Composite nanoparticles with bimodal imaging function and preparation method and application thereof

Abstract

The application relates to the field of nanomaterials, in particular to a composite nanoparticle with a bimodal imaging function, a preparation method and application; the composite nanoparticle is a multilayer core-shell structure, wherein the core is a composite metal nanoparticle, the shell is a mesoporous MnO2 layer, the composite metal nanoparticle and the mesoporous MnO2 layer are connected through a functional group of polyethyleneimine, and the particle size of the composite nanoparticle is 20nm-30nm; since the MnO2 material has the characteristics of reaction under an inflammatory microenvironment, magnetic resonance imaging and fluorescence quenching, and the composite metal nanoparticle is matched with the core, the composite nanoparticle not only has good fluorescence / magnetic resonance imaging capacity under a specific inflammatory environment in the body, good stability, safety and metabolizable capacity in a biological environment, but also has the advantages of a simple, universal, safe, economical and repeatable preparation process.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of nanomaterials, in particular to a composite nanoparticle with dual-mode imaging function, a preparation method and application thereof. BACKGROUND

[0002] The microenvironment of central nervous system is mainly composed of neurons and glial cells, including microglia, astrocytes and oligodendrocytes. Microglia is a macrophage resident in the brain, which is the main immune effector cell in the central nervous system and exhibits macrophage immune activity in inflammation and immune response. Under pathological conditions, activated microglia rapidly transforms into an amoeboid shape, participates in synaptic pruning and migrates to the lesion area to provide strong phagocytic activity, which is an unbalanced polarization of microglia, i.e. excessive activation of classical M1 microglia and dysfunction of M2 microglia, which promotes neuroinflammatory damage and pathological damage. Therefore, it is very important to conduct in vivo imaging of microglia in the microenvironment of central nervous system chronic inflammation, and in vivo imaging is helpful to guide the immunotherapy of central chronic inflammation related diseases and predict and evaluate the treatment effect.

[0003] At present, molecular imaging technology is mainly used for in vivo imaging. Molecular imaging technology relies on specially synthesized drugs to recognize specific target cells at the molecular level and mark them in a special way, so that the target cells have obvious fluorescence, CT, magnetic resonance and other signals, which can greatly reduce the difficulty of clinicians in accurately positioning the lesion site. However, the imaging method using only fluorescence, CT or magnetic resonance in molecular imaging technology has low accuracy, so the current research focuses on combining fluorescence, CT or magnetic resonance for imaging. However, in the dual-mode imaging technology of fluorescence and magnetic resonance imaging, there is a lack of nanoparticles with high stability and high imaging efficiency. Therefore, how to provide a nanoparticle suitable for fluorescence and magnetic resonance imaging to realize stable imaging and high imaging efficiency is a technical problem to be solved at present. SUMMARY

[0004] The present application provides a composite nanoparticle with dual-mode imaging function, a preparation method and application thereof, to solve the technical problem that the nanoparticles used in the combination technology of fluorescence and magnetic resonance imaging at present cannot have high stability and high imaging efficiency.

[0005] In a first aspect, the present application provides a composite nanoparticle with dual-mode imaging function, which is a core-shell structure, wherein the core is a composite metal nanoparticle, the shell is a mesoporous MnO2 layer, the composite metal nanoparticle and the mesoporous MnO2 layer are connected through the functional groups of polyethyleneimine, and the particle size of the composite nanoparticle is 20-30 nm.

[0006] Optionally, the composite metal nanoparticles include a metal nanocore and a nano metal shell, wherein the metal nanocore comprises NaYF4 material doped with rare earth elements, and the nano metal shell comprises NaYF4 material.

[0007] Optionally, the rare earth element includes Nd.

[0008] Optionally, the Nd content is 2% to 7%.

[0009] Optionally, the thickness of the mesoporous MnO2 layer is ≥2nm.

