Preparation method and application of near-infrared long afterglow luminescent nano probe

Abstract

The application relates to the technical field of long-afterglow materials, and particularly provides a preparation method of a near-infrared long-afterglow luminescent nano probe and application thereof. The preparation method of the near-infrared long-afterglow luminescent nano probe comprises the following steps: dissolving water-soluble zinc salt, water-soluble tin salt, water-soluble gallium salt, water-soluble chromium salt and water-soluble yttrium salt in water to prepare a metal mixed solution with a salt concentration of 0.1-2 mol / L; adding mesoporous silica powder into the metal mixed solution, uniformly dispersing, stirring for 30 min-48 hours, adding an alkaline precipitant drop by drop until the pH is 8-10, collecting the precipitate, drying, high-temperature calcining, and obtaining doped particles; and coating manganese dioxide on the surface of the doped particles, and the near-infrared long-afterglow luminescent nano probe has the characteristics of slow afterglow decay.

Description

Technical Field

[0001] This application relates to the field of long afterglow materials technology, specifically to a method for preparing a near-infrared long afterglow luminescent nanoprobe and its application. Background Technology

[0002] Near-infrared long-afterglow luminescent nanoprobes are used for imaging in living organisms. They have the characteristics of high imaging sensitivity, high resolution, real-time performance, and no radiation. They have many applications in the medical field. For example, they can be used for the resection of tumor tissue in vivo to avoid adverse situations such as tumor recurrence and deterioration caused by residual tumor tissue after surgical resection due to unclear tumor tissue.

[0003] The applicant has published Chinese invention patent CN116103034A, which describes the use of mesoporous silica as a carrier to adsorb zinc, gallium, tin, chromium and yttrium metals, and after coating with manganese dioxide, surface modification and coupling with the targeting molecule pleroxafer, to obtain a near-infrared long afterglow luminescent nanoprobe with high imaging sensitivity, short imaging time and high biocompatibility in the tumor microenvironment. Summary of the Invention

[0004] The applicant has continuously modified the preparation method of near-infrared long-afterglow luminescent nanoprobes. The inventors discovered that the method in existing technology CN116103034A, due to the use of nano-sized mesoporous silica powder for adsorption of metal ions, suffers from limited adsorption capacity due to the extremely small pore size of the nano-sized mesoporous silica powder, resulting in insufficient product performance, particularly in the rapid afterglow decay rate. Therefore, this application provides a preparation method for near-infrared long-afterglow luminescent nanoprobes and their applications.

[0005] The technical solution adopted in this application is as follows:

[0006] A method for preparing a near-infrared long-afterglow luminescent nanoprobe, comprising the following steps:

[0007] S1. Dissolve water-soluble zinc salt, water-soluble tin salt, water-soluble gallium salt, water-soluble chromium salt, and water-soluble yttrium salt in water to prepare a mixed metal solution with a salt concentration of 0.1-2 mol / L;

[0008] S2. Add mesoporous silica powder to the metal mixed solution described in step S1, disperse it evenly, stir for 30 min to 48 hours, add alkaline precipitant dropwise until the pH is 8 to 10, collect the precipitate, dry it, and calcine it at high temperature to obtain doped particles;

[0009] S3. Coat the surface of the doped particles described in step S2 with manganese dioxide to obtain the near-infrared long afterglow luminescent nanoprobe.

[0010] Preferably, the molar ratio of the water-soluble zinc salt, the water-soluble tin salt, the water-soluble gallium salt, the water-soluble chromium salt, and the water-soluble yttrium salt in step S1 is 1:0.1-0.3:1-1.3:0.002-0.005:0.0015-0.003.

[0011] Preferably, the weight ratio of the metal mixture solution and the mesoporous silica powder in step S2 is 1:0.05-0.5.

[0012] Preferably, the average particle size of the mesoporous silica powder in step S2 is 10-500 nm.

[0013] Preferably, the alkaline precipitant in step S2 is selected from one or more of alkali metal hydroxides, ammonia, carbonates, and bicarbonates.

