Nd < 3 + >-sensitized and TiO2-modified up-conversion nano composite material as well as preparation method and application thereof

Abstract

The invention discloses an up-conversion nano composite material sensitized by Nd < 3 + > and modified by TiO2 as well as a preparation method and application of the up-conversion nano composite material. Nd < 3 + > ion-doped up-conversion nanoparticles (UCNPs) with a core-shell structure are used as seed crystals, and titanium dioxide (TiO2) epitaxially grows on the surface of the UCNPs to form a shell, so that the TiO2-modified rare earth up-conversion nano composite material with interface nucleation growth is formed; wherein under the excitation of 808 nm near-infrared light, after the UCNPs captures low-energy photons, energy is transferred to adjacent TiO2 nanoparticles through resonance energy transfer, so that enough reactive oxygen species (ROS) is generated to meet the requirements of photodynamic therapy; the nano composite material prepared by the invention is uniform in size, good in stability and good in biocompatibility, and a good opportunity is provided for potential application of the nano composite material in emerging fields such as biosensors, photodynamic therapy and drug release.

Description

Technical Field

[0001] The present invention relates to the technical field of nano-biomaterials, and in particular to a Nd 3+ Sensitized, TiO2-modified upconversion nanocomposites, preparation methods, and applications thereof. Background Art

[0002] Cancer has become a major threat to human health. Traditional anti-cancer methods have limitations, such as resistance to chemotherapy, severe side effects from radiotherapy, and high recurrence rates with surgery. Photodynamic therapy (PDT) has garnered widespread attention in the field of cancer treatment due to its precise and predictable response to specific lesions. PDT is a minimally invasive cancer treatment. Its principle is that when a photosensitizer is excited by light in the presence of oxygen, it produces cytotoxic reactive oxygen species (ROS), which kill cancer cells. Therefore, improving and evaluating ROS production is crucial for practical applications.

[0003] As optical nanoconverters, lanthanide-doped upconversion nanoparticles (UCNPs) can emit high-energy ultraviolet (UV) or visible light when excited by low-energy near-infrared (NIR) light. They have the advantages of no fluorescence background interference, high sensitivity, and no damage to cells and biological tissues. In addition, due to their unique optical properties, UCNPs have been widely reported as imaging indicators in biodiagnosis and treatment processes. At the same time, combined with photosensitizers, they have been given a variety of functions, such as fluorescence imaging-guided photodynamic therapy. In order to achieve efficient energy transfer from UCNPs to photosensitizers, the photosensitizer should be as close to the UCNPs as possible, and the absorption of the photosensitizer should overlap as much as possible with the emission of the UCNPs. At the same time, semiconductor TiO2 is often used in photodynamic therapy of malignant tumor cells because of its ability to absorb UV and generate ROS.

[0004] To this end, the present invention designs a Nd 3+ Sensitized, TiO2-modified upconversion nanocomposites, by modifying TiO2 particles on the surface of UCNPs, cleverly achieve low-energy near-infrared light excitation of UCNPs to produce high-energy ultraviolet light emission. Through efficient resonance energy transfer (FRET), the TiO2 particles adjacent to UCNPs absorb high-energy ultraviolet light to produce a large amount of reactive oxygen species (ROS), thereby killing cancer cells and achieving the desired therapeutic effect. In addition, it is worth noting that the use of 808 nm light (via Nd 3+ The sensitized upconversion process can effectively avoid the heating effect induced by laser radiation (because biological tissue has minimal absorption at this wavelength). Summary of the Invention

[0005] The purpose of the present invention is to provide a Nd3+ The sensitized, TiO2-modified upconversion nanocomposites, their preparation methods and their applications in photodynamic therapy aim to develop rare earth upconversion integrated diagnosis and treatment nanocomposites that meet the needs of photodynamic therapy and have fluorescence imaging capabilities.

