A polymetal borate nanoparticle, a preparation method and application thereof

Abstract

The application discloses a kind of polymetal borate nanoparticles and preparation method and application thereof.The preparation method is that in the presence of small molecule with alkyl chain, organic metal compound or metal salt compound precursor, organic borate ester is high-temperature thermal decomposition in solvent, then pass through centrifugation, modification, ultrafiltration, dialysis, and obtain polymetal borate nanoparticles.The preparation method of the application has the characteristics of mild, efficient and strong controllability.The polymetal borate nanoparticles prepared by the application have monodisperse size, higher magnetic performance and good biocompatibility.The polymetal borate nanoparticles prepared by the application not only have multi-modal imaging functions such as magnetic resonance imaging, near-infrared two-zone imaging, nuclear medical imaging and magnetic particle imaging, but also can be used for magnetic heating treatment and boron neutron capture therapy and other treatment methods, have potential advantages in magnetic targeted tumor treatment, imaging contrast agent and other biomedical applications, and have high practical value.

Description

Technical Field

[0001] This invention belongs to the fields of nanomaterials and biomedicine, specifically relating to a polymetallic borate nanoparticle, its preparation method, and its application. Background Technology

[0002] Cancer is currently one of the leading causes of death worldwide, especially due to its difficulty in early diagnosis and the lack of highly targeted treatments, leading to high recurrence rates and poor prognoses. Achieving precise diagnosis and treatment of tumors is a major research direction in medicine and materials science. Precision diagnosis and treatment of tumors not only requires accurate localization and imaging of the tumor site but also demands highly selective treatment that minimizes damage to normal tissues.

[0003] In recent years, with the rapid development of nanotechnology and medical imaging technology, targeted therapy based on nanomaterials has made significant progress, especially the combination of magnetic targeted therapy, which has attracted widespread attention. Magnetic targeted therapy uses an external magnetic field to guide magnetic nanoparticles, causing them to accumulate specifically at the tumor site, thereby increasing drug concentration and reducing systemic side effects. This approach not only achieves precise drug delivery but also directly enhances the therapeutic effect at the tumor site through magnetic field control.

[0004] Currently, targeted magnetic nanoparticles are often combined with multimodal imaging to achieve real-time tumor monitoring. With the assistance of various imaging techniques such as magnetic resonance imaging (MRI), near-infrared II imaging (NIR-II), and magnetic particle imaging (MPI), precise data support can be provided for tumor localization and real-time monitoring of treatment effects. Therefore, developing multifunctional nanomaterials with both imaging and therapeutic functions is an important approach and direction for achieving precise tumor diagnosis and treatment.

[0005] Traditional magnetic nanoparticles, such as iron oxide (Fe3O4), have seen initial applications in tumor imaging and magnetic targeted therapy. These particles can be guided by an external magnetic field to achieve a certain degree of aggregation at the tumor site. However, existing magnetic nanomaterials still have many shortcomings, such as weak magnetism, leading to low efficiency in the targeted aggregation process; and limited targeting and specificity, making it difficult to achieve the ideal tumor enrichment effect. These problems greatly limit the further promotion and application of traditional magnetic nanomaterials in clinical practice.

[0006] Current research also indicates that multimetallic magnetic nanomaterials can exhibit better magnetic properties and magnetic targeting than traditional single-metal magnetic nanomaterials. However, the synthesis of existing multimetallic magnetic nanoparticles mostly employs complex oil-phase systems, requiring multiple reaction steps and various chemical reagents. This process is not only cumbersome but also difficult to control the reaction conditions, resulting in inconsistent particle size and morphology, which affects their feasibility for clinical applications. Summary of the Invention

[0007] To address the problems existing in the prior art, this invention provides a polymetallic borate nanoparticle, its preparation method, and its applications. This polymetallic borate nanoparticle not only possesses multimodal imaging capabilities such as magnetic resonance imaging, near-infrared II imaging, nuclear medicine imaging, and magnetic particle imaging, but can also be used for various treatment methods such as magnetothermal therapy and boron neutron capture therapy. It has high practical value and is expected to be applied in the biomedical field, especially for the precise diagnosis and treatment of tumors.

[0008] To solve the above-mentioned technical problems, the present invention is achieved through the following technical solution:

[0009] A method for preparing polymetallic borate nanoparticles includes the following steps:

[0010] Step 1) Dissolve the organometallic compound or metal salt compound as a precursor, as well as small molecules with alkyl chains and organoboroesters in the first solvent to form the first mixed reaction solution.

[0011] Step 2) Dissolve the alcohol compound in the second solvent to form a second mixed reaction solution;

[0012] Step 3) Under the protection of an inert gas, the first mixed reaction solution is heated to 50-150°C with a certain stirring speed and held for a period of time, and then the temperature is raised to 200-350°C.

[0013] Step 4) Under the protection of inert gas, the second mixed reaction solution preheated to 50-150°C is injected into the first mixed reaction solution after being heated in step 3). After the temperature stabilizes at 200-350°C, it is kept at a certain stirring speed for a period of time to form the third mixed reaction solution.

[0014] Step 5) The third mixed reaction solution is naturally cooled to room temperature, and then centrifuged and purified to obtain polymetallic borate nanoparticles. The polymetallic borate nanoparticles have a size of 1 to 100 nanometers and are monodisperse.

[0015] Furthermore, in step 1), the organometallic compound is an organic complex containing a transition metal or a rare earth metal, such as an organometallic complex of iron, cobalt, nickel, manganese, neodymium or other lanthanide and actinide rare earth metals, and its ligands include acetylacetone, carbonyl, phenylacetylacetone, and cyclopentadiene.

[0016] Examples of the organometallic compounds include, but are not limited to, one or more of the following: iron triacetylacetone, iron diacetylacetone, iron pentacarbonyl, iron phenylacetylacetone, neodymium triacetylacetone, neodymium diacetylacetone, neodymium pentacarbonyl, neodymium phenylacetylacetone, manganese diacetylacetone, manganese phenylacetylacetone, nickel diacetylacetone, nickel tetracarbonyl, cobalt diacetylacetone, cobalt octacarbonyl, gadolinium triacetylacetone, gadolinium tricyclopentadiene, dysprosium triacetylacetone, holmium acetylacetone, etc.

