Rare earth upconversion nanocrystal heterostructure composite material, preparation method and application

Abstract

The application relates to the technical field of nanobiomaterials, and discloses a rare earth upconversion nanocrystal heterostructure composite material, a preparation method and application. The composite material is formed by taking 3,4-dihydroxyphenylpropionic acid with carboxyl on the surface as a core of oil-soluble rare earth upconversion nanocrystals, taking epitaxially grown metal organic frameworks as a shell, and forming a heterostructure; then growing manganese dioxide on the surface of the heterostructure in situ; and finally wrapping polyallylamine hydrochloride, polyacrylic acid and polyethylene glycol with amino on the surface of the manganese dioxide to obtain a composite material of a manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure with a multilayer structure and good biocompatibility. The composite material provided by the application is uniform in size, high in stability and good in biocompatibility, and can be applied to upconversion fluorescence / magnetic resonance dual-mode imaging guided photodynamic therapy. The preparation method provided by the application has the characteristics of mild and simple synthesis conditions, high repeatability and the like.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of nanobiomaterials, and particularly to a manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material, a preparation method and applications thereof. BACKGROUND

[0002] The incidence of cancer in China is still on the rise, and most cancers are discovered late, making treatment more difficult or even impossible. Therefore, the preparation of new composite materials with integrated diagnosis and treatment functions has become a new hotspot in cancer treatment.

[0003] In the prior art, metal organic frameworks are one of the most outstanding candidates for catalysis and biomedical applications due to their tunable physical and chemical properties, including high porosity, well-defined topological structure, component diversity, and multiple coordination sites. In particular, nanoscale porphyrin metal organic frameworks, in which porphyrin-derived molecules are uniformly dispersed throughout the metal organic framework matrix, have received more widespread attention as a powerful light harvesting platform for the rapid generation and diffusion of singlet oxygen in photodynamic therapy. However, this singlet oxygen generation system is strongly dependent on the supply of a large amount of oxygen, which is insufficient in the hypoxic tumor microenvironment.

[0004] There are many methods in the prior art to address oxygen deficiency, such as directly using oxygen-loaded nanoparticles, or using peroxidase-like (Pt, Au, etc.), natural catalase to convert intracellular hydrogen peroxide into oxygen to alleviate tumor hypoxia and enhance the effect of photodynamic therapy. Natural enzymes have some inherent defects, such as low stability and high cost, which greatly limit their practical application in the biomedical field. Pt, Au, etc. heavy metals have better stability than natural enzymes, and also have good catalytic effect, but have greater toxicity. Therefore, it is necessary to find a hydrogen peroxide catalase with strong stability and low toxicity.

[0005] It has been found in the prior art that, to date, the poor penetration ability of visible light into tissues has become an obstacle to the application of porphyrin metal organic frameworks in deep photodynamic therapy, and therefore it is necessary to develop a technology to broaden the light harvesting system based on metal organic frameworks. Upconversion rare earth nanocrystals are a promising wavelength shifting platform that can adjust the light harvesting properties of metal organic frameworks. However, due to the large lattice mismatch and uncontrollable nucleation / growth rate of metal organic frameworks, the controllable and precise self-assembly of high-crystalline upconversion rare earth nanocrystals and metal organic framework nanocrystals remains a great challenge.

[0006] At present, fluorescence imaging has become one of the research hotspots in optical imaging technology, because fluorescence imaging has the advantages of high sensitivity, no damage to cells and biological tissues, etc. In addition to widening the light collection system based on metal organic frameworks, rare earth upconversion nanocrystals can also realize upconversion fluorescence imaging. This low-energy excitation and high-energy emission mode for biological imaging can not only eliminate the interference of biological background fluorescence, but also has a set tissue penetration depth. Magnetic resonance imaging can perform three-dimensional imaging of tissues without penetration depth limitation and has good spatial resolution. However, the sensitivity of magnetic resonance imaging is not high enough, and it is difficult to perform imaging at the cell and tissue level. Therefore, the combination of upconversion fluorescence imaging and magnetic resonance imaging can realize high sensitivity and high resolution of imaging at the same time, and improve the accurate diagnosis rate of early cancer.

[0007] Therefore, it is necessary to study a new bimodal diagnosis and treatment integrated manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material. SUMMARY

[0008] The purpose of the present application is to solve the problems of diagnosis and treatment separation in the prior art, poor photodynamic therapy effect under the hypoxic environment of tumor, and difficulty in precise self-assembly controllable synthesis of metal organic framework coated rare earth upconversion nanocrystals. A rare earth upconversion nanocrystal heterostructure composite material, a preparation method and an application are provided. The metal organic framework coated rare earth upconversion nanocrystal heterostructure is controllably synthesized by a "solvent assisted self-assembly" method, and manganese dioxide is grown in situ on the surface of the metal organic framework to obtain a multi-layer manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material. Under the excitation of near-infrared laser (808±3 or 980±3 nanometers), the upconversion emission of the UCNP is transferred to the metal organic framework by fluorescence resonance energy transfer, and the manganese dioxide acts as a peroxide catalase to decompose hydrogen peroxide to generate oxygen, achieving the purpose of relieving hypoxia and improving the photodynamic therapy effect. In addition, the composite material can realize upconversion fluorescence imaging and magnetic resonance imaging.

[0009] The present application also provides a preparation method of the composite material, and optimizes the preparation process thereof.

[0010] The present application also provides the application of the composite material as a raw material, preparation as a photodynamic therapy agent drug, excellent photodynamic therapy effect under hypoxic conditions, or preparation as an upconversion fluorescence imaging agent and a magnetic resonance imaging agent.

[0011] To achieve the above-mentioned purposes, the technical scheme adopted by the present application is:

[0012] A rare earth upconversion nanocrystal heterostructure composite material is characterized in that it is formed by taking oil-soluble rare earth upconversion nanocrystals with carboxyl on the surface of 3,4-dihydroxyphenyl propionic acid as the core, taking epitaxially grown metal organic frameworks as the shell to form a heterostructure, then growing manganese dioxide on the surface of the heterostructure in situ, and finally wrapping polyallylamine hydrochloride, polyacrylic acid and polyethylene glycol with amino on the surface of the manganese dioxide to obtain a composite material of manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure with a multi-layer structure and good biocompatibility.

[0013] The manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material, wherein the oil-soluble rare earth upconversion nanocrystal is taken as an Er light center, and is specifically one of NaYF4:Yb / Er, NaYF4:Yb / Er / Tm, NaYbF4:Er, NaGdF4:Yb / Er, NaYF4:Yb / Er@NaYF4, NaYbF4:Er@NaYF4, NaGdF4:Yb / Er@NaYF4, NaYF4:Yb / Er@NaYF4:Yb / Nd, etc.

