CN103097895B - 核酸或免疫色谱法用试剂组合物、核酸或免疫色谱法测定方法及核酸或免疫色谱法测定用试剂盒 - Google Patents
核酸或免疫色谱法用试剂组合物、核酸或免疫色谱法测定方法及核酸或免疫色谱法测定用试剂盒 Download PDFInfo
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- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
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- Investigating Or Analysing Biological Materials (AREA)
Abstract
本发明提供一种试剂组合物,其在进行核酸色谱法或免疫色谱法测定时,通过降低由分析对象物以外的成分的非特异性反应产生的结合,且提高分析对象物的分散能力,将色谱载体上的展开性优化,同时促进特异性反应,从而即使使用低浓度的分析对象物也能够进行准确且迅速的判断。一种核酸色谱法或免疫色谱法用试剂组合物,其含有重均分子量为8000以上的水溶性高分子化合物、2价或3价的金属的盐、非离子性表面活性剂、及水溶性非质子性有机化合物。
Description
技术领域
本发明涉及核酸色谱法或免疫色谱法中使用的试剂组合物、使用其的核酸色谱法或免疫色谱法测定方法、及包含其的核酸色谱法或免疫色谱法测定用试剂盒。
背景技术
以往,在核酸色谱法或免疫色谱法测定中,为了提高灵敏度,惯用方法是增加涂布到固相上的抗体、核酸的量或者增加与标记物结合的抗体、核酸的量。
但是,存在以下问题:若增加抗体、核酸等反应体,则容易产生非特异性的反应,此外,若为少量则得不到充分的灵敏度。
在核酸色谱法或免疫色谱法中,出于各种目的而使用各种试剂成分。进行以下尝试:添加聚阴离子等水溶性高分子化合物、无机盐类、表面活性剂等添加物,来抑制非特异性的反应、或者提高灵敏度(专利文献1~11)。
但是,所有添加物的组合均尚未充分达成非特异性反应的抑制或灵敏度、色谱载体上的展开性的提高。
现有技术文献
专利文献
专利文献1:日本特开2001-21560号公报
专利文献2:日本特开2006-215044号公报
专利文献3:日本特开2006-317226号公报
专利文献4:日本特开2007-121204号公报
专利文献5:日本特开2007-121205号公报
专利文献6:日本特开2007-322310号公报
专利文献7:日本特开2009-52945号公报
专利文献8:日本特开2010-14507号公报
专利文献9:日本特开2010-19794号公报
专利文献10:日本特开2010-44094号公报
专利文献11:日本特表2010-50055号小册子
发明内容
发明要解决的问题
本发明的课题在于,在进行核酸色谱法或免疫色谱法测定时,通过降低由分析对象物以外的成分的非特异性反应产生的结合,且提高分析对象物的分散能力而将色谱载体上的展开性优化,同时促进特异性反应,从而即使使用低浓度的分析对象物也能够进行准确且迅速的判断。
用于解决问题的方案
本发明人发现,通过使用特定的添加剂的组合可解决上述的课题,从而达成本发明。
本发明为一种核酸色谱法或免疫色谱法用试剂组合物,其含有重均分子量为8000以上的水溶性高分子化合物、2价或3价的金属的盐、非离子性表面活性剂、及水溶性非质子性有机化合物。
本发明为一种核酸色谱法或免疫色谱法测定方法,其包括使用上述的核酸色谱法或免疫色谱法用试剂组合物将待测物展开的工序。
本发明为一种核酸色谱法或免疫色谱法测定用试剂盒,其包含上述的色谱法用试剂组合物作为待测物的展开液。
