CN117504806A - 改进的磁性粒子及其用途 - Google Patents
改进的磁性粒子及其用途 Download PDFInfo
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- CN117504806A CN117504806A CN202311503653.7A CN202311503653A CN117504806A CN 117504806 A CN117504806 A CN 117504806A CN 202311503653 A CN202311503653 A CN 202311503653A CN 117504806 A CN117504806 A CN 117504806A
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- Prior art keywords
- acid
- magnetic
- metal
- composition
- silicate
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Abstract
本发明涉及改进的磁性粒子及其用途。本公开提供用于核酸捕获、富集、分析和/或纯化的改进的磁性玻璃粒子。描述了对所公开的组合物及其使用方法、装置和试剂盒的各种修改。
Description
本申请是申请号为201880070748.5、申请日为2018年10月31日、同题的中国专利申请的分案申请。
技术领域
公开了用于配置为进行核酸分析、捕获、富集和纯化的样品处理小管(sampleprocessing tubule)的改进的磁性玻璃粒子。
背景技术
许多生物材料,尤其是核酸在从它们的天然环境中分离它们的方面存在特殊挑战。一方面,它们通常以极小浓度存在,另一方面,通常在许多其它固体和溶解物质存在下发现以致它们难以分离或测量,特别是在生物特异性测定中。
在核酸纯化领域中,广泛使用磁性二氧化硅粒子。亚铁磁性纳米粒子通常不可购得并仅从学术出版物中获知。这样的出版物包括具有二氧化硅涂层的纳米粒子(Chen等人;J.of alloys and compounds 497(2010)221-227;Wang等人;Bioresource Technology101(2010)8931-8935;Reza等人;Cent.Eu.J.Chem 5(2010)1041-1048)。但是,许多磁性二氧化硅粒子可购得,其中大多表现出超顺磁行为。市售粒子通常根据方法由具有硅烷涂层的磁芯制成(/>等人,J.Colloid Interface Sci.,1968,26,62)。在少数已知实例中,二氧化硅源基于可溶性硅酸盐(液体玻璃)(Philipse等人,Langmuir,1994,10,92–99;Bolle等人,2015,EP2916327B1)。对于磁芯,通常使用具有超顺磁行为的3-10nm的纳米粒子或具有铁磁行为的大于60nm的纳米粒子。Liu等人(Angew.Chem.Int.Ed.,2009,48,5875–5879)展示了具有超顺磁行为的大于60nm的纳米粒子的实例,但这样的粒子尚未用于核酸纯化。EP2110175公开了涂布磁珠在PCR应用中的用途,其中磁珠具有被聚合物或二氧化硅涂层覆盖的由金属或合金制成的磁芯。但是,EP2110175没有公开珠粒的任何优选性质(例如超顺磁性质),也没有公开此类珠粒的溶剂热生产。WO2014/090838公开了具有构成磁性二氧化硅粒子的25-85%(按重量计)的含SiO2表面并具有30μm或更小的粒度的磁性粒子。在此使用沉淀反应制造磁芯粒子。在第二步骤中用二氧化硅涂布粒子,其中涂布若干芯粒子或其附聚物以形成磁性二氧化硅粒子。因此,该磁性二氧化硅粒子表现出厚二氧化硅涂层。此外,WO 2014/090838中公开的生产方法不能生产超粒子体(supraparticles)(即磁性纳米粒子的清晰(defined)聚集体),其中只有超粒子体被薄二氧化硅涂层覆盖。但是,具有厚涂层的粒子已表明不适用于具有挑战性的和高要求的反应条件的***。
此类粒子在(可能存在于样品处理小管中和/或实现短周转时间所要求的)某些条件下的核酸纯化中的使用要求该粒子表现出强磁响应、低剩磁和对核酸的高和快速结合能力,以及核酸的快速洗脱性质,这不是此类市售粒子的情况。因此,本说明书的目的是提供实现这些性质的粒子。
发明内容
在一个方面中,本公开提供一种磁珠的组合物,所述磁珠包含(a)稳定剂和在溶剂热条件下制成的磁芯,(b)液体玻璃涂层,其中所述磁珠是超顺磁性的。在一些实施方案中,磁珠具有大于100nm的粒度。在一些实施方案中,直径在大约80-500nm之间,更尤其在大约150-450nm之间,更尤其在大约200-400nm之间,再更尤其在大约250-400nm之间。在某些实施方案中,磁珠具有200-400nm的粒度。在一些实施方案中,磁芯的直径在大约50-450nm之间,更尤其在大约100-400nm之间,更尤其在大约150-350nm之间,更尤其为大约200-350nm。在特定实施方案中,磁芯在大约250-320nm之间,更尤其在大约260-300nm之间,更尤其在大约270-290nm之间。在一些实施方案中,磁珠具有30–80Am2/kg,更尤其50-70Am2/kg的饱和磁化强度。在一些实施方案中,磁珠具有低于5Am2/kg,更尤其低于3Am2/kg,再更尤其低于2Am2/kg的剩磁。在一些实施方案中,磁珠具有低于3Am2/kg的剩磁。在一些实施方案中,液体玻璃涂层包含硅酸盐。在特定实施方案中,硅酸盐选自硅酸钠、硅酸钾、硅酸钙、硅酸锂和硅酸镁。在一些实施方案中,硅酸盐是硅酸钠。在一些实施方案中,液体玻璃涂层具有20nm或更低的厚度。在某些实施方案中,液体玻璃涂层具有10nm或更低的厚度。在一些实施方案中,磁芯是含稳定剂的磁性纳米粒子的清晰聚集体。在一些实施方案中,稳定剂选自柠檬酸盐、组氨酸、十六烷基三甲基溴化铵(CTAB)、十六烷基三甲基氯化铵(CTAC)、油酸钠、聚丙烯酸。在一个特定实施方案中,稳定剂是柠檬酸钠。在一些实施方案中,磁芯是含至少一种稳定剂的磁性纳米粒子的清晰聚集体。在一些实施方案中,磁芯是磁性纳米粒子的清晰聚集体,其中磁性纳米粒子具有<30nm的尺寸并且其中磁性纳米粒子的清晰聚集体的直径在50-450nm之间,更尤其在大约100-400nm之间,更尤其在大约150-350nm之间,更尤其为大约200-350nm。在本文中,磁芯提供超顺磁性质。在一个实施方案中,稳定剂在磁性纳米粒子的所述清晰聚集体的形成过程中存在或原位添加。在一些实施方案中,所述至少一种稳定剂选自柠檬酸盐、组氨酸、十六烷基三甲基溴化铵(CTAB)、十六烷基三甲基氯化铵(CTAC)、油酸钠、聚丙烯酸或其中两种或更多种的混合物。在一个特定实施方案中,稳定剂的混合物包含柠檬酸钠。在一些实施方案中,磁芯是Fe3O4、α-Fe2O3、γ-Fe2O3、MnFexOy、CoFexOy、NiFexOy、CuFexOy、ZnFexOy、CdFexOy、BaFexO和SrFexO,其中x和y随合成方法而变,且其中x优选是1至3,更优选2的整数,且其中y优选是3或4,最优选Fe3O4。在特定实施方案中,磁芯是磁铁矿芯。在一些实施方案中,溶剂热条件是包括190-250℃和1-20巴的提高的压力的条件。在一些实施方案中,磁珠是基本球形的。
在另一个方面中,本公开提供一种磁珠的悬浮液,其包含上述组合物和液体,其中将所述悬浮液混合至均匀。在一些实施方案中,悬浮液包含5至200mg/mL磁珠。在另一些实施方案中,悬浮液包含5至100mg/mL磁珠。在另一些实施方案中,悬浮液包含5至60mg/mL磁珠。在某些实施方案中,悬浮液包含25至50mg/mL磁珠。在一些实施方案中,液体包含缓冲水溶液。在一些实施方案中,缓冲水溶液包含三羟甲基胺(TRIS)、磷酸盐、N-(2-羟乙基)哌嗪-N'-(2-乙磺酸)(HEPES)及其混合物。在一些实施方案中,缓冲水溶液进一步包含离液剂。在某些实施方案中,离液剂以2-8mol/L的浓度存在于悬浮液中。在一些实施方案中,离液剂选自碘化钠、高氯酸钠、硫氰酸胍、异硫氰酸胍和盐酸胍(guanidinium hydrochlorite)。
在另一个方面中,本公开提供一种配置为进行样品的核酸分析的装置,所述装置包括
