CN108289956A - 与5-氨基乙酰丙酸缀合的量子点纳米颗粒 - Google Patents
与5-氨基乙酰丙酸缀合的量子点纳米颗粒 Download PDFInfo
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- CN108289956A CN108289956A CN201680054241.1A CN201680054241A CN108289956A CN 108289956 A CN108289956 A CN 108289956A CN 201680054241 A CN201680054241 A CN 201680054241A CN 108289956 A CN108289956 A CN 108289956A
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Abstract
在光动力疗法中,通过施用与5‑氨基乙酰丙酸缀合的量子点纳米颗粒作为荧光标记物和光敏剂的前体,将与5‑氨基乙酰丙酸缀合的量子点纳米颗粒用于治疗癌症。
Description
相关申请的交叉引用
本申请要求2015年8月17日提交的美国临时申请62/205,998的权益。
关于联邦资助的研究或开发的声明:
不适用
技术领域
本发明涉及与量子点纳米颗粒缀合的5-氨基乙酰丙酸及其衍生物,以及制备与量子点纳米颗粒缀合的5-氨基乙酰丙酸及其衍生物的方法。本发明还涉及在光动力疗法中通过施用与量子点纳米颗粒缀合的5-氨基乙酰丙酸及其衍生物作为荧光标记物和光敏剂的前体来治疗癌症的方法。
背景技术
相关技术的描述,这些描述包括根据37CFR1.97和1.98而公开的信息。
光动力疗法(PDT)是一种使用被称为光敏剂(PS)的光敏药物和光来杀死癌细胞的治疗方法。这些药物仅在被光活化后才起作用。用适当的光辐照后,光敏剂产生破坏赘生组织的活性氧物种(ROS)。
5-氨基乙酰丙酸(5-ALA)是批准用于PDT的PS并且被广泛使用。5-ALA的衍生物和类似物也被提议用作用于PDT的PS;特别是WO 2002009690中公开的5-ALA的酯衍生物,该申请的全部内容通过引用并入本文。5-ALA及其衍生物和类似物是前药,一旦内化到肿瘤细胞中,就会转化为天然光敏剂原卟啉IX(PpIX)。与外源施用的PS不同,如(卟吩姆钠)[CONCORDIA LABORATORIES INC.ST.MICHAEL BARBADOS BB11005(康考迪亚实验室有限责任公司,圣米迦勒,巴巴多斯)],光动力无活性、无选择性且无毒的5-ALA在细胞内被代谢为光动力活性并具有荧光性质的PpIX。随后用光(例如蓝光)照射肿瘤位点,激活PpIX,触发氧化损伤并诱导细胞毒性。
但是,5-ALA是极性分子。5-ALA的两性离子性质和亲水性极大地限制了其渗透通过组织(例如未损伤的皮肤、结节性皮肤损伤)和细胞膜,导致细胞摄取缓慢以及PpIX在肿瘤细胞中的积聚不一致。因此,5-ALA渗透通过细胞膜和靶向递送至肿瘤细胞是改进PDT功效和特异性的难题。
此外,5-ALA也可以是癌症(诸如神经胶质瘤和黑素瘤等)的荧光引导手术中的标记物。上述限制也使5-ALA作为标记剂的能力不足以满足该应用。
发明内容
在光疗、显示、照明、太阳能和生物成像中,2nm~100nm范围内的颗粒(通常被称为量子点,作为化合物半导体)的制备和表征已经引起人们极大的关注。