发明的效果
根据本发明,在进行核酸色谱法或免疫色谱法测定时,通过降低由分析对象物以外的成分的非特异性反应产生的结合,且提高分析对象物的分散能力,同时促进特异性反应,从而即使使用低浓度的分析对象物也能够进行准确且迅速的判断。
附图说明
图1是核酸色谱法测定的简略工序图。
图2是核酸色谱法测定用试剂盒的简略图。
图3是表示核酸色谱法测定的测定原理的简略图。
具体实施方式
本发明的核酸色谱法或免疫色谱法用试剂组合物含有重均分子量为8000以上的水溶性高分子化合物、2价或3价的金属的盐、非离子性表面活性剂、及水溶性非质子性有机化合物。
(重均分子量为8000以上的水溶性高分子化合物)
重均分子量为8000以上的水溶性高分子化合物只要是重均分子量为8000以上、并且具有水溶性的化合物,则没有特别限定。重均分子量优选为10000以上。前述水溶性高分子只要重均分子量为8000以上则可以使用重均分子量已知的市售的化合物。当使用合成的水溶性高分子时,使用通过高分子的分子量测定中通用的凝胶渗透色谱法(以下GPC)测定得到的重均分子量为8000以上的化合物。当重均分子量低于8000时,在核酸的杂交、抗原抗体反应中见到的形成与分析对象物的特异性复合体的结合力降低,利用色谱法检测的检测灵敏度降低。更优选使用重均分子量为2万~100万的水溶性高分子。重均分子量为8000以上的水溶性高分子化合物的“水溶性”是指,相对于1L的 20℃的水,10g以上、优选50g以上的化合物发生溶解。
重均分子量为8000以上的水溶性高分子化合物例如为选自由聚乙二醇、聚丙二醇、聚乙二醇/聚丙二醇嵌段共聚物等聚亚烷基二醇类;甲基纤维素、乙基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素等纤维素类;聚乙烯基吡咯烷酮、聚乙烯醇、聚乙烯基甲基醚等乙烯基系高分子类;聚甲基丙烯酰胺、聚丙烯酰胺等酰胺系高分子类;及聚阴离子组成的组中的1种以上。
作为聚阴离子,可列举出多糖阴离子、聚谷氨酸、聚天冬氨酸等合成肽系阴离子、合成核酸系聚阴离子,优选多糖阴离子。
作为多糖阴离子,例如可列举出选自由硫酸葡聚糖、硫酸乙酰肝素、硫酸软骨素、硫酸皮肤素、硫酸角质素、透明质酸、肝素及其盐组成的组中的1种以上。作为盐,有钠、钾、镁盐等。其中,从获得的容易性和经济性出发,更优选硫酸葡聚糖及其盐。
相对于试剂组合物,重均分子量为8000以上的水溶性高分子化合物的量优选为0.1~5重量%,更优选为0.5~3重量%。
分子量为8000以上的水溶性高分子化合物提高形成与分析对象物的特异性复合体的结合力,促进特异性反应。
(2价或3价的金属的盐)
2价或3价的金属只要是2价或3价的金属则没有特别限定,例如可列举出镁、钙等碱土金属(2价)、硼、铝等铝族金属(3价),优选镁、钙或铝,特别优选镁或钙,最优选镁。当使用碱金属(1价)时,展开速度降低,并且非特异反应也增大。
2价或3价的金属的盐的阴离子没有特别限定,例如可列举出氯化物、溴化物等卤化物;硫酸盐;磷酸盐;碳酸盐;硼酸 盐。优选使用氯化物、溴化物等卤化物。
2价或3价的金属的盐优选为选自由氯化镁、硫酸镁、磷酸镁、碳酸镁等镁盐;氯化钙、硫酸钙、磷酸钙等钙盐及氯化铝、硫酸铝、碳酸铝等铝盐组成的组中的1种以上。
相对于试剂组合物,2价或3价的金属的盐的量优选为0.1~100mM,更优选为0.5~50mM,进一步优选为1~10mM。
2价或3价的金属的盐提高毛细管现象的展开速度,且不会引起免疫复合体的非特异反应。
(非离子性表面活性剂)
