Rare earth up-conversion nanocrystalline particle-hydrogen bond organic framework composite material and preparation method thereof

Abstract

The invention belongs to the field of biomedical luminescent composite materials, and particularly relates to a rare earth up-conversion nanocrystalline particle-hydrogen bond organic framework composite material and a preparation method thereof.The rare earth up-conversion nanocrystalline particle NaGdF4: Yb / Er serves as a core of the composite material, a hydrogen bond organic framework serves as a shell of the composite material, and the rare earth up-conversion nanocrystalline particle-hydrogen bond organic framework composite material is prepared. The advantages of the rare earth up-conversion nanocrystal particles and the hydrogen bond organic framework are ingeniously combined, the rare earth up-conversion nanocrystal particles and the hydrogen bond organic framework form a synergistic system, active oxygen is generated under excitation of 980 nm near-infrared light during photodynamic therapy, meanwhile, generation of the active oxygen is more efficient, the killing efficiency on tumor cells is improved, and the application prospect is wide. The rare earth up-conversion nanocrystal particle is suitable for deep tumor (such as brain glioma) treatment, meanwhile, the porphyrin core of TCPP is matched with the visible light emission spectrum of the rare earth up-conversion nanocrystal particle, efficient energy transfer is achieved, and the singlet oxygen yield is remarkably higher than that of a traditional PDT material.

Description

Technical Field

[0001] The present invention belongs to the field of biomedical luminescent composite materials, and specifically relates to a rare earth upconversion nanocrystalline particle-hydrogen bond organic framework composite material and a preparation method thereof. In the composite material, hydrogen bond organic frameworks (HOFs) tightly wrap upconversion nanoparticles to form good fluorescence resonance energy transfer, and the hydrogen bond organic frameworks HOFs are excited to produce a large amount of singlet oxygen, which can induce oxidative stress damage to tumor cells, and has good treatment prospects for deep tumors such as brain gliomas. Background Art

[0002] Cancer is a very harmful disease that seriously threatens the health of all mankind. Cancer treatments include surgery, radiotherapy, chemotherapy, immunotherapy, phototherapy, targeted therapy, etc. Among them, photodynamic therapy (PDT) in phototherapy is a non-invasive, low-toxic, high-temporal and spatial precision treatment with few side effects. It has good prospects in cancer treatment and is considered a promising cancer treatment. The principle of photodynamic therapy is to use a laser of a specific wavelength to irradiate the photosensitizer to excite it. The excited photosensitizer transfers energy to the surrounding oxygen to generate reactive oxygen species. The reactive oxygen species undergoes an oxidation reaction with the adjacent biomacromolecules to produce cytotoxicity, which in turn causes cell damage or even death. Photodynamic therapy is inseparable from the three conditions of photosensitizer, excitation light source, and oxygen. Currently, the most commonly used photosensitizer molecules mainly absorb light in the ultraviolet or visible light region. However, due to the limited penetration depth of short-wavelength light, there are certain limitations for the treatment of tumors in deep tissues. At the same time, the reactive oxygen molecules generated by the photosensitizer have a short life span and limited diffusion distance, which also limits the application of PDT in the treatment of tumors deep in tissues or larger in size.

[0003] Therefore, it is urgent to find a photosensitizer with a simple synthesis process that can directly generate reactive oxygen species under the same visible light or near-infrared (NIR) light trigger. At present, organic framework compounds formed by metal coordination bonds and covalent bonds have the characteristics of structural adjustability, high specific surface area and ordered pore structure, and are widely used in biomedical imaging and cancer treatment. Materials such as metal organic frameworks (MOFs) and covalent organic frameworks (COFs) can be used for tumor cell phototherapy. However, the preparation process of MOFs and COFs requires the introduction of metal ions or organic solvents, which will bring potential toxicity problems to practical applications.

[0004] Hydrogen-bonded organic frameworks (HOFs) are self-assembled through hydrogen-bond interactions between organic ligands. They have mild preparation conditions, no metal doping, good biosafety and excellent biocompatibility, rich chemical functions and adjustable porosity, and have unique advantages in the fields of biotechnology and biomedicine. At present, the application of HOFs in the biomedical field is mainly used as a carrier for enzyme / protein protection. For example, CN119524159A discloses a sonodynamic targeted drug-loaded nanoparticle, including a porous carrier, a drug loaded in the porous carrier, and a targeting ligand chemically modified on the outer surface of the porous carrier; the porous carrier is a hydrogen-bonded organic framework; the building unit of the hydrogen-bonded organic framework is a metal porphyrin complex. CN119431813A discloses a hydrogen-bonded organic framework material for flue gas desulfurization, wherein the organic soft porous framework material is activated at minus 87°C to minus 20°C, and the activated crystal powder is placed in a carbon dioxide atmosphere for 6 to 12 hours. A vacuum pump is used to evacuate for 1 to 2 hours to remove the carbon dioxide molecules to obtain the hydrogen-bonded organic framework material. CN118240228A discloses a hypoxia-responsive protein-carrying hydrogen-bonded organic framework, which increases the physiological stability of the hydrogen-bonded organic framework by modifying polyethylene glycol molecules on the side arms of the ligand molecules, and uses azo bonds as hypoxia-responsive elements to achieve the response of the hydrogen-bonded organic framework to the hypoxic environment and the controllable protein release effect. At the same time, the application of the hypoxia-responsive protein-carrying hydrogen-bonded organic framework in the preparation of anti-tumor drugs is provided.