[0014] Preferably, a surfactant is also added to the metal mixture solution in step S2, and the weight of the surfactant is 0.01-2 wt% of the weight of the metal mixture solution.

[0015] Preferably, the high-temperature calcination in step S2 is carried out at a temperature of 900-1100°C for 2-6 hours.

[0016] Preferably, the steps further include step S4: the surface of the near-infrared long afterglow luminescent nanoprobe is sequentially modified with carboxylic acid and coupled with pleroxafer.

[0017] More preferably, the carboxylic acid-modifying modifier is selected from polyacrylic acid and its derivatives.

[0018] The near-infrared long-afterglow luminescent nanoprobe prepared by any of the above technical solutions is applied as an imaging material in the medical field.

[0019] In summary, this application has the following beneficial effects:

[0020] 1. In this application, after the metal mixed solution adsorbs metal ions by mesoporous silica powder, an alkaline precipitant is used to form a sol for some of the metal ions, so that more metal ions are coated on the surface of the mesoporous silica powder. After calcination, the mesoporous silica powder adsorbs more metals and / or metal oxides, which can achieve a slower afterglow decay rate.

[0021] 2. In this application, the addition of a surfactant to the metal mixture solution can reduce the surface tension of the metal mixture solution, allowing the metal mixture solution to enter more of the pores of the mesoporous silica powder, thereby increasing the adsorption capacity of the mesoporous silica powder for metal ions and further reducing the afterglow decay rate. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be described in detail below.

[0023] Throughout this specification, unless otherwise specified, the terminology used herein should be understood as having the meaning commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the event of any conflict, this specification shall prevail.

[0024] On the one hand, this application proposes a method for preparing near-infrared long-afterglow luminescent nanoprobes, the steps of which include:

[0025] S1. Dissolve water-soluble zinc salt, water-soluble tin salt, water-soluble gallium salt, water-soluble chromium salt, and water-soluble yttrium salt in water to prepare a mixed metal solution with a salt concentration of 0.1-2 mol / L;

[0026] S2. Add mesoporous silica powder to the metal mixed solution in step S1, disperse it evenly, stir for 30 min to 48 hours, add alkaline precipitant dropwise until the pH is 8 to 10, collect the precipitate, dry it, and calcine it at high temperature to obtain doped particles.

[0027] S3. Coat the surface of the doped particles in step S2 with manganese dioxide to obtain the near-infrared long-afterglow luminescent nanoprobe of this application.

[0028] The amount of metal adsorbed by mesoporous silica powder determines the luminescence intensity and light decay rate of near-infrared long-afterglow luminescent nanoprobes. Generally, the more metal adsorbed, the higher the luminescence intensity and the slower the light decay rate. To address the problem of low metal ion adsorption capacity of mesoporous silica powder in existing technologies, this application involves adding an alkaline precipitant after dispersing the mesoporous silica powder in a metal mixed solution and allowing it to adsorb. The metal mixed solution forms a sol, enabling more metal ions to be loaded onto the mesoporous silica powder, thereby increasing the adsorption capacity of metal ions on the mesoporous silica powder.

[0029] In this application, there are no particular restrictions on water-soluble zinc salts, which can be selected from zinc chloride, zinc sulfate, zinc nitrate, zinc acetate, etc.; there are no particular restrictions on water-soluble tin salts, which can be selected from tin chloride, tin nitrate, etc.; there are no particular restrictions on water-soluble gallium salts, which can be selected from gallium nitrate, gallium chloride, etc.; there are no particular restrictions on water-soluble chromium salts, which can be selected from chromium acetate, chromium nitrate, chromium chloride, chromium sulfate, etc.; and there are no particular restrictions on water-soluble yttrium salts, which can be selected from yttrium chloride, yttrium nitrate, yttrium sulfate, etc. In a preferred embodiment of this application, the molar ratio of water-soluble zinc salt, water-soluble tin salt, water-soluble gallium salt, water-soluble chromium salt, and water-soluble yttrium salt in step S1 is 1:0.1-0.3:1-1.3:0.002-0.005:0.0015-0.003. For example, the molar ratio of water-soluble zinc salt, water-soluble tin salt, water-soluble gallium salt, water-soluble chromium salt, and water-soluble yttrium salt can be 1:0.2:1.2:0.003:0.0025, 1:0.1:1:0.002:0.0015, 1:0.3:1.3:0.005:0.003, 1:0.15:1.1:0.004:0.002, 1:0.25:1.3:0.004:0.002, etc.

