A rare earth upconversion nanocrystal particle-hydrogen bond organic framework composite material and a preparation method thereof

Abstract

The present invention belongs to the field of biomedical luminescent composite materials, and particularly relates to a rare earth upconversion nanocrystal particle-hydrogen bond organic framework composite material and a preparation method thereof. The composite material has a core of rare earth upconversion nanocrystal particles NaGdF4:Yb / Er and a shell of hydrogen bond organic framework. The present invention ingeniously combines the advantages of rare earth upconversion nanocrystal particles and hydrogen bond organic framework, and the two form a synergistic system, realizing the generation of reactive oxygen species under the excitation of 980 nm near-infrared light during photodynamic therapy. At the same time, the generation of reactive oxygen species is more efficient, improving the killing efficiency of tumor cells, and is applicable to the treatment of deep tumors (such as glioblastoma). At the same time, the porphyrin core of TCPP matches the visible light emission spectrum of rare earth upconversion nanocrystal particles, realizing efficient energy transfer, and the singlet oxygen yield is significantly higher than that of traditional PDT materials.

Description

Technical Field

[0001] The present invention belongs to the field of biomedical luminescent composite materials, and particularly relates to a rare earth upconversion nanocrystal particle-hydrogen bond organic framework composite material and a preparation method thereof. In this composite material, the hydrogen bond organic framework (HOFs) tightly coats the upconversion nanoparticles to form good fluorescence resonance energy transfer, and the excited HOFs generate a large amount of singlet oxygen, which can cause oxidative stress damage to tumor cells and has good therapeutic prospects for deep tumors such as glioblastoma multiforme. Background Art

[0002] Cancer is a disease with great harm and seriously threatens the health of all mankind. The treatment methods for cancer include surgery, radiotherapy, chemotherapy, immunotherapy, phototherapy, targeted therapy, etc. Among them, photodynamic therapy (PDT) in phototherapy is a non-invasive, low-toxic, high spatiotemporal precision and low-side-effect treatment method, which has good prospects in cancer treatment and is considered a promising cancer treatment method. The principle of photodynamic therapy is that by irradiating a photosensitizer with a laser of a specific wavelength to excite it, the excited photosensitizer transfers energy to the surrounding oxygen to generate reactive oxygen species, and the reactive oxygen species react with adjacent biological macromolecules to produce cytotoxicity, thereby causing cell damage and even death. Photodynamic therapy relies on these three conditions: photosensitizer, excitation light source, and oxygen. Currently, the photosensitizer molecules used more often 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 short lifetime and limited diffusion distance of the reactive oxygen species generated by the photosensitizer also limit the application of PDT in the treatment of tumors in deep tissues or with larger sizes.

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

[0004] Hydrogen-bonded organic frameworks (HOFs) are self-assembled through hydrogen-bonding interactions between organic ligands. They are prepared under mild conditions, free of metal doping, and have good biosafety, excellent biocompatibility, rich chemical functions, and tunable porosity, thus possessing unique advantages in the fields of biotechnology and biomedicine. Currently, the application of HOFs in the biomedical field is mainly as carriers for enzyme / protein protection. For example, CN119524159A discloses a sonodynamic targeting drug-loaded nanoparticle, which includes 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. The organic soft porous framework material is activated under the condition of -87°C to -20°C, and the activated crystal powder is left standing in a carbon dioxide atmosphere for 6 to 12 hours. Then, it is evacuated with a vacuum pump for 1 to 2 hours to remove carbon dioxide molecules, thereby obtaining the hydrogen-bonded organic framework material. CN118240228A discloses an oxygen-deficient responsive protein-loaded hydrogen-bonded organic framework. The physiological stability of the hydrogen-bonded organic framework is increased by modifying polyethylene glycol molecules on the side arms of ligand molecules, and an azo bond is used as an oxygen-deficient responsive element to achieve the response of the hydrogen-bonded organic framework to an oxygen-deficient environment and the effect of controllable protein release. At the same time, the application of the oxygen-deficient responsive protein-loaded hydrogen-bonded organic framework in the preparation of anti-tumor drugs is provided.