[0017] Furthermore, in step 1), the metal salt compound is a salt or hydrate containing transition metals and rare earth metals, such as oleate, stearate, fatty acid salt, trifluoroacetate, gluconate, citrate, oxalate, chloride, sulfate, nitrate and their hydrates of iron, cobalt, nickel, manganese, neodymium or other lanthanide and actinide rare earth metals.

[0018] Examples of the metal salt compounds include, but are not limited to: ferric oleate, ferric stearate, ferric acetate, ferric citrate, ferric oxalate, ferric chloride, ferrous chloride, ferric chloride tetrahydrate, ferric chloride hexahydrate, ferric nitrate, ferric sulfate, neodymium oleate, neodymium stearate, neodymium acetate, neodymium citrate, neodymium oxalate, neodymium trichloride, hydrated neodymium trichloride, neodymium nitrate, neodymium sulfate, cobalt oleate, cobalt stearate, cobalt acetate, cobalt citrate, cobalt oxalate, cobalt decanoate, cobalt trichloride, manganese acetate, oxalic acid Manganese, manganese chloride, manganese nitrate, manganese sulfate, gadolinium oleate, gadolinium stearate, gadolinium acetate, gadolinium chloride, gadolinium chloride trihydrate, gadolinium chloride hexahydrate, gadolinium nitrate, dysprosium acetate, dysprosium chloride, dysprosium chloride trihydrate, dysprosium chloride hexahydrate, dysprosium nitrate, holmium acetate, holmium chloride, holmium chloride trihydrate, holmium chloride hexahydrate, holmium nitrate, erbium acetate, erbium chloride, erbium chloride trihydrate, erbium chloride hexahydrate, erbium nitrate, thulium acetate, thulium chloride, thulium chloride trihydrate, thulium chloride hexahydrate, thulium nitrate, etc.

[0019] Furthermore, in step 1), the concentration of the organometallic compound or the inorganic metal salt compound is 0.001–1 mol / L;

[0020] Furthermore, in step 1), the small molecule with an alkyl chain is one or more of a small molecule amine with an alkyl chain, a small molecule carboxylic acid with an alkyl chain, or a small molecule alcohol with an alkyl chain, and the number of CH2 units in its alkyl chain is 4 to 24; the small molecule with an alkyl chain may also be a derivative, analogue, or functionally equivalent compound of the small molecules with alkyl chains listed above.

[0021] Furthermore, in step 1), the concentration of the small molecule amine with an alkyl chain, the small molecule carboxylic acid with an alkyl chain, or the small molecule alcohol with an alkyl chain is 0.001 to 1 mol / L.

[0022] Further, in step 1), the organoboroester is one or more selected from trimethyl borate, triethyl borate, tripropyl borate, tributyl borate, tripentyl borate, trihexyl borate, triheptyl borate, trioctyl borate, trinonyl borate, and tridecyl borate, and the number of CH2 units in its alkyl chain is 1 to 24. The organoboroester may also be a derivative, analogue, or functionally equivalent compound of the organoboroesters listed above.

[0023] Furthermore, in step 1), the concentration of the organoboroate ester is 0.001 to 1 mol / L.

[0024] Further, in step 1), the first solvent is one or a mixture of several of the following: 1-hexadecene, 1-tetradecene, n-octadecane, n-hexadecane, paraffin oil, mineral oil, diphenyl ether, trioctylamine, dioctyl ether, oleylamine, 1-eicosene, and 1-tetradecane. The first solvent may also be a derivative, analogue, or functionally equivalent compound of the solvents listed above.

[0025] Furthermore, in step 1), the molar ratio of the organometallic compound or metal salt compound to the organoboroester is 1:(0.1 to 10).

[0026] Furthermore, in step 2), the alcohol compound is one or more selected from octanol, nonanol, decanol, undecylol, dodecanol, tridecanol, tetradecanol, or pentadecylol, and the number of CH2 units in its alkyl chain is 4 to 24. The alcohol compound may also be a derivative, analogue, or functionally equivalent compound of the alcohol compounds listed above.

[0027] Further, in step 2), the second solvent is one or a mixture of several of the following: 1-hexadecene, 1-tetradecene, n-octadecane, n-hexadecane, paraffin oil, mineral oil, diphenyl ether, trioctylamine, dioctyl ether, oleylamine, 1-eicosene, and 1-tetradecane. The second solvent may also be a derivative, analogue, or functionally equivalent compound of the solvents listed above.

[0028] Furthermore, in step 3), the inert gas is one or more of helium, neon, argon, xenon, krypton, and nitrogen.

[0029] Furthermore, in step 3), the stirring speed of the first mixed reaction solution is 100-1500 rpm, and the holding time after heating to 50-150°C is 5-60 minutes.

[0030] Furthermore, in step 4), the inert gas is one or more of helium, neon, argon, xenon, krypton, and nitrogen.

[0031] Furthermore, in step 4), the stirring speed of the first mixed reaction solution and the second mixed reaction solution is 100 to 1500 rpm, and the holding time after the temperature stabilizes at 200 to 350°C is 1 minute to 36 hours.

[0032] Furthermore, in step 5), when centrifuging the third mixed reaction solution, the precipitant added to the third mixed reaction solution is one or a combination of ethanol, methanol, and acetone; and the volume of the precipitant is 2 to 50 times the volume of the third mixed reaction solution. The precipitate is separated using magnetic separation or centrifugal separation techniques.

[0033] Furthermore, in step 5), the method for separating the precipitate is as follows: the precipitate is cyclically washed and separated once or multiple times using the precipitating agent. This can improve the purity of the obtained magnetic nanoparticle product. The number of washing and separation cycles can be 1 to 5 times. The magnetic nanoparticles can be separated by magnetic separation or centrifugal separation.

[0034] The method for preparing polymetallic borate nanoparticles of the present invention can further prepare water-soluble polymetallic borate nanoparticles, including the following subsequent steps:

[0035] Step 6) Dissolve the polymetallic borate nanoparticles obtained in Step 5) in the third solvent, add biocompatible molecules, and then stir at a certain stirring speed, heat at 40-100℃ or sonicate for a period of time to form the fourth mixed reaction solution.

