A bio-optical temperature sensor and its preparation method and application

Abstract

The present invention discloses a bio-optical temperature sensor and its preparation method and application, belonging to the field of advanced nonferrous metal material technology. A composite nanoprobe comprises a gold nanorod and rare earth-doped nanoparticles. The two ends of the gold nanorod are coated with mesoporous silica. The surface and pores of the mesoporous silica are loaded with rare earth-doped nanoparticles. The composite nanoprobe has a dumbbell-shaped structure. The rare earth-doped nanoparticles are Gd2O3 nanoparticles doped with Yb 3+ 、Er 3+ and Ho 3+ Metal ions. The composite nanoprobe of the present invention utilizes a specific dumbbell-shaped structure, utilizing the dumbbell-shaped localized surface electric field generated by the gold nanorod to enhance the luminescence of the rare earth-doped nanoparticles loaded at both ends of the gold nanorod in the near-infrared region II, thereby increasing the emission intensity. The composite nanoprobe of the present invention can be used to prepare bio-optical temperature sensors.

Description

Technical Field

[0001] The present invention relates to the technical field of advanced nonferrous metal materials, and more particularly to a bio-optical temperature sensor and a preparation method and application thereof. Background Art

[0002] In recent years, the incidence of cancer has continued to rise, with cancer becoming increasingly prevalent among younger patients, making it the leading cause of death and harm to human health. Currently, the main treatments for tumors include chemotherapy and radiotherapy, with photothermal therapy emerging as a new treatment option in recent years. Photothermal therapy (PTT) involves converting near-infrared (NIR) photon energy into heat through the absorption of photothermal therapy agents (PTA). PTT uses appropriate high temperatures to target and destroy cell membranes and proteins in tumor tissue, causing irreversible damage to the cells, thereby achieving minimal trauma and high-precision treatment. Compared with traditional chemotherapy, surgery, and radiotherapy, PTT offers advantages such as faster treatment and less harm to the human body.

[0003] In conventional photothermal therapy, the therapeutic effect depends on the heat converted from the energy absorbed by the photothermal agent from near-infrared light. However, due to inevitable heat diffusion during photothermal therapy, the temperature at the edge of the tumor tissue decreases, while the temperature of surrounding normal tissue increases. To achieve tumor eradication, the excitation light power must be increased to maintain a sufficiently high temperature at the tumor edge, but this can inadvertently damage normal tissue. Reducing the laser power too much to ensure normal tissue is intact can result in some tumor cells surviving. Therefore, effective and safe photothermal therapy requires precise control of tissue temperature and a real-time temperature monitoring system. Temperature monitoring of the target treatment area can not only effectively prevent incomplete treatment due to insufficient heat and damage to normal tissue due to excessive heat, but also improve the safety and effectiveness of photothermal therapy and provide a deeper understanding of the internal conditions of the human body. Because traditional temperature measurement methods (such as mercury thermometers, thermocouple thermometers, and thermal imagers) are limited by the structure of human tissue and measurement tools, they cannot accurately and noninvasively measure internal temperature. Only by creatively inventing new temperature measurement methods can efficient, accurate, and non-contact temperature monitoring be achieved.

[0004] After being excited, electrons in the 4f energy level of rare earth ions transition to lower energy levels through radiative relaxation, emitting light of various wavelengths. Rare earth ion luminescence exhibits low photobleaching, large anti-Stokes shifts, and narrow emission peaks. Therefore, it exhibits broad application prospects in biomedical imaging and therapy, temperature sensing, solar cells, and printing anti-counterfeiting treatment.

[0005] Rare earth ions can be used for temperature measurement, which is based on their microscopic properties. Due to the temperature dependence of energy transfer (ET) and multiphonon relaxation (MPR) during the luminescence process of rare earth ions, as the temperature rises, both the transfer efficiency and relaxation rate increase, thereby affecting the luminescence intensity and fluorescence lifetime. Therefore, rare earth-doped nanoparticles can be used as optical temperature sensors, with the characteristics of non-contact, high sensitivity and spatial resolution, and rapid response. For different rare earth ions, due to their different energy level distributions, the efficiency of ET and MPR varies, and the relative rate of change affected by temperature also varies.

[0006] Therefore, based on the principle of rare earth nanothermometers, the luminescence intensity ratio can be used to monitor the temperature of tumor tissue. This will enable real-time monitoring of tissue temperature during photothermal therapy, forming a real-time isotherm map to observe the heat diffusion between tumor and normal tissue during photothermal therapy, providing some reference for controlling the excitation light power.