美国专利7,588,828(2007年9月10日提交,2009年9月15日授权)、美国专利7,803,423(2005年4月27日提交,2010年9月28日授权)、美国专利7,867,556、美国专利7,985,446(2010年8月11日提交,2011年7月26日授权)、美国专利8,062,703(2010年8月10日提交,2011年11月22日授权),申请人共同拥有的美国申请14/207,084、申请人共同拥有的美国申请14/212,702和申请人共同拥有的美国申请14/208,311(其全部内容通过引用整体并入本文),描述了生产大量高品质、单分散QD的方法。以足够大的工业应用规模,在分子簇化合物存在下,在保持分子簇完整并用作定义明确的预制种子或模板以提供与化学前体反应的成核中心从而产生高品质纳米颗粒的条件下,来提供QD前体。
QD颗粒可以用有机端基官能化以用于进一步的化学操作。一个示例是钝化层。在制备QD过程中,在任何纳米颗粒中最终无机表面原子的配位都可能是不完全的,在颗粒表面上具有高度反应性的未完全配位的原子“悬挂键(dangling bond)”,这可能导致颗粒团聚。为了克服该问题,可以采用有机钝化层,以用保护性有机基团封盖裸露的表面原子。钝化层提供有机官能团,通过这些有机官能团可以与其他材料化学连接。
本发明提供了一种缀合物,其包含与纳米颗粒缀合物缀合的5-ALA、5-ALA的衍生物及类似物。在本发明的一个方面中,提供了一种与5-氨基乙酰丙酸缀合的官能化量子点纳米颗粒。在一个实施方式中,5-ALA与纳米颗粒结合。量子点纳米颗粒可以是核-壳纳米颗粒。5-ALA可以与纳米颗粒共价地、物理地、离子配对地或范德华相互作用地缀合。上述结合可以直接在量子点纳米颗粒的无机表面上或在用于使纳米颗粒呈现水溶性和生物相容性的有机电晕层上通过酰胺、酯、硫酯或硫醇锚定基团形成。
在一个实施方式中,5-ALA-纳米颗粒缀合物包含:分子簇化合物、半导体材料核,和外层,其中,所述外层包含R,其中,所述R是:
在另一个实施方式中,纳米颗粒是合金化量子点。与核壳结构纳米颗粒不同,合金化纳米颗粒没有确定的核-壳构型,而具有梯度带隙。
官能化量子点纳米颗粒可以包含能够靶向癌细胞的配体。所述配体可以是PLZ4。所述纳米颗粒可以基本不含镉。
实施方式还提供制备上述5-ALA-纳米颗粒缀合物的方法,所述方法包括以下步骤:1)使纳米颗粒与5-ALA偶联以得到粗制的5-ALA-纳米颗粒缀合物,其中,所述纳米颗粒包含具有羧基的外层;2)纯化所述粗制的5-ALA-纳米颗粒缀合物;和3)分离所述5-ALA-纳米颗粒缀合物。所述制备5-ALA-纳米颗粒缀合物的方法可以包括以下步骤:提供包含分子簇化合物、半导体材料核和外层的纳米颗粒;提供偶联剂;提供5-ALA、5-ALA衍生物或5-ALA类似物;孵育上述混合物以形成粗制的5-ALA-纳米颗粒缀合物;纯化所述粗制的5-ALA-纳米颗粒缀合物,和分离所述5-ALA-纳米颗粒缀合物。所述偶联剂可以是1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐。上述方法还可以包括使5-ALA-纳米颗粒缀合物与能够靶向癌细胞的配体缀合。
实施方式提供用于荧光标记剂和光敏剂的系统,所述系统包括5-ALA-纳米颗粒缀合物,所述5-ALA-纳米颗粒缀合物包含具有外层的量子点,所述外层包含R,其中,R是
实施方式提供了治疗癌症的方法,所述方法包括在光动力疗法中施用5-ALA-纳米颗粒缀合物作为荧光标记物和光敏剂的前体,以及随后辐照该光敏剂的步骤。
实施方式提供诱导细胞凋亡的方法,所述方法包括在光动力疗法中施用5-ALA-纳米颗粒缀合物作为荧光标记物和光敏剂的前体,以及随后辐照该光敏剂的步骤。所述诱导细胞凋亡的方法可以包括以下步骤:将与多个5-氨基乙酰丙酸缀合的官能化纳米颗粒施用于细胞,使5-氨基乙酰丙酸形成代谢物和辐照所述代谢物。上述细胞可以是哺乳动物的细胞。可以将与多个5-氨基乙酰丙酸缀合的官能化纳米颗粒施用于有需要的哺乳动物。所述代谢物可以是原卟啉IX。辐照步骤可以由纳米颗粒执行。所述纳米颗粒可以发射375nm~475nm范围内的光。辐照步骤可足以产生活性氧物种。所述官能化纳米颗粒可进一步包含能够靶向癌细胞的配体。所述方法可进一步包括配体与癌细胞结合的步骤。