a.适用于接收样品试样的样品引入口;
b.包含如本文所述的含磁珠的组合物的隔室;和
c.PCR分析区,其包括一个或多个附加隔室,所述隔室各自配置为进行所述PCR分析的一个或多个步骤,包括试剂制备、靶富集、抑制剂除去、核酸提取、扩增和实时检测。
在另一个方面中,本公开提供一种包括如本文中公开的装置的试剂盒。在一些实施方案中,所述试剂盒包括任何制品(例如包装或容器),其包括至少一个用于特异性扩增、捕获、标记/转化或检测如本文所述的靶核酸序列的装置,其中本文所述的组合物包含在所述装置中或作为单独的试剂盒组件、管瓶或容器提供。在一些实施方案中,所述试剂盒进一步包括使用说明书、补充试剂、控制材料和/或用于本文所述的扩增法或其步骤的组件或模块的任一种。
在另一个方面中,本公开提供一种包含上文公开的组合物的试剂盒。在一些实施方案中,所述组合物可在本文所述的装置中提供。在一些实施方案中,所述组合物在包装或容器中提供。在一些实施方案中,所述试剂盒进一步包含下列组分的至少一种:核苷三磷酸、核酸聚合酶和核酸聚合酶的工作所必需的缓冲液。在一些实施方案中,试剂盒组分作为分开的组分在分开的管瓶或容器中包含在试剂盒中。在一些实施方案中,一种或多种试剂盒组分在相同管瓶或容器中包含在试剂盒中。在一些实施方案中,所述试剂盒进一步包含洗脱剂或洗脱缓冲液。在一些实施方案中,所述试剂盒进一步含有具有5’至3’核酸外切酶活性的聚合酶。在一些实施方案中,所述试剂盒含有具有逆转录酶活性的酶。在一些实施方案中,所述试剂盒含有具有5’至3’核酸外切酶活性和逆转录酶活性的聚合酶。
在再一个方面中,本公开提供一种制造本文所述的磁珠的组合物的方法,其包括以下步骤
a.在溶剂热条件下使稳定剂和来自选自以下物质的任一种材料的纳米粒子接触,以形成大于100nm的受控尺寸的聚集体以形成超顺磁性的磁芯,所述物质为包含至少一种过渡金属的金属、金属盐、金属碳化物、金属氮化物、金属硫化物、金属磷化物、金属氧化物或金属螯合物;
b.用液体玻璃涂布在步骤(a)中形成的磁芯。
在一些实施方案中,涂布磁珠的直径在大约80-500nm之间,更尤其在大约150-450nm之间,更尤其在大约200-400nm之间,再更尤其在大约250-400nm之间。在某些实施方案中,磁珠具有200-400nm的粒度。在一些实施方案中,磁芯的直径在大约50-450nm之间,更尤其在大约100-400nm之间,更尤其在大约150-350nm之间,更尤其为大约200-350nm。在特定实施方案中,磁芯在大约250-320nm之间,更尤其在大约260-300nm之间,更尤其在大约270-290nm之间。在一些实施方案中,稳定剂选自柠檬酸盐、组氨酸、十六烷基三甲基溴化铵(CTAB)、十六烷基三甲基氯化铵(CTAC)、油酸钠、聚丙烯酸。在一个特定实施方案中,稳定剂是柠檬酸钠。在一些实施方案中,磁芯是Fe3O4、α-Fe2O3、γ-Fe2O3、MnFexOy、CoFexOy、NiFexOy、CuFexOy、ZnFexOy、CdFexOy、BaFexO和SrFexO,其中x和y随合成方法而变,且其中x优选是1至3,更优选2的整数,且其中y优选是3或4,最优选Fe3O4。在特定实施方案中,磁芯是磁铁矿芯。在一些实施方案中,溶剂热条件是包括190-250℃和1-20巴的提高的压力的条件。在一些实施方案中,磁珠是基本球形的。在一些实施方案中,液体玻璃涂层包含硅酸盐。在特定实施方案中,硅酸盐选自硅酸钠、硅酸钾、硅酸钙、硅酸锂和硅酸镁。在一些实施方案中,硅酸盐是硅酸钠。在一些实施方案中,液体玻璃涂层具有20nm或更低的厚度。在某些实施方案中,液体玻璃涂层具有10nm或更低的厚度。在一些实施方案中,步骤a.包括在稳定剂存在下还原金属盐。在某些实施方案中,金属盐是FeCl3且稳定剂是柠檬酸钠以形成磁铁矿芯。在某些实施方案中,液体玻璃是硅酸钠。在某些实施方案中,所述方法包括以下步骤:
a.通过在乙酸钠、柠檬酸钠和乙二醇存在下在升高的温度下还原FeCl3最多18小时而形成磁铁矿芯;
b.用液体玻璃,优选硅酸钠涂布在步骤(a)中形成的磁铁矿芯。
附图说明
图1A图示说明可用于生成本文所述的粒子的磁铁矿芯的溶剂热反应。图1B进一步图示说明将稳定剂添加到磁铁矿芯中。示例性地,柠檬酸盐围绕磁铁矿纳米粒子配位以产生超粒子体。
图2图示说明可用于制造本文所述的粒子的磁铁矿芯的化学反应的可能机理。
图3A图示说明原硅酸四乙酯(TEOS)涂布反应。图3B图示说明液体玻璃涂布反应。
图4A-4C包括显示试剂浓度对本文所述的MGP的形态的影响的对比SEM分析。图4A:比例因子1(MC13);图4B:比例因子2(MC15);图4C:比例因子4(MC06)。
图5图示说明可与本文所述的珠粒一起使用的样品处理装置。
图6图示说明粒子(MC48样品)的等电点对二氧化硅涂层厚度的依赖性。
图7A-7C图示说明MC48样品的测得FluA CT值(图7A)、FluB CT值(图7B)和RSV CT值(图7C)对它们的等电点的依赖性。
图8图示说明MC47样品的测得FluA、FluB、RSV和内部阳性对照(IPC)CT值对它们的等电点的依赖性。
图9图示说明MC48样品的测得的FluACT值对二氧化硅涂层厚度的依赖性。
图10A-10C图示说明磁性玻璃粒子MC14,无涂层(图10A)、具有根据本公开的液体玻璃涂层的低涂层厚度(图10B)和使用原硅酸四乙酯(TEOS)涂布程序的高涂层厚度(图10C)。
具体实施方式
定义
除非在本文中另行规定,本文所用的科学和技术术语具有本领域普通技术人员通常理解的含义。此外,除非上下文另行要求,单数术语包括复数并且复数术语包括单数。冠词“一个”和“一种”在本文中用于表示一个或多于一个(即至少一个)该冠词的语法对象。例如,“一个要素”是指一个要素或多于一个要素。
术语“检测”和类似术语在本申请中用于广义地表示发现或测定某物存在或不存在、以及程度、量或水平或出现概率的方法。例如,术语“检测”在用于靶核酸序列时可以是指发现或测定该序列存在、不存在、水平或量、以及存在或不存在的概率或可能性。要理解的是,表达“检测存在或不存在”、“存在或不存在的检测”和相关表达包括定性和定量检测。
术语“核酸”、“多核苷酸”和“寡核苷酸”是指核苷酸的聚合物(例如核糖核苷酸或脱氧核糖核苷酸)并包括天然存在(腺苷、胍、胞嘧啶、尿嘧啶和胸苷)、非天然存在和修饰的核酸。该术语不受聚合物的长度(例如单体数)限制。核酸可以是单链或双链的并通常含有5’-3’磷酸二酯键,尽管在一些情况下,核苷酸类似物可具有其它键。单体通常被称为核苷酸。术语“非天然核苷酸”或“修饰核苷酸”是指含有修饰含氮碱基、糖或磷酸基或在其结构中并入非天然基团的核苷酸。非天然核苷酸的实例包括双脱氧核苷酸、生物素化的、胺化的、脱氨基的、烷基化的、苄基化的和荧光体标记的核苷酸。
术语“样品”或“生物样品”是指含有或推定含有来自个体的核酸的任何组合物。该术语包括细胞、组织或血液的纯化或分离组分,例如DNA、RNA、蛋白质、无细胞部分或细胞裂解液。在一个实施方案中,样品是全血样品。本文所用的“全血样品”包括未从中除去任何成分,如血浆或血小板的取自身体的血液。通常,除存在抗凝剂外,该样品未改性。样品也可指其它类型的生物样品,例如血浆、血清、血液成分(血沉棕黄层)和干血点。样品也可包括获自个体的细胞的体外培养物的成分和组分,包括细胞系。生物样品的具体的附加实例包括粪便、粘膜拭子、组织抽出物、组织匀浆、细胞培养物和细胞培养上清液(包括真核和原核细胞的培养物)、尿液、唾液、痰和脑脊液样品。
在生产化合物的溶剂热合成方法中应用“溶剂热”条件。在本文中,溶剂热合成能够精确控制金属氧化物纳米粒子或纳米结构的尺寸、形状分布和结晶度。可通过改变某些实验参数,包括反应温度、反应时间、溶剂类型、表面活性剂类型和前体类型来改变这些特征(R.Xu等人,Modern Inorganic Synthetic Chemistry,Elsevier,2011,Amsterdam,第63页)。
本文所用的术语“亚铁磁性”是指由具有相反但不均匀分布的磁矩的原子群组成的材料,因此一旦施加外磁场就产生磁饱和和剩磁。
术语“顺磁性”是指某种形式的磁性,由此某些材料被外加磁场弱吸引并在施加磁场的方向上形成内部感应磁场。由于在该材料中存在不成对电子而发生顺磁性,因此具有未完全填满的原子轨道的所有原子是顺磁性的。由于它们的自旋,不成对电子具有磁偶极矩并表现得像微小磁体。外电场导致电子的自旋平行于该场配向,以造成净吸引。顺磁性材料包括铝、氧、钛和铁氧化物(FeO)。特别地,在不存在外加磁场的情况下,顺磁体不保留任何磁化,因为热运动使自旋取向随机化。因此,当移除外加场时总磁化降至0。