[0007] Previous temperature probes used in photothermal therapy were mostly excited by visible light, but visible light cannot penetrate thick biological tissues. In recent years, it has been discovered that the second near-infrared region (NIR-II) has unique advantages in the biomedical field, greatly promoting the optical imaging of biological tissues, the diagnosis and treatment of diseases, and especially the in-depth understanding of the dynamic information of molecular activities in organisms.

[0008] Prior art CN113801653A discloses a near-infrared second-zone luminescence / temperature measurement nanoprobe, comprising a SiO2 core and four shell layers covering the SiO2 core, wherein the shell layers are an activation layer, a transition layer, a sensitizing layer, and an inert layer from the inside out; the activation layer is doped with Er 3+ and Yb 3+ Gd2O3 layer; the transition layer is doped with Yb 3+ Gd2O3 layer; the sensitizing layer is doped with Nd 3+ and Yb 3+ The nanoprobe emits light in the second near-infrared region and can be used in nano-temperature sensors. However, the near-infrared luminescence intensity of the nanoprobe is weak, and the maximum temperature sensitivity of the temperature sensor based on the near-infrared emission intensity is only 1.29% K. -1 , while the maximum temperature sensitivity around 313-343K is only 0.12%K -1 . Summary of the Invention

[0009] The technical problem to be solved by the present invention is that the existing near-infrared second-zone luminescence / temperature measurement nanoprobes have defects and shortcomings such as poor near-infrared luminescence intensity and low temperature measurement sensitivity. A composite nanoprobe is provided to improve the near-infrared photoluminescence intensity and have higher temperature measurement sensitivity.

[0010] Another object of the present invention is to provide a method for preparing the composite nanoprobe.

[0011] Another object of the present invention is to provide a bio-optical temperature sensor.

[0012] Another object of the present invention is to provide a bio-optical temperature sensor for application in bio-optical temperature measurement.

[0013] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0014] A composite nanoprobe comprising a gold nanorod and rare earth-doped nanoparticles, wherein both ends of the gold nanorod are coated with mesoporous silica, and the rare earth-doped nanoparticles are loaded on the surface and in the pores of the mesoporous silica. The composite nanoprobe has a dumbbell-shaped structure.

[0015] Wherein, the rare earth doped nanoparticles are Gd2O3 nanoparticles doped with Yb 3+ 、Er 3+ and Ho 3+ Metal ions.

[0016] The composite nanoprobe of the present invention has a specific dumbbell-shaped structure and utilizes the dumbbell-shaped surface local electric field generated by the nanogold rod to enhance the luminescence of rare earth-doped nanoparticles loaded at both ends of the nanogold rod in the near-infrared region II, thereby enhancing the emission intensity.

[0017] Among them, it should be noted that:

[0018] The composite nanoprobe of the present invention, the rare earth doped nanoparticles can emit near infrared second region fluorescence under the irradiation of excitation light, and with the strong absorption of excitation light by the nano-gold rod and the longitudinal surface plasmon resonance characteristics, a dumbbell-shaped local electric field is generated at both ends of the gold rod, which can react with the excitation field and Yb 3+ Absorption forms a ternary resonance, and the induced local electric field can greatly enhance the photoluminescence properties of rare earth-doped nanoparticles in the near-infrared region II.

[0019] The composite nanoprobe of the present invention has a dumbbell-shaped structure. The local electric field on the surface of the composite nanoprobe presents a dumbbell-shaped distribution, which is consistent with the local electric field distribution generated by the nanogold rod. It can maximize the coverage of rare earth-doped nanoparticles, maximize the enhancement of rare earth photoluminescence, and improve the near-infrared photoluminescence intensity of the probe.

[0020] The composite nanoprobe of the present invention utilizes the temperature-dependent characteristics of energy level transitions of rare earth luminescent ions (erbium ions and holmium ions) in the near-infrared region II, and performs near-infrared region II optical temperature sensing based on the changes in near-infrared fluorescence intensity, fluorescence intensity ratio and fluorescence lifetime with temperature, showing excellent photostability and relative sensitivity of temperature sensing.

[0021] Preferably, in the rare earth doped nanoparticles, Gd 3+ 、Yb 3+ 、Er 3+ and Ho 3+ The molar ratio is (80~96) : (2~18) : (0.2~4) : (0.2~4).

[0022] In order to further improve the luminescence intensity and relative sensitivity of optical temperature sensing of the composite nanoprobe, preferably, in the rare earth doped nanoparticles, Gd 3+ 、Yb 3+ 、Er 3+ and Ho 3+ The molar ratio is (91-95):(5-10):(0.5-1.5):(0.5-1.5).

[0023] More preferably, in the rare earth doped nanoparticles, Gd 3+ 、Yb 3+ 、Er 3+ and Ho 3+ The molar ratio is 92:6:1:1.