非离子性表面活性剂例如可列举出聚氧乙烯烷基醚、聚氧乙烯烷基苯酚醚、烷基葡糖苷、聚氧乙烯脂肪酸酯、蔗糖脂肪酸酯、山梨糖醇酐脂肪酸酯、聚氧乙烯山梨糖醇酐脂肪酸酯、脂肪酸链烷醇酰胺。非离子性表面活性剂的HLB优选为10~18,更优选为13~18。作为非离子性表面活性剂,优选聚氧乙烯山梨糖醇酐脂肪酸酯,例如特别优选选自由单月桂酸聚氧乙烯山梨糖醇酐、单硬脂酸聚氧乙烯山梨糖醇酐、三硬脂酸聚氧乙烯山梨糖醇酐及单油酸聚氧乙烯山梨糖醇酐组成的组中的1种以上。
相对于试剂组合物,非离子性表面活性剂的量优选为0.1~5重量%,更优选为0.5~2.5重量%,进一步优选为0.5~1重量%。
(水溶性非质子性有机化合物)
水溶性非质子性有机化合物只要是为水溶性、且不具有质子性的有机化合物则没有特别限定。“水溶性”是指在不发生相分离的情况下可与水以任意的比率混合的性质,优选为相对于1L的20℃的水,10g以上、优选50g以上化合物发生溶解的有机化合物。“非质子性”是指不含酸性氢,不作为氢键供体起作用的性质。
作为水溶性非质子性有机化合物,可列举出亚砜类、N,N’-二烷基酰胺类、酮类、腈类、环状醚类等。
作为亚砜类,可列举出二甲基亚砜、甲基乙基亚砜、二乙基亚砜、丁基乙基亚砜等。
作为N,N’-二烷基酰胺类,可列举出二甲基乙酰胺等二烷基乙酰胺、二甲基甲酰胺等二烷基甲酰胺、N-甲基-吡咯烷酮、N-乙基-吡咯烷酮、N-(2-羟基乙基)-2-吡咯烷酮等N-烷基吡咯烷酮等。
作为酮类,可列举出丙酮、乙酰丙酮、二乙酮、甲乙酮、甲基丙酮、异丁基甲酮、γ-丁内酯、γ-戊内酯等。
作为腈类,可列举出乙腈、丙腈、丁腈等。
作为环状醚类,可列举出四氢呋喃、2-甲基四氢呋喃、1,4-二噁烷等。
作为水溶性非质子性有机化合物,优选亚砜类、N,N’-二烷基酰胺类,特别优选亚砜类。
相对于试剂组合物,水溶性非质子性有机化合物的量优选为0.2~5重量%,更优选为0.5~3重量%。
水溶性非质子性有机化合物改善在利用毛细管现象的展开中因分析对象物以外的成分融合、聚集而引起的展开液的不均一性,使其不易引起非特异性反应。
本发明的试剂组合物通常包含水作为溶剂,可以通过将上述的成分混合到水、例如超纯水中而得到。
(核酸色谱法或免疫色谱法)
本发明的试剂组合物用于核酸色谱法或免疫色谱法中。
核酸色谱法是基于核酸的杂交的方法。
免疫色谱法只要是基于抗原抗体反应的方法,则没有特别限定,例如有竞争法、夹心法,其中通用的是夹心法。
核酸色谱法或免疫色谱法中,为了标记作为分析对象物的核酸或抗原等,可以使用金、银或铂等贵金属胶体颗粒、氧化铁等金属氧化物胶体颗粒、胶乳颗粒等作为标记物,优选使用金胶体颗粒。这些胶体状金属颗粒的平均粒径优选为1~500nm,特别优选为可得到强的色调的10nm~150nm,更优选为40~100nm的范围内。标记物只要满足如下方式即可:与对分析对象物具有结合能力的蛋白质、具有特异性结合能力的互补核酸或抗体形成复合体从而作为对分析对象物进行标记的标记试剂使用,且在色谱介质上将标记试剂展开时可以与含有分析对象物的试样同时、或者在其后展开。标记试剂可以在干燥保持在色谱介质的任意部位中后,将展开液或试样稀释液供给、滴加到其上游的样品垫(试样添加部分)等中使其展开,从标记试剂保持部位溶出而展开。此外,也可以分散到展开液或稀释液中制成分散液,在色谱介质上展开而使用。从保存的观点出发,优选将标记试剂预先干燥保持在色谱介质的任意部位中。
本发明的试剂组合物优选包含封闭剂、例如牛血清白蛋白、牛奶来源的蛋白质、脱脂牛奶、酪蛋白、明胶等蛋白质、以及Blocking Peptide Fragment(封闭肽片段)(TOYOBO)、变性鱼DNA、酵母来源的tRNA、CE510(JSR Corporation)等市售的亲水性高分子聚合物等封闭剂。通过使封闭剂共存,能够在不降低灵敏度的情况下降低背景,所以能够改善S/N比。