[0010] Secondly, this application provides a method for preparing the composite nanoparticles described in the first aspect, the method comprising:

[0011] Y salt, Nd salt, octadecene and oleic acid were mixed and subjected to a first stirring, heating and cooling in an anaerobic environment. Then F salt and sodium oleate were added and subjected to a first impurity removal, a second stirring, heating and cooling, to obtain Nd-doped mixed NaYF4 material.

[0012] The Y salt, the octadecene, and the oleic acid are added to the Nd-doped mixed NaYF4 material, and the first stirring, heating, and cooling are performed in an anaerobic environment. Then, the F salt and the sodium oleate are added, and the first impurity removal, the second stirring, heating, and cooling are performed to obtain a composite metal nanoparticle solution containing NaYF4 material and mixed NaYF4 material.

[0013] The composite metal nanoparticle solution and organic solvent are mixed and centrifuged to remove the supernatant, followed by a second impurity removal process to obtain ligand-free composite metal nanoparticles.

[0014] Polyethyleneimine and Mn-containing compounds were added to the ligand-free composite metal nanoparticles. 7+ The solution was stirred and centrifuged to obtain composite nanoparticles with a mesoporous MnO2 layer encapsulating the composite metal nanoparticles.

[0015] Optionally, the Y in the composite metal nanoparticles 3+ and Nd 3+ The molar ratio of the substances is 19 to 39.

[0016] Optionally, the final temperature of the first stirring and heating is 120℃~160℃, and the stirring time of the first stirring and heating is 0.5h~1.5h; and / or,

[0017] The endpoint temperature of the second stirring and heating is 310℃~330℃, and the heating rate of the second stirring and heating is 28℃·min. -1 ~32℃·min -1The second stirring and heating time is 0.2h to 0.8h.

[0018] Optionally, the first impurity removal includes removing impurities by alternating gradient stirring heating and cooling; and / or,

[0019] The second impurity removal includes impurity removal using ultrasonic cleaning and deionized water washing, wherein the ultrasonic cleaning time is...

[0020] ≥10min.

[0021] Thirdly, this application provides an application of nanoparticles with dual-modal imaging capabilities, the application including using the composite nanoparticles described in the first aspect in molecularly responsive fluorescence and magnetic resonance dual-modal imaging under special conditions of neuroinflammation.

[0022] The technical solutions provided in this application have the following advantages compared with the prior art:

[0023] This application provides a composite nanoparticle with dual-modal imaging capabilities. It utilizes a composite metal nanoparticle as its core, and then uses a water-soluble polymer such as polyethyleneimine to reduce a high-valence Mn-containing salt to obtain mesoporous MnO2 particles. Simultaneously, the reduction reaction is controlled to occur on the surface of the composite metal nanoparticle, allowing the polyethyleneimine to connect the surface of the composite metal nanoparticle and the mesoporous MnO2 particles. This results in a uniform and stable MnO2 nanomaterial coating on the nanoparticle surface, leading to highly stable, high-imaging-efficiency composite nanoparticles with a particle size between 20 nm and 30 nm. Because MnO2 material exhibits properties such as reaction in inflammatory microenvironments, magnetic resonance imaging, and fluorescence quenching, combined with its core composite metal nanoparticle, this composite nanoparticle not only demonstrates excellent fluorescence / magnetic resonance imaging capabilities under specific in vivo inflammatory conditions but also exhibits good stability, safety, and metabolic capacity in biological environments. Furthermore, the preparation process of this composite nanoparticle is simple, universal, safe, economical, and reproducible. Attached Figure Description

[0024] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with this application and, together with the description, serve to explain the principles of this application.

[0025] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0026] Figure 1This is a schematic diagram of the structure of the composite nanoparticles provided in the embodiments of this application;

[0027] Figure 2 This is a schematic diagram of the method for preparing composite nanoparticles provided in the embodiments of this application;

[0028] Figure 3 A schematic diagram illustrating the principle of preparing composite nanoparticles provided in the embodiments of this application;

[0029] Figure 4 Transmission electron microscope (TEM) images of the materials obtained in each step of the embodiments of this application;

[0030] Figure 5 X-ray photoelectron spectroscopy (XPS) results of composite nanoparticles provided in the embodiments of this application;

[0031] Figure 6 The near-infrared fluorescence spectrum detection results of NPs and NPs@MnO2 provided in the embodiments of this application are shown in the figure.

