CN1761880A - 减少分析装置中的钩状效应 - Google Patents
减少分析装置中的钩状效应 Download PDFInfo
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- CN1761880A CN1761880A CNA2004800073280A CN200480007328A CN1761880A CN 1761880 A CN1761880 A CN 1761880A CN A2004800073280 A CNA2004800073280 A CN A2004800073280A CN 200480007328 A CN200480007328 A CN 200480007328A CN 1761880 A CN1761880 A CN 1761880A
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Abstract
提供了检测试样中被分析物的存在或量的基于膜的分析装置。该装置利用包含所感兴趣的被分析物的特异性结合元件的缀合探针。当互相接触时,该特异性结合元件优先与试样内的被分析物络合。保持与特异性结合元件未络合的过量被分析物经历非特异结合例如至疏水性域。结果,未络合被分析物与装置检测区中的络合被分析物的竞争能力受到限制。因此,以简单、有效和相对便宜的方式控制“假阴性”的发生率。
Description
发明背景
多种分析方法和装置通常用于流过式分析,以确定可能存在于试样中的被分析物的存在和/或浓度。例如,免疫测定利用免疫系统的机理,其中响应对生物体来说具有致病性或为外源的抗原的存在产生抗体。这些抗体和抗原,即免疫反应物,能够彼此结合,从而产生可以用来确定生物试样中特定抗原的存在或浓度的高度特异性反应机理。
存在几种公知的免疫测定方法,使用标记有可检测成分的免疫反应物,使得可以分析检测被分析物。例如,“夹层型”分析通常包括混合试样和可检测探针例如染色胶乳或放射性同位素,所述探针与用于被分析物的特异性结合元件缀合。该缀合探针与被分析物形成络合物。然后这些络合物到达其中抗体和被分析物之间结合形成三元“夹层络合物”的固定抗体区(zone)。夹层络合物被局限在该区以检测被分析物。该技术可以用于获得定量或半定量结果。该夹层型分析的一些实例描述于Grubb等人的美国专利号4,168,146和Tom等人的美国专利号4,366,241。
然而,许多常规的“夹层型”分析模式当暴露至较高的被分析物浓度时遇到明显错误。具体地,当被分析物以高浓度出现时,试样中相当大部分的被分析物不能与缀合的探针形成络合物。因此,到达检测区时,未络合被分析物与络合的被分析物竞争接合点。因为未络合被分析物没有用探针标记,因此它不能被检测。因此,如果很多接合点被未络合被分析物占据,那么该分析可能显示出“假阴性”。该问题通常称为“钩状效应(hook effect)”。
已经提出多种用于减少免疫测定中“钩状效应”的技术。例如,Neumann等人的美国专利号6,184,042描述了用于减少夹层分析中钩状效应的技术。该技术包括在固相存在下培养样品和至少两种能够与被分析物结合的受体。第一种受体是选自抗体、抗体片段和其混合物的结合分子的低聚物。第二种受体结合至固相,或能够结合至固相。使用可溶低聚物抗体据说减少“钩状效应”。
然而,现在仍然需要以简单有效和相对便宜的方式减少“钩状效应”的改进技术。
发明概述
根据本发明的一个实施方案,公开了检测试样中被分析物的存在或量的方法。该方法包括:
i)提供一种流过式分析装置,该装置包括与能够产生检测信号的检测探针联系的多孔膜,检测探针与被分析物的特异性结合元件缀合,多孔膜限定接受材料被固定其中的检测区;
ii)使包含被分析物的试样与缀合的检测探针接触,以便形成被分析物/探针络合物和未络合被分析物;
iii)令未络合被分析物经历非特异性结合;和
iv)在被分析物/探针络合物和检测区内的接受材料之间形成三元络合物,其中接受材料保持相对不含未络合被分析物。
例如在一个实施方案中,未络合被分析物非特异地结合至存在于至少一部分缀合检测探针上的域(domain)上。在这种情况下,包含该域的缀合检测探针可以单独地限定构成约20%至约100%被探针占据的空间体积的中空内部。这些“中空”探针可以具有内表面和外表面,其中内表面包括所述域。一个实施方案中,所述域是疏水性的。
根据本发明的另一个实施方案,公开了一种用于检测试样中被分析物的存在或量的流过式分析装置。该流过式分析装置包括与能够产生检测信号的检测探针联系的多孔膜。检测探针与被分析物的特异性结合元件缀合,并当接触试样中被分析物时与其结合,以便形成被分析物/探针络合物和未络合被分析物。缀合检测探针还包含能够非特异结合至未络合被分析物的域。多孔膜还限定接受材料被固定于其中的检测区,该区配置为结合至被分析物/探针络合物。该缀合检测探针能够在检测区内部产生检测信号,以便可根据所述检测信号测定试样内被分析物的量。
在下文中更详细地讨论本发明的其它特征和方面。
附图简述
参考附图,说明书的其余部分更特别地列出针对本领域普通技术人员的本发明完整和能够实现的公开内容,包括其最佳方式,在附图中:
图1是本发明流过式分析装置的一个实施方案的透视图;
图2图解说明了共价缀合抗体至中空探针的一个实施方案;
图3是本发明流过式分析装置的一个实施方案的示意图;
图4是实施例3结果的图解图;
图5是实施例4结果的图解图;和
图6是实施例1中使用的中空颗粒的SEM照片(放大倍数为100倍)。
本说明书和附图中重复使用的参考符号用来表示本发明相同或类似的特征或元件。
代表性实施方案的详细说明
定义