[0005] With the advancement of technology, studies have found that some hydrogen-bonded organic frameworks (HOFs) exhibit certain optical activity due to the specific functional organic molecules contained in their structures, which can be used to achieve energy transfer; in addition, studies have also found that some HOFs contain components suitable for producing singlet oxygen or other active oxygen species, which can directly participate in the photosensitization process in photodynamic therapy. For example, CN113150297B discloses a two-dimensional mesoporous hydrogen-bonded organic framework material and a preparation method thereof. The tetracarboxylic acid monomer molecules constituting the hydrogen-bonded organic framework material are synthesized by Suzuki coupling reaction. The hydrogen-bonded organic framework material has a large pore size, a high specific surface area, and excellent thermal stability and chemical stability; the hydrogen-bonded organic framework material can be loaded onto a cotton textile by a drop coating method to obtain a hydrogen-bonded organic framework fiber composite material. The composite material can efficiently kill bacteria under light conditions. CN117701281A discloses a metal-organic framework and fluoride nanocrystal composite photon functional material, which uses a composite strategy driven by electrostatic interaction to directly interact and composite different metal-organic frameworks with the surface of fluoride nanocrystals to form a rich photon functional composite material. The composite material combines the excellent biocompatibility of metal-organic framework materials and the upconversion fluorescence performance of fluoride nanocrystals, can be further functionalized and modified, and is a biological nanoprobe material with great application prospects. CN109172587A discloses a preparation method of a metal-organic framework-upconversion nanosystem with pH-responsive dual-drug release, which uses a polymer modification method to improve the water solubility of upconversion nanocrystals with core-shell structure, and then grows the metal-organic framework on the surface of upconversion luminescent nanocrystals to obtain a metal-organic framework-coated upconversion nanosystem; connects doxorubicin hydrochloride containing an amino group to the surface of the metal-organic framework, and then adsorbs other anticancer drugs into the porous structure of the metal-organic framework to obtain a dual-drug loaded metal-organic framework-upconversion nanosystem.

[0006] Although hydrogen-bonded organic frameworks (HOFs) have excellent properties, existing HOFs often have active sites that participate in the construction of hydrogen-bonded networks and are occupied, and light excitation in the visible light region leads to deficiencies in the treatment of deep-seated tumors in the body, which affects their further effective use. Therefore, it is necessary to develop new HOFs composite materials through structural modification, surface modification and other methods, in order to obtain materials with efficient photosensitization ability and near-infrared excitation to solve the problem of tissue penetration depth. Summary of the invention

[0007] In order to solve the defects in the prior art, the present invention provides a rare earth upconversion nanocrystalline particle-hydrogen bond organic framework composite material and a preparation method thereof. The composite material is composed of rare earth upconversion nanocrystalline particles NaGdF 4:Yb / Er as the core and the hydrogen bond organic framework as the shell. The composite material generates active oxygen under the excitation of 980 nm near-infrared light when used in photodynamic therapy. The rare earth upconversion nanocrystalline particles NaGdF 4 :Yb / Er, the amount of Yb is NaGdF 4 The molar amount of Er is 15% to 35%, and the amount of Er is NaGdF 4 The molar amount is 1% to 5%, and the hydrogen-bonded organic framework is formed by self-assembly of the hydrogen-bonded network of the carboxylic acid group of meso-tetra(4-carboxyphenyl)porphine. The design of the rare earth upconversion nanocrystal particle-hydrogen-bonded organic framework (HOFs) composite material of the present invention combines the unique optical properties of rare earth upconversion nanocrystals and the multifunctionality of hydrogen-bonded organic frameworks, thereby improving the effect of photodynamic therapy (PDT). The rare earth upconversion nanocrystal particles (NaGdF 4 :Yb / Er) can convert low-energy near-infrared light into higher-energy visible or ultraviolet light through a multiphoton absorption process under 980 nm near-infrared light excitation. This property is particularly suitable for deep penetration of biological tissues without causing significant thermal damage. The converted high-energy light can be used to activate photosensitizers to produce singlet oxygen or other reactive oxygen species (ROS), which is crucial for killing tumor cells. The hydrogen-bonded organic framework (HOFs) shell not only provides physical protection to prevent the core rare earth upconversion nanocrystals from degradation or inactivation in the in vivo environment, but also may contain or load additional photosensitizer molecules, which can efficiently generate reactive oxygen species in the microenvironment provided by HOFs, enhancing the overall photodynamic therapy effect. The interaction between the high-energy light generated by the rare earth upconversion nanocrystals and the photosensitizers in the HOFs forms a synergistic system, making the generation of reactive oxygen species more efficient, thereby improving the killing efficiency of tumor cells. At the same time, hydrogen-bonded organic frameworks (HOFs) have good biocompatibility and low toxicity, and have great potential in the field of photodynamic therapy, especially in the treatment of deep tumors.