术语“超顺磁性”是指在小铁磁性或亚铁磁性纳米粒子中出现的某种形式的磁性。在不存在外磁场的情况下,纳米粒子的磁化看起来平均为0。这一状态被理解为超顺磁状态。在这种状态下,外磁场能将纳米粒子磁化,其中超顺磁性粒子的磁化率比顺磁性粒子大得多。
磁性粒子
本公开要解决的问题可被看作提供用于样品制备和用于生物测定,特别用于在样品处理小管中进行的自动化方法的具有改进的性质的磁性粒子。使用样品处理小管的***,如 System中描述的那些,对磁性粒子提出极具挑战性的要求。在这样的***中,洗涤、培养和洗脱步骤不是在几分钟内而是在几秒内发生,因此提高对粒子的要求。特别地,粒子应该提供强磁响应、应该具有小粒度并且应该表现出低剩磁。在一些方面中显示有益的是,粒子是超顺磁性的并具有>200nm的粒度,否则粒子分离太慢。
通过根据本公开的粒子提供对此问题的解决方案,所述粒子表现出低剩磁和快速磁性分离时间、对核酸的高和快速结合能力及核酸的快速洗脱性质的所需性质。特别地,根据本公开的粒子提供相对较高的可用表面积(用于高和快速结合能力)、低涂层厚度(用于磁饱和)、大约大于100nm的粒度(用于快速磁性分离时间)和超顺磁性的磁芯(用于低剩磁)。
在一个方面中,本公开提供一种磁性粒子或磁珠,其包含在溶剂热条件下制成的磁芯和基于液体玻璃的涂层,其中磁性粒子或磁珠是超顺磁性的。更具体地,本公开提供一种磁性粒子组合物。本文所用的“粒子”(或“珠粒”)是指具有相对较小直径的固体材料。本文中设想的粒子是具有基于液体玻璃的涂层的小磁芯的固体分散体。该粒子较小并且是基本球形的。应该指出,术语“粒子”和“珠粒”以及“磁性粒子”和“磁珠”可互换使用。这样的粒子或珠粒的优点包括但不限于:
·提高的粒度,例如大于100nm,例如100-500nm,更尤其200-400nm,以提供快速磁性分离时间、缓慢沉降时间和提高的外表面积之间的良好平衡;
·窄粒度分布,以产生均匀和可再现的结果;
·使用超顺磁性粒子,以产生低剩磁并在引入磁力后没有附聚倾向;
·使用相对较薄的液体玻璃涂层,以造成高饱和磁化强度;
·易制造性和工艺可规模化;和
·磁铁矿芯和涂层的优化合成,以降低制造时间和商品成本,废料减少。
在本文中,要指出,尺寸不是粒子的磁性质的唯一决定因素。例如,铁氧化物,如Fe3O4可以具有不同性质的不同变型存在。特别地,微晶的尺寸可与粒子的磁性质相关。例如,小微晶可表现出明显较低的剩磁并因此提供超顺磁性质,而尺寸为200nm或更大的微晶可能不表现出超顺磁性质。在一个具体实施方案中,根据本公开的粒子的磁芯由小微晶构成(例如进一步包含稳定剂的磁性纳米粒子的清晰聚集体)。因此,根据本公开的粒子达到100-500nm,更尤其200-400nm的尺寸,但仍表现出超顺磁性质。此外,超顺磁性质对该技术应用可以是决定性的,因为如果粒子与磁体接触几次,粒子可不附聚。
本公开的一个方面是磁性粒子的组合物,所述磁性粒子是基本球形的并具有小直径并含有至少一个直径大于100nm的磁性物体。在某些方面中,该直径在大约80-500nm之间,更尤其在大约150-450nm之间,更尤其在大约200-400nm之间,再更尤其在大约250-400nm之间。在某些方面中,磁芯的直径在大约50-450nm之间,更尤其在大约100-400nm之间,更尤其在大约150-350nm之间,更尤其为大约200-350nm。在特定方面中,磁芯在大约250-320nm之间,更尤其在大约260-300nm之间,更尤其在大约270-290nm之间。根据本公开的磁性粒子是玻璃微滴,其中分散着极小的非聚集磁性物体。因此,本文所述的磁性粒子也可被称为“磁性玻璃粒子(“MGP”)。被称为磁性的那些物体是指磁体,即铁磁性或超顺磁性材料。铁磁性材料可包括尚未预磁化的材料。预磁化在本文中被理解为是指与磁体接触,这提高剩磁。更具体地,根据本公开的磁性粒子的磁芯是超顺磁性的。用于生成超顺磁珠的合适材料是包含至少一种过渡金属的金属、金属盐、金属碳化物、金属氮化物、金属硫化物、金属磷化物、金属氧化物或金属螯合物。根据本公开的优选过渡金属包括但不限于铬、锰、铁、钴、镍、锌、镉、镍、钆、铜和钼。更优选地,该金属、金属碳化物、金属氮化物、金属硫化物、金属磷化物、金属氧化物或金属螯合物包含至少铁。更优选地,磁芯包含铁氧化物,特别是选自Fe3O4、α-Fe2O3、γ-Fe2O3、MnFexOy、CoFexOy、NiFexOy、CuFexOy、ZnFexOy、CdFexOy、BaFexO和SrFexO的铁氧化物,其中x和y随合成方法而变,且其中x优选是1至3,更优选2的整数,且其中y优选是3或4。最优选地,磁芯包含Fe3O4。更具体地,优选的磁性材料是铁或铁氧化物,例如磁铁矿(Fe3O4)或Fe2O3。
根据本公开,上文规定的磁芯材料包含含稳定剂的磁性纳米粒子的清晰聚集体。合适的稳定剂选自由二羧酸、三羧酸、聚丙烯酸、氨基酸、表面活性剂和脂肪酸构成的组的至少一员,包括所提到的化合物的盐和衍生物,如酯和聚合物。因此要理解的是,上文提到的组包括所提到的化合物的盐和衍生物,如酯和聚合物。因此,稳定剂优选选自由二羧酸、二羧酸盐、二羧酸衍生物、三羧酸、三羧酸盐、三羧酸衍生物、聚丙烯酸、聚丙烯酸盐、聚丙烯酸衍生物、氨基酸、氨基酸盐、氨基酸衍生物、表面活性剂、表面活性剂的盐、脂肪酸、脂肪酸盐和脂肪酸衍生物构成的组的至少一员。在一个方面中,在形成表现出超顺磁性质的根据本公开的粒子的磁芯的粒子聚集体(所谓的超粒子体)的形成过程中原位加入稳定剂,如柠檬酸盐。在本文中,在粒子聚集体形成后后续加入稳定剂没有提供相同结果。
作为脂肪酸、脂肪酸盐或脂肪酸衍生物,优选选择能够结合到超粒子体的表面由此稳定超粒子体的此类化合物。用作稳定剂的脂肪酸优选是具有末端羧基(—COOH)和对磁性粒子表面的高亲和吸附(例如化学吸附或物理吸附)的含有8至22个碳原子的烷基的单链。该脂肪酸具有多重功能,包括保护磁性粒子芯免受氧化和/或在水存在下的水解,所述氧化和/或水解会显著降低纳米粒子的磁化(Hutten等人(2004)J.Bio-tech.112:47-63);稳定纳米粒子芯;等等。术语“脂肪酸”包括饱和或不饱和,特别是不饱和脂肪酸。示例性的饱和脂肪酸包括月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、花生酸、丙酸、丁酸、戊酸、己酸、庚酸、辛酸、壬酸、癸酸、十一烷酸、十三烷酸、十五烷酸、十七烷酸、十九烷酸、二十一烷酸(heneicosylic acid)、山嵛酸、二十三烷酸(tricosylic acid)、二十四烷酸、二十五烷酸(pentacosylic acid)、蜡酸、二十七烷酸(heptacosylic acid)、褐煤酸、二十九烷酸(nonacosylic acid)、蜂花酸、三十一烷酸(henatriacontylic acid)、三十二烷酸、三十三烷酸、三十四烷酸(geddic acid)、三十五烷酸(ceroplastic acid)、三十六烷酸、三十七烷酸和三十八烷酸等。示例性的不饱和脂肪酸包括油酸、亚油酸、亚麻酸、花生四烯酸、十六碳三烯酸、十八碳四烯酸、二十碳三烯酸、二十碳四烯酸、二十碳五烯酸、二十一碳五烯酸、二十二碳五烯酸、鲽鱼酸(clupanodonic acid)、二十二碳六烯酸、二十四碳五烯酸、二十四碳六烯酸、十八碳三烯酸、二十碳二烯酸、二十二碳二烯酸、肾上腺酸、二十二碳五烯酸、二十四碳四烯酸(tetracosatetraenoic acid)、二十四碳五烯酸、5-十二碳烯酸、7-十四碳烯酸、棕榈油酸、异油酸、二十烯酸(paullinic acid)、15-二十二碳烯酸、17-二十四碳烯酸、反油酸、gondoic acid、二十碳三烯酸(mead acid)、芥酸、神经酸、十八碳二烯酸(rumenicacid)、十八碳三烯酸、蓝花楹酸(jacaric acid)、桐酸、梓树酸(catalpic acid)、石榴酸、rumelenic acid、十八碳四烯酸、bosseopentaenoic acid、皮诺敛酸(pinolenic acid)、罗汉松酸等。脂肪酸可以是合成的或使用成熟的方法从天然来源分离。此外,脂肪酸可以是衍生物,如脂肪酸烯醇酯(即与丙酮的烯醇形式反应的脂肪酸)、脂肪酯(即具有被一元醇的烷基替代的活性氢的脂肪酸)、脂肪胺或脂肪酰胺,或在特定实施方案中,如上所述的脂肪醇。特别优选的脂肪酸是油酸。