[0024] Preferably, in the composite nanoprobe, the atomic ratio of rare earth element to gold element is (0.3-0.9):1.

[0025] The rare earth elements include rare earth doped nanoparticles on the surface of mesoporous silica and in the pores of mesoporous silica.

[0026] More preferably, in the composite nanoprobe, the atomic ratio of rare earth element to gold element is (0.6-0.85):1.

[0027] The present invention also protects a method for preparing the composite nanoprobe, comprising the following steps:

[0028] S1. Prepare gold nanorod solution and rare earth-doped nanoparticles respectively;

[0029] S2. Covering both ends of the gold nanorods in S1 with mesoporous silica;

[0030] S3. Ultrasonic oscillation is performed on the mesoporous silica-coated nanogold rod solution of S2 and the nano-rare earth particles of S1 to obtain the composite nanoprobe.

[0031] In the present invention:

[0032] The preparation method of the gold nanorod solution can be an existing preparation method, such as a seed growth method.

[0033] The preparation method of rare earth-doped nanoparticles may be an existing preparation method, such as a direct colloidal precipitation method by dehydration of a high-boiling-point polyol.

[0034] In step S2 of the present invention, mesoporous silica can be covered on both ends of the gold nanorods by a sol-gel method with controlled surfactant, and the silica pores can be cleaned by refluxing in a hydrochloric acid-ethanol solution and activating the surface dangling bonds.

[0035] The invention anchors rare earth doped nanoparticles in the mesoporous silica pores and on the surface of the mesoporous silica through ultrasonic oscillation nano-cascade assembly technology.

[0036] The preparation method of the nano-gold rod solution may include the following steps: preparation of the seed solution: dissolving hexadecyltrimethylammonium bromide in deionized water, adding chloroauric acid solution and sodium borohydride (NaBH4) ice water solution, stirring, and standing to obtain a nano-gold rod seed solution. Preparation of the growth solution: dissolving hexadecyltrimethylammonium bromide in deionized water, adding chloroauric acid solution, AgNO3 solution and HCl in sequence, and adding ascorbic acid during stirring. After the solution is stirred until colorless, the prepared seed solution is added and gently stirred, and the solution is allowed to stand. Centrifugation is collected, and after removing the supernatant, it is dispersed in deionized water to obtain a nano-gold rod solution.

[0037] The preparation of rare earth-doped nanoparticles may include the following steps: a rare earth aqueous solution and diethylene glycol are vigorously stirred in an oil bath, and a sodium hydroxide aqueous solution is added. The mixture is heated and stirred to obtain a pale yellow colloidal solution. An appropriate amount of deionized water is added to the solution, and after centrifugation, the precipitate is dried in a drying oven to obtain the rare earth-doped nanoparticles.

[0038] Covering both ends of the gold nanorods in S1 with mesoporous silica may include the following steps: taking a gold nanorod solution, adding CTAB, ultrasonically dispersing it in deionized water, and adding a NaOH solution. Adding a TEOS ethanol solution while slowly stirring, and continuing to stir. Centrifuging, and washing with alcohol and deionized water. Dispersing the resulting solid in a CTAB aqueous solution, adding a NaOH solution, and adding a TEOS ethanol solution while slowly stirring. Centrifuging, and washing with a hydrochloric acid ethanol solution and deionized water.

[0039] Step S3 of the present invention may include the following steps: mixing a nanogold rod solution with mesoporous silica at both ends, a nanorare earth particle solution and deionized water, ultrasonicating, vibrating, centrifuging and collecting, and then washing with anhydrous ethanol and deionized water to obtain the composite nanoprobe.

[0040] The present invention also protects a bio-optical temperature sensor, comprising any one of the composite nanoprobes described above.

[0041] The present invention also protects the application of the above-mentioned bio-optical temperature sensor in bio-optical temperature measurement.

[0042] The bio-optical temperature sensor of the present invention can be used for monitoring biomedical diagnosis and treatment, and is particularly suitable for bio-optical temperature measurement. For example, optical temperature sensing can utilize photoelectric signals for non-contact, real-time monitoring of tumor temperature. Because rare earth luminescence has a temperature-dependent luminescence energy level, the luminescence intensity ratio or fluorescence lifetime can be used to monitor tumor tissue temperature, enabling real-time photothermal therapy.

[0043] The bio-optical temperature sensor of the present invention can be used for simultaneous diagnosis, treatment and monitoring of tumors.

[0044] Preferably, the temperature of the temperature measurement is 313-343K.

[0045] The bio-optical temperature sensor of the present invention can realize temperature measurement in the range of 313-343K, is particularly suitable for the temperature range of 313-343K photothermal therapy, and has extremely high absolute sensitivity and relative sensitivity.