[0008] To achieve the above-mentioned purpose of the present invention, the present invention provides a rare earth upconversion nanocrystalline particle-hydrogen bond organic framework composite material, wherein the rare earth upconversion nanocrystalline particle NaGdF 4 :Yb / Er is used as the core and the hydrogen bond organic framework is used as the shell. The composite material produces active oxygen under the excitation of 980 nm near-infrared light when used in photodynamic therapy.

[0009] Furthermore, the rare earth upconversion nanocrystalline particles NaGdF 4 :Yb / Er, the amount of Yb is NaGdF 4 The molar amount of Er is 15% to 35%, and the amount of Er is NaGdF 4 The rare earth up-conversion nanocrystalline particles are Yb3+ Absorbs near-infrared light and transmits it to Er 3+ , emitting visible light, such as 540 nm green light and 660 nm red light, which can effectively penetrate biological tissues and reduce photodamage. 3+ As a sensitizer, high doping ratio improves near-infrared light absorption efficiency; Er 3+ As an activator, low doping avoids concentration quenching and ensures efficient upconversion luminescence.

[0010] Furthermore, the hydrogen-bonded organic framework is formed by self-assembly of meso-tetra(4-carboxyphenyl)porphine through the hydrogen-bonded network of carboxylic acid groups. The porphyrin core of meso-tetra(4-carboxyphenyl)porphine (TCPP) acts as a photosensitizer, efficiently generates reactive oxygen species (ROS) under visible light excitation, and enhances the photodynamic therapy effect. At the same time, the porous structure of the hydrogen-bonded network can load drug molecules (such as chemotherapeutic drugs) to achieve synergistic therapy.

[0011] Furthermore, the NaGdF 4 :Yb / Er was prepared by the following method: 1) Preparation of oleic acid-coated NaGdF 4 :Yb / Er upconversion nanocrystalline particles: Mix a mixed solution containing gadolinium acetate, erbium acetate, ytterbium acetate, oleic acid and 1-octadecene, heat it to 150-180°C and keep it for 40-60 minutes; cool it to room temperature and then add NH 4 F methanol solution and NaOH methanol solution, heated to 45-55℃ and maintained for 60min, then continued to heat to 100-120℃ and maintained for 40min; introduced inert gas and continued to heat to 300-320℃ and maintained for 100min, centrifuged after the reaction, and washed and dried the obtained solid to obtain NaGdF; high temperature thermal decomposition method can improve the crystallinity of the product, and high temperature reaction at 300-320℃ ensures that NaGdF 4 The nanocrystals have a hexagonal structure, which improves the upconversion luminescence efficiency.

[0012] 2) Take 10 mg of oleic acid-coated NaGdF 4 :Yb / Er and 3 mg tetrafluoroborate nitrosoion were added to 3 mL DMF and ultrasonically treated for 15 min, filtered and the residue was dispersed in 10 mL acetone, centrifuged at 12000 rpm for 30 min, and dried. The size of nanoparticles was regulated by oleic acid / 1-octadecene ligand system to avoid agglomeration.

[0013] Furthermore, the gadolinium acetate, erbium acetate, ytterbium acetate, NH 4The molar ratio of F to NaOH is 100:1-5:15-35:600-700:40-80; the molar ratio of gadolinium acetate to the volume of oleic acid is 1mmol:20mL; the molar ratio of gadolinium acetate to the volume of 1-octadecene is 1mmol:30mL; the NH 4 The concentration of the F methanol solution is 0.50 mol / L; the concentration of the NaOH methanol solution is 1 mol / L.

[0014] Furthermore, the NaGdF 4 : The mass ratio of Yb / Er to hydrogen-bonded organic framework material is 1:4~10. With this ratio, the shell thickness can be reasonably regulated, the light energy transfer efficiency and ROS generation capacity can be balanced, and the optimal photodynamic therapy effect of the composite material can be maintained.