[0014] The preparation method of the manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material is characterized in that it comprises the following steps:

[0015] (1) Preparation of rare earth upconversion nanocrystals with carboxyl sites DHCA-UCNP: mix oil-soluble rare earth upconversion nanocrystals dispersed in cyclohexane with 3,4-dihydroxyphenyl propionic acid solution, stir at a set temperature for a set time, centrifuge and wash, take the solid and disperse it in N,N-dimethylformamide to obtain a first dispersion liquid;

[0016] (2) Preparation of metal organic framework coated rare earth upconversion nanocrystal heterostructure UM: disperse zirconium chloride and meso-tetra(4-carboxyphenyl) porphyrin (H2TCPP) in a set volume ratio of N,N-dimethylformamide and ethanol mixed solution respectively, after ultrasonic dispersion, add a set amount of the first dispersion liquid, react at a set temperature for a set time, centrifuge and wash, take the solid and disperse it in deionized water to obtain a second dispersion liquid;

[0017] (3) Preparation of manganese dioxide modified heterostructure UMMn: add a set amount of polyallylamine hydrochloride and potassium permanganate into the second dispersion liquid in sequence, ultrasonic stir, centrifuge and wash, take the solid and disperse it in deionized water to obtain a third dispersion liquid;

[0018] (4) Preparation of a composite material of manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure with good biocompatibility: the third dispersion liquid is stirred with cationic polymer polyallylamine hydrochloride and anionic polymer polyacrylic acid for a set time, centrifuged and washed, and the solid is redispersed and reacted with polyethylene glycol with an amino group and 1-ethyl-(3-dimethylaminopropyl) carbonyl diimide overnight, centrifuged and washed, and the solid is dispersed in deionized water to obtain a composite material with good biocompatibility.

[0019] The first dispersion liquid in step (1) is prepared, and the specific steps are as follows:

[0020] 0.5 mL of oil-soluble rare earth upconversion nanocrystals is taken, dispersed in 1 mL of chloroform after standing and volatilization, and 5 mL of a 3,4-dihydroxyphenylpropionic acid solution with a concentration of 5-20 mg / mL is added thereto, and the mixture is stirred at 45°C for 12-24 hours, centrifuged and washed until the supernatant is colorless, and the solid is dispersed in N,N-dimethylformamide to obtain the first dispersion liquid;

[0021] The second dispersion liquid in step (2) is prepared, and the specific steps are as follows:

[0022] A mixture solution of N,N-dimethylformamide and ethanol with a volume ratio of (5:1) to (1:1) is prepared, 4.5 mg of zirconium chloride and 1.5 mg of meso-tetra(4-carboxyphenyl) porphyrin are added to the mixture solution, respectively, and then the zirconium chloride solution is added dropwise into the meso-tetra(4-carboxyphenyl) porphyrin solution, and the mixture is ultrasonically stirred for 10-20 minutes to obtain a mixed solution, 1-3 mL of the first dispersion liquid with a concentration of 1 mg / mL is added dropwise into the mixed solution, and the mixture is reacted at 90-120°C for 4-6 hours, cooled to room temperature, centrifuged and washed, and the solid is dispersed in 1-3 mL of deionized water to obtain the second dispersion liquid;

[0023] The third dispersion liquid in step (3) is prepared, and the specific steps are as follows:

[0024] 1 mL of the second dispersion liquid (5 mg / mL) is prepared, 5-20 mg of polyallylamine hydrochloride is added thereto, and the mixture is stirred at 600-900 rpm for 2 hours, then 100-300 μL of a potassium permanganate aqueous solution (10 mg / mL) is added dropwise, and the mixture is continuously stirred for 2 hours, centrifuged and washed, and the solid is dispersed in 1 mL of deionized water to obtain the third dispersion liquid;

[0025] The specific steps in step (4) are as follows:

[0026] Take 50-100 mg of polyallylamine hydrochloride, 20-50 mg of polyacrylic acid, 20-50 mg of polyethylene glycol with amino group, 10-25 mg of 1-ethyl-(3-dimethylaminopropyl) carbonyl diimide, respectively, disperse in 10 mL of water to obtain the corresponding aqueous solution, take 1 mL of the third dispersion (5 mg / mL) and stir with the polyallylamine hydrochloride aqueous solution for 2 hours, then centrifuge and wash with water, then add the polyacrylic acid aqueous solution, stir for 2 hours, then centrifuge and wash, finally add the polyethylene glycol with amino group aqueous solution and the 1-ethyl-(3-dimethylaminopropyl) carbonyl diimide aqueous solution, stir for 12 hours, centrifuge and wash, take the solid and disperse in 1 mL of deionized water to obtain a high biocompatibility composite material.

[0027] The application of the manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material is characterized in that it is used as a raw material for preparing an upconversion fluorescence / magnetic resonance dual-mode imaging agent.

[0028] The application of the manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material is characterized in that it is used as a raw material for preparing a photodynamic therapy agent, and under the excitation of near-infrared laser (808±3 or 980±3 nanometers), the upconversion emission of the UCNP is transferred to the metal organic framework through fluorescence resonance energy transfer, and at the same time, the manganese dioxide acts as a peroxide catalase to decompose hydrogen peroxide into oxygen, so as to relieve hypoxia and improve the photodynamic therapy effect.

[0029] The wavelength of the near-infrared laser is 808±3 nanometers or 980±3 nanometers.

[0030] The advantages of the present application are:

[0031] (1) The manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material provided by the application focuses on the problems of diagnosis and treatment separation in the prior art, poor photodynamic therapy effect under the tumor hypoxic environment, and precise self-assembly controllable synthesis of high crystalline metal organic framework coated rare earth upconversion nanocrystal, and provides a manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material, a preparation method and application. The metal organic framework coated rare earth upconversion nanocrystal heterostructure is controllably synthesized by using a "solvent assisted self-assembly" method, and manganese dioxide is in-situ grown on the surface of the metal organic framework. The diagnosis and treatment preparation (or adjuvant) prepared from the composite material can transfer the upconversion emission of the UCNP to the metal organic framework by fluorescence resonance energy transfer under the excitation of near-infrared laser (808±3 or 980±3 nanometers), and manganese dioxide acts as a peroxide catalase to decompose hydrogen peroxide to generate oxygen, so that the purposes of relieving hypoxia and improving the photodynamic therapy effect are achieved. In addition, the composite material can realize synchronous upconversion fluorescence imaging and magnetic resonance imaging under the excitation of near-infrared laser.

[0032] (2) The manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material and the preparation method thereof provided by the application have the advantages of good dispersity, strong stability and good biocompatibility.

[0033] (3) The application of the manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material solves the problem of poor treatment effect of ordinary photodynamic therapy materials under the tumor hypoxic environment, and also realizes upconversion fluorescence imaging and magnetic resonance imaging.

