JP2007510161A - 分析物を検出するための半透性センサ - Google Patents
分析物を検出するための半透性センサ Download PDFInfo
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- JP2007510161A JP2007510161A JP2006538238A JP2006538238A JP2007510161A JP 2007510161 A JP2007510161 A JP 2007510161A JP 2006538238 A JP2006538238 A JP 2006538238A JP 2006538238 A JP2006538238 A JP 2006538238A JP 2007510161 A JP2007510161 A JP 2007510161A
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Abstract
Description
1つの側面において、本発明は、分析物を検出するためのセンサ、ヒドロゲルを含むコア(core)を含んだセンサ、コア中に配置された蛍光試薬、コアを囲む半透性コーティング、ここでこの半透性コーティングは約4kDaから約18kDaの分子量及び1超の多分散性指数を有する多分散ポリマーを含む、及び半透性コーティングを囲む生体適合性コーティングを特徴とする。いくつかの実施態様において、多分散ポリマーは約8kDaから約12kDaの分子量を有する。他の実施態様において、多分散ポリマーは約9kDaから約10kDaの分子量を有する。一つの実施態様において、多分散ポリマーは約9.4kDaの分子量を有する。いくつかの実施態様において、多分散ポリマーは1超から約1.5までの多分散性指数を有する。他の実施態様において、多分散ポリマーはポリリジンを含む。
本発明に関して、これらの用語は下記の意味を有する:
センサは、ポリマーマトリクス及びポリマーマトリクス中に配置した試薬を含むコア、コアを囲む多分散ポリマーを含む半透性コーティング、並びに半透性コーティングを囲む生体適合性コーティングを含む。センサは、分析物が関係する生理的状態についての有意義な情報を提供する速度で、分析物がセンサに拡散しそしてセンサから出て行くことを可能とするのと同時に、試薬を保持するように構築されている。センサはin vivo、in vitro又はそれらの組み合わせでの使用に適するように構築することができ、そして例えば体液(例えば、血液、血漿、血清、皮下液、及び腹水)などを含む様々な液体中で分析物を検出するのに使用することができる。次に、センサの試薬を励起しそしてセンサにより放射される放射線を検出することにより、分析物を検出(及び、任意に定量化)する。
FRETは一般に、2つの蛍光因子の間、すなわち一方はエネルギードナー(D)と他方はエネルギーアクセプタ(A)との間のエネルギーの非放射性転移を伴う。任意の適切に選択されたドナー−アクセプタ対を使用することができるが、但し、ドナーの発光がアクセプタの励起スペクトルとオーバラップし、両メンバーが1つの波長で光エネルギーを吸収し、異なる波長の光エネルギーを放射することができることを条件とする。
一般的に、分析物検出のために2つの方法のうちの一方でFRETを用いる。第1の方法は、検出される分析物に対するアナログ並びにアナログ及び分析物双方に結合可能なリガンドが、その一方がドナー蛍光因子で、他方がアクセプタ蛍光因子でラベルされる競合アッセイである。従って、アナログはドナーで、リガンドはアクセプタでラベルすることができ、或いは、アナログはアクセプタで、リガンドはドナーでラベルすることができる。ラベルされた試薬が分析物と接触すると、分析物はリガンドに結合したアナログと置き換わる。リガンド及びアナログはもはやFRETが起こるほど十分に互いに近接していないので、FRETによる蛍光シグナルは減少する;この減少は分析物の濃度と相関がある(その相関は、事前の較正段階において確立することができる)。
本実施例で使用される試験手順には次のようなものがある。
センサを調製し、そして各センサ中に存在する蛍光試薬の量を計算する。センサを、過剰のpH7.4の10mM HEPES/0.15M生理食塩水中に置き、そしてセンサの表面上の残留物を取り除くため37℃で一晩インキュベートする。センサから上清を取り除き、そして上清の蛍光放射スペクトルをModel QM−1 PTI Quantum Master Spectrofluorimeter(ニュージャージー州, サウスブラウンズウィック,PTI Quantum Master)を用いて測定する。試薬の蛍光因子の励起最大の付近で上清を励起し、そして蛍光因子の放射最大を含む波長範囲で放射を測定することにより、放射スペクトルを測定する。複数の異なる蛍光因子が蛍光試薬の中に存在する場合は、その前段階をそれぞれの異なる蛍光因子に対して繰り返す。次に、センサを追加の過剰な体積の新たなHEPES/生理食塩水中に置き、そしてセンサを37℃で一晩インキュベートして、その後HEPES/生理食塩水を取り除いた。
pH7.4の10mM HEPES/0.15Mの生理食塩水中のCy3.5 HSA(ヒト血清アルブミン、分子量66,430 g/mol)及びCy5.5−ConA(コンカナバリンA、分子量104,000 g/mol)のある体積の溶液を、HEPES/0.15Mの食塩水中の殺菌した3%アルギン酸の等容積に加える。その溶液を5分間ロッカー(rocker)上で混合する。次に、その混合液を遠心分離機にかけ、そして14ゲージのカテーテルを備えた注射器に引き入れる。サンプルから気泡を取り除く。14ゲージのカテーテルを取り除き、24ゲージのカテーテルと交換する。次に、シリンジのプランジャをゆっくりと押して、25mlのHEPES/食塩水及び1.5%(w/v)の無水塩化カルシウムを含む試験管にアルギン酸を滴下する。そのビーズを20分間浸す。