[0006] In order to achieve the above-mentioned object of the invention, the present invention first provides a Nd 3+ Sensitized, TiO2-modified upconversion nanocomposites with Nd 3+ Ion-doped upconversion nanoparticles (UCNPs) with a core-shell structure serve as seeds, allowing titanium dioxide (TiO2) to epitaxially grow as a shell on the surface of UCNPs, thereby forming an interface-nucleated TiO2-modified rare earth upconversion nanocomposite material; under near-infrared light (NIR) excitation, the upconversion emission of UCNPs is transferred to adjacent TiO2 nanoparticles through fluorescence resonance energy transfer (FRET), which can generate reactive oxygen species (ROS) in an aerobic environment to meet the needs of photodynamic therapy (PDT); among them, UCNPs and TiO2 nanoparticles work together to achieve integrated diagnosis and treatment.

[0007] As some embodiments of the present invention, the upconversion luminescent nanoparticles include: LiYbF4:Tm; LiYF4:Yb / Tm / Nd; LiYbF4:Tm@LiYF4:Yb / Nd; LiYbF4:Tm@LiLuF4:Yb / Nd; LiYF4:Yb / Tm@LiYF4:Yb / Nd; LiYF4:Yb / Tm@LiYF4:Yb / Nd; LiYF4:Yb / Tm@LiYF4:Yb / Nd; LiYbF4:Tm@LiYF4:Yb@LiYF4:Yb / Nd or one or more of the following.

[0008] As some embodiments of the present invention, the aforementioned Nd 3+ The sensitized, TiO2-modified upconversion nanocomposite material is characterized in that the wavelength of the NIR laser is 808±10 nm.

[0009] The present invention further provides the above-mentioned Nd 3+ Application of sensitized, TiO2-modified upconversion nanocomposites in photodynamic therapy, photosensitizers, or imaging agents for fluorescence imaging.

[0010] As some embodiments of the present invention, when used in photodynamic therapy, under NIR laser irradiation, UCNPs convert NIR into ultraviolet light emission through an upconversion process, and its high-energy ultraviolet light is transmitted to the photosensitizer TiO2 through the FRET process, generating ROS in an aerobic environment, thereby playing a therapeutic role in killing cancer cells.

[0011] The present invention also provides the aforementioned Nd 3+The preparation method of the sensitized, TiO2-modified upconversion nanocomposite material comprises the following steps: (1) Disperse UCNPs without oleic acid ligands in deionized water containing polyvinylpyrrolidone (PVP) and ultrasonically stir for 1 h to 2 h. Then add ethanol and mix with these PVP-coated UCNPs under magnetic stirring for 30 min to 120 min.

[0012] (2) Add TiF4 aqueous solution dropwise to the solution in step (1) and keep stirring for 2 min to 10 min.

[0013] (3) The entire reaction solution in step (2) is placed in a polytetrafluoroethylene liner, and then transferred to a high-pressure reactor, heated to 150°C to 200°C and kept warm for 4 h to 8 h.

[0014] (4) After cooling to room temperature, the precipitate was collected by centrifugation and washed three times with deionized water and ethanol respectively. Finally, the finished product was placed in a 65°C forced air drying oven and dried overnight.

[0015] Compared with the prior art, the present invention has the following beneficial effects: The nanocomposite material provided by the present invention has uniform size, good stability, good biocompatibility, and has the effect of photodynamic therapy. It can be applied to fields such as upconversion fluorescence imaging and photodynamic therapy, meeting the needs of integrated clinical diagnosis and treatment.

[0016] The preparation method provided by the present invention obtains a nanocomposite material of rare earth upconversion nanoparticles epitaxially grown titanium dioxide by an epitaxial growth method at room temperature, that is, obtains a rare earth upconversion nanocomposite material having both upconversion luminescence imaging and photodynamic therapy. The preparation method has few steps, an efficient, stable and highly repeatable preparation process, is easy to industrialize, and the obtained products have uniform size, stable performance and good consistency. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 is Nd in Example 1 of the present invention 3+ Schematic diagram of the structure of the sensitized, TiO2-modified upconversion nanocomposite; Figure 2 is Nd in Example 1 of the present invention 3+ Transmission electron microscopy (TEM) images of sensitized, TiO2-modified upconversion nanocomposites; Figure 3 is Nd in Example 1 of the present invention 3+ XRD patterns of sensitized, TiO2-modified upconversion nanocomposites; Figure 4 is Nd in Example 1 of the present invention 3+Upconversion fluorescence spectra of sensitized, TiO2-modified upconversion nanocomposites and TiO2-coated upconversion nanocomposites; Figure 5 This is the time-dependent degradation of the ROS indicator 1,3-diphenylisobenzofuran (DPBF) in Example 1 of the present invention.