[0030] In this application, salt concentration refers to the sum of the concentrations of water-soluble zinc salt, water-soluble tin salt, water-soluble gallium salt, water-soluble chromium salt, and water-soluble yttrium salt in the metal mixed solution. Specifically, there are no particular limitations on the salt concentration, and it can be 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, 0.4 mol / L, 0.5 mol / L, 0.6 mol / L, 0.7 mol / L, 0.8 mol / L, 0.9 mol / L, 1 mol / L, 1.1 mol / L, 1.2 mol / L, 1.3 mol / L, 1.4 mol / L, 1.5 mol / L, 1.6 mol / L, 1.7 mol / L, 1.8 mol / L, 1.9 mol / L, 2 mol / L, etc.

[0031] In a preferred embodiment of this application, the weight ratio of the metal mixture solution to the mesoporous silica powder in step S2 is 1:0.05-0.5. Further, the weight ratio of the metal mixture solution to the mesoporous silica powder is 1:0.1-0.4. For example, the weight ratio can be 1:0.1, 1:0.12, 1:0.15, 1:0.18, 1:0.2, 1:0.22, 1:0.25, 1:0.27, 1:0.3, 1:0.33, 1:0.35, 1:0.38, 1:0.4, etc.

[0032] In a preferred embodiment of this application, the average particle size of the mesoporous silica powder in step S2 is 10-500 nm. Further, the average particle size of the mesoporous silica powder is 50-350 nm; for example, the average particle size can be 50 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 350 nm, etc.

[0033] In this application, the addition of an alkaline precipitant allows the mixed metal solution to form a sol, which can carry more metal ions that have not yet formed a sol and adsorb them onto the surface of the mesoporous silica powder. In a preferred embodiment of this application, the alkaline precipitant in step S2 is selected from one or more of alkali metal hydroxides, ammonia, carbonates, and bicarbonates. Further, the alkaline precipitant can be sodium hydroxide, ammonia, ammonium bicarbonate, ammonium carbonate, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium carbonate, etc. More preferably, the alkaline precipitant is ammonia, ammonium carbonate, or ammonium bicarbonate, which can volatilize under heating or decompose and then volatilize without leaving any residue.

[0034] In a preferred embodiment of this application, a surfactant is further added to the metal mixture solution in step S2, with the surfactant weight being 0.01-2 wt% of the weight of the metal mixture solution. Mesoporous silica powder has very low porosity, generally below 20 nm, or even 10 nm or less. If the surface tension of the metal mixture solution is high, it is difficult for it to penetrate into the pores of the mesoporous silica powder. The inventors have found that this is one of the reasons for the low adsorption content of metal ions by the mesoporous silica powder. In this application, the surface tension of the mixed metal solution is relatively high. Adding a surfactant can significantly reduce the surface tension of the mixed metal solution, for example, reducing it to below 30 mN / m, or even below 25 mN / m, allowing the mixed metal solution to penetrate into the pores of the mesoporous silica powder more quickly and in greater quantities. In this application, there are no particular limitations on the surfactant; it can be an organic fluorine surfactant, an organic silicone surfactant, or a hydrocarbon surfactant, or it can be a nonionic surfactant, anionic surfactant, or a cationic surfactant. Specifically, the surfactant can be a fluorocarbon nonionic surfactant, weighing 0.01-0.1 wt% of the metal mixture solution; the surfactant can also be a polyether-modified polysiloxane surfactant, weighing 0.1-0.5 wt% of the metal mixture solution; or the surfactant can be a hydrocarbon surfactant, weighing 0.5-2 wt% of the metal mixture solution. Examples of surfactants include sodium dodecylbenzenesulfonate, sodium dodecyl sulfate, AEO-6, AEO-9, penetrant JFC, and OP-10.

