WO2017157311A1 - 一种核壳型纳米发光材料及其制备方法 - Google Patents

一种核壳型纳米发光材料及其制备方法 Download PDF

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WO2017157311A1
WO2017157311A1 PCT/CN2017/076897 CN2017076897W WO2017157311A1 WO 2017157311 A1 WO2017157311 A1 WO 2017157311A1 CN 2017076897 W CN2017076897 W CN 2017076897W WO 2017157311 A1 WO2017157311 A1 WO 2017157311A1
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core
ucnps
luminescent material
type nano
shell type
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French (fr)
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杨海朋
陈雪妮
张凯
刘旭昇
戈早川
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深圳大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/08—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials
    • C09K11/77—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing rare earth metals
    • C09K11/7766—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing rare earth metals containing two or more rare earth metals
    • C09K11/7772—Halogenides
    • C09K11/7773—Halogenides with alkali or alkaline earth metal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0089—Particulate, powder, adsorbate, bead, sphere
    • A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
    • A61K49/0093—Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1878—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles the nanoparticle having a magnetically inert core and a (super)(para)magnetic coating
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/08—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials
    • C09K11/77—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing rare earth metals

Definitions

  • the invention relates to the field of medical marking and imaging, in particular to a core-shell type nano luminescent material and a preparation method thereof.
  • Rare earth upconverting nanomaterials are a class of nanomaterials that emit visible light under infrared excitation. This type of material has a wide range of applications, such as infrared detectors, biomolecular fluorescent markers, three-dimensional display, anti-counterfeiting and solar upconversion devices. Among them, in the field of medical labeling and imaging, rare earth upconversion nanomaterials can eliminate background interference from biological endogenous fluorescent substances, and have high sensitivity to the object to be imaged, which has attracted widespread attention.
  • Magnetic resonance imaging is a type of tomography that uses magnetic resonance to obtain electromagnetic signals from the human body and reconstruct human information. Magnetic resonance imaging can obtain tomographic images in any direction, three-dimensional body images. Further use of MRI contrast agent can significantly shorten the resonance time of the tissue under the action of external magnetic field, increase the difference of contrast signals, and improve imaging contrast and sharpness.
  • MRI contrast agents commonly used in clinical practice are small molecule ruthenium complex contrast agents.
  • UCNPs luminescent materials and MRI contrast agents in medical analysis/imaging
  • researchers have developed new materials with both up-conversion luminescence and MRI angiography.
  • doped NaGdF 4 nanomaterials have good fluorescence and paramagnetic properties.
  • they can also be used as contrast agents in magnetic resonance detection, which can enhance resolution and be suitable for biological applications.
  • the above nanomaterials are labeled and then enter specific tumor cells, and then imaged by a detection instrument.
  • the accuracy of imaging depends on the ability of nanomaterials to recognize tumors. Unsuccessful labeling or unsuccessful identification of nanoparticles can randomly enter normal cells, thereby identifying normal cells as tumor cells in subsequent imaging, causing interference in detection and treatment.
  • the object of the present invention is The invention provides a core-shell type nano luminescent material and a preparation method thereof, aiming at solving the problem that the existing nano material has low imaging recognition rate of tumor cells.
  • a core-shell type nano luminescent material wherein the core of the core-shell type nano luminescent material is UCNPs, and the outer shell is an alkaline manganese compound.
  • the core-shell type nano luminescent material wherein the UCNPs are one of a fluoride, an oxide, a sulfur-containing compound, a oxyfluoride, and a halide.
  • the core-shell type nano luminescent material wherein the UCNPs are granular or rod-shaped.
  • the core-shell type nano luminescent material wherein the basic manganese compound is MnO 2 , Mn(OH) 2 or MnCO 3 .
  • the core-shell type nano luminescent material wherein the surface of the basic manganese compound is labeled with one or more antibodies.
  • the surface of the inner core is covered with a layer of basic manganese compound, and the UCNPs with the basic manganese compound as the outer shell are obtained, that is, the core-shell type nano luminescent material is obtained.
  • the preparation method of the core-shell type nano luminescent material wherein 1-5 g of NaOH, 2-10 mL of distilled water, 2-15 mL of ethanol, 5-30 mL of oleic acid, 0.1-2.0 g of surfactant are mixed, and magnetic stirring is performed to form a transparent solution. Further, add 0.0775 g of YbCl 3 •6H 2 O, 0.2367 g of YCl 3 •6H 2 O and 0.00541 g of ErCl 3 in 2 mL of a rare earth mixed aqueous solution in a transparent solution, and stir uniformly; after stirring uniformly, 5 mL of 1 mol/L was added dropwise.