在这里使用的术语“被分析物”通常是指待检测的物质。例如,被分析物可以包括抗原物质、半抗原、抗体和其组合。被分析物包括但是不局限于毒素、有机化合物、蛋白质、肽、微生物、氨基酸、核酸、荷尔蒙、类固醇、维生素、药物(包括给药用于治疗用途的以及给药用于不正当用途的)、药物中间体或副产物、细菌、病毒颗粒和任何上述物质的代谢物或抗体。一些被分析物的具体实例包括铁蛋白;肌酸酐激酶MIB(CK-MB);异羟基洋地黄毒苷;二苯乙内酰脲;苯巴比妥;酰胺咪嗪;万古霉素;庆大霉素;茶碱;丙戊酸;奎尼丁;促黄体生成激素(LH);促卵泡激素(FSH);雌二醇、孕酮;C-反应蛋白;脂肪分解酶(lipocalins);免疫球蛋白E抗体;维生素B2微球蛋白;糖化血红蛋白(glycated hemoglobin,Gly.Hb);氢化可的松;洋地黄毒苷;N-乙酰基普鲁卡因酰胺(NAPA);普鲁卡因酰胺;风疹抗体,例如风疹免疫球蛋白G和风疹免疫球蛋白M;弓形体病抗体,例如弓形体病免疫球蛋白G(Toxo-Ig G)和弓形体病免疫球蛋白M(Toxo-Ig M);睾丸激素;水杨酸酯;退热净;乙型肝炎病毒表面抗原(HBsAg);乙型肝炎核心抗原抗体,例如抗乙型肝炎核心抗原免疫球蛋白G和免疫球蛋白M(Anti-HBC);人免疫缺陷病毒1和2(HIV1和2);人T细胞白血病毒1和2(HTLV);乙型肝炎e抗原(HBeAg);乙型肝炎e抗原抗体(Anti-HBe);流感病毒;促甲状腺激素(TSH);甲状腺素(T4);全部的三碘甲腺原氨酸(Total T3);自由三碘甲腺原氨酸(Free T3);癌胚抗原(CEA);甲胎蛋白(AFP)。滥用药物和受控物质包括,但是不限于安非他明;脱氧麻黄碱;巴比妥酸盐,例如异戊巴比妥、司可巴比妥、戊巴比妥、苯巴比妥和巴比妥;苯并二氮杂,例如利眠宁和安定;大麻,例如大麻麻醉剂和大麻;古柯碱;芬太奴;LSD;甲苯喹唑酮;鸦片制剂,例如海洛因、吗啡、可待因、氢吗啡酮、氢可酮、美沙酮、氧可酮、氧吗啡酮和鸦片;苯西克定;和丙氧芬(propoxyhene)。其它可能的被分析物描述于Everhart等人的美国专利号6,436,651和Tom等人的美国专利号4,366,241。
在这里使用的术语“试样”泛指怀疑包含被分析物的材料。可以直接使用从来源获得的试样或先进行样品性质改性预处理。试样可以衍生自任何生物来源,例如生理性液体,包括血液、组织液、唾液、眼球晶状体液、脑脊液、汗水、尿、牛奶、腹水液体、沙哑、滑膜液、腹膜液、阴道液体、羊水等。可以在使用前预先处理试样,例如从血液制备血浆、稀释粘性流体等。处理方法可以包括过滤、沉淀、稀释、蒸馏、混合、浓缩、干扰成分的灭活和加入试剂。除生理性液体之外,可以使用其它液体样品例如水、食品等用于环境分析或食品生产分析。此外,可以使用怀疑包含被分析物的固体材料作为试样。在有些情况下,改性固体试样以形成液体介质或释放被分析物可解是有益的。
详细说明
现在将详细描述本发明的多个实施方案,以下说明其中的一个或多个实施例。每个实施例是为说明本发明提供的,不限制本发明。实际上,对于本技术领域技术人员来说显而易见的是,在不脱离本发明的范围或精神的情况下,在本发明中能够进行各种改进和变化。例如,作为一个实施方案的部分而图解或描述的特征,可以用于另一个实施方案以产生更多实施方案。因此,本发明拟覆盖所附权利要求和其同等物范围内的这种改变和变化。
通常,本发明涉及检测试样中被分析物的存在或量的基于膜的分析设备。该设备利用缀合探针,该探针包含所关心的被分析物的特异性结合元件。特异性结合元件优选当和试样接触时与试样内的被分析物络合。未与特异性结合元件络合的过量被分析物可以经历非特异性的结合,例如与域(例如表面、分子等)结合。结果,限制了未络合被分析物与设备检测区中的络合被分析物竞争的能力。因此,以简单、有效和相对便宜的方式限制“假阴性”的发生率。
例如,参考图1,现在将更详细地描述一个可以根据本发明形成的流过式分析装置20的实施方案。如图所示,装置20包含任选被刚性材料21支撑的多孔膜23。通常,多孔膜23可以由试样能够通过的多种材料中的任何一种制成。例如,用于形成多孔膜23的材料可以包括但是不局限于天然、合成或合成改性的天然存在的材料,例如多糖(例如纤维素材料如纸和纤维素衍生物,例如醋酸纤维素和硝化纤维素);聚醚砜;尼龙膜;二氧化硅;无机材料,例如钝化矾土、硅藻土、MgSO4,或其它均匀分散在多孔聚合物基体中的无机细分散材料,和聚合物例如氯乙烯、氯乙烯-丙烯共聚物和氯乙烯-醋酸乙烯共聚物;布料,包括天然存在的(例如棉花)和合成的(例如尼龙或人造丝);多孔凝胶,例如硅胶、琼脂糖、右旋糖酐和明胶;聚合物薄膜,例如聚丙烯酰胺等。在一个特定的实施方案中,多孔膜23由硝化纤维素和/或聚酯砜材料形成。应当理解术语“硝化纤维素”是指纤维素的硝酸酯,其可以是单独的硝化纤维素,或硝酸和其它酸的混合酯,例如具有1至7个碳原子的脂族羧酸。
装置20还可以包含毛细垫28。毛细垫28通常接受已经迁移通过整个多孔膜23的流体。如本领域众所周知,毛细垫28可能有助于促进毛细作用和流体流过式膜23。
为了开始检测试样内部被分析物,使用者可以直接施加试样至一部分多孔膜23,然后该试样可以通过其运行。或者,试样可以首先施加至样品衬垫(没有显示),其与多孔膜23保持流体联系。一些可以用于形成样品衬垫的合适材料包括但是不局限于硝化纤维素、纤维素、多孔聚乙烯衬垫和玻璃纤维过滤纸。如果需要,样品衬垫还可以包含一种或更多种分析预处理试剂,分散或非分散地与其相连接。
在举例说明的实施方案中,试样从样品衬垫(没有显示)行进至与样品衬垫一端联系的缀合垫22。缀合垫22由试样能够通过的材料形成。例如,在一个实施方案中,缀合垫22由玻璃纤维形成。虽然仅显示了一个缀合垫22,应当理解在本发明中还可以使用其它缀合垫。
为了促进精确检测试样内部是否存在被分析物,在装置20的不同位置上施加探针以便检测和/或标定。在下文中将更详细地描述,探针通常包含标记有信号产生物质的颗粒或珠子。例如,多种合适的标记物包括但是不局限于生色团;催化剂;荧光化合物;化学发光化合物;磷光化合物;放射性化合物;直接可见标记物,包括胶态金属(例如金)和非金属物质颗粒,染色颗粒、酶或底物、或有机聚合物胶乳颗粒;脂质体或包含信号产生物质的其它囊泡等。例如,Litman等人的美国专利号4,275,149中公开了一些适合用作探针的酶,其中内容在这里全部引入作为各方面参考。酶/底物体系的一个实例是酶碱性磷酸酶和底物硝基蓝四唑鎓-5-溴-4-氯-3-吲哚基磷酸酯,或其衍生物或类似物,或底物4-甲基伞形酮酰-磷酸酯。其它合适的标记物可以描述于Jou等人的美国专利号5,670,381和Tarcha等人的美国专利号5,252,459,其中全部公开内容此处引入作为参考。