实施方式进一步提供5-ALA-纳米颗粒缀合物与组织特异性配体的缀合,所述组织特异性配体例如是能够靶向摄取5-ALA-纳米颗粒缀合物的特定组织的肽。这类肽的一个示例是能够靶向癌细胞和包括肿瘤在内的赘生组织的抗体。所靶向的癌症的示例包括前列腺癌、乳腺癌、结肠癌、皮肤癌、子宫颈癌、膀胱癌、肺癌和胃癌。能够靶向特定组织的肽可以共价地、物理地、通过离子配对地或范德华相互作用地与纳米颗粒缀合。上述结合可以直接在量子点纳米颗粒的无机表面上或在用于使纳米颗粒呈现水溶性和生物相容性的有机电晕层上通过酰胺、酯、硫酯或硫醇锚定基团形成。
实施方式包括皮下、静脉内、肌内、局部和口服施用5-ALA-纳米颗粒缀合物。示例包括弹丸式注射或IV输注。
实施方式还包括诊断癌症的方法,所述方法包括以下步骤:在光动力学诊断中施用5-ALA-纳米颗粒缀合物作为荧光标记物和光敏剂的前体;使5-ALA与纳米颗粒解离并形成PpIX;和激发已解离的纳米颗粒以发射375nm~475nm的蓝光;激活PpIX的荧光性质;和使荧光成像以检测癌症。
实施方式还包括手术切除肿瘤细胞的方法,所述方法包括以下步骤:在光动力学诊断中施用5-ALA-纳米颗粒缀合物作为荧光标记物和光敏剂的前体;使5-ALA与纳米颗粒解离并形成PpIX;激发已解离的纳米颗粒以发射375nm~475nm的蓝光;以及激活PpIX的荧光性质,由此检测和去除肿瘤细胞。
实施方式还包括检测癌细胞的方法,所述方法包括以下步骤:在光动力学诊断中施用5-ALA-纳米颗粒缀合物作为荧光标记物和光敏剂的前体;使5-ALA与纳米颗粒解离;使5-ALA形成PpIX;激发已解离的纳米颗粒以发射375nm~475nm的蓝光;激活PpIX的荧光性质;以及使荧光成像。施用步骤可通过注射执行。注射可以是静脉内注射。纳米颗粒可以是合金化量子点。
应当理解的是,在不脱离所附权利要求书限定的本发明范围的情况下,可以对本发明的上述实施方式进行许多修改。此外,一个或多个上述优选实施方式可以与一个或多个其他优选实施方式相结合以适合于特定应用。
可选的和/或优选的特征可用于本文所述组合以外的其他组合中,并且在适当的情况下,在本发明一个方面中描述的可选的和/或优选的特征也可存在于本发明另一方面中。
所描述和说明的各方面应视为说明性的而不是限制性的,应当理解的是,仅示出和描述了优选的方面,并且落入由权利要求书限定的本发明范围内的所有改变和修改都请求被保护。应当理解的是,虽然在说明书中使用诸如“优选的”、“优选地”、“优选”或“更优选”等词可以表明如此描述的特征是所期望的,但它并不是必需的,并且没有这些特征的各方面视为在如所附权利要求书所限定的本发明范围内。在权利要求书中,当诸如“一个”、“一种”或“至少一个”等词语用于某特征前面时,无意将该权利要求限制为仅一个这样的特征,除非在权利要求中明确有相反的说法。
附图说明
图1是制备5-ALA-纳米颗粒缀合物的方法的示意图。
图2示出5-ALA与附接于其上的表面结合的配体的纳米颗粒(由实心圆表示)的缀合。在该代表性示图中,X=表面结合的配体(硫醇、胺、膦、氧化膦、羧酸等),Y=连接基团(包含一个或多个烷基、烯基、炔基的烃链;诸如PEG、PPO、PEO、硅橡胶、聚乙烯、丙烯酸树脂、聚氨酯、聚丙烯和聚甲基丙烯酸甲酯等的聚合物;共聚物;嵌段共聚物等),Z=羧酸、酯、酰氯、酸酐或醛。