[0018] Figure 6 is Nd in Example 1 of the present invention 3+ Sensitized, TiO2-modified upconversion nanocomposites generate ROS-induced time-dependent degradation of the indicator 1,3-diphenylisobenzofuran (DPBF) upon 808 nm laser irradiation.

[0019] Figure 7 is Nd in Example 1 of the present invention 3+ Fitting curve of the absorbance change of indicator 1,3-diphenylisobenzofuran (DPBF) over time caused by ROS generated by sensitized, TiO2-modified upconversion nanocomposite under 808nm laser irradiation. DETAILED DESCRIPTION

[0020] The following will be combined with specific embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only a small part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work, any modifications, equivalent replacements, improvements, etc., should be included in the scope of protection of the present invention. The present invention will be further described in detail below with reference to the drawings and specific embodiments.

[0021] Example 1: This example uses LiYbF4:Tm@LiYF4:Yb / Nd as the seed Nd 3+ Preparation of sensitized, TiO2-modified upconversion nanocomposites: Core Preparation: First, a 0.4 mmol rare earth acetate solution (5 mL of OA, 5 mL of LOD, (1-x) mmol of ytterbium acetate, and x mmol (0.002-0.008) of thulium acetate) was added to a 50 mL two-necked flask. The flask was then transferred to a 150°C oil bath and magnetically stirred for 50 min. The solution was then cooled to room temperature. The precursor flask was placed in a 50°C oil bath. Once the temperature stabilized, 4 mL of 0.4 mol / L NH4F and 2 mL of 0.5 mol / L LiOH methanol solution were transferred to a 15 mL centrifuge tube and thoroughly mixed by sonication for 10 s. The mixture was then rapidly poured into the flask. (Note: To prevent LiF precipitates from the NH4F and LiOH methanol solutions from adhering to the walls of the centrifuge tube, the mixture must be poured into the flask immediately after thorough mixing.) The mixture was then magnetically stirred at 50°C for 40 min. After removing the two-necked flask from the oil bath and wiping the bottom clean, the flask was transferred to a heating mantle and heated to 100°C at a rate of 10°C / min (for a total of 30 minutes of heating and holding) to ensure removal of the methanol solution. The flask was then evacuated for 5 minutes and filled with argon for 1 minute, repeated twice. The flask was then heated to 290°C under argon and held for 90 minutes. After the reaction was complete, the solution was allowed to cool, and anhydrous ethanol was added in a 1:1 volume ratio. After mixing thoroughly, the solution was centrifuged at 6000–8000 rpm for 3–5 minutes. Cyclohexane solution was added to the solid precipitate, and the nanoparticles were dispersed by sonication. This resulted in a solution of LiYbF4:Tm upconversion core nanocrystals.

[0022] Shelling process: Following the previous experimental steps, a certain ratio of rare earth ion trifluoroacetate and a certain amount of lithium trifluoroacetate solution were added to a 50 mL two-necked flask containing 5 mL of OA and 5 mL of ODE. LiYF4 was then coated according to the same steps as above. This resulted in a solution containing LiYbF4:Tm@LiYF4:Yb / Nd upconversion core-shell nanocrystals.