[0015] Another object of the present invention is to provide a method for preparing a rare earth upconversion nanocrystalline particle-hydrogen bond organic framework composite material. The composite material is NaGdF 4 :Yb / Er is the core, the hydrogen bond organic framework is the shell, and the NaGdF 4 : The mass ratio of Yb / Er to hydrogen bond organic framework material is 1:4-10, and the preparation method comprises the following steps: 1) Preparation of NaGdF 4 :Yb / Er upconversion nanocrystalline particles: Preparation of acid-coated NaGdF 4 :Yb / Er, a mixed solution containing gadolinium acetate, erbium acetate, ytterbium acetate, oleic acid and 1-octadecene was mixed, heated to 150-180°C and maintained for 40-60 min; after cooling to room temperature, 0.50 mol / L NH 4 F methanol solution and 1 mol / L NaOH methanol solution, heating to 45-55°C and maintaining for 60 min, continuing to heat to 100-120°C and maintaining for 40 min; introducing inert gas and continuing to heat to 300-320°C and maintaining for 100 min, centrifuging after the reaction, and washing and drying the obtained solid, wherein the gadolinium acetate, erbium acetate, ytterbium acetate, NH 4 The molar ratio of F and NaOH is 100:1-5:15-35:600-700:40-80, the molar ratio of gadolinium acetate to the volume of oleic acid is 1mmol:20mL, and the molar ratio of gadolinium acetate to the volume of 1-octadecene is 1mmol:30mL; 10 mg of oleic acid-coated NaGdF 4 : Yb / Er and 3 mg of tetrafluoroborate nitrite ion were added to 3 mL of DMF and ultrasonically treated for 15 min, filtered and the residue was dispersed in 10 mL of acetone, centrifuged at 12000 rpm for 30 min, and dried; 2) Prepared NaGdF 4 :Yb / Er upconversion nanocrystal particles are dispersed in 5 mL DMF, 3 mg polyvinyl pyrrolidone is added, and 10 mg of meso-tetrakis(4-carboxyphenyl)porphine is added after stirring for 10 h. After continuing to stir for 30 min, 10 mL of deionized water is added, and after continuing to stir for 10 min, 8 mL of anhydrous ethanol is added dropwise, and stirring is continued for 24 h. The product is centrifuged, washed, and dried to obtain.

[0016] Furthermore, the stirring speed is 500-1500 rpm; the washing is performed by rinsing with ethanol and acetone, and the drying is performed at 40-70°C.

[0017] The present invention also provides an application of a rare earth up-conversion nanocrystalline particle-hydrogen bond organic framework composite material, which is used as a raw material to prepare a photodynamic therapy agent.

[0018] Furthermore, the composite material activates the multi-photon transition of upconversion luminescent particles through near-infrared laser irradiation, excites rare earth ions to produce corresponding visible light, and since hydrogen-bonded organic frameworks (HOFs) tightly wrap the upconversion nanoparticles to form a good fluorescence resonance energy transfer, HOFs are excited to produce a large amount of singlet oxygen, which can induce oxidative stress damage to tumor cells, and has good treatment prospects for deep tumors such as brain gliomas.

[0019] Compared with the prior art, the technical solution of the present invention has the following beneficial effects: 1. The composite material of the present invention combines the unique optical properties of rare earth upconversion nanocrystals with the multifunctionality of hydrogen-bonded organic frameworks, effectively improving the effect of photodynamic therapy (PDT). The composite material can enhance near-infrared light absorption and conversion, and the core material can convert low-energy near-infrared light into higher-energy visible light or ultraviolet light through a multiphoton absorption process under 980 nm near-infrared light excitation. The shell of the hydrogen-bonded organic framework is self-assembled through a hydrogen-bonded network formed by carboxylic acid groups. TCPP is a known photosensitizer with good photosensitization ability and strong absorption in the visible light range. The setting of the composite material can make the core produce high-energy visible light under 980 nm near-infrared light excitation. These lights can be effectively absorbed by TCPP, thereby promoting the generation of reactive oxygen species, realizing energy conversion from near-infrared to visible light, and then to an efficient chain reaction of reactive oxygen generation. This composite material has shown great potential in the field of photodynamic therapy, especially in the treatment of deep tumors. By using 980 nm near-infrared light excitation, it can effectively penetrate deep tissues and produce reactive oxygen species at the target location, achieving the purpose of local efficient treatment.

[0020] 2. The composite material has good biocompatibility. The shell of HOFs formed by TCPP self-assembly has good biocompatibility and low toxicity. It not only helps to maintain the stability of the internal rare earth upconversion nanocrystal particles, but also can be used as a drug carrier to achieve controlled release of photosensitizers or other therapeutic drugs, thereby improving the therapeutic effect and reducing side effects. This material is expected to become a safe and effective cancer treatment direction. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is a transmission electron microscope (TEM) photograph of the composite material prepared in Example 1 of the present invention; Figure 2 This is a scanning electron microscope (SEM) photograph of the composite material prepared in Inventive Example 1. DETAILED DESCRIPTION

[0022] In order to make the technical problems solved by the present invention, the technical solutions adopted and the technical effects achieved clearer, the technical solutions of the embodiments of the present invention are further described in detail below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0023] It should be noted that the reference to "embodiment" in this document means that the specific features, structures or characteristics described in conjunction with the embodiment may be included in at least one embodiment of the present application. The appearance of this phrase in various places in the specification does not necessarily refer to the same embodiment, nor is it an independent or alternative embodiment that is mutually exclusive with other embodiments. It is explicitly and implicitly understood by those skilled in the art that the embodiments described herein may be combined with other embodiments.

[0024] The experimental methods in the following examples are conventional methods unless otherwise specified. The materials, reagents, etc. used in the following examples are commercially available unless otherwise specified.