如本公开中所用的表面活性剂是两亲的,即含有疏水基团和亲水基团的有机化合物。优选选择能够结合到超粒子体的表面由此优选稳定超粒子体的表面活性剂,可以根据应用使用具有各种链长、亲水-亲脂平衡(HLB)值和表面电荷的表面活性剂。优选地,根据本公开的表面活性剂是季铵盐、烷基苯磺酸盐、木质素磺酸盐、聚氧乙氧基化物(polyoxylethoxylate)或硫酸盐酯。表面活性剂的非限制性实例是十六烷基三甲基溴化铵(CTAB)、十六烷基三甲基氯化铵(CTAC)、壬基酚聚氧乙烯醚(即NP-4、NP-40和NP-7)、十二烷基苯磺酸钠、十二烷基硫酸铵、月桂基聚氧乙烯醚硫酸钠、十四烷基聚氧乙烯醚硫酸钠、多库酯(docusate)、全氟辛烷磺酸盐、全氟丁烷磺酸盐、烷基芳基醚磷酸盐、烷基醚磷酸盐、硬脂酸钠、2-丙烯酰氨基-2-甲基丙磺酸、全氟壬酸铵、月桂基聚氧乙烯醚硫酸镁、全氟壬酸、全氟辛酸、磷脂、十二烷基硫酸钾、烷基硫酸钠、十二烷基硫酸钠、月桂酸钠、月桂酰基肌氨酸钠、壬酰氧基苯磺酸钠、烷基聚氧乙烯醚硫酸钠(sodium pareth sulfate)、山嵛基三甲基氯化铵、烷基苄基二甲基氯化铵、异辛基苯氧基乙氧基乙基苄基二甲基氯化铵、bronidox、二甲基双十八烷基溴化铵、二甲基双十八烷基氯化铵、月桂基甲基葡糖聚氧乙烯(10)醚羟基丙基二甲基氯化铵、奥替尼啶双盐酸盐、奥拉氟(olaflur)、N-油基-1,3-丙二胺、硬脂基二甲基苄基氯化铵、四甲基氢氧化铵、通佐溴铵、cetomacrogol 1000、十六/十八醇、鲸蜡醇、椰油酰基二乙醇胺、椰油酰基单乙醇胺、癸基聚葡糖、椰油酰两性基二乙酸二钠、甘油单硬脂酸酯、聚乙二醇异鲸蜡醚、辛基苯氧基聚乙氧基乙醇、月桂基葡糖苷、麦芽糖苷、甘油单月桂酸酯(monolaurin)、抗霉枯草菌素(mycosubtilin)、壬基酚聚氧乙烯醚、八乙二醇单十二烷基醚、N-辛基β-D-硫代吡喃葡萄糖苷、辛基葡糖苷、油醇、五乙二醇单-十二烷基醚、聚桂醇(polidocanol)、聚氧乙烯聚氧丙烯嵌段共聚物、聚乙氧基化牛油胺、聚甘油聚蓖麻酸酯、聚山梨酯、失水山梨醇、失水山梨醇单月桂酸酯、失水山梨醇单硬脂酸酯、失水山梨醇三硬脂酸酯、硬脂醇、表面活性素(surfactin)、Triton X-100、Tween 80、椰油酰氨基丙基甜菜碱、椰油酰氨基丙基羟基丙基磺基甜菜碱、二棕榈酰基磷脂酰胆碱、羟基磺基甜菜碱(hydroxysultaine)、月桂基二甲基氧化胺、卵磷脂、十四烷基氧化胺、peptitergents、月桂酰两性基乙酸钠和双(2-乙基己基)磺基琥珀酸酯。
所用的术语“氨基酸”在本公开的含义内是指天然或非天然氨基酸或氨基酸衍生物,以及氨基酸的盐。优选选择能够结合到超粒子体的表面由此优选稳定超粒子体的氨基酸。示例性的氨基酸包括半胱氨酸、蛋氨酸、组氨酸、丙氨酸、精氨酸、天冬酰胺、天冬氨酸、谷氨酸、谷氨酰胺、甘氨酸、异亮氨酸、亮氨酸、赖氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸、缬氨酸、硒半胱氨酸、吡咯赖氨酸、半胱氨酸、脱氢丙氨酸、enduracididine、羊毛硫氨酸、正缬氨酸及其衍生物。
术语“二羧酸”在本公开的含义内是指含有两个羧酸官能团的烃或取代烃(即R1-(C(O)OH)2),其中R1是(a)含有0-18个碳单元的直链烃或(b)含有3-8个碳单元的环烃,作为芳环或非芳环。该术语包括脂肪酸的盐和衍生物,如脂肪酸的酯。代表性的二羧酸是例如丙二酸、丁二酸、戊二酸、己二酸、庚二酸、辛二酸、壬二酸、癸二酸、十一烷二酸、十二烷二酸、十六烷二酸、马来酸、富马酸、戊烯二酸、愈伤酸、粘康酸、戊炔二酸、柠康酸、中康酸、苹果酸、天冬氨酸、谷氨酸、丙醇二酸、酒石酸、二氨基庚二酸、葡糖二酸、丙酮二酸、草酰乙酸、丙酮二甲酸、***糖二酸(arabinaric acid)、邻苯二甲酸、间苯二甲酸、对苯二甲酸、联苯二甲酸、2,6-萘二甲酸。
术语“三羧酸”在本公开的含义内是指含有三个羧酸官能团的烃或取代烃(即R1-(C(O)OH)3),其中R1是(a)含有3-18个碳单元的直链烃或(b)含有3-8个碳单元的环烃,作为芳环或非芳环。该术语包括脂肪酸的盐和衍生物,如脂肪酸的酯。代表性的三羧酸是例如柠檬酸(2-羟基丙烷-1,2,3三甲酸)、异柠檬酸(l-羟基丙烷-1,2,3三甲酸)、乌头酸(丙-1-烯-1,2,3三甲酸)、丙烷-1,2,3-三甲酸、偏苯三甲酸(苯-1,2,4-三甲酸)、均苯三甲酸(苯-l,3,5-三甲酸)、草酰琥珀酸(1-氧代丙烷-1,2,3-三甲酸)或连苯三甲酸(苯-l,2,3-三甲酸)。优选地,该三羧酸是柠檬酸,包括柠檬酸盐,即柠檬酸的盐和衍生物。
优选地,稳定剂选自柠檬酸、组氨酸、十六烷基三甲基溴化铵(CTAB)、十六烷基三甲基氯化铵(CTAC)、油酸钠、聚丙烯酸或其中两种或更多种的混合物,包括各自的盐或其衍生物。因此,本公开还涉及如上所述的磁性粒子,其中磁芯优选由超粒子体组成,所述超粒子体由含至少一种稳定剂的聚集磁性纳米粒子组成,其中所述至少一种稳定剂选自柠檬酸盐、组氨酸、十六烷基三甲基溴化铵(CTAB)、十六烷基三甲基氯化铵(CTAC)、油酸钠、聚丙烯酸或其中两种或更多种的混合物。在一个特定实施方案中,稳定剂是柠檬酸钠。稳定剂的量优选在基于稳定剂和超粒子体的总重量计1至80重量%的范围内,更优选在5至70重量%的范围内,更优选在10至50重量%的范围内,最优选20至40%。
在某些方面中,在溶剂热条件下制造MGP的磁芯。溶剂热条件被理解为包括大约190-250℃和大约1-20巴的提高的压力。
还提供一种磁珠的悬浮液,例如其可通过将液体添加到MGP的组合物中并将该悬浮液混合至均匀制成。该悬浮液中可用的液体可包括不影响磁性粒子的稳定性并可用于制造均匀悬浮液的任何液体。使用适用于分子生物学中的工艺,特别是利用这些物质在某些条件下与玻璃粒子的结合的脱氧核糖核酸(DNA)或核糖核酸(RNA)纯化工艺的合适的液体。替代性的液体包括醇或其与水或酮的任何混合物。在一个实施方案中,悬浮液可含有5至200mg/mL MGP。在另一些实施方案中,悬浮液可含有5至100mg/mL MGP。在另一些实施方案中,悬浮液可含有5至60mg/mL MGP。在某些实施方案中,悬浮液可含有25至50mg/mLMGP。
替代性地或附加地,将MGP悬浮在可任选含有离液剂的缓冲水溶液中。在此,浓度可在2至8mol/l之间,例如在4至6mol/l之间。离液盐可以是碘化钠、高氯酸钠、硫氰酸胍、异硫氰酸胍或盐酸胍。本文所用的“离液剂”包括干扰液态水的有序结构并具有如果在含DNA或RNA的溶液中存在这一试剂则DNA或RNA将结合到MGP上的作用的任何化学物质。可用于分子生物学用途的缓冲体系可见于例如Sambrook等人(1989)、Molecular Cloning,ColdSpring Harbor University Press,New York,N.Y.,USA。优选的缓冲物质是三羟甲基胺(TRIS)、磷酸盐、N-(2-羟乙基)哌嗪-N'-(2-乙磺酸)(HEPES)、其盐或其它合适的物质。另外,可存在改变该溶液的离子强度的物质,例如NaCl、KCl或CaCl2或作为金属阳离子配合剂的物质,例如乙二胺四乙酸(EDTA)或其盐。在另一实施方案中,MGP的悬浮液可另外含有任选与蛋白质、脂肪酸、碳水化合物和来自生物来源的其它材料混合的DNA或RNA。在另一实施方案中,该液体可含有选自醇、酮、缓冲水溶液、离液剂、改变溶液的离子强度的物质、配合剂、生物材料、DNA或RNA(都具有如上所述的特征)的一种或多种成分的混合物。
可用于MGP的磁性材料可通过本领域中已知的任何合适的方法表征。例如,磁饱和是在施加的外部磁场的提高无法进一步提高材料的磁化时达到的状态,因此总磁通密度或多或少趋平。同样地,剩磁或剩余磁化强度或残余磁性是在移除外部磁场后在铁磁材料(如铁)中留下的磁化。在一个实施方案中,本文中设想的MGP具有30–80Am2/kg,更尤其50-70Am2/kg的饱和磁化强度和低于5Am2/kg,更尤其低于3,再更尤其低于2的剩磁。