[0005] With the progress of technology, studies have found that some hydrogen-bonded organic frameworks (HOFs) exhibit certain optical activities due to the inclusion of specific functional organic molecules in their structures, which can be utilized to achieve energy transfer. In addition, studies have also found that some HOFs contain components suitable for generating singlet oxygen or other reactive 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 its preparation method. The tetracarboxylic acid monomer molecules constituting the hydrogen-bonded organic framework material are synthesized through Suzuki coupling reaction. The hydrogen-bonded organic framework material has large pore sizes, high specific surface areas, and excellent thermal and chemical stabilities. The hydrogen-bonded organic framework material can be loaded onto cotton fabrics by a drop-coating method to obtain a hydrogen-bonded organic framework fiber composite material. Under light illumination conditions, this composite material can efficiently kill bacteria. CN117701281A discloses a metal-organic framework and fluoride nanocrystal composite photon-functional material. Using a composite strategy driven by electrostatic interaction, different metal-organic frameworks are directly interacted and composite with the surface of fluoride nanocrystals to form rich photon-functional composite materials. This composite material combines the excellent biocompatibility of metal-organic framework materials and the upconversion fluorescence properties of fluoride nanocrystals, and can be further functionalized and modified, making it a highly promising bio-nanoprobe material. CN109172587A discloses a preparation method of a pH-responsive dual-drug release metal-organic framework-upconversion nanosystem. It uses a polymer modification method to improve the water solubility of upconversion nanocrystals with a core-shell structure, and then grows metal-organic frameworks on the surface of upconversion luminescent nanocrystals to obtain a metal-organic framework-coated upconversion nanosystem. Doxorubicin hydrochloride containing amino groups is connected to the surface of the metal-organic framework, and other anti-cancer drugs are adsorbed into the porous structure of the metal-organic framework, thus obtaining a dual-drug-loaded metal-organic framework-upconversion nanosystem.

[0006] Although hydrogen-bonded organic framework (HOFs) materials have excellent properties, existing HOFs often have active sites occupied by participating in the construction of hydrogen bond networks, and photoexcitation in the visible light region leads to deficiencies in the treatment of deep-seated tumors in the body, affecting their further effective utilization. Therefore, it is necessary to develop new HOFs composite materials through methods such as structural modification and surface modification, with the expectation of obtaining high-efficient photosensitization ability and near-infrared excitation to solve the problem of tissue penetration depth. Summary of the Invention

[0007] To solve the defects in the prior art, the present invention provides a rare-earth upconversion nanocrystal particle-hydrogen-bonded organic framework composite material and its preparation method. This composite material uses rare-earth upconversion nanocrystal particles NaGdF 4: The core is Yb / Er and the shell is a hydrogen-bonded organic framework. When this composite material is used for photodynamic therapy, reactive oxygen species are generated under the excitation of 980 nm near-infrared light. The rare-earth upconversion nanocrystal particles NaGdF 4 : In Yb / Er, the dosage of Yb is 15% - 35% of the molar amount of NaGdF 4 and the dosage of Er is 1% - 5% of the molar amount of NaGdF 4 The hydrogen-bonded organic framework is formed by the self-assembly of meso-tetrakis(4-carboxyphenyl) porphine through the hydrogen-bond network of carboxylic acid groups. 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 versatility of hydrogen-bonded organic frameworks, enhancing the effect of photodynamic therapy (PDT). Among them, the rare-earth upconversion nanocrystal particles (NaGdF 4 :Yb / Er) can convert low-energy near-infrared light into higher-energy visible light or ultraviolet light through a multi-photon absorption process under the excitation of 980 nm near-infrared light. 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 generate 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 degradation or inactivation of the core rare-earth upconversion nanocrystals in the in vivo environment, but may also contain or load additional photosensitizer molecules. These photosensitizers 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 rare-earth upconversion nanocrystals and the photosensitizers in 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, the hydrogen-bonded organic framework (HOFs) has good biocompatibility and low toxicity, and has great potential in the field of photodynamic therapy, especially in the treatment of deep tumors.

[0008] To achieve the above object of the present invention, the present invention provides a rare-earth upconversion nanocrystal particle - hydrogen-bonded organic framework composite material, which is composed of a core of rare-earth upconversion nanocrystal particles NaGdF 4 :Yb / Er and a shell of hydrogen-bonded organic framework. When this composite material is used for photodynamic therapy, reactive oxygen species are generated under the excitation of 980 nm near-infrared light.

