JP2011177171A - アフィニティヒドロゲルとその標識非依存性検出方法 - Google Patents
アフィニティヒドロゲルとその標識非依存性検出方法 Download PDFInfo
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- NKSJNEHGWDZZQF-UHFFFAOYSA-N ethenyl(trimethoxy)silane Chemical compound CO[Si](OC)(OC)C=C NKSJNEHGWDZZQF-UHFFFAOYSA-N 0.000 description 1
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- UUORTJUPDJJXST-UHFFFAOYSA-N n-(2-hydroxyethyl)prop-2-enamide Chemical compound OCCNC(=O)C=C UUORTJUPDJJXST-UHFFFAOYSA-N 0.000 description 1
- ZEMHQYNMVKDBFJ-UHFFFAOYSA-N n-(3-hydroxypropyl)prop-2-enamide Chemical compound OCCCNC(=O)C=C ZEMHQYNMVKDBFJ-UHFFFAOYSA-N 0.000 description 1
- BONNRKLSQRLNHV-UHFFFAOYSA-N n-methylmethanamine;prop-2-enamide Chemical compound CNC.NC(=O)C=C BONNRKLSQRLNHV-UHFFFAOYSA-N 0.000 description 1
- QNILTEGFHQSKFF-UHFFFAOYSA-N n-propan-2-ylprop-2-enamide Chemical compound CC(C)NC(=O)C=C QNILTEGFHQSKFF-UHFFFAOYSA-N 0.000 description 1
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- BWAUQTFFVCLSOS-UHFFFAOYSA-N sodiosodium hydrate Chemical compound O.[Na].[Na] BWAUQTFFVCLSOS-UHFFFAOYSA-N 0.000 description 1
- RPENMORRBUTCPR-UHFFFAOYSA-M sodium;1-hydroxy-2,5-dioxopyrrolidine-3-sulfonate Chemical compound [Na+].ON1C(=O)CC(S([O-])(=O)=O)C1=O RPENMORRBUTCPR-UHFFFAOYSA-M 0.000 description 1
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- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- GQIUQDDJKHLHTB-UHFFFAOYSA-N trichloro(ethenyl)silane Chemical compound Cl[Si](Cl)(Cl)C=C GQIUQDDJKHLHTB-UHFFFAOYSA-N 0.000 description 1
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- YVRYYVDHGQKMMU-BQYQJAHWSA-N trichloro-[(e)-oct-1-enyl]silane Chemical compound CCCCCC\C=C\[Si](Cl)(Cl)Cl YVRYYVDHGQKMMU-BQYQJAHWSA-N 0.000 description 1
- UMFJXASDGBJDEB-UHFFFAOYSA-N triethoxy(prop-2-enyl)silane Chemical compound CCO[Si](CC=C)(OCC)OCC UMFJXASDGBJDEB-UHFFFAOYSA-N 0.000 description 1
- QQQSFSZALRVCSZ-UHFFFAOYSA-N triethoxysilane Chemical compound CCO[SiH](OCC)OCC QQQSFSZALRVCSZ-UHFFFAOYSA-N 0.000 description 1