37℃まで加熱したHEPES/生理食塩水の緩衝原液中で33ペプチド残基を有する1%単分散ポリリジンから0.2%単分散ポリリジン(Boehringer Mannheim)コーティング溶液(HEPES/食塩水中の)を調製する。第一のコーティング溶液の体積は、表面を覆ったマイクロスフェアビーズの体積の15倍である。2番目のコーティング溶液の体積は、表面を覆ったマイクロスフェアビーズの体積の10倍である。双方の溶液を滅菌濾過し、そして37℃で保持する。
ポリリジンで表面を覆ったマイクロスフェアビーズを比較例1の記載の通りに調製するが、比較例2のポリリジンは47ペプチド残基を有していた。
ポリリジンで表面を覆ったマイクロスフェアビーズを比較例1の記載の通りに調製するが、比較例2のポリリジンは60ペプチド残基を有していた。
pH7.4で2mM塩化カルシウムを有するHEPES/食塩水の原液中の1%多分散ポリリジンから、0.2%多分散ポリリジン(Sigma Chemical Company)コーティング溶液(HEPES/食塩水中の)を調製する。0.2%の多分散ポリリジン組成物を37℃まで加熱する。多分散ポリリジンは、11,200 Daの重量平均分子量、9800 Daの数平均分子量及び1.14の多分散性指数を有していた。
Claims (21)
- 分析物を検出するためのセンサであって:
ヒドロゲルを含んで成るコア;
コア中に配置された蛍光試薬;
コアを囲む半透性コーティング、ここで当該半透性コーティングは約4kDaから約18kDaの重量平均分子量及び1超の多分散性指数を有する多分散ポリマーを含んで成る;及び
半透性コーティングを囲む生体適合性コーティング、
を含んで成るセンサ。 - 前記生体適合性コーティングが約1μmから約25μmの厚さを有している、請求項1に記載のセンサ。
- 前記蛍光試薬がコア中で移動可能である、請求項1に記載のセンサ。
- 前記多分散ポリマーがポリリジンを含んで成る、請求項1に記載のセンサ。
- 前記センサが1mm超の直径を有している、請求項1に記載のセンサ。
- 前記センサが少なくとも1.25mmの直径を有している、請求項1に記載のセンサ。
- 前記分析物がグルコースを含んで成る、請求項1に記載のセンサ。
- 前記センサが非放射性蛍光共鳴エネルギー転移に基づいた分析物の検出が可能である、請求項1に記載のセンサ。
- 前記蛍光試薬がカルボシアニン色素、スルホン化アミノクマリン色素、スルホン化ローダミン色素、及びそれらの組み合わせから成る群から選択される、請求項1に記載のセンサ。
- 前記蛍光試薬がグルコース結合タンパク質及びグリコシル化基質を含んで成る、請求項1に記載のセンサ。
- 前記グルコース結合タンパク質がコンカナバリンAを含んで成り、且つ前記基質がヒト血清アルブミンを含んで成る、請求項10に記載のセンサ。
- 前記蛍光試薬が、約581nmでの励起最大及び約596nmでの放射最大を有する第一のカルボシアニン色素、コンカナバリンA、約675nmでの励起最大及び約694nmでの放射最大を有する第二のカルボシアニン色素、及びヒト血清アルブミンを含んで成る、請求項1に記載のセンサ。
- 前記グルコース結合タンパク質が組み換えコンカナバリンAを含んで成る、請求項11に記載のセンサ。
- 前記第一のカルボシアニン色素のコンカナバリンAに対するモル比率が約0.1から約0.4である、請求項12に記載のセンサ。
- 前記第二のカルボシアニン色素のヒト血清アルブミンに対するモル比率が約0.5から約0.9である、請求項12に記載のセンサ。
- 前記ヒト血清アルブミンがグリコシル化されている、請求項12に記載のセンサ。
- 前記蛍光試薬が、約578nmでの励起最大及び約603nmでの放射最大を有する第一の色素、コンカナバリンA、約650nmでの励起最大及び約665nmでの放射最大を有する第二の色素、及びヒト血清アルブミンを含んで成る、請求項1に記載のセンサ。
- 蛍光試薬を含むコアを含んで成るセンサの作製方法であって、
第一の水性アルギン酸組成物の液滴とグループIIカチオンを含んで成るイオン溶液とを接触させて、架橋ゲルコアを形成すること、ここで当該第一の水性アルギン酸組成物は水、アルギン酸、及び任意に蛍光試薬を含んで成る、
を含んで成る方法であって、さらに少なくとも、
コアと蛍光試薬とを接触させること、及び
コアと1超の多分散性指数を有する多分散ポリマーを含んで成る組成物とを接触させること、
の1つを含んでなる方法。 - 前記多分散ポリマーがコア上にコーティングを形成し、前記方法が生体適合性組成物で多分散ポリマーコーティングの表面を覆うことをさらに含んで成る、請求項18に記載の方法。
- 前記センサが、pH7.4の10mM HEPES/0.15M 食塩水中において37℃で2週間保存した場合に、1モル%未満の蛍光試薬の漏出を示す、請求項1に記載のセンサ。
- 分析物を検出するためのセンサであって:
ポリマーマトリクスを含んで成るコア;
コア中に配置された蛍光試薬;
コアを囲む半透性コーティング、ここで当該半透性コーティングは多分散ポリマーを含んで成る;及び
半透性コーティングを囲む生体適合性コーティング、
pH7.4の10mM HEPES/0.15M 食塩水中において37℃で2週間保存した場合に、1モル%未満の蛍光試薬の漏出を示すセンサ、
を含んで成るセンサ。
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US10/698,591 US20050095174A1 (en) | 2003-10-31 | 2003-10-31 | Semipermeable sensors for detecting analyte |
PCT/US2004/035789 WO2005044100A1 (en) | 2003-10-31 | 2004-10-28 | Semipermeable sensors for detecting analyte |
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