[0036] Step 7) The fourth mixed solution is naturally cooled to room temperature, and then centrifuged and purified to obtain water-soluble polymetallic borate nanoparticles. The water-soluble polymetallic borate nanoparticles have a size of 1 to 100 nanometers and are monodisperse.

[0037] Furthermore, in step 6), the third solvent is one or a mixture of any two of the following: dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, ethylene glycol, dimethyl ether, dioxane, pyridine, dimethylformamide, and dimethyl sulfoxide.

[0038] Furthermore, in step 6), the biocompatible molecule is one or more of bovine serum albumin, human serum albumin, dextran, polyethylene glycol, polyvinylpyrrolidone, polyethyleneimine, chitosan, or derivatives of the biocompatible molecules listed above.

[0039] Furthermore, in step 6), the stirring speed of the polymetallic borate nanoparticles and the biocompatible molecules in the third solvent is 100-1500 rpm, and the heating or ultrasonication time at 40-100°C is 10 minutes to 48 hours.

[0040] Furthermore, in step 7), when centrifuging the fourth mixed reaction solution, the precipitant added to the fourth mixed reaction solution is one or a combination of cyclohexane, n-hexane, benzene, and toluene; and the volume of the precipitant is 2 to 50 times the volume of the fourth mixed reaction solution. The precipitate is separated using magnetic separation or centrifugal separation techniques.

[0041] Furthermore, in step 7), the method for separating the precipitate is as follows: the precipitate is cyclically washed and separated once or multiple times using the precipitating agent. This can improve the purity of the obtained magnetic nanoparticle product. The number of washing and separation cycles can be 1 to 5 times. The magnetic nanoparticles can be separated by magnetic separation or centrifugal separation.

[0042] A polymetallic borate nanoparticle or water-soluble polymetallic borate nanoparticle is prepared using the above-described method. The prepared polymetallic borate nanoparticle or water-soluble polymetallic borate nanoparticle possesses good magnetic targeting properties and biocompatibility, and can be used for tumor diagnosis and treatment.

[0043] Furthermore, the polymetallic borate nanoparticles or the water-soluble polymetallic borate nanoparticles have a size of 1 to 100 nanometers and are monodisperse.

[0044] The application of polyborate nanoparticles or water-soluble polyborate nanoparticles prepared by the above preparation method in the precise targeted therapy of tumors, especially in the combined therapy of magnetic resonance imaging (MRI), near-infrared 2D imaging, nuclear medicine imaging, magnetic particle imaging, magnetothermal therapy and boron neutron capture therapy, can significantly improve the diagnostic accuracy and therapeutic effect of tumors.

[0045] A polymetallic borate nanoparticle or water-soluble polymetallic borate nanoparticle prepared by the above preparation method can be used as a carrier for tumor-targeted delivery to achieve effective drug delivery. It can also be used as an synergist in magnetothermal therapy and has broad prospects for biomedical applications.

[0046] The beneficial effects of this invention are as follows:

[0047] This invention synthesizes polymetallic borate nanoparticles in a one-step thermal decomposition method. The materials used are organometallic compounds or metal salt precursors and organoboroester esters. The reaction conditions are mild, requiring no complex multi-step reaction process, making the operation simple and easily achievable for large-scale preparation with high yield. The prepared polymetallic borate nanoparticles exhibit good magnetic properties and biocompatibility. Guided by an external magnetic field, they can achieve efficient enrichment at tumor sites, thereby enhancing the efficacy of targeted therapy. The rare earth elements in the nanoparticles endow the material with near-infrared II (NIR-II) imaging capabilities. This imaging mode has greater tissue penetration depth and higher imaging resolution, which helps to achieve precise localization and real-time monitoring of deep tumors.

[0048] The polymetallic borate nanoparticles of this invention also contain borate ions, which can be used in boron neutron capture therapy (BNCT). By inducing a nuclear reaction after boron atoms capture neutrons, high-linear-energy alpha particles are released, selectively killing tumor cells with minimal damage to normal tissues, making them particularly suitable for treating certain refractory tumors. Furthermore, the nanoparticles of this invention can serve as drug carriers for targeted delivery in tumor therapy and as synergists in magnetocaloric therapy, significantly increasing drug concentration at the tumor site and reducing side effects on normal tissues. Overall, these nanoparticles have broad biomedical application prospects in the precise diagnosis and personalized treatment of tumors.

[0049] The above description is merely an overview of the technical solution of the present invention. In order to better understand the technical means of the invention and to implement it according to the contents of the specification, the preferred embodiments of the present invention are described in detail below with reference to the accompanying drawings. Specific embodiments of the present invention are given in detail below with reference to the accompanying drawings. Attached Figure Description

[0050] The accompanying drawings, which are included to provide a further understanding of the invention and form part of this application, illustrate exemplary embodiments of the invention and, together with their description, serve to explain the invention and do not constitute an undue limitation thereof. In the drawings:

[0051] Figure 1 The images shown are: transmission electron microscopy (a), high-resolution electron microscopy (b), particle size distribution (c), powder diffraction pattern (d), STEM-Mapping pattern (eh), and XPS pattern (il) of the neodymium iron borate nanoparticles prepared in Example 1 of this invention.

[0052] Figure 2 The images show the solution of neodymium iron borate nanoparticles prepared in Example 1 of this invention under a magnetic field: (a), saturation magnetization curve (b), low-field saturation magnetization curve (c), near-infrared II emission spectrum (d), ultraviolet absorption spectrum (e), and fluorescence spectrum (f).

[0053] Figure 3 The images shown are: transmission electron microscopy (TEM) image (a), hydrated particle size diagram (b), hydrated particle size variation diagram (c), photograph of the solution under a magnetic field (d), saturation magnetization curve (e), and low-field saturation magnetization curve (f) of the water-soluble neodymium iron borate nanoparticles prepared in Example 2 of this invention.

[0054] Figure 4 The images show the magnetic resonance imaging (a), relaxation rate (b), near-infrared II emission (c), ultraviolet absorption spectrum (d), and fluorescence spectrum (f) of the water-soluble neodymium iron borate nanoparticles prepared in Example 2 of this invention.