  • the NaF solution was stirred for 10 min, transferred to a 50 mL reaction vessel, reacted at 160-240 ° C for 2-24 h, and naturally cooled to room temperature in an oven; taken out, dissolved and collected with cyclohexane, and then ethanol was added to precipitate the sample.
  • the mixture was centrifuged at 8000 rpm/min for 10 min, and the resulting precipitate was washed 2-3 times with ethanol and distilled water, and finally dried at 90 ° C for 4 h in a vacuum oven to obtain UCNPs.
  • the method for preparing a core-shell type nano luminescent material characterized in that the surfactant comprises an ionic, nonionic, polar and non-polar surfactant.
  • the method for preparing a core-shell type nano luminescent material wherein, after obtaining the UCNP, the method further comprises: weighing the UCNPs mentioned above 50mg dissolved in 50mL of distilled water, formulated into a 1mg / mL solution, adding 0.1mol / L HCl, adjust the pH of the solution to 4.0, magnetic stirring for 2h, to obtain protonated oleic acid UCNPs, that is, water-soluble good water-soluble UCNPs .
  • the core-shell type nano luminescent material of the invention can realize fluorescent labeling/imaging function, and the basic manganese compound can realize MRI of tumor cells Imaging.
  • the core-shell type nano luminescent material of the invention can be used for high-sensitivity fluorescence detection and MRI imaging analysis of tumor cells and tumor tissues, and provides more accurate information for medical detection and treatment.
  • Example 1 is a topographical view of a large-shell core-shell type nano luminescent material obtained by SEM in Example 1 of the present invention.
  • Example 2 is a topographical view of a small-shell core-shell type nano luminescent material obtained by SEM in Example 1 of the present invention.
  • FIG. 3 is a topographical view of a rod-shaped core-shell type nano luminescent material obtained by SEM in Example 1 of the present invention.
  • the present invention provides a core-shell type nano luminescent material and a preparation method thereof.
  • the present invention will be further described in detail below. It is understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
  • the invention provides a core-shell type nano luminescent material, wherein the core of the core-shell type nano luminescent material is UCNPs, and the outer shell is an alkaline manganese compound.
  • the basic manganese compound is not dissolved, and thus the manganese ions cannot be released, and the core UCNPs cannot be released, so that they do not participate in magnetic resonance imaging and fluorescence imaging, and can greatly Improve the recognition rate of tumor cells.
  • the basic manganese compound is decomposed, and on the one hand, manganese ions are released as a nuclear magnetic imaging agent.
  • the luminescent core encapsulated by the decomposition of the manganese compound is exposed, and the upconversion can be realized. Fluorescence imaging / marking function. Therefore, UCNPs as the core can realize fluorescent labeling/imaging function, and the basic manganese compound as the outer shell can realize MRI imaging of tumor cells, thereby achieving dual-function imaging.
  • the core-shell type nano luminescent material of the invention can be used for high-sensitivity fluorescence detection and MRI imaging analysis of tumor cells and tumor tissues, and provides more accurate information for medical detection and treatment.
  • the UCNPs as the core material may be any compound containing a rare earth ion having an up-conversion luminescence function.
  • the UCNPs of the present invention may be, but not limited to, one of a fluoride, an oxide, a sulfur-containing compound, a oxyfluoride, a halide, and the like.
  • the above UCNPs can be used as the core material in the present invention.
  • NaYF 4 :Er, Yb ie, bismuth double doping material, Er as activator, Yb as sensitizer
  • the UCNPs of the present invention may be in the form of granules or rods.
  • the basic manganese compound as the outer shell material may be an alkaline manganese compound such as MnO 2 , Mn(OH) 2 or MnCO 3 .
  • the surface of the basic manganese compound of the present invention is labeled with one or more antibodies. That is, the surface of the basic manganese compound of the present invention may be labeled with an antibody capable of recognizing specific tumor cells to ensure that the core-shell type nano luminescent material can enter a specific tumor cell; the surface of the basic manganese compound may also be marked with A variety of antibodies that recognize specific tumor cells to ensure that core-shell nanoluminescent materials can enter a variety of tumor cells, enabling simultaneous detection of a variety of tumor cells.
  • the present invention further provides a method for preparing a core-shell type nano luminescent material according to any one of the above, comprising the steps of:
  • the surface of the inner core is covered with a layer of basic manganese compound, and the UCNPs with the basic manganese compound as the outer shell are obtained, that is, the core-shell type nano luminescent material is obtained.