[0034] (4) The metal organic framework coated rare earth upconversion nanocrystal heterostructure is controllably synthesized by using a "solvent assisted self-assembly" method in the application, and different volume ratios of N,N-dimethylformamide and ethanol solvents are used as the reaction environment for the epitaxial growth of the metal organic framework on the surface of the rare earth upconversion nanocrystal. N,N-dimethylformamide controls the deprotonation degree of the carboxylic acid ligand, ethanol acts as a structure directing agent in the crystal growth process to affect the bridging mode of the ligand and the polarity of the solvent medium, and adjusts the coordination environment in the assembly process. Therefore, a suitable solvent ratio is beneficial to the synthesis of a dispersed and stable heterostructure.

[0035] (5) In the application, the reaction of polyallylamine hydrochloride and potassium permanganate enables manganese dioxide to be in-situ grown on the surface of the metal organic framework coated rare earth upconversion nanocrystal heterostructure, the synthesis method is mild and simple, and the structure of manganese dioxide does not have long-term toxicity problems when used in the body.

[0036] The application will be further described in detail below with reference to the drawings and specific embodiments. BRIEF DESCRIPTION OF DRAWINGS

[0037] Figure 1 is a transmission electron microscope (TEM) photo of the manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material prepared in Embodiment 1 of the present application;

[0038] Figure 2 is an upconversion fluorescence spectrum of the manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material prepared in Embodiment 2 of the present application and an ultraviolet absorption spectrum of H2TCPP;

[0039] Figure 3 is a curve graph of the absorbance ratio of 1,3-diphenyl isobenzofuran (DPBF) caused by singlet oxygen generated under near-infrared light irradiation of the manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material prepared in Embodiment 5 of the present application and other control groups;

[0040] Figure 4 is a cell survival rate graph of the metal organic framework coated rare earth upconversion nanocrystal heterostructure prepared in Embodiment 6 of the present application after being co-incubated with HeLa cells;

[0041] Figure 5 is a cell survival rate graph of the manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material prepared in Embodiment 7 of the present application after being co-incubated with HeLa cells. DETAILED DESCRIPTION

[0042] Embodiment 1

[0043] Referring to the accompanying drawings, Figure 1 the present application provides a rare earth upconversion nanocrystal heterostructure composite material, a preparation method and an application. The rare earth upconversion nanocrystal is a core-shell structure with inert yttrium as a matrix, ytterbium as a sensitizer and Er as a light-emitting center, specifically, NaYF4:Yb / Er@NaYF4. The composite material is prepared for photodynamic therapy, and the near-infrared laser wavelength for exciting the photodynamic therapy effect is 980±3 nanometers.

[0044] The preparation method of the rare earth upconversion nanocrystal heterostructure composite material provided in the present embodiment comprises the following steps:

[0045] (1) Preparation of rare earth upconversion nanocrystal with carboxyl sites DHCA-UCNP: Take 0.5 mL of oil-soluble rare earth upconversion nanocrystal, and after standing and volatilization, disperse it in 1 mL of chloroform. After ultrasonic dispersion, add 5 mL of 3,4-dihydroxyphenylpropionic acid solution with a concentration of 10 mg / mL, stir at 45°C for 12 hours, centrifuge and wash until the supernatant is colorless, and disperse the solid in N,N-dimethylformamide to obtain a first dispersion liquid;

[0046] (2) Preparation of metal organic framework coated rare earth upconversion nanocrystal heterostructure UM: 4.5 mg of zirconium chloride and 1.5 mg of meso-tetra(4-carboxyphenyl) porphyrin were added to a mixed solution of N,N-dimethylformamide and ethanol in a volume ratio of (3:1) to obtain a corresponding solution, and then the zirconium chloride solution was added dropwise into the meso-tetra(4-carboxyphenyl) porphyrin solution, and the mixed solution was ultrasonically stirred for 10 minutes to obtain a first dispersion liquid with a concentration of 1 mg / mL, which was then added dropwise into 2 mL of the first dispersion liquid, and reacted at 120°C for 4 hours. After cooling to room temperature, centrifugal washing was performed, and the solid was dispersed in 2 mL of deionized water to obtain a second dispersion liquid;

[0047] (3) Preparation of manganese dioxide modified heterostructure UMMn: 10 mg of polyallylamine hydrochloride was added to 1 mL of the second dispersion liquid (5 mg / mL), and stirred at 600 rpm for 2 hours, and then 200 μL of an aqueous potassium permanganate solution (10 mg / mL) was added dropwise, and stirring was continued for 2 hours. After centrifugal washing, the solid was dispersed in 1 mL of deionized water to obtain a third dispersion liquid;

[0048] (4) Preparation of a composite material of a metal organic framework coated rare earth upconversion nanocrystal heterostructure with good biocompatibility and manganese dioxide modification UMMnP: 70 mg of polyallylamine hydrochloride, 25 mg of polyacrylic acid, 25 mg of polyethylene glycol with an amino group, and 25 mg of 1-ethyl-(3-dimethylaminopropyl) carbodiimide were dispersed in 10 mL of water to obtain corresponding aqueous solutions. 1 mL of the third dispersion liquid (5 mg / mL) was stirred with the polyallylamine hydrochloride aqueous solution for 2 hours, and then centrifugal washing was performed. Subsequently, the polyacrylic acid aqueous solution was added, and stirring was continued for 2 hours. After centrifugal washing, the polyethylene glycol aqueous solution with an amino group and the 1-ethyl-(3-dimethylaminopropyl) carbodiimide aqueous solution were added, and stirring was continued for 12 hours. After centrifugal washing, the solid was dispersed in 1 mL of deionized water to obtain a composite material of a metal organic framework coated rare earth upconversion nanocrystal heterostructure with good biocompatibility and manganese dioxide modification.

[0049] The preparation method of the above-mentioned composite material of a metal organic framework coated rare earth upconversion nanocrystal heterostructure with manganese dioxide modification provided in the present embodiment uses a "solvent-assisted self-assembly" method to controllably synthesize a dispersed and stable metal organic framework coated rare earth upconversion nanocrystal heterostructure, and manganese dioxide is grown in situ on the surface thereof. Finally, polyallylamine hydrochloride, polyacrylic acid, and polyethylene glycol with an amino group are used to improve biocompatibility. The obtained multi-layer structure composite material has the advantages of good dispersity, strong stability, and good biocompatibility, and the preparation method has the characteristics of mild conditions and strong repeatability.

[0050] The application of the manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material provided in the embodiment is to prepare the composite material into a photodynamic therapy agent. Under excitation of near-infrared laser (980±3 nm), the upconversion emission of the UCNP is transferred to the metal organic framework through fluorescence resonance energy transfer, and the manganese dioxide acts as a hydrogen peroxide catalase to decompose hydrogen peroxide into oxygen, so as to relieve hypoxia and improve the photodynamic therapy effect. In addition, the composite material can be used as a raw material to prepare an upconversion fluorescence imaging / magnetic resonance imaging agent capable of realizing upconversion fluorescence imaging and magnetic resonance imaging simultaneously.