[0046] Preferably, in the temperature measurement, the excitation light wavelength of the bio-optical temperature sensor is 900-1100 nm.

[0047] The bio-optical temperature sensor of the present invention can use near-infrared light with an excitation wavelength of 980nm as the excitation light. This excitation wavelength is within the biological transparency window of 680-1100nm, in which soft tissue does not strongly absorb or scatter. Therefore, rare earth ions can be excited at a higher tissue depth than the ultraviolet-visible light excitation source. The two wavelengths of light converted by the probe (1201nm and 1535nm) are in the near-infrared second region NIR-II, and have a stronger ability to penetrate human tissue, thereby completing the temperature measurement function.

[0048] Compared with the prior art, the present invention has the following beneficial effects:

[0049] The composite nanoprobe of the present invention, through a specific dumbbell-shaped structure, utilizes the dumbbell-shaped surface local electric field generated by the nanogold rod to enhance the luminescence of rare earth-doped nanoparticles loaded at both ends of the nanogold rod in the near-infrared second region, thereby enhancing the emission intensity by two orders of magnitude.

[0050] The composite nanoprobe of the present invention utilizes the temperature-dependent characteristics of energy level transitions of rare earth luminescent ions (erbium ions and holmium ions) in the near-infrared region II to perform near-infrared region II optical temperature sensing based on the changes in near-infrared fluorescence intensity, fluorescence intensity ratio, and fluorescence lifetime with temperature. It exhibits excellent photostability, absolute temperature sensing sensitivity, and relative temperature sensing sensitivity. The relative sensitivity based on the 1201nm holmium ion emission lifetime at 338K is as high as 7.25%K -1 The relative sensitivity of the 1535nm erbium ion emission lifetime at 343K also reached 5.38% K. -1 . BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 a is an electron microscope image of the rare earth-doped nanoparticles in Example 1.

[0052] Figure 1 b is a high-resolution electron microscope image of a single particle of the rare earth-doped nanoparticles in Example 1.

[0053] Figure 1 c, Figure 1 d is Figure 1 a Fourier transform and inverse Fourier transform of rare earth-doped nanoparticles.

[0054] Figure 1 e and Figure 1 f is the TEM image and EDS spectrum of the composite nanoprobe of Example 1.

[0055] Figure 1 g- Figure 1 k is the line scan and element scan of the composite nanoprobe EDS spectrum of Example 1.

[0056] Figure 2 a is the absorption spectrum of the gold nanorod and the composite nanoprobe of Example 1.

[0057] Figure 2 b is the emission spectrum of the composite nanoprobe of Example 1 and the rare earth-doped nanoparticles of Comparative Example 1.

[0058] Figure 2 c is the luminescence energy level diagram of the composite nanoparticles of Example 1.

[0059] Figure 3 a is the NIR absorption cross section simulated using the finite-difference time-domain (FDTD) algorithm.

[0060] Figure 3 b is the electric field enhancement curve along the x-axis under different incident excitations.

[0061] Figure 3 c is the simulated structural model of the nanoprobe.

[0062] Figure 3 d is the local electric field E distribution.

[0063] Figure 4 a, Figure 4 b is the emission spectra of the composite nanoprobe of Example 1 measured at six temperature gradients of 313-343 K and the curve of the emission peak intensity at 1201 nm and 1535 nm changing with temperature.

[0064] Figure 4 c is the relative sensitivity of the composite nanoprobe of Example 1 in each NIR-II single peak luminescence intensity and luminescence intensity ratio.

[0065] Figure 4 d is the five cycles of heating and cooling measured by the composite nanoprobe of Example 1 based on ratiometric fluorescence thermometry.

[0066] Figure 5 a, Figure 5 b is the curve of the change of the emission peak fluorescence lifetime of the composite nanoprobe in Example 1 at 1201 nm and 1535 nm at six temperature gradients of 313-343 K.

[0067] Figure 5 c is the variation law of the luminescence lifetime of the composite nanoprobe in Example 1 with temperature.

[0068] Figure 5 d is the relative sensitivity curve of the composite nanoprobe optical temperature sensing in Example 1.

[0069] Figure 5 e and Figure 5 f is the 1201 nm emission lifetime and 1535 nm emission lifetime of the composite nanoprobe of Example 1 at 313 K and 343 K in five cycles.

[0070] In the accompanying drawings, "AuNRs" refers to gold nanorods.

[0071] "Gd2O3:Yb 3+ / Er 3+ / Ho 3+ ” refers to rare earth-doped nanoparticles.