  • the UCNPs are prepared in advance in the present invention, and then the surface of the obtained UCNPs is covered with a basic manganese compound to obtain UCNPs having a basic manganese compound as a shell, that is, the core-shell type nano luminescent material of the present invention.
  • the core-shell type nano luminescent material of the invention can simultaneously realize fluorescence detection and magnetic resonance imaging analysis functions.
  • the step A is: 1-5 g NaOH, 2-10 mL distilled water, 2-15 mL ethanol, 5-30 mL oleic acid, 0.1-2.0 g surfactant mixed, magnetically stirred to form a transparent solution, and then in a transparent solution.
  • the surfactants of the present invention include ionic, nonionic, polar and non-polar surfactants.
  • Surfactants have an effect on the morphology of the fluorescent upconverting luminescent particles.
  • the polar surfactant may be, but not limited to, polyvinylpyrrolidone;
  • the non-polar surfactant may be, but not limited to, carboxymethylcellulose;
  • the ionic surfactant may be, but not limited to, Triton;
  • the nonionic surfactant can be, but is not limited to, sodium 16-alkyl sulfonate.
  • the method further includes: weighing the UCNPs mentioned above 50mg dissolved in 50mL of distilled water, formulated into a 1mg / mL solution, adding 0.1mol / L HCl, adjust the pH of the solution to 4.0, magnetic stirring for 2h, to obtain protonated oleic acid UCNPs, that is, water-soluble good water-soluble UCNPs .
  • the buffer solution was mixed with 250 ⁇ L of 10 mmol/L KMnO 4 ; the solution became a brown colloid after 30 minutes, and was centrifuged, washed with deionized water, and the supernatant was removed to obtain UCNPs having MnO 2 as a shell.
  • the acid buffer solution was mixed by adding 250 ⁇ L of 10 mmol/L KMnO 4 . After 30 minutes, the solution became a brown colloid, which was separated by centrifugation, washed with deionized water, and the supernatant was removed to obtain UCNPs having MnO 2 as a shell.
  • the combined aqueous solution was added to 20 mL of ethylene glycol, stirred well, and solution B was obtained after 10 minutes.
  • Solution B was quickly poured into Solution A, and the mixed solution was rapidly stirred with a glass plate for about 10 minutes.
  • (4) After uniformly stirring, the prepared solution was transferred to a 100 mL reaction vessel, sealed, and placed in an oven at 200 ° C for 10 hours.
  • (5) Take out the sample, wash, separate, and dry. After the reaction was completed, after the sample was naturally cooled, the sample was transferred to a separation vessel, centrifuged at 8000 rpm/min for 10 min, repeated 3 times, and washed 4 times with ethanol to obtain a relatively pure sample. The sample was then transferred to a beaker, and the sample was placed in an oven and vacuum dried at 90 ° C for 5 h to obtain a solid powder sample, which gave UCNPs.
  • the antibody was labeled on the surface of Mn(OH) 2 .
  • the antibody was labeled on the surface of Mn(OH) 2 .
  • the heating device was removed and the solution was slowly cooled to room temperature with stirring.
  • the contents of the flask were transferred to a 15 mL centrifuge tube, the flask was rinsed with ethanol and the solution was transferred to a centrifuge tube, and centrifuged at 6000 rpm/min for 3 min at room temperature, and the supernatant was removed.
  • An additional 8 mL of ethanol was added to the centrifuge tube, and the mixed solution was centrifuged at 6000 rpm/min for 3 min at room temperature, and the supernatant was removed.
  • the above 8 mL of ethanol was added to the centrifuge tube by using a mixture of 4 mL of ethanol and 4 mL of methanol, and the procedure was repeated.
  • the NaGdF4:Yb/Tm nanomaterial was dispersed in 4 mL of cyclohexane in a centrifuge tube to obtain UCNPs.
  • Modification of MnCO 3 shell on UCNPs Transfer 1 mL (2 mg/mL) of the above UCNPs to a 5 mL centrifuge tube, add 500 ⁇ L of 0.1 mol/LMnCl 2 solution, and then add 1 mL of 0.1 mol/dropwise with stirring. L Na 2 CO 3 solution. After 30 min, it was separated by centrifugation, washed with deionized water, and the supernatant was removed to obtain UCNPs having MnCO 3 as a shell.
  • the antibody was labeled on the surface of MnCO 3 .
  • the present invention provides a core-shell type nano luminescent material and a preparation method thereof, wherein the core of the core-shell type nano luminescent material is UCNPs, and the outer shell is an alkaline manganese compound.
  • the UCNPs as the core can realize the fluorescent labeling/imaging function, and the basic manganese compound as the outer shell can realize MRI imaging of tumor cells.