一些实施方案中,标记物可以包含产生可检测信号的荧光化合物。荧光化合物可以是荧光分子、聚合物、树枝状聚合物、颗粒等。合适的荧光分子的一些实例例如包括但是不局限于荧光黄、铕螯合物、藻胆蛋白、若丹明和其衍生物和类似物。视觉上可检测的有色化合物也可以用作标记物,从而提供样品中被分析物的存在或浓度的直接染色读数,不需要其它的信号产生试剂。
通常,用感兴趣的被分析物的特异性结合元件修饰探针颗粒以形成缀合探针。特异性结合元件是指特异结合对的成员,所述特异结合对即两种不同的分子,其中一种分子化学和/或物理结合至第二种分子。例如,免疫活性特异结合元件可以包括抗原、半抗原、适配子(aptamers)、抗体、和其络合物,包括由重组DNA方法或肽合成形成的。抗体可以是单克隆或多克隆抗体、重组蛋白质或其混合物(一种或多种)或片段(一种或多种),以及抗体和其它特异性结合元件的混合物。该抗体的制备细节和其用作特异性结合元件的适合性是本领域熟练技术人员公知的。其它常见特异性结合对包括但是不局限于生物素和抗生物素蛋白、碳水化合物和植物血凝素、互补核苷酸序列(包括探针和DNA杂交分析中使用的用于检测目标核酸序列的捕获核酸序列)、互补肽序列,包括由重组方法形成的、效应物和受体分子、荷尔蒙和荷尔蒙结合蛋白、酶辅因子和酶、酶抑制剂和酶等。此外,特异结合对可以包括原始特异性结合元件的类似物。例如,可以使用被分析物的衍生物或片段即被分析物类似物,只要它具有至少一种与被分析物相同的表位。
可以使用多种公知的技术中的任何一种连接该特异性结合元件至颗粒。例如,可以使用羧基、氨基、醛基、溴乙酰基、碘乙酰基、硫醇、环氧基和其它反应性或连接官能团,以及残留自由基和自由基阳离子,共价连接特异性结合元件至颗粒,通过其可以完成蛋白质偶联反应。还可以加入表面官能团作为官能化共单体,因为颗粒表面可以包含相对高表面浓度的极性基团。此外,虽然经常在合成后官能化颗粒,但在某些情况下,例如聚(硫苯酚),该颗粒能够直接和蛋白质共价链接,不需要进一步改性。例如,参考图2,举例说明了一个共价缀合颗粒的本发明实施方案。如图所示,缀合的第一步是使用碳化二亚胺活化颗粒表面上的羧基。第二步骤中,活化羧酸基与抗体的氨基反应形成酰胺键。活化和/或抗体偶联可以在缓冲剂例如磷酸盐缓冲盐水(PBS)(例如,pH=7.2)或2-(N-吗啉代)乙烷磺酸(MES)(例如,pH=5.3)中进行。如图所示,然后例如可以用乙醇胺封端得到的中空颗粒,以封闭任何留下的活化点。总之,该方法形成缀合物,其中抗体共价连接至颗粒。除共价键之外,其它连接技术,例如物理吸附,也可以用于本发明。
再次参考图1,分析装置20还可以包含检测区31,在其上固定能够结合至缀合探针的接受材料。例如,在一些实施方案中,接受材料可以是生物学接受材料。该生物学接受材料是本领域熟知的,可以包括但是不局限于抗原、半抗原、抗体、蛋白质A或G,抗生物素蛋白、抗生蛋白链菌素、二级抗体和其络合物。有时候,期望生物学接受材料能够结合至探针上存在的特异性结合元件(例如抗体)。此外,还期望它可以利用多种非生物材料用于接受材料。例如,在一些实施方案中,接受材料可以包括聚合电解质。聚合电解质可以具有净正电荷或负电荷,以及通常中性的净电荷。例如,一些具有净正电荷的聚合电解质的合适实例包括但是不局限于聚赖氨酸(可从Sigma-Aldrich Chemi cal Co.,Inc of St.Louis,MO.商购),聚乙烯亚胺;环氧氯丙烷-官能化多胺和/或聚酰氨基胺,例如聚(二甲胺-共-环氧氯丙烷);聚二烯丙基二甲基氯化铵;阳离子纤维素衍生物,例如纤维素共聚物或接枝有季铵水溶性单体的纤维素衍生物等。在一个特定的实施方案中,可以使用CelQuatSC-230M或H-100(可从National Starch&Chemical,Inc.得到),其是包含季铵水溶性单体的纤维素衍生物。此外,一些具有净负电荷的聚合电解质合适实例包括但是不局限于聚丙烯酸,例如聚(乙烯-共-甲基丙烯酸,钠盐)等。还应该理解也可以使用其它聚合电解质,例如两性聚合电解质(即具有极性和非极性部分)。例如,一些合适的两性聚合电解质实例包括但是不局限于聚(苯乙烯基-b-N-甲基2-乙烯基吡啶鎓碘化物)和聚(苯乙烯基-b-丙烯酸),两者都可以从PolymerSource,Inc of Dorval,Canada获得。
接受材料用作被分析物/探针络合物的静止结合点。具体地,被分析物,例如抗体、抗原等通常具有两个结合点。到达检测区31时,这些结合点的一个被缀合探针的特异性结合元件占据。然而,被分析物的自由结合点可以结合至固定的接受材料。当结合至固定接受材料时,络合的探针形成新三元夹层络合物。
检测区31通常可以提供许多不同的检测区,使得用户可以更好地测定试样内部特定被分析物的浓度。每个区域(region)可以包含相同的接受材料,或可以包含不同的接受材料用于捕获多种被分析物。例如,检测区31可以包括两个或更多不同的检测区(例如直线、点等)。检测区可以在基本上垂直于试样流过式分析装置20的方向以线的形式布置。同样地,在一些实施方案中,检测区可以在基本上平行于试样流过式分析装置的方向以线的形式布置。
虽然检测区31可以指示被分析物的存在,但是单独使用检测区31经常难于测定试样内部被分析物的相对浓度。因此,分析装置20还可以包括标定区32。在该实施方案中,标定区32在多孔膜23上形成,并位于检测区31下游。标定区32具有能够结合至任何通过膜23长度的未捕获探针的接受材料。在标定区32中使用的接受材料可以与检测区31使用的接受材料相同或不同。此外,类似于检测区31,标定区32还可以在任何方向提供任何数量的不同的校正区域,使得使用者可以更好地测定试样内部特定被分析物的浓度。每个区域可以包含相同的接受材料,或可以包含不同的接受材料用于捕获不同探针。
