JP4829240B2 - マイクロ流体制御による区画化されたスクリーニング - Google Patents
マイクロ流体制御による区画化されたスクリーニング Download PDFInfo
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Description
(a) それらは、各々がほとんど同一のきわめて小さいマイクロ反応装置として機能する、きわめて単分散のマイクロカプセル(1.5%未満の多分散性)の形成を可能にする。
(b) マイクロカプセルは、約1フェムトリットル〜約ナノリットルの範囲の体積を有することができる。
(c) マイクロカプセル内の区画化が、放物流に起因する拡散および分散を妨害する。
(d) ペルフルオロカーボン担体流を使用することにより、マイクロカプセル間の分子の交換を妨げることが可能である。
(e) マイクロカプセル内の化合物は、不活性ペルフルオロカーボン担体流体の層により分離されることから、マイクロチャンネルの構造と反応することも相互作用することもできない。
(f) マイクロカプセルを10,000秒−1以下で作り出すことができ、又、同じ速度で光学的方法を用いてスクリーニングできる。これは一日最高109の処理量である。
(g) マイクロカプセルを2つ以上のより小さいマイクロ液滴に分割でき、その中に含まれた試薬を並行して異なる一連の分子と反応させるかまたはマルチプリケートで検定することを可能にする。
(h) マイクロカプセルを融合させることができる。こうして分子を(a)希釈させ、(b)その他の分子と混合物させ、(c)精確に定義された時刻に反応を開始、終結または変調させることができる。
(i) カオス的移流を用いてマイクロカプセル内で非常に急速に試薬を混合させることができ(2ms未満)、高速運動測定および非常に高い処理量を可能にする。
(j) 組合せ式に試薬を混合させることができ、例えば、テストすべき標的に対する化合物ライブラリ内の化合物の考えられる全ての対様組合せの効果を可能にする。
(k) マイクロカプセルの安定流をマイクロチャンネル状に形成し、その相対的位置により同定することができる。
(l) 反応に光シグナル(例えば蛍光変化)にが随伴する場合、マイクロ流体ネットワークの空間分解された光学画像が各々のマイクロカプセル内の反応の時間分解測定を可能にする。
(m) マイクロカプセルは、それに含まれる分子の回収およびさらなる分析または操作を可能にするべくマイクロ流体流選別装置を用いて分離可能である。
a) レパートリの1サブセットのみが、任意のマイクロカプセル内において多重コピーで代表されるような形で、化合物をマイクロカプセルに区画化する工程;および
b) 所望の活性を有する化合物を同定する工程、
を含み、工程a)およびb)のうちの一方または両方が流体種のマイクロ流体制御下で実施される方法が提供されている。
(a) レパートリの1サブセットのみがいずれか1つのマイクロビーズ上で代表されるような形で、マイクロビーズ上に化合物のレパートリを付着させる工程、
(b) マイクロビーズをマイクロカプセルに区画化させる工程、
を含み、かくして任意の1つのマイクロカプセル内において多重コピーで該レパートリの1サブセットが代表されることになるように修飾される。
(a) レパートリの1サブセットのみが任意の1マイクロビーズ上で代表されるような形で、化合物レパートリをマイクロビーズ上に付着させる工程;
(b) マイクロビーズをマイクロカプセルに区画化する工程、
(c) 任意には、マイクロビーズから化合物を放出する工程;および
(d) 所望の活性を有する化合物を同定する工程、
を含み、工程a)およびb)の一方または両方が流体種のマイクロ流体制御下で実施される方法が提供されている。
(I) 第1の実施形態においては、マイクロカプセルは、マイクロカプセルを全体として検出可能にする化合物またはその誘導体の活性に従ってスクリーニングされる。従って、本発明は、所望の活性をもつ化合物が、その化合物を含むマイクロカプセルの同定を可能にするマイクロカプセル内の変化またはマイクロカプセル内部の1つ以上の分子の修飾を誘発している方法を提供している。従って、この実施形態では、該マイクロカプセルは、(a)中に含まれている化合物の活性に従って互いに物理的に選別され、選別されたマイクロカプセルの中味が任意に1つ以上の共通区画内にプールされ、マイクロカプセルの中味が、該化合物の同一性を判定するべく分析されるか;または(b)該マイクロカプセルに入っている化合物の同一性を判定するべく選別なしで直接分析されるかのいずれかである。マイクロカプセルがマイクロビーズを含有する場合、マイクロビーズを分析してそれらをコーティングしている化合物を判定することができる。
本明細書で使用される「または」という用語は、「包含的にまたは」、すなわち、多くの要素の2つ以上または要素のリストの2つ以上を含めた少なくとも1つの包含を意味するものとして理解されるべきである。これとは対照的に、「排他的にまたは」という用語は、多くの要素の正確に1つの要素または要素のリストのうちの正確に1つの要素の包含を意味する。
