CN110358530A - 一种稀土核壳纳米颗粒及其制备和应用 - Google Patents
一种稀土核壳纳米颗粒及其制备和应用 Download PDFInfo
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- CN110358530A CN110358530A CN201910735220.1A CN201910735220A CN110358530A CN 110358530 A CN110358530 A CN 110358530A CN 201910735220 A CN201910735220 A CN 201910735220A CN 110358530 A CN110358530 A CN 110358530A
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Classifications
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- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
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- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
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- 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
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- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
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- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/02—Use of particular materials as binders, particle coatings or suspension media therefor
- C09K11/025—Use of particular materials as binders, particle coatings or suspension media therefor non-luminescent particle coatings or suspension media
-
- 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
- C09K11/7756—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing rare earth metals containing neodynium
- C09K11/7757—Halogenides
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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Abstract
本发明涉及一种稀土核壳纳米颗粒及其制备方法和应用。该制备方法以超小纳米晶体为反应原料,在高沸点溶剂十八烯和油酸体系中,通过调控加入超小纳米晶体的种类和浓度来控制最终纳米晶体的组分、壳层厚度、光学和磁学性质。该制备方法所得纳米晶体尺寸均一,结晶度高,光学和磁学性质可调,本发明还公开了稀土核壳纳米颗粒在制备近红外二区光学造影剂和/或磁共振造影剂中的应用。
Description
技术领域
本发明涉及生物医学领域,尤其涉及一种具有近红外二区光学血管造影和磁共振血管造影功能的稀土核壳纳米颗粒及其制备和应用。
背景技术