  • the core-shell type nano luminescent material of the invention can be used for high-sensitivity fluorescence detection and MRI imaging analysis of tumor cells and tumor tissues, and provides more accurate information for medical detection and treatment.

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Abstract

一种核壳型纳米发光材料及其制备方法，其中，所述核壳型纳米发光材料的内核为UCNPs，外壳为碱性锰化合物。作为内核的UCNPs可实现荧光标记/成像功能，作为外壳的碱性锰化合物可实现肿瘤细胞的MRI成像。即便由于识别率未达到100％，有少量上述材料进入正常细胞，由于正常细胞内酸性比较低，碱性锰化合物不溶解，因而不能释放锰离子，内核UCNPs也不能被释放出来，因而不参与核磁共振成像和荧光成像，所以正常细胞不被检出，可以大大提高肿瘤细胞的识别率。上述核壳型纳米发光材料可用于肿瘤细胞和肿瘤组织的高灵敏度荧光检测和MRI成像分析，为医学检测和治疗提供更准确的信息。

Description

一种核壳型纳米发光材料及其制备方法 技术领域
本发明涉及医学标记和成像领域，尤其涉及一种核壳型纳米发光材料及其制备方法。
背景技术
稀土上转换纳米材料（UCNPs）是一类可以在红外光激发下发出可见光的纳米材料。该类材料具有广泛的应用空间，如红外探测器件、生物分子荧光标记、三维显示、防伪和太阳能上转换器件等。其中在医学标记和成像领域，稀土上转换纳米材料能够消除来自生物内源性荧光物质的背景干扰，对所要成像的对象具有很高灵敏度，引起了人们广泛的关注。
磁共振成像（MRI）是断层成像的一种，它利用磁共振现象从人体中获得电磁信号，并重建出人体信息。磁共振成像可以得到任何方向的断层图像，三维体图像。进一步采用MRI造影剂，可显著缩短组织在外磁场作用下的共振时间、增大对比信号的差异、提高成像对比度和清晰度。临床上常用的MRI造影剂是小分子的钆配合物造影剂。
鉴于UCNPs发光材料和MRI造影剂在医学分析/成像领域的广泛应用，研究人员已经开发出了具有上转换发光和MRI造影两种功能的新材料。如掺杂的NaGdF4纳米材料具有良好的荧光和顺磁特性能，除了荧光标记和成像功能，在磁共振检测当中也可以作为造影剂，能够增强分辨率，适合生物体的应用。
在具体使用中，上述纳米材料经标记后进入特定肿瘤细胞，进而经检测仪器成像。其成像精确程度依赖于纳米材料对肿瘤的识别能力，标记不成功或识别不成功的纳米颗粒可以随机进入正常细胞，从而在后续成像中把正常细胞识别为肿瘤细胞，对检测和治疗造成干扰。
因此，现有技术还有待于改进和发展。
 技术问题
鉴于上述现有技术的不足，本发明的目的 在 于提供一种核壳型纳米发光材料及其制备方法，旨在解决现有纳米材料对肿瘤细胞的成像识别率低问题。
技术解决方案
本发明的技术方案如下：
一种核壳型纳米发光材料，其中，所述核壳型纳米发光材料的内核为UCNPs，外壳为碱性锰化合物。
所述的核壳型纳米发光材料，其中，所述UCNPs为氟化物、氧化物、含硫化合物、氟氧化物、卤化物中的一种。
所述的核壳型纳米发光材料，其中，所述UCNPs为颗粒状或棒状。
所述的核壳型纳米发光材料，其中，所述碱性锰化合物为MnO2、Mn(OH)2或MnCO3。
所述的核壳型纳米发光材料，其中，所述碱性锰化合物的表面标记有一种或多种的抗体。
一种如上任一所述的核壳型纳米发光材料的制备方法，其中，包括步骤：
A、采用水热法制备UCNPs；
B、以UCNPs为内核，内核表面覆盖一层碱性锰化合物，得到碱性锰化合物为外壳的UCNPs，即制得核壳型纳米发光材料。