別段の定義のないかぎり、本明細書で使用されている全ての技術的および科学的用語は、(例えば細胞培養、分子遺伝学、核酸化学、ハイブリダイゼーション技術および生化学などにおいて)当業者により一般に理解されるものと同じ意味を有する。分子、遺伝子および生化学的方法(一般に、本明細書に参照により援用されているサンブルック(Sambrook)ら、「Molecular Cloning:A Laboratory Manual」、第2版(1989年)、Cold Spring Harbor Laboratory Press、Cold Spring Harbor、N.Y.およびアウスベル(Ausubel)ら、Short Protocols in Molecular Biology(1999年)第4版、John Wiley & Sons、Inc.を参照のこと)および化学的方法については、標準的方法が使用される。さらに、標準的な免疫学的技術のためには、ハーロウ(Harlow)およびレーン(Lane)、A Laboratory Manual Cold Spring Harbor、N.Yが参照される。
本発明のマイクロカプセルは、本発明の機能を可能にするべく適切な物理的特性を必要とする。
(a) それらは、各々がほぼ同一の非常に小さい超小型反応器として機能する高単分散性のマイクロカプセル(<?1.5%未満の多分散性)の形成を可能する、b)マイクロカプセルは約1フェムトリットルから約1ナノリットルの範囲の体積を有することが可能である、c)マイクロカプセルの区画化は放物線流に起因する拡散および分散を防止する。
(b) ペルフルオロカーボン担体流体を用いることにより、マイクロカプセル間の分子交換を防止することが可能である。
(c) マイクロカプセル内の化合物は、不活性ペルフルオロカーボン担体流体層により分離されるためマイクロチャンネルの構造と反応または相互作用できない。
(d) マイクロカプセルを10,000秒−1以下で作り出し、かつ同じ速度で光学的方法を用いてスクリーニングされ得る。これは一日あたり最高109の処理量である。
(a) マイクロカプセルは2つ以上のより小さいマイクロ液滴に分割され得、かくして中に含まれた試薬を並行して一連の異なる分子と反応させるかまたは多系(multiplicate)で検定することができるようにする。
(b) マイクロカプセルを融合することができる。こうして、分子は(a)希釈され得、(b)その他の分子と混合され得、かつ(c)反応が精確に定義された時刻に開始、終結または変調され得ることになる。
(c) カオス的移流を用いてマイクロカプセル内できわめて迅速に(2ms未満で)試薬を混合でき、かくして高速の反応速度測定および非常に高い処理量が可能となる。
(d) 試薬を組合せにより混合できる。例えば、テストすべき標的に対する、化合物ライブラリ内の化合物の考えられる全ての対様の組合せの効果を可能にする。
(a) マイクロカプセルの安定流をマイクロチャンネル内に形成し、その相対的位置により同定することができる。
(b) 反応に光シグナル(例えば蛍光変化)が随伴する場合、マイクロ流体ネットワークの空間的に分解された光学的画像が、各マイクロカプセル内の反応の時間分解測定を可能にする。
(c) マイクロカプセルが含む分子の回収およびさらなる分析または操作を可能にするべくマイクロ流体フロー選別装置を用いてマイクロカプセルを分離することができる。
さらにもう1つの態様においては、本発明は、一部のケースでは液体中の流体液滴を比較的高い速度でスクリーニングまたは選別するためのシステムおよび方法を提供している。例えば、液滴の特性を検知しかつ/または何らかの形で(例えば以下で詳述する通り)判定することができ、その後該液滴を、例えば選別またはスクリーニングを目的としてデバイスの特定の領域に向かって導くことができる。
標的に結合するかまたはその活性を変調させる化合物をスクリーニングするために、1つ以上の化合物または化合物でコーティングされたマイクロビーズと共にマイクロカプセルに標的を区画化する。有利には、各々のマイクロカプセルは単一種の化合物のみ、ただしその数多くのコピーを含んでいる。有利には、各々のマイクロビーズは単一種の化合物のみ、ただしその数多くのコピーでコーティングされている。有利には、化合物は、開裂可能なリンカーを介してマイクロビーズに連結され、それらが区画内でマイクロビーズから放出され得るようにしている。有利には、各々のマイクロカプセルまたはマイクロビーズは、マイクロカプセル内の含まれたまたはマイクロビーズに付着した化合物の同定を可能にするべく、光学的にタグ付けされている。
標的に対する結合について、直接化合物をスクリーニングすることができる。この実施形態においては、該化合物がマイクロビーズに付着されかつ標的に対する親和性を有する場合、それは標的による結合を受けることになる。反応の終りで、全てのマイクロカプセルは組合わされ、全てのマイクロビーズは1つの環境内で一緒にプールされる。標的に特異的に結合するかまたは標的と特異的に反応する分子を用いた親和性精製により、所望の結合を示す化合物を担持するマイクロビーズを選択することができる。
(1) 化合物自体は、例えば蛍光性であるといった独特の光学特性を有する可能性がある。
(2) 例えば化合物の蛍光を結合時点で消光または増強させるといったように、標的に対する結合時点で化合物の光学特性を修飾させることができる(ヴォス(Voss)、1993年;増井および倉光、1998年)。