[0051] The rare earth upconversion nanocrystal heterostructure composite material prepared in the embodiment is prepared by taking the oil-soluble rare earth upconversion nanocrystal with carboxyl on the surface of 3,4-dihydroxyphenylpropionic acid as a core, taking the epitaxially grown metal organic framework as a shell to form a heterostructure, growing manganese dioxide on the surface of the heterostructure in situ, and finally wrapping the polyallylamine hydrochloride, polyacrylic acid and polyethylene glycol with amino on the surface of the manganese dioxide to obtain the manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material with a multi-layer structure and good biocompatibility.

[0052] Figure 1 The TEM photo of the manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material prepared in the embodiment is shown in Fig. 2. Figure 1 It can be seen that the composite material has uniform particle size distribution, and the average particle size is about 50-60 nm. It is indicated that the method can obtain the composite material with uniform size and good monodispersity. Since the spherical and small-size material is more easily endocytosed by cells, it is of great significance for its use as a biological probe (or preparation into a corresponding reagent) to circulate in the body.

[0053] Embodiment 2

[0054] The rare earth upconversion nanocrystal heterostructure composite material, the preparation method and the application provided in the embodiment are basically the same as those in Embodiment 1, and the difference is that the rare earth upconversion nanocrystal in the embodiment is a core-shell structure taking inert gadolinium as a matrix, ytterbium as a sensitizer and Er as a light emitting center, specifically NaGdF4:Yb / Er@NaYF4. The preparation of the composite material produces a near-infrared excitation wavelength of 980±3 nm for photodynamic therapy effect.

[0055] The preparation method of the rare earth upconversion nanocrystal heterostructure composite material includes the following steps:

[0056] (1) Preparation of rare earth upconversion nanocrystals with carboxyl sites DHCA-UCNP: Take 0.5 mL of oil-soluble rare earth upconversion nanocrystals, and after standing and volatilization, disperse them in 1 mL of chloroform. After ultrasonic dispersion, add 5 mL of 3,4-dihydroxyphenylpropionic acid solution with a concentration of 15 mg / mL. Stir at 45°C for 12 hours. Centrifugal wash until the supernatant is colorless. Disperse the solid in N,N-dimethylformamide to obtain a first dispersion liquid;

[0057] (2) Preparation of metal organic framework coated rare earth upconversion nanocrystal heterostructure UM: Add 4.5 mg of zirconium chloride and 1.5 mg of meso-tetra(4-carboxyphenyl) porphyrin to a mixed solution of N,N-dimethylformamide and ethanol with a volume ratio of (3:1) to obtain corresponding solutions. Then, add the zirconium chloride solution dropwise into the meso-tetra(4-carboxyphenyl) porphyrin solution, and ultrasonic stir for 15 min to obtain a mixed solution. Add 1.5 mL of the first dispersion liquid with a concentration of 1 mg / mL dropwise into the mixed solution, and react at 120°C for 5 hours. Cool to room temperature, centrifugal wash, and disperse the solid in 1.5 mL of deionized water to obtain a second dispersion liquid;

[0058] (3) Preparation of manganese dioxide modified heterostructure UMMn: Add 10 mg of polyallylamine hydrochloride to 1 mL of the second dispersion liquid (5 mg / mL), and stir at 900 rpm for 2 hours. Then, add 300 μL of potassium permanganate aqueous solution (10 mg / mL) dropwise, and continue to stir for 2 hours. Centrifugal wash, and disperse the solid in 1 mL of deionized water to obtain a third dispersion liquid;

[0059] (4) Preparation of a composite material UMMnP of manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure with good biocompatibility: Disperse 50 mg of polyallylamine hydrochloride, 30 mg of polyacrylic acid, 30 mg of polyethylene glycol with amino groups, and 30 mg of 1-ethyl-(3-dimethylaminopropyl) carbonyldiimidazole in 10 mL of water to obtain corresponding aqueous solutions. Stir 1 mL of the third dispersion liquid (5 mg / mL) with the polyallylamine hydrochloride aqueous solution for 2 hours, and then centrifugal wash. Then, add the polyacrylic acid aqueous solution, and stir for 2 hours. After centrifugal washing, finally add the polyethylene glycol aqueous solution with amino groups and the 1-ethyl-(3-dimethylaminopropyl) carbonyldiimidazole aqueous solution, stir for 12 hours, centrifugal wash, and disperse the solid in 1 mL of deionized water to obtain a rare earth upconversion nanocrystal heterostructure composite material with high biocompatibility.

[0060] Figure 2The upconversion fluorescence spectrum of the manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material prepared in the embodiment under 980nm laser excitation and the ultraviolet absorption spectrum of H2TCPP are shown in the drawings. It is observed from the upconversion fluorescence spectrum that the composite material has emission peaks at 540nm and 654nm, which correspond to the 4I13 / 2→4I15 / 2 and 4I11 / 2→4I15 / 2 transitions of Er ions. 4 S 3 / 2 / 2 H 11 / 2 → 4 H 15 / 2 and 4 F 9 / 2 → 4 I 15 / 2 absorption peaks of H2TCPP at 536nm to 561nm and 637nm to 656nm are just overlapped with the emission peaks of Er ions at 540nm and 654nm, which meets the condition of fluorescence resonance energy transfer and supports the generation of subsequent photodynamic therapy, and the luminescence intensity of the composite material can still support upconversion fluorescence imaging.

[0061] Example 3

[0062] The rare earth upconversion nanocrystal heterostructure composite material, the preparation method and the application provided in the embodiment are basically the same as those in Examples 1 to 2, and the difference is that the rare earth upconversion nanocrystal in the embodiment is a core-shell structure with ytterbium as a matrix and a sensitizer and Er as a luminescent center, specifically NaYbF4:Er@NaYF4, and the near-infrared laser excitation wavelength for generating the photodynamic therapy effect of the composite material preparation is 980±3nm.

[0063] The preparation method of the rare earth upconversion nanocrystal heterostructure composite material comprises the following steps:

[0064] (1) Preparation of rare earth upconversion nanocrystal with carboxyl site DHCA-UCNP: take 0.5mL oil-soluble rare earth upconversion nanocrystal, disperse in 1mL chloroform after volatilization, and then add 5mL 3,4-dihydroxyphenylpropionic acid solution with a concentration of 20mg / mL, stir at 45℃ for 24 hours, centrifuge and wash until the supernatant is colorless, disperse the solid in N,N-dimethylformamide to obtain a first dispersion liquid;

[0065] (2) Preparation of metal organic framework coated rare earth upconversion nanocrystal heterostructure UM: 4.5 mg of zirconium chloride and 1.5 mg of meso-tetra(4-carboxyphenyl) porphyrin were added to a mixed solution of N,N-dimethylformamide and ethanol in a volume ratio of (5:1) respectively, then the zirconium chloride solution was added dropwise into the meso-tetra(4-carboxyphenyl) porphyrin solution, and a mixed solution was obtained by ultrasonic stirring for 10 min. 2 mL of the first dispersion solution with a concentration of 1 mg / mL was added dropwise into the mixed solution, and the reaction was carried out at 90°C for 5 hours. After cooling to room temperature, centrifugal washing was performed, and the solid was dispersed in 2 mL of deionized water to obtain a second dispersion solution;