[0009] Further, in the rare-earth upconversion nanocrystal particles NaGdF 4 :Yb / Er, the dosage of Yb is 15% - 35% of the molar amount of NaGdF 4 and the dosage of Er is 1% - 5% of the molar amount of NaGdF 4 The rare-earth upconversion nanocrystal particles are doped with Yb3+ Absorb near-infrared light and transfer it to Er 3+ , emit visible light, such as 540 nm green light and 660 nm red light, effectively penetrate biological tissues and reduce light damage. Yb 3+ As a sensitizer, a high doping ratio improves the 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 self-assembled by the hydrogen-bonding network of meso-tetrakis(4-carboxyphenyl) porphine through carboxylic acid groups. Among them, the porphyrin core in meso-tetrakis(4-carboxyphenyl) porphine (TCPP) acts as a photosensitizer, which can efficiently generate reactive oxygen species (ROS) under visible light excitation, enhancing the photodynamic therapy effect. At the same time, the porous structure of the hydrogen-bonding network can load drug molecules (such as chemotherapeutic drugs) to achieve synergistic therapy.

[0011] Furthermore, the NaGdF 4 :Yb / Er is prepared by the following method:

[0012] 1) Prepare oleic acid-coated NaGdF 4 :Yb / Er upconversion nanocrystal particles: After mixing a mixed solution containing gadolinium acetate, erbium acetate, ytterbium acetate, oleic acid and 1-octadecene, heat it up to 150~180 °C and keep it for 40~60 min; after cooling to room temperature, successively add NH 4 F methanol solution and NaOH methanol solution, heat it up to 45~55 °C and keep it for 60 min, then continue to heat it up to 100~120 °C and keep it for 40 min; pass in an inert gas and continue to heat it up to 300~320 °C and keep it for 100 min. After the reaction is completed, centrifuge and wash and dry the obtained solid to obtain it; the high-temperature thermal decomposition method can improve the crystallinity of the product, and the high-temperature reaction at 300~320 °C ensures that the NaGdF 4 nanocrystals are in a hexagonal phase structure, improving the upconversion luminescence efficiency.

[0013] 2) Take 10 mg of oleic acid-coated NaGdF 4 :Yb / Er and 3 mg of nitrosyl tetrafluoroborate ion and add them to 3 mL of DMF, ultrasonically treat for 15 min, filter and disperse the filter residue into 10 mL of acetone, centrifuge at 12000 rpm for 30 min, and dry to obtain it. The size of the nanoparticles is regulated by the oleic acid / 1-octadecene ligand system to avoid aggregation.

[0014] Furthermore, the gadolinium acetate, erbium acetate, ytterbium acetate, NH 4The molar ratio of the dosages of F and NaOH is 100:1 to 5:15 to 35:600 to 700:40 to 80; the dosage ratio of the molar amount of gadolinium acetate to the volume of oleic acid is 1 mmol:20 mL; the dosage ratio of the molar amount of gadolinium acetate to the volume of 1-octadecene is 1 mmol:30 mL; the 4 concentration of the F methanol solution is 0.50 mol / L; the concentration of the NaOH methanol solution is 1 mol / L.

[0015] Further, the mass ratio of NaGdF 4 :Yb / Er to the hydrogen-bonded organic framework material is 1:4 to 10. With this ratio, the shell thickness can be reasonably regulated, the light energy transfer efficiency and the ROS generation ability can be balanced, and the optimal photodynamic therapy effect of the composite material can be maintained.

[0016] Another object of the present invention is to provide a preparation method of a rare earth upconversion nanocrystal particle-hydrogen-bonded organic framework composite material. The composite material uses NaGdF 4 :Yb / Er as the core and the hydrogen-bonded organic framework as the shell. The mass ratio of NaGdF 4 :Yb / Er to the hydrogen-bonded organic framework material is 1:4 to 10. The preparation method includes the following steps:

[0017] 1) Prepare NaGdF 4 :Yb / Er upconversion nanocrystal particles: Prepare acid-coated NaGdF 4 :Yb / Er. After mixing a mixed solution containing gadolinium acetate, erbium acetate, ytterbium acetate, oleic acid and 1-octadecene, heat it up to 150-180 °C and keep it for 40-60 min; after cooling to room temperature, sequentially add 0.50 mol / L NH 4 F methanol solution and 1 mol / L NaOH methanol solution, heat it up to 45-55 °C and keep it for 60 min, then continue to heat it up to 100-120 °C and keep it for 40 min; introduce an inert gas and continue to heat it up to 300-320 °C and keep it for 100 min. After the reaction is completed, centrifuge, and wash and dry the obtained solid. Among them, the molar ratio of the dosages of gadolinium acetate, erbium acetate, ytterbium acetate, NH 4 F and NaOH is 100:1 to 5:15 to 35:600 to 700:40 to 80. The dosage ratio of the molar amount of gadolinium acetate to the volume of oleic acid is 1 mmol:20 mL, and the dosage ratio of the molar amount of gadolinium acetate to the volume of 1-octadecene is 1 mmol:30 mL; take 10 mg of oleic acid-coated NaGdF 4: Yb / Er and 3 mg of nitrous ion tetrafluoroborate were added to 3 mL of DMF and sonicated for 15 min. After filtration, the residue was dispersed in 10 mL of acetone and centrifuged at 12,000 rpm for 30 min, followed by drying to obtain the product.

[0018] 2) The prepared NaGdF 4 : Yb / Er upconversion nanocrystal particles were dispersed in 5 mL of DMF, 3 mg of polyvinylpyrrolidone was added, and after stirring for 10 h, 10 mg of meso-tetrakis(4-carboxyphenyl)porphine was added. 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 absolute ethanol was added dropwise. After continuing to stir for 24 h, the product was centrifuged, washed, and dried to obtain the product.

[0019] Furthermore, the stirring speed was 500 - 1500 rpm; the washing was performed by rinsing with ethanol and acetone, and the drying was carried out at 40 - 70 °C.

[0020] The present invention also provides an application of the rare earth upconversion nanocrystal particle - hydrogen bond organic framework composite material, using it as a raw material to prepare a photodynamic therapy agent.

[0021] Furthermore, the composite material activates the multi-photon transition of the upconversion luminescent particles through near-infrared laser irradiation, exciting the rare earth ions to generate corresponding visible light. Due to the tight coating of the hydrogen bond organic framework (HOFs) on the upconversion nanoparticles to form good fluorescence resonance energy transfer, a large amount of singlet oxygen is generated by exciting the HOFs, which can trigger the oxidative stress damage of tumor cells and has good therapeutic prospects for deep tumors such as glioblastoma.

[0022] Compared with the prior art, the beneficial effects of the technical solution of the present invention are as follows:

[0023] 1. The composite material of the present invention combines the unique optical properties of rare-earth upconversion nanocrystals with the versatility of hydrogen-bonded organic frameworks, effectively improving the effect of photodynamic therapy (PDT). This composite material can enhance the absorption and conversion of near-infrared light. The core material can convert low-energy near-infrared light into higher-energy visible light or ultraviolet light through a multi-photon absorption process under the excitation of 980 nm near-infrared light. The hydrogen-bonded organic framework shell is self-assembled through a hydrogen-bond 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 this composite material enables the high-energy visible light generated by the core under the excitation of 980 nm near-infrared light to be effectively absorbed by TCPP, thereby promoting the generation of reactive oxygen species, realizing an efficient chain reaction from near-infrared to visible light energy conversion and then to reactive oxygen species generation. This composite material shows great potential in the field of photodynamic therapy, especially in treating deep tumors. By using 980 nm near-infrared light excitation, it can effectively penetrate deep tissues and generate reactive oxygen species at the target position, achieving the purpose of local high-efficiency treatment.

[0024] 2. This composite material has good biocompatibility. The shell is HOFs formed by the self-assembly of TCPP, which 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 realize the controlled release of photosensitizers or other therapeutic drugs, improving the treatment effect while reducing side effects. This material is expected to become a safe and effective cancer treatment direction. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 It is a transmission electron microscope (TEM) photograph of the composite material prepared in Example 1 of the present invention;

[0026] Figure 2 It is a scanning electron microscope (SEM) photograph of the composite material prepared in Example 1 of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0027] To make the technical problems solved, the technical solutions adopted, and the technical effects achieved by the present invention clearer, the technical solutions of the embodiments of the present invention will be further described in detail below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative efforts belong to the scope of protection of the present invention.