所述的核壳型纳米发光材料的制备方法，其中，1-5g NaOH，2-10mL蒸馏水，2-15mL乙醇，5-30mL油酸, 0.1-2.0g表面活性剂混合，磁力搅拌形成透明溶液，在透明溶液中再加入0.0775g YbCl3•6H2O、0.2367g YCl3•6H2O和0.00541g ErCl3的2mL稀土混合的水溶液，搅拌均匀；搅拌均匀后，逐滴加入5mL 1mol/L的NaF溶液，搅拌10min，转移至50mL的反应釜，在160-240℃反应2-24 h，在烘箱内自然冷却到室温；取出，用环己烷溶解和收集，再加入乙醇使样品析出，以8000rpm/min离心分离10min，得到的沉淀用乙醇和蒸馏水洗涤2-3次，最后以90℃在真空烘箱干燥4h，即得UCNPs。
所述的核壳型纳米发光材料的制备方法，其特征在于，所述表面活性剂包括离子型、非离子型、极性和非极性表面活性剂。
所述的核壳型纳米发光材料的制备方法，其中，得UCNP后，还包括：称取上述的UCNPs 50mg溶于50mL的蒸馏水，配成1mg/mL的溶液，加入0.1mol/L的HCl，调节溶液pH至4.0，磁力搅拌2h，得到质子化的油酸UCNPs，即得水溶性好的水溶性UCNPs。
所述的核壳型纳米发光材料的制备方法，其中，所述步骤B具体包括：将上述水溶性UCNPs移取250μL加到2mL的离心管中，再加入250μL 0.1mol/L pH=6的2-（N-吗啉代）乙磺酸缓冲溶液，加入250μL 10mmol/LKMnO4进行混合；溶液30min后变成布朗胶体，经过离心分离，用去离子水清洗，除去上清液，即得到MnO2为外壳的UCNPs。
 有益效果
本发明的 核壳型纳米发光材料 可实现荧光标记 / 成像功能，碱性锰化合物可实现肿瘤细胞的 MRI 成像。本发明 核壳型纳米发光材料可用于肿瘤细胞和肿瘤组织的高灵敏度荧光检测和 MRI 成像分析，为医药检测和治疗提供更准确的信息。
附图说明
图1为本发明实施例1中采用SEM得到的大颗粒的核壳型纳米发光材料形貌图。
图2为本发明实施例1中采用SEM得到的小颗粒的核壳型纳米发光材料形貌图。
图3为本发明实施例1中采用SEM得到的棒状的核壳型纳米发光材料形貌图。
 本发明的实施方式
本发明提供一种核壳型纳米发光材料及其制备方法，为使本发明的目的、技术方案及效果更加清楚、明确，以下对本发明进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
本发明提供一种核壳型纳米发光材料，其中，所述核壳型纳米发光材料的内核为UCNPs，外壳为碱性锰化合物。本发明上述材料进入正常细胞后，由于正常细胞内酸性比较低，碱性锰化合物不溶解，因而不能释放锰离子，内核UCNPs也不能被释放出来，因而不参与核磁共振成像和荧光成像，可以大大提高肿瘤细胞的识别率。而在肿瘤细胞内，由于酸性较高，碱性锰化合物被分解，一方面释放出锰离子，作为核磁成像剂，另一方面，锰化合物分解后被包裹的发光内核裸露出来，可实现上转换荧光成像/标记功能。因此，作为内核的UCNPs可实现荧光标记/成像功能，作为外壳的碱性锰化合物可实现肿瘤细胞的MRI成像，从而实现双功能成像。本发明的核壳型纳米发光材料可用于肿瘤细胞和肿瘤组织的高灵敏度荧光检测和MRI成像分析，为医学检测和治疗提供更准确的信息。
作为内核材料的UCNPs可以是任意具有上转换发光功能的含有稀土离子的化合物。例如，本发明所述UCNPs可以为但不限于氟化物、氧化物、含硫化合物、氟氧化物、卤化物等中的一种。上述UCNPs均可用作本发明中的内核材料。其中，NaYF4:Er，Yb（即镱铒双掺杂材料，Er作为激活剂，Yb作为敏化剂）是上转换发光效率极高的一种材料。优选地，本发明所述UCNPs可以为颗粒状或棒状。
作为外壳材料的碱性锰化合物可以为MnO2、Mn(OH)2或MnCO3等碱性锰化合物。本发明的核壳型纳米发光材料进入肿瘤细胞后，由于肿瘤细胞中的pH值偏酸性，碱性锰化合物分解释放出MRI造影剂Mn2+离子，从而实现对肿瘤细胞和肿瘤组织的MRI成像。如果核壳型纳米发光材料进入的是正常细胞，则由于正常细胞的pH值为中性，碱性锰化合物不分解，MRI仅有较弱的背景成像，从而实现对肿瘤细胞的准确检测。