图3示出了从图2所示的5-ALA-纳米颗粒缀合物代谢为光敏剂原卟啉IX(PpIX或PROTO)的代谢途径。
具体实施方式
在图1中,通过使纳米颗粒与5-ALA反应来提供5-ALA-纳米颗粒缀合物。作为示例,该纳米颗粒包含分子簇化合物、半导体材料核和外层。该外层包含与5-ALA反应以形成连接部的羧基。应当理解,5-ALA的衍生物和类似物可以单独使用或组合使用。还应当理解,也可以使用合金化纳米颗粒。另外,可以使用核-壳纳米颗粒和合金化纳米颗粒的组合。
5-ALA的衍生物包括但不限于:
5-ALA正烷基酯;
5-ALA甲酯(氨基乙酰丙酸甲酯,商品名METVIVTM)
5-ALA乙酯
5-ALA丙酯
5-ALA丁酯
5-ALA戊酯
5-ALA己酯(氨基乙酰丙酸己酯,商品名HEXVIXTM)
5-ALA辛酯,
还有:
5-ALA(羟甲基)四氢呋喃酯;和
5-ALA聚乙二醇衍生物;
和盐,诸如:5-ALA·HCl。
核-壳型纳米颗粒包括但不限于包含以下类型的材料核:
IIA-VIB(2-16)材料,由选自周期表第2族的第一元素和选自周期表第16族的第二元素组成,并且还包括三元和四元材料以及掺杂材料。纳米颗粒材料包括但不限于:MgS、MgSe、MgTe、CaS、CaSe、CaTe、SrS、SrSe、SrTe、BaS、BaSe、BaTe。
IIB-VIB(12-16)材料,由选自周期表第12族的第一元素和选自周期表第16族的第二元素组成,并且还包括三元和四元材料以及掺杂材料。纳米颗粒材料包括但不限于:ZnS、ZnSe、ZnTe、CdS、CdSe、CdTe、HgS、HgSe、HgTe。
II-V材料,由选自周期表第12族的第一元素和选自周期表第15族的第二元素组成,并且还包括三元和四元材料以及掺杂材料。纳米颗粒材料包括但不限于:Zn3P2、Zn3As2、Cd3P2、Cd3As2、Cd3N2、Zn3N2。
III-V材料,由选自周期表第13族的第一元素和选自周期表第15族的第二元素组成,并且还包括三元和四元材料以及掺杂材料。纳米颗粒材料包括但不限于:BP、AlP、AlAs、AlSb;GaN、GaP、GaAs、GaSb;InN、InP、InAs、InSb、AlN、BN。
III-IV材料,由选自周期表第13族的第一元素和选自周期表第14族的第二元素组成,并且还包括三元和四元材料以及掺杂材料。纳米颗粒材料包括但不限于:B4C、Al4C3、Ga4C。
III-VI材料,由选自周期表第13族的第一元素和选自周期表第16族的第二元素组成,并且还包括三元和四元材料。纳米颗粒材料包括但不限于:Al2S3、Al2Se3、Al2Te3、Ga2S3、Ga2Se3、GeTe;In2S3、In2Se3、Ga2Te3、In2Te3、InTe。
IV-VI材料,由选自周期表第14族的第一元素和选自周期表第16族的第二元素组成,并且还包括三元和四元材料以及掺杂材料。纳米颗粒材料包括但不限于:PbS、PbSe、PbTe、Sb2Te3、SnS、SnSe、SnTe。
纳米颗粒材料,由选自周期表过渡金属中任何族的第一元素和选自周期表d区元素中任何族的第二元素组成,并且还包括三元和四元材料以及掺杂材料。纳米颗粒材料包括但不限于:NiS、CrS、CuInS2。
就本说明书及其权利要求书的目的而言,术语“掺杂的纳米颗粒”是指上述纳米颗粒和包含一种或多种主族元素或稀土元素的掺杂剂。这通常是过渡金属或稀土元素,例如但不限于具有锰的硫化锌,例如掺杂有Mn+的ZnS纳米颗粒。
在一个实施方式中,优选无镉纳米颗粒。
在一个实施方式中,纳米颗粒包括第一层,该第一层包括设置在纳米颗粒核上的第一半导体材料。包括第二半导体材料的第二层可以设置在该第一层上。