[0025] The reactive oxygen production rate was detected and calculated in the following way: DPBF was used as a singlet oxygen detector and dissolved in an aqueous solution containing 1% dimethyl sulfoxide (DMSO). DMSO can increase the solubility of DPBF. The indicator solution was mixed with the nanoparticles, and then the DPBF absorbance of the composite materials of different concentrations was detected after irradiation with a 980 nm high-stability infrared laser. Example 1 A rare earth upconversion nanocrystalline particle-hydrogen bond organic framework composite material, based on NaGdF 4: Yb / Er is used as the core and a hydrogen-bonded organic framework is used as the shell to form an in-situ composite. The hydrogen-bonded organic framework is formed by self-assembly of a hydrogen-bonded network of carboxylic acid groups of meso-tetra(4-carboxyphenyl)porphine and is prepared by the following method: 1) Preparation of NaGdF 4 :Yb / Er upconversion nanocrystalline particles: Preparation of oleic acid-coated NaGdF 4 :Yb / Er, weigh the raw materials according to the following ratio, the ratio is gadolinium acetate: erbium acetate: ytterbium acetate: NH 4 F: NaOH: oleic acid: 1-octadecene is 100mol: 1mol: 15mol: 600mol: 40mol: 2000L: 3000L. Add the weighed gadolinium acetate, erbium acetate and ytterbium acetate to the mixed solution of oleic acid and 1-octadecene in turn, stir until uniformly dispersed, heat to 150℃ and keep for 40min; cool to room temperature and add 0.50mol / L NH4 F Methanol solution and 1 mol / L NaOH methanol solution, heated to 45 °C and maintained for 60 min, then continued to heat to 100 °C and maintained for 40 min; introduced inert gas and continued to heat to 300 °C and maintained for 100 min. After the reaction was completed, centrifuged, and the obtained solid was washed with ethanol and acetone and dried at 40 °C; 10 mg of oleic acid-coated NaGdF 4 :Yb / Er and 3 mg of tetrafluoroborate nitrosoion were added to 3 mL of DMF and ultrasonically treated for 15 min, filtered and the residue was dispersed in 10 mL of acetone, centrifuged at 12000 rpm for 30 min, and dried at 40 °C; 2) Prepared NaGdF 4 : 1 mg of Yb / Er upconversion nanocrystal particles was dispersed in 5 mL of DMF, 3 mg of polyvinyl pyrrolidone was added, and 10 mg of meso-tetrakis(4-carboxyphenyl)porphine was added after stirring at 500 rpm for 10 h. After continuing to stir for 30 min, 10 mL of deionized water was added, and after continuing to stir for 10 min, 8 mL of anhydrous ethanol was added dropwise. After continuing to stir for 24 h, the product was centrifuged, rinsed with ethanol and acetone, and dried at 40 °C.

[0026] Figure 1 This is a transmission electron microscope photo of the composite material, from which the upconversion nanoparticles NaGdF can be clearly seen. 4 :Yb / Er is wrapped inside HOFs with a size of 50nm; Figure 2 This is a scanning electron microscope (SEM) photo of the prepared composite material. From the picture, we can see that the particles are regular overall and no obvious NaGdF 4 :Yb / Er nanocrystalline particles, indicating that NaGdF 4:Yb / Er and HOFs were successfully compounded together, and in-situ polymerization made the upconversion luminescent nanocrystals coated with HOFs, and the overall stability of the material was improved. The prepared composite material was tested, and the ROS yield was measured to reach 2.4μM / min. After continuous laser irradiation for 60 min, the TCPP retention rate was 93%, indicating that HOFs can effectively protect the photosensitizer.

[0027] Example 2 A rare earth upconversion nanocrystalline particle-hydrogen bond organic framework composite material, based on NaGdF 4 : Yb / Er is used as the core and a hydrogen-bonded organic framework is used as the shell to form an in-situ composite. The hydrogen-bonded organic framework is formed by self-assembly of a hydrogen-bonded network of carboxylic acid groups of meso-tetra(4-carboxyphenyl)porphine and is prepared by the following method: 1) Preparation of NaGdF 4 :Yb / Er upconversion nanocrystalline particles: Preparation of oleic acid-coated NaGdF 4 :Yb / Er, weigh the raw materials according to the following ratio, the ratio is gadolinium acetate: erbium acetate: ytterbium acetate: NH 4 F: NaOH: oleic acid: 1-octadecene is 100mol: 5mol: 35mol: 700mol: 80mol: 2000L: 3000L. The weighed gadolinium acetate, erbium acetate and ytterbium acetate are added to the mixed solution of oleic acid and 1-octadecene in sequence, stirred until uniformly dispersed, heated to 180°C and maintained for 60min; cooled to room temperature and then added 0.50mol / L NH4 F Methanol solution and 1 mol / L NaOH methanol solution were heated to 55°C and maintained for 60 min, and then continued to heat to 120°C and maintained for 40 min; inert gas was introduced and continued to heat to 320°C and maintained for 100 min. After the reaction was completed, the solid was centrifuged and washed with ethanol and acetone and dried at 70°C; 10 mg of oleic acid-coated NaGdF 4 :Yb / Er and 3 mg of tetrafluoroborate nitrosoion were added to 3 mL of DMF and ultrasonicated for 15 min, filtered and the residue was dispersed in 10 mL of acetone, centrifuged at 12000 rpm for 30 min, and dried at 70 °C; 2) Prepared NaGdF 4 : 2.5 mg of Yb / Er upconversion nanocrystal particles were dispersed in 5 mL of DMF, 3 mg of polyvinyl pyrrolidone was added, and 10 mg of meso-tetrakis(4-carboxyphenyl)porphine was added after stirring at 1500 rpm for 10 h. After continuing to stir for 30 min, 10 mL of deionized water was added, and after continuing to stir for 10 min, 8 mL of anhydrous ethanol was added dropwise. After continuing to stir for 24 h, the product was centrifuged, rinsed with ethanol and acetone, and dried at 70 °C.