(3) 例えば標的の蛍光を結合時点で消光または増強させるといったように、化合物の結合時点で、標的の光学特性を修飾させることができる(ギシェ(Guixe)ら、1998年;キー(Qi)およびグラボウスキー(Grabowski)、1998年)。
(4) 例えば標的から化合物(またはその逆)への蛍光共鳴エネルギー転移(FRET)が存在する可能性があり、その結果として励起が「ドナー」吸収波長にある場合「アクセプタ」発光波長での発光をもたらすといったように、結合時点で標的および化合物の両方の光学特性を修飾させる(ハイム(Heim)およびツィン(Tsien)、1996年;マハヤン(Mahajan)ら、1998年;宮脇ら、1997年)。
一変形実施形態においては、生化学プロセスを調節するように作用する化合物をスクリーニングするために本発明を使用することができる。化合物が標的の結合活性を活性化する場合、活性化される標的についてのリガンドを、当業者にとってなじみの深いさまざまな手段によりマイクロビーズに付着させることができる(例えば(ハーマンソン、1996年)を参照のこと)。反応の終りで、全てのマイクロカプセルは組合わされ、全てのマイクロビーズは1つの環境内で一緒にプールされる。所望の結合を示す化合物を担持するマイクロビーズを、標的に対し特異的に結合するかまたは標的と特異的に反応する分子を用いて親和性精製により選択することができる。
(1) リガンド自体は、独特の光学特性を有する可能性がある、例えば蛍光性である。
(2) 標的に対する結合時点でリガンドの光学特性を修飾させることができる、例えばリガンドの蛍光を結合時点で消光または増強させる(ヴォス(Voss)、1993年;増井(Masui)および倉光、1998年)。
(3) リガンドの結合時点で、標的の光学特性を修飾させることができる、例えば標的の蛍光を結合時点で消光または増強させる(ギシェ(Guixe)ら、1998年;キー(Qi)およびグラボウスキー(Grabowski)、1998年)。
(4) 結合時点で標的およびリガンドの両方の光学特性を修飾させる、例えば標的からリガンド(またはその逆)への蛍光共鳴エネルギー転移(FRET)が存在し得、その結果として励起が「ドナー」吸収波長にある場合「アクセプタ」発光波長での発光をもたらす(ハイム(Heim)およびツィン(Tsien)、1996年;マハヤン(Mahajan)ら、1998年;宮脇ら、1997年)。
一変形実施形態においては、本発明は所望の活性を有する化合物がマイクロカプセルの光学特性の変化を誘発し、かくして該化合物そして任意にはその中に含まれているマイクロビーズを同定し任意には選別できるようにする方法を提供している。マイクロカプセルの光学特性は、次のいずれかにより修飾可能である:
(1) グリコシダーゼ、ホスファターゼ、ペプチターゼおよびプロテアーゼのための基質を内含する、異なる光学特性をもつ調節された反応の生成物および基質(数多くの蛍光発生酵素基質が市販されている、例えば(ホーグランド(Haugland)、1996年およびwww.probes.com)を参照のこと)、または
(2) マイクロカプセル内の調節された反応の生成物(または基質)に対し特異的に結合するかまたはそれと特異的に反応し、かくしてマイクロカプセルの光学特性の変化を誘発しその同定を可能にする試薬の存在。
(1) 例えば
(a) グリコシダーゼ、ホスファターゼ、ペプチターゼおよびプロテアーゼのための基質を含む異なる光学特性をもつ基質および生成物(数多くの蛍光発生酵素基質が市販されている(例えばホーグランド、1996年およびwww.probes.com参照)または
(b) 類似の光学特性を有するものの、基質ではなく生成物のみがマイクロビーズに結合するかまたはこれと反応する、基質および生成物、
に起因して、基質−マイクロビーズ複合体の中には見られない特徴的光学特性を有する生成物−マイクロビーズ複合体、かまたは
(2) 生成物(基質)に対し特異的に結合するかまたはそれと特異的に反応しかくしてその同定を可能にするマイクロビーズの光学特性の変化を誘発する試薬を添加すること(マイクロカプセルの破壊およびマイクロビーズのプールの前後に、これらの試薬を添加できる)。試薬は、
(a) 基質および生成物の両方がマイクロビーズに付着している場合、生成物に対し特異的に結合するかまたはそれと特異的に反応するが、基質とはしない(またはその逆)
(b) 生成分のみがマイクロビーズに結合するかまたはこれと反応する場合、任意には基質と生成物の両方に結合する(またはその逆)。
ある種の標的について特異性および選択性を有するもののその他については有していない化合物は、1つの基質を用いた反応の調節のための正のスクリーンおよびもう1つの基質との反応の調節のための負のスクリーンを実施することにより、特異的に同定可能である。例えば、2つの異なる標的酵素に特異的な2つの基質が、各々異なる蛍光発生部分で標識される。各々の標的酵素は、2つの標的のための化合物の特異性に応じてマイクロカプセルの異なる光学特性を結果としてもたらす異なる蛍光スペクトルをもつ生成物の生成の触媒として作用する。
現行の薬物発見パラダイムにおいては、有効な組換え型標的がインビトロの高速大量処理スクリーニング(HTS)検定の基礎を成している。しかしながら単離されたタンパク質を、複雑な生体系を代表するものとみなすことはできない。従って、細胞ベースの系は、無傷の生体系の中での化合物活性に対する信頼性を高くすることができる。リード薬物のための広範囲の細胞ベースの検定が当業者にとって既知である。油中水型エマルジョンの微水滴といったようなマイクロカプセルに、細胞を区画化することができる(ガデシー(Ghadessy)、2001年)。標的に対する化合物の効果は、化合物と共にマイクロカプセルに細胞を区画化し、細胞に対する所望の効果をもつ化合物を含むこれらの区画を同定するために適切な細胞ベースの検定を用いることにより、判定可能である。フッ化炭素中水型エマルジョンの使用が特に有用であり得る。フッ化炭素の高いガス溶解能力は、呼吸ガスの交換を支援することができ、又、細胞培養系にとって有益であることが報告されている(ルーヴ(Lowe)、2002年)。
本発明の好ましい実施形態においては、マイクロカプセルまたはマイクロビーズは、フローサイトメトリーにより分析され、任意には選別される。マイクロカプセルの数多くのフォーマットがフローサイトメトリーを用いて分析され、任意には直接選別される。
(1) 定評のあるメーカー(例えばベクトン・ディッキンソン(Becton−Dickinson)、カルター(Coulter)、サイトメーション(Cytomation))製の蛍光活性化細胞選別装置は、毎秒最高100,000個のマイクロカプセルまたはマイクロビーズの速度での分析および選別を可能にする。
(2) 各々のマイクロカプセルまたはマイクロビーズからの蛍光シグナルは、存在する蛍光分子の数に密に対応する。マイクロカプセルまたはマイクロビーズ1個あたり数百個の蛍光分子という少量の分子を定量的に検出することができる。
(3) 蛍光検出器の広いダイナミックレンジ(標準的に4log単位)は、選別手順のストリンジェンシーを容易に設定できるようにし、かくして出発プールからの最適な数のマイクロカプセルまたはマイクロビーズの回収が可能となる(実施中の選択に応じて小さい蛍光差をもつマイクロカプセルまたはマイクロビーズを分離するかまたは大きな蛍光差をもつマイクロカプセルまたはマイクロビーズのみを分離するようにゲートを設定できる)。
(4) 蛍光活性化細胞選別装置は、多数の波長で同時励起および検出を実施することができ(シャピロ(Shapiro)、1995年)、2〜13個(またはそれ以上)の蛍光マーカーでのマイクロカプセルまたはマイクロビーズの標識を監視することにより正および負の選択を実施できるようにする。例えば、2つの交番標的のための基質が異なる蛍光タグで標識される場合、マイクロカプセルまたはマイクロビーズを、調節対象標的に応じて異なる蛍光プローブで標識することができる。
本発明は、利用中の選別技術によりそれが可能となっている場合には、無傷のマイクロカプセルの同定そして任意にはその選別を提供する。所望の化合物によって誘発された変化がマイクロカプセルの表面で発生するかまたは現われるかまたはマイクロカプセルの外側から検出可能である場合、マイクロカプセルを同定し、任意にそのように選別することができる。変化は、化合物の直接的作用によってひき起こされてもよいし、または、所望の活性をもつ化合物がそのうちの1つに関与している一連の反応がその変化を導く間接的作用によってひき起こされてもよい。例えば、マイクロカプセルが膜形成性マイクロカプセルである場合、そのマイクロカプセルは、標的を含む生化学系のコンポーネントがその表面で表示され、かくしてマイクロカプセル内部のマイクロビーズ上の化合物によって調節される生化学系の中の変化を検出し得る試薬にアクセス可能であるような形で構成され得る。
化合物ライブラリをさまざまな商業的供給源から得ることができる。ライブラリ内の化合物は、当業者にとって周知のさまざまな手段により作ることができる。任意には、1ビーズ−1化合物ライブラリを生成するべく、空間分解された並行合成または分割合成を用いて、組合せ合成により化合物ライブラリを作ることができる。該化合物は任意にはビーズ上で合成可能である。これらのビーズは、マイクロカプセルに直接区画化され得、そうでなければ化合物は区画化の前に放出される。
マイクロカプセル内またはマイクロビーズ上の化合物をさまざまな方法で同定することができる。同定されたマイクロカプセルが(例えば蛍光活性化細胞選別装置−FACSを使用することにより)選別される場合、化合物は例えば質量分析などの直接的分析によって同定可能である。化合物が(例えば親和性精製による)選択または(例えばFACSを用いた)選別の結果として単離されたビーズに付着した状態にとどまっている場合、それらは、同様に直接的分析例えば質量分析によっても同定され得る。マイクロカプセルまたはビーズは、当業者にとって周知のさまざまな手段および、ビーズに付着した化合物を同定するのに用いられるタグにより、タグ付けすることもできる(セザルニク(Czarnik)、1997年)。化合物をコード化するための化学的、分光的、電子的および物理的方法が全て使用可能である。好ましい実施形態においては、マイクロカプセルまたはビーズは異なる光学特性を有し、従って光学的にコード化される。好ましい実施形態においては、コード化は、異なる蛍光特性をもつマイクロカプセルまたはビーズに基づいている。きわめて好ましい実施形態においては、マイクロカプセルまたはビーズはその中に異なる濃度で存在する蛍光量子ドットを用いてコード化される(ハン、2001年)。マイクロ流体チャンネル内を整然とした順序で流れるマイクロカプセルは同様に、マイクロカプセル流内のそれらのシーケンスによっても(全体的にまたは部分的に)コード化され得る(位置的コード化)。