本文所述的MGP中所用的磁芯材料包括由非晶材料构成的涂层,其含有液体玻璃涂层,例如钠液体玻璃涂层。未涂布的磁芯粒子具有大约250-320nm,更尤其260-300nm,更尤其270-290nm的直径。在施加液体玻璃涂层后,涂布的珠粒分别具有大约270-340nm,更尤其280-320nm的直径,磁化到50-70Am2/kg。
制造磁性粒子的方法
在本文中进一步公开了制造上文公开的磁珠的组合物的方法。在此,在第一步骤中,在溶剂热条件下使稳定剂与来自选自以下物质的任一种材料的纳米粒子接触,所述物质为包含至少一种过渡金属的金属、金属盐、金属碳化物、金属氮化物、金属硫化物、金属磷化物、金属氧化物或金属螯合物。由此制成具有大于100nm的受控尺寸的聚集体,其形成超顺磁性的磁芯。在第二步骤中,用液体玻璃涂布磁芯以形成根据本公开的磁珠。
该反应在升高的温度,优选190-250℃,和升高的压力,优选1-20巴下进行。在这样的溶剂热条件下,稳定剂围绕磁性纳米粒子在表面上配位以产生超粒子体。因此,磁芯包含由聚集的、稳定剂涂布的纳米粒子(它们互相聚集)构成的超粒子体。在此,涂层是覆盖各纳米粒子的至少一部分,优选整个表面的稳定剂。优选地,也在这种情况下,各纳米粒子包含选自金属、金属盐、金属碳化物、金属氮化物、金属硫化物、金属磷化物、金属氧化物、金属螯合物和其中两种或更多种的混合物的化合物。要理解的是,超粒子体中存在的各纳米粒子可包含上文提到的组中的两种或更多种的混合物,即金属、金属盐、金属碳化物、金属氮化物、金属硫化物、金属磷化物、金属氧化物、金属螯合物和其中两种或更多种的混合物中的两种或更多种。此外,也可想到两种或更多种不同金属、两种或更多种不同金属盐、两种或更多种不同金属氧化物、两种或更多种不同金属碳化物、两种或更多种不同金属氮化物、两种或更多种不同金属硫化物、两种或更多种不同金属螯合物或两种或更多种不同金属磷化物的混合物。更优选地,超粒子体中的各纳米粒子包含金属氧化物或金属碳化物。在一个优选实施方案中,该金属是过渡金属。根据本公开的优选过渡金属包括但不限于铬、锰、铁、钴、镍、锌、镉、镍、钆、铜和钼。该金属最优选是铁。根据一个特定实施方案,超粒子体中包含的各纳米粒子是金属氧化物纳米粒子,最优选铁氧化物纳米粒子,特别是Fe3O4-纳米粒子。
因此,本公开还涉及如上所述的磁性粒子,以及通过上述方法获得或可获得的磁性粒子,其中磁芯包含或优选由超粒子体组成,所述超粒子体由聚集纳米粒子组成,其中所述纳米粒子优选被至少一种稳定剂涂布。
优选地,磁芯具有在80至500nm的范围内,更尤其在大约150-450nm之间,更尤其在大约200-400nm之间,再更尤其在大约250-400nm之间的直径。在某些实施方案中,磁珠具有在200-400nm之间的粒度。在一些实施方案中,磁芯的直径在大约50-450nm之间,更尤其在大约100-400nm之间,更尤其在大约150-350nm之间,更尤其为大约200-350nm。在特定实施方案中,磁芯在大约250-320nm之间,更尤其在大约260-300nm之间,更尤其在大约270-290nm之间。
优选地,稳定剂选自由二羧酸、三羧酸、聚丙烯酸、氨基酸、表面活性剂和脂肪酸构成的组的至少一员。因此要理解的是,上文提到的组包括所提到的化合物的盐和衍生物,如酯和聚合物。因此,稳定剂优选选自由二羧酸、二羧酸盐、二羧酸衍生物、三羧酸、三羧酸盐、三羧酸衍生物、聚丙烯酸、聚丙烯酸盐、聚丙烯酸衍生物、氨基酸、氨基酸盐、氨基酸衍生物、表面活性剂、表面活性剂的盐、脂肪酸、脂肪酸盐和脂肪酸衍生物构成的组的至少一员。
本文所用的术语“涂布的”或“涂布”用于表示磁性纳米粒子和稳定剂的吸附、范德华力和/或非极性基团相互作用(例如化学吸附或物理吸附)或共价结合的过程。
在图1A中所示的一个特定实施方案中,在溶剂热条件下将铁(III)盐还原成Fe3O4以形成磁性纳米粒子。还原剂可选自醇,优选多元醇,如乙二醇、二乙二醇、三乙二醇。此外,在反应混合物中存在稳定剂。如图1B中所示,稳定剂,如柠檬酸钠,围绕磁性纳米粒子在表面上配位,这提供具有受控尺寸的纳米粒子聚集体的原位形成以形成所谓的超粒子体。
在第二步骤中,用选自二氧化硅、硅酸盐、硅烷和其中两种或更多种的混合物的涂层涂布超粒子体。本领域中已知的方法是根据方法(/>等人,J.ColloidInterface Sci.,1968,26,62)使用原硅酸四乙酯(TEOS)。如图3A中所示,在加入TEOS前将超粒子体与乙醇和H2O混合。在15-35℃的温度下搅拌该混合物8至24小时提供被TEOS覆盖的磁珠。
此外,该涂层可选自二氧化硅(例如原硅酸四乙酯、甲基丙烯酸3-(三甲氧基甲硅烷基)丙酯、乙烯基三甲氧基硅烷、乙烯基三乙氧基硅烷、烯丙基三甲氧基硅烷、烯丙基三乙氧基硅烷、三乙氧基乙烯基硅烷、丙烯酸3-(三甲氧基甲硅烷基)丙酯、三甲氧基(7-辛烯-1-基)硅烷、三甲氧基甲基硅烷、三乙氧基甲基硅烷、乙基三甲氧基硅烷、三乙氧基(乙基)硅烷、三甲氧基苯基硅烷、三甲氧基(2-苯基乙基)硅烷、三甲氧基(丙基)硅烷、正丙基三乙氧基硅烷、异丁基(三甲氧基)硅烷、异丁基三乙氧基硅烷)或硅酸盐(例如硅酸钠、硅酸钾、硅酸钙、硅酸锂和硅酸镁)。如图3B中所示,可通过在加入HCl前将超粒子体与H2O和钠液体玻璃(例如硅酸钠)混合而对超粒子体施以液体玻璃(“LG”)涂布。在15-35℃的温度下搅拌该混合物2至12小时提供具有液体玻璃涂层的磁珠。根据涂布效力,液体玻璃涂布步骤可至少再重复一次。通过将HCl缓慢滴加和施加到该溶液中,可以精确调节涂层厚度。因此,在将HCl添加到该溶液时可使用明确受控的条件获得极薄涂层。如下列实施例章节中所示,例如在测定中,太厚的涂层导致结果受损。
测定***&样品处理装置
本文所述的MGP可用于任何手动扩增测定法或自动化核酸扩增***或样品制备***。在一个实施方案中,该MGP可用于任何合适的市售PCR仪器和/或样品制备***,包括但不限于6800/8800System、/>4800System、/>AmpliPrep Instrument、 System、/>p630Instrument、/>s201 System、/>48Analyzer、/>Analyzer、/>1536System、/>2.0System、/>480System、/>96System、MagNA Pure 96System、MagNAPure Compact System、MagNA Pure LC 2.0System或FLOW Solution(参见例如www.molecular.roche.com/systems)。
在一个具体实施方案中,本文所述的MGP用于配置为进行核酸扩增技术的样品处理装置。从生物样品中提取的核酸可通过使用上述任一方法扩增核酸而进一步处理。在一个具体实施方案中,从生物体中提取的核酸是RNA且它们的处理包括使用酶如Tth聚合酶和Taq聚合酶或逆转录酶和Taq聚合酶的组合的联合逆转录和聚合酶链式反应(RT-PCR)。在一些实施方案中,带切口的环形核酸探针可使用T4 DNA连接酶或AmpligaseTM和指导核酸环化(circularized),接着在体外选择过程后检测封闭环化探针的形成。这样的检测可通过使用本领域技术人员已知的酶的PCR、TMA、RCA、LCR、NASBA或SDAR。在示例性实施方案中,可使用荧光标记核酸探针或DNA嵌入染料以及在分子分析仪中的光度计或电荷耦合器件以检测在核酸扩增过程中的荧光增强来实时检测核酸的扩增。这些荧光标记探针使用本领域技术人员已知的检测方案(即TaqManTM、molecular beaconsTM、荧光共振能量转移(FRET)探针、scorpionTM探针)并通常使用荧光淬灭以及淬灭的释放或从一个报道子到另一报道子的荧光能量转移以检测特定核酸的合成或存在。
在一个实施方案中,本文中公开的MGP用于包括自容式(self-contained)微观至宏观通道、室、储器、检测区和处理区的装置。该装置可以是如例如美国专利6,440,725;6,783,934;6,818,185;6,979,424;8,580,559;和8,940,526(它们的公开内容全文经此引用并入本文)中描述的盒、装置、容器或袋,以及如可获自Cepheid Corp.、Idaho Technology,Inc.和/或Biofire Diagnostics,Inc.的装置。