[0028] The prepared composite material was tested and the ROS production rate was measured to be 3.7μM / min. After continuous laser irradiation for 60 minutes, the TCPP retention rate was 95%, indicating that HOFs can effectively protect the photosensitizer.

[0029] Example 3 A rare earth upconversion nanocrystalline particle-hydrogen bond organic framework composite material, based on NaGdF 4 : Yb / Er is used as the core and a hydrogen-bonded organic framework is used as the shell to form an in-situ composite. The hydrogen-bonded organic framework is formed by self-assembly of a hydrogen-bonded network of carboxylic acid groups of meso-tetra(4-carboxyphenyl)porphine and is prepared by the following method: 1) Preparation of NaGdF 4 :Yb / Er upconversion nanocrystalline particles: Preparation of oleic acid-coated NaGdF 4 :Yb / Er, weigh the raw materials according to the following ratio, the ratio is gadolinium acetate: erbium acetate: ytterbium acetate: NH 4 F: NaOH: oleic acid: 1-octadecene is 100mol: 3mol: 25mol: 650mol: 60mol: 2000L: 3000L. Add the weighed gadolinium acetate, erbium acetate and ytterbium acetate to the mixed solution of oleic acid and 1-octadecene in turn, stir until uniformly dispersed, heat to 160℃ and keep for 60min; cool to room temperature and add 0.50mol / L NH4 F Methanol solution and 1 mol / L NaOH methanol solution were heated to 50°C and maintained for 60 min, and then continued to heat to 110°C and maintained for 40 min; inert gas was introduced and continued to heat to 310°C and maintained for 100 min. After the reaction was completed, the solid was centrifuged and washed with ethanol and acetone and dried at 60°C; 10 mg of oleic acid-coated NaGdF 4 :Yb / Er and 3 mg of tetrafluoroborate nitrosoion were added to 3 mL of DMF and ultrasonicated for 15 min, filtered and the residue was dispersed in 10 mL of acetone, centrifuged at 12000 rpm for 30 min, and dried at 70 °C; 2) Prepared NaGdF 4 : 1.5 mg of Yb / Er upconversion nanocrystal particles were dispersed in 5 mL of DMF, 3 mg of polyvinyl pyrrolidone was added, and 10 mg of meso-tetrakis(4-carboxyphenyl)porphine was added after stirring at 1000 rpm for 10 h. After continuing to stir for 30 min, 10 mL of deionized water was added, and after continuing to stir for 10 min, 8 mL of anhydrous ethanol was added dropwise. After continuing to stir for 24 h, the product was centrifuged, rinsed with ethanol and acetone, and dried at 70 °C.

[0030] The prepared composite material was tested and the ROS production rate was measured to be 3.3μM / min. After continuous laser irradiation for 60 minutes, the TCPP retention rate was 97%, indicating that HOFs can effectively protect the photosensitizer.

[0031] Comparative Example 1 A rare earth upconversion nanocrystalline particle-hydrogen bond organic framework composite material, based on NaGdF 4 : Yb / Er is used as the core and a hydrogen-bonded organic framework is used as the shell to form an in-situ composite. The hydrogen-bonded organic framework is formed by self-assembly of a hydrogen-bonded network of carboxylic acid groups of meso-tetra(4-carboxyphenyl)porphine and is prepared by the following method: 1) Preparation of NaGdF 4 :Yb / Er upconversion nanocrystalline particles: Preparation of NaGdF 4 :Yb / Er, weigh the raw materials according to the following ratio, the ratio is gadolinium acetate: erbium acetate: ytterbium acetate: NH 4 F: NaOH: oleic acid: 1-octadecene is 100mol: 0.5mol: 40mol: 550mol: 85mol: 2500L: 1000L. The weighed gadolinium acetate, erbium acetate and ytterbium acetate are added to the mixed solution of oleic acid and 1-octadecene in sequence, stirred until uniformly dispersed, heated to 160℃ and maintained for 60min; cooled to room temperature and then added 0.50mol / L NH4 F Methanol solution and 1 mol / L NaOH methanol solution were heated to 310°C and maintained for 200 min after inert gas was introduced. After the reaction was completed, the solid was centrifuged and washed with ethanol and acetone and dried at 60°C. 10 mg of the prepared NaGdF 4 :Yb / Er and 3 mg of tetrafluoroborate nitrosoion were added to 3 mL of DMF and ultrasonicated for 15 min, filtered and the residue was dispersed in 10 mL of acetone, centrifuged at 12000 rpm for 30 min, and dried at 70 °C; 2) The NaGdF obtained in step 1) 4 : 1.5 mg of Yb / Er particles were dispersed in 5 mL of DMF, 3 mg of polyvinyl alcohol was added, and 10 mg of meso-tetrakis(4-carboxyphenyl)porphine was added after stirring at 1000 rpm for 10 h. After continuing to stir for 30 min, 10 mL of deionized water was added, and after continuing to stir for 10 min, 8 mL of anhydrous ethanol was added. After continuing to stir for 24 h, the product was centrifuged, rinsed with ethanol and acetone, and dried at 70 °C.