[0035] In a preferred embodiment of this application, the high-temperature calcination in step S2 is carried out at a temperature of 900-1100°C for 2-6 hours. Under these calcination conditions, the adsorbed metal material is better able to form near-infrared long-afterglow luminescent material.

[0036] In a preferred embodiment of this application, the steps further include step S4: the surface of the near-infrared long-afterglow luminescent nanoprobe is sequentially modified with carboxylic acid and coupled with praxafol. The surface of the near-infrared long-afterglow luminescent nanoprobe is modified with carboxylic acid and coupled with praxafol, an anti-tumor drug. The near-infrared long-afterglow luminescent nanoprobe can release praxafol while imaging in the tumor microenvironment, thus exerting a therapeutic effect. Specific methods for carboxylic acid modification and praxafol coupling can be found in prior art CN116103034A.

[0037] In a more preferred embodiment of this application, the carboxylic acid-modifying modifier is selected from polyacrylic acid and its derivatives. For example, polyacrylic acid and its derivatives may be polyacrylic acid, partially neutralized polyacrylic acid, or acrylic acid-acrylate copolymers. Acrylic acid-acrylate copolymers may be ethyl acrylate copolymers, butyl acrylate copolymers, butyl methacrylate copolymers, etc., wherein the molar content of acrylic acid in the acrylic acid-acrylate copolymer is not less than 60%.

[0038] On the other hand, this application proposes an application of the near-infrared long-afterglow luminescent nanoprobe prepared by the preparation method of any of the above technical solutions, which is used as an imaging material in the medical field.

[0039] The technical solution of this application will be described in detail below with reference to embodiments and comparative examples.

[0040] Example 1

[0041] Zinc nitrate, tin chloride, gallium nitrate, chromium sulfate, and yttrium sulfate were dissolved in water in a molar ratio of 1:0.2:1.2:0.003:0.0025 to prepare a mixed metal solution with a salt concentration of 1 mol / L.

[0042] Mesoporous silica powder with an average particle size of 100 nm was added to the above metal mixed solution. The weight ratio of mesoporous silica powder to metal mixed solution was 0.15:1. The mixture was ultrasonically dispersed for 5 min, stirred at 300 rpm for 1 hour, and a 15 wt% ammonium carbonate aqueous solution was added dropwise until the pH of the reaction system was 9-9.5. The mixture was centrifuged at 12000 rpm for 20 min, and the precipitate was collected. The precipitate was dried in a 110℃ forced-air drying oven for 1 hour, removed, and heated to 950℃ at a heating rate of 5℃ / min. The calcined precipitate was then calcined for 3 hours to obtain doped particles.

[0043] The doped particles were dispersed in deionized water to prepare a dispersion with a concentration of 10 g / L. A 10 g / L potassium permanganate aqueous solution was gradually added at 0.2 times the volume of the dispersion while stirring at 300 rpm. After stirring for 10 min, formamide was added at 0.04 times the volume of the dispersion. The mixture was sonicated for 25 min, centrifuged at 10000 rpm for 15 min, and the solid was collected. The solid was washed three times with pure water, dried overnight at 60°C, and pulverized to obtain a near-infrared long-afterglow luminescent nanoprobe.

[0044] Example 2

[0045] The difference between Example 2 and Example 1 is that in Example 1, the stirring time of 1 hour at 300 rpm was changed to 3 hours. The remaining steps remain unchanged.

[0046] Example 3

[0047] The difference between Example 3 and Example 1 is that in Example 1, 0.7% by weight of the penetrant JFC was added to the metal mixture solution, followed by the addition of mesoporous silica powder. The remaining steps remained unchanged.