例如,该装置可以是如美国申请公开201000056383(其公开内容经此引用并入本文)的图1中所示的自容式核酸分析袋,其包括细胞裂解区、核酸制备区、一级扩增区、二级扩增区。该袋包括各种通道和各种尺寸的泡体(blisters)并布置成使样品流经该***和各种区域并相应地处理。样品处理在位于袋内的各种泡体中发生。提供许多通道以使样品在处理区内和在处理区之间移动,同时提供另一些通道以将流体和试剂传送至样品或从样品中除去此类流体和试剂。通过压力,例如气动压力使袋内的液体在泡体之间移动。在这一特定实施方案中,在配置为容纳MGP并与一个或其它通道和泡体流体连通的隔室中提供本文所述的MGP以使MGP可并入样品处理工作流程中并相应地处理。
在一个替代实例中,该装置可以是如美国专利9,322,052(其经此引用并入本文)的图3-5和9中所示的自容式核酸分析盒。该盒尤其包括多个室,所述室包括用于容纳经入口引入的流体样品的样品室、用于容纳洗涤溶液的洗涤室、用于容纳裂解试剂的试剂室、裂解室、用于接收用过的样品和洗涤溶液的废物室、用于容纳中和剂的中和剂室和用于容纳预混液(master mix)(例如扩增试剂和荧光探针)和用于将试剂和探针与从流体样品中分离的被分析物混合的预混液室、反应容器和检测室。在这一实施方案中,在配置为容纳MGP并与一个或其它通道和泡体流体连通的隔室中提供本文所述的MGP以使MGP可并入样品处理工作流程中并相应地处理。
在一个具体实施方案中,本文所述的方法在样品处理装置,如美国专利No.7,718,421(其公开内容经此引用并入本文)中所述的样品处理装置中进行。分段装置,如美国专利7,718,421中描述的那些,提供用于接收、储存、处理和/或分析生物样品的方便的容器。在某些实施方案中,分段装置有利于涉及多个处理步骤的样品处理程序。在某些实施方案中,可将样品收集在样品装置中,然后将该装置安置在分析仪中,所述分析仪控制该装置及其内容物以处理样品。
一个特定实施方案包括柔性装置(flexibledevice),其已通过可破坏密封件分隔成隔室。各段可含有用于处理样品的各种试剂和缓冲剂。夹具和致动器可以各种组合和在各种时机施加到该装置以指导流体的移动和使可破坏密封件爆裂。可破坏密封件的这种爆裂可留下基本不阻碍流体流体的装置内表面。在一个实施方案中,随着处理进行,可将生物样品的流动导向该装置的远端,同时可迫使废物流朝该装置的开口(最初在此输入样品)反向运动。可用具有闭锁机构的盖子密封这一样品入口,可能永久密封,并且废物室可位于盖子中以接收废物以供储存。这种方法的明显益处在于,处理过的样品不与已接触未处理的样品的表面接触。因此,可能涂布装置壁的未处理的样品中存在的痕量反应抑制剂较不可能污染处理过的样品。
样品处理装置显示在图5中并可包括透明柔性装置10,其能够配置成多个段,如16、110、120、130、140、150、160、170、180和/或190,并通过压缩基本压平(flattened)。在一个实施方案中,装置可具有至少两段。在一个实施方案中,装置可具有至少三段。该柔性装置可提供在在大约2-105℃之间的操作功能、与样品、靶和试剂的相容性、低气体渗透性、最小荧光性质和/或在反复压缩和弯曲循环过程中的回弹性。该装置可由各种材料制成,其实例包括但不限于:聚烯烃如聚丙烯或聚乙烯、聚氨酯、聚烯烃共聚物和/或提供合适特征的其它材料。
在示例性实施方案中,一种或多种试剂可作为干物质和/或作为液体溶液储存在装置段中。在试剂以干燥形式储存的实施方案中,可将液体溶液储存在相邻段中以促进试剂溶液的重构。典型试剂的实例包括:裂解试剂、洗脱缓冲液、洗涤缓冲液、DNase抑制剂、RNase抑制剂、蛋白酶抑制剂、螯合剂、中和试剂、离液盐溶液、洗涤剂、表面活性剂、抗凝剂、germinant溶液、异丙醇、乙醇溶液、抗体、核酸探针、肽核酸探针和硫代磷酸酯(phosphothioate)核酸探针。在试剂之一是离液盐溶液的实施方案中,优选组分是异氰酸胍盐或盐酸胍盐或其组合。在一些实施方案中,相对于输入样品的开口,试剂可储存在装置中的顺序反映了在利用该管的方法中可使用试剂的顺序。在优选实施方案中,试剂包括能够特异性结合到样品的预选组分上的物质。例如,一种物质可能特异性结合到核酸上,或核酸探针可能特异性结合到具有特定碱基序列的核酸上。
可使用连接到块体(block)的传感器,如光度计、分光仪、CCD实现来自装置段的信号的实时检测。在示例性实施方案中,可通过装置段上的致动器施加压力以合适地限定该装置段的形状。信号的格式可以是特定波长的光,如荧光的强度、光谱和/或图像,如细胞或人造元素,如量子点的图像。对于荧光检测,可使用来自光学***的光的激发照亮反应,并可通过光度计检测发射光。为了检测具有特定波长的多个信号,可通过专用检测通道或分光仪串联或并联检测不同的波长信号。
试剂盒
在一些实施方案中,本文所述的MGP及其组合物和悬浮液包括在试剂盒或其组件中。本文中设想的试剂盒可包括任何制品(例如包装或容器),其包括至少一个用于特异性扩增、捕获、标记/转化或检测如本文所述的靶核酸序列的装置,其中本文所述的组合物包括在所述装置中或作为单独的试剂盒组件、管瓶或容器提供。试剂盒可进一步包括使用说明书、补充试剂、控制材料和/或用于本文所述的扩增法或其步骤的组件或模块。试剂盒还可包括下列组分的至少一种:核苷三磷酸、核酸聚合酶和核酸聚合酶的工作所必需的缓冲液。一种或多种试剂盒组分可作为分开的组分包括在试剂盒中,例如在包装在一起的分开的管瓶或容器中,或一种或多种试剂盒组分可在相同管瓶或容器中包括在试剂盒中。
这样的试剂盒可包括在样品制备程序的过程中可用的组件/组分,例如96-或384-孔格式的微量滴定板或例如Eppendorf,Hamburg,Germany制造的普通反应管和用于使用本文所述的控制材料进行核酸扩增的所有其它试剂。试剂盒可包含如本文所述的MGP。试剂盒可进一步或另外包含蛋白酶试剂和含有例如能使细胞裂解的离液剂、洗涤剂或醇或其混合物的裂解缓冲液。试剂盒的这些组分可单独在管或储存容器中提供。根据组分的性质,这些可在单个管或储存容器中提供。试剂盒可进一步或另外包含当核酸结合到磁性玻璃粒子上时适用于磁性玻璃粒子的洗涤步骤的洗涤溶液。这种洗涤溶液可含有在一种或多种缓冲溶液中的乙醇和/或离液剂,在没有如上所述的乙醇和/或离液剂的情况下具有酸性pH。洗涤溶液或其它溶液通常作为必须在使用前稀释的原液提供。
试剂盒可进一步包含洗脱剂或洗脱缓冲液,即溶液或缓冲液(例如10mM Tris、1mMEDTA、pH 8.0)或纯水以洗脱结合到磁性玻璃粒子上的核酸。此外,可存在可用于核酸纯化的附加试剂或缓冲溶液。
在一个具体实施方案中,试剂盒含有具有5’至3’核酸外切酶活性的聚合酶。试剂盒还可含有具有逆转录酶活性的酶。在另一实施方案中,试剂盒含有具有5’至3’核酸外切酶活性和逆转录酶活性的聚合酶。
磁性粒子的使用方法及用途
本文所述的MGP(及其组合物和悬浮液)可用于分析任何靶核酸,包括但不限于,与细菌性病原体(例如耐甲氧西林金黄色葡萄球菌、艰难梭菌、结核、B组链球菌、脓毒症、衣原体和淋病)、病毒性病原体(例如流感、HIV、HCV和HBV)、肿瘤细胞(例如膀胱癌、肺癌、乳腺癌、结肠癌和白血病)、染色体改变,如基因复制、基因缺失或基因易位、表达特异性细胞表面标志物的细胞如CD4+细胞、基因突变/改变如单核苷酸多态性(SNP)和基因的甲基化状态的检测关联的核酸。
在一个实施方案中,MGP可用于包括包括核酸捕获、富集、分析和/或纯化的测定。例如,本文所述的MGP可用于捕获靶核酸。捕获可助于富集靶核酸和从样品中除去反应抑制剂。MGP可在限定的化学和温度条件下用于捕获、富集和/或纯化,并可在不同的化学和温度条件下释放组分。
在一个具体实施方案中,MGP用于通过核酸扩增法分析样品中的核酸。核酸扩增法可包括但不限于连接酶链式反应(LCR;Wu D.Y.和Wallace R.B.,Genomics 4(1989)560-69;和Barany F.,Proc.Natl.Acad.Sci.USA 88(1991)189-193);聚合酶连接酶链式反应(Barany F.,PCR Methods and Applic.1(1991)5-16);Gap-LCR(WO 90/01069);修复链式反应(Repair Chain Reaction)(EP 0439182 A2)、3SR(Kwoh D.Y.等人,Proc.Natl.Acad.Sci.USA 86(1989)1173-1177;Guatelli J.C.等人,Proc.Natl.Acad.Sci.USA 87(1990)1874-1878;WO 92/08808)和NASBA(US 5,130,238)。此外,本文所述的MGP也可用于下列方法:链置换扩增(SDA)、转录介导的扩增(TMA)和Qb-扩增(关于综述,参见例如Whelen A.C.和Persing D.H.,Annu.Rev.Microbiol.50(1996)349-373;Abramson R.D.和Myers T.W.,Curr Opin Biotechnol 4(1993)41-47)。