[0032] The prepared composite material was tested and the ROS production rate was measured to be 1.1μM / min. After continuous laser irradiation for 60 minutes, the TCPP retention rate was 68%, and the stability of the composite material was slightly poor.

[0033] Comparative Example 2 A rare earth upconversion nanocrystalline particle-hydrogen bond organic framework composite material, composed of NaGdF 4 : Yb / Er, a hydrogen-bonded organic framework material is mixed, wherein the hydrogen-bonded organic framework is formed by self-assembly of a hydrogen-bonded network of meso-tetra(4-carboxyphenyl)porphine through carboxylic acid groups, and is prepared by the following method: 1) Preparation of NaGdF by thermal decomposition 4 :Er: 0.78mmol gadolinium chloride hexahydrate and 0.02mmol erbium chloride hexahydrate were dispersed in a mixed solvent of 10mL oleic acid and 15mL octadecene, and then the mixed system was heated to 160℃ under argon atmosphere and maintained at this temperature for 1h to form a stable and uniform rare earth ion-oleic acid precursor mixed system, and then cooled naturally to room temperature; 5mL methanol solution containing 2.5mmol NaOH and 5mL methanol solution containing 2.75mmol NH 4 1 mL of methanol solution of F was quickly mixed and then quickly added to the mixed system, the temperature was raised to 50°C, maintained for 30 min, then raised to 140°C and maintained for 2 h to fully volatilize the methanol, the obtained mixture was heated to 320°C and maintained for 2.5 h, then cooled to room temperature, ethanol was added to precipitate the solid particles, centrifuged and dried; 2) Prepared NaGdF 4 : 1.5 mg of Er upconversion nanocrystal particles were dispersed in 5 mL of DMF, 3 mg of polyvinyl pyrrolidone was added, and stirred at 1000 rpm for 10 h; 3) Add 10 mg of meso-tetrakis(4-carboxyphenyl)porphine to 5 mL of DMF with stirring. After stirring for 30 min, add the mixed system obtained in step 2) and continue stirring for 30 min. Then add 10 mL of deionized water. After continuing stirring for 10 min, add 8 mL of anhydrous ethanol dropwise and continue stirring for 24 hours. Centrifuge the product, rinse with ethanol and acetone, and dry at 70°C to obtain the product.

[0034] The prepared composite material was tested and the ROS yield was measured to be 0.2μM / min. After 60 minutes of continuous laser irradiation, the TCPP retention rate was 17%, and a small amount of upconversion luminescent particles were dispersed and attached to the pores of the HOFs material, and the two did not form a stable composite material.

[0035] It can be seen from the test results of the embodiments of the present invention and the comparative examples that the embodiment product of the present invention can achieve NaGdF 4 : In-situ composite of Yb / Er upconversion nanocrystals with hydrogen-bonded organic frameworks, NaGdF 4:Yb / Er upconversion nanocrystal particles are uniformly coated by HOFs, and the composite material has high stability. The composite material can generate high-energy visible light under 980 nm near-infrared light excitation and is effectively absorbed by TCPP, thereby promoting HOFs to produce reactive oxygen species, realizing energy conversion from near-infrared to visible light, and then to efficient chain reaction of reactive oxygen generation. The yield of reactive oxygen species is relatively stable. After continuous laser irradiation for 60 min, the TCPP retention rate is high, and the composite material has good stability. It can significantly improve the ROS generation efficiency of near-infrared light excitation, solve the penetration depth limitation of traditional PDT, and has certain clinical transformation potential in the treatment of brain glioma.

[0036] The above is a detailed introduction to a rare earth up-conversion nanocrystalline particle-hydrogen bond organic framework composite material and its preparation method. The above content is a further detailed description of the present invention in combination with a specific preferred embodiment, and it cannot be determined that the specific implementation of the present invention is limited to these descriptions. For ordinary technicians in the technical field to which the present invention belongs, without departing from the concept of the present invention, its architecture can be flexible and can derive a series of products. Just making a few simple deductions or substitutions should be regarded as belonging to the scope of patent protection of the present invention determined by the submitted claims.

Claims

1. A rare earth upconversion nanocrystal-hydrogen bond organic framework composite material, which is composed of rare earth upconversion nanocrystal particles NaGdF4:Yb / Er as the core and a hydrogen bond organic framework as the shell, characterized in that: When used in photodynamic therapy, the composite material generates reactive oxygen species under the excitation of 980 nm near-infrared light.