[0028] It should be noted that referring to "embodiment" in this text means that the specific features, structures or characteristics described in connection with the embodiment may be included in at least one embodiment of the present application. The phrase appears in various positions in the specification does not necessarily refer to the same embodiment, nor is it an independent or alternative embodiment mutually exclusive with other embodiments. Those skilled in the art explicitly and implicitly understand that the embodiments described herein can be combined with other embodiments.

[0029] The experimental methods in the following embodiments are all conventional methods unless otherwise specified. The materials, reagents, etc. used in the following embodiments can all be obtained from commercial sources unless otherwise specified.

[0030] The reactive oxygen species yield is detected and calculated in the following manner: DPBF is used as a singlet oxygen detector and is dissolved in an aqueous solution containing 1% dimethyl sulfoxide (DMSO). DMSO can increase the solubility of DPBF. The indicator solution is mixed with the nanoparticles, and then the absorbance of DPBF after irradiation of composites with different concentrations by a 980 nm highly stable infrared laser is detected.

[0031] Example 1

[0032] A rare earth upconversion nanocrystal particle - hydrogen bond organic framework composite material is in-situ composite formed with NaGdF 4 :Yb / Er as the core and a hydrogen bond organic framework as the shell. The hydrogen bond organic framework is self-assembled by the hydrogen bond network of meso-tetrakis(4-carboxyphenyl) porphine and is prepared by the following method:

[0033] 1) Prepare NaGdF 4 :Yb / Er upconversion nanocrystal particles: Prepare 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 = 100 mol: 1 mol: 15 mol: 600 mol: 40 mol: 2000 L: 3000 L. Add the weighed gadolinium acetate, erbium acetate, and ytterbium acetate to the mixed solution composed of oleic acid and 1-octadecene in sequence, stir until evenly dispersed, heat up to 150 °C and keep for 40 min; after cooling to room temperature, add 0.50 mol / L NH4 F methanol solution and 1 mol / L NaOH methanol solution in sequence, heat up to 45 °C and keep for 60 min, continue to heat up to 100 °C and keep for 40 min; introduce inert gas and continue to heat up to 300 °C and keep for 100 min. After the reaction ends, centrifuge, and rinse the obtained solid with ethanol and acetone and dry at 40 °C; take 10 mg of oleic acid-coated NaGdF4 : Yb / Er and 3 mg of nitrous tetrafluoroborate ions were added to 3 mL of DMF and sonicated for 15 min, filtered, and the filter residue was dispersed in 10 mL of acetone, centrifuged at 12000 rpm for 30 min, and dried at 40 °C;

[0034] 2) 1 mg of the prepared NaGdF 4 :Yb / Er upconversion nanocrystal particles were dispersed in 5 mL of DMF, 3 mg of polyvinylpyrrolidone was added, stirred at 500 rpm for 10 h, 10 mg of meso-tetra(4-carboxyphenyl)porphine was added, stirred for another 30 min, 10 mL of deionized water was added, stirred for 10 min, 8 mL of absolute ethanol was added dropwise, and stirred for 24 h. The product was centrifuged, rinsed with ethanol and acetone, and dried at 40 °C to obtain.

[0035] Figure 1 is the transmission electron microscopy image of the prepared composite material, from which it can be clearly seen that the upconversion nanoparticles NaGdF 4 :Yb / Er are encapsulated inside the HOFs, with a size of 50 nm; Figure 2 is the scanning electron microscopy (SEM) image of the prepared composite material. It can be seen from the figure that the particles are overall regular and no obvious NaGdF 4 :Yb / Er nanocrystal particles appear, indicating that NaGdF 4 :Yb / Er and HOFs are successfully compounded together. In-situ polymerization enables the upconversion luminescent nanocrystal particles to be coated by HOFs, and the overall stability of the material. The prepared composite material was tested, and the ROS production rate was measured to reach 2.4 μM / min. After continuous laser irradiation for 60 min, the retention rate of TCPP was 93%, indicating that HOFs can effectively protect the photosensitizer.