[0055] Figure 5 This is a SPECT scan image taken in Example 3 of the present invention, showing an N52 neodymium iron boron permanent magnet placed in a tumor on the right side of a mouse.

[0056] Figure 6 SPECT-CT images of mice with subcutaneous melanoma C57BL / 6 after injection of 99mTc-labeled water-soluble neodymium iron borate nanoparticles in Example 3 of this invention.

[0057] Figure 7 This is the time-dependent signal of 99mTc-labeled water-soluble neodymium iron borate nanoparticles in two mouse tumors in Example 3 of this invention. Detailed Implementation

[0058] The preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings to provide a clearer understanding of the invention's purpose, features, and advantages. It should be understood that the embodiments shown in the drawings are not intended to limit the scope of the invention, but are merely illustrative of the essential spirit of the invention's technical solution.

[0059] In the following description, certain specific details are set forth for the purpose of illustrating various disclosed embodiments in order to provide a thorough understanding of the various disclosed embodiments. However, those skilled in the art will recognize that embodiments may be practiced without one or more of these specific details. In other instances, well-known apparatuses, structures, and techniques associated with this application may not have been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments.

[0060] Unless the context requires otherwise, throughout the specification and claims, the word “comprising” and its variations, such as “including” and “having”, shall be understood to have an open, inclusive meaning, that is, to be interpreted as “including, but not limited to”.

[0061] Throughout this specification, references to "an embodiment" or "an embodiment" indicate that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Therefore, the appearance of "in an embodiment" or "an embodiment" in various places throughout the specification does not necessarily refer to the same embodiment. Furthermore, a particular feature, structure, or characteristic may be combined in any manner in one or more embodiments.

[0062] The singular forms “a” and “the” used in this specification and the appended claims include plural references unless otherwise expressly stated herein. It should be noted that the term “or” is generally used to mean “and / or” unless otherwise expressly stated herein.

[0063] Furthermore, the technical features involved in the different embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other. Unless otherwise specified, all reagents and materials used in the present invention are commercially available.

[0064] This invention develops a multi-metallic borate nanoparticle with excellent magnetic targeting properties and biocompatibility. The nanoparticle comprises borate nanoparticles containing one or more metal elements, namely iron, neodymium, manganese, copper, dysprosium, terbium, and other rare earth or transition metals or combinations thereof. Furthermore, the nanoparticle is prepared by high-temperature thermal decomposition of organometallic compounds or metal salt compounds with organoboronate esters in a solvent in the presence of small molecules with alkyl chains.

[0065] The specific method for preparing the polymetallic borate nanoparticles of this invention is as follows:

[0066] Step 1) Dissolve the organometallic compound or metal salt compound as a precursor, as well as small molecules with alkyl chains and organoboroesters in the first solvent to form a first mixed reaction solution.

[0067] The organometallic compound is an organic complex containing a transition metal or rare earth metal, such as an organometallic complex of iron, cobalt, nickel, manganese, neodymium, or other lanthanide or actinide rare earth metals, whose ligands include acetylacetone, carbonyl, phenylacetylacetone, and cyclopentadiene. Examples of the organometallic compound include, but are not limited to, iron triacetylacetone, iron diacetylacetone, iron pentacarbonyl, iron phenylacetylacetone, neodymium triacetylacetone, neodymium diacetylacetone, neodymium pentacarbonyl, neodymium phenylacetylacetone, manganese diacetylacetone, manganese phenylacetylacetone, nickel diacetylacetone, nickel tetracarbonyl, cobalt diacetylacetone, cobalt octacarbonyl, gadolinium triacetylacetone, gadolinium tricyclopentadiene, dysprosium triacetylacetone, holmium acetylacetone, and one or more mixtures thereof.

[0068] The metal salt compound is a salt or hydrate containing transition metals and rare earth metals, such as oleates, stearates, fatty acid salts, trifluoroacetates, gluconates, citrates, oxalates, chlorides, sulfates, nitrates, and hydrates of iron, cobalt, nickel, manganese, neodymium, or other lanthanide and actinide rare earth metals. Examples of the metal salt compound include, but are not limited to: ferric oleate, ferric stearate, ferric acetate, ferric citrate, ferric oxalate, ferric chloride, ferrous chloride, ferric chloride tetrahydrate, ferric chloride hexahydrate, ferric nitrate, ferric sulfate, neodymium oleate, neodymium stearate, neodymium acetate, neodymium citrate, neodymium oxalate, neodymium trichloride, hydrated neodymium trichloride, neodymium nitrate, neodymium sulfate, cobalt oleate, cobalt stearate, cobalt acetate, cobalt citrate, cobalt oxalate, cobalt decanoate, cobalt trichloride, manganese acetate, and oxalic acid. Manganese, manganese chloride, manganese nitrate, manganese sulfate, gadolinium oleate, gadolinium stearate, gadolinium acetate, gadolinium chloride, gadolinium chloride trihydrate, gadolinium chloride hexahydrate, gadolinium nitrate, dysprosium acetate, dysprosium chloride, dysprosium chloride trihydrate, dysprosium chloride hexahydrate, dysprosium nitrate, holmium acetate, holmium chloride, holmium chloride trihydrate, holmium chloride hexahydrate, holmium nitrate, erbium acetate, erbium chloride, erbium chloride trihydrate, erbium chloride hexahydrate, erbium nitrate, thulium acetate, thulium chloride, thulium chloride trihydrate, thulium chloride hexahydrate, thulium nitrate, etc.

[0069] The alkyl-chain-containing small molecule is one or more of the following: alkyl-chain-containing small molecule amine, alkyl-chain-containing small molecule carboxylic acid, or alkyl-chain-containing small molecule alcohol, and the number of CH2 units in its alkyl chain is 4 to 24; the alkyl-chain-containing small molecule may also be a derivative, analogue, or functionally equivalent compound of the alkyl-chain-containing small molecule listed above.