[0023] Removal of oleic acid ligands: First, measure a certain amount of HCl and dilute it to 0.25 mol / L with deionized water for later use. Add 0.5 mL of the UCNPs cyclohexane solution and 1 mL of ethanol to a 2 mL centrifuge tube and centrifuge at 8500 rpm for 7 minutes to remove the cyclohexane. After decanting the supernatant, add 0.5 mL of the diluted HCl to the precipitate and sonicate in an ultrasonic cleaner to redisperse the precipitate. Continue ultrasonically stirring the resulting mixture at 40°C for 30 minutes and then allow it to stand for 10 minutes. At this point, brown oil droplets should be visible on the walls of the centrifuge tube. Add 1 mL of ethanol to the same centrifuge tube and centrifuge at 15000 rpm for 30 minutes. After decanting the supernatant, a transparent precipitate should be visible at the bottom of the tube. Finally, redisperse the precipitate in 0.5 mL of DMF for later use.

[0024] Titanium dioxide coating process: Then 0.3mL of oleic acid-free ligand UCNPs was dispersed in 4mL of deionized water containing 1.3gPVP and ultrasonically stirred for 1h. Then 20mL of ethanol was added and mixed with these PVP-coated UCNPs under magnetic stirring for 30min. 2.5mL of 0.025mol / LTiF4 aqueous solution was added dropwise to the above solution and kept stirring for 5min. The entire reaction solution was placed in a 50mL polytetrafluoroethylene liner and then transferred to a high-pressure reactor, heated to 180°C and kept warm for 4h. After cooling to room temperature, the precipitate was collected by centrifugation and washed three times with deionized water and ethanol respectively. Finally, the finished product was placed in a 65°C forced air drying oven and dried overnight. The obtained sample was then dissolved in cyclohexane to finally obtain a solution of upconversion core-shell nanocrystals containing LiYbF4:Tm@LiYF4:Yb / Nd@TiO2. The structure of the material is shown in the figure below. Figure 1 As shown in the transmission electron microscopy images Figure 2 As shown, the XRD pattern is Figure 3 The fluorescence spectrum is shown in Figure 4 As shown, the time-dependent degradation Figure 5 、 6 The absorbance fitting curve is shown in Figure 7 shown.

[0025] Example 2: This example uses LiYbF4:Tm@LiLuF4:Yb / Nd as the Nd seed 3+ Preparation of sensitized, TiO2-modified upconversion nanocomposites: Core Preparation: First, a 0.4 mmol rare earth acetate solution (5 mL of OA, 5 mL of LOD, (1-x) mmol of ytterbium acetate, and x mmol (0.002-0.008) of thulium acetate) was added to a 50 mL two-necked flask. The flask was then transferred to a 150°C oil bath and magnetically stirred for 50 minutes. The solution was then cooled to room temperature. The precursor flask was placed in a 50°C oil bath. Once the temperature stabilized, 4 mL of NH4F and LiOH methanol solution was transferred to a 15 mL centrifuge tube and thoroughly mixed by sonication for 10 seconds. The mixture was then quickly poured into the flask. (Note: To prevent LiF precipitates from the NH4F and LiOH methanol solutions from adhering to the walls of the centrifuge tube, the mixture must be poured into the flask immediately after thorough mixing.) The mixture was then magnetically stirred at 50°C for 40 minutes. After removing the double-necked flask from the oil bath and wiping the bottom clean, transfer the flask to a heating mantle and heat it to 100°C at a heating rate of 10°C / min (the heating and insulation process takes a total of 30 minutes) to ensure the removal of the methanol solution. Then evacuate for 5 minutes and fill with argon for 1 minute, repeat twice, and then heat it to 290°C in an argon atmosphere and keep it for 90 minutes. After the reaction is completed, wait for the reaction solution to cool, add anhydrous ethanol at a volume ratio of 1:1, mix well, and place it in a centrifuge at a centrifugal speed of 6000 r / min and a centrifugal time of 4 minutes. Add cyclohexane solution to the solid precipitate from the centrifuge and ultrasonicate to disperse the nanoparticles. According to the previous experimental steps, a certain proportion of rare earth ion trifluoroacetate and a certain amount of lithium trifluoroacetate solution were added to a 50 mL double-necked flask containing 5 mL OA and 5 mL ODE. Shelling process: Follow the same steps as above to coat LiLuF4 to obtain a solution of upconversion core-shell nanocrystals containing LiYbF4:Tm@LiLuF4:Yb / Nd.