[0066] (3) Preparation of manganese dioxide modified heterostructure UMMn: 10 mg of polyallylamine hydrochloride was added to 1 mL of the second dispersion solution (5 mg / mL), and stirred at 600 rpm for 2 hours. Then, 200 μL of potassium permanganate aqueous solution (10 mg / mL) was added dropwise, and the stirring was continued for 2 hours. After centrifugal washing, the solid was dispersed in 1 mL of deionized water to obtain a third dispersion solution;

[0067] (4) Preparation of a composite material of manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure with good biocompatibility UMMnP: 70 mg of polyallylamine hydrochloride, 25 mg of polyacrylic acid, 25 mg of polyethylene glycol with amino group, and 25 mg of 1-ethyl-(3-dimethylaminopropyl) carbodiimide were dispersed in 10 mL of water respectively to obtain corresponding aqueous solutions. 1 mL of the third dispersion solution (5 mg / mL) was stirred with the polyallylamine hydrochloride aqueous solution for 2 hours, and then centrifugal washing was performed. Subsequently, the polyacrylic acid aqueous solution was added, and stirring was continued for 2 hours. After centrifugal washing, the polyethylene glycol aqueous solution with amino group and the 1-ethyl-(3-dimethylaminopropyl) carbodiimide aqueous solution were finally added, and stirring was continued for 12 hours. After centrifugal washing, the solid was dispersed in 1 mL of deionized water to obtain a rare earth upconversion nanocrystal heterostructure composite material with high biocompatibility.

[0068] Example 4

[0069] The rare earth upconversion nanocrystal heterostructure composite material, preparation method and application provided in the embodiment are basically the same as those in Examples 1-3, and the difference is that the rare earth upconversion nanocrystal in the embodiment is a core-shell structure with inert yttrium as a matrix, neodymium as a sensitizer, and Er as a luminescent center, specifically NaYF4: Yb / Er@NaYF4: Yb / Nd. The near-infrared laser excitation wavelength of the preparation of the composite material is 808±3 nm.

[0070] The preparation method of the rare earth upconversion nanocrystal heterostructure composite material comprises the following steps:

[0071] (1) Preparation of rare earth upconversion nanocrystals with carboxyl sites DHCA-UCNP: Take 0.5 mL of oil-soluble rare earth upconversion nanocrystals, and after standing and volatilization, disperse them in 1 mL of chloroform. After ultrasonic dispersion, add 5 mL of 3,4-dihydroxyphenylpropionic acid solution with a concentration of 15 mg / mL. Stir at 45°C for 24 hours. Centrifugal wash until the supernatant is colorless. Disperse the solid in N,N-dimethylformamide to obtain a first dispersion liquid;

[0072] (2) Preparation of metal organic framework coated rare earth upconversion nanocrystal heterostructure UM: Add 4.5 mg of zirconium chloride and 1.5 mg of meso-tetra(4-carboxyphenyl) porphyrin to a mixed solution of N,N-dimethylformamide and ethanol in a volume ratio of (1:1) to obtain corresponding solutions. Then, add the zirconium chloride solution dropwise into the meso-tetra(4-carboxyphenyl) porphyrin solution, and ultrasonically stir for 10 minutes to obtain a mixed solution. Add 1 mL of the first dispersion liquid with a concentration of 1 mg / mL dropwise into the mixed solution, and react at 110°C for 6 hours. Cool to room temperature, centrifugal wash, and disperse the solid in 1 mL of deionized water to obtain a second dispersion liquid;

[0073] (3) Preparation of manganese dioxide modified heterostructure UMMn: Add 10 mg of polyallylamine hydrochloride to 1 mL of the second dispersion liquid (5 mg / mL), and stir at 900 rpm for 2 hours. Then, add 150 μL of potassium permanganate aqueous solution (10 mg / mL) dropwise, and continue to stir for 2 hours. Centrifugal wash, and disperse the solid in 1 mL of deionized water to obtain a third dispersion liquid;

[0074] (4) Preparation of a composite material of manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure with good biocompatibility UMMnP: Disperse 60 mg of polyallylamine hydrochloride, 20 mg of polyacrylic acid, 20 mg of polyethylene glycol with amino groups, and 20 mg of 1-ethyl-(3-dimethylaminopropyl) carbonyldiimidazole in 10 mL of water to obtain corresponding aqueous solutions. Stir 1 mL of the third dispersion liquid (5 mg / mL) with the polyallylamine hydrochloride aqueous solution for 2 hours, and then centrifugal wash. Then, add the polyacrylic acid aqueous solution, stir for 2 hours, centrifugal wash, and finally add the polyethylene glycol aqueous solution with amino groups and the 1-ethyl-(3-dimethylaminopropyl) carbonyldiimidazole aqueous solution, stir for 12 hours, centrifugal wash, and disperse the solid in 1 mL of deionized water to obtain a rare earth upconversion nanocrystal heterostructure composite material with high biocompatibility.

[0075] Example 5

[0076] The rare earth upconversion nanocrystal heterostructure composite material, the preparation method and the application provided by the embodiment are basically the same as those of the embodiments 1-4, and the difference is that the rare earth upconversion nanocrystal in the embodiment is a core structure with inert yttrium as a matrix, ytterbium as a sensitizer and Er as a light-emitting center, specifically NaYF4:Yb / Er. The excitation wavelength of the near-infrared laser for producing the photodynamic therapy effect of the preparation of the composite material is 980±3 nanometers.

[0077] The preparation method of the rare earth upconversion nanocrystal heterostructure composite material comprises the following steps:

[0078] (1) Preparation of rare earth upconversion nanocrystal with carboxyl site DHCA-UCNP: Take 0.5 mL of oil-soluble rare earth upconversion nanocrystal, disperse in 1 mL of chloroform after standing and volatilizing, and then add 5 mL of 3,4-dihydroxyphenylpropionic acid solution with a concentration of 10 mg / mL. Stir at 45℃ for 24 hours, centrifuge and wash until the supernatant is colorless, disperse the solid in N,N-dimethylformamide to obtain a first dispersion liquid;

[0079] (2) Preparation of metal organic framework coated rare earth upconversion nanocrystal heterostructure UM: Add 4.5 mg of zirconium chloride and 1.5 mg of meso-tetra(4-carboxyphenyl) porphyrin to a mixed solution of N,N-dimethylformamide and ethanol with a volume ratio of (3:1) to obtain a corresponding solution. Then, add the zirconium chloride solution dropwise into the meso-tetra(4-carboxyphenyl) porphyrin solution, and ultrasonically stir for 10 minutes to obtain a mixed solution. Take 2 mL of the first dispersion liquid with a concentration of 1 mg / mL and add it into the mixed solution. React at 120℃ for 5 hours, cool to room temperature, centrifuge and wash, and disperse the solid in 2 mL of deionized water to obtain a second dispersion liquid;