校正区域可以是预载在多孔膜23上具有不同量的接受材料,以便探针迁移时每个校正区域产生不同的信号强度。可以利用不同尺寸校正区域和/或改变每个校正区域中接受材料浓度或体积来改变每个校正区域内部结合剂的总量。如果需要,分析设备20可以使用过量探针,使得每个校正区域达到其全部和预定的信号强度潜能。也就是说,沉积在校正区域上的探针量是预定的,因为校正区域上使用的接受材料量设置在预定的已知水平。
不考虑分析设备的准确结构,缀合探针包含所关心被分析物的特异性结合元件。结果,缀合探针在接触被分析物时能够与被分析物络合。不幸地,试样中存在的被分析物量有时可能超过特异性结合元件提供的络合位点数。通常,该未络合被分析物将与络合被分析物竞争位于检测区31的接受材料。为了抑制该“钩状效应”,本发明利用优先的和非特异性的结合。具体地,由于其互相的高亲合性,探针的特异性结合元件优先与被分析物结合。当特异性结合元件被完全占据时,则试样中未络合被分析物可自由进行另外的结合。
因此,根据本发明,未络合被分析物经历“非特异性的”结合。“非特异性的”结合泛指被分析物与不是被分析物特异性结合元件的分子或表面的分子间吸引。非特异性的结合可以以各种方法完成。例如,在一个实施方案中,通过两个疏水性域(例如表面、分子等)之间的吸引出现非特异性的结合。即,虽然包含被分析物的试样可以是水基的,但被分析物本身包含疏水性域。因此,未络合被分析物的疏水性域可以非特异地与另一个疏水性域经过疏水性吸引而结合。疏水性相互作用通常描述水性环境中非极性基团/分子/表面之间的吸引。人们相信疏水作用主要通过与从疏水性表面释放水分子相关的自由能获得而出现,即接触疏水性表面的水分子处于与整体相中水分子相比自由能较差的状态。更详细的疏水作用论述公开于Israelachvili and Wennerstrom,Nature,1996,379,219-225;Israelachvili,Intermolecular and Surface Forces(第二版),Academic Press,1991;Van Oss,Int erfacial Forces in AqueousMedia,Marcel Dekker,1994。除疏水作用之外,也可能出现其它非特异性的结合。例如,静电引力例如氢键或离子键可以发生以降低钩状效应。
为了避免降低分析设备的准确度,通常期望使用的非特异性的结合技术能够区分络合和未络合被分析物。大多数实施方案中,该区别是通过尺寸区分来完成的。例如,缀合探针可以包含孔隙,其足够大以令更小的未络合被分析物经过,但是足够小以阻挡更大的络合被分析物。例如,孔隙可以具有低于约100纳米的平均尺寸,在一些实施方案中约5至约100纳米,在一些实施方案中,约0.1至约60纳米。通过包含某个尺寸的孔隙,缀合探针可以区分络合和未络合被分析物,仅令未络合被分析物通过。
此外,在一些实施方案中,缀合探针还可以是“中空”的,即,单独限定中空内部,其构成约20%至约100%,和在一些实施方案中,约30%至约100%的被探针占据的空间体积。即,每个中空探针相当大的空间体积部分保留空的。存在中空内部可以提供很多好处。例如,在一些实施方案中,颗粒内表面可以是相对疏水性的。结果,当未络合被分析物移动通过孔隙时,可以经过疏水性相互作用非特异地与疏水性内表面结合。在一个实施方案中,中空探针是胶乳基空心珠子,由聚丙烯酸壳聚合物和聚苯乙烯核聚合物形成。聚苯乙烯核聚合物形成可以非特异地与未络合被分析物结合的疏水性内表面。虽然该吸引不如被分析物和特异性结合元件之间形成的键坚固,但人们相信该吸引仍然足够强至抑制未络合被分析物以后与检测区的络合被分析物竞争。然而,应该了解如果需要,内表面还可以是亲水性的。
此外,有时未络合被分析物可解被捕俘在中空探针内表面内部。该情况中,未络合被分析物可能不与络合被分析物竞争检测区的结合部位,不论是否存在相当大的非特异性结合。例如,在一个实施方案中,中空探针可以包含亲水性的内表面和疏水性或外表面。虽然一些未络合被分析物将非特异地与外表面结合,但它还可以捕俘在内部亲水性表面内。此外,进入探针中空区域的未络合被分析物可以简单地被减慢,因此它仅在络合被分析物与其中包含的接受材料结合后,达到检测区31。
当使用时,中空探针的形状通常可以改变。例如,在一个特定实施方案中,中空探针是球形。然而,应当理解其它形状也可以用于本发明,例如板、杆、盘、条、管、不规则形状等。此外,中空探针的尺寸也可以改变。例如,中空颗粒的平均尺寸(例如直径)可以为约0.1纳米至约1,000微米,在一些实施方案中,约0.1纳米至约100微米,在一些实施方案中,约1纳米至约10微米。例如,通常需要“微米级”颗粒。当使用时,该“微米级”颗粒可以具有约1微米至约1,000的平均尺寸,在一些实施方案中约1微米至约100微米,在一些实施方案中,约1微米至约10微米。同样地,还可以使用“纳米级”颗粒。该“纳米级”颗粒可以具有约0.1至约10纳米的平均尺寸,在一些实施方案中约0.1至约5纳米,在一些实施方案中,约1至约5纳米。
虽然如上所述颗粒的形状和尺寸可以改变,经常要求颗粒是“单分散的”,因为给定胶体分散体内部的颗粒具有大致相同的尺寸和/或形状。由于其通常均匀的性质,单分散的中空探针可以提供改进的可靠性和可重现性。
除了其尺寸和形状,形成中空探针的材料(一种或多种)也可以改变。中空探针可以例如是有机和/或无机性质,并可以是聚合物、低聚物、分子等。例如,中空颗粒可以由聚合物例如聚苯乙烯、(甲基)丙烯酸酯聚合物或共聚物、偏二氯乙烯/丙烯腈共聚物等形成。其它合适的中空聚合颗粒可以描述于Kowalski等人的美国专利号4,427,836;Craig等人的US4,480,042;Mc Donald等人的US4,973,670;Choi等人的US5,618,888;Blankenship等人的美国专利号6,139,961,其全部内容在此引入作为参考。可以使用的其它中空颗粒包括无机材料例如玻璃中空颗粒。例如,ECCOSPHERES是衍生自可从Emerson and Cuming Composite Materials,Inc商购的硼硅酸钠的中空玻璃颗粒。衍生自无机材料的其它代表性的中空颗粒包括例如得自Miyoshi Kasei,Inc商品名为“SILICA BEADS S700”的硅石中空微球体。其它中空无机颗粒的实例描述于Radin等人的美国专利号6,416,774,其中内容此处引入作为参考。