[0072] “AuNR@Gd2O3:Yb 3+ / Er 3+ / Ho 3+ ” refers to composite nanoprobes. DETAILED DESCRIPTION

[0073] The present invention will be further described below in conjunction with specific embodiments, but the examples do not limit the present invention in any form. Unless otherwise specified, the raw materials and reagents used in the examples of the present invention are conventionally purchased raw materials and reagents.

[0074] Example 1

[0075] A composite nanoprobe comprising a gold nanorod and rare earth-doped nanoparticles, wherein both ends of the gold nanorod are coated with mesoporous silica, and the surface and pores of the mesoporous silica are loaded with rare earth-doped nanoparticles. The composite nanoprobe has a dumbbell-shaped structure.

[0076] Among them, rare earth doped nanoparticles are Gd2O3 nanoparticles doped with Yb 3+ 、Er 3+ and Ho 3+ Metal ions, rare earth doped nanoparticles, Gd 3+ 、Yb 3+ 、Er 3+ and Ho 3+ The molar ratio is 92:6:1:1;

[0077] In the composite nanoprobe, the atomic ratio of rare earth elements to gold elements is 0.82:1.

[0078] The preparation method of the composite nanoprobe comprises the following steps:

[0079] S1. Preparation of gold nanorods: Preparation of seed solution: Dissolve 0.364g of hexadecyltrimethylammonium bromide (CTAB) in 9.17mL of deionized water, add 242μL of 0.012386mol / L chloroauric acid solution, and then add 0.58mL of 0.02mol / L sodium borohydride (NaBH4) ice water solution. Immediately stir rapidly (350r / min) for two minutes and let stand in a 27°C water bath for 2h to obtain the gold nanorod seed solution. Preparation of growth solution: Dissolve 1.82g of CTAB in 44mL of deionized water, add 2.907mL of 0.012386mmol / L chloroauric acid solution, 1.04mL of 0.005mol / L AgNO3 solution, and 0.4mL of HCl (37%) in sequence, and add 1.64mL of 0.05mol / L ascorbic acid while stirring. After the solution was stirred until colorless, 50 μL of the prepared seed solution was added and gently stirred for 10 seconds (110 rpm). The solution was then allowed to stand in a 27°C water bath for 12 hours. The solution was collected by centrifugation at 10,000 rpm for 15 minutes, the supernatant was removed, and the solution was dispersed in 25 mL of deionized water to obtain a gold nanorod solution.

[0080] Preparation of rare earth doped nanoparticles: Take 20mL of 0.2mol / L rare earth aqueous solution (molar ratio of Gd 3+:Yb 3+ :Er 3+ :Ho 3+ =92:6:1:1) and 20 mL of diethylene glycol (DEG) were placed in an Erlenmeyer flask and vigorously stirred in an 80°C oil bath (750 rpm) for 1 hour. Then, 1 mL of a 0.1 mol / L aqueous NaOH solution was quickly added. The mixture was heated to 140°C and stirred for another hour, then to 180°C and stirred for another 4 hours to obtain a pale yellow colloidal solution. An appropriate amount of deionized water was added to the solution, and the mixture was centrifuged at 2500 rpm for 10 minutes. The supernatant was discarded, and an appropriate amount of deionized water was added. The mixture was then centrifuged twice at 10,000 rpm for 7 minutes. After centrifugation, the precipitate was dried in a drying oven to obtain rare earth-doped nanoparticles.

[0081] S2. Cover both ends of the gold nanorods in S1 with mesoporous silica:

[0082] Take the gold nanorod solution prepared in the previous step and centrifuge it twice at 9000 rpm. Remove the supernatant, add 0.008 g of CTAB, and ultrasonically disperse it in 40 mL of deionized water. Add 0.4 mL of 0.025 mol / L NaOH solution. While slowly stirring, add 0.4 mL of 4% (volume fraction) TEOS ethanol solution every 30 minutes, for a total of four additions. Continue stirring for 12 hours. Centrifuge, wash once with alcohol and once with deionized water, and repeat this process three times. Dissolve 0.029 g of CTAB in 40 mL of deionized water, ultrasonically disperse the resulting AuNR@SiO2 in this CTAB solution, add 0.5 mL of 0.025 mol / L NaOH solution, and while slowly stirring, add 0.8 mL of 8% (volume fraction) TEOS ethanol solution every 30 minutes, for a total of four additions. Centrifuge, and wash twice with hydrochloric acid ethanol solution and deionized water.

[0083] S3. Mix 5 mL of the centrifugally washed gold nanorod solution obtained in step S2, 1 mL of the 0.2 mol / L rare earth nanoparticle solution obtained in step S1, and 4 mL of deionized water. Ultrasonicate at room temperature for 3 hours and then shake for 3 hours. Collect by centrifugation (10,000 rpm, 20 minutes), wash once with anhydrous ethanol, and once with deionized water to obtain a composite nanoprobe, which is then stored in 10 mL of deionized water.