[0080] (3) Preparation of manganese dioxide modified heterostructure UMMn: Add 10 mg of polyallylamine hydrochloride to 1 mL of the second dispersion liquid (5 mg / mL) and stir at 900 r / min for 2 hours. Then, add 200 μL of potassium permanganate aqueous solution (10 mg / mL) dropwise, continue to stir for 2 hours, centrifuge and wash, and disperse the solid in 1 mL of deionized water to obtain a third dispersion liquid;

[0081] (4) Preparation of manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material UMMnP: 70 mg of polyallylamine hydrochloride, 25 mg of polyacrylic acid, 25 mg of polyethylene glycol with amino group, and 25 mg of 1-ethyl-(3-dimethylaminopropyl) carbonyl diimide are dispersed in 10 mL of water to obtain corresponding aqueous solutions. 1 mL of the third dispersion (5 mg / mL) is stirred with the polyallylamine hydrochloride aqueous solution for 2 hours, and then centrifuged and washed with water. Subsequently, the polyacrylic acid aqueous solution is added, stirred for 2 hours, and then centrifuged and washed. Finally, the polyethylene glycol with amino group aqueous solution and the 1-ethyl-(3-dimethylaminopropyl) carbonyl diimide aqueous solution are added, stirred for 12 hours, and then centrifuged and washed. The solid is dispersed in 1 mL of deionized water to obtain a rare earth upconversion nanocrystal heterostructure composite material with high biocompatibility.

[0082] Figure 3 is a curve graph of the absorbance ratio of 1,3-diphenyl isobenzofuran (DPBF) caused by singlet oxygen generated by the manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material prepared in this example and other control groups under near-infrared light irradiation. H2O, UM, UMMnP, and UMMnP+H2O2 are mixed with the singlet oxygen indicator DPBF. The decrease in the absorbance ratio of DPBF under 980 nm laser excitation proves the generation of singlet oxygen. The more the absorbance ratio decreases, the more singlet oxygen is generated. As can be seen from the graph, the absorbance ratio of UMMnP+H2O2 decreases the most, thereby proving that MnO2 has the function of a catalase-like hydrogen peroxide catalase.

[0083] Example 6

[0084] The rare earth upconversion nanocrystal heterostructure composite material, preparation method, and application provided in this example are basically the same as those in Examples 1-5, except that the preparation method uses inert gadolinium as the matrix, ytterbium as the sensitizer, and Er as the luminescent center of the core structure, specifically NaGdF4:Yb / Er. The preparation of the composite material produces a photodynamic therapy effect under near-infrared laser excitation at a wavelength of 980±3 nm.

[0085] The preparation method of the rare earth upconversion nanocrystal heterostructure composite material includes the following steps:

[0086] (1) Preparation of rare earth upconversion nanocrystals with carboxyl sites DHCA-UCNP: Take 0.5 mL of oil-soluble rare earth upconversion nanocrystals, and after standing and volatilization, disperse them in 1 mL of chloroform. After ultrasonic dispersion, add 5 mL of 3,4-dihydroxyphenylpropionic acid solution with a concentration of 15 mg / mL. Stir at 45°C for 12 hours. Centrifugal wash until the supernatant is colorless. Disperse the solid in N,N-dimethylformamide to obtain a first dispersion liquid;

[0087] (2) Preparation of metal organic framework coated rare earth upconversion nanocrystal heterostructure UM: Add 4.5 mg of zirconium chloride and 1.5 mg of meso-tetra(4-carboxyphenyl) porphyrin to a mixed solution of N,N-dimethylformamide and ethanol with a volume ratio of (3:1) to obtain corresponding solutions. Then, add the zirconium chloride solution dropwise into the meso-tetra(4-carboxyphenyl) porphyrin solution, and ultrasonically stir for 15 min to obtain a mixed solution. Add 2 mL of the first dispersion liquid with a concentration of 1 mg / mL dropwise into the mixed solution, and react at 120°C for 5 hours. Cool to room temperature, centrifugal wash, and disperse the solid in 2 mL of deionized water to obtain a second dispersion liquid;

[0088] (3) Preparation of manganese dioxide modified heterostructure UMMn: Add 10 mg of polyallylamine hydrochloride to 1 mL of the second dispersion liquid (5 mg / mL), and stir at 900 rpm for 2 hours. Then, add 200 μL of potassium permanganate aqueous solution (10 mg / mL) dropwise, continue to stir for 2 hours, centrifugal wash, and disperse the solid in 1 mL of deionized water to obtain a third dispersion liquid;

[0089] (4) Preparation of a composite material UMMnP of a metal organic framework coated rare earth upconversion nanocrystal heterostructure with good biocompatibility modified by manganese dioxide: Disperse 100 mg of polyallylamine hydrochloride, 50 mg of polyacrylic acid, 50 mg of polyethylene glycol with amino groups, and 50 mg of 1-ethyl-(3-dimethylaminopropyl) carbonyldiimidazole in 10 mL of water to obtain corresponding aqueous solutions. Stir 1 mL of the third dispersion liquid (5 mg / mL) with the polyallylamine hydrochloride aqueous solution for 2 hours, and then centrifugal wash. Then, add the polyacrylic acid aqueous solution, stir for 2 hours, centrifugal wash, and finally add the polyethylene glycol aqueous solution with amino groups and the 1-ethyl-(3-dimethylaminopropyl) carbonyldiimidazole aqueous solution, stir for 12 hours, centrifugal wash, and disperse the solid in 1 mL of deionized water to obtain a rare earth upconversion nanocrystal heterostructure composite material with high biocompatibility and good biocompatibility.

[0090] Figure 4Figure 4 is a cell survival rate diagram of the metal organic framework coated rare earth upconversion nanocrystal heterostructure prepared in the embodiment and HeLa cells after co-incubation, from which it can be seen that the cell survival rate of the HeLa cells after co-incubation with 0-200 μg / mL UM for 12 hours is above 80%, and the cytotoxicity can be basically ignored.

[0091] Embodiment 7

[0092] The rare earth upconversion nanocrystal heterostructure composite material, the preparation method and the application provided in the embodiment are basically the same as those in Embodiments 1-6, and the difference is that the rare earth upconversion nanocrystal in the embodiment is a core structure with ytterbium as a matrix and a sensitizer and Er as a luminescent center, specifically NaYbF4:Er. The laser excitation wavelength for producing a photodynamic therapy effect of the preparation of the composite material is 980±3 nanometers.