[0070] The organoboroester is one or more selected from trimethyl borate, triethyl borate, tripropyl borate, tributyl borate, tripentyl borate, trihexyl borate, triheptyl borate, trioctyl borate, trinonyl borate, and tridecyl borate, and the number of CH2 units in its alkyl chain is 1 to 24. The organoboroester may also be a derivative, analogue, or functionally equivalent compound of the organoboroesters listed above.

[0071] The first solvent is one or a mixture of several of the following: 1-hexadecene, 1-tetradecene, n-octadecane, n-hexadecane, paraffin oil, mineral oil, diphenyl ether, trioctylamine, dioctyl ether, oleylamine, 1-eicosene, and 1-tetradecane. The first solvent may also be a derivative, analogue, or functionally equivalent compound of the solvents listed above.

[0072] The concentration of organometallic compounds or inorganic metal salt compounds is 0.001–1 mol / L. The concentration of small molecule amines, small molecule carboxylic acids, or small molecule alcohols with alkyl chains is 0.001–1 mol / L. The concentration of organoboroesters is 0.001–1 mol / L. The molar ratio of organometallic compounds or metal salt compounds to organoboroesters is 1:(0.1–10).

[0073] Step 2) Dissolve the alcohol compound in the second solvent to form a second mixed reaction solution.

[0074] The alcohol compound is one or more selected from octanol, nonanol, decanol, undecylol, dodecanol, tridecanol, tetradecanol, or pentadecylol, and the number of CH2 units in its alkyl chain is 4 to 24. The alcohol compound may also be a derivative, analogue, or functionally equivalent compound of the alcohol compounds listed above.

[0075] The second solvent is one or a mixture of several of the following: 1-hexadecene, 1-tetradecene, n-octadecane, n-hexadecane, paraffin oil, mineral oil, diphenyl ether, trioctylamine, dioctyl ether, oleylamine, 1-eicosene, and 1-tetradecane. The second solvent may also be a derivative, analogue, or functionally equivalent compound of the solvents listed above.

[0076] Step 3) Under the protection of one or more inert gases selected from helium, neon, argon, xenon, krypton, and nitrogen, the first mixed reaction solution is heated to 50-150°C with a stirring speed of 100-1500 rpm and held for 5-60 minutes, and then the temperature is increased to 200-350°C.

[0077] Step 4) Under the protection of one or more inert gases selected from helium, neon, argon, xenon, krypton, and nitrogen, the second mixed reaction solution, preheated to 50-150°C, is injected into the first mixed reaction solution after being heated in step 3). After the temperature stabilizes at 200-350°C, the mixture is kept at a stirring speed of 100-1500 rpm for 1 minute to 36 hours to form the third mixed reaction solution.

[0078] Step 5) The third mixed reaction solution is naturally cooled to room temperature, and then centrifuged and purified to obtain polymetallic borate nanoparticles. The polymetallic borate nanoparticles have a size of 1 to 100 nanometers and are monodisperse.

[0079] The precipitant added to the third mixed reaction solution is one or a combination of ethanol, methanol, and acetone; and the volume of the precipitant is 2 to 50 times the volume of the third mixed reaction solution. The precipitate is separated using magnetic separation or centrifugal separation techniques.

[0080] The method for separating the precipitate is as follows: the precipitate is circulated and washed and separated once or multiple times using the precipitating agent. This can improve the purity of the obtained magnetic nanoparticle product. The number of washing and separation cycles can be 1 to 5 times. The magnetic nanoparticles can be separated by magnetic separation or centrifugal separation.

[0081] This invention can further prepare water-soluble polymetallic borate nanoparticles, including the following subsequent steps:

[0082] Step 6) Dissolve the polymetallic borate nanoparticles obtained in Step 5) in the third solvent, add biocompatible molecules, and then stir at 100-1500 rpm, heat at 40-100℃ or sonicate for 10 minutes to 48 hours to form the fourth mixed reaction solution.

[0083] The third solvent is one or a mixture of any two of the following: dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, ethylene glycol, dimethyl ether, dioxane, pyridine, dimethylformamide, and dimethyl sulfoxide.

[0084] The biocompatible molecule is one or more of bovine serum albumin, human serum albumin, dextran, polyethylene glycol, polyvinylpyrrolidone, polyethyleneimine, chitosan, or derivatives of the biocompatible molecules listed above.

[0085] Step 7) The fourth mixed solution is naturally cooled to room temperature, and then centrifuged and purified to obtain water-soluble polymetallic borate nanoparticles. The water-soluble polymetallic borate nanoparticles have a size of 1 to 100 nanometers and are monodisperse.

[0086] The precipitant added to the fourth mixed reaction solution is one or a combination of cyclohexane, n-hexane, benzene, and toluene; and the volume of the precipitant is 2 to 50 times the volume of the fourth mixed reaction solution. The precipitate is separated using magnetic separation or centrifugal separation techniques.

[0087] The method for separating the precipitate is as follows: the precipitate is circulated and washed and separated once or multiple times using the precipitating agent. This can improve the purity of the obtained magnetic nanoparticle product. The number of washing and separation cycles can be 1 to 5 times. The magnetic nanoparticles can be separated by magnetic separation or centrifugal separation.

[0088] The preparation method of the polymetallic borate nanoparticles of the present invention and the related test results will be described in detail below with specific embodiments.

[0089] Example 1: Preparation of neodymium iron borate nanoparticles:

[0090] The preparation method of neodymium iron borate nanoparticles is as follows:

[0091] Step 1) Dissolve 0.75 mmol neodymium acetylacetonate, 0.75 mmol iron acetylacetonate, and 0.75 mmol tributyl borate in 20 mL of 1-octadecene to form mixed reaction solution 1;

[0092] Step 2) Dissolve decanol in 7 mL of 1-octadecene to form mixed reaction solution 2;

[0093] Step 3) Under argon protection, heat solution 1 to 110°C with a stirring speed of 500 rpm and maintain for 30 minutes, then raise the temperature to 320°C;

[0094] Step 4) Under argon protection, inject solution 2, which has been preheated to 80°C, into solution 1. After the temperature stabilizes at 320°C, keep it warm for 1 hour with a stirring speed of 500 rpm.

[0095] Step 5) After naturally cooling to room temperature, add 2 times the volume of acetone and centrifuge the precipitate. Wash three times to obtain purified neodymium iron borate nanoparticles, dissolve in cyclohexane, and store at 4°C.