只要发挥本发明的效果,本发明的试剂组合物可以包含磷酸盐、三羟甲基氨基甲烷盐酸盐、碳酸盐、甘氨酸等氨基酸、Good’s缓冲液等缓冲剂、作为核酸色谱法或免疫色谱法用的试剂组合物惯用的成分。
本发明的试剂组合物可以作为核酸色谱法或免疫色谱法中的展开液使用。作为展开液,通常,使用水作为溶剂,在其中 添加重均分子量为8000以上的水溶性高分子化合物、2价或3价的金属的盐、非离子性表面活性剂、及水溶性非质子性有机化合物。添加的顺序没有特别限定,也可以同时添加。当作为展开液使用时,可以将预先将包含所检测的分析对象物的试样和展开液混合而成的溶液供给、滴加到色谱介质、标记试剂保持部位、或者样品垫上使其展开,也可以先将试样供给、滴加到样品垫上,然后将展开液供给、滴加到样品垫上使其展开。当作为试样稀释液使用时,将试样稀释而成的稀释液可以通过直接作为展开液供给、滴加到色谱介质、标记试剂保持部位、或者样品垫上而使用。此外,本发明的试剂组合物在核酸色谱法或免疫色谱法中也可以预先保持在样品垫或标记试剂的干燥保持部位中。作为稀释剂使用的本发明的试剂组合物、保持在样品垫或标记试剂的干燥保持部位的本发明的试剂组合物在之后的工序中作为展开液或其一部分使用。由于当保持在标记试剂的干燥保持部位中时,有时在展开时产生一些聚集,所以优选预先保持在展开液、稀释液或它们的一部分、或者样品垫中的方式。
作为本发明的分析对象物,只要是存在或者能够制造与其特异性结合的物质即可,没有特别限定。“特异性结合”是指基于生物体分子所具有的亲和力而结合。作为这样的基于亲和力的结合,具代表性的是抗原与抗体的结合,在免疫测定法中被广泛利用,不仅这样的结合,本发明中,也可以利用糖与凝集素的结合、激素与受体的结合、酶与抑制剂的结合、核酸与互补的核酸、核酸与具有与核酸的结合能力的蛋白质的结合等。分析对象物可以是完全抗原这样的其自身具有抗原性的物质,或者半抗原(不完全抗原)这样的其自身不具有抗原性但通过制成化学改性物而具有抗原性的物质。只要是存在或者能够制造 与这些分析对象物特异性结合的检测物质即可,作为检测物质,可列举出与分析对象物的核酸互补的核酸或核酸结合蛋白质、单克隆抗体或多克隆抗体等。若例示出本发明的分析对象物,可列举出培养细胞株、末梢血或者细菌、病毒等微生物等中所含的核酸(单链核酸或者双链核酸)或其扩增物、癌胚抗原(CEA)、HER2蛋白、前立腺特异抗原(PSA)、CA19-9、α-甲胎蛋白(AFP)、免疫抑制酸性蛋白(IPA)、CA15-3、CA125、雌激素受体、孕酮受体、大便潜血、肌钙蛋白I、肌钙蛋白T、CK-MB、CRP、人绒毛膜促性腺激素(HCG)、促黄体生成素(LH)、卵泡刺激素(FSH)、梅毒抗体、流感病毒、衣原体抗原、A族β溶血性链球菌抗原、HBs抗体、HBs抗原、轮状病毒、腺病毒、白蛋白、糖化白蛋白及花粉、螨、室内尘埃、食品等变应原、变应原特异性IgE等。优选使用培养细胞株、末梢血或者细菌、病毒等微生物等中包含的核酸,具体而言,可列举出DNA、RNA、寡核苷酸、多核苷酸、它们的扩增物等。它们可以将核酸自身作为分析对象物,也可以是被具有与标记试剂的结合能力的结合基或结合蛋白质修饰过的核酸。
作为包含上述被检测物质的试样,例如可列举出生物试样、即全血、血清、血浆、尿、唾液、吐的痰、鼻腔或咽头擦拭液、髓液、羊水、乳头分泌液、泪、汗、来自皮肤的渗出液、来自组织或细胞及粪便的提取液等以及牛奶、鸡蛋、小麦、豆、牛肉、猪肉、鸡肉等或包含它们的食品等的提取液等。此外,可列举出培养细胞株、末梢血或者细菌、病毒等微生物等中包含的核酸的提取液、包含所提取的核酸的扩增物的液体、或者包含被与这些核酸具有结合能力的结合基或结合蛋白质修饰过的核酸的液体,但并不限定于这些。