[0026] Removal of oleic acid ligands: First, measure a certain amount of HCl and dilute it to 0.25 mol / L with deionized water for later use. Add 0.5 mL of the UCNPs cyclohexane solution and 1 mL of ethanol to a 2 mL centrifuge tube and centrifuge at 8500 rpm for 7 minutes to remove the cyclohexane. After decanting the supernatant, add 0.5 mL of the diluted HCl to the precipitate and sonicate in an ultrasonic cleaner to redisperse the precipitate. Continue ultrasonically stirring the resulting mixture at 40°C for 30 minutes and then allow it to stand for 10 minutes. At this point, brown oil droplets should be visible on the walls of the centrifuge tube. Add 1 mL of ethanol to the same centrifuge tube and centrifuge at 15000 rpm for 30 minutes. After decanting the supernatant, a transparent precipitate should be visible at the bottom of the tube. Finally, redisperse the precipitate in 0.5 mL of DMF for later use.

[0027] Titanium dioxide coating process: 0.3 mL of oleic acid-free UCNPs were dispersed in 4 mL of deionized water containing 1.3 g of PVP and ultrasonically stirred for 1 hour. 20 mL of ethanol was then added and mixed with the PVP-coated UCNPs under magnetic stirring for 30 minutes. 2.5 mL of a 0.025 mol / L TiF4 aqueous solution was dropwise added to the solution and stirred for 5 minutes. The entire reaction solution was placed in a 50 mL polytetrafluoroethylene-lined autoclave, heated to 180°C, and held there for 4 hours. After cooling to room temperature, the resulting precipitate was collected by centrifugation and washed three times with deionized water and ethanol. Finally, the product was dried in a 65°C forced air drying oven overnight. The resulting sample was then dissolved in cyclohexane to obtain a solution containing LiYbF4:Tm@LiLuF4:Yb / Nd@TiO2 upconversion core-shell nanocrystals.

[0028] Example 3: This example uses LiYF4:Yb / Tm@LiLuF4:Yb / Nd as the Nd seed 3+ Preparation of sensitized, TiO2-modified upconversion nanocomposites: Core Preparation: First, add 5 mL of OA, 5 mL of LOD, (1-xy) mmol of yttrium acetate, y mmol (0.12-0.2) of ytterbium acetate, and x mmol (0.002-0.008) of thulium acetate, totaling 0.4 mmol, to a 50 mL two-necked flask. The flask is then transferred to a 150°C oil bath and magnetically stirred for 50 min. The solution is then cooled to room temperature. The precursor flask is placed in a 50°C oil bath. Once the temperature stabilizes, 4 mL of NH4F and LiOH methanol solution is transferred to a 15 mL centrifuge tube and thoroughly mixed by sonication for 10 s. The mixture is then quickly poured into the flask. (Note: To prevent LiF precipitates from the NH4F and LiOH methanol solutions from adhering to the walls of the centrifuge tube, pour the mixture into the flask immediately after thorough mixing.) The mixture is then magnetically stirred at 50°C for 40 min. After removing the double-necked flask from the oil bath and wiping the bottom clean, transfer the flask to a heating mantle and heat it to 100°C at a heating rate of 10°C / min (the heating and insulation process takes a total of 30 minutes) to ensure the removal of the methanol solution. Then, evacuate for 5 minutes and fill with argon for 1 minute, repeat twice, and then heat it to 290°C in an argon atmosphere and keep it warm for 90 minutes. After the reaction is completed, wait for the reaction solution to cool down, add anhydrous ethanol at a volume ratio of 1:1, mix well, and place it in a centrifuge at a centrifugal speed of 6000 r / min and a centrifugal time of 4 minutes. Add cyclohexane solution to the solid precipitate from the centrifuge and ultrasonicate to disperse the nanoparticles. According to the previous experimental steps, a certain proportion of rare earth ion trifluoroacetate and a certain amount of lithium trifluoroacetate solution were added to a 50 mL double-necked flask containing 5 mLOA and 5 mL ODE. Shelling process: Follow the same steps as above to coat LiLuF4 to obtain a solution of upconversion core-shell nanocrystals containing LiYF4:Yb / Tm@LiLuF4:Yb / Nd.