[0096] The prepared neodymium iron borate nanoparticles were subjected to the following tests, and the following results were obtained:

[0097] See Figure 1 As shown in a, Figure 1 a is a transmission electron microscope (TEM) image of the neodymium iron borate nanoparticles prepared in this embodiment. Figure 1 As can be seen from a, the neodymium iron borate nanoparticles prepared in this embodiment have a monodisperse size.

[0098] See Figure 1 As shown in b. Figure 1 b is a high-resolution electron microscope image of the neodymium iron borate nanoparticles prepared in this embodiment. Figure 1 As can be seen from b, the neodymium iron borate nanoparticles prepared in this embodiment have excellent crystallinity.

[0099] See Figure 1 As shown in c. Figure 1 c is a particle size distribution chart of the neodymium iron borate nanoparticles prepared in this embodiment. Figure 1 As can be seen from Figure c, the neodymium iron borate nanoparticles prepared in this embodiment have excellent monodispersity, with an average particle size of 7.7 nm and a size standard deviation of 10.4%.

[0100] See Figure 1 As shown in d, Figure 1 d is the powder diffraction pattern of the neodymium iron borate nanoparticles prepared in this embodiment. Figure 1 As can be seen from d, the neodymium iron borate nanoparticles prepared in this embodiment are not compatible with borate and neodymium borate.

[0101] See Figure 1 e- Figure 1 As shown in h, Figure 1 e- Figure 1 h is the STEM-Mapping image of the neodymium iron borate nanoparticles prepared in this embodiment. Figure 1 e- Figure 1 As can be seen from h, the neodymium iron borate nanoparticles prepared in this embodiment contain two metal elements, Fe and Nd.

[0102] See Figure 1 i- Figure 1 As shown in l, Figure 1 i- Figure 1 l is the XPS image of the neodymium iron borate nanoparticles prepared in this embodiment. Figure 1 i- Figure 1 As can be seen from the figure, the neodymium iron borate nanoparticles prepared in this embodiment contain four elements: Fe, Nd, B, and O.

[0103] See Figure 2 a- Figure 2 As shown in c. Figure 2 a- Figure 2 c represents a photograph, a saturation magnetization curve, and a low-field saturation magnetization curve of the neodymium iron borate nanoparticles prepared in this embodiment being attracted by a magnet, respectively. Figure 2 a- Figure 2 As can be seen from c, the neodymium iron borate nanoparticles prepared in this embodiment have excellent magnetic properties, with a saturation magnetization as high as 103.4 emu / g.

[0104] See Figure 2 d- Figure 2 As shown in f, Figure 2 d- Figure 2 f represents the near-infrared II emission spectrum, ultraviolet absorption spectrum, and fluorescence spectrum of the neodymium iron borate nanoparticle sample prepared in this embodiment, respectively. Figure 2 d- Figure 2 As can be seen from f, the neodymium iron borate nanoparticles prepared in this embodiment have excellent near-infrared II luminescence properties.

[0105] Example 2: Preparation of water-soluble neodymium iron borate nanoparticles:

[0106] Based on Example 1, the preparation method of water-soluble neodymium iron borate nanoparticles is as follows:

[0107] Step 6) Dissolve 10 mg of neodymium iron borate nanoparticles in 4 mL of tetrahydrofuran to form a solution, add 100 mg of bisphosphonic acid polyethylene glycol with a molecular weight of 2000, stir at 500 rpm and heat at 50°C for 24 hours.

[0108] Step 7) After naturally cooling to room temperature, add 2 times the volume of cyclohexane and centrifuge the precipitate. Wash three times to obtain purified water-soluble neodymium iron borate nanoparticles, dissolve in deionized water, and store at 4°C.

[0109] The prepared water-soluble neodymium iron borate nanoparticles were subjected to the following tests, and the following results were obtained:

[0110] See Figure 3 As shown in a, Figure 3 a is a transmission electron microscope (TEM) image of the water-soluble neodymium iron borate nanoparticles prepared in this embodiment. Figure 3 As can be seen from a, the water-soluble neodymium iron borate nanoparticles prepared in this embodiment have a monodisperse size.

[0111] See Figure 3 As shown in b. Figure 3 b is the hydration particle size diagram of the water-soluble neodymium iron borate nanoparticles prepared in this embodiment. Figure 3 As can be seen from b, the kinetic size of the water-soluble neodymium iron borate nanoparticles prepared in this embodiment is 27.6 nm.

[0112] See Figure 3 As shown in c. Figure 3 c is a graph showing the change in the hydrated particle size of the water-soluble neodymium iron borate nanoparticles prepared in this embodiment. Figure 3 As can be seen from Figure c, the water-soluble neodymium iron borate nanoparticles prepared in this embodiment showed no significant change in kinetic size within 30 days, demonstrating excellent colloidal stability.

[0113] See Figure 3 e- Figure 3 As shown in f, Figure 3 e- Figure 3 f is the saturation magnetization curve of the water-soluble neodymium iron borate nanoparticles prepared in this embodiment. Figure 3 e- Figure 3 As can be seen from f, the water-soluble neodymium iron borate nanoparticles prepared in this embodiment have excellent magnetic properties, with a saturation magnetization as high as 132.7 emu / g.

[0114] See Figure 4 a- Figure 4 As shown in b. Figure 4 a- Figure 4 b represents the magnetic resonance imaging and relaxation rate of the water-soluble neodymium iron borate nanoparticles prepared in this embodiment. Figure 4 a- Figure 4 As can be seen from b, the water-soluble neodymium iron borate nanoparticles prepared in this embodiment have excellent T2 imaging performance.

[0115] See Figure 4 d- Figure 4As shown in f, Figure 4 d- Figure 4 f represents the near-infrared II emission spectrum, ultraviolet absorption spectrum, and fluorescence spectrum of the water-soluble neodymium iron borate nanoparticles prepared in this embodiment, respectively. Figure 4 d- Figure 4 As can be seen from f, the water-soluble neodymium iron borate nanoparticles prepared in this embodiment have excellent near-infrared II luminescence properties.