以下,对于核酸色谱法,采用夹心法对检测方法、判定方法及检测原理的例子进行说明。
(检测方法的例子)
将检测方法的例子示于图1中。(i)采集分析试样(例如、鼻涕)。(ii)从分析试样中提取病毒等基因等。(iii)根据需要,利用PCR法等并使用基因扩增装置将所提取的基因等进行扩增。(iv)将基因等添加到免疫测定用试剂盒中。(v)添加展开液将基因等展开。(vi)在例如15分钟后,判定阳性或阴性。
(判定方法)
将判定方法示于图2中。阳性或阴性的判定以红线的有无来决定。若在Test线(T位置)上出现红线,则作为对象病毒等阳性(图2(b)),若没有出现,则作为对象病毒等阴性(图2(a))。此时内部控制线(internal control line)(I位置)对于从患者的鼻子等中采集病毒等检体时一起包含的患者自身的正常人细胞进行检测。因此,当采集检体时的分析试样的采集不适当时(例如,鼻腔擦拭不充分时)、或者在基因等的扩增(PCR)中产生不良情况时,内部控制线不出现,需重做检查。此外当不出现流动控制线(C位置)时,为在测定中产生不良情况,需再次检查。
(检测原理)
图3中示出测定原理。添加到免疫测定用试剂盒中的扩增基因(例如经生物素修饰的扩增的单链DNA)等例如介由生物素-链霉亲和素结合在标记物(例如,金胶体)上。然后,若添加展开液,则扩增基因-金胶体复合体通过毛细管现象在固定于T线及I线中的DNA上移动。由于T线中预先固定仅与对象病毒等来源的DNA结合的互补DNA,I线中预先固定仅与正常人细胞来源的DNA结合的互补DNA,所以在阳性的情况下形成由金胶体形成的红线。
C线中固定与标记物(例如链霉亲和素结合金胶体)结合的例如生物素标记蛋白质,在展开良好地进行的情况下,C线处产生由金胶体形成的红线。
本发明进一步为核酸色谱法或免疫色谱法测定方法,该方法包括使用前述的试剂组合物将待测物展开的工序。该工序包括使用前述的试剂组合物作为测定试样的稀释剂、或者预先保持在样品垫中并在之后的展开时将其作为展开液的至少一部分的方式。
本发明为核酸色谱法或免疫色谱法测定试剂盒,该试剂盒包含前述的试剂组合物作为待测物的展开液。该试剂盒也包括包含前述的试剂组合物作为待测物的稀释剂,或者,预先保持在样品垫等中,在稀释后,使用其作为展开液的方式。即,展开液可以为了与包含所检测的分析对象物的试样预先混合而使用,也可以将该混合液供给、滴加到色谱介质、标记试剂保持部位、或者样品垫上使其展开。此外,也可以先将试样供给、滴加到样品垫上后,将展开液供给、滴加到样品垫上使其展开。当使用展开液作为试样稀释液时,将试样稀释而成的稀释液可以通过直接作为展开液供给、滴加到色谱介质、标记试剂保持部位、或者样品垫上而使用。此外,展开液在核酸色谱法或免疫色谱法中也可以预先保持在样品垫或标记试剂的干燥保持部位中。作为稀释剂使用的展开液或保持在样品垫或者标记试剂的干燥保持部位中的展开液作为之后的展开工序中的展开液的全部或其一部分使用。由于当保持在标记试剂的干燥保持部位中时,有时在展开时产生一些聚集,所以不优选,优选将前述的试剂组合物预先保持在展开液(包括作为稀释液的使用)或其一部分、或者样品垫中的方式。
[实施例]
通过实施例及比较例对本发明更详细地进行说明。%为重 量基准。
1.核酸色谱法
〔1.捕获探针用稀释液的制作〕
称量87.7g氯化钠、及44.1g柠檬酸钠2水合物,溶解到纯化水800mL中,将pH调节成7.0。将该溶液定容为1000mL,进行高压釜灭菌,制作了捕获探针用稀释液。
〔2.色谱介质上的反应部位的制作〕