[0093] The preparation method of the rare earth upconversion nanocrystal heterostructure composite material comprises the following steps:

[0094] (1) Preparation of rare earth upconversion nanocrystal with carboxyl sites DHCA-UCNP: Take 0.5 mL of oil-soluble rare earth upconversion nanocrystal, disperse in 1 mL of chloroform after standing and volatilizing, and then add 5 mL of 3,4-dihydroxyphenylpropionic acid solution with a concentration of 20 mg / mL. Stir at 45°C for 24 hours, centrifuge and wash until the supernatant is colorless, disperse the solid in N,N-dimethylformamide to obtain a first dispersion liquid;

[0095] (2) Preparation of metal organic framework coated rare earth upconversion nanocrystal heterostructure UM: Add 4.5 mg of zirconium chloride and 1.5 mg of meso-tetra(4-carboxyphenyl) porphyrin to a mixed solution of N,N-dimethylformamide and ethanol with a volume ratio of (5:1) to obtain corresponding solutions, then add the zirconium chloride solution dropwise into the meso-tetra(4-carboxyphenyl) porphyrin solution, and ultrasonically stir for 10 minutes to obtain a mixed solution. Take 2 mL of the first dispersion liquid with a concentration of 1 mg / mL and add it into the mixed solution, and react at 120°C for 5 hours. Cool to room temperature, centrifuge and wash, and disperse the solid in 2 mL of deionized water to obtain a second dispersion liquid;

[0096] (3) Preparation of manganese dioxide modified heterostructure UMMn: Add 10 mg of polyallylamine hydrochloride to 1 mL of the second dispersion liquid (5 mg / mL) and stir at 600 rpm for 2 hours, then add 200 μL of potassium permanganate aqueous solution (10 mg / mL) dropwise, continue to stir for 2 hours, centrifuge and wash, and disperse the solid in 1 mL of deionized water to obtain a third dispersion liquid;

[0097] (4) Preparation of manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material UMMnP with good biocompatibility: 70 mg of polyallylamine hydrochloride, 25 mg of polyacrylic acid, 25 mg of polyethylene glycol with amino group, and 25 mg of 1-ethyl-(3-dimethylaminopropyl) carbodiimide were dispersed in 10 mL of water to obtain corresponding aqueous solutions. 1 mL of the third dispersion (5 mg / mL) was stirred with the polyallylamine hydrochloride aqueous solution for 2 hours, and then centrifuged and washed with water. Subsequently, the polyacrylic acid aqueous solution was added, stirred for 2 hours, and then centrifuged and washed. Finally, the polyethylene glycol with amino group aqueous solution and the 1-ethyl-(3-dimethylaminopropyl) carbodiimide aqueous solution were added, stirred for 12 hours, and then centrifuged and washed. The solid was dispersed in 1 mL of deionized water to obtain a rare earth upconversion nanocrystal heterostructure composite material with high biocompatibility.

[0098] Figure 5 Figure is a cell survival rate diagram of the manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material prepared in this embodiment after being incubated with HeLa cells. As can be seen from the figure, after 0-200 μg / mL of UMMnP was incubated with HeLa cells for 12 hours, the cell survival rate was all above 83%, and the cytotoxicity could be basically ignored.

[0099] The manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material of each of the foregoing embodiments is used as a raw material for preparing an upconversion imaging / magnetic resonance imaging agent, and an upconversion imaging / magnetic resonance imaging agent is prepared.

[0100] The manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material of each of the foregoing embodiments is used as a raw material to prepare a photodynamic therapy agent. Under the excitation of near-infrared laser (808±3 or 980±3 nanometers), the upconversion emission of the UCNP is transferred to the metal organic framework through fluorescence resonance energy transfer, and at the same time, the manganese dioxide acts as a peroxide catalase to decompose hydrogen peroxide to generate oxygen, achieving the purpose of relieving hypoxia and improving the effect of photodynamic therapy.

[0101] The application provides a manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material, a preparation method and application, and the metal organic framework coated rare earth upconversion nanocrystal heterostructure is controllably synthesized in dispersion and stability by adopting a "solvent assisted self-assembly" method, mainly by adjusting the volume ratio of solvents, and then manganese dioxide is in-situ grown on the surface of the metal organic framework. The composite material can be prepared into a photodynamic therapy agent, under excitation of near-infrared laser (808±3 or 980±3 nanometers), upconversion emission of the UCNP is transferred to the metal organic framework through fluorescence resonance energy transfer, and the manganese dioxide acts as a peroxide catalase to decompose hydrogen peroxide into oxygen, so that the purpose of relieving hypoxia and improving photodynamic therapy effect is achieved. In addition, the composite material can also be prepared into a diagnosis and treatment preparation, and synchronous upconversion fluorescence imaging and magnetic resonance imaging are realized.

[0102] The application is not limited to the above-mentioned embodiments, and other heterostructures based on the metal organic framework coated rare earth upconversion nanocrystals, such as Er ion doped rare earth upconversion nanocrystals NaYF4:Yb / Er, NaYF4:Yb / Er / Tm, NaYF4:Yb / Er@NaYF4, NaYbF4:Er, NaYbF4:Er@NaYF4, NaGdF4:Yb / Er, NaGdF4:Yb / Er@NaYF4, NaYF4:Yb / Er@NaYF4:Yb / Nd and the like with different cores, core-shell and core-shell-shell structures, obtained by the same or similar method can also achieve the technical effects described in the application.

[0103] The composite material of the manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure, the preparation method provided by the embodiment of the application have the focuses that first, the oil-soluble rare earth upconversion nanocrystal (UCNP) is functionalized to carboxyl on the surface by 3,4-dihydroxyphenyl propionic acid (DHCA) through ligand exchange method, the carboxyl site can be coordinated with metal, so that the metal organic framework is epitaxially grown on the surface of the rare earth upconversion nanocrystal and forms a heterostructure; second, the polyallylamine hydrochloride is reacted with potassium permanganate to make manganese dioxide grow in situ on the surface of the heterostructure; finally, the biocompatibility of the composite material is improved by using polyallylamine hydrochloride, polyacrylic acid and polyethylene glycol with amino groups, so that the composite material of the manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure with good biocompatibility is obtained. Under the excitation of near-infrared laser (808±3 or 980±3 nanometers), the upconversion emission of the UCNP is transferred to the metal organic framework through fluorescence resonance energy transfer, and the manganese dioxide acts as a hydrogen peroxide catalase to decompose hydrogen peroxide to generate oxygen, so as to relieve anoxia and improve the effect of photodynamic therapy. The composite material provided by the application has uniform size, strong stability and good biocompatibility, and can be applied to upconversion fluorescence / magnetic resonance dual-mode imaging guided photodynamic therapy. The preparation method provided by the application has the characteristics of mild and simple synthesis conditions, high repeatability and the like.

[0104] The above description is only the preferred embodiment of the application, and does not limit the application in any form. Any person skilled in the art can make many possible changes or equivalent modifications to the technical solution of the application within the scope of the application without departing from the scope of the application. Therefore, equivalent modifications made according to the structure, configuration and principle of the application within the scope of the application should be covered by the protection scope of the application.