标准的缀合化学可以用于缀合。例如,制备5-ALA-纳米颗粒缀合物的方法可包括以下步骤:提供纳米颗粒;提供偶联剂;提供5-ALA、5-ALA衍生物(例如,其酯衍生物)、5-ALA类似物;孵育上述混合物以形成粗制的5-ALA-纳米颗粒缀合物。然后可以纯化并分离该粗制的5-ALA-纳米颗粒缀合物以获得5-ALA-纳米颗粒缀合物。
可以选择孵育条件以允许形成酰胺或酯。应当理解,可以形成其他键(例如,共价键和非共价键)。在一个实施方式中,5-ALA与纳米颗粒结合。5-ALA可以与纳米颗粒共价地、物理地、离子配对地或范德华相互作用地缀合。上述结合可以直接在量子点纳米颗粒的无机表面上或在用于使纳米颗粒呈现水溶性和生物相容性的有机电晕层上通过酰胺、酯、硫酯或硫醇锚定基团形成。
可以采用偶联的标准孵育条件。例如,偶联条件可以是在溶液中保持0.5小时~4小时。偶联条件的温度范围可以为100℃~200℃。在反应期间偶联条件可以恒定不变,也可以改变。例如,反应条件可以是在130℃下保持1小时,然后升至140℃保持3小时。
可使用接头在纳米颗粒的羧基官能团与5-ALA的羧基或氨端基之间形成酰胺基团或酯基团。接头或偶联剂可以包括六氟磷酸苯并三唑氧基-三(二甲基氨基)鏻(BOP)和碳化二亚胺,诸如:二环己基碳化二亚胺(DCC)、二异丙基碳化二亚胺(DIC)和1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDC)。EDC是用作酰胺偶联剂的优选碳化二亚胺。
在一个示例中,5-ALA和带有羧基端基的量子点纳米颗粒可以在溶剂中混合。可以将偶联剂如EDC添加到该混合物中。可以孵育反应混合物。可以对粗制的5-ALA-QD纳米颗粒缀合物进行纯化以获得5-ALA-QD纳米颗粒缀合物。
可以使用标准的固态纯化方法。为了除去过量的未反应的5-ALA和EDC,可能需要用合适的溶剂进行几次过滤和洗涤循环。
在另一个实施方式中,5-ALA-纳米颗粒缀合物可以进一步包含能够靶向癌细胞的配体。例如,可以将化学化合物或肽(例如抗体)与5-ALA-纳米颗粒缀合物缀合以进一步增效5-ALA-纳米颗粒缀合物的细胞摄取以用于光检测或光疗。肽的一个示例是PLZ4(QDGRMGF),它是一种可以选择性与膀胱癌细胞结合的肽。肽可以通过它们的胺基团或羧酸基团与官能化的纳米颗粒形成酰胺键或酯键。
一旦选择性地与癌细胞结合后,5-ALA纳米颗粒缀合物将被细胞摄取。一旦内化后,5-ALA转化为天然光敏剂原卟啉IX(PpIX)。随后用光(例如375nm~475nm范围内的蓝光)照射肿瘤部位,激活PpIX,通过释放的活性氧物种(ROS)触发氧化损伤并诱导细胞毒性或细胞凋亡。
因此,本文公开的实施方式可用于诱导细胞(例如哺乳动物细胞)凋亡的方法,该方法包括以下步骤:向有需要的哺乳动物施用5-ALA-纳米颗粒缀合物;使5-ALA形成代谢物,如PpIX;和辐照该代谢物。辐照步骤可以通过激发纳米颗粒(例如已解离的纳米颗粒)来完成。
实施方式还包括通过使哺乳动物成像来检测癌细胞的方法。
可以肠内或肠胃外施用5-ALA-纳米颗粒缀合物。例如,可以皮下、静脉内、肌内、局部和口服施用5-ALA-纳米颗粒缀合物。示例包括弹丸式注射或IV输注。
与游离5-ALA相比,本发明的5-ALA-QD纳米颗粒缀合物具有以下优点。
首先,所述5-ALA-QD纳米颗粒缀合物具有增强的细胞渗透性并且可以被癌细胞更有效地摄取,特别是被非常活跃的癌症干细胞更有效地摄取。一般来讲,纳米颗粒在癌细胞中比在正常细胞中的积聚更多。所述QD纳米颗粒用作矢量化递送系统。