- RKLXSINPXIQKIB-UHFFFAOYSA-N trimethoxy(oct-7-enyl)silane Chemical compound CO[Si](OC)(OC)CCCCCCC=C RKLXSINPXIQKIB-UHFFFAOYSA-N 0.000 description 1
- LFRDHGNFBLIJIY-UHFFFAOYSA-N trimethoxy(prop-2-enyl)silane Chemical compound CO[Si](OC)(OC)CC=C LFRDHGNFBLIJIY-UHFFFAOYSA-N 0.000 description 1
- YUYCVXFAYWRXLS-UHFFFAOYSA-N trimethoxysilane Chemical compound CO[SiH](OC)OC YUYCVXFAYWRXLS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54366—Apparatus specially adapted for solid-phase testing
- G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
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Abstract
Description
実施形態において、化学式(I)のポリマは、R,R’、S、W、及びXを組み入れる特定の構造を有し得る。例えば、Rは、水素であり、又は、1から4までの炭素原子を有する置換若しくは未置換のアルキルである。R’は、1から10までの炭素原子を有する2価のヒドロカルビル残基である。R’’は、2から6までの炭素原子を有する置換若しくは未置換の2価のヒドロカルビル残基である。Sは、不飽和のシラン若しくはメルカプトシラン基板である。Wは、例えば、イミノ二酢酸、ニトリロ三酢酸、トリアザシクロノナン、アミノエチルエタノールアミン、トリエチレンテトラミン、2ヒドロキシプロパン‐1,2,3‐トリカルボン酸、及び同様のそれらの置換基若しくは誘導体若しくは塩類、又はそれらの組合せのうちの少なくとも1つであり得る。Xは、−NH−であり、モル比x:(y+z)は、約2:1から約1:2までである。
有する基板表面と、活性化剤とを接触させて、活性置換基を用いて修飾されたカルボキシ基を有する活性化ポリマ(図示せず)を形成するステップと、当該得られた活性化ポリマをキレート基フォーマに接触させて、[化4]に示された化学式(IV)
の特定のポリマ等の化学式(I)のポリマを形成するステップを含む。
は
表面に関連付けられたポリマである。
VI)のポリマにおいて示されているように、表面のポリマに、残留イオン化カルボン酸基(x’)が通常ほとんど存在しないか又は全く存在しない点である。
本開示は、高タンパク質固定化容量を有し且つ高リガンド結合応答を与え得るセンサを準備する方法を提供する。高タンパク質固定化容量及び高リガンド結合応答とは、既知のタンパク質固定化容量及びリガンド結合応答を有する既知のセンサに匹敵するか又は既知のセンサよりも大であるこという。開示されたセンサは、Epic(登録商標)において、例えば、4000ピコメートル(pm)の固定化応答性及び20pmの結合応答性を提供し得る。1pmの応答は、吸着分子の約5pg/mm2(5pg/mm2/pm)に対応する。したがって、4000pm固定化応答は、20ナノグラム/mm2の固定されたタンパク質に等しい。そして、20pmの結合応答性は、100pg/mm2の固定されたタンパク質に等しい。
ほとんど全ての無標識検出プラットフォームを実装するのに簡単であり、ほとんど全ての無標識検出プラットフォームに適合性がある。
タグ付けされた生体分子等のエンティティが固定化のために複合化し得る。
その後に、第3のステップは、ニッケル塩を有するPMA−NTAポリマの処理を伴って、実行されて(図示せず)、例えば、ポリマ修飾表面を用いたNi2+イオン錯体を生じせしめる。
3.5−4のpHを与える酢酸を含む(Sigma-Aldrichから入手した)2wt%のメタクリロキシプロピルトリメトキシシラン(MOPS:methacryloxypropyltrimethoxysilane)水溶液が、クリアになるまで(例えば、約15分室温にて)準備され且つ攪拌された。(付加的洗浄ステップなして受信されるものとして用いられて)(コーニング社から入手した)露出したEpic(登録商標)インサートが、MOPS溶液に2時間接触され、次に、乾燥されたアルゴンフローに接触されて、50℃にて1時間乾燥された。これは、インサート表面を用いてシランの凝縮を確実にするためである。そして、MOPSによって処理されたインサートは、室温まで冷却されて、DI水で洗浄され、次に、IPAで洗浄され、最終的に、アルゴンフロー下で乾燥された。