作为一种临床影像诊断工具,磁共振成像不仅能不受组织穿透深度限制、无创检测病变软组织,而且能通过对比剂增强造影实现微小病灶部位的高分辨检测,如可以通过血管造影来评估血管病变。目前临床所采用的磁共振纵向弛豫增强对比剂(如各类钆螯合剂)的血液半衰期较短,其较快的肾脏清除率导致难以获得清晰的血管造影图像。近年来发展的具有长循环时间、高纵向弛豫率的纳米颗粒,诸如超小四氧化三铁纳米颗粒、空心多孔的氧化铁纳米盒、氧化钆-氧化铁复合纳米片以及超小NaGdF4纳米点,作为磁共振造影剂能获得分辨率更高的血管造影图像。尽管基于这一影像技术能够无创地观察内脏血管系统(腹主动脉、下腔静脉等),但受限于时空分辨率难以获得实时动态的高灵敏诊断图像。
相比而言,作为一种快速发展的成像模式,光学成像能够快速且高灵敏地进行活体生物过程的观察。相比于可见光(500~700nm)和近红外一区(NIRI,700~900nm)窗口,近红外二区窗口(NIRII,1000~1700nm)的生物成像具有更深的组织穿透深度、较低的自荧光和光子散射。已经报道的一系列具有NIRII光学性质的探针,例如单层碳纳米管、有机小分子染料、量子点、AIE探针以及稀土掺杂纳米颗粒,不仅能够实现全身、脑部以及肿瘤的血管造影,相比于近红外一区以及可见光窗口的光学成像,在相同的深度具有更高的空间分辨率。因此,设计同时具有近红外二区光学血管造影和磁共振血管造影功能的纳米颗粒能够有效的弥补单一成像模式的不足,能够更灵敏有效精准的诊断血管病变灶点。
为构建具有这类性质的纳米颗粒,申请号为201710046027.8的专利公开了利用醇-水-油三相体系一锅法制备实心或空心含锰氟化物纳米晶体,其具有荧光成像和核磁共振成像特性。CN104987866A公开了一种NaREF4@Fe2O3核壳纳米颗粒及其制备方法,所制备的油溶性稀土纳米颗粒转入水相后,利用外延生长的方法首先在其表面形成非晶的Fe(OH)3,再经过晶化处理后形成NaREF4@Fe2O3核壳纳米颗粒。CN103450875A公开了一种800nm连续激光激发的稀土上转换纳米颗粒及其制备方法和用途,该方法在进行每一壳层包覆时都需要纯化核或是核壳颗粒,而且所得纳米颗粒的发射波长小于1000nm。
发明内容
为解决上述技术问题,本发明的目的是提供一种具有近红外二区光学血管造影和磁共振血管造影功能的稀土核壳纳米颗粒及其制备和应用,该稀土核壳纳米颗粒制备方法简单,利用室温成核、高温生长的方法可通过控制壳层厚度及组分调控纳米颗粒的光学和磁学性质。
本发明的第一个目的是提供一种稀土核壳纳米颗粒,包括核层纳米颗粒、至少一层包覆于所述核层纳米颗粒外部的壳层以及包覆于所述壳层外部的两亲性聚合物,所述核层纳米颗粒和壳层分别独立地选自AREF4,其中,A为Na或K,RE为Nd、Gd、Eu、Tb、Ho、Er或Dy。
优选地,A为Na。优选地,核层纳米颗粒和壳层中的RE元素不同。优选地,核层纳米颗粒为ANdF4或AErF4,A为Na或K。
进一步地,核层纳米颗粒的粒径为4-20nm,所述稀土核壳纳米颗粒的粒径为6-30nm,所述核层纳米颗粒的粒径和壳层的厚度之比为1-10。
进一步地,两亲性聚合物为磷脂聚乙二醇(DSPE-mPEG)、聚己内酯-聚乙二醇(PEG-PCL)和聚乙二醇-聚乳酸(PEG-PLA)中的一种或几种。
进一步地,稀土核壳纳米颗粒具有近红外二区(1000-1700nm)光学造影和磁共振造影功能。
本发明的第二个目的是提供一种上述稀土核壳纳米颗粒的制备方法,包括以下步骤:
(1)将第一稀土纳米晶体前驱物溶液加入油酸和十八烯的混合溶液中,在惰性气氛中加热至50-100℃,以去除低沸点溶剂,然后再升温至200-300℃,保温5min-2h,降温至70℃,得到所述核层纳米颗粒;
(2)以下步骤至少进行一次,得到至少包覆一层壳层的纳米颗粒:向步骤(2)的产物中加入第二稀土纳米晶体前驱物溶液,在惰性气氛中加热至50-100℃,以去除低沸点溶剂,然后再升温至200-300℃,保温5min-2h,降温至70℃;
所述第一稀土纳米晶体前驱物和第二稀土纳米晶体前驱物独立地选自AREF4稀土纳米晶体前驱物溶液,其中,A为Na或K,RE为Nd、Gd、Eu、Tb、Ho、Er或Dy;所述NaREF4稀土纳米晶体前驱物溶液的制备方法包括以下步骤:
将含稀土离子的水溶液、碱金属氟化物水溶液、碱性水溶液、醇和油酸混匀,并在10-40℃下反应,反应完全后纯化出NaREF4稀土纳米晶种,所述纳米晶种的粒径为1-10nm;然后将所述NaREF4纳米晶种分散于有机溶剂中,得到所述NaREF4稀土纳米晶体前驱物溶液;稀土离子为Nd、Gd、Eu、Tb、Ho、Er或Dy;所述碱金属氟化物水溶液为NaF、NH4F、KF的水溶液;含稀土离子的水溶液中的稀土离子和碱金属氟化物的摩尔比为1:4。
优选地,NaREF4稀土纳米晶体前驱物溶液中所用有机溶剂为环己烷。
(3)将步骤(2)得到的至少包覆一层壳层的纳米颗粒与两亲性聚合物在有机溶剂中混匀,静置至有机溶剂挥发,然后加水分散,离心分离出所述稀土核壳纳米颗粒。
进一步地,在步骤(2)中,所述含稀土离子的水溶液为稀土金属盐酸盐、稀土离子硝酸盐或稀土金属氧化物的水溶液,所述含稀土离子的水溶液的浓度为0.1-5mol/L。
进一步地,稀土金属盐酸盐为NdCl3·6H2O,GdCl3·6H2O,DyCl3·6H2O,EuCl3·6H2O,HoCl3·6H2O,ErCl3·6H2O或TbCl3·6H2O;稀土离子硝酸盐为Nd(NO3)3·5H2O,Gd(NO3)3·5H2O,Dy(NO3)3·6H2O,Eu(NO3)3·5H2O,Ho(NO3)3·6H2O,Er(NO3)3·5H2O或Tb(NO3)3·6H2O;稀土金属氧化物为Nd2O3,Gd2O3,Dy2O3,Eu2O3,Ho2O3,Er2O3或Tb2O3。
进一步地,在步骤(2)中,制备NaREF4所述碱性水溶液为氢氧化钠水溶液,制备KREF4所述碱性水溶液为氢氧化钾水溶液。
进一步地,在步骤(1)中,所述第一稀土纳米晶体前驱物溶液、油酸和十八烯的体积比为0.17-1:1:1-5;所述第一稀土纳米晶体前驱物溶液的浓度为0.08-1mol/L。
进一步地,在步骤(2)中,所述第二稀土纳米晶体前驱物溶液的浓度为0.02-1mol/L;所述第二稀土纳米晶体前驱物溶液与步骤(1)中的第一稀土纳米晶体前驱物溶液种的稀土离子的摩尔比为1:4-4:1。
进一步地,惰性气氛为氮气、氩气。
进一步地,在步骤(1)中,升温速率为5℃/min-20℃/min。
进一步地,在步骤(3)中,有机溶剂为氯仿、环己烷、正己烷、四氢呋喃。
进一步地,在步骤(3)中,离心分离转速为3000~26000rpm,离心时间为5~20min。
进一步地,在步骤(3)中,所述至少包覆一层壳层的纳米颗粒与两亲性聚合物的摩尔比为4-20:1。
本发明基于醇-水-油三相体系在低温下制备的不同稀土纳米晶体,以此为原料制备核壳结构的稀土纳米晶体,核的大小可以通过反应温度和时间调控,壳层的厚度和成分可以通过纳米晶体原料的浓度和种类调控,而且还可以“一锅法”实现不同种类和厚度壳层包覆的核壳纳米颗粒的构建。所得纳米颗粒具有较强的近红外二区发光(1000-1700nm)和弛豫率,可用于近红外二区荧光成像和核磁共振成像。
本发明的第三个目的是要求保护本发明的上述稀土核壳纳米颗粒在制备近红外二区光学造影剂和/或磁共振造影剂中的应用。
进一步地,近红外二区光学造影剂和/或磁共振造影剂应用于血管显像中。
进一步地,当作为近红外二区光学造影剂时,其发射波长为1000-1700nm,激发波长为700-1100nm,激发功率密度为45~200mW/cm2。
进一步地,当作为磁共振造影剂时,磁场强度为0.5-4.7T。
借由上述方案,本发明至少具有以下优点:
本发明提供的是一种能够实现近红外二区光学血管造影和磁共振血管造影功能的稀土核壳纳米颗粒及其制备方法,在室温下合成超小纳米颗粒,以此为反应原料在高温溶剂中制备具有近红外二区光学以及磁学性质的纳米颗粒,通过调控壳层成分以及厚度来优化两种性质,同时选择合适的表面配体使其具有优异的生物相容性,进而使其具有近红外二区光学造影和磁共振造影性,所制备的纳米颗粒粒径均一、结晶度高且具有较优异的光学和磁学性质。
上述说明仅是本发明技术方案的概述,为了能够更清楚了解本发明的技术手段,并可依照说明书的内容予以实施,以下以本发明的较佳实施例并配合附图详细说明如后。
附图说明
图1是本发明实施例1所得室温NaNdF4纳米晶体前驱物的透射电镜照片。
图2是本发明实施例1所得室温制备的NaNdF4和NaGdF4纳米晶体前驱物的粉末X射线衍射图谱。