一种核酸扩增方法是美国专利4,683,202、4,683,195、4,800,159和4,965,188等参考文献中公开的聚合酶链式反应(PCR)。PCR通常使用两种或更多种结合到所选核酸模板(例如DNA或RNA)上的寡核苷酸引物。可用于核酸分析的引物包括能够充当靶核酸的核酸序列内的核酸合成的起始点的寡核苷酸。引物可通过常规方法从限制酶切消化(restrictiondigest)中纯化,或其可合成生产。引物优选是单链的以使扩增中的效率最大化,但引物可以是双链的。首先将双链引物变性,即处理以分离链。使双链核酸变性的一种方法是通过加热。“热稳定聚合酶”是热稳定的聚合酶,即其是催化与模板互补的引物延伸产物的形成并在经受升高的温度持续实现双链模板核酸的变性所必需的时间时不会不可逆变性的酶。通常,在各引物的3’端引发合成并沿模板链在5’至3’方向继续。热稳定聚合酶已例如分离自黄栖热菌(Thermus flavus)、T.ruber、嗜热栖热菌(T.thermophilus)、水生栖热菌(T.aquaticus)、T.lacteus、红色栖热菌(T.rubens)、嗜热脂肪芽孢杆菌和Methanothermusfervidus。但是,在PCR测定中也可使用非热稳定的聚合酶,只要补充酶。
如果模板核酸是双链的,在其可用作PCR中的模板之前必须分离两个链。可通过任何合适的变性方法实现链分离,包括物理、化学或酶促手段。一种分离核酸链的方法涉及加热核酸直至其大部分变性(例如大于50%、60%、70%、80%、90%或95%变性)。使模板核酸变性所必需的加热条件取决于例如缓冲盐浓度和变性的核酸的长度和核苷酸组成,但通常为大约90℃至大约105℃,时间取决于反应的特征,如温度和核酸长度。变性通常进行大约5s至9min。为了不使各自的聚合酶太长时间暴露于如此高的温度并因此具有功能酶损失风险,优选使用短变性步骤。在一个具体实施方案中,变性步骤为最多30s,例如最多20s、最多10s、最多5s,尤其是大约5s。
如果通过热使双链模板核酸变性,允许反应混合物冷却到促进各引物退火到其在靶核酸上的靶序列的温度。用于退火的温度优选为大约35℃至大约70℃,更优选大约45℃至大约65℃;更优选大约50℃至大约60℃,更优选大约55℃至大约58℃。退火时间可为大约10s至大约1min(例如大约20s至大约50s;大约30s至大约40s)。在这种情况下,有利的是使用不同的退火温度以提高各自测定的包容性(inclusivity)。简言之,这意味着在相对较低的退火温度下,引物也可结合到具有单错配(single mismatches)的靶,因此也可扩增某些序列的变异体。如果例如某一生物体具有已知或未知的遗传变异体(这也应该检测),这可是理想的。另一方面,相对较高的退火温度具有提供较高特异性的优点,因为在较高温度下,引物结合到不完全匹配的靶序列上的可能性持续降低。为了获益于这两个现象,在本公开的一些实施方案中,上述方法优选包括在不同温度下退火,优选首先在较低温度下,然后在较高温度下退火。如果例如初次培养在55℃下进行大约5个周期,可能(预)扩增不完全匹配的靶序列。此后可以例如在58℃下大约45个周期,以在实验的大部分过程中提供更高的特异性。由此,不会遗失可能重要的遗传变异体,同时特异性保持相对较高。
然后将反应混合物调节到促进或优化聚合酶的活性的温度,即足以从退火引物发生延伸以生成与待分析的核酸互补的产物的温度。温度应该足以合成从退火的各引物到核酸模板的延伸产物,但不应高到使延伸产物从其互补模板变性(例如,用于延伸的温度通常为大约40℃至80℃(例如大约50℃至大约70℃;大约60℃))。延伸时间可为大约10秒至大约5分钟,优选大约15s至2min,更优选大约20s至大约1min,更优选大约25s至大约35s。新合成的链形成可用于该反应的后续步骤的双链分子。链分离、退火和伸长步骤可视需要经常重复以产生所需量的对应于靶核酸的扩增产物。该反应中的限制因素是该反应中存在的引物、热稳定酶和核苷三磷酸的量。循环步骤(即变性、退火和延伸)优选重复至少一次。为了用于检测,循环步骤数取决于例如样品的性质。如果样品是核酸的复杂混合物,需要更多的循环步骤扩增靶序列以足够用于检测。通常,循环步骤重复至少大约20次,但可重复多达40、60或甚至100次。
实施例
磁芯的合成
通过在如文献[3],即Liu等人(Angew.Chem.Int.Ed.,2009,48,5875–5879)中所述的溶剂热条件下将氯化铁(III)还原成铁(II,III)氧化物(Fe3O4),合成磁芯。简言之,通过将800毫升乙二醇用氩气脱气1小时来制造磁芯(“MC珠粒”)。加入FeCl3(44克)并溶解,将该溶液转移到压力反应器。加入柠檬酸钠(9.7克)和乙酸钠(51.9克)并将混合物加热到160℃,持续1小时,然后将温度提高到200℃并保持18小时。对该混合物施以使用乙醇和水的磁洗(3x乙醇、3x水)。所得MC珠粒是超顺磁性的。反应图式显示在图1A和1B中。在此,使用乙酸钠作为质子受体,而如图1B中所示加入柠檬酸钠以促进清晰纳米粒子聚集体的形成。可能的还原机理显示在图2中。
磁芯的涂布
根据方法(/>等人,J.Colloid Interface Sci.,1968,26,62)如下用原硅酸四乙酯(TEOS)涂布一部分MC珠粒:将0.4克通过上述方法制成的MC珠粒与1280毫升乙醇、312毫升H2O和16毫升NH4OH混合。将该混合物添加到活化30分钟的流通US池中。加入TEOS(2毫升)并将该混合物在25℃下搅拌16小时。对该混合物施以使用乙醇和水的磁洗(3x乙醇、3x水)。
通过在带有流通US池的250毫升玻璃反应器中将0.5克珠粒与160毫升H2O和40毫升钠液体玻璃混合(并预混合10分钟),对另一部分MC珠粒施以液体玻璃(“LG”)涂布。加入HCl(1M,66mL),继续搅拌该混合物并施加到流通US池2小时。然后对该混合物施以磁洗(3x水)并将上述液体玻璃涂布步骤至少再重复一次。示例性的珠粒是MC13-LG至MC17-LG。
通过在带有流通US池的玻璃反应器中以最多250毫升的总体积将MC珠粒(2-15g/L)与各种量的钠液体玻璃(38-100mL)混合(并预混合10分钟),对另一部分MC珠粒施以液体玻璃(“LG”)涂布。逐滴加入HCl(1-3M,45-110mL),继续搅拌该混合物并施加到流通US池4-6小时。然后对该混合物施以磁洗(3x水)。示例性的珠粒是MC47-LG和MC48-LG。
结果
未涂布的MC珠粒具有大约270nm的直径,TEOS涂布的粒子具有大约400nm的直径,且液体玻璃涂布的粒子具有大约280nm的直径,分别磁化到46.7(TEOS)和54(LG)A*m2/kg。
与根据文献[3],即Liu等人中提出的方法合成的珠粒相比较,使用未涂布的MC珠粒的实验的综述显示在表1中。
表1–未涂布珠粒的表征
/>
较高浓度反应的收率线性提高。另外,观察到饱和磁化强度(“Magn.”)的提高。剩磁(“Rem.”)也提高。SEM分析显示试剂浓度对纳米MGP的形态的影响,如图4A-C中图示说明。
如上文概述,该涂布方法改编自EP2916327B1。反应时间从超过2天减少到4小时并使用旁路探针(bypass probe)优化超声程序,这使得该涂布程序容易规模化并通过成功涂布10克展示,而在EP2916327B1中使用500毫克批料。为了比较,也通过方法涂布磁芯,其中使用TEOS作为试剂。表2显示不同的合成条件。
表2-涂布珠粒的表征