在一个特定实施方案中,中空颗粒可以由一种或多种天然或合成乳胶聚合物形成。该胶乳基中空颗粒的实例描述于Jones等的美国专利号5,663,213,其中内容此处全部引入作为参考,和可从Rohm&Haas of Philadelphia、宾夕法尼亚商购得到,商品名为SunSpheres。’213专利描述该胶乳基中空颗粒(一般尺寸为“微米级”)用于防护日光的能力。然而,本发明人还发现胶乳基中空颗粒在分析设备中具有出乎意外的用途。
胶乳基中空颗粒一般包含核聚合物和壳聚合物。用于形成核和壳聚合物的单体通常可以改变。例如,可以选择壳聚合物以提供足以支持颗粒空洞的高玻璃化转变温度(Tg),例如大于约50℃,在一些实施方案中大于约60℃,在一些实施方案中,大于约70℃。可以用于形成壳聚合物的合适单体实例包括但不限于非离子烯属不饱和单体、包含至少一个羧基的单烯属不饱和单体等。
形成核聚合物的单体可以包括一种或多种包含至少一个羧基的单烯属不饱和单体。在一些实施方案中,例如至少约5wt%核聚合物的单烯属不饱和单体包含至少一种羧酸,基于核单体总重量。包含至少一个羧基的合适单烯属不饱和单体实例包括但不限于(甲基)丙烯酸、丙烯酰氧基丙酸、(甲基)丙烯酰氧基丙酸、衣康酸、乌头酸、马来酸或酸酐、富马酸、巴豆酸、马来酸单甲基酯、富马酸单甲基酯、衣康酸单甲基酯等。在这里使用的术语“(甲基)丙烯酸”是包括丙烯酸和甲基丙烯酸的通用表达。
在一个实施方案中,共聚合包含至少一个羧酸基团的单烯属不饱和单体与一种或多种非离子(例如不具有可电离的基团)烯属不饱和单体。一些合适的非离子烯属不饱和单体包括但不限于苯乙烯、乙烯基甲苯、乙烯、乙酸乙烯酯、氯乙烯、偏二氯乙烯、丙烯腈、(甲基)丙烯酰胺、(甲基)丙烯酸的(C1-C20)烷基或(C3-C20)链烯基酯,例如(甲基)丙烯酸甲酯、(甲基)丙烯酸乙酯、(甲基)丙烯酸丁酯、(甲基)丙烯酸2-乙基己酯、(甲基)丙烯酸苄基酯、(甲基)丙烯酸月桂基酯、(甲基)丙烯酸油基酯、(甲基)丙烯酸棕榈基酯、(甲基)丙烯酸硬脂基酯等。
核聚合物和/或壳聚合物可以任选包含约0.1wt%至约20wt%,在一些实施方案中,约0.1wt%至约3wt%多烯属不饱和单体,基于聚合物全部单体重量。该不饱和单体的实例包括但不限于二(甲基)丙烯酸乙二醇酯、(甲基)丙烯酸烯丙基酯、二(甲基)丙烯酸1,3-丁二醇酯、二(甲基)丙烯酸二甘醇酯、三羟甲基丙烷三(甲基)丙烯酸酯或二乙烯基苯。如果需要,核聚合物和/或壳聚合物可以包含约0.1wt%至约60wt%丁二烯,基于聚合物全部单体重量。
为了在胶乳颗粒中产生空洞,一般用包含一种或多种挥发性组分的溶胀剂膨胀核。溶胀剂渗透壳以溶胀核。然后可以通过干燥胶乳颗粒除去溶胀剂的挥发性组分,从而导致在胶乳颗粒内形成空洞。虽然不需要如此,但溶胀剂可以是水溶性碱。合适的水溶性碱实例包括但不限于氨水、氢氧化铵、碱金属氢氧化物,例如氢氧化钠或挥发性胺例如三甲胺或三乙胺。还可以用其它方法除去模板核,例如在高温锻烧或通过使核材料溶解的化学反应。
除了核-壳中空颗粒,还可以使用其它公知的技术形成中空颗粒。例如,Caruso等人的美国专利号6,479,146描述了使用静电力形成的中空颗粒,其中内容此处引入作为参考。特别地,使用模板静电的层-层(“LBL”)沉积纳米颗粒-聚合物多层形成中空颗粒,随后除去模板核。模板颗粒可以例如包含有机聚合物胶乳,例如聚苯乙烯或苯乙烯共聚物胶乳。
模板颗粒交替地涂有聚电解质分子和纳米颗粒。聚电解质通常是具有可离解基团的聚合物,所述基团可以是聚合物链的成分或取代基。纳米颗粒一般是陶瓷颗粒,例如二氧化硅、二氧化钛和二氧化锆,任选掺杂有其它金属氧化物;磁性颗粒,例如Fe3O4;磁光颗粒;氮化(nitridic)陶瓷颗粒,例如Si3N4,碳化(carbidic)陶瓷颗粒;金属颗粒,例如金、银和钯;含硫或含硒(selene)颗粒,例如硫化镉、硒化镉等。
在一个实施方案中,在施加纳米颗粒和聚电解质交替层或交替的纳米颗粒层之前,模板颗粒首先用几层电性相反的阳离子和阴离子聚电解质涂覆。通常,模板颗粒涂有至少两个直至最多六个电性相反的阳离子和阴离子聚电解质的层,例如具有三个层。最外面的聚电解质层通常相对于待沉积纳米颗粒具有相反的电荷。在大多数实施方案中,模板颗粒在涂布完成后至少部分解体。它们可以溶解在合适的溶剂中和/或热溶解(例如通过煅烧至至少约500℃的温度)。在溶解模板颗粒后,残留的中空壳由纳米颗粒材料和任选聚电解质材料组成。
如果需要,可以改性静电形成的颗粒以便在至少一个层中含有孔隙。可以由聚电解质或纳米颗粒本身形成该孔隙。例如,沉积聚电解质使用的高盐浓度的介质可以导致壳壁的强渗透性。另一方面,用于沉积纳米颗粒(例如SiO2)的高盐浓度介质可能产生低渗透性的纳米颗粒。因此,通过调节沉积介质中盐的浓度,按照需要可以控制壳的渗透性。此外,通过选择分解核的条件例如通过选择煅烧过程中的温度和加热条件,可以改变壳的渗透性能。
通常,根据本发明可以构建多种流过式分析设备。在这方面,现在将更详细地描述本发明的多种实施方案。然而,应该了解,以下讨论的实施方案仅仅是示例性的,其它实施方案也可以用于本发明。例如,参见图3,显示了一个其中的检测探针41包含中空颗粒的特定实施方案。该实施方案中,检测探针41用于缀合垫22,因此当接触试样时能够流过设备20(方向箭头L指示)。检测探针41与被分析物A的特异性结合元件90缀合,以致接触被分析物A时,探针41优先与其络合形成被分析物/探针络合物49。此后,任何残留被分析物进入探针41内部(未显示),此处它可以非特异地与探针内表面结合或捕俘于其中。