图3是本发明实例2所得KNdF4纳米颗粒的透射电镜照片。
图4是本发明实例2所得KNdF4纳米颗粒的下转换荧光光谱。
图5是本发明实施例3所得NaNdF4@NaREF4(RE=Gd、Eu、Tb、Ho、Dy)稀土核壳纳米颗粒的下转换荧光光谱。
图6是本发明实施例4所得不同壳层厚度的NaNdF4@NaGdF4稀土核壳纳米颗粒的透射电镜照片。
图7是本发明实施例4所得不同壳层厚度的NaNdF4@NaGdF4稀土核壳纳米颗粒的粉末X射线衍射图谱。
图8是本发明实施例4所得不同壳层厚度的NaNdF4@NaGdF4稀土核壳纳米颗粒的下转换荧光光谱。
图9是本发明实施例5所得磷脂聚乙二醇修饰的NaNdF4@NaGdF4(Nd:Gd=1:2)稀土核壳纳米颗粒的透射电镜照片。
图10是本发明实施例6所得磷脂聚乙二醇修饰的不同壳层厚度的NaNdF4@NaGdF4稀土核壳纳米颗粒的体外纵向质子弛豫图像。
图11是本发明实施例6所得磷脂聚乙二醇修饰的不同壳层厚度的NaNdF4@NaGdF4稀土核壳纳米颗粒的体外纵向质子弛豫率图。
图12是本发明实施例7所得稀土核壳纳米颗粒用于小鼠近红外二区血管显影图。
图13是本发明实施例8所得小鼠的磁共振血管显影图。
具体实施方式
下面结合附图和实施例,对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明,但不用来限制本发明的范围。
实施例1:室温制备AREF4(RE=Nd、Gd、Eu、Tb、Ho、Er或Dy)稀土纳米晶体前驱物
将1.2g氢氧化钠(或1.68g氢氧化钾)完全溶于4mL水中,加入8mL无水乙醇和20mL油酸,搅拌约10分钟。然后逐滴加入1mL的稀土离子水溶液(0.5M),其中,稀土离子水溶液中的稀土离子为Nd3+、Gd3+、Eu3+、Tb3+、Ho3+、Er3+或Dy3+。待稀土离子水溶液滴加完毕后,再向其中滴加4mL氟化钠(或氟化钾)水溶液(0.5M),滴加完毕后室温搅拌1h,反应结束后用35mL无水乙醇沉淀,以10000rpm离心2min得到产物,之后用环己烷和无水乙醇以1:5比例洗涤两次。当上述步骤中选用氢氧化钠和氟化钠时,所制备的为NaREF4稀土纳米晶体前驱物。当上述步骤中选用氢氧化钾和氟化钾时,所制备的为KREF4稀土纳米晶体前驱物。附图1为室温下所制备的NaNdF4纳米晶体前驱物的透射电镜照片,附图2为室温制备的NaNdF4和NaGdF4纳米晶体前驱物的粉末X射线衍射图谱。
实施例2:制备ANdF4或AErF4(A=Na或K)纳米颗粒
在100mL三口烧瓶中加入6mL油酸和10mL十八烯,并向烧瓶中加入实施例1制备的ANdF4(A=Na或K)纳米晶体前驱物溶液(0.25M,2mL),在氮气氛围下,70℃保持30min除尽低沸点溶剂和氧气,以10℃/min升温至280℃,反应30min后降至室温,将反应液转移至50mL离心管,以10000rpm转速离心1min,用环己烷和无水乙醇洗涤沉淀,最后用分散至氯仿中,即得到ANdF4(A=Na或K)纳米颗粒。
当制备AErF4(A=Na或K)纳米颗粒时,按照上述步骤进行,不同之处在于,将ANdF4(A=Na或K)替换为AErF4(A=Na或K)。
附图3为所制备KNdF4纳米颗粒透射电镜照片,附图4为所制备KNdF4纳米颗粒的下转换荧光光谱,其激发波长为808nm。
实施例3:制备不同壳层的纳米颗粒
在100mL三口烧瓶中加入6mL油酸和10mL十八烯,并向烧瓶中加入实施例1制备的NaNdF4纳米晶体前驱物溶液(0.25M,2mL),以其作为核层纳米晶体前驱物溶液,在氮气氛围下,70℃保持30min除尽低沸点溶剂和氧气,以10℃/min升温至280℃,反应30min后降温至70℃,再加入0.5mmol实施例1制备的AREF4(A=Na或K;RE=Nd、Gd、Eu、Tb、Ho、Er和Dy中的一种)纳米晶体前驱物溶液(0.25M,2mL),以其作为壳层其中,纳米晶体前驱物溶液,70℃保持30min除尽低沸点溶剂,以10℃/min升温至280℃,反应30min后降至室温。将反应液转移至50mL离心管,以10000rpm转速离心1min,用环己烷和无水乙醇洗涤沉淀,最后用分散至氯仿中,即得到不同组成的核壳纳米颗粒,如以NaNdF4为核,以NaREF4(RE=Gd、Eu、Tb、Ho、Dy)为壳的纳米颗粒,以下简称为NaNdF4@NaREF4。
按照上述方法还可制备以KNdF4、NaErF4或KErF4为核的纳米颗粒,不同之处在于,将核层纳米晶体前驱物溶液替换为KNdF4、NaErF4或KErF4纳米晶体前驱物溶液。
附图5为NaNdF4@NaREF4(RE=Gd、Eu、Tb、Ho或Dy)纳米颗粒的下转换荧光光谱,其激发波长为808nm。
实施例4:制备不同壳层厚度的纳米颗粒
在100mL三口烧瓶中加入6mL油酸和10mL十八烯,以及室温制备的NaNdF4纳米晶体前驱物溶液(0.25M,2mL),在氮气氛围下,70℃保持30min除尽低沸点溶剂和氧气,以10℃/min升温至280℃,反应30min后降温至70℃,按以上方法做三组平行实验。然后向各组产物中分别加入不同摩尔量的NaGdF4壳层纳米晶体前驱物溶液(0.25M;0.5mL、1mL、2mL),70℃保持30min除尽低沸点溶剂,以10℃/min升温至280℃,反应30min后降至室温。将反应液转移至50mL离心管,以10000rpm转速离心1min,用环己烷和无水乙醇洗涤沉淀,最后用分散至氯仿中。后续壳层厚度的增加重复如前所述的操作步骤,且壳层纳米晶体前驱物摩尔量不超过核层纳米晶体前驱物的摩尔量。
附图6为不同壳层厚度的NaNdF4@NaGdF4纳米颗粒的透射电镜照片。图6a、b、c分别表示NaGdF4壳层厚度为0nm、2.1nm、4nm。
附图7为不同壳层厚度的NaNdF4@NaGdF4纳米颗粒的粉末X射线衍射图谱,其中,NaNdF4、NaGdF4指的是纯纳米晶体前驱物的测试结果,2.1nm、4nm分别代表NaNdF4@NaGdF4的壳层厚度为2.1nm和4nm。较高的反应温度使纳米晶体的结晶度提高,因此纳米晶体的X-射线衍射峰较为尖锐,不同于室温制备的稀土纳米晶体前驱物的测试结果(图2)。附图8为上述不同壳层厚度的NaNdF4@NaGdF4纳米颗粒的下转换荧光光谱,其激发波长为808nm,其中的2.1nm和4nm与图7中的含义相同。
实施例5:制备磷脂聚乙二醇包覆的不同壳层厚度的稀土核壳纳米颗粒
将实施例4制备的NaNdF4@NaGdF4纳米颗粒与磷脂聚乙二醇摩尔比为8:1混合于氯仿溶剂中,静置敞口挥发至成膜,75℃加热10min除尽氯仿,加适量水超声1min,将反应液以26000rpm高速离心10min,取沉淀复溶与水中,存放至玻璃瓶内,置于5℃冰箱存放。附图9为磷脂聚乙二醇修饰的NaNdF4@NaGdF4(Nd:Gd=1:2,摩尔比)稀土核壳纳米颗粒的透射电镜照片。
实施例6:磷脂聚乙二醇包覆的不同壳层厚度的稀土核壳纳米颗粒体外弛豫率测试
取不同浓度梯度(2mM、1mM、0.5mM、0.25mM、0.125mM、0.0625mM)实施例5制备的稀土核壳纳米颗粒溶液于特定容器中,在磁场强度为3T的MRI中进行测试。附图10为磷脂聚乙二醇修饰的不同壳层厚度的NaNdF4@NaGdF4稀土核壳纳米颗粒的体外纵向质子弛豫图像。图10中,左侧的数字0、2.1和4表示稀土核壳纳米颗粒中的壳层厚度为0、2.1nm和4nm,上方的数字2、1、1/2、1/4、1/8、0表示含义是稀土核壳纳米颗粒溶液的浓度为2mM、1mM、0.5mM、0.25mM、0.125mM、0mM(空白对照)。附图11为磷脂聚乙二醇修饰的不同壳层厚度(0、2.1、4nm)的NaNdF4@NaGdF4稀土核壳纳米颗粒的体外纵向质子弛豫率图。
实施例7:磷脂聚乙二醇修饰的稀土核壳纳米颗粒用于近红外二区血管造影
取适量磷脂聚乙二醇修饰的稀土核壳纳米颗粒(NaNdF4@NaGdF4)溶液(浓度0.89mg/mL,200μL)尾静脉注射至处于液体麻醉状态的小鼠体内,采用808nm激光器,分别用1000nm和1250nm长通滤光片,相同曝光时间200ms,对应功率密度45mW/cm2和100mW/cm2,观察纳米颗粒溶液注射后不同波段(1060nm和1340nm)在血管成像上的差异性。附图12为采用1340nm发射光成像时的小鼠近红外二区血管显影图。
实施例8:磷脂聚乙二醇修饰的稀土核壳纳米颗粒用于磁共振血管造影