Claims

1. A method for preparing a rare earth upconversion nanocrystal heterostructure composite material, characterized in that, The method comprises the following steps: (1) preparing rare earth upconversion nanocrystals with carboxyl sites DHCA-UCNP: mixing oil-soluble rare earth upconversion nanocrystals dispersed in cyclohexane with 3,4-dihydroxyphenyl propionic acid solution, stirring at a set temperature for a set time, centrifugal washing, taking the solid and dispersing in N,N-dimethylformamide to obtain a first dispersion liquid; The oil-soluble rare earth upconversion nanocrystals are one of NaYF4:Yb / Er, NaYF4:Yb / Er / Tm, NaYbF4:Er, NaGdF4:Yb / Er, NaYF4:Yb / Er@NaYF4, NaYbF4:Er@NaYF4, NaGdF4:Yb / Er@NaYF4, and NaYF4:Yb / Er@NaYF4:Yb / Nd, with Er as the light-emitting center; (2) preparing a metal organic framework coated rare earth upconversion nanocrystal heterostructure UM: dispersing zirconium chloride and meso-tetra (4-carboxyphenyl) porphyrin H2TCPP in a mixed solution of N,N-dimethylformamide and ethanol in a set volume ratio, ultrasonic dispersion, then adding a set amount of the first dispersion liquid, reacting at a set temperature for a set time, centrifugal washing, taking the solid and dispersing in deionized water to obtain a second dispersion liquid; (3) preparing a manganese dioxide modified heterostructure UMMn: adding a set amount of polyallylamine hydrochloride and potassium permanganate into the second dispersion liquid in sequence, ultrasonic stirring, centrifugal washing, taking the solid and dispersing in deionized water to obtain a third dispersion liquid; (4) preparing a manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material UMMnP with good biocompatibility: stirring the third dispersion liquid with cationic polymer polyallylamine hydrochloride and anionic polymer polyacrylic acid for a set time, centrifugal washing, taking the solid, re-dispersing and reacting with polyethylene glycol with amino groups and 1-ethyl- (3-dimethylaminopropyl) carbonyl diimide overnight, centrifugal washing, taking the solid and dispersing in deionized water to obtain the final manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material with good biocompatibility.

2. The production method according to claim 1, characterized by, The first dispersion liquid in the preparation step (1) has the following specific steps: 0.5 mL of oil-soluble rare earth upconversion nanocrystals are taken, volatilized and dispersed in 1 mL of chloroform, ultrasonic dispersion is performed, 5 mL of 3,4-dihydroxyphenyl propionic acid solution with a concentration of 5-20 mg / mL is added, stirring is performed at 45°C for 12-24 hours, centrifugal washing is performed until the supernatant is colorless, the solid is taken and dispersed in N,N-dimethylformamide to obtain the first dispersion liquid.

3. The preparation method according to claim 1, characterized in that, The second dispersion liquid in the preparation step (2) has the following specific steps: To the mixed solution of N,N-dimethylformamide and ethanol with volume ratio of (5:1)~(1:1), 4.5mg zirconium chloride, 1.5 mg meso-tetra(4-carboxyphenyl)porphyrin were added respectively to obtain the corresponding solution, then the zirconium chloride solution was added dropwise into the meso-tetra(4-carboxyphenyl)porphyrin solution, and a mixed solution was obtained by ultrasonic stirring for 10~20 minutes, 1~3 mL of the first dispersion liquid with a concentration of 1 mg / mL was added dropwise, and the reaction was carried out at 90~120℃ for 4~6 hours, then the solution was cooled to room temperature, centrifuged and washed, the solid was dispersed in 1~3 mL of deionized water to obtain the second dispersion liquid.

4. The method of claim 1, wherein, The third dispersion liquid was prepared according to the preparation step (3), and the specific steps were as follows: To 1 mL of the second dispersion liquid with a concentration of 5 mg / mL, 5~20 mg of polyallylamine hydrochloride was added, and stirred at 600~900 rpm for 2 hours, then 100~300 μL of potassium permanganate aqueous solution with a concentration of 10 mg / mL was added dropwise, and the stirring was continued for 2 hours, then the solution was centrifuged and washed, the solid was dispersed in 1 mL of deionized water to obtain the third dispersion liquid.

5. The preparation method according to claim 1, characterized in that, The specific steps in step (4) were as follows: 50~100 mg of polyallylamine hydrochloride, 20~50 mg of polyacrylic acid, 20~50 mg of polyethylene glycol with amino group, and 10~25 mg of 1-ethyl-(3-dimethylaminopropyl) carbodiimide were dispersed in 10 mL of water respectively to obtain the corresponding aqueous solution, 1 mL of the third dispersion liquid with a concentration of 5 mg / mL was stirred with the polyallylamine hydrochloride aqueous solution for 2 hours, then centrifuged and washed with water, then the polyacrylic acid aqueous solution was added, and stirred for 2 hours, then centrifuged and washed, finally the polyethylene glycol with amino group aqueous solution and the 1-ethyl-(3-dimethylaminopropyl) carbodiimide aqueous solution were added, and stirred for 12 hours, then centrifuged and washed, and the solid was dispersed in 1 mL of deionized water to obtain the high biocompatibility manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material.

6. A rare earth upconversion nanocrystal heterostructure composite material, characterized in that, It is obtained by the preparation method of claim 1, using 3,4-dihydroxyphenylpropionic acid with carboxyl on the surface as the oil-soluble rare earth upconversion nanocrystal as the core, and using the epitaxially grown metal organic framework as the shell to form a heterostructure, then growing manganese dioxide on the surface of the heterostructure in situ, and finally wrapping polyallylamine hydrochloride, polyacrylic acid and polyethylene glycol with amino group on the surface of the manganese dioxide to obtain the manganese dioxide modified metal organic framework coated rare earth upconversion nanocrystal heterostructure composite material with a multi-layer structure and good biocompatibility.

7. The use of a rare earth upconversion nanocrystal heterostructure composite according to claim 6, wherein, It is used as a raw material for preparing an upconversion fluorescence / magnetic resonance dual-mode imaging agent, and the upconversion fluorescence / magnetic resonance dual-mode imaging agent prepared therefrom can simultaneously perform upconversion fluorescence imaging and magnetic resonance imaging under near-infrared laser excitation.

8. The use of the rare earth upconversion nanocrystal heterostructure composite material according to claim 6, characterized in that, It is used as a raw material for preparing a photodynamic therapy agent, and the photodynamic therapy agent prepared therefrom can transfer the upconversion emission of the UCNC to the metal organic framework through fluorescence resonance energy transfer under near-infrared light excitation, and the manganese dioxide acts as a peroxide catalase to decompose hydrogen peroxide into oxygen.

9. Use of a rare earth upconversion nanocrystal heterostructure composite material according to one of claims 7 or 8, characterized in that, The wavelength of the near-infrared laser is 808±3 nanometers or 980±3 nanometers. The wavelength of the near-infrared laser is 808±3 nanometers or 980±3 nanometers.

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