有利には、各々のマイクロカプセルが同じ標的の多重コピーを含むような形でマイクロカプセルに多数の異なる標的を区画化することができる。例えば、化合物の特異性を判定できるようにするため、多数のタンパク質キナーゼまたは単独の標的の多数の多型変種を区画化することができる。マイクロカプセル内の標的の同一性は、例えば上述の通りのマイクロカプセルまたはマイクロビーズの光学的コード化または位置的コード化によって判定され得る。
有利には、マイクロカプセルの融合後、融合されたマイクロカプセルの中に含まれた試薬は、カオス的移流を用いて急速に混合可能である。液滴内部の流体の層流線を分断するチャンネルの中に液滴を通過させることにより、その中味を迅速に混合し、あらゆる化学的反応を完全に開始させることができる。
本発明のある態様においては、流体液滴の1つ以上の特性を判定できるようにする形で、流体液滴の1つ以上の特性および/または該流体液滴を含む流体システム(例えば該流体液滴を取り囲む液体)の一部分の1特性を検知および/または判定できるセンサーが提供されている。液滴に関して判定可能でありかつ本発明において使用可能である特性は、当業者が同定可能である。かかる特性の制限的意味の無い例としては、蛍光、質量分析(例えば光学、赤外線、紫外線など)、放射能、質量、体積、密度、温度、粘度、pH生物学的物質(例えばタンパク質、核酸など)といった均質の濃度、などが含まれる。
本発明のマイクロ流体システムおよびデバイスの上述のコンポーネントのいずれかを形成するためには、本発明のある態様に従ってさまざまな材料および方法を使用することができる。一部のケースでは、選択されたさまざまな材料が、さまざまな方法に役立つ。例えば、本発明のさまざまなコンポーネントを固体材料で形成させることができ、ここでは、マイクロマシニング、スピンコーティングおよび化学蒸着といったような膜蒸着プロセス、レーザー製造、フォトリソグラフィ技術、湿式化学またはプラズマプロセスを含めたエッチング方法などを介してチャンネルを形成させることができる。例えばScientific American、第248号44〜55頁、1983年(エンジェル(Angell)、ら)を参照のこと。一実施形態においては、シリコンチップ内にフィーチャをエッチングすることにより、流体システムの少なくとも一部分がシリコンで形成される。シリコンを用いた本発明のさまざまな流体システムおよびデバイスの精確で効率の良い製造のための技術が知られている。もう1つの実施形態においては、本発明のシステムおよびデバイスのさまざまなコンポーネントが、例えばポリジメチルシロキサン(「PDMS」)、ポリテトラフルオロエチレン(「PTFE」またはTeflon(登録商標))などといったようなエラストマ重合体などの重合体で形成され得る。
マイクロ流体デバイスの概略的表示が、図15に示されている。マイクロチャンネルを、ポリ(ジメチルシロキサン)(PDMS)(マクドナルド(McDonald)およびホワイトサイズ、2002年)での高速プロトタイプ製造を用いて矩形断面を伴って製造し、(ソングおよびイスマギロフ(Ismagilov)、2003年)の通りに疎水性にした。フローを駆動するには、シリンジポンプを使用した(ハーバード・アパレイタス(Harvard Apparatus)PHD、2000還流ポンプ)。水溶液のためには、27ゲージの取外し可能な針のついた250μl入りのハミルトン・ガスタイト(Hamilton Gastight)シリンジ(1700シリーズ、TLL)を、30ゲージのテフロン管類(ウェイコ・ワイヤー・アンド・ケーブル(Weico Wire and Cable))と共に使用する。担体流体のためには、ハミルトン製の1つのハブ付き30ゲージのテフロン針(ソングおよびイスマギロフ、2003年)と共に、1ml入りのハミルトン・ガスタイトシリンジ(1700シリーズ、TLL)を使用する。担体流体は、ペルフルオロデカリン(PFD)中の9%(v/v)のC6F11C2H4OHである(ソングら、2003年)。マイクロ流体デバイスは、一連の相互接続されたモジュールから成る。各モジュールは、特定の機能を有する。これらのモジュールには、液滴を生成する、液滴を融合する、液滴を混合する、液滴を反応させる、液滴を検出するおよび液滴を選別するモジュールが含まれる(図16参照)。1つの実施例においては、異なる分子または異なる濃度の分子から成る液滴が作られる。液滴は最高104秒−1の速度で作られ、1.5%未満の多分散性および1μm〜100μmの範囲内のサイズで作られる。各々の液滴は第2組の反応物質を含む第2の液滴と融合され、急速に混合されて化学反応を開始する。この化学反応は、各液滴を遅延チャンネルの中で通過させることによって各液滴内で進行できるようになっている。次に各々の液滴は第2の組の反応物質を含むもう1つの液滴と融合され、その後第2の化学反応を開始させるべく急速に混合される。第2の反応が遅延モジュール内で進行した後、反応の結果は、光センサーまたはその他の形態の検出モジュールを用いて判定される。最終的に、所望の液滴は、光学検出モジュールからのシグナルに基づいて2つの集団内に選別され、一方の集団はさらなる処理のために保たれ、もう一方は廃棄される。これらのおよびその他のモジュールを、この組合せまたはその他の組合せで使用することができる。
