JP2011506965A - 質量分析によってエストロンを検出するための方法 - Google Patents
質量分析によってエストロンを検出するための方法 Download PDFInfo
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- JP2011506965A JP2011506965A JP2010538047A JP2010538047A JP2011506965A JP 2011506965 A JP2011506965 A JP 2011506965A JP 2010538047 A JP2010538047 A JP 2010538047A JP 2010538047 A JP2010538047 A JP 2010538047A JP 2011506965 A JP2011506965 A JP 2011506965A
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Abstract
Description
サンプル中の他の成分(例えば、タンパク質)に対してエストロンを富化するために用いられ得る方法としては、例えば、濾過、遠心分離、薄層クロマトグラフィー(TLC)、電気泳動、例えば、キャピラリー電気泳動、アフィニティ分離、例えば、イムノアフィニティー分離、抽出方法、例えば、酢酸エチル抽出およびメタノール抽出、ならびにカオトロピック剤の使用または上記の任意の組み合わせなどが挙げられる。
種々の実施形態では、試験サンプル中に存在するエストロンを当業者に公知の任意の方法によってイオン化してもよい。質量分析は、質量分析計を用いて行い、この質量分析計には、さらなる分析のために断片化されたサンプルをイオン化し、荷電された分子を作製するためのイオン源を備える。例えば、サンプルのイオン化は、電子イオン化、化学的イオン化、エレクトロスプレーイオン化(ESI)、光子イオン化、大気圧化学イオン化(APCI)、光イオン化、大気圧光イオン化(APPI)、高速原子衝撃(FAB)、液体二次イオン化(LSI)、マトリックス支援レーザー脱離イオン化(MALDI)、フィールド・イオン化、フィールド・デソープション、熱スプレー/プラズマスプレーイオン化、表面増強レーザー脱離イオン化(SELDI)、誘導結合プラズマ(ICP)および粒子ビームイオン化によって行ってもよい。当業者は、イオン化方法の選択は、測定されるべき分析物、サンプルの種類、検出器の種類、正対負のモードの選択などに基づいて決定できることを理解するであろう。
血液は、添加物なしでVacutainer中に収集して、室温、18〜25℃で30分間凝固させた。全体的な溶血、脂肪血症および/または黄疸を呈したサンプルは除外した。
液体クロマトグラフィー(LC)サンプルは、200μLの標準、コントロール、または患者サンプルを96−ウェルのプレートにピペッティングすることによって準備した。さらに、300μLの20%ギ酸を、各々のウェルに約11%(V/V)の最終濃度で与えた。最終的に、50μLの5000pg/mLのd4−エストロン標準を各々のウェルに添加した。このサンプルをLCの前に30分間室温でインキュベートした。
MS/MSは、Finnigan TSQ Quantum Ultra MS/MSシステム(Thermo Electron Corporation)を用いて行った。全てがThermoElectronの以下のソフトウェアプログラムを、本明細書に記載の実施例に用いた:Tune Master V1.2、またはそれより新しいもの、Excalibur V2.0 SR1、またはそれより新しいもの、TSQ Quantum 1.4またはそれより新しいもの、LCQuan V2.5 SUR1またはそれより新しいもの、およびXReport 1.0またはそれより新しいもの。分析HPLCカラムを出ていく液体の溶媒/分析物は、Thermo Finnigan MS/MSアナライザーの加熱されたネブライザー界面に流れた。その溶媒/分析物混合物を、界面の加熱配管中で蒸気に変換した。噴霧された溶媒中の分析物を、界面のコロナ放電針によってイオン化し、これによって噴霧された溶媒/分析物混合物に電圧を印加した。
3つの品質管理(QC)プールをチャコール剥離血清から調製して、25、200および800pg/mLの濃度までエストロンでスパイクした。
エストロンのゼロ標準を、10個の複製で行って、測定された値の方がそれにともなう不確実度よりも大きいポイントである、アッセイの検出限界を決めた。LODは、ゼロ濃度からの2標準偏差(SD)として適宜決定した。ゼロ標準についての得られたピーク面積比を統計学的に分析し、ここでは0.014の平均値および0.004のSDであった。エストロンのアッセイのLODは2.0pg/mLであった。
アッセイ中のエストロン検出の直線性を確立するため、ゼロ標準に割り当てた1つのブランク、および10個のスパイクした血清標準を調製して、5つの別の日に分析した。5つの連続試行からの二次回帰で0.995以上の相関係数が得られ、ここでは±20%の精度で10〜2000pg/mLの定量可能な線形範囲が明らかになった。
基質特異性は、水、剥離血清およびBiocell正常ヒト血清を用いて評価して、患者サンプルが線形の方式で希釈できるか否かを決定した。中間のコントロール(MC)および高いコントロール(HC)を2倍および4倍希釈した。このサンプルは、較正実施後に二連で行った。精度は以下のとおりであった:
Claims (21)
- 体液サンプル中のエストロンの量を決定するための方法であって:
(a)前記体液サンプルを、前記体液サンプル中に存在し得るタンパク質由来の遊離のエストロンに対して十分な量の試薬を用いて酸性にする工程と;
(b)前記体液サンプルからエストロンを液体クロマトグラフィーによって精製する工程と;
(c)前記体液サンプルから精製された前記エストロンをイオン化して、タンデム型質量分析によって検出可能な1つ以上のイオンを作製する工程と:
(d)前記エストロンイオン(単数または複数)の量をタンデム型質量分析によって負のイオンモードで検出し、ここで前記エストロンイオン(単数または複数)の量が前記体液サンプル中のエストロンの量に対して関連付けられる工程と、
を含む方法。 - 前記方法が500pg/mL以下の定量限界を有する、請求項1に記載の方法。
- 前記エストロンが、質量分析の前に誘導体化されない、請求項1〜2のいずれかに記載の方法。
- 前記液体クロマトグラフィーが高速液体クロマトグラフィー(HPLC)である、請求項1〜3のいずれかに記載の方法。
- 前記精製工程がさらに、高乱流液体クロマトグラフィー(HTLC)、続いて高速液体クロマトグラフィー(HPLC)を含む、請求項1〜4のいずれかに記載の方法。
- 前記酸性化試薬がギ酸である、請求項1〜5のいずれかに記載の方法。
- 前記エストロンイオンが、269.07±0.5、145.03±0.5および143.02±0.5の質量/電荷比を有するイオンからなる群より選択される1つ以上のイオンを含む、請求項1〜6のいずれかに記載の方法。
- 前記イオン化が、269.07±0.5の質量/電荷比を有する前駆イオンを作製する工程と、145.03±0.5、および143.02±0.5の質量/電荷比を有するイオンからなる群より選択される1つ以上の断片イオンを作製する工程とを含む、請求項1〜7のいずれかに記載の方法。
- 前記体液サンプル中に存在するグルクロン酸化エストロンおよび非グルクロン酸化エストロンの両方が前記方法によって検出および測定される、請求項1〜7のいずれかに記載の方法。
- 前記体液サンプルが血清、血漿または尿である、請求項1〜8のいずれかに記載の方法。
- タンデム型質量分析によって体液サンプル中のエストロンの量を決定するための方法であって:
(a)前記体液サンプルから液体クロマトグラフィーによってエストロンを精製する工程と;
(b)269.07±0.5の質量/電荷比を有している前記エストロンの前駆イオンを作製する工程と;
(c)前記前駆イオンの1つ以上の断片イオンを作製する工程であって、前記1つ以上の断片イオンの少なくとも1つが、143.02±0.5の質量/電荷比を有しているイオンフラグメントを含む工程と;
(d)工程(b)もしくは(c)またはその両方で作製される1つ以上の前記イオンの量を検出する工程、および前記体液サンプル中の前記エストロンの量に対して前記検出されたイオンを関連付ける工程、
を含む方法。 - 前記方法が500pg/mL以下の定量限界を有する、請求項11に記載の方法。
- 前記エストロンが質量分析前に誘導体化されない、請求項11〜12のいずれかに記載の方法。
- 前記液体クロマトグラフィーが高速液体クロマトグラフィー(HPLC)である、請求項11〜13のいずれかに記載の方法。
- 前記精製工程がさらに、高乱流液体クロマトグラフィー(HTLC)続いて、高速液体クロマトグラフィー(HPLC)を含む、請求項11〜14のいずれかに記載の方法。
- 前記前駆イオンが269.07±0.5の質量/電荷比を有し、前記1つ以上の断片イオンが、145.03±0.5の質量/荷電比を有する断片イオンを含む、請求項11〜15のいずれかに記載の方法。
- 前記イオン化工程の前に前記体液サンプルに存在し得るタンパク質からエストロンを遊離させるのに十分な量で、試薬が前記体液サンプルに添加される、請求項11〜16のいずれかに記載の方法。
- 前記試薬が前記体液サンプルを酸性にするのに十分な量で添加される、請求項11〜17のいずれかに記載の方法。
- 前記試薬がギ酸である、請求項18に記載の方法。
- 前記体液中に存在するグルクロン酸化エストロンおよび非グルクロン酸化エストロンの両方が前記方法によって検出および測定される、請求項11〜19のいずれかに記載の方法。
- 前記体液サンプルが血清、血漿または尿である、請求項11〜20のいずれかに記載の方法。
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CN105929014A (zh) | 2016-09-07 |
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US20170269107A1 (en) | 2017-09-21 |
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US8916385B2 (en) | 2014-12-23 |
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CA2709156A1 (en) | 2009-06-18 |
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