hisタグ付きCAII固定化は、50マイクロg/mLのタンパク質にて、実施例1のLIDセンサ上においてpH=7.4のhepes+150mMのNaCl緩衝液中で、実行された。固定化を完了せしめるために、プレートは一晩4℃にて培養された。第2ステップにおいて、洗浄後に、EDC/NHS処理(200mM/50mM)が、固定されたタンパク質を有する表面に対して実行された。そして、エタノールアミンが、残存する活性化エステルを遮断するのに用いられた。この実験は、異なるPAA−NTA化学物質を有する数個の検出表面を用いて、同一条件にて実行された。AA:DMAモノマ比は、例えば、約75:25〜約30:70(wt/wt)、相対モル比(mol/mol%)又はmolパーセント(mol%)まで変更され得る。これら組成の異なるPAA/DMAmマトリックスは、実施例1に係るPAA−NTAアフィニティ表面にさらに修飾された。
同一の実施例1の化学的処理が、PAA−NTA表面修飾によって被覆された384ウェルのマイクロプレートを準備するのに用いられた。ニッケル溶液は、マイクロプレートの3分の1だけに添加された。そして、Hisタグ付き炭酸アンヒドラーゼ(Hisタグ付きCAII)が、ニッケル錯体形成がある場合又はない場合において、50マイクロg/mLにて、PAA−NTA表面上においてhepes+150mMのNaCl緩衝液内で一晩、固定された。平行実験において、天然のCAIIが、PAA−NTA上において50マイクログラム/mLのhepes+塩類において、固定された。Hisタグ付きCAII露出マイクロプレートをPBSを用いて洗浄し、それに続いてDI水洗浄を熱心に行った後に、共有結合後処理は、EDC/NHS処理(200mM/50mM)を用いて、30分間、水中にて実行され、それに続いて、エタノールアミン阻止ステップ(ホウ酸塩緩衝液にて0.2M)が実行された。図6に示されているように、PAA−NTA(600)上の8His−CAII、PAA−NTA(610)上のCAIIネイティブ、及びNiイオンが存在しないPAA−NTA上の8His−CAII(620)に対する固定化レベルが、Epic(登録商標)装置を使用して、測定された。8His−CAII Iは、8ヒスチジン基(ヘキサヒスチジン6His−CAIIの代わりにオクタキサヒスチジン)を有するテールによりタグ付けされたカルボニックアンヒドラーゼである。多くの数のヒスチジン残基は、錯体の安定性を改善する。
実施例1の処理手順は、PAA−NTA表面修飾を有する384ウェルのマイクロプレートを準備するために繰り返された。Hisタグカルボニックアンヒドラーゼが、PAA−NTA修飾マイクロプレートを用いて、約16時間、hepes+150mmのNaCl緩衝液中で、50マイクログラム/mLにて、固定された。PBSにより洗浄してDI水で洗浄した後に、EDC/NHS処理(200mM/50mM)は、30分間、水中にて実行され、それに続いて、(アフィニティ/共有結合性相互作用に対応する)マイクロプレートの半分の領域のみにおけるエタノールアミン阻止ステップ(ホウ酸塩緩衝液にて0.2M)が実行された。マイクロプレートの一方の半分はソーキングバッファ(PBS+DMSO)に載置された。そして、固定化レベルは、図7に示されているように、Epic(登録商標)装置を使用して、測定された。そして、固定されたタンパク質を高品質なソーフィングバッファの添加剤及び混合体に接触させた後に、タンパク質の浸出は、図8に示されているように、Epic(登録商標)装置で測定された。
実施例1の処理手順は、(40/60及び30/70のAA/DMA比を有するPAA/DMAマトリックスに基づいて)PAA−NTA被膜表面を有する384ウェルのマイクロプレートを準備するために繰り返された。SET9(ヒストンH3メチルトランスフェラーゼ)及びGLKタンパク質(グルコキナーゼ)(双方のタンパク質に対してpI=4.8)等の低pIのhisタグ付きタンパク質は、約16時間、hepes+塩類緩衝液中で、50マイクログラム/mLにて、固定された。第2ステップにおいて、PBSにより洗浄してDI水で徹底的に洗浄した後に、EDC/NHS処理(200mM/50mM)は、30分間、水中にて実行され、それに続いて、エタノールアミン阻止ステップが実行された。固定化レベルは、図9に示されているように、Epic(登録商標)装置を使用して、測定された。比較として、また、同一の低pIタンパク質も、アミン結合されたd−EMA上の50マイクログラム/mlにて酢酸緩衝液(pH=5.5)において固定された。あらかじめ遮断されたアミンのようなポリ(エチレンalt無水マレイン酸)(d−EMA)等のポリマエンティティ等の比較的結合力のあるポリマは、2006年6月7日に出願された共有であり且つ譲渡された米国特許出願第11/448,486号、「SUