JP5410464B2 - 標的分析物検出および溶液中の標的分析物濃度の決定のための方法およびアレイ - Google Patents
標的分析物検出および溶液中の標的分析物濃度の決定のための方法およびアレイ Download PDFInfo
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- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
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Description
米国政府は、国防総省、国防総省国防高等研究事業局(DARPA)海軍研究事務所によって供与された規約番号N00014−01−1に従って、本発明において所定の権利を有し得る。
高感受性かつ低いレベルの分析物の検出を迅速かつ再現可能な実験プロトコルと組み合わせて実施する方法は、近代的な分析学的測定法の礎石である。現在、サンプルマトリックス中の低レベルの標的分析物を定量するための最も知られている技術は、レポーター分子の数を増大させてそれにより測定可能なシグナルを得る増幅手順を用いる。かかる公知の方法として、抗体に基づくアッセイにおいてシグナルを増幅するための酵素結合免疫吸着検定法(ELISA)、ならびにDNAに基づくアッセイにおいて標的DNA鎖を増幅するためのポリメラーゼ連鎖反応(PCR)が挙げられる。免疫PCRと称される、より感受性であるが間接的なタンパク質標的増幅技術(Sano, T.; Smith, C. L.; Cantor, C. R. Science 1992, 258, 120-122を参照)は、オリゴヌクレオチドマーカーを利用し、オリゴヌクレオチドマーカーを、その後PCRを用いて増幅し、DNAアッセイを用いて検出することができる(Nam, J. M.; Thaxton, C. S.; Mirkin, C. A. Science 2003, 301, 1884-1886; Niemeyer, C. M.; Adler, M.; Pignataro, B.'; Lenhert, S.; Gao, S.; Chi, L. F.; Fuchs, H.; Blohm, D. Nucleic Acids Research 1999, 27, 4553-4561; and Zhou, H.; Fisher, R. J.; Papas, T. S. Nucleic Acids Research 1993, 21, 6038-6039を参照)。免疫PCR法によって超低レベルのタンパク質の検出が可能となるが、これは複雑なアッセイ手順であり、擬陽性シグナルを生じる傾向があり得る(Niemeyer, C. M.; Adler, M.; Wacker, R. Trends in Biotechnology 2005, 23, 208- 216を参照)。
一態様において、本発明は、サンプル中の標的分析物を検出する方法に関する。該方法は、各々の位置(site)が捕獲成分(capture component)を含む複数の位置を含むアレイを提供すること、および、複数の位置のサブセット中の各々の位置が単一の標的分析物を含有するように、アレイとサンプルとを接触させること、を包含する。各々の標的分析物は、酵素成分を含む。該方法はさらに、アレイを酵素基質と接触させること、および、位置の各々における光学特性の変化を標的分析物の存在の指標として検出すること、を包含する。
本発明は、サンプル中の標的分析物または標的分析物(複数)の酵素による検出および定量のための方法、システムおよびデバイスに関する。より具体的には、本発明は、捕獲成分を含有するマイクロからナノスケールのサイズの反応容器のアレイを用いての、酵素による標的分析物の検出および定量に関する。一態様によれば、捕獲成分を含有する反応容器のアレイを、少なくとも1つの標的分析物を含有するサンプルと接触させる。次いで、色素生産性の基質を添加し、生じる酵素反応の色素生産性生成物により、分析物の検出が可能となる。さらに、一態様によれば、捕獲された標的分析物を有する反応容器のパーセンテージを用いて、バイナリ読み出し法を使用してサンプル中の標的分析物の量を計算することができる。
本発明は、複数のアッセイ位置を含む表面を備えた第1の基材を少なくとも含む、アレイの組成を提供する。本明細書における「アレイ」とは、アレイ形式における複数の捕獲成分を意味する。アレイのサイズは、アレイの組成および最終用途に依存する。約2個から数百万個の異なる捕獲成分を含有するアレイ、ならびに非常に大きな光学アレイを含む非常に大きなアレイを作製することができる。一般に、アレイは、ウェルおよび基材のサイズ、ならびにアレイの最終用途に依存して、2個〜10億個もの多数またはそれより多くの捕獲成分を含み、したがって、非常に高密度、高密度、中程度の密度、低密度および非常に低密度のアレイを作製することができる。非常に高密度のアレイのための好ましい範囲は、約10,000,000個〜約2,000,000,000個であり、約100,000,000個〜約1,000,000,000個が好ましい。高密度アレイは、約100,000個〜約10,000,000個の範囲であり、約1,000,000個〜約5,000,000個が特に好ましい。中程度の密度のアレイは、約10,000個〜約50,000個の範囲であることが特に好ましく、約20,000個〜約30,000個が特に好ましい。低密度アレイは、一般に、10,000個より少なく、約1,000個〜約5,000個であることが好ましい。非常に低密度のアレイは、1,000個より少なく、約10個〜約1000個が好ましく、約100個〜約500個が特に好ましい。一部の態様において、複数の基材を用いてもよく、異なった組成であっても同一の組成であってもよい。したがって、例えば、大きなアレイは、複数のより小さい基材を含んでもよい。
本発明のマイクロウェルは、少なくとも1つの捕獲成分を含む。捕獲成分(また、「捕獲結合リガンド」、「結合リガンド」、「捕獲結合種」、または「捕獲プローブ」としても言及される)は、標的分析がアッセイの間固定されるように、標的分析物を基材上のマイクロウェル中で探る(probe)か、これに付着するか、結合するか、または他の方法でこれを捕獲するために用いることができる、任意の分子、化合物、またはマイクロウェルの修飾である。一般に、捕獲結合リガンドまたは成分は、検出、定量または他の分析の目的のための、標的分析物のマイクロウェルへの付着を可能にする。
本明細書において議論されるように、本発明のアレイは、標的分析の検出、定量、およびさらなる分析を提供する。本明細書における「標的分析物」または「分析物」または文法的に同等のものにより、検出されるか、または結合パートナーについて評価されるべき任意の原子、分子、イオン、分子イオン、化合物または粒子を意味する。
標的分析物(単数または複数)がマイクロウェル(単数または複数)中に捕獲された後(および特定の態様によれば洗浄の工程の後)で、反応成分がアレイに添加される。本明細書において使用される場合、「反応成分」により、酵素または酵素性分子と接触した場合に酵素反応に影響を及ぼす分子を意味する。「影響を及ぼす」により、反応または阻害反応を活性化するか、または改変する(例えば、遅延または加速させる)か、または反応を阻害することを含むことを意味するが、これらに限定されない。一態様によれば、反応成分は、色素生産性酵素基質である。「色素生産性酵素基質」とは、本明細書において使用される場合、酵素によって酵素反応の結果として色素生産性生成物に変換されるあらゆる分子である「色素生産性」とは、光学(可視光)スペクトルにおける色または色素への関連を意味し、蛍光発生性を含む。
本発明のアレイは、いくつかの異なるアッセイ方法のために用いることができる。より具体的には、本発明は、(a)標的分析物の検出、および(b)サンプル中の標的分析物濃度の定量を提供する。
本発明の一局面において、本発明のアレイは、サンプル中の標的分析物の存在を検出するために用いることができる。より具体的には、本発明は、酵素反応の生成物を標的分析物の存在の指標として検出するための方法を提供する。
1つの検出の態様によれば、センサー冗長性(sensor redundancy)が用いられる。この態様において、「亜集団」として言及される同一の捕獲成分を含む複数の反応容器が用いられる。すなわち、各々の亜集団は、アレイのマイクロウェル中に存在する複数の同一の捕獲成分を含む。さらに、一態様によれば、各々の亜集団は、同一の捕獲成分を含む複数のマイクロウェルを含む。所与のアレイについて多数の同一の捕獲成分を用いることにより、各々のマイクロウェルからの光学シグナルを、亜集団について組み合わせることができ、以下に概説するように、任意の数の統計学的分析を行うことができる。このことは、多様な理由のために行い得る。
センサー冗長性に加えて、一態様による本発明のアレイは、単一の標的分析物に指向するが同一ではない複数の捕獲成分を利用する。この態様は、1より多くの異なる捕獲成分を各々のマイクロウェル中に、または、異なるマイクロウェル中に異なる捕獲成分を、提供する。一例において、単一の2または3以上の捕獲成分が結合することができる標的分析物を提供することができる。このことにより、非特異的結合相互作用が統計学的に最少化されるので、信頼のレベルが高まる。この態様において、タンパク質性標的分析物を評価する場合、好ましい態様は、標的の異なる部分に結合する捕獲成分を利用する。例えば、同一の標的タンパク質の異なる部分に対する2または3以上の抗体(または抗体フラグメント)を捕獲成分として使用し、好ましい態様は、異なるエピトープに対する抗体を利用する。
別の態様によれば、本発明のアレイは、複数の標的分析物に指向された複数の異なる捕獲成分を利用する。この態様は、各々のマイクロウェル中に1より多くの異なる捕獲成分、または異なるマイクロウェル中に異なる捕獲成分を含む。一例において、同一のマイクロウェルまたは異なるマイクロウェル中の2または3以上の捕獲成分が結合することができる、2または3以上の標的分析物を提供してもよい。
異なる標的分析物に指向された捕獲成分亜集団および同一の標的分析物に指向された複数の捕獲成分を含む上記の異なるアッセイの構成の各々はまた、以下に記載する定量のために利用してもよいことに注意されたい。
本発明の一態様によれば、本発明は、サンプル中の標的分析物の検出のために用いるのみならず、またサンプル中の標的分析物の定量のために用いることもできる。すなわち、標的分析物を含有する反応容器のパーセンテージと、サンプル中の標的分析物の濃度との間に、相関関係が存在する。したがって、本発明の定量方法により、標的分析物を捕獲したマイクロウェルのパーセンテージに基づき、サンプル中の標的分析物の量の計算が可能となる。
方程式1: Pμ(v)=e−μ(μv/v!)
本発明の一態様は、上記の単一分子の検出および定量の多様な態様についてシグナルおよび感受性を増大させるために、生体分子、および好ましくは複数の生体分子(例えばオリゴヌクレオチド)、に付着した金属または半導体のナノ粒子を企図する。一態様において、生体分子(例えばオリゴヌクレオチド)は、ナノ粒子に付着していない末端において蛍光分子で標識される。本発明は、ナノ粒子の型またはアッセイにおける1つのみの型のナノ粒子の使用に限定されることを意図しない。一部の態様において、2または3以上の異なる型またはサイズのナノ粒子が用られる。例えば、異なるサイズ(例えば、直径50nmおよび100nm)の金ナノ粒子は、異なる色の光を分散し(それらの異なる表面プラズモン共鳴に起因する)、これらは、同一のアレイにハイブリダイズされた異なるDNA標的を標識するために用いることができる。
本発明のシステムおよびアレイは多くの用途を有する。例えば、アレイは、基礎的な酵素学的研究、ならびにデジタル濃度測定への適用を有する。さらに、アレイは、複数の異なる酵素による研究を可能にし、タンパク質分子およびDNA標的に対する超低濃度検出の限界を拡大する。反応容器の大きなアレイを同時にモニタリングする能力とともに、分子酵素学を用いてバルク動的シグナルからの個々の酵素分子の動態(KoffおよびKon)を分けることができる。
この例において、フェムトリットルサイズの反応容器のアレイにおける酵素シグナル増幅を用いて、実際に可能であることを示す結合アッセイを行う。より具体的には、本発明のビオチン化アレイを用いて溶液中の多様な量のストレプトアビジン−β−ガラクトシダーゼ(SβG)を検出するために、多様なアッセイを行い、次いで、捕獲されたSβG分子を有するウェルの数とサンプル中のSβGの濃度との相関関係を試験する。
この例における反応容器のアレイを、4.5μmの24,000個からなる研磨された1mmの光ファイバーアレイの遠位面の酸エッチングを用いて作製する。コアファイバー材料はシリカであり、各々のファイバーの周囲の被覆剤はゲルマニウムによりドーピングされたシリカであり、これはより遅い速度で腐食する。4.5μmのファイバーを、2.9μmの深さまでエッチングし、各々が46Lの容積を有する反応容器を作製する(図1aを参照)。
第1に、捕獲成分の有効性を試験した。基材のビオチン化の有効性を試験するために、研磨されたファイバーおよび未研磨のファイバーの両方の表面上のビオチン基に、ストレプトアビジンAlexa Fluor 568(登録商標)を直接付着させ、その後、修飾された表面の画像を得た(図3を参照)。図3は、(a)未研磨のビオチン修飾光ファイバーアレイおよび(b)研磨されたビオチン修飾光ファイバーアレイに結合しているストレプトアビジンAlexa Fluor 568(登録商標)を示す。結合がマイクロウェル反応器の表面のみにおいて起きた(b)と比較した場合、画像(a)において観察されるように、ストレプトアビジンの結合は、全ての表面において起きた。したがって、未研磨のファイバーは、被覆表面を含むアレイ全体にわたって色素を示すが、研磨されたファイバーは、ウェル表面においてのみ局在した色素を示す。
図5は、サンプル中に存在する標的のモルのlog対logプロット、およびその結果得られる活性な反応容器のパーセンテージを表す。図5に示される活性な反応容器のパーセンテージとlog対logでの標的のモルと間の直線的関係は、DNAおよび抗原などの実際の標的の検出のためにバイナリ読み出し検出法を用い得ることを示唆する。この方法により、直接的なアッセイの手段を維持しつつ、デジタル読み出しを介した迅速な分析および正確な濃度情報が可能となる。
この例において、β−ガラクトシダーゼの単一の分子を、2.0×105個の個々に密封されたフェムトリットルのマイクロウェル反応器にわたって、直径1mmの光ファイバー束を用いてモニタリングした。反応容器のアレイにわたる単一の酵素分子の触媒からの蛍光生成物の蓄積を観察し、ポワソン統計学分析を適用することにより、デジタル濃度読み出しを得た。
1mmの束にした4.5μmの光ファイバーを、Illumina(San Diego、CA)から購入した。β−ガラクトシダーゼおよびRu(bpy)3Cl2を、Sigma- Aldrich(St. Louis、MO)から得た、レゾルフィン−D−β−ガラクトピラノシドを、Molecular Probes(Eugene、OR)から購入した。0.01インチの非強化ガラスシリコーンシート材料を、Specialty Manufacturing Inc.(Saginaw、MI)から購入した。使用した全ての他の化学物質は、試薬グレードであり、Sigma- Aldrich(St. Louis、MO)から得た。
アッセイ
β−ガラクトシダーゼアッセイのために用いられた基質は、レゾルフィン−β−D−ガラクトピラノシドであった。アレイ中の個々のウェルを酵素および基質の存在下において密封した後、容器のアレイにわたり、酵素生成物であるレゾルフィン(ex 558nm/em 573nm)について蛍光強度をモニタリングした。2.0mMのKClおよび0.lmMのMgCl2を含む100μMのTrisバッファーpH 8.0中、100μMのレゾルフィン−β−D−ガラクトピラノシド(RDG)の溶液を調製した。全ての酵素溶液を、同じ反応バッファーから予め分注して凍結したストックサンプルから調製した。実験の直前に、2つのサンプルを2分間7000RPMで遠心分離し、シリコーンによる密封の機序に干渉し得る全ての粒子状の物質を除去した。およそ1cm2のシリコーンと顕微鏡スライドグラスとを無水エタノールで洗浄した。シリコーンシート材をガラス表面に置き、接着させた。その後、75μLの容積の酵素およびRDG溶液を、シリコーンのガスケット上でピペットを用いて混合した。ガスケットを、ファイバー束の遠位端に向かって、密封が形成されたことを示唆する抵抗を感じるまで機械的に上昇させた。最初の蛍光画像を得、その後、およそ2時間にわたり定期的に画像を得た。
フェムトリットルアレイを密封するために、0.01インチの厚みのシリコーンエラストマーのガスケットを、顕微鏡スライドグラスとファイバーアレイとの間で、機械的プラットフォームを用いてサンドウィッチした。プラットフォームは、束全体にわたって、ガスケット材に均一な圧力を適用し、各々のマイクロウェルを密封して反応容器を作製した。
DI水中、1mMのRu(bpy)3C12の溶液を、光脱色実験のために用いた。およそ1cm2のシリコーン片および顕微鏡スライドグラスを、糸くずの出ないスワブを用いて無水エタノールで洗浄した。シリコーンシート材を、ガラスの表面上に置き、接着させた。50μLのRu(bpy)3C12溶液をシリコーン上に置き、その後ファイバー束と接触させ、個々の容器中に溶液を封入した。イメージングシステムの視野絞りを用いて、UV光を用いてアレイの小さな部分に10分間照射し、Ru(bpy)3C12を光脱色した。次いで、視野絞りを開放し、蛍光の差異を示す異なる画像を得た。次いで、アレイを、密封が維持された状態で静置した。最後の画像を60分後に取得し、密封の完全性を確認した。
図8に示すように、β−ガラクトシダーゼアッセイについて、異なるバルク溶液酵素濃度は、容器容積に対する酵素の異なる比に対応し、酵素分子を含有する容器のパーセンテージの変化をもたらした。図8は、β−ガラクトシダーゼの単一分子の活性の検出を表す。図8aは、アレイの一部のバックグラウンド画像であり、一方、図8bは、酵素対容器が1:5であるアッセイの一部を取得した画像を表し、図8cは、酵素対容器が1:80であるアッセイを示す。
この例において、モデル酵素−阻害剤ペアとして、β−ガラクトシダーゼを競合的阻害剤であるD−ガラクタル(D-galactal)(D−ガラクトースの遷移状態の類似体)の存在下において研究した。しかし、この適用の範囲は、特定の酵素−阻害剤ペアに限定されない。β−ガラクトシダーゼは四量体であり、D−ガラクタルは比較的遅い結合および放出を示すことが知られる。図9は、単一分子阻害を測定するためならびに阻害剤放出の検出のためのスキームの一態様を示す。第1の工程において、酵素および阻害剤を、リン酸バッファー(この特定の態様においては、PBS/MgCl2バッファー:2.7mM KCl、KH2PO4、1.5mM KH2PO4、136mM NaCl、8.1mM Na2HPO4、1mM MgCl2、pH7.3)などの水性バッファー系において、バルクにおいて、阻害剤濃度([阻害剤])が阻害剤結合のための解離定数(Ki)より高くなり、酵素の活性部位の全てがブロックされるかまたは占有されるように、プレインキュベートする。Kiは異なる酵素/阻害剤ペアにより異なるので、阻害剤の濃度を調製しなければならない。この実験において用いたこの特定の酵素/阻害剤ペアを用いる場合、100mM〜20μMの間の範囲で多様な阻害剤開始濃度を用いることができる。この態様において、[阻害剤]は、100μM(〜7×Ki(14μM))であった。第2の工程において、水性バッファー系(この特定の態様においては:PBS/MgCl2バッファー)中の1または2以上の基質(例えば、レゾルフィン−β−ガラクトピラノシド RGP)を、好ましくは高い過剰濃度(10倍〜100,000倍の間)において、添加する。さらなる成分(この特定の態様においては、位置のアレイの表面への非特異的結合を防止するため、1%(w/v)のウシ血清アルブミン(BSA)を、バッファー系に添加してもよい。第三の工程において、バルク溶液を位置のアレイに添加する。各々の位置は、規定の容積(10アトリットル〜50ピコリットルの間、より好ましくはフェムトリットル、この態様においては:46フェムトリットル)を有する。この時点において、阻害剤はもはや過剰量ではない。実際には、[阻害剤]<<Kiである(100,000分子より少ない阻害剤、および10,000分子より少ない阻害剤、およびさらにより好ましくは3,000分子より少ない阻害剤が、溶液中に残る)。酵素濃度(1.8nMを、工程2における1,000倍希釈により、いくつかの位置において各々のアレイの位置において単一の酵素のみが存在し、他においては酵素が存在しないように調製する。図9は、四量体の活性部位の1つがブロックされておらず活性である場合の状況を、模式的に示す。この活性部位は、レポーター部分を含む基質と相互作用することができる。このドメインは、酵素分解により発光性および蛍光性シグナルを生じるものであり得るが、これらに限定されない。好ましくは、蛍光シグナルが発生し、より好ましくは、RGPが蛍光発生基質として用いられる。この方法において、かかる活性を有するアレイ中の位置を、容易に検出することができる(図10)。
一態様において、ナノ粒子は、標的の濃度のデジタル読み出しのために利用する。ナノ粒子は、酵素のデジタル読み出しに対して、いくつかの利点を有する。酵素のアプローチを用いる場合、濃度が増加するにつれて、ポワソン分布に従うデジタル読み出しの直線性が失われる。蛍光種により官能化されたナノ粒子を用いて、本発明は、一態様において、デジタル読み出し、ならびに本発明者らの研究室において広範に用いられる古典的なバルク光度読み出しを行うことができることを企図する。デジタル読み出しの直線性が失われるにつれて、分析を、デジタル読み出しからナノ粒子を用いる古典的な光度読み出しへとシフトすることができる。次いで、シグナルを、濃度と相関する、アレイの各々の位置の平均光度(例えば、平均ウェル光度)として読むことができ、このシステムにより読むことができる濃度の範囲を著しく増大する。ナノ粒子を用いる一部の態様において、アレイを密封しない。
金粒子は、多数の方法により調製することができる(Analytical Chemistry, 2000, 72, 5535-5541; Science, 2002, 296, 1836-1838; Science, 2002 295, 1503-1506; J. Am. Chem. Soc. 2004, 126, 5932-5933)。ある場合において、金コロイド(直径13nm)を、Frens, Nature Phys. Sci., 241, 20(1973)およびGrabar, Anal Chem., 67, 735(1995)に記載されるように、HAuCl4のクエン酸による還元により調製する。簡単に述べると、全てのガラス器具を使用する前に王水(3部のHCl、1部のHNO3)中で洗浄し、NanopureH2Oでリンスし、次いでオーブンで乾燥する。HAuCl4およびクエン酸ナトリウムは、Aldrich Chemical Companyから購入する。水性のHAuCl4(1mM、500mL)を、攪拌しながら還流させる。次いで、38.8mMのクエン酸ナトリウム(50mL)を素早く添加する。溶液の色は、淡黄色から赤紫色(burgundy)に変化し、還流を15分間続けるべきである。室温に冷却した後で、赤色の溶液を、Micron Separations Inc.の1マイクロンのフィルターを通してろ過してもよい。金コロイドは、Hewlett Packard 8452Aダイオードアレイ分光光度計を用いるUV/可視光分光法により、およびHitachi 8100透過型電子顕微鏡を用いる透過型電子顕微鏡法(TEM)により、容易に特徴付けられる。直径13nmの金粒子は、標的およびプローブの10〜35ヌクレオチドの範囲のオリゴヌクレオチド配列とともに凝集した場合、目に見える色の変化を生じる。
この例において、ファイバーアレイを用いる。研磨されたファイバーアレイを、115秒間0.025MのHClでエッチングし、46fLのウェルを得る。洗浄のために、エッチングされたファイバーを、沸騰するNanopure水で10分間インキュベートする。
2ナノモルのチオール修飾(保護)DNAを、110μLのPBS pH7.4中で再構成する。10μLのDTT(ジチオスレイトール)ストック(1.0M)を保護されたDNA溶液に添加し、2時間室温でインキュベートする。NAP-5カラム(GE Healthcare)を用いて脱保護したDNAを精製した。カラムをNanopure水で平衡化した。
標的分析物(この場合は核酸)に対して特異的なリガンド(この場合はプローブ)を、アレイの位置に直接付着させても、またはナノ粒子(例えば金粒子)に付着させ、次いで複合体(DNA−金ナノ粒子)をアレイに導入してもよい。この例において、マレイミド処理されたファイバーを、チオール脱保護されたDNA溶液(1μM)中で2時間室温でインキュベートした。ファイバーを、PBS7.4でリンスし、結合していないDNAを除去し、アレイをスワブして、被覆材に結合したDNAプローブを除去した。金ナノ粒子(この場合80nm)を、次いで、ファイバーと共にインキュベートし、予備的な実験により、成功的な結合を示す(図16)。
この例は、合成一本鎖DNAの半導体ナノ粒子量子ドット(QD)上への固定化を記載する。ネイティブなCdSe/ZnSのコア/シェルQD(−4nm)は、有機溶媒中でのみ可溶性であり、アルキルチオ末端を有する一本鎖DNAとの直接的反応は困難である。この問題は、Mirkinらにより、QDを3−メルカプトプロピオン酸でまずキャッピングすることにより回避される。次いで、4−(ジメチルアミノ)ピリジンでカルボン酸基を脱保護し、粒子を水溶性にし、QDと3’−プロピルチオールまたは5’−ヘキシルチオール修飾オリゴヌクレオチド配列のいずれかとの反応を促進する。DNA修飾の後で、透析により未反応のDNAから粒子を分離する。次いで、「リンカー」DNA鎖を、表面結合の配列にハイブリダイズし、拡大したナノ粒子の集合体を生成する。QD集合体は、TEM、UV/可視光分光法および蛍光分光法により容易に特徴付けられる。繰り返し、溶液の温度を制御することにより、これらを可逆的に集合させることができる。結果として、QD集合体および合成物集合体を、QDとナノ粒子との間で形成することができる(例えば、およそ13nmの金ナノ粒子)。
図2a、2bおよび2cは、本発明の一態様によるサンドウィッチアッセイを表す、横から見た断面模式図である。
Claims (12)
- サンプル中の標的分析物の濃度を測定する方法であって、
(a)分析物が反応容器において捕獲される条件下で、サンプルを複数の反応容器に露出すること、ここで各々の反応容器は、捕獲成分を含み、10アトリットル〜50ピコリットルの間で規定された容積を有し、ここで標的分析物分子の反応容器の数に対する比は、1:1より小さい、
(b)標的分析物の濃度を測定するための捕獲された標的分析物分子を含む反応容器のパーセンテージを決定すること、
を含む、前記方法。 - 各々の反応容器の内容物が該反応容器から漏出しないように、反応容器を密封成分で密封することをさらに含む、請求項1に記載の方法。
- 標的分析物分子が、反応容器を密封する前に捕獲されている、請求項2に記載の方法。
- 標的分析物が、第1の型の標的分析物および第2の型の標的分析物を含む、請求項1〜3のいずれか一項に記載の方法。
- 標的分析物が、タンパク質、核酸、脂質、炭水化物、ホルモン、サイトカイン、細胞抗原、受容体および細胞からなる群から選択される、請求項1〜4のいずれか一項に記載の方法。
- 反応容器の壁が、そこに固定化された捕獲成分を有する結合表面を規定する、請求項1〜5のいずれか一項に記載の方法。
- 複数の反応容器を酵素成分と接触させること、および、任意に、複数の反応容器を酵素基質とさらに接触させることをさらに含む、請求項1〜6のいずれか一項に記載の方法。
- ナノ粒子を分析物に対して結合するか、あるいは他の方法で固定することをさらに含み、ここで任意に、ナノ粒子は金ナノ粒子である、またはここで任意に、ナノ粒子は各々蛍光種により官能化されている、請求項1〜6のいずれか一項に記載の方法。
- 比が、(i)1:5より小さい、または、(ii)1:5〜1:500の間、または、(iii)1:10である、請求項1〜8のいずれか一項に記載の方法。
- 各々の位置の規定された容積が、30フェムトリットル〜60フェムトリットルの範囲である、請求項1〜9のいずれか一項に記載の方法。
- 複数の反応容器が、(i)少なくとも約1000個の反応容器、または、(ii)20,000〜10,000,000個の間の反応容器、または、(iii)20,000〜30,000個の間の反応容器、または、(iv)100,000〜10,000,000個の間の反応容器、または、(v)10,000〜50,000個の間の反応容器を含む、請求項1〜10のいずれか一項に記載の方法。
- 決定することが、位置における光学特性の変化を標的分析物分子の存在の指標として検出することを含む、請求項1〜11のいずれか一項に記載の方法。
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JP2009529658A (ja) | 2009-08-20 |
WO2007098148A3 (en) | 2008-10-16 |
EP2538220A1 (en) | 2012-12-26 |
CA2643993C (en) | 2015-12-15 |
US20220099678A1 (en) | 2022-03-31 |
CA2643993A1 (en) | 2007-08-30 |
US20170038390A1 (en) | 2017-02-09 |
WO2007098148A2 (en) | 2007-08-30 |
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US8460879B2 (en) | 2013-06-11 |
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US9395359B2 (en) | 2016-07-19 |
JP4790026B2 (ja) | 2011-10-12 |
ES2530203T3 (es) | 2015-02-27 |
ES2613083T3 (es) | 2017-05-22 |
US8460878B2 (en) | 2013-06-11 |
US10261089B2 (en) | 2019-04-16 |
US8492098B2 (en) | 2013-07-23 |
US20070259448A1 (en) | 2007-11-08 |
AU2007217819A1 (en) | 2007-08-30 |
US20150233905A1 (en) | 2015-08-20 |
US11874279B2 (en) | 2024-01-16 |
EP2538220B1 (en) | 2016-11-09 |
US20240159765A1 (en) | 2024-05-16 |
EP1996717A2 (en) | 2008-12-03 |
JP2011137830A (ja) | 2011-07-14 |
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