[0029] Removal of oleic acid ligands: First, measure a certain amount of HCl and dilute it to 0.25 mol / L with deionized water for later use. Add 0.5 mL of the UCNPs cyclohexane solution and 1 mL of ethanol to a 2 mL centrifuge tube and centrifuge at 8500 rpm for 7 minutes to remove the cyclohexane. After decanting the supernatant, add 0.5 mL of the diluted HCl to the precipitate and sonicate in an ultrasonic cleaner to redisperse the precipitate. Continue ultrasonically stirring the resulting mixture at 40°C for 30 minutes and then allow it to stand for 10 minutes. At this point, brown oil droplets should be visible on the walls of the centrifuge tube. Add 1 mL of ethanol to the same centrifuge tube and centrifuge at 15000 rpm for 30 minutes. After decanting the supernatant, a transparent precipitate should be visible at the bottom of the tube. Finally, redisperse the precipitate in 0.5 mL of DMF for later use.

[0030] Titanium dioxide coating process: 0.3 mL of oleic acid-free UCNPs were dispersed in 4 mL of deionized water containing 1.3 g of PVP and ultrasonically stirred for 1 hour. 20 mL of ethanol was then added and mixed with the PVP-coated UCNPs under magnetic stirring for 30 minutes. 2.5 mL of a 0.025 mol / L TiF4 aqueous solution was dropwise added to the solution and stirred for 5 minutes. The entire reaction solution was placed in a 50 mL polytetrafluoroethylene-lined autoclave, heated to 180°C, and held there for 4 hours. After cooling to room temperature, the resulting precipitate was collected by centrifugation and washed three times with deionized water and ethanol. Finally, the product was dried in a 65°C forced air drying oven overnight. The resulting sample was then dissolved in cyclohexane to obtain a solution containing LiYF4:Tm / Yb@LiLuF4:Yb / Nd@TiO2 upconversion core-shell nanocrystals.

[0031] Example 4: This example uses LiYF4:Yb / Tm@LiYF4:Nd / Yb as the seed crystal of Nd 3+ Preparation of sensitized, TiO2-modified upconversion nanocomposites: Core Preparation: First, a 50 mL two-necked flask was added with 5 mL of OA, 5 mL of LOD, (1-xy) mmol of yttrium acetate, y mmol (0.12-0.2) of ytterbium acetate, and x mmol (0.002-0.008) of thulium acetate, totaling 0.4 mmol of rare earth acetate solution. The flask was then transferred to a 150°C oil bath and magnetically stirred for 50 min. The solution was then cooled to room temperature. The precursor flask was placed in a 50°C oil bath. Once the temperature stabilized, 4 mL of NH4F and LiOH methanol solution was transferred to a 15 mL centrifuge tube and thoroughly mixed by sonication for 10 s. The mixture was then quickly poured into the flask. (Note: To prevent LiF precipitates from the NH4F and LiOH methanol solutions from adhering to the walls of the centrifuge tube, the mixture must be poured into the flask immediately after thorough mixing.) The mixture was then magnetically stirred at 50°C for 40 min. After removing the double-necked flask from the oil bath and wiping the bottom clean, transfer the flask to a heating mantle and heat it to 100°C at a heating rate of 10°C / min (the heating and insulation process takes a total of 30 minutes) to ensure the removal of the methanol solution. Then evacuate for 5 minutes and fill with argon for 1 minute, repeat twice, and then heat to 290°C in an argon atmosphere and keep warm for 90 minutes. After the reaction is completed, wait for the reaction solution to cool, add anhydrous ethanol at a volume ratio of 1:1, mix well, and place in a centrifuge at a centrifugal speed of 6000 r / min for 4 minutes. Add cyclohexane solution to the solid precipitate and ultrasonicate to disperse the nanoparticles. According to the previous experimental steps, a certain proportion of rare earth ion trifluoroacetate and a certain amount of lithium trifluoroacetate solution were added to a 50 mL double-necked flask containing 5 mLOA and 5 mL ODE. Shelling process: LiYF4 was coated according to the same steps as above to obtain a solution of LiYF4:Yb / Tm@LiYF4:Yb / Nd upconversion core-shell nanocrystals.