[0084] Example 2

[0085] A composite nanoprobe, which differs from Example 1 in that: in the rare earth doped nanoparticles, Gd 3+ 、Yb 3+ 、Er 3+ and Ho 3+ The molar ratio is 90:6:2:2.

[0086] The difference between the preparation method and Example 1 is that step S1: Gd 3+ 、Yb 3+ 、Er 3+ and Ho 3+ The molar ratio is =90:6:2:2.

[0087] Example 3

[0088] A composite nanoprobe is different from Example 1 in that: in the composite nanoprobe, the atomic ratio of rare earth element to gold element is 0.4:1.

[0089] The difference between the preparation method and Example 1 is that step S3: 5 mL of the nanogold rod solution obtained in step S2 after centrifugation and washing, 0.5 mL of the 0.2 mol / L nano rare earth particle solution obtained in step S1, and 4 mL of deionized water are mixed.

[0090] Comparative Example 1

[0091] A rare earth-doped nanoparticle, the preparation method of which is the same as that of the rare earth-doped nanoparticle in Example 1.

[0092] Result detection

[0093] The composite nanoprobes of the above examples and comparative examples were tested for relevant properties:

[0094] Figure 1 a is an electron microscope image of the rare earth-doped nanoparticles in Example 1. It can be seen that the size of the rare earth-doped nanoparticles is about 3 nm, and they have good dispersion and uniformity. Figure 1 b is a high-resolution electron microscope image of a single rare earth-doped nanoparticle in Example 1. It can be seen that the single rare earth-doped nanoparticle has obvious lattice fringes, which proves the excellent crystallization characteristics of the particle. Figure 1 c, Figure 1 d is Figure 1 From the Fourier transform and inverse Fourier transform diagrams of the rare earth-doped nanoparticles in a, it can be observed that the two-dimensional lattices of the rare earth-doped nanoparticles are mostly of the crystal plane index 420 and 123 type, which are cubic crystal phase particles.

[0095] Figure 1 e and Figure 1 f is the TEM image and EDS spectrum of the composite nanoprobe of Example 1, which proves that the composite nanoprobe has a dumbbell morphology, the atomic ratio of rare earth elements to gold elements is about 4:5, and the composite nanoprobe has an excellent rare earth loading rate. Figure 1 g- Figure 1k is the line scan and element scan of the composite nanoprobe EDS spectrum of Example 1, indicating that the rare earth-doped nanoparticles are mostly loaded on the surface of the mesoporous silica.

[0096] Figure 2 a is the absorption spectrum of the gold nanorods and the composite nanoprobe of Example 1, indicating that the absorption peak of the composite nanoprobe is red-shifted relative to that of the rare earth-doped nanoparticles, and has strong absorption near 940 nm.

[0097] Figure 2 b is the emission spectrum of the composite nanoprobe of Example 1 and the rare earth doped nanoparticles of Comparative Example 1. The integrated intensity ratio (i.e., enhancement factor EF) of the number of emitted photons of the composite nanoprobe formed by the rare earth doped nanoparticles of Example 1 relative to the single rare earth doped nanoparticles of Comparative Example 1 is 0. 3+ The emission peak is 97.2, while the Er 3+ The emission peak is enhanced by 102, indicating that the integrated intensity of emitted photons after rare earth-doped nanoparticles are loaded on both ends of the gold nanorods is increased by about 100 times after removing the dark current background.

[0098] Figure 2 c is the luminescence energy level diagram of the composite nanoprobe of Example 1. It shows that the Yb doped in the rare earth doped nanoparticles 3+ The ions can absorb 980nm excitation light and undergo energy level transitions through energy transfer (ET) and multi-phonon relaxation (MPR) between the internal energy levels of the ions, making Er 3+ with Ho 3+ The ions emit near-infrared IIb light at 1201nm and 1535nm, respectively, achieving optical conversion in the near-infrared region. Due to the strong absorption of the gold nanorods near 980nm, the excitation field can be significantly enhanced. However, the presence of the Purcell effect may lead to slight differences in the luminescence enhancement amplitude at 1201nm and 1535nm.