进一步地，本发明所述碱性锰化合物的表面标记有一种或多种抗体。即本发明所述碱性锰化合物的表面可以标记有一种可识别特异肿瘤细胞的抗体，以保证核壳型纳米发光材料能够进入特定的肿瘤细胞；所述碱性锰化合物的表面还可以标记有多种可识别特异肿瘤细胞的抗体，以保证核壳型纳米发光材料能够进入多种肿瘤细胞，实现对多种肿瘤细胞的同时检测。
基于上述核壳型纳米发光材料，本发明还提供一种如上任一所述的核壳型纳米发光材料的制备方法，其中，包括步骤：
A、采用水热法制备UCNPs；
B、以UCNPs为内核，内核表面覆盖一层碱性锰化合物，得到碱性锰化合物为外壳的UCNPs，即制得核壳型纳米发光材料。
即本发明预先制备UCNPs，然后在制得的UCNPs表面覆盖一层碱性锰化合物，得到碱性锰化合物为外壳的UCNPs，即本发明的核壳型纳米发光材料。本发明的核壳型纳米发光材料可同时实现荧光检测和磁共振成像分析功能。
具体地，所述步骤A为，1-5g NaOH，2-10mL 蒸馏水，2-15mL乙醇，5- 30mL油酸，0.1-2.0g表面活性剂混合，磁力搅拌形成透明溶液，在透明溶液中再加入0.0775g YbCl3•6H2O、0.2367g YCl3•6H2O和0.00541g ErCl3的2mL稀土混合的水溶液，搅拌均匀；搅拌均匀后，逐滴加入5mL 1mol/L的NaF溶液，搅拌10min，转移至50mL的反应釜，在160-240℃反应2-24h，在烘箱内自然冷却到室温；取出，用环己烷溶解和收集，再加入乙醇使样品析出，以8000rpm/min离心分离10min，得到的沉淀用乙醇和蒸馏水洗涤2-3次，最后以90℃在真空烘箱干燥4h，即得UCNPs。
优选地，本发明所述表面活性剂包括离子型、非离子型、极性和非极性表面活性剂。表面活性剂对荧光上转换发光颗粒的形貌有影响。更优选的，极性表面活性剂可以为但不限于聚乙烯吡咯酮；非极性表面活性剂可以为但不限于羧甲基纤维素；离子型表面活性剂可以为但不限于曲拉通；非离子型表面活性剂可以为但不限于16-烷基磺酸钠。
具体地，得UCNP后，还包括：称取上述的UCNPs 50mg溶于50mL的蒸馏水，配成1mg/mL的溶液，加入0.1mol/L的HCl，调节溶液pH至4.0，磁力搅拌2h，得到质子化的油酸UCNPs，即得水溶性好的水溶性UCNPs。
具体地，所述步骤B具体包括：将将上述水溶性UCNPs移取250μL加到2mL的离心管中，再加入250μL 0.1mol/L pH=6的2-（N-吗啉代）乙磺酸缓冲溶液，加入250μL 10mmol/LKMnO4进行混合；溶液30min后变成布朗胶体，经过离心分离，用去离子水清洗，除去上清液，即得到MnO2为外壳的UCNPs。
下面通过具体实施例对本发明制备方法进行详细说明。
实施例1
2g NaOH，7mL蒸馏水，12mL乙醇，20mL油酸混合，1.0g聚乙烯吡咯酮混合，磁力搅拌形成透明溶液，在透明溶液中再加入0.0775g YbCl3•6H2O、0.2367g YCl3•6H2O和0.00541g ErCl3的2mL稀土混合的水溶液(摩尔分数：78%Y，20%Yb，2%Er），搅拌均匀。搅拌均匀后，逐滴加入5mL 1mol/L的NaF溶液，搅拌10min，转移至50mL的反应釜，在180℃反应8h，在烘箱内自然冷却到室温。取出，用环己烷溶解和收集，再加入乙醇使样品析出，以8000rpm/min离心分离10min，得到的沉淀用乙醇和蒸馏水洗涤3次，最后以90℃在真空烘箱干燥4h，即得UCNPs。采用SEM得到的大颗粒核壳型纳米发光材料、小颗粒核壳型纳米发光材料和棒状核壳型纳米发光材料形貌图分别如图1、图2、图3所示。
水溶性UCNPs的合成：称取上述的UCNPs 50mg溶于50mL的蒸馏水，配成1mg/mL的溶液，加入0.1mol/L的HCl，调节溶液pH至4.0，磁力搅拌2h，得到质子化的油酸UCNPs，即得水溶性好的水溶性UCNPs。
在UCNPs修饰MnO2外壳：将上述水溶性UCNPs移取250μL（1mg/mL）加到2mL的离心管中，再加入250μL 0.1mol/L pH=6的2-（N-吗啉代）乙磺酸缓冲溶液，加入250μL 10mmol/LKMnO4进行混合。溶液30min后变成布朗胶体，经过离心分离，用去离子水清洗，除去上清液，即得到MnO2为外壳的UCNPs。