取适量磷脂聚乙二醇修饰的稀土核壳纳米颗粒(NaNdF4@NaGdF4)溶液(浓度3.64mg/mL,200μL)尾静脉注射至处于气体麻醉状态的小鼠体内,采用AspectM7核磁共振分析仪(磁体强度为1T,样品仓口径为90mm,采用30mm的小鼠体线圈)观察纳米颗粒溶液注射后小鼠内脏系统的动静脉血管。附图13为小鼠的磁共振血管显影图,能清晰的看到各血管,图中标号说明:1.颈动脉;2.颈静脉;3.腋静脉;4.主动脉弓;5.主动脉;6.门静脉;7.肠系膜静脉;8.下腔静脉。
以上所述仅是本发明的优选实施方式,并不用于限制本发明,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明技术原理的前提下,还可以做出若干改进和变型,这些改进和变型也应视为本发明的保护范围。
Claims (10)
1.一种稀土核壳纳米颗粒,其特征在于:包括核层纳米颗粒、至少一层包覆于所述核层纳米颗粒外部的壳层以及包覆于所述壳层外部的两亲性聚合物,所述核层纳米颗粒和壳层分别独立地选自AREF4,其中,A为Na或K,RE为Nd、Gd、Eu、Tb、Ho、Er或Dy。
2.根据权利要求1所述的稀土核壳纳米颗粒,其特征在于:所述核层纳米颗粒的粒径为4-20nm,所述稀土核壳纳米颗粒的粒径为6-30nm,所述核层纳米颗粒的粒径和壳层的厚度之比为1-10。
3.根据权利要求1所述的稀土核壳纳米颗粒,其特征在于:所述两亲性聚合物为磷脂聚乙二醇、聚己内酯-聚乙二醇和聚乙二醇-聚乳酸中的一种或几种。
4.一种权利要求1-3中任一项所述的稀土核壳纳米颗粒的制备方法,其特征在于,包括以下步骤:
(1)将第一稀土纳米晶体前驱物溶液加入油酸和十八烯的混合溶液中,在惰性气氛中加热至50-100℃,以去除低沸点溶剂,然后再升温至200-300℃,保温5min-2h,降温至50-100℃,得到所述核层纳米颗粒;
(2)以下步骤至少进行一次,得到至少包覆一层壳层的纳米颗粒:向步骤(2)的产物中加入第二稀土纳米晶体前驱物溶液,在惰性气氛中加热至50-100℃,以去除低沸点溶剂,然后再升温至200-300℃,保温5min-2h,降温至50-100℃;
所述第一稀土纳米晶体前驱物和第二稀土纳米晶体前驱物独立地选自AREF4稀土纳米晶体前驱物,其中,A为Na或K,RE为Nd、Gd、Eu、Tb、Ho、Er或Dy;所述AREF4稀土纳米晶体前驱物的制备方法包括以下步骤:
将含稀土离子的水溶液、碱金属氟化物水溶液、碱性水溶液、醇和油酸混匀,并在10-40℃下反应,反应完全后纯化出AREF4纳米晶种,所述纳米晶种的粒径为1-10nm;然后将所述AREF4纳米晶体分散于有机溶剂中,得到所述稀土纳米晶体前驱物溶液;水溶液中的稀土离子和碱金属氟化物中氟元素的摩尔比为1:4。
(3)将步骤(2)得到的至少包覆一层壳层的纳米颗粒与两亲性聚合物在有机溶剂中混匀,静置至有机溶剂挥发,然后加水分散,离心分离出所述稀土核壳纳米颗粒。
5.根据权利要求4所述的制备方法,其特征在于:在步骤(2)中,所述含稀土离子的水溶液为稀土金属盐酸盐、稀土离子硝酸盐或稀土金属氧化物的水溶液,所述含稀土离子的水溶液的浓度为0.1-5mol/L。
6.根据权利要求4所述的制备方法,其特征在于:在步骤(2)中,所述碱性水溶液为氢氧化钠水溶液。
7.根据权利要求4所述的制备方法,其特征在于:在步骤(1)中,所述第一稀土纳米晶体前驱物溶液、油酸和十八烯的体积比为0.17-1:1:1-5;所述第一稀土纳米晶体前驱物溶液的浓度为0.08-1mol/L。
8.根据权利要求4所述的制备方法,其特征在于:在步骤(2)中,所述第二稀土纳米晶体前驱物溶液的浓度为0.02-1mol/L;所述第二稀土纳米晶体前驱物溶液与步骤(1)中的第一稀土纳米晶体前驱物溶液中的稀土离子的摩尔比为1:4–4:1。
9.根据权利要求4所述的制备方法,其特征在于:在步骤(3)中,所述至少包覆一层壳层的纳米颗粒与两亲性聚合物的摩尔比为4-20:1。
10.权利要求1-3中任一项所述的稀土核壳纳米颗粒在制备近红外二区光学造影剂和/或磁共振造影剂中的应用。
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