[0116] Example 3: Detection of the magnetic targeting effect of water-soluble neodymium iron borate nanoparticles:

[0117] The magnetic targeting effect of the water-soluble neodymium iron borate nanoparticles prepared in Example 2 was tested, and the specific method is as follows:

[0118] Step 8) Dissolve 200 μg of water-soluble neodymium iron borate nanoparticles in 1 mL of water, add 1 mCi99mTc and 20 μg of stannous chloride, heat at 37 °C for 30 minutes, then use a 30 kDa membrane for ultrafiltration and concentrate to 200 μL to achieve 99mTc labeling of nanoparticles.

[0119] Step 9) The above drugs were injected via the tail vein into C57BL / 6 mice with subcutaneous melanoma in both legs, followed by single-photon emission computed tomography (SPECT-CT). See also Figure 5 As shown, an N52 neodymium iron boron permanent magnet was placed in the tumor on the right side of the mouse, and SPECT scans were performed at 0h, 1h, 2h, 4h, 6h and 8h.

[0120] See Figure 6 As shown, Figure 6 SPECT-CT images of C57BL / 6 mice with subcutaneous melanoma injected with 99mTc-labeled water-soluble neodymium iron borate nanoparticles. The results showed that the signal of the right-sided tumor gradually increased under magnetic targeting, reaching a peak at 8 hours. Therefore, water-soluble magnetic nanoparticles can achieve high tumor targeting and reduce drug distribution to non-target sites. This method provides strong data support for magnetic targeted therapy of tumors.

[0121] See Figure 7 As shown, Figure 7 The time-dependent signaling of 99mTc-labeled water-soluble neodymium iron borate nanoparticles in two mouse tumors was investigated. The results showed that magnetic targeting significantly enhanced drug accumulation at the target tumor site, with the maximum signal intensity occurring at 8 hours (8.4%). In contrast, drug accumulation in non-magnetically targeted tumors gradually decreased, reaching only 0.5% at 8 hours, demonstrating the effectiveness of magnetic targeting.

[0122] Example 4: Boron neutron capture therapy using water-soluble neodymium iron borate nanoparticles in melanoma mice:

[0123] Based on Example 3, water-soluble neodymium iron borate nanoparticles were used for boron neutron capture therapy in melanoma mice. The specific method is as follows:

[0124] Step 10) 200 μg of water-soluble neodymium iron borate nanoparticles were injected into C57BL / 6 mice with subcutaneous melanoma in the back of the neck via the tail vein, and N52 neodymium iron boron permanent magnets were placed at the tumor site for 2 hours.

[0125] Step 11) Apply neutron beam irradiation to tumor-bearing C57BL / 6 mice 2 hours after magnetic targeting.

[0126] Through magnetic targeting, neodymium iron borate nanoparticles were enriched in large quantities at the tumor site in mice. Combined with boron neutron capture therapy, this significantly reduced the growth rate of melanoma and prolonged the survival time of tumor-bearing mice.

[0127] The present invention also provides an application of polymetallic borate nanoparticles or water-soluble polymetallic borate nanoparticles prepared by the above preparation method in the precise targeted therapy of tumors, especially in the combined therapy of magnetic resonance imaging (MRI), near-infrared 2D imaging, nuclear medicine imaging, magnetic particle imaging, magnetothermal therapy and boron neutron capture therapy, which can significantly improve the diagnostic accuracy and therapeutic effect of tumors.

[0128] The present invention also provides a method for preparing polymetallic borate nanoparticles or water-soluble polymetallic borate nanoparticles using the above preparation method, which can be used as carriers for tumor-targeted delivery to achieve effective drug delivery, and can also be used as synergists in magnetothermal therapy, with broad prospects for biomedical applications.

[0129] This invention proposes a polymetallic borate nanoparticle that, due to its unique magnetism, multifunctionality, and good biocompatibility, holds promise as a next-generation probe platform for cancer diagnosis and treatment. Unlike traditional single-metal magnetic nanomaterials, polymetallic borate nanoparticles significantly enhance their magnetic properties by doping with rare earth or transition metal elements, such as neodymium, yttrium, or gadolinium. This doping strategy results in higher saturation magnetization and better magnetic targeting, enabling efficient tumor enrichment even at lower magnetic field strengths.

[0130] The introduction of rare earth elements enables this material to achieve near-infrared II imaging (NIR-II), an imaging mode with advantages such as large penetration depth and high resolution, which helps in the precise localization and diagnosis of deep tumors. Furthermore, this material also shows certain application value in magnetic resonance imaging (MRI) and magnetic particle imaging (MPI), and can be used to assist in the diagnosis and monitoring of tumors during treatment. Simultaneously, the borate ions in the material can be used for boron neutron capture therapy (BNCT). BNCT is a highly selective and low-toxicity tumor treatment method. By introducing boron-containing compounds into tumor cells and then irradiating them with a neutron beam, boron atoms are induced to capture neutrons and undergo nuclear reactions, releasing high-linear-energy alpha particles, thereby selectively killing tumor cells with minimal damage to normal tissues, making it particularly suitable for the treatment of certain refractory tumors.

[0131] The present invention discloses a method for preparing polymetallic borate nanoparticles. This method involves a thermal decomposition reaction at high temperature using organometallic compounds or metal salt compounds as precursors and organoboroate esters in the presence of small molecules with alkyl chains. This successfully produces polymetallic borate nanoparticles with high magnetic properties and good biocompatibility. The preparation method is simple and efficient, with easily controllable reaction conditions. The resulting nanoparticles exhibit monodisperse size and good morphological consistency, overcoming the problems of existing methods for synthesizing polymetallic magnetic nanoparticles, which are not only cumbersome and difficult to control under varying reaction conditions, but also struggle to maintain consistency in size and morphology.

[0132] The polymetallic borate nanoparticles of this invention not only possess multimodal imaging capabilities but can also be used for multimodal tumor therapy, particularly in fields such as magnetic resonance imaging, nuclear medicine imaging, magnetic particle imaging, magnetic targeted therapy, and boron neutron capture therapy, demonstrating significant application value. The broad application prospects of this material in precision tumor diagnosis and personalized treatment offer an innovative and practical solution to addressing many challenges faced by traditional magnetic nanomaterials in practical applications.