在第三步骤中,在上验证MGP的功能性。/>System是一种即时***(point-of-care system),其在/>Analyzer上完全自动化进行样品制备、PCR扩增和靶DNA/RNA序列的实时检测。周转时间(TAT)非常快,为10-20分钟。纳米MGP核酸结合、富集和纯化的总时间可短到5分钟或更短。在这些试验中,将10微升各纳米MGP在25mg/mL浓度下填充到/>管中。使用艰难梭菌(C.diff)、甲型流感(FluA)、乙型流感(FluB)和人呼吸道合胞病毒(RSV)作为靶核酸。低循环阈值(Ct)和高扩增(Amp)值是优选的。MC-LG珠粒表现出用于检测来自细菌或病毒生物体的DNA或RNA靶的一致性能,而MC-TEOS表现出延迟的Ct值和低Amp值。MGP的功能性能的结果概括在表3中。
表3-MGP的功能性能
涂布粒子的物理性质
通过在带有流通US池的玻璃反应器中以最多250毫升的总体积将MC珠粒(2-15g/L)与各种量的钠液体玻璃(38-100mL)混合(并预混合10分钟),对MC47和MC48珠粒施以液体玻璃(“LG”)涂布。根据所需涂层厚度逐滴加入HCl(1-3M,45-110mL),继续搅拌该混合物并施加到流通US池4-6小时。然后对该混合物施以磁洗(3x水)。
表4-MGP的等电点和二氧化硅涂层
样品 | 二氧化硅涂层l重量%l | 等电点 |
MC48 | 0 | 4.5 |
MC48LG2 | 15 | 1.5 |
MC48LG3 | 13 | 1.8 |
MC48LG5 | 7 | 2.5 |
MC48LG6 | 8 | 2.4 |
MC48LG7 | 20 | 1.2 |
MC48LG9 | 8 | 2.4 |
图6和表4显示粒子的等电点对粒子的涂层厚度(即二氧化硅含量)的依赖性。在此清楚显示,随着二氧化硅涂层增加,等电点的值降低。
随后,分析粒子的等电点对粒子在测定中的性能的影响。在此,使用来自/>FluA/B RSV试验的试剂在标准条件下对如上所述的二氧化硅涂布的MC47和MC48珠粒施以PCR扩增/检测反应。MC48珠粒对FluA(图7A)、FluB(图7B)和RSV(图7C)的测得循环阈值(CT)对等电点的依赖性的结果提供在图7中。在图8中,图示说明MC47样品的测得FluA、FluB、RSV和内部阳性对照(IPC)CT值对它们的等电点的依赖性。在表5中提供使用MC47和MC48涂布珠粒生成的CT值和它们与等电点值的相关性的概要。
表5-MC47和MC48珠粒的FluA、FluB、RSVCT和等电点值
样品 | 等电点 | FluA CT | Flub CT | RSV CT |
MC47LG1 | 2.7 | 31.1 | 31.7 | 31.0 |
MC47LG2 | 2.6 | 30.5 | 30.5 | 31.2 |
MC47LG3 | 2.9 | 31.0 | 30.9 | 31.4 |
MC47LG6 | 2.5 | 30.7 | 30.8 | 31.4 |
MC47LG7 | 2.4 | 31.4 | 32.0 | 31.0 |
MC47LG8 | 2.3 | 31.0 | 31.8 | 31.5 |
MC47LG12 | 2.2 | 31.0 | 31.5 | 31.7 |
MC47LGl4 | 1.5 | 35.8 | 39.1 | 33.1 |
MC47LG17 | 2.8 | 31.8 | 32.6 | 31.6 |
MC47LG19 | 3.2 | 31.4 | 31.9 | 31.0 |
MC47LG20 | 3.5 | 33.8 | 34.0 | 33.5 |
MC47LG21 | 3.2 | 31.4 | 32.0 | 31.1 |
MC47LG22 | 2.8 | 31.4 | 32.2 | 31.0 |
MC48LG2 | 1.5 | 33.0 | 33.7 | 31.8 |
MC48LG3 | 1.8 | 32.0 | 32.4 | 31.6 |
MC48LG5 | 2.5 | 31.3 | 32.2 | 31.2 |
MC48LG6 | 2.4 | 31.4 | 31.9 | 30.9 |
MC48LG7 | 1.2 | 34.3 | 35.7 | 33.9 |
MC48LG9 | 2.4 | 31.6 | 32.2 | 31.0 |
由这些数据可以推断,粒子在测定中的性能依赖于粒子的等电点。此外,显而易见,太高和太低的等电点值都会导致粒子性能受损。因此,由于粒子的等电点直接与粒子的涂层厚度相关联,非常重要的是控制粒子的涂层厚度,这根据本公开通过将HCl添加到粒子/硅酸盐悬浮液中实现。在显示涂层厚度与提高的CT值之间的直接相关性的图9中提供太厚的涂层导致粒子在PCR测定中的性能受损的进一步指示。在查看图l0中显示的SEM显微照片时,有益涂层的结构直接可见。比较未涂布的MC14珠粒(图10A)、使用根据本公开的方法涂布的MC14珠粒(图10B)和用上述TEOS方法涂布的MC14珠粒(图10C),显而易见,使用硅酸钠的液体玻璃涂层的涂层厚度极薄,而用TEOS涂布提供明显更厚的涂层。在此,上述TEOS涂布珠粒的延迟CT值也符合该数据,其表明厚涂层导致在PCR测定中的性能受损。
总之,上述数据清楚显示,根据本公开的涂布珠粒表现出比使用现有技术方法制造和涂布的磁珠有益的性质。在此,通过磁铁矿纳米粒子的受控聚集体构建磁芯粒子。借此,该粒子表现出极低的剩磁以及80-500nm的粒度。仅通过在溶剂热反应中原位加入稳定剂而形成受控聚集体。此外,必须具体控制粒子的玻璃涂层的厚度,因为应该避免太厚的涂层以及涂布粒子的太高和太低的等电点值。
本申请在范围上不受本文描述的具体实施方案限制。实际上,本领域技术人员由上述说明书和附图显而易见除本文描述的那些外的各种修改。这样的修改意图落在权利要求书的范围内。本文引用了各种出版物,它们的公开内容全文经此引用并入本文。
Claims (14)
1.一种磁珠的组合物,所述磁珠包含(a)稳定剂和在溶剂热条件下制成的磁芯,(b)液体玻璃涂层,其中每个磁珠都是超顺磁性的,其中所述液体玻璃涂层包含硅酸盐并具有20nm或更低的厚度,
其中所述磁芯是磁性纳米粒子的清晰聚集体,所述磁性纳米粒子具有<30nm的尺寸,并且其中所述磁芯的直径在100-400nm之间。
2.权利要求1的组合物,其中所述磁珠具有200-400nm的粒度。
3.权利要求1或2的组合物,其中所述磁珠具有50–70Am2/kg的饱和磁化强度。
4.权利要求1或2的组合物,其中所述磁珠具有低于3Am2/kg的剩磁。
5.权利要求1或2的组合物,其中所述硅酸盐选自硅酸钠、硅酸钾、硅酸钙、硅酸锂和硅酸镁。
6.权利要求1或2的组合物,其中所述稳定剂选自柠檬酸盐、组氨酸、十六烷基三甲基溴化铵(CTAB)、十六烷基三甲基氯化铵(CTAC)、油酸钠、聚丙烯酸。
7.权利要求1或2的组合物,其中所述磁芯是Fe3O4、α-Fe2O3、γ-Fe2O3、MnFexOy、CoFexOy、NiFexOy、CuFexOy、ZnFexOy、CdFexOy、BaFexO和SrFexO,其中x和y随合成方法而变,且其中x是1至3的整数,且其中y是3或4。
8.一种磁珠的悬浮液,包含根据权利要求1至7任一项的组合物和液体,其中将所述悬浮液混合至均匀。
9.权利要求8的悬浮液,其包含5–200mg/mL磁珠。
10.权利要求8至9任一项的悬浮液,其中所述液体包含缓冲水溶液。
11.权利要求10的悬浮液,其进一步包含离液剂。
12.一种配置为进行样品的核酸分析的装置,所述装置包括
(a)适用于接收样品试样的样品引入口;
(b)包含权利要求1至7任一项的组合物的隔室;和
(c)PCR分析区,其包括一个或多个附加隔室,所述隔室各自配置为进行所述PCR分析的一个或多个步骤,包括试剂制备、靶富集、抑制剂除去、核酸提取、扩增和实时检测。
13.一种试剂盒,包含权利要求1至7任一项的组合物。
14.一种制造根据权利要求1至7任一项的磁珠的组合物的方法,其包括以下步骤
a.在溶剂热条件下使稳定剂和来自选自以下物质的任一种材料的纳米粒子接触,以形成具有大于100nm的受控尺寸的磁性纳米粒子的聚集体以形成直径在100-400nm之间的超顺磁性的磁芯,其中所述物质为包含至少一种过渡金属的金属、金属盐、金属碳化物、金属氮化物、金属硫化物、金属磷化物、金属氧化物或金属螯合物,其中所述磁性纳米粒子具有<30nm的尺寸;
b.用液体玻璃涂布在步骤(a)中形成的所述磁芯,其中所述液体玻璃涂层包含硅酸盐并具有20nm或更低的厚度。
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