[0036] Example 2

[0037] A rare earth upconversion nanocrystal particle - hydrogen bond organic framework composite material, which is in-situ compounded with NaGdF 4 :Yb / Er as the core and hydrogen bond organic framework as the shell. The hydrogen bond organic framework is formed by self-assembly of meso-tetra(4-carboxyphenyl)porphine through the hydrogen bond network of carboxylic acid groups, and is prepared by the following method:

[0038] 1) Preparation of NaGdF 4 :Yb / Er upconversion nanocrystal particles: Preparation of oleic acid-coated NaGdF 4 :Yb / Er, weigh the raw materials according to the following ratio, and the ratio is gadolinium acetate: erbium acetate: ytterbium acetate: NH 4F: NaOH: oleic acid: 1-octadecene = 100 mol: 5 mol: 35 mol: 700 mol: 80 mol: 2000 L: 3000 L. Gadolinium acetate, erbium acetate, and ytterbium acetate were successively added to the mixed solution composed of oleic acid and 1-octadecene, stirred until evenly dispersed, heated to 180 °C and maintained for 60 min; after cooling to room temperature, 0.50 mol / L NH F methanol solution and 1 mol / L NaOH methanol solution were added successively, heated to 55 °C and maintained for 60 min, and then continuously heated to 120 °C and maintained for 40 min; an inert gas was introduced and the temperature was continuously raised to 320 °C and maintained for 100 min. After the reaction ended, centrifugation was carried out, and the obtained solid was rinsed with ethanol and acetone and dried at 70 °C; 10 mg of oleic acid-coated NaGdF 4 :Yb / Er and 3 mg of nitrosyl tetrafluoroborate ion were added to 3 mL of DMF, sonicated for 15 min, filtered, and the filter residue was dispersed in 10 mL of acetone, centrifuged at 12000 rpm for 30 min, and dried at 70 °C;

[0039] 2) 2.5 mg of the prepared NaGdF 4 :Yb / Er upconversion nanocrystal particles were dispersed in 5 mL of DMF, 3 mg of polyvinylpyrrolidone was added, stirred at 1500 rpm for 10 h, then 10 mg of meso-tetrakis(4-carboxyphenyl)porphine was added, stirred for another 30 min, then 10 mL of deionized water was added, stirred for 10 min, 8 mL of absolute ethanol was added dropwise, and stirred for 24 h. The product was centrifuged, rinsed with ethanol and acetone, and dried at 70 °C to obtain.

[0040] The prepared composite material was tested. After measurement, the ROS production rate reached 3.7 μM / min. After continuous laser irradiation for 60 min, the retention rate of TCPP was 95%, indicating that HOFs can effectively protect the photosensitizer.

[0041] Example 3

[0042] A rare earth upconversion nanocrystal particle - hydrogen bond organic framework composite material is in-situ composite with NaGdF 4 :Yb / Er as the core and a hydrogen bond organic framework as the shell. The hydrogen bond organic framework is formed by self-assembly of meso-tetrakis(4-carboxyphenyl)porphine through a hydrogen bond network of carboxylic acid groups, and is prepared by the following method:

[0043] 1) Preparation of NaGdF 4 :Yb / Er upconversion nanocrystal particles: Preparation of oleic acid-coated NaGdF 4 :Yb / Er. The raw materials were weighed according to the following ratio. The ratio was gadolinium acetate: erbium acetate: ytterbium acetate: NH 4F: NaOH: oleic acid: 1-octadecene is 100 mol: 3 mol: 25 mol: 650 mol: 60 mol: 2000 L: 3000 L. The weighed gadolinium acetate, erbium acetate, and ytterbium acetate are successively added to the mixed solution composed of oleic acid and 1-octadecene, stirred until evenly dispersed, heated to 160 °C and maintained for 60 min; after cooling to room temperature, 0.50 mol / L NH F methanol solution and 1 mol / L NaOH methanol solution are added successively, heated to 50 °C and maintained for 60 min, and then continuously heated to 110 °C and maintained for 40 min; an inert gas is introduced and the temperature is continuously raised to 310 °C and maintained for 100 min. After the reaction is completed, centrifugation is carried out, and the obtained solid is rinsed with ethanol and acetone and dried at 60 °C; 10 mg of oleic acid-coated NaGdF 4 :Yb / Er and 3 mg of nitrosyl tetrafluoroborate ion are added to 3 mL of DMF, ultrasonically treated for 15 min, filtered, and the filter residue is dispersed in 10 mL of acetone, centrifuged at 12,000 rpm for 30 min, and dried at 70 °C;