マイクロ流体システム内のマイクロカプセルを用いたタンパク質チロシンホスファターゼ1B(PTP1B)阻害物質についてのスクリーニング
PTP1Bは、インシュリンおよびレプチンシグナル形質導入の負の調節因子である。インシュリンおよびレプチンに対する耐性は、2型真性糖尿病および肥満の特質であり、従ってPTP1Bは、糖尿病および肥満療法のための魅力的な薬物標的である(ジョンソン(Johnson)ら、2002年)。実施例1で記述されている通りのマイクロ流体デバイスを使用して、マイクロ流体システムの中でマイクロカプセルを用いていかにPTP1B阻害物質をスクリーニングできるかを記述する。
96の水性混合物を、(反応を防ぐため)氷上で作る。第1の混合物は、ビス−ジフルオロメチレンホスホナートを有しかつ既知のPTP1B阻害物質(ジョンソンら、2002年)である100μMの化合物2(図17)、および585nm、655nmおよび705nmの発光極大をもつ予め定義された比率のQdot(商標)ストレプトアビジンコンジュゲート(カンタム・ドット・コーポレーション(Quantum Dot Corporation)、Hayward、カリフォルニア州)を、PTP1B活性と相容性ある緩衝液(25mMのHEPES、pH7.4、125mMのNaCl、10%のグリセロール、1mMのEDTA)(ドマン(Doman)ら、2002年)中で含有している。95のその他の水性混合物は上述のものと同一であるが、各々化合物2の代りにカルボン酸有機ビルディングブロックライブラリ(アルドリッチ)からの95のカルボン酸のうちの1つおよび585nm、655nmおよび705nmの発光極大をもつ異なる比率のQdot(商標)ストレプトアビジンコンジュゲートを含有している。全ての混合物において、705nmQdot(商標)ストレプトアビジンコンジュゲートの濃度は100nMであり、585nmおよび655nmのQdot(商標)ストレプトアビジンコンジュゲートの濃度は、0、11、22、33、44、55、66、77、88または100nMのいずれかである。従って、Qdot(商標)ストレプトアビジンコンジュゲート濃度の100(10×10)個の順列が存在し、これが、各化合物を含有するマイクロカプセルに、705nm、585nmおよび655nmでの蛍光の蛍光比を判定することによって読取られる独特の蛍光サインをもたせることを可能にしている。
オレンジ色(585nm)および赤色(>650nm)の蛍光色素(フルトンら、1997年)を精確な比率で取込んだ結果として、表面上にカルボキシラート官能基を担持する直径5.5μmのポリスチレンマイクロビーズが光学タグ付けされた形で市販されている(www.luminexcorp.com)。各々独特の光学サイン(www.luminexcorp.com)をもつこのような100個のビーズのセットを余剰のエチレンジアミンおよびEDC(l−エチル−3−(3−ジメチルアミノプロピル)カルボジイミドヒドロクロリド(ピアース(Pierce)を用いて(ハーマンソン、1996年)の通りに修飾し、表面上に一級アミン基を作り上げる。該光開裂可能リンカー、4−(4−ヒドロキシメチル−2−メトキシ−5−ニトロフェノキシ)ブタン酸(ノバビオケム(NovaBiochem))(ホームズ(Holmes)およびジョーンズ(Jones)、1995年)を次に、上述のとおりEDCを用いてアミド結合を形成することによってビーズに付着させる。カルボン酸有機ビルディングブロックライブラリ(ブロック・ライブラリ(Block Library)(アルドリッチ))からの100個の異なるカルボン酸を次に、リンカーアルコールと反応させることによりビーズにカップリングさせて、カルボキシラートエステルを形成するが、ここで100個の異なる光学タグ付けされたビーズが異なるカルボン酸にカップリングされており、各ビーズは最高約106個のカルボン酸分子で誘導体化されている。最高5cmの距離からB100AP354nmのUV灯(UVP)を用いて氷上で4分間照射した結果、カルボン酸としてビーズから化合物が放出される。
オレンジ色(585nm)および赤色(>650nm)の蛍光色素(フルトンら、1997年)を精確な比率で取込んだ結果として、表面上にカルボキシラート官能基を担持する直径5.5μmのポリスチレンマイクロビーズが光学タグ付けされた形で市販されている(www.luminexcorp.com)。まず最初に、マイクロビーズ上のカルボキシラート官能基を、実施例6にある通り、エチレンジアミンおよびEDCを用いて一級アミンに転換させる。その後、PTP1Bのためのホスホペプチド基質、ウンデカペプチド(EGFR988−998(DADEpYLIPQQG)(チャン(Zhang)ら、1993年))を、EDCを用いて表面アミノ基を介してマイクロビーズの両方のセットにカップリングさせる。