[0032] Removal of oleic acid ligands: First, measure a certain amount of HCl and dilute it to 0.25 mol / L with deionized water for later use. Add 0.5 mL of the UCNPs cyclohexane solution and 1 mL of ethanol to a 2 mL centrifuge tube and centrifuge at 8500 rpm for 7 minutes to remove the cyclohexane. After decanting the supernatant, add 0.5 mL of the diluted HCl to the precipitate and sonicate in an ultrasonic cleaner to redisperse the precipitate. Continue ultrasonically stirring the resulting mixture at 40°C for 30 minutes and then allow it to stand for 10 minutes. At this point, brown oil droplets should be visible on the walls of the centrifuge tube. Add 1 mL of ethanol to the same centrifuge tube and centrifuge at 15000 rpm for 30 minutes. After decanting the supernatant, a transparent precipitate should be visible at the bottom of the tube. Finally, redisperse the precipitate in 0.5 mL of DMF for later use.

[0033] Titanium dioxide coating process: 0.3 mL of oleic acid-free UCNPs was dispersed in 4 mL of deionized water containing 1.3 g of PVP and ultrasonically stirred for 1 hour. 20 mL of ethanol was then added and mixed with the PVP-coated UCNPs under magnetic stirring for 30 minutes. 2.5 mL of a 0.025 mol / L TiF4 aqueous solution was dropwise added to the solution and stirred for 5 minutes. The entire reaction solution was placed in a 50 mL polytetrafluoroethylene-lined autoclave, heated to 180°C, and maintained for 4 hours. After cooling to room temperature, the resulting precipitate was collected by centrifugation and washed three times with deionized water and ethanol. Finally, the product was dried in a 65°C forced air drying oven overnight. The resulting sample was then dissolved in cyclohexane to obtain a solution containing LiYF4:Tm / Yb@LiYF4:Yb / Nd@TiO2 upconversion core-shell nanocrystals.

[0034] It can be seen from the above four embodiments that the preparation method provided by the present invention has the advantages of compact process, high efficiency, convenient operation, easy structure control, and good repeatability; the nanomaterials and applications provided by the present invention have multiple uses and can significantly improve the diagnosis and treatment effects, and can achieve the diagnosis and treatment effects of cancer.

[0035] The Nd prepared in the above examples 3+ Sensitized, TiO2-modified upconversion nanocomposites can be used as imaging directors in fluorescence imaging.

[0036] The Nd prepared in the above examples 3+Sensitized, TiO2-modified upconversion nanocomposites can be used in photodynamic therapy. Under NIR laser irradiation, UCNPs convert NIR into visible light emission through the upconversion process. The visible light energy is transferred to the photosensitizer TiO2 through the FRET process, generating ROS in an aerobic environment, thereby playing a therapeutic role in killing cancer cells.

[0037] The Nd provided by the present invention 3+ Sensitized, TiO2-modified upconversion nanocomposite materials have integrated diagnostic and therapeutic functions, and also have the functions of upconversion luminescence imaging and photodynamic therapy.

[0038] In the above embodiments, the epitaxial growth method is used to grow Nd 3+ Titanium dioxide is epitaxially grown on the surface of sensitized oil-free ligand upconversion luminescent nanoparticles to obtain a nanocomposite material of rare earth upconversion nanoparticles and epitaxially grown titanium dioxide, that is, a rare earth upconversion nanocomposite material having both photodynamic therapy and upconversion fluorescence imaging.

[0039] The present invention is not limited to the above-mentioned embodiments. Methods of epitaxially growing titanium dioxide nanocomposites using other rare earth upconversion nanoparticles obtained by the same or similar methods, such as upconversion nanocrystals doped with different rare earth ions or with different core-shell structure designs (LiYF4:Yb / Tm / Nd; LiYbF4:Tm@LiYF4:Yb@LiYF4:Yb / Nd; etc.), as well as changing the specific values ​​within the proportion range of the components recorded in the present invention, are all within the scope of protection of the present invention.

Claims

1. A Nd 3+ Sensitized, TiO2-modified upconversion nanocomposite material, characterized in that It is based on Nd 3+ Ion-doped UCNPs with a core-shell structure serve as seeds, allowing TiO2 to epitaxially grow as a shell on the surface of the UCNPs, thereby forming an interfacial nucleation-grown TiO2-modified rare earth upconversion nanocomposite material. Under near-infrared light excitation, the upconversion emission of UCNPs is transferred to nearby TiO2 nanoparticles through fluorescence resonance energy, which can produce reactive oxygen species in an aerobic environment to meet the needs of photodynamic therapy; among them, UCNPs and TiO2 nanoparticles cooperate with each other.

2. A Nd according to claim 1 3+ Sensitized, TiO2-modified upconversion nanocomposite material, characterized in that The UCNPs are one or more of LiYbF4:Tm; LiYF4:Yb / Tm / Nd; LiYbF4:Tm@LiYF4:Yb / Nd; LiYbF4:Tm@LiLuF4:Yb / Nd; LiYF4:Yb / Tm@LiYF4:Yb / Nd; LiYF4:Yb / Tm@LiYF4:Yb / Nd; LiYbF4:Tm@LiYF4:Yb@LiYF4:Yb / Nd; LiYbF4:Tm@LiYF4:Yb@LiYF4:Yb / Nd.

3. A Nd according to claim 1 3+ Sensitized, TiO2-modified upconversion nanocomposite material, characterized in that The wavelength of the near-infrared light is 808±10 nm.

4. A method for preparing the Nd as claimed in claim 1 or 2 3+ A method for sensitizing a TiO2-modified upconversion nanocomposite material, characterized in that The following steps are involved: (1) Disperse UCNPs without oleic acid ligands in deionized water containing polyvinyl pyrrolidone and stir them ultrasonically for 1 h to 2 h. Then add ethanol and mix them under magnetic stirring for 30 min to 120 min. (2) Add TiF4 aqueous solution dropwise to the solution in step (1) and keep stirring for 2 min to 10 min; (3) The entire reaction solution in step (2) is placed in a polytetrafluoroethylene liner, and then transferred to a high-pressure reactor, heated to 150°C to 200°C and kept warm for 4 h to 8 h; (4) After cooling to room temperature, the precipitate was collected by centrifugation and washed three times with deionized water and ethanol respectively. Finally, the finished product was placed in a 65°C forced air drying oven and dried overnight.

5. A Nd as claimed in claim 1 or 2 3+ Application of sensitized, TiO2-modified upconversion nanocomposites, characterized in that, It is used as an imaging indicator in fluorescence imaging.

6. A Nd as claimed in claim 1 or 2 3+ Application of sensitized, TiO2-modified upconversion nanocomposites, characterized in that, It is used as a photosensitizer.

7. A Nd as claimed in claim 1 or 2 3+ Application of sensitized, TiO2-modified upconversion nanocomposites, characterized in that, It is used in photodynamic therapy.

8. A Nd according to claim 7 3+ Application of sensitized, TiO2-modified upconversion nanocomposites, characterized in that, Under near-infrared laser irradiation, UCNPs convert near-infrared light into ultraviolet light emission through an upconversion process. Its high-energy ultraviolet light is transferred to the photosensitizer TiO2 through the fluorescence resonance energy transfer process, generating reactive oxygen in an aerobic environment, thereby playing a therapeutic role in killing cancer cells.

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