[0048] Example 4

[0049] The difference between Example 4 and Example 1 is that in Example 1, 0.2% by weight of the organosilicon surfactant Silwet L-77 was added to the metal mixture solution, followed by the addition of mesoporous silica powder. The remaining steps remained unchanged.

[0050] Comparative Example 1

[0051] The difference between Comparative Example 1 and Example 1 is that in Example 1, the step of "adding a 15wt% ammonium carbonate aqueous solution until the pH of the reaction system is 9-9.5" is omitted. The remaining steps remain unchanged.

[0052] Comparative Example 2

[0053] The difference between Comparative Example 2 and Example 1 is that in Example 1, sodium carbonate aqueous solution was added dropwise until the pH of the reaction system was 10.5-11. The remaining steps remained unchanged.

[0054] Comparative Example 3

[0055] Zinc nitrate, tin chloride, gallium nitrate, chromium sulfate, and yttrium sulfate were dissolved in water in a molar ratio of 1:0.2:1.2:0.003:0.0025 to prepare a mixed metal solution with a salt concentration of 1 mol / L.

[0056] Mesoporous silica powder with an average particle size of 100 nm was added to the above metal mixed solution. The weight ratio of mesoporous silica powder to metal mixed solution was 0.15:1. The mixture was ultrasonically dispersed for 5 min, and the moisture was evaporated at 60 °C and -0.098 MPa. The temperature was then increased to 900 °C at a heating rate of 5 °C / min and calcined for 3 hours to obtain doped particles.

[0057] The doped particles were coated with manganese dioxide according to the steps in Example 1 to obtain near-infrared long afterglow luminescent nanoprobes.

[0058] Example 5

[0059] Zinc nitrate, tin chloride, gallium nitrate, chromium nitrate, and yttrium nitrate were dissolved in water in a molar ratio of 1:0.2:1.2:0.0025:0.0025 to prepare a mixed metal solution with a salt concentration of 0.6 mol / L.

[0060] Mesoporous silica powder with an average particle size of 150 nm was added to the above metal mixed solution. The weight ratio of mesoporous silica powder to metal mixed solution was 0.35:1. Then, 0.8% of AEO-9 by weight of the metal mixed solution was added. The mixture was ultrasonically dispersed for 5 min, stirred at 350 rpm for 2 hours, and a 10 wt% ammonium carbonate aqueous solution was added dropwise until the pH of the reaction system was 8-8.5. The mixture was centrifuged at 12000 rpm for 20 min, and the precipitate was collected. The precipitate was dried in a 110℃ forced-air drying oven for 1 h, removed, and heated to 980℃ at a heating rate of 5℃ / min. The calcined precipitate was then calcined for 3 hours to obtain doped particles.

[0061] The doped particles were dispersed in deionized water to prepare a dispersion with a concentration of 15 g / L. A 15 g / L potassium permanganate aqueous solution was gradually added at 0.15 times the volume of the dispersion while stirring at 300 rpm. After stirring for 10 min, formamide was added at 0.035 times the volume of the dispersion. The mixture was sonicated for 25 min, centrifuged at 10,000 rpm for 15 min, and the solid was collected. The solid was washed three times with pure water, dried overnight at 60°C, and pulverized to obtain a near-infrared long-afterglow luminescent nanoprobe.

[0062] Example 6

[0063] The difference between Example 6 and Example 5 is that in Example 5, the molar ratio of zinc nitrate, tin chloride, gallium nitrate, chromium nitrate, and yttrium nitrate was adjusted from 1:0.2:1.2:0.0025:0.0025 to 1:0.1:1:0.002:0.0015. The remaining steps remain unchanged.

[0064] Example 7

[0065] The difference between Example 7 and Example 5 is that in Example 5, the molar ratio of zinc nitrate, tin chloride, gallium nitrate, chromium nitrate, and yttrium nitrate was adjusted from 1:0.2:1.2:0.0025:0.0025 to 1:0.3:1.3:0.005:0.003. The remaining steps remain unchanged.