このペプチドは、カルボキシラート−O−アリルエステルを用いた側鎖カルボキシラート基上の直交保護を伴うSieberアミド樹脂((9−Fmoc−アミノ−キサンテン−3−イルオキシ−Merrifield樹脂)(ノバビオケム))上の固相合成によって作られる。テトラデカン二酸から成るリンカーをN−末端にカップリングし、1%のTFAを用いてビーズからペプチドを開裂させて、C末端アミドを伴うペプチドを生成する。リンカーを介して該ペプチドをビーズにカップリングし(EDCを用いて)、1ビードあたり最高105個のペプチドを得る。その後残った表面アミノ基を、実施例6にあるように光化学的に開裂可能なリンカー、4−(4−ヒドロキシメチル−2−メトキシ−5−ニトロフェノキシ)ブタン酸を付着させることによって修飾する。その後Pd(Ph3)4/CHCl3/HOAc/N−メチルモルホリンを用いて、ペプチドの側鎖カルボキシラート上の保護基を除去する。最初のマイクロビーズセットを、既知のPTP1B阻害物質である化合物3−(4−ジフルオロホスホノメチルフェニル)プロパン酸(化合物1、図17)、で誘導体化する(ジョンソンら、2002年)。第1のビーズセットとは相異なる光学タグを伴う第2のビーズセットを、PTP1B阻害物質でない化合物であるヒドロ桂皮酸(アルドリッチ)で誘導体化する。各々のケースにおいて、リンカーアルコールと反応させることによって化合物をカップリングして、実施例6にあるように、カルボキシラートエステルを形成させる。各々のマイクロビーズを、最高106個の分子(フルトンら、1997年)で誘導体化させる。
オレンジ色(585nm)および赤色(>650nm)の蛍光色素(フルトンら、1997年)を精確な比率で取込んだ結果として、各々独特の光学シグニチャーを伴う、表面上にカルボキシラート官能基を担持する直径5.5μmのポリスチレンマイクロビーズ100個のセット(www.luminexcorp.com)を、PTP1Bのためのホスホペプチド基質、ウンデカペプチドEGFR988−998(DADEpYLIPQQG)(チャンら、1993年)、および実施例4にあるように各々光化学的に開裂可能なリンカーを介して付着されている100個の異なるカルボン酸を用いて誘導体化する。これらのカルボン酸のうちの1つは、既知のPTP1B阻害物質である化合物(ジョンソンら、2002年)、3−(4−ジフルオロホスホノメチルフェニル)プロパン酸(化合物1、図17)である。その他の99のカルボン酸は、実施例4の通り、カルボン酸有機ビルディングブロックライブラリ(Carboxylic Acid Organic Building Block Library)(アルドリッチ)からのものである。次に、100ビーズセットの各々同数を、実施例5と同様に、混合し、スクリーニングする。主に、PTPIB阻害物質、3−(4−ジフルオロホスホノメチルフェニル)プロパン酸(化合物1、図17)でコーティングされたマイクロビーズ上でのみペプチドの脱リン酸化が見られ、その他の化合物でコーティングされたマイクロビーズ上には見られない。
基本的に(サトラーら、1996年)の通りに、14μmのフィルター(オスモニックス(Osmonics)を通した押出し(15回)によってかまたは5mmの分散工具と共にUltra−Turrax T8ホモジナイザー(IKA)を用いた25,000r.p.m.で5分間の均質化によって、95%(v/v)のペルフルオロオクチルプロミド、溶解状態の問題の分子を含む5%(v/v)のリン酸緩衝生理食塩水そして界面活性剤としての2%(w/v)のC8F17C11H22OP(O)[N(CH2CH2)2O]2(F8H11DMP)を含有するフッ化炭素中水エマルジョンを形成させた。100μmから2mMの濃度で水相中に溶解した一連の小さい蛍光分子を含有するエマルジョンを作った。カルセイン、テキサスレッド、フルオレセイン、クマリン102、7−ヒドロキシクマリン−3−カルボン酸および7−ジエチルアミノ−4−メチルクマリン(クマリン1)を含むこれらの分子は、SRCのLogKow/KowWinプログラム(メイラン(Meylan)およびハワード(Howard)、1995年)を用いて計算された−0.49〜4.09の範囲内のLogP値と203〜625Daの分子量を有していた。ボルテックス処理により、異なる色の蛍光色素を含むエマルジョンを混合した。混合型エマルジョンの落射蛍光顕微鏡法により区画化を観察した。混合後24時間、区画間に交換が全くないことを観察した(図19参照)。
基本的に、実施例1に記述されている通りに、多重液滴発生モジュールを用いて、95%(v/v)のペルフルオロオクチルプロミド、溶解状態の問題の分子を含む5%(v/v)のリン酸緩衝生理食塩水そして界面活性剤としての2%(w/v)のC8F17C11H22OP(O)[N(CH2CH2)2O]2(F8H11DMP)を含有するフッ化炭素中水エマルジョンを形成させた。各ノズルにおいて水相は、100μmから2mMの濃度で溶解した異なる小さな蛍光分子を含有していた。カルセイン、テキサスレッド、フルオレセイン、クマリン102、7−ヒドロキシクマリン−3−カルボン酸および7−ジエチルアミノ−4−メチルクマリン(クマリン1)を含むこれらの分子は、SRCのLogKow/KowWinプログラム(メイラン(Meylan)およびハワード(Howard)、1995年)を用いて計算された−0.49〜4.09の範囲内のLogP値と203〜625Daの分子量を有していた。全てのタイプの液滴を含有する単一の流れの中に異なるフルオロファーを有する液滴を担持する流れを組合わせることにより、異なる色の蛍光色素を含有するエマルジョンを混合した。液滴収集物を担持する流れはこのとき、デバイス上の深いウェル内に出され、ここで液滴は近接して保管され最高24時間にわたり監視可能である。液滴間の交差汚染は全く観察されない。