[0133] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing a polymetalloborate nanoparticle, characterized by, The method comprises the following steps: Step 1) dissolving an organic metal compound or a metal salt compound as a precursor, and a small molecule with an alkyl chain and an organic borate in a first solvent to form a first mixed reaction solution; The organic metal compound is an organic complex containing a transition metal or a rare earth metal; The metal salt compound is a salt or a hydrate thereof containing a transition metal and a rare earth metal; The transition metal and / or the rare earth metal contain one or more metal elements; The metal elements include but are not limited to iron, neodymium, manganese, copper, dysprosium, and cerium; The concentration of the organic metal compound or the metal salt compound is 0.001-1 mol / L; The small molecule with an alkyl chain is one or more of a small molecule amine, a small molecule carboxylic acid, or a small molecule alcohol with an alkyl chain, and the number of CH2 units in the alkyl chain is 4-24; The concentration of the small molecule amine, the small molecule carboxylic acid, or the small molecule alcohol with an alkyl chain is 0.001-1 mol / L; The organic borate is one or more of trimethyl borate, triethyl borate, tripropyl borate, tributyl borate, triamyl borate, trihexyl borate, triheptyl borate, trioctyl borate, trinonyl borate, and tridecyl borate, and the number of CH2 units in the alkyl chain is 1-24; The concentration of the organic borate is 0.001-1 mol / L; Step 2) dissolving an alcohol compound in a second solvent to form a second mixed reaction solution; The alcohol compound is one or more of octanol, nonanol, decanol, undecanol, dodecanol, tridecanol, tetradecanol, and pentadecanol, and the number of CH2 units in the alkyl chain is 4-24; Step 3) under the protection of an inert gas, the first mixed reaction solution is heated to 50-150°C at a stirring speed of 100-1500 rpm and kept for 5-60 minutes, and then heated to 200-350°C; Step 4) under the protection of an inert gas, the second mixed reaction solution preheated to 50-150°C is injected into the first mixed reaction solution heated in step 3), and after the temperature is stabilized to 200-350°C, the solution is kept for 1 minute to 36 hours at a stirring speed of 100-1500 rpm to form a third mixed reaction solution; Step 5) the third mixed reaction solution is naturally cooled to room temperature, and then centrifuged and purified to obtain polyborate nanoparticles, which have a size of 1-100 nanometers and are monodisperse.

2. The method for preparing a polymetalloborate nanoparticle according to claim 1, wherein The method further comprises the following steps: Step 6) dissolving the polyborate nanoparticles obtained in step 5) in a third solvent, adding a biocompatible molecule, and then stirring at a certain stirring speed, heating at 40-100°C, or ultrasonicating for a period of time to form a fourth mixed reaction solution; Step 7) the fourth mixed solution is naturally cooled to room temperature, and then centrifuged and purified to obtain water-soluble polyborate nanoparticles, which have a size of 1-100 nanometers and are monodisperse.

3. The method for preparing polymetallic borate nanoparticles according to claim 1, characterized in that, In step 1), The organic borate is a derivative, an analogue or a functionally equivalent compound of the above-mentioned listed organic borate; The first solvent is one or a mixture of several of 1-hexadecene, 1-tetradecene, n-octadecane, n-hexadecane, paraffin oil, mineral oil, diphenyl ether, trioctylamine, dioctyl ether, oleylamine, 1-eicosene, 1-tetradecane, or a derivative, an analogue or a functionally equivalent compound of the above-mentioned listed solvent.

4. The method for preparing polymetallic borate nanoparticles according to claim 1, characterized in that, In step 2), The second solvent is one or a mixture of several of 1-hexadecene, 1-tetradecene, n-octadecane, n-hexadecane, paraffin oil, mineral oil, diphenyl ether, trioctylamine, dioctyl ether, oleylamine, 1-eicosene, 1-tetradecane, or a derivative, an analogue or a functionally equivalent compound of the above-mentioned listed solvent.

5. The method for preparing polymetallic borate nanoparticles according to claim 1, characterized in that, In step 3) and step 4), The inert gas is one or several of helium, neon, argon, xenon, krypton, nitrogen.

6. The method for preparing polymetallic borate nanoparticles according to claim 1, characterized in that, In step 5), When centrifuging the third mixed reaction solution, the precipitant added into the third mixed reaction solution is one or a combination of several of ethanol, methanol, acetone; The volume of the precipitant is 2-50 times of the volume of the third mixed reaction solution; The method for separating the precipitate is that the precipitate is washed and separated one or more times by the precipitant.

7. The method for preparing polymetallic borate nanoparticles according to claim 2, characterized in that, In step 6), The third solvent is one or a mixture of two of dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, ethylene glycol, dimethyl ether, dioxane, pyridine, dimethylformamide, dimethyl sulfoxide; The biocompatible molecule is one or more of bovine serum albumin, human serum albumin, dextran, polyethylene glycol, polyvinylpyrrolidone, polyethyleneimine, chitosan, or a derivative of the above-mentioned listed biocompatible molecule; The stirring speed of the polyborate nanoparticles and the biocompatible molecule in the third solvent is 100-1500 rpm, and the heating or ultrasonic time is 10 minutes-48 hours at 40-100℃.

8. The method for preparing polymetallic borate nanoparticles according to claim 2, characterized in that, In step 7), When centrifuging the fourth mixed reaction solution, the precipitant added into the fourth mixed reaction solution is one or a combination of several of cyclohexane, n-hexane, benzene, toluene; The volume of the precipitant is 2-50 times of the volume of the fourth mixed reaction solution; The method for separating the precipitate is that the precipitate is washed and separated one or more times by the precipitant.

9. A polymetalloborate nanoparticle characterized by, The polyborate nanoparticles are prepared by the method of any one of claims 1-8.

10. Use of the polyborate nanoparticles prepared by the method of any one of claims 1-8 and / or the polyborate nanoparticles of claim 9 in magnetic resonance imaging, near-infrared two-zone imaging, nuclear medical imaging, magnetic particle imaging, magnetic hyperthermia therapy and boron neutron capture therapy.

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