使用探针用稀释液将甲型流感病毒(influenza A virus)捕获探针稀释至2.0μM的浓度。将该溶液用涂布机(BioDot公司制)涂布到25×2.5cm的硝基纤维素膜(Millipore Corporation制)上,在50℃下干燥5分钟后,进一步在80℃下干燥1小时,制作了色谱介质上的反应部位。
〔3.标记试剂溶液的制作〕
在金胶体悬浮液(田中贵金属工业株式会社制:平均粒径为40nm)20mL中添加40mM的磷酸缓冲液(pH8.5)1mL并进行搅拌。接着,添加4mL用磷酸缓冲液(pH8.5)稀释至0.01mg/mL的浓度的链霉亲和素,在室温下静置15分钟。接着,添加1mLCE510(JSR Corporation),在室温下静置15分钟。以8000×g进行15分钟离心分离。在离心分离后,除去上清,添加含有1重量%的牛血清白蛋白(BSA)的缓冲液(pH7.4)4mL,制作了标记试剂溶液。
〔4.色谱介质的制作〕
将上述3中制作的标记试剂溶液400μL均一地添加到玻璃纤维制垫(16mm×100mm)上后,利用真空干燥机进行干燥,作为标记试剂保持构件。接着,在由支撑片构成的基材上贴合上述调制的色谱介质、标记试剂保持构件、添加试样的部分中所用的样品垫(Millipore Corporation制:300mm×30mm)、及用于 吸收展开的试样、剩余的标记试剂的吸收垫。最后,用切割机切割成5mm宽度,作为色谱介质。
〔5.展开液的调制〕
(实施例1~8及比较例1~4)
以表1中记载的量,在超纯水中添加10%Tween20、0.1M硫酸镁、二甲基亚砜、20%葡聚糖硫酸钠(重均分子量:50万)、及达到2%的CE510(JSR Corporation)并混合。进一步添加作为防腐剂的10%叠氮化钠使其达到0.05%并混合,得到试剂组合物。
[表1]
(实施例9~14及比较例5~9)
在超纯水中以表2所示那样的种类添加2%的重均分子量为8000以上的水溶性高分子、5mM的2价或3价的金属的盐、1%的非离子性表面活性剂、0.95%的水溶性非质子性有机化合物、及2%的CE510(JSR Corporation)并混合。进一步添加作为防腐剂的10%叠氮化钠使其达到0.05%并混合,得到实施例9~14的试剂组合物。
在超纯水中以表2中所示那样的种类,添加2%的水溶性高分子、5mM的金属盐、1%的表面活性剂、0.95%的异丙醇、2%的CE510及0.05%的叠氮化钠并混合,得到比较例5~9的试剂组合物。
[表2]
〔6.测定〕
使用上述制作的色谱介质,通过以下的方法测定试样中的甲型流感病毒是否存在。即在将从流感病毒感染患者的鼻涕中提取的甲型流感病毒的基因扩增时,以被生物素修饰的单链 DNA形式进行扩增,得到2.0×106copies/μL(copy=复制物1分子)的阳性检体。将其15μL添加到试样添加孔中。然后,立即将展开液100μL添加到试样添加孔中。在15分钟后通过目视确认有无形成线。另外,对于从没有感染甲型流感病毒的正常人采集的阴性检体,也从鼻涕中提取并同样地制作及测定。
〔7.试验例1〕
认为在分析对象物(DNA量)与线的颜色的浓淡(即显色强度)之间成立y=βM的关系(表4)。其理由是,由于准备了充分量固定于金胶体及硝基纤维素膜上的互补DNA,所以根据添加的DNA的量形成于硝基纤维素膜的T线或者I线上的复合体的量增加,得到强的显色强度。当DNA没有进入分析试样中时仅金胶体与展开液一起展开,但该金胶体不会与固定于膜上的DNA发生反应,不会形成T线。
使用实施例1~8及比较例1~4的试剂组合物作为展开液,试验阳性检体(2.0×106copies/μL)的4倍稀释液、6倍稀释液及8倍稀释液以及阴性检体各自的显色及展开不均。