実施例1に記述されているとおりのマイクロ流体デバイスを用いて、我々は、フェニルエチルβ−D−チオガラクトピラノシド(PETG)による酵素、大腸菌□−ガラクトシダーゼ(LacZ)の阻害様式が競合的であることを実証し、いかにして、PETGの阻害定数(Ki)を得ることができるかを示している。酵素阻害検定においては、触媒作用速度は、LacZについての非蛍光性基質、フルオレセインモノ−□−D−ガラクトシド(FMG)(FMG)を使用し、蛍光性生成物フルオレセインの外観(励起488nm、発光514nm)を測定することによって決定される。LacZ阻害検定の全てのコンポーネントは、検定緩衝液(10mMのMgCl2、50mMのNaCl、1mMのDTT、100μg/mlのBSA、10mMのTris−HCl、pH7.9)の中で溶解させられる。
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Claims (4)
- 化合物レパートリ内の所望の活性を有する1つ以上の化合物を同定するための方法であって、
a) 前記レパートリの1サブセットのみが、任意のマイクロカプセル内において多重コピーとして示されるように、化合物をマイクロカプセルに区画化する工程;および
b) 所望の活性を有する化合物を区画化する前記マイクロカプセルの光学特性の少なくとも1つの変化を検出することに基づく、所望の活性を有する化合物を同定する工程、
を含み、工程a)およびb)のうちの一方または両方がマイクロ流体制御下で実施される、方法。 - 所望の活性を有する化合物のスクリーニング方法であって、
(a) 化合物のレパートリの1サブセットのみが、任意の1マイクロカプセル内において多重コピーとして示されるように、化合物をマイクロカプセルに区画化する工程;
(b) その光学特性の変化を用いて、所望の活性を有する化合物を含有する前記マイクロカプセルを同定および選別する工程;および
(c) 所望の活性を有する化合物を同定およびスクリーニングする工程、
を含み、工程a)およびb)のうちの一方または両方がマイクロ流体制御下で実施される、方法。 - 標的の活性を変調させる能力をもつ1つ以上の化合物をスクリーニングする方法であって、
(a) 化合物のレパートリの1サブセットのみが、任意の1マイクロカプセル内において多重コピーとして示されるように、化合物をマイクロカプセルに区画化する工程;
(b) その光学特性の変化を用いて、所望の活性を有する化合物を含有する前記マイクロカプセルを同定および選別する工程;および
(c) 所望の活性を有する標的を1つ以上の化合物と接触させ、前記1つ以上の化合物による前記標的の活性の変調を監視する工程、
を含み、工程a、bおよびcのうちの1つ以上のものがマイクロ流体制御下で実施される、方法。 - 標的をスクリーニングする方法であって、
(a) 少なくとも1つの工程が化合物によって容易になる、反応を標的に提供する工程;
(b) この工程を容易にする前記化合物を調製する工程;
(c) 前記化合物のレパートリの1サブセットのみが、任意の1マイクロカプセル内において多重コピーとして示されるように、前記標的および前記化合物をマイクロカプセルに区画化する工程;
(d) その光学特性の変化を用いて、所望の活性を有する前記化合物を含有する前記マイクロカプセルを同定および選別する工程;および
(e) 合成の関連工程を容易にするべく(d)で同定された前記化合物を使用して前記標的をスクリーニングする工程、
を含み、工程a〜eのうちの1つ以上のものがマイクロ流体制御下で実施される、方法。
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WO2006040551A2 (en) | 2006-04-20 |
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AU2005293367A1 (en) | 2006-04-20 |
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EP3153231B1 (en) | 2019-03-13 |
EP3153231A1 (en) | 2017-04-12 |
JP2008516251A (ja) | 2008-05-15 |
EP3527978A2 (en) | 2019-08-21 |
EP3527978A3 (en) | 2019-09-25 |
US20190317085A1 (en) | 2019-10-17 |
US20050221339A1 (en) | 2005-10-06 |
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