[0066] Example 8

[0067] The difference between Example 8 and Example 5 is that in Example 5, the molar ratio of zinc nitrate, tin chloride, gallium nitrate, chromium nitrate, and yttrium nitrate was adjusted from 1:0.2:1.2:0.0025:0.0025 to 1:0.15:1.1:0.004:0.002. The remaining steps remain unchanged.

[0068] Performance Tests and Results

[0069] Optical decay rate test: The probe sample was pre-excited for 3 minutes using a biological window excitation light source (659 nm). After excitation was stopped, the relative intensities of afterglow emission β0, β1, β5, and β at 0 min, 1 min, 5 min, and 10 min were measured. 10 The decay residual rates β1 / β0, β5 / β0, and β5 / β0 of the relative intensity of afterglow emission at 1 min, 5 min, and 10 min were compared respectively. 10 / β 0。 The higher the residual decay rate, the slower the decay.

[0070] The results are shown in Table 1 below.

[0071] Table 1

[0072] <![CDATA[β1 / β0]]> <![CDATA[Β5 / β0]]> <![CDATA[Β 10 / β0<!-- 5 --> ]]> Example 1 0.27 0.16 0.12 Example 2 0.28 0.17 0.13 Example 3 0.29 0.18 0.15 Example 4 0.29 0.17 0.14 Comparative Example 1 0.21 0.11 0.07 Comparative Example 2 0.21 0.11 0.07 Comparative Example 3 0.2 0.13 0.08 Example 5 0.27 0.16 0.13 Example 6 0.26 0.15 0.11 Example 7 0.27 0.15 0.12 Example 8 0.26 0.16 0.12

[0073] As can be seen from the data results in Table 1, Comparative Examples 4 and 5 are based on existing technologies. The afterglow decay rate of Example 1 is significantly lower than that of Comparative Examples 4 and 5. Comparing Example 1 with Examples 2-4, the afterglow decay rate can be reduced by extending the adsorption time of the mesoporous silica powder on the metal mixed solution or by increasing the penetration of the metal mixed solution into the mesoporous silica powder.

[0074] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A method for preparing a near-infrared long-afterglow luminescent nanoprobe, characterized in that the steps include... include: S1. Dissolve water-soluble zinc salt, water-soluble tin salt, water-soluble gallium salt, water-soluble chromium salt, and water-soluble yttrium salt in water to prepare a mixed metal solution with a salt concentration of 0.1-2 mol / L, wherein the molar ratio of the water-soluble zinc salt, the water-soluble tin salt, the water-soluble gallium salt, the water-soluble chromium salt, and the water-soluble yttrium salt is 1:0.1-0.3:1-1.3:0.002-0.005:0.0015-0.003; S2. Add surfactant and mesoporous silica powder to the metal mixed solution described in step S1, disperse evenly, stir for 30 min to 48 hours, add alkaline precipitant dropwise until pH is 8 to 10, collect the precipitate, dry it, and calcine it at high temperature to obtain doped particles; The weight ratio of the metal mixture solution to the mesoporous silica powder is 1:0.05-0.5, and the average particle size of the mesoporous silica powder is 10-500 nm. The surfactant is present in an amount of 0.01-2 wt% of the weight of the metal mixture solution. The high-temperature calcination temperature is 900-1100℃, and the time is 2-6 hours; S3. Coat the surface of the doped particles described in step S2 with manganese dioxide to obtain the near-infrared long afterglow luminescent nanoprobe. S4. The surface of the near-infrared long afterglow luminescent nanoprobe is sequentially modified with carboxylic acid and coupled with pleroxafer.

2. The method for preparing near-infrared long-afterglow luminescent nanoprobes according to claim 1, characterized in that, The carboxylic acid modification agent is selected from polyacrylic acid and its derivatives.

3. A near-infrared long-afterglow luminescent nanoprobe prepared by a method according to any one of claims 1-2.