对于显色,按以下的基准在试样展开10分钟后通过目视评价显色强度。
+++:非常强地确认到标记物的红色。
++:较强地确认到标记物的红色。
+:确认到标记物的红色。
±:显色弱而难以确认到标记物的红色。
-:没有确认到标记物的红色。
展开不均通过目视观察展开中的红色金胶体的前端流动形状的方法进行评价。
将试验结果示于表3中。
[表3]
〔8.试验例2〕
使用实施例9~14及比较例5~9的试剂组合物作为展开液,试验阳性检体的4倍稀释液、6倍稀释液及8倍稀释液以及阴性检体各自的显色及展开不均。将其结果示于表4中。
[表4]
2.免疫色谱法
〔1.捕获抗体用稀释液的制作〕
将异丙醇用50mM磷酸缓冲液(pH为7.4)混合稀释至达到5%,制作了捕获抗体用稀释液。
〔2.色谱介质上的反应部位的制作〕
使用抗体用稀释液将甲型流感病毒捕获抗体(小鼠来源的抗流感A单克隆抗体(一抗))稀释至1.0mg/ml的浓度。将该溶液用涂布机(BioDot公司制)涂布到25×2.5cm的硝基纤维素膜(Millipore Corporation制)上,在50℃下干燥5分钟后,进一步在室温下干燥1小时,制作了色谱介质上的反应部位。
〔3.标记物溶液的制作〕
在金胶体悬浮液(田中贵金属工业株式会社制:平均粒径为40nm)0.5ml中添加用磷酸缓冲液(pH为7.4)稀释至0.05mg/ml的浓度的小鼠来源的抗流感A单克隆抗体(二抗)0.1ml,在室温下静置10分钟。接着,添加0.1ml含有1重量%的牛血清白蛋白(BSA)的磷酸缓冲液(pH为7.4),进一步在室温下静置10分钟。然后,充分搅拌后,以8000×g进行15分钟离心分离,除去上清后,添加2ml含有0.5重量%的BSA的磷酸缓冲液(pH为7.4)。按照以上的步骤制作了标记试剂溶液。
〔4.色谱介质的制作〕
将上述制作的标记试剂溶液均一地添加到15mm×300mm的玻璃纤维垫(Millipore Corporation制)上后,利用真空干燥机使其干燥,制作了标记试剂保持构件。接着,在由支撑片构成的基材上贴合上述制作的色谱法介质、标记试剂保持构件、添加试样的部分中使用的样品垫(Millipore Corporation制:300mm×30mm)、及用于吸收展开的试样、剩余的标记试剂的吸收垫。最后用切割机切割成5mm宽度,作为色谱介质。
〔5.展开液的调制〕
(实施例15及比较例10~13)
如表5中记载的那样,在超纯水中添加1%的10%Tween20、5mM的0.1M硫酸镁、0.95%的二甲基亚砜、2%的20%葡聚糖硫酸钠(重均分子量:50万)、及2%的CE510(JSR Corporation)并混合。进一步添加作为防腐剂的10%叠氮化钠使其达到0.05%并混合,得到实施例15及比较例10~13的试剂组合物。
[表5]
成分 | 添加量 | 实施例15 | 比较例10 | 比较例11 | 比较例12 | 比较例13 |
葡聚糖硫酸钠 | 2% | ○ | ○ | ○ | ○ | |
硫酸镁 | 5mM | ○ | ○ | ○ | ○ | |
DMDO | 0.95% | ○ | ○ | ○ | ○ | |
吐温20 | 1% | ○ | ○ | ○ | ○ |
〔6.测定〕
使用上述制作的色谱介质,通过以下的方法测定试样中的甲型流感病毒是否存在。将吸捕器的一个管插入空吸泵中,将另一个管插入至没有感染流感A的人的鼻腔的内部,将空吸泵设定为负压而采集鼻涕。将采集的鼻涕用上述制作的展开液稀释至20倍,将其作为阴性检体试样。此外,在阴性检体试样中按照蛋白浓度达到25ng/mL、50ng/mL的方式添加市售的灭活甲型流感病毒,作为阳性检体试样。
〔7.试验例1〕
