亮单色上转换纳米探针及其制备方法和应用
Ilves et al. Multimodal upconversion CaF2: Mn/Yb/Er/Si nanoparticles
CN105602566B (zh) 一种稀土掺杂NaGdF4上转换纳米晶及其制备方法
Pilch-Wróbel et al. The influence of Ce3+ codoping and excitation scheme on spectroscopic properties of NaYF4: Yb3+, Ho3+
Secu et al. Gd3+ co-doping influence on the morphological, up-conversion luminescence and magnetic properties of LiYF4: Yb3+/Er3+ nanocrystals
Gómez-González et al. Lanthanide vanadate-based trimodal probes for near-infrared luminescent bioimaging, high-field magnetic resonance imaging, and X-ray computed tomography
Secu et al. Synthesis and up-conversion luminescence properties of BaFBr-Er3+@ SiO2 core/shell heterostructures
Zhai et al. Synthesis of small-sized hexagonal NaREF4 (RE= Yb, Lu) nanocrystals through accelerating phase transformation
CN115785944A (zh) 一种NIR-IIb/c荧光纳米探针及其制备方法和应用
Min et al. Rare-earth doped hexagonal NaYbF 4 nanoprobes with size-controlled and NIR-II emission for multifunctional applications
Girija et al. Synthesis of NIR emitting rare earth doped fluorapatite nano-particles for bioimaging applications
CN116023944A (zh) 一种h+离子掺杂增强发光的稀土无机纳米发光材料及其制备方法和应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20910945

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2020910945

Country of ref document: EP

Effective date: 20220803