在二氧化锰表面标记抗体。
实施例2
稀土氯化物水溶液的配制。将2mL稀土氯化物(0.5mol/L LnCl3，Ln为78%Y+20%Yb+2%Er (摩尔分数))水溶液加入到20mL乙二醇中，搅拌均匀，10分钟后得到溶液A。具体称量数据如下：0.0775g YbCl3•6H2O、0.2367g YCl3•6H2O和0.00541g ErCl3(2)NaF溶液的配置：称量0.18900g NaF，加入4.5mL水，配置为1.0 mol/L的水溶液。将配合的水溶液加入到20mL乙二醇中，搅拌均匀，10分钟后得到溶液B。(3)将A与B溶液混合。将溶液B快速倒入溶液A中，用玻璃板快速搅拌混合溶液约10min。(4)均匀搅拌后，将配好的溶液转移到100mL反应釜中，封好并放到200℃的烤箱当中反应10h。(5) 取出样品，洗涤，分离，烘干。反应结束后，待样品自然冷却后，把样品转移到分离容器中，用8000rpm/min离心分离10min，重复3次，并且用乙醇洗涤4次，即可得到较纯的样品。然后把样品转移到烧杯中，把样品放到烤箱中，用90℃真空干燥5h，得到固体粉末样品，即得UCNPs。
在UCNPs上修饰 Mn(OH)2外壳：将上述UCNPs移取250μL（1mg/mL）加到2mL的离心管中，再加入250μL 0.1mol/L pH=8.0的磷酸盐缓冲溶液，加入250μL 10mmol/LKMnO4进行混合。30min后经过离心分离，用去离子水清洗，除去上清液，即得到Mn(OH)2为外壳的UCNPs。
在Mn(OH)2表面标记抗体。
实施例3
NaOH 1.2g，9mL H2O，10mL乙醇，20mL油酸，2.0g羧甲基纤维素形成混合物；0.6mmol (1.2mL、0.5M)稀土混合物在磁力搅拌下加入。1M 4mL的NaF 逐滴加入溶液，混合10min，转移到50mL反应釜160℃下8h，自然冷却到室温，样品在底部。环己烷收集。乙醇沉淀。经离心得到，再用乙醇清洗油酸和油酸钠。干燥，即得UCNPs。
水溶性UCNPs：0.1gUCNPs加入100mL环己烷、7mL叔丁醇、10mL去离子水、5wt%碳酸钾，室温搅拌20min，逐滴加入20mL（0.01801g KMnO4+0.4492gNaIO4）在40℃下搅拌超过48h，得到样品通过离心分离并用丙酮、乙醇、去离子水清洗。样品在pH=4-5的盐酸中搅拌30min，离心分离用去离子水清洗，干燥。
在UCNPs上修饰Mn(OH)2外壳：将上述UCNPs移取250μL（1mg/mL）加到2mL的离心管中，再加入250μL 0.1mol/L pH=8.0 的磷酸盐缓冲溶液，加入250μL 10mmol/LKMnO4进行混合。30min后经过离心分离，用去离子水清洗，除去上清液，即得到Mn(OH)2为外壳的UCNPs。
在Mn(OH)2表面标记抗体。
实施例4
在室温下，加1mL 0.2mol/L Gd(CH3CO2)3，0.98mL 0.2mol/L Yb(CH3CO2)3 ，0.02mL 0.2mol/LTm(CH3CO2)3 ，4mL油酸和6mL1-十八稀到50mL三口烧瓶，用热电偶温度传感器加热搅拌溶液到150℃，保持该温度40min。而后，关上加热装置，搅拌溶液自然冷却到室温。在室温下，移取1mL1mol/LNaOH-甲醇溶液和3.3mL 0.4mol/L NH4F-甲醇溶液到15mL的离心管，密封，通过涡流10s混合溶液。然后快速加入到三口烧瓶，加热溶液到50℃，并保持30min进行反应，再加热溶液温度到100℃。连接真空装置，抽真空10min，再充入氩气，以10℃/min进行升温到280℃，溶液温度在280℃保持1.5h。移除加热装置，搅拌缓慢冷却溶液至室温。把烧瓶的物质转移到15mL的离心管中，用乙醇冲洗烧瓶并转移溶液到离心管中，在室温下以6000rpm/min离心3min，移除上清液。加4mL环己烷到离心管，搅拌混合再分散产品。再加8mL乙醇到离心管，混合溶液在室温下以6000rpm/min离心3min，再移除上清液。用4mL乙醇和4mL甲醇混合液代替上述8mL乙醇加到离心管，重复一遍。在离心管中在4mL的环己烷进行分散NaGdF4:Yb/Tm纳米材料，即得UCNPs。