[0044] 2) 1.5 mg of the prepared NaGdF 4 :Yb / Er upconversion nanocrystal particles are dispersed in 5 mL of DMF, 3 mg of polyvinylpyrrolidone is added, stirred at 1000 rpm for 10 h, then 10 mg of meso-tetrakis(4-carboxyphenyl)porphine is added, stirred for another 30 min, then 10 mL of deionized water is added, stirred for 10 min, 8 mL of absolute ethanol is added dropwise, and stirred for 24 h. The product is centrifuged, rinsed with ethanol and acetone, and dried at 70 °C to obtain.

[0045] The prepared composite material is tested. After measurement, the ROS production rate reaches 3.3 μM / min. After continuous laser irradiation for 60 min, the retention rate of TCPP is 97%, indicating that HOFs can effectively protect the photosensitizer.

[0046] Comparative Example 1

[0047] A rare earth upconversion nanocrystal particle - hydrogen bond organic framework composite material is in-situ composite formed with NaGdF 4 :Yb / Er as the core and a hydrogen bond organic framework as the shell. The hydrogen bond organic framework is self-assembled by the hydrogen bond network of meso-tetrakis(4-carboxyphenyl)porphine through carboxylic acid groups, and is prepared by the following method:

[0048] 1) Preparation of NaGdF 4 :Yb / Er upconversion nanocrystal 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 4F: NaOH: oleic acid: 1-octadecene is 100 mol: 0.5 mol: 40 mol: 550 mol: 85 mol: 2500 L: 1000 L. The weighed gadolinium acetate, erbium acetate, and ytterbium acetate are successively added to the mixed solution composed of oleic acid and 1-octadecene, stirred until evenly dispersed, heated to 160 °C and maintained for 60 min; after cooling to room temperature, 0.50 mol / L NH4 F methanol solution and 1 mol / L NaOH methanol solution are added successively, an inert gas is introduced, heated to 310 °C and maintained for 200 min. After the reaction is completed, centrifugation is carried out, and the obtained solid is rinsed with ethanol and acetone and dried at 60 °C; Take 10 mg of the prepared NaGdF 4 :Yb / Er and 3 mg of nitrosyl tetrafluoroborate ions are added to 3 mL of DMF, ultrasonically treated for 15 min, filtered, and the filter residue is dispersed in 10 mL of acetone, centrifuged at 12000 rpm for 30 min, and dried at 70 °C;

[0049] 2) Disperse 1.5 mg of the NaGdF 4 :Yb / Er particles obtained in step 1) in 5 mL of DMF, add 3 mg of polyvinyl alcohol, stir at 1000 rpm for 10 h, then add 10 mg of meso-tetrakis(4-carboxyphenyl)porphine, continue to stir for 30 min, then add 10 mL of deionized water, continue to stir for 10 min, then add 8 mL of absolute ethanol, continue to stir for 24 h, centrifuge the product, rinse with ethanol and acetone, and dry at 70 °C to obtain.

[0050] The prepared composite material was tested, and the ROS production rate was measured to be 1.1 μM / min. After continuous laser irradiation for 60 min, the retention rate of TCPP was 68%, and the stability of the composite material was slightly poor.

[0051] Comparative Example 2

[0052] A rare earth upconversion nanocrystal particle - hydrogen bond organic framework composite material, which is composed of NaGdF 4 :Yb / Er and a hydrogen bond organic framework material. The hydrogen bond organic framework is formed by self-assembly of meso-tetrakis(4-carboxyphenyl)porphine through a hydrogen bond network of carboxylic acid groups, and is prepared by the following method:

[0053] 1) Preparation of NaGdF by thermal decomposition method 4: Er: Disperse 0.78 mmol of gadolinium chloride hexahydrate and 0.02 mmol of erbium chloride hexahydrate in a mixed solvent of 10 mL of oleic acid and 15 mL of octadecene. Then, heat the mixed system to 160 °C under the protection of an argon atmosphere and maintain this temperature for 1 h to form a stable and uniform rare earth ion-oleic acid precursor mixed system. Naturally cool it to room temperature; quickly mix a 5 mL methanol solution containing 2.5 mmol of NaOH and a 1 mL methanol solution containing 2.75 mmol of NH 4 F, and then quickly add the mixture to the mixed system. Raise the temperature to 50 °C, keep it for 30 min, then raise the temperature to 140 °C, and keep it warm for 2 h to fully volatilize methanol. Raise the temperature of the obtained mixture to 320 °C, keep it warm for 2.5 h, then cool it to room temperature, add ethanol to precipitate the solid particles and centrifuge and separate them, and dry them;

[0054] 2) Disperse 1.5 mg of the prepared NaGdF 4 :Er upconversion nanocrystal particles in 5 mL of DMF, add 3 mg of polyvinylpyrrolidone, and stir at 1000 rpm for 10 h;

[0055] 3) Stir 10 mg of meso-tetrakis(4-carboxyphenyl)porphine and add it to 5 mL of DMF. After stirring for 30 min, add the mixed system obtained in step 2) thereto, continue stirring for 30 min, then add 10 mL of deionized water, continue stirring for 10 min, then add 8 mL of absolute ethanol dropwise, and continue stirring for 24 h. Centrifuge the product, rinse it with ethanol and acetone, and dry it at 70 °C to obtain it.

[0056] Test the prepared composite material. After measurement, the ROS production rate is 0.2 μM / min. After continuous laser irradiation for 60 min, the TCPP retention rate is 17%. A small amount of upconversion luminescent particles are dispersed and attached to the pores of the HOFs material, and the two do not form a stable composite material.

[0057] It can be seen from the test results of the examples and comparative examples of the present invention that the product of the example adopting the solution of the present invention can realize the in-situ composite of NaGdF 4 :Yb / Er upconversion nanocrystal particles and hydrogen-bonded organic frameworks, NaGdF 4:The Yb / Er upconversion nanocrystal particles are uniformly coated by HOFs. The composite material has high stability. This composite material can generate high-energy visible light under the excitation of 980 nm near-infrared light and be effectively absorbed by TCPP, thereby promoting the generation of reactive oxygen species (ROS) by HOFs, realizing an efficient chain reaction from near-infrared to visible light energy conversion and then to ROS generation. The yield of ROS is relatively stable. After continuous laser irradiation for 60 min, the retention rate of TCPP is high and the stability of the composite material is good. It can significantly improve the efficiency of ROS generation under near-infrared light excitation, solve the penetration depth limitation of traditional PDT, and has certain potential for clinical translation in the treatment of glioblastoma.

[0058] The above has introduced in detail a rare earth upconversion nanocrystal 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 specific preferred embodiments, and it cannot be determined that the specific implementation of the present invention is only limited to these descriptions. For those of ordinary skill in the technical field to which the present invention pertains, without departing from the concept of the present invention, its architecture form can be flexibly changed and a series of products can be derived. Just making several simple deductions or replacements should be regarded as belonging to the patent protection scope determined by the claims submitted for the present invention.

Claims

1. A rare earth upconversion nanocrystal-hydrogen bond organic framework composite material, characterized in that: The composite material is composed of rare earth upconversion nanocrystalline particles NaGdF4:Yb / Er as the core and a hydrogen-bonded organic framework as the shell. The hydrogen-bonded organic framework is self-assembled by meso-tetra(4-carboxyphenyl)porphine through the hydrogen-bonded network of carboxylic acid groups. The mass ratio of NaGdF4:Yb / Er to the hydrogen-bonded organic framework material is 1:4-10. When the composite material is used for photodynamic therapy, it produces reactive oxygen 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 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.

4. The rare earth upconversion nanocrystal-hydrogen bond organic framework composite material according to claim 3, 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.

5. A method for preparing a rare earth upconversion nanocrystal-hydrogen bonded organic framework composite material, wherein the composite material has NaGdF4:Yb / Er as the core and the hydrogen bonded 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.

6. A method for preparing the rare earth upconversion nanocrystalline particle-hydrogen bond organic framework composite material according to claim 5, 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.

7. 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.

8. The use according to claim 7, characterized in that: The photodynamic therapy agent is used for treating brain glioma.

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