[0032] Figure 7 Near-infrared fluorescence spectra of NPs@MnO2 after adding different concentrations of GSH, as provided in the embodiments of this application;

[0033] Figure 8 T1-weighted MRI images and relaxation rate results of NPs@MnO2 in GSH solutions of different concentrations for 24 hours, provided for embodiments of this application. Detailed Implementation

[0034] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0035] Unless otherwise specified, all raw materials, reagents, instruments and equipment used in this application can be purchased from the market or prepared by existing methods.

[0036] The creative thinking behind this application is:

[0037] The rapid development of near-infrared (NIR-II, 1000-1700nm) technology has provided researchers with a powerful tool for non-invasive in vivo bioimaging and biosensing. The NIR-II bioimaging window greatly reduces photon scattering, absorption, and autofluorescence in tissues, providing a higher signal-to-noise ratio and deeper tissue penetration. Currently, there are studies on NIR-II fluorescence imaging that can penetrate the skull, with a penetration depth of over 3cm. Therefore, extending molecular imaging technology to the NIR-II window will greatly improve imaging performance and provide more detailed and accurate information about biological systems.

[0038] Because MnO2 materials exhibit properties related to inflammatory microenvironments, magnetic resonance imaging, and fluorescence quenching, they can be combined with various nanomaterials, making them promising for applications in the medical field. Furthermore, many studies have explored the role of MnO2 in MRI contrast agents. 2+ Excellent MRI imaging capabilities; furthermore, near-infrared fluorescence can be effectively quenched by MnO2 bound to the nanoparticle surface, and this MnO2-induced quenching effect can be reversed by adding a small amount of reducing agent, such as glutathione (GSH), to the solution to reduce MnO2 to divalent form, thus allowing MnO2 to quench. 2+ Separation from the surface of nanoparticles.

[0039] However, the main methods for coating MnO2 onto nanomaterials currently include:

[0040] (1) Using KMnO4 as the Mn source and 2-(N-morpholino)-ethanesulfonic acid as the reducing agent, amorphous polymer nanosheets are grown in situ on the surface of NPs. However, this method cannot control the growth process of MnO2 on the surface of NPs, and it is difficult to ensure that MnO2 is evenly distributed on the nanomaterial. Furthermore, the resulting MnO2 nanosheets have low stability.

[0041] (2) Introducing mSiO2 or CaF2 as an intermediate layer to synthesize NPs@mSiO2 / CaF2@MnO2, but this method can achieve uniform coating of MnO2, but it will reduce the fluorescence imaging efficiency of nanoparticles.

[0042] (3) Using C as a structure directing agent, relatively uniform MnO2 can be synthesized directly on the surface of NPs. However, this method is complicated, time-consuming, and has certain safety risks during operation.

[0043] Therefore, how to provide a nanoparticle with high stability, high imaging efficiency and simple preparation with dual-modal imaging function is a technical problem that urgently needs to be solved.

[0044] This application utilizes common water-soluble polymers used for surface modification of nanomaterials, employing polyethyleneimine (PEI) to reduce KMnO4, thereby preparing a uniform and stable MnO2 nanomaterial coating on the surface of near-infrared II fluorescence imaging nanoparticles, endowing the nanoparticles with molecularly responsive fluorescence / magnetic resonance dual-modal imaging capabilities under the special environment of neuroinflammatory conditions.

[0045] like Figure 1 As shown, this application provides a composite nanoparticle with dual-modal imaging function. The composite nanoparticle has a core-shell structure, wherein the core is a composite metal nanoparticle and the outer shell is a mesoporous MnO2 layer. The composite metal nanoparticle and the mesoporous MnO2 layer are connected by functional groups of polyethyleneimine. The particle size of the composite nanoparticle is 20 nm to 30 nm.