其次,所述QD的发射可以调节为与PpIX的吸收重叠。一旦QD-5ALA颗粒内化到癌细胞中,5-ALA将被释放并在几小时内转变成PpIX。然后QD可用作光或FRET供体以增强所产生的PpIX的激发。由于QD纳米颗粒与诸如PpIX等小分子染料相比,分子消光系数高10~100倍,因此可吸收更多光线,产生更强的信号,从而提高信噪比检测率。
第三,高光吸收强度还可以增加PpIX产生单线态氧作为光动力学治疗(PDT)剂的功效。
第四,QD纳米颗粒的可调性和用于多光子激发(包括双光子激发)的潜势可以实现更深的组织检测和更深的PDT,不同于单独的5-ALA,其仅可达到几毫米的组织深度。
第五,双光子激发或多光子激发提供了激发波长大于700nm的手段,并且使PDT具有高度集中的光剂量。
根据前述说明书,本发明的这些优点以及其他优点对于本领域技术人员来讲是清楚的。因此,本领域技术人员将认识到,在不脱离本发明广义的发明构思的情况下,可以对上述实施方式进行改变或修改。应当理解的是,本发明不限于本文描述的特定实施方式,而旨在包括在本发明范围和精神内的所有改变和修改。
Claims (20)
1.一种与5-氨基乙酰丙酸缀合的官能化量子点纳米颗粒。
2.根据权利要求1所述的5-ALA-纳米颗粒缀合物,其中,所述纳米颗粒通过酰胺键或酯键与5-ALA共价连接。
3.根据权利要求1所述的官能化量子点纳米颗粒,其中,所述量子点纳米颗粒是核壳纳米颗粒。
4.根据权利要求1所述的官能化量子点纳米颗粒,进一步包含能够靶向癌细胞的配体。
5.根据权利要求1所述的官能化量子点纳米颗粒,其中,所述配体是PLZ4。
6.根据权利要求1所述的官能化量子点纳米颗粒,其中,所述量子点纳米颗粒基本不含镉。
7.一种制备5-ALA-纳米颗粒缀合物的方法,所述方法包括以下步骤:
提供包含分子簇化合物、半导体材料核和外层的纳米颗粒;
提供偶联剂;
提供5-ALA、5-ALA衍生物或5-ALA类似物;
孵育上述混合物以形成粗制的5-ALA-纳米颗粒缀合物;
纯化所述粗制的5-ALA-纳米颗粒缀合物;和
分离所述5-ALA-纳米颗粒缀合物。
8.根据权利要求7所述的方法,其中,所述偶联剂是1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐。
9.根据权利要求7所述的方法,进一步包括使所述5-ALA-纳米颗粒缀合物与能够靶向癌细胞的配体缀合的步骤。
10.一种诱导细胞凋亡的方法,所述方法包括以下步骤:
向有需要的哺乳动物施用与多个5-氨基乙酰丙酸缀合的官能化纳米颗粒;
使5-氨基乙酰丙酸形成代谢物;和
辐照所述代谢物。
11.根据权利要求10所述的方法,其中,所述代谢物是原卟啉IX。
12.根据权利要求10所述的方法,其中,辐照步骤由所述纳米颗粒执行。
13.根据权利要求12所述的方法,其中,所述纳米颗粒发射375nm~475nm范围内的光。
14.根据权利要求10所述的方法,其中,辐照步骤足以产生活性氧物种。
15.根据权利要求10所述的方法,其中,所述官能化纳米颗粒进一步包含能够靶向癌细胞的配体。
16.根据权利要求15所述的方法,进一步包括所述配体与癌细胞结合的步骤。
17.一种检测癌细胞的方法,所述方法包括以下步骤:
在光动力学诊断中施用5-ALA-纳米颗粒缀合物作为荧光标记物和光敏剂的前体;
使5-ALA与纳米颗粒解离;
使5-ALA形成PpIX;
激发解离的纳米颗粒以发射375nm~475nm的蓝光;
激活PpIX的荧光性质;和
使荧光成像。
18.根据权利要求17所述的方法,其中,施用步骤通过注射来执行。
19.根据权利要求18所述的方法,其中,所述注射通过静脉内注射来执行。
20.根据权利要求19所述的方法,其中,所述纳米颗粒是合金化量子点。
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