然后探针/被分析物络合物49从缀合垫22流过多孔膜23,直至它们达到检测区31,在此它们与接受材料91例如抗体结合,形成夹层络合物53。因为未络合被分析物捕俘在探针41内部,它不能与络合被分析物竞争接受材料。因此,在检测区31,可以根据检测探针41的信号强度确定被分析物的量。如果需要,设备20还可以使用流向标定区32的校正探针43,其与接受材料(未显示)例如聚电解质结合。该情况下,可以由在标定区32的校正探针43的信号强度校准检测区31的信号强度。可以目视测量信号强度或通过设备的辅助装置,例如荧光读数器测量信号强度。
虽然多种设备结构的实施方案已经如上所述,但应该了解,本发明设备通常可以具有任何所需结构,并且不必包含如上所述全部成分。多种其它设备结构和/或分析格式例如描述于Lambotte等的美国专利号5,395,754;Jou等人的美国专利号5,670,381;Malick等人的美国专利号6,194,220,其中内容此处全部引入作为参考。
参考下列实施例可以更好地理解本发明。
实施例1
提供了SunSphereTM中空颗粒(可从Rohm&Haas获得)。颗粒具有约26%的固体含量和300纳米的平均测量尺寸(基于SEM和颗粒筛分器)。图6中显示出该中空颗粒的SEM照片。用2-(N-吗啉代)乙磺酸缓冲剂(MES,pH=5.3)洗涤500微升颗粒溶液两次,每次1毫升。向1毫升颗粒/MES缓冲溶液加入30毫克碳二亚胺(Polysciences,Inc.)。旋转令反应进行10分钟。
然后从反应溶液中分离中空颗粒,并用1毫升硼酸盐缓冲剂洗涤。加入1毫克荧光染料,即(5-(和-6)-((N-(5-氨基戊基)氨基)羰基)四甲基若丹明-(四甲基若丹明尸胺)至硼酸盐缓冲溶液。恒定旋转下令反应进行1小时。反应完成后,排除上清液并用硼酸盐缓冲剂洗涤中空颗粒,直到上清液变清以除去任何游离荧光染料。然后在1毫升硼酸盐缓冲剂中再悬浮中空颗粒作为贮液。从贮备溶液中取出100微升并在500微升硼酸盐缓冲剂中稀释。向中空颗粒溶液加100微升单克隆抗体Mab 5811(BiosPacific,6.4毫克每毫升),并令反应在恒定旋转下进行超过56小时。用200微升乙醇胺结束反应,用PBS缓冲剂洗涤中空颗粒,最后保存在500毫升包含0.1摩尔PBS、0.15摩尔NaCl、1%BSA、5%丙三醇和0.1%NaN3的存储缓冲剂中。
实施例2
证明了根据本发明形成横流式分析的能力。最初,层压MilliporeHF120硝化纤维素膜到相应的长度大约为30厘米的支撑卡片上。将CelQuat100-H(可从National Starch&Chemical,Inc.获得的纤维素聚电解质衍生物)水溶液汽提到膜上形成控制线。将C-活性蛋白的单克隆抗体Mab 5804(1毫克每毫升,从BiosPacific,Inc.获得)固定到多孔膜样品上以形成检测线。然后在37℃下干燥膜样品1小时。在膜一端连接纤维素纤维毛细垫(Millipore Co.)并切成4mm的半试条。
将半粘试条投入各微孔中,其中混合实施例1的20微升荧光中空探针缀合物和20微升CRP抗原溶液或20微升TBS缓冲剂。包含缓冲剂的微孔作为阴性对照物,而包含CRP抗原的微孔作为阳性样品。当分析完成时,取出半粘条,然后使用Fluorolog IIISpectrof luoremeter(SPEX Industries,Inc.Edison,NJ)以直角模式测量检测线上的荧光强度。检测线上的荧光强度直接与抗原的夹层络合物的数量相关,因此直接与CRP抗原的浓度相关。
结果示于下表1中,其中“I”代表荧光中空探针的信号强度。将阴性对照物的信号强度背景,并将其从包含CRP被分析物的样品信号强度中减去。应当注意到,甚至在5000纳克每毫升的被分析物浓度下,也没有观察到钩状效应。
表I:信号强度结果
被分析物(纳克每毫升) | 信号强度“I” |
0(对照物) | 44 |
5 | 115 |
50 | 160 |
500 | 240 |
2500 | 320 |
5000 | 454 |
实施例3
为了对比,形成不利用根据本发明的非特异性结合的分析设备。最初,通过用2-(N-吗啉代)乙磺酸缓冲剂(MES,pH=5.3)洗涤125微升蓝色胶乳颗粒(可从Bangs Laboratory,Inc.获得,10%,尺寸0.3微米)两次(每次1毫升),形成缀合胶乳珠粒。将胶乳颗粒再悬浮到500微升MES缓冲剂中。将50毫克碳化二亚胺溶解到500微升MES缓冲剂中,然后和500微升胶乳颗粒溶液混合。令活化反应进行30分钟。从反应溶液分离颗粒后,用硼酸盐缓冲剂洗涤两次。将颗粒再悬浮到1毫升硼酸盐缓冲剂中,加入45微升单克隆CRP抗体Mab 5811,并进行反应2.5小时。用1毫升乙醇胺淬灭胶乳颗粒30分钟,此外用PBS缓冲剂洗涤两次,最后保存在1毫升储存缓冲剂中。
为了形成该分析设备,将Millipore HF120硝化纤维素膜层压到长度大约为30厘米的相应支撑卡片上。将CelQuat100-H(可从National Starch&Chemical,Inc.获得的纤维素聚电解质衍生物)水溶液汽提到膜上形成控制线。将C-活性蛋白的单克隆抗体Mab5804(1毫克每毫升,从BiosPacific,Inc获得)固定到多孔膜样品上以形成检测线。然后在37℃下干燥膜样品1小时。在膜一端连接纤维素纤维毛细垫(Millipore Co.)并切成4mm的半试条。将半粘试条投入各微孔,其中混合19微升2%Tween 20溶液和1微升缀合胶乳珠粒及20微升CRP抗原溶液或20微升TBS缓冲剂。包含缓冲剂的微孔作为阴性对照物,同时包含CRP抗原的微孔作为阳性样品。
当分析完成时,取出半粘条,并用基于反射比的读数器测量检测线上的强度。结果显示于图4,其中显示出强度(检测线范围内的像素)对被分析物浓度。如图所示,“钩状效应”出现在低CRP浓度,即约250至500纳克每毫升。