2. The rare earth upconversion nanocrystal-hydrogen bond organic framework composite material according to claim 1, characterized in that: In the rare earth up-conversion nanocrystalline particles NaGdF4:Yb / Er, the amount of Yb is 15% to 35% of the molar amount of NaGdF4, and the amount of Er is 1% to 5% of the molar amount of NaGdF4.

3. The rare earth upconversion nanocrystal-hydrogen bond organic framework composite material according to claim 1, characterized in that: The hydrogen-bonded organic framework is formed by self-assembly of meso-tetra(4-carboxyphenyl)porphine through a hydrogen-bonded network of carboxylic acid groups.

4. The rare earth upconversion nanocrystal-hydrogen bond organic framework composite material according to claim 3, characterized in that: The NaGdF4:Yb / Er is prepared by the following method: 1) Preparation of oleic acid-coated NaGdF4:Yb / Er upconversion nanocrystalline particles: After mixing a mixed solution containing gadolinium acetate, erbium acetate, ytterbium acetate, oleic acid and 1-octadecene, heat it to 150-180°C and keep it for 40-60 minutes; after cooling to room temperature, add NH4F methanol solution and NaOH methanol solution in sequence, heat it to 45-55°C and keep it for 60 minutes, continue to heat it to 100-120°C and keep it for 40 minutes; introduce inert gas and continue to heat it to 300-320°C and keep it for 100 minutes. After the reaction is completed, centrifuge it, and wash and dry the obtained solid to obtain; 2) Take 10 mg of oleic acid-coated NaGdF4:Yb / Er and 3 mg of tetrafluoroborate nitrite ion, add them to 3 mL of DMF and ultrasonicate for 15 min, filter and disperse the residue in 10 mL of acetone, centrifuge at 12000 rpm for 30 min, and dry.

5. The rare earth upconversion nanocrystal-hydrogen bond organic framework composite material according to claim 4, characterized in that: The molar ratio of the gadolinium acetate, erbium acetate, ytterbium acetate, NH4F and NaOH is 100:1~5:15~35:600~700:40~80; the molar ratio of the gadolinium acetate to the volume of the oleic acid is 1mmol:20mL; the molar ratio of the gadolinium acetate to the volume of the 1-octadecene is 1mmol:30mL; the concentration of the NH4F methanol solution is 0.50mol / L; and the concentration of the NaOH methanol solution is 1mol / L.

6. The rare earth upconversion nanocrystal-hydrogen bond organic framework composite material according to claim 1, characterized in that: The mass ratio of the NaGdF4:Yb / Er to the hydrogen-bonded organic framework material is 1:4-10.

7. A method for preparing a rare earth upconversion nanocrystal-hydrogen bond organic framework composite material, wherein the composite material has NaGdF4:Yb / Er as the core and the hydrogen bond organic framework as the shell, and the mass ratio of the core to the shell is 1:4-10, characterized in that: The steps include: 1) Preparation of NaGdF4:Yb / Er upconversion nanocrystalline particles: To prepare oleic acid-coated NaGdF4:Yb / Er, raw materials were weighed according to the following ratio: gadolinium acetate: erbium acetate: ytterbium acetate: NH4F: NaOH: oleic acid: 1-octadecene = 100 mol: (1-5) mol: (15-35) mol: (600-700) mol: (40-80) mol: 2000 L: 3000 L. Gadolinium acetate, erbium acetate and ytterbium acetate were added to a mixed solution of oleic acid and 1-octadecene and stirred. Stir until uniformly dispersed, heat to 150-180°C and keep for 40-60 min, cool to room temperature, add 0.50 mol / L NH4F methanol solution and 1 mol / L NaOH methanol solution in sequence, heat to 45-55°C and keep for 60 min, continue to heat to 100-120°C and keep for 40 min; introduce inert gas and continue to heat to 300-320°C and keep for 100 min. After the reaction is completed, centrifuge, wash and dry the obtained solid; take 10 mg of oleic acid-coated NaGdF4:Yb / Er and 3 mg of tetrafluoroborate nitrosamine ion, add them to 3 mL DMF and ultrasonically treat for 15 min, filter and disperse the residue in 10 mL acetone, centrifuge at 12000 rpm for 30 min, and dry; 2) Disperse the prepared NaGdF4:Yb / Er upconversion nanocrystalline particles in 5 mL DMF, add 3 mg polyvinyl pyrrolidone, stir for 10 h, then add 10 mg of meso-tetrakis(4-carboxyphenyl)porphine, continue stirring for 30 min, then add 10 mL of deionized water, continue stirring for 10 min, then add 8 mL of anhydrous ethanol dropwise, continue stirring for 24 h, centrifuge, wash, and dry the product.

8. A method for preparing the rare earth upconversion nanocrystalline particle-hydrogen bond organic framework composite material according to claim 7, characterized in that: The stirring speed is 500-1500 rpm; the washing is performed by rinsing with ethanol and acetone; and the drying is performed at 40-70° C.

9. An application of the rare earth upconversion nanocrystalline particle-hydrogen bond organic framework composite material according to any one of claims 1 to 3, characterized in that: It is used as raw material to prepare photodynamic therapy agent.

10. The use according to claim 9, characterized in that: The photodynamic therapy agent is used for treating brain glioma.

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