[0099] The finite-difference time-domain method (FDTD) was used to calculate the surface local electric field distribution of the composite nanoprobe of Example 1 under different structural parameter conditions. Figure 3 a is the NIR absorption cross section simulated by the finite-difference time-domain (FDTD) algorithm. The simulated absorption cross section of the composite nanoprobe has a peak at 950 nm, which is basically consistent with the longitudinal absorption peak measured experimentally. Figure 3 b is the electric field enhancement curve along the x-axis under different incident excitations. When the incident excitation wavelength is 980 nm, the fixed Y position is 56 nm, and the Z position is 0 nm (i.e., at the outer surface of the composite nanoparticles), the electric field along the x-axis is significantly enhanced. Figure 3 c is the simulated structural model of the composite nanoprobe, Figure 3d is the corresponding local electric field E distribution, indicating that the local electric field enhancement is mainly distributed at the two ends of the composite nanoprobe, which is consistent with the dumbbell-shaped probe structure. This shows that the rare earth doped particles are mainly distributed in the local electric field enhancement range, which can maximize the use of local electric field to enhance rare earth photoluminescence. The excitation light wavelength of 980nm is also close to the longitudinal near-infrared resonance peak of the composite nanoprobe. The charge separation caused by the surface plasmon resonance effect is more obvious, and the dumbbell end Yb 3+ The excitation efficiency of ions is improved, so the gold nanorods promote the improvement of near-infrared photoluminescence efficiency.

[0100] Due to the temperature dependence of energy transfer and multiphonon relaxation, temperature changes can significantly affect the population of rare earth ion particles at various energy levels, altering energy transfer efficiency and non-radiative relaxation rates, thereby affecting luminescence intensity and fluorescence lifetime. This study evaluated the temperature sensing properties of the prepared composite nanoprobe by measuring the emission spectra and fluorescence lifetimes at the stimulated emission peaks (1201nm and 1535nm) produced by 980nm near-infrared light excitation at the same power at different temperatures. Figure 4 a, Figure 4 b is the emission spectrum of the composite nanoprobe of Example 1 at six temperature gradients of 313-343K and the curve of the emission peak intensity at 1201nm and 1535nm as a function of temperature. It can be seen that as the temperature increases from 313K to 343K, the emission peak intensity at 1201nm Ho 3+ and 1535nm Er 3+ The emission intensity near both emission peaks decreases with increasing temperature, with a certain degree of monotonicity. The variation of the light intensity at 1201nm with temperature generally follows a monotonic decreasing pattern, exhibiting a certain linear characteristic within this range, while the variation of the light intensity at 1535nm with temperature generally follows an exponential decreasing pattern. Taking the logarithm of the light intensity at 1535nm, the ratio of the logarithm of the light intensity at 1201nm to the logarithm of the light intensity at 1535nm at different temperatures shows a linear relationship with a small error, making it very useful for temperature measurement calibration.

[0101] Relative sensitivity (Sr) is an important parameter used to quantitatively evaluate the performance of optical temperature sensors. It can be used to compare the advantages and disadvantages of different temperature measurement methods. It is usually defined as: Sr = (1 / SP) | dSP / dT | × 100%. SP represents the spectral parameters used for temperature sensing, including single-peak luminescence intensity, double-peak luminescence intensity ratio, and single-peak fluorescence lifetime. Figure 4 c is the relative sensitivity of the composite nanoprobe in each NIR-II single peak luminescence intensity and luminescence intensity ratio of Example 1. As the temperature increases, they all increase monotonically. The temperature measurement sensitivity based on the near infrared region 1535nm is as high as 7.45% K at 343K. -1The intensity ratio also has a high temperature measurement sensitivity, which can reach 3.94% K at 343K. -1 Ratiometric nanothermometry avoids the influence of fluorescence attenuation and rare-earth-doped nanoparticle concentration by measuring two fluorescence signals simultaneously, and can obtain more accurate and reliable information than single emission intensity. Figure 4 d is the five cycles of heating and cooling measured by the composite nanoprobe in Example 1 based on ratio fluorescence thermometry. The fluorescence intensity ratio of the composite nanoprobe remains basically unchanged in the high temperature section and the low temperature section, proving that the composite nanoprobe prepared in Example 1 has excellent optical temperature sensing stability.

[0102] Fluorescence lifetime is a spectral parameter that characterizes the fluorescence decay rate. It is independent of the concentration of the nanoprobe, the irradiation power of the exogenous excitation light, and the medium through which the fluorescence penetrates. It is determined by the intrinsic properties of the nanoprobe itself, such as its structural composition. Therefore, optical temperature sensing based on fluorescence lifetime is also a very stable temperature measurement method. Figure 5 a, Figure 5 b is the curve of the change of the fluorescence lifetime of the composite nanoprobe at 1201nm and 1535nm with temperature at six temperature gradients of 313-343K. The change of the fluorescence lifetime of the composite nanoprobe with temperature basically conforms to the exponential increasing law ( Figure 5 c). Relative sensitivity curve of composite nanoprobe optical temperature sensing ( Figure 5 d) The relative sensitivity of the 1201nm emission lifetime at 338K is as high as 7.25%K. -1 The relative sensitivity of the 1535nm emission lifetime at 343K also reached 5.38% K. -1 At the same time, the 1201nm emission lifetime and 1535nm emission lifetime values ​​at 313K and 343K under five cycles were detected and remained basically unchanged ( Figure 5 e and Figure 5 f) 313-343K is the temperature range for photothermal therapy. The composite nanoprobe exhibits extremely high optical temperature sensing sensitivity in this range, which means that the composite nanoprobe prepared in Example 1 has good optical temperature sensing applications.