实施例4
为了对比,形成不利用根据本发明的非特异性结合的分析设备。最初,通过缀合尺寸为40纳米的金颗粒(在530纳米波长,吸收率=1)和单克隆抗体Mab 5811形成探针。为了形成该分析设备,将MilliporeHF120硝化纤维素膜层压到长度大约为30厘米的相应支撑卡片上。将CelQuat100-H(可从National Starch&Chemical,Inc.获得的纤维素聚电解质衍生物)水溶液汽提到膜上形成控制线。将C-活性蛋白的单克隆抗体Mab 5804(1毫克每毫升,从BiosPacific,Inc获得)固定到多孔膜样品上以形成检测线。然后在37℃下干燥膜样品1小时。在膜一端连接纤维素纤维毛细垫(Millipore Co)并切成4mm的半试条。将半粘试条投入各微孔,其中混合19微升2%Tween 20溶液和1微升缀合金颗粒及20微升CRP抗原溶液或20微升TBS缓冲剂。包含缓冲剂的微孔作为阴性对照物,同时包含CRP抗原的微孔作为阳性样品。
当分析完成时,取出半粘条,并用基于反射比的读数器测量检测线上的强度。结果显示于图5,其中显示出强度(检测线范围内的像素)对被分析物浓度。如图所示,“钩状效应”出现在低CRP浓度,即约250至500纳克每毫升。
虽然本发明已经参考其特定实施方案进行了详细描述,但本领域技术人员在理解上述内容后,可以容易地想出上述实施方案的各种变化及等同物。因此,本发明范围应该由所附权利要求和其等价物确定。
Claims (28)
1.一种检测试样中被分析物的存在或量的方法,该方法包括:
i)提供一种流过式分析装置,该装置包括与能够产生检测信号的检测探针联系的多孔膜,所述检测探针与被分析物的特异性结合元件缀合,所述多孔膜限定接受材料被固定于其中的检测区;
ii)使包含被分析物的试样与所述缀合的检测探针接触,以便形成被分析物/探针络合物和未络合被分析物;
iii)令所述未络合被分析物经历非特异性结合;和
iv)在所述被分析物/探针络合物和所述检测区内的所述接受材料之间形成三元络合物,其中所述接受材料保持相对不含所述未络合被分析物。
2.权利要求1的方法,其中所述未络合被分析物非特异地结合至存在于所述缀合检测探针的至少一部分上的域上。
3.权利要求2的方法,其中包含所述域的缀合检测探针单独限定中空的内部,其构成约20%至约100%被所述探针占据的空间体积,所述探针具有内表面和外表面。
4.权利要求3的方法,其中所述内表面包括所述域。
5.权利要求3的方法,其中所述缀合检测探针具有球形。
6.权利要求3的方法,其中所述缀合检测探针由核聚合物和壳聚合物形成。
7.权利要求3的方法,其中通过静电层沉积形成所述缀合检测探针。
8.权利要求2的方法,其中所述域是疏水性的。
9.权利要求1的方法,其中所述缀合检测探针限定了平均尺寸小于约100纳米的孔隙。
10.权利要求1的方法,其中所述缀合检测探针的平均尺寸为约0.1纳米至约100微米。
11.权利要求1的方法,其中所述缀合检测探针包含选自生色团、催化剂、荧光化合物、化学发光化合物、磷光化合物、放射性化合物、直接可见标签、脂质体和其组合的物质。
12.一种检测试样中被分析物的存在或量的方法,所述方法包括:
i)提供一种流过式分析装置,该装置包括与能够产生检测信号的检测探针联系的多孔膜,所述检测探针与被分析物的特异性结合元件缀合并单独限定中空的内部,其构成约20%至约100%被所述探针占据的空间体积,所述探针具有内表面和外表面,所述多孔膜限定接受材料被固定于其中的检测区;
ii)使包含被分析物的试样与所述缀合的检测探针接触,以便形成被分析物/探针络合物和未络合被分析物;
iii)令所述未络合被分析物非特异地结合至所述缀合检测探针的内表面;和
iv)在所述检测区内在所述被分析物/探针络合物和所述接受材料之间形成三元络合物,其中所述接受材料保持相对不含所述未络合被分析物。
13.权利要求12的方法,其中至少一部分所述内表面是疏水性的。
14.权利要求12的方法,其中所述缀合检测探针限定了平均尺寸小于约100纳米的孔隙。
15.权利要求12的方法,其中所述缀合检测探针具有球形。
16.权利要求12的方法,其中所述缀合检测探针由核聚合物和壳聚合物形成。
17.权利要求12的方法,其中通过静电层沉积形成所述缀合检测探针。
18.权利要求12的方法,其中所述缀合检测探针的平均尺寸为约0.1纳米至约100微米。
19.一种用于检测试样中被分析物的存在或量的流过式分析装置,所述流过式分析装置包括与能够产生检测信号的检测探针联系的多孔膜,所述检测探针和被分析物的特异性结合元件缀合,并被配置为当与试样中的被分析物接触时与其结合,以便形成被分析物/探针络合物和未络合被分析物,所述缀合检测探针进一步包含能够非特异结合至所述未络合被分析物的域,所述多孔膜限定接受材料被固定于其中的检测区,其被配置为结合至所述被分析物/探针络合物,其中所述缀合检测探针能够在所述检测区内产生检测信号,以便根据所述检测信号确定试样内被分析物的量。
20.权利要求19的流过式分析装置,其中包含所述域的所述缀合检测探针单独限定中空的内部,其构成约20%至约100%被所述探针占据的空间体积,所述探针具有内表面和外表面。
21.权利要求20的流过式分析装置,其中所述内表面包括所述域。
22.权利要求20的流过式分析装置,其中所述缀合检测探针具有球形。
23.权利要求20的流过式分析装置,其中所述缀合检测探针由核聚合物和壳聚合物形成。
24.权利要求20的流过式分析装置,其中通过静电层沉积形成所述缀合检测探针。
25.权利要求19的流过式分析装置,其中所述域是疏水性的。
26.权利要求19的流过式分析装置,其中所述缀合检测探针限定了平均尺寸小于约100纳米的孔隙。
27.权利要求19的流过式分析装置,其中所述缀合检测探针的平均尺寸为约0.1纳米至约100微米。
28.权利要求19的流过式分析装置,其中所述缀合检测探针包含选自生色团、催化剂、荧光化合物、化学发光化合物、磷光化合物、放射性化合物、直接可见标签、脂质体和其组合的物质。