在UCNPs上修饰 MnCO3外壳：将上述UCNPs移取1mL（2mg/mL）加到5 mL的离心管中，再加入500μL 0.1mol/LMnCl2溶液，然后在搅拌条件下逐滴加入1mL 0.1mol/L Na2CO3溶液。30min后经过离心分离，用去离子水清洗，除去上清液，即得到MnCO3为外壳的UCNPs。
在MnCO3表面标记抗体。
综上所述，本发明提供的一种核壳型纳米发光材料及其制备方法，其中，所述核壳型纳米发光材料的内核为UCNPs，外壳为碱性锰化合物。作为内核的UCNPs可实现荧光标记/成像功能，作为外壳的碱性锰化合物可实现肿瘤细胞的MRI成像。本发明的核壳型纳米发光材料可用于肿瘤细胞和肿瘤组织的高灵敏度荧光检测和MRI成像分析，为医药检测和治疗提供更准确的信息。
应当理解的是，本发明的应用不限于上述的举例，对本领域普通技术人员来说，可以根据上述说明加以改进或变换，所有这些改进和变换都应属于本发明所附权利要求的保护范围。

Claims (10)

  1. 一种核壳型纳米发光材料，其特征在于，所述核壳型纳米发光材料的内核为UCNPs，外壳为碱性锰化合物。
  2. 根据权利要求1所述的核壳型纳米发光材料，其特征在于，所述UCNPs为氟化物、氧化物、含硫化合物、氟氧化物、卤化物中的一种。
  3. 根据权利要求1所述的核壳型纳米发光材料，其特征在于，所述UCNPs为颗粒状或棒状。
  4. 根据权利要求1所述的核壳型纳米发光材料，其特征在于，所述碱性锰化合物为MnO2、Mn(OH)2或MnCO3。
  5. 根据权利要求1所述的核壳型纳米发光材料，其特征在于，所述碱性锰化合物的表面标记有一种或多种的抗体。
  6. 一种如权利要求1~5任一所述的核壳型纳米发光材料的制备方法，其特征在于，包括步骤：
    A、采用水热法制备UCNPs；
    B、以UCNPs为内核，内核表面覆盖一层碱性锰化合物，得到碱性锰化合物为外壳的UCNPs，即制得核壳型纳米发光材料。
  7. 根据权利要求6所述的核壳型纳米发光材料的制备方法，其特征在于，1-5g NaOH，2-10mL蒸馏水，2-15mL乙醇，5-30mL油酸, 0.1-2.0g表面活性剂混合，磁力搅拌形成透明溶液，在透明溶液中再加入0.0775g YbCl3•6H2O、0.2367g YCl3•6H2O和0.00541g ErCl3的2mL稀土混合的水溶液，搅拌均匀；搅拌均匀后，逐滴加入5mL 1mol/L的NaF溶液，搅拌10min，转移至50mL的反应釜，在160-240℃反应2-24 h，在烘箱内自然冷却到室温；取出，用环己烷溶解和收集，再加入乙醇使样品析出，以8000rpm/min离心分离10min，得到的沉淀用乙醇和蒸馏水洗涤2-3次，最后以90℃在真空烘箱干燥4h，即得UCNPs。
  8. 根据权利要求7所述的核壳型纳米发光材料的制备方法，其特征在于，所述表面活性剂包括离子型、非离子型、极性和非极性表面活性剂。
  9. 根据权利要求7所述的核壳型纳米发光材料的制备方法，其特征在于，得UCNP后，还包括：称取上述的UCNPs 50mg溶于50mL的蒸馏水，配成1mg/mL的溶液，加入0.1mol/L的HCl，调节溶液pH至4.0，磁力搅拌2h，得到质子化的油酸UCNPs，即得水溶性好的水溶性UCNPs。
  10. 根据权利要求9所述的核壳型纳米发光材料的制备方法，其特征在于，所述步骤B具体包括：将上述水溶性UCNPs移取250μL加到2mL的离心管中，再加入250μL 0.1mol/L pH=6的2-（N-吗啉代）乙磺酸缓冲溶液，加入250μL 10mmol/LKMnO4进行混合；溶液30min后变成布朗胶体，经过离心分离，用去离子水清洗，除去上清液，即得到MnO2为外壳的UCNPs。
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