将150μL阴性检体试样、阳性检体试样都放置到免疫色谱法用试验片的样品垫上使其展开,15分钟后进行目视判定。显色强度及展开不均的基准设定为与核酸色谱法同样的基准。
将试验结果示于表6中。
[表6]
产业上的可利用性
根据本发明,在核酸色谱法或免疫色谱法测定中,通过降低由分析对象物以外的成分的非特异性反应产生的结合,且提高分析对象物的分散能力,同时促进特异性反应,从而即使使用低浓度的分析对象物也能够进行准确且迅速的判断。
附图标记说明
1:色谱介质
2:扩增的基因
3:展开液
4:阴性的显色条带
5:阳性的显色条带
6:扩增的DNA
7:展开液
8:金胶体
9:膜固定探针
10:硝基纤维素膜
Claims (11)
1.一种核酸色谱法或免疫色谱法用试剂组合物,其含有重均分子量为8000以上的水溶性高分子化合物、2价或3价的金属的盐、非离子性表面活性剂、及水溶性非质子性有机化合物,
重均分子量为8000以上的水溶性高分子化合物为选自由聚亚烷基二醇类、纤维素类、乙烯基系高分子类、酰胺系高分子类及聚阴离子组成的组中的1种以上,
水溶性非质子性有机化合物为选自由亚砜类及N,N’-二烷基酰胺类组成的组中的1种以上。
2.根据权利要求1所述的试剂组合物,其中,聚阴离子为多糖阴离子。
3.根据权利要求2所述的试剂组合物,其中,多糖阴离子为选自由硫酸葡聚糖、硫酸乙酰肝素、硫酸软骨素、硫酸皮肤素、硫酸角质素、透明质酸、肝素及其盐组成的组中的1种以上。
4.根据权利要求1~3中任一项所述的试剂组合物,其中,2价或3价的金属的盐为选自由镁盐、钙盐及铝盐组成的组中的1种以上。
5.根据权利要求1~3中任一项所述的试剂组合物,其中,非离子性表面活性剂为选自由单月桂酸聚氧乙烯山梨糖醇酐、单硬脂酸聚氧乙烯山梨糖醇酐、三硬脂酸聚氧乙烯山梨糖醇酐及单油酸聚氧乙烯山梨糖醇酐组成的组中的1种以上。
6.根据权利要求1~3中任一项所述的试剂组合物,其用于核酸色谱法。
7.根据权利要求1~3中任一项所述的试剂组合物,其用于免疫色谱法。
8.根据权利要求1~3中任一项所述的试剂组合物,其用于使用金胶体颗粒作为标记物的核酸色谱法或免疫色谱法。
9.根据权利要求1~3中任一项所述的试剂组合物,其作为核酸色谱法或免疫色谱法中的展开液使用。
10.一种核酸色谱法或免疫色谱法测定方法,其包括使用权利要求1~9中任一项所述的试剂组合物将待测物展开的工序。
11.一种核酸色谱法或免疫色谱法测定用试剂盒,其包含权利要求1~9中任一项所述的试剂组合物作为待测物的展开液。
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AU2011300193A1 (en) | 2013-04-18 |
AU2011300193B2 (en) | 2015-05-14 |
WO2012032794A1 (ja) | 2012-03-15 |
EP2615457A4 (en) | 2014-03-05 |
JP2012058058A (ja) | 2012-03-22 |
JP4638555B1 (ja) | 2011-02-23 |
EP2615457A1 (en) | 2013-07-17 |
KR20130138775A (ko) | 2013-12-19 |
EP2615457B1 (en) | 2016-01-13 |
CA2810789C (en) | 2017-05-23 |
CA2810789A1 (en) | 2012-03-15 |
CN103097895A (zh) | 2013-05-08 |
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