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US10/406,631 US7851209B2 (en) | 2003-04-03 | 2003-04-03 | Reduction of the hook effect in assay devices |
US10/406,631 | 2003-04-03 | ||
PCT/US2004/006414 WO2004095030A1 (en) | 2003-04-03 | 2004-03-03 | Reduction of the hook effect in assay devices |
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US6818456B2 (en) | 2001-07-20 | 2004-11-16 | Varian, Inc. | Color contrast system for lateral flow immunoassay tests |
WO2003058246A1 (en) | 2001-12-24 | 2003-07-17 | Kimberly-Clark Worldwide, Inc. | Flow-through assay with an internal calibration system using polyelectrolyte |
US20030153011A1 (en) * | 2002-02-08 | 2003-08-14 | Bell Michael L. | Methods and reagents for conducting multiplexed assays of multiple analytes |
US7214427B2 (en) | 2002-03-21 | 2007-05-08 | Aviva Biosciences Corporation | Composite beads comprising magnetizable substance and electro-conductive substance |
US20030232340A1 (en) * | 2002-06-13 | 2003-12-18 | David Anderson | Nanoporous particle with a retained target |
-
2003
- 2003-04-03 US US10/406,631 patent/US7851209B2/en not_active Expired - Fee Related
-
2004
- 2004-03-03 CN CN2004800073280A patent/CN1761880B/zh not_active Expired - Fee Related
- 2004-03-03 WO PCT/US2004/006414 patent/WO2004095030A1/en active Application Filing
- 2004-03-03 AU AU2004232218A patent/AU2004232218A1/en not_active Abandoned
- 2004-03-03 CA CA2513895A patent/CA2513895C/en not_active Expired - Lifetime
- 2004-03-03 EP EP04716888A patent/EP1608981B1/en not_active Expired - Lifetime
- 2004-03-03 MX MXPA05009835A patent/MXPA05009835A/es active IP Right Grant
- 2004-03-03 KR KR1020057017436A patent/KR101057918B1/ko active IP Right Grant
- 2004-03-19 TW TW093107368A patent/TW200426369A/zh unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104034893A (zh) * | 2013-03-08 | 2014-09-10 | 北京普析通用仪器有限责任公司 | 一种基于胶乳的三聚氰胺快速检测方法及试剂盒 |
CN104034893B (zh) * | 2013-03-08 | 2016-04-20 | 北京普析通用仪器有限责任公司 | 一种基于胶乳的三聚氰胺快速检测方法及试剂盒 |
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MXPA05009835A (es) | 2005-12-05 |
CN1761880B (zh) | 2010-05-26 |
WO2004095030A1 (en) | 2004-11-04 |
CA2513895A1 (en) | 2004-11-04 |
TW200426369A (en) | 2004-12-01 |
US7851209B2 (en) | 2010-12-14 |
KR101057918B1 (ko) | 2011-08-19 |
AU2004232218A1 (en) | 2004-11-04 |
US20040197820A1 (en) | 2004-10-07 |
CA2513895C (en) | 2013-07-02 |
KR20050113231A (ko) | 2005-12-01 |
EP1608981B1 (en) | 2013-01-09 |
EP1608981A1 (en) | 2005-12-28 |
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