[0046] In this embodiment, by controlling the specific particle size of the composite nanoparticles, since MnO2 material has the characteristics of reaction in inflammatory microenvironment, magnetic resonance imaging and fluorescence quenching, the composite nanoparticles formed by the mesoporous MnO2 layer encapsulating the composite metal nanoparticles within the particle size range of the composite nanoparticles can not only have good fluorescence / magnetic resonance imaging capabilities and good stability, safety and metabolic capacity in biological environment under specific inflammatory conditions in vivo, but also the preparation process of the composite nanoparticles is simple, universal, safe, economical and reproducible.

[0047] The particle size of the composite nanoparticles can be 20nm, 21nm, 22nm, 23nm, 24nm, 25nm, 26nm, 27nm, 28nm, 29nm, or 30nm.

[0048] In some alternative embodiments, the composite metal nanoparticles include a metal nanocore and a nano-metal shell, wherein the metal nanocore comprises NaYF4 material doped with rare earth elements, and the nano-metal shell comprises NaYF4 material.

[0049] In some alternative implementations, the rare earth element includes Nd.

[0050] In some alternative embodiments, the Nd content is 2% to 7%.

[0051] In this embodiment, NaYF4 material doped with rare earth elements is used as the metal nanocore, and NaYF4 material is used as the nano metal shell, thereby obtaining composite metal nanoparticles with a core-shell structure of NaYF4 material encapsulating rare earth element-doped NaYF4 material. At the same time, the specific materials of the metal nanocore and the nano metal shell are refined. Since NaYF4 material is currently the matrix material with the lowest phonon energy and the highest fluorescence efficiency among fluoride upconversion fluorescent materials, and rare earth elements are doped into this material, the excitation light of the material can be converted into infrared light. Since the light transmission window of biological tissue is in the infrared band, the use of this material and the rare earth element-doped material can realize in vivo fluorescence imaging. Combined with the shell of mesoporous MnO2 layer, it can have good fluorescence / magnetic resonance imaging capabilities in specific inflammatory environments in vivo, and has good stability, safety and metabolic capacity in biological environments.

[0052] By controlling the specific content of the rare element Nd, it is possible to achieve high-efficiency fluorescence imaging in vivo, since rare earth elements can convert the excitation light of NaYF4 material into infrared light.

[0053] In some alternative embodiments, the thickness of the mesoporous MnO2 layer is ≥2 nm.

[0054] In this embodiment, by controlling the specific thickness of the mesoporous MnO2 layer, the composite metal nanoparticles can be encapsulated by the mesoporous MnO2 layer. By utilizing the properties of the mesoporous MnO2 layer in reacting to inflammatory microenvironments, magnetic resonance imaging, and fluorescence quenching, the composite nanoparticles can achieve dual-modal imaging functions of fluorescence and magnetic resonance.

[0055] like Figure 2 As shown, based on a general inventive concept, this application provides a method for preparing the composite nanoparticles, the method comprising:

[0056] S1. Mix Y salt, Nd salt, octadecene and oleic acid, and perform a first stirring, heating and cooling in an anaerobic environment. Then add F salt and sodium oleate, and perform a first impurity removal, a second stirring, heating and cooling to obtain Nd-doped mixed NaYF4 material.

[0057] S2. Add the Y salt, the octadecene, and the oleic acid to the Nd-doped mixed NaYF4 material, and perform the first stirring, heating, and cooling in an anaerobic environment. Then add the F salt and the sodium oleate, and perform the first impurity removal, the second stirring, heating, and cooling to obtain a composite metal nanoparticle solution containing NaYF4 material and mixed NaYF4 material.

[0058] S3. Mix the composite metal nanoparticle solution with an organic solvent and centrifuge to remove the supernatant, then perform a second impurity removal to obtain ligand-free composite metal nanoparticles.