[0103] It can be seen from Example 1 and Comparative Example 1 that in the composite nanoprobe with a specific structure of the present invention, the surface local electric field generated by the nanogold rod can enhance the near-infrared second-region luminescence of the rare earth-doped nanoparticles loaded at both ends of the nanogold rod, and the luminescence intensity is increased by two orders of magnitude.

[0104] The luminescence intensity and optical temperature sensing relative sensitivity of the composite nanoprobe obtained in Example 2 are slightly lower than those of the composite nanoprobe in Example 1, but significantly better than those of Comparative Example 1.

[0105] The relative optical temperature sensing sensitivity of the composite nanoprobe obtained in Example 3 was slightly lower than the luminescence intensity and relative optical sensitivity of the composite nanoprobe in Example 1, but significantly better than those of Comparative Example 1. This may be due to the slightly lower content of rare earth-doped nanoparticles loaded on the surface and in the mesopores of the mesoporous silica in the composite nanoprobe in Example 3, which slightly reduced the ability of the gold nanorod plasmon resonance to enhance rare earth photoluminescence, resulting in a slightly lower relative optical temperature sensing sensitivity of the composite nanoprobe.

[0106] In actual temperature measurement applications, the enhanced NIR-II region spectral parameters of the nanoprobe obtained by spectrometer detection can be directly used for high-resolution fluorescence imaging, and the spectral parameters can achieve high-sensitivity local temperature sensing after specific data conversion.

[0107] Obviously, the above embodiments of the present invention are merely examples for the purpose of clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Those skilled in the art will appreciate that other variations or modifications can be made based on the above description. It is not necessary and impossible to enumerate all embodiments here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention are intended to be included within the scope of protection of the claims of the present invention.

Claims

1. A composite nanoprobe, characterized in that: The composite nanoprobe comprises a gold nanorod and rare earth-doped nanoparticles, wherein both ends of the gold nanorod are coated with mesoporous silica, and the surface and pores of the mesoporous silica are loaded with the rare earth-doped nanoparticles, and the composite nanoprobe has a dumbbell-shaped structure; Wherein, the rare earth doped nanoparticles are Gd2O3 nanoparticles doped with Yb 3+ 、Er 3+ and Ho 3+ Metal ions.

2. The composite nanoprobe according to claim 1, wherein: In the rare earth doped nanoparticles, Gd 3+ 、Yb 3+ 、Er 3+ and Ho 3+ The molar ratio is (80~96)∶(2~18)∶(0.2~4)∶(0.2~4).

3. The composite nanoprobe according to claim 2, wherein: In the rare earth doped nanoparticles, Gd 3+ 、Yb 3+ 、Er 3+ and Ho 3+ The molar ratio is (91~95):(5~10):(0.5~1.5):(0.5~1.5).

4. The composite nanoprobe according to claim 1, wherein: In the composite nanoprobe, the atomic ratio of rare earth element to gold element is (0.3-0.9):

1.

5. The composite nanoprobe according to claim 4, wherein: In the composite nanoprobe, the atomic ratio of rare earth element to gold element is (0.6-0.85):

1.

6. The method for preparing the composite nanoprobe according to any one of claims 1 to 5, characterized in that: The steps include: S1. Preparation of gold nanorod solution and rare earth-doped nanoparticles; S2. Covering both ends of the gold nanorods in S1 with mesoporous silica; S3. Ultrasonic oscillation is performed on the mesoporous silica-coated gold nanorod solution of S2 and the rare earth-doped nanoparticles of S1 to obtain the composite nanoprobe.

7. A bio-optical temperature sensor, characterized in that: The composite nanoprobe comprises the composite nanoprobe according to any one of claims 1 to 5.

8. Application of the bio-optical temperature sensor according to claim 7 in bio-optical temperature measurement.

9. The use according to claim 8, characterized in that The temperature of the temperature measurement is 313-343K.

10. The use according to claim 8, characterized in that In the temperature measurement, the excitation light wavelength of the bio-optical temperature sensor is 900-1100 nm.

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