[0059] S4. Add polyethyleneimine and Mn-containing compounds to the ligand-free composite metal nanoparticles. 7+ The solution was stirred and centrifuged to obtain composite nanoparticles with a mesoporous MnO2 layer encapsulating the composite metal nanoparticles.

[0060] In this embodiment, a rare-earth-doped NaYF4 material is formed by using Y salt, Nd salt, octadecene, and oleic acid. Then, another NaYF4 material is formed on the basis of the rare-earth-doped NaYF4 material using Y salt, octadecene, and oleic acid. This results in a core-shell structured composite metal nanoparticle core. Polyethyleneimine is then used to reduce the surface of the composite metal nanoparticle core with high-valence Mn ions, thereby coating the surface of the composite metal nanoparticle with a mesoporous MnO2 layer, thus obtaining the desired composite nanoparticle.

[0061] This method is implemented for the above-mentioned composite nanoparticles. The specific composition of the composite nanoparticles can be referred to in the above embodiments. Since this method adopts some or all of the technical solutions of the above embodiments, it has at least all the beneficial effects brought about by the technical solutions of the above embodiments, which will not be elaborated here.

[0062] In some alternative embodiments, the composite metal nanoparticles contain Y 3+ and Nd 3+ The molar ratio of the substances is 19 to 39.

[0063] In this embodiment, the Y content in the NPS nanomaterial is controlled. 3+ and Nd 3+ The specific molar ratio can make Y 3+ It can form NaYF4 material, while Nd 3+ It can be incorporated into NaYF4 material as a rare earth element to obtain rare earth-doped NaYF4 material and composite metal nanoparticles of NaYF4 material.

[0064] In some optional embodiments, the endpoint temperature of the first stirring and heating is 120°C to 160°C, and the stirring time of the first stirring and heating is 0.5h to 1.5h; and / or,

[0065] The endpoint temperature of the second stirring and heating is 310℃~330℃, and the heating rate of the second stirring and heating is 28℃·min. -1 ~32℃·min -1The second stirring and heating time is 0.2h to 0.8h.

[0066] In this embodiment, controlling the specific temperature and stirring time of the first stirring and heating can ensure that the Y salt, Nd salt, octadecene and oleic acid are fully mixed and form the precursor of NaYF4 material.

[0067] The final temperature of the first stirring and heating can be 120℃, 125℃, 130℃, 135℃, 140℃, 145℃, 150℃, 155℃, or 160℃.

[0068] The initial stirring and heating time can be 0.5 hours, 1 hour, or 1.5 hours.

[0069] By controlling the specific temperature and stirring time of the second stirring and heating, the reaction between the precursor of NaYF4 material and F salt and sodium oleate can be fully achieved, thereby obtaining NaYF4 material doped with Nd.

[0070] The final temperature of the second stirring and heating process can be 310℃, 315℃, 320℃, 325℃, or 330℃.

[0071] The heating rate for the second stirring heating can be 28℃·min. -1 It can also be 29℃·min -1 It can also be 30℃·min -1 It can also be 31℃·min -1 It can also be 32℃·min -1 .

[0072] The second stirring and heating time can be 0.2h, 0.3h, 0.4h, 0.5h, 0.6h, 0.7h, or 0.8h.

[0073] In some alternative embodiments, the first impurity removal includes performing impurity removal using a gradient stirring heating and cooling alternating method; and / or,

[0074] The second impurity removal includes ultrasonic impurity removal and deionized water cleaning, wherein the ultrasonic impurity removal time is ≥10 min.

[0075] In this embodiment of the application, the specific method of controlling the first impurity removal can remove impurities introduced by the precursor of NaYF4 material during the formation of NaYF4 material, thereby obtaining pure NaYF4 material.

[0076] The specific method for controlling the second impurity removal is to effectively remove the OA ligands attached to the surface of the composite metal nanoparticles by ultrasound, thereby obtaining ligand-free composite metal nanoparticles. This facilitates the subsequent use of polyethyleneimine to remove Mn-containing impurities. 7+ During the reduction process of the solution, a mesoporous MnO2 layer is formed on the surface of the composite metal nanoparticles.

[0077] Based on a general inventive concept, embodiments of this application provide an application of nanoparticles with dual-modal imaging capabilities, the application including using the composite nanoparticles in molecularly responsive fluorescence and magnetic resonance dual-modal imaging under specific conditions of neuroinflammation.

[0078] This application is based on composite nanoparticles. The specific structure of the composite nanoparticles can be referred to in the above embodiments. Since this application adopts some or all of the technical solutions of the above embodiments, it has at least all the beneficial effects brought about by the technical solutions of the above embodiments, which will not be elaborated here.

[0079] The present application is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the application. Experimental methods in the following embodiments that do not specify specific conditions are generally determined according to national standards. If there is no corresponding national standard, then general international standards, conventional conditions, or conditions recommended by the manufacturer are followed.

[0080] Example 1

[0081] like Figure 3 As shown, core-shell structured nanoparticles of NaYF4:5%Nd / NaYF4 were prepared by a layer-by-layer synthesis method. The specific steps are as follows:

[0082] 0.475 mol of Y(C2H3O2)3, 0.025 mol of Nd(C2H3O2)3, 7 mL of ODE, and 3 mL of OA were added to a 100 mL three-necked flask. Under argon protection and stirring, the reaction solution was heated to 140 °C and stirred for 1 h for the first stirring and heating process. The solution was then cooled to room temperature. A total of 6 mL of a methanol solution containing 1 mol / mL NH4F and 1 mol / mL sodium oleate was added and mixed. The reaction mixture was then heated to 50 °C and stirred for 0.5 h to remove methanol. The solution was then cooled to room temperature, and under vacuum, it was heated to 100 °C and stirred for 10 min to remove impurities and dissolved oxygen, achieving the first impurity removal.

[0083] The solution was cooled to room temperature and then, under argon protection, incubated at approximately 30 °C / min. -1The mixture was heated to 320°C at a certain rate, stirred for 0.5 h, and then allowed to cool naturally to room temperature. The reaction product was then centrifuged, washed once with anhydrous ethanol, and dispersed in 5 mL of n-hexane for later use, resulting in 5% Nd / NaYF4 material with a doping amount of 5%.

[0084] Add 0.5 mol Y(C2H3O2)3, 7 mL ODE, and 3 mL OA to a 100 mL three-necked flask, repeat the above steps, and then cool the solution to room temperature. Simultaneously add 2.5 mL of the above 5% Nd / NaYF4 material, and a total of 6 mL of a methanol solution containing 1 mol / mL NH4F and 1 mol / mL sodium oleate. Repeat the above steps, and cool the solution to room temperature. Under argon protection, incubate at approximately 30 °C·min. -1 Heat to 320°C at a constant rate, stir for 0.5 hours, and allow to cool naturally to room temperature.

[0085] The reaction product was centrifuged, washed once with anhydrous ethanol, and dispersed in 5 ml of n-hexane for further use, yielding core-shell structured nanoparticles of NaYF4:5%Nd / NaYF4 containing OA ligands.

[0086] Example 2

[0087] Based on the core-shell structured nanoparticles obtained in Example 1, further processing is carried out, specifically the following steps:

[0088] Add 15 mL of anhydrous ethanol to 5 mL of NaYF4:5% Nd / NaYF4 n-hexane solution, centrifuge at 10000 rpm to remove the supernatant, add 15 mL of anhydrous ethanol containing 2 wt% HCl, sonicate for 10 min to remove OA ligands, centrifuge at 13000 rpm to remove the supernatant, wash twice with deionized water, and then disperse the sample in 10 mL of deionized water to obtain ligand-free nanoparticles.

[0089] 10 mL of PEI (molecular weight 25000) aqueous solution (concentration 10 mg / mL) was added to the nanoparticle solution, and the mixture was stirred at room temperature for 2 h. The reaction product was centrifuged at 11000 rpm, washed three times with deionized water, and dispersed in 10 mL of deionized water. 1 mL of KMnO4 (concentration 20 mg / mL) aqueous solution was added to the above solution, and the mixture was stirred at room temperature for 6 h. After centrifugation, the mixture was washed with deionized water to obtain NaYF4:5% Nd / NaYF4@MnO2. By repeating the above process, multilayer coating of mesoporous MnO2 can be achieved, and the thickness of the mesoporous MnO2 shell can be controlled.

[0090] Relevant experimental and effect data:

[0091] The 5% Nd / NaYF4 material obtained in Examples 1 and 2, the core-shell nanoparticles of NaYF4:5% Nd / NaYF4 containing OA ligands, the core-shell nanoparticles of NaYF4:5% Nd / NaYF4 (NNPs), the polyethyleneimine-modified NPs (NNPs-PEI), and the NPs@MnO2 were observed using transmission electron microscopy. The results are as follows: Figure 4 As shown, the results indicate that the composite nanoparticles obtained in this application are first obtained by coating the surface of 5% Nd / NaYF4 material with NaYF4 material to obtain composite metal nanoparticles, then modified with PEI, and finally a mesoporous MnO2 layer is formed on the surface of the modified composite metal nanoparticles.

[0092] X-ray photoelectron spectroscopy was performed on the NPs@MnO2 obtained in Example 2, and the results are as follows: Figure 5 As shown, a mesoporous MnO2 layer is formed on the surface of the composite metal nanoparticles.

[0093] Near-infrared fluorescence spectroscopy was performed on the NNPs and NPs@MnO2 materials obtained in Examples 1 and 2, as shown in the results. Figure 6 As shown, different concentrations of GSH were added to NNPs and NPs@MnO2 materials respectively, and near-infrared fluorescence spectroscopy was performed. The results are as follows. Figure 7 As shown, the results indicate that the NPs@MnO2 material exhibits good fluorescence imaging capabilities under specific in vivo inflammatory conditions and good stability, safety, and metabolic capacity in biological environments.

[0094] The NPs@MnO2 material obtained in Example 2 was incubated in a concentrated GSH solution for 24 hours, followed by T1-weighted magnetic resonance imaging, and the relaxation rate was statistically analyzed. The results are as follows: Figure 8 As shown, this indicates that the NPs@MnO2 material has good magnetic resonance imaging capabilities under specific inflammatory conditions in vivo.

[0095] In summary, the composite nanoparticles with dual-modal imaging function provided in this application not only have good fluorescence / magnetic resonance imaging capabilities under specific in vivo inflammatory conditions and good stability, safety and metabolic capacity in biological environments, but their preparation process is also simple, universal, safe, economical and reproducible.

[0096] The composite nanoparticles with dual-modal imaging function provided in this application have a good effect on in vivo imaging of microglia in the chronic inflammatory microenvironment of the central nervous system, and have the ability of preliminary semi-quantitative analysis. They can also help guide the immunotherapy of diseases related to chronic inflammation of the central nervous system and predict and evaluate their therapeutic effects.

[0097] Various embodiments of this application may exist in the form of a range; it should be understood that the description in the form of a range is merely for convenience and brevity and should not be construed as a hard limitation on the scope of this application; therefore, it should be considered that the range description has specifically disclosed all possible sub-ranges and single numerical values ​​within that range. For example, it should be considered that the range description from 1 to 6 has specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and single numbers within the range, such as 1, 2, 3, 4, 5, and 6, regardless of the range. Furthermore, whenever a numerical range is referred to herein, it means including any referenced number (fraction or integer) within the referred range.

[0098] In this application, unless otherwise stated, directional terms such as "upper" and "lower" specifically refer to the drawing directions in the accompanying drawings. Furthermore, in the description of this application, terms such as "comprising" and "including" mean "including but not limited to." In this document, relational terms such as "first" and "second" are used merely to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. In this document, "and / or" describes the relationship between related objects, indicating that three relationships can exist; for example, A and / or B can represent: A alone, A and B simultaneously, or B alone. A and B can be singular or plural. In this document, "at least one" means one or more, and "more than one" means two or more. "At least one," "at least one of the following," or similar expressions refer to any combination of these items, including any combination of single or plural items. For example, "at least one of a, b, or c" or "at least one of a, b, and c" can both mean: a, b, c, ab (i.e., a and b), ac, bc, or abc, where a, b, and c can be a single or multiple.

[0099] The above description is merely a specific embodiment of this application, enabling those skilled in the art to understand or implement this application. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of this application. Therefore, this application is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features claimed herein.

Claims

1. A composite nanoparticle with dual-modal imaging function, characterized in that, The composite nanoparticles have a multi-layer core-shell structure, wherein the core is a composite metal nanoparticle and the outer shell is a mesoporous MnO2 layer. The composite metal nanoparticles and the mesoporous MnO2 layer are connected by functional groups of polyethyleneimine. The particle size of the composite nanoparticles is 20nm to 30nm. They are used for molecularly responsive fluorescence and magnetic resonance dual-modal imaging under special conditions of neuroinflammation. The composite metal nanoparticles include a metal nanocore and a nano metal shell. The metal nanocore is a NaYF4 material doped with rare earth element Nd, and the nano metal shell is also a NaYF4 material. The Nd content is 2% to 7%, and the thickness of the mesoporous MnO2 layer is ≥2 nm.

2. A method for preparing the composite nanoparticles as described in claim 1, characterized in that, The method includes: Y salt, Nd salt, octadecene and oleic acid were mixed and subjected to a first stirring, heating and cooling in an anaerobic environment. Then F salt and sodium oleate were added and subjected to a first impurity removal, a second stirring, heating and cooling, to obtain Nd-doped mixed NaYF4 material. The Y salt, the octadecene, and the oleic acid are added to the Nd-doped mixed NaYF4 material, and the first stirring, heating, and cooling are performed in an anaerobic environment. Then, the F salt and the sodium oleate are added, and the first impurity removal, the second stirring, heating, and cooling are performed to obtain a composite metal nanoparticle solution containing NaYF4 material and mixed NaYF4 material. The composite metal nanoparticle solution and organic solvent are mixed and centrifuged to remove the supernatant, followed by a second impurity removal process to obtain ligand-free composite metal nanoparticles. Polyethyleneimine and Mn-containing compounds were added to the ligand-free composite metal nanoparticles. 7+ The solution was stirred and centrifuged to obtain composite nanoparticles with a mesoporous MnO2 layer encapsulating the composite metal nanoparticles.

3. The method according to claim 2, characterized in that, Y in composite metal nanoparticles 3+ and Nd 3+ The molar ratio of the substances is 19 to 39.

4. The method according to claim 2, characterized in that, The endpoint temperature of the first stirring and heating is 120℃~160℃, and the stirring time of the first stirring and heating is 0.5h~1.5h; and / or, The endpoint temperature of the second stirring and heating is 310℃~330℃, and the heating rate of the second stirring and heating is 28℃·min. -1 ~32℃·min -1 The second stirring and heating time is 0.2h to 0.8h.

5. The method according to claim 2, characterized in that, The first impurity removal includes removing impurities by alternating gradient stirring heating and cooling; and / or, The second impurity removal includes ultrasonic impurity removal and deionized water cleaning, wherein the ultrasonic impurity removal time is ≥10 min.

6. An application of a nanoparticle with dual-modal imaging capability, characterized in that, The application includes using the composite nanoparticles as described in claim 1 in the preparation of formulations for fluorescent and magnetic resonance dual-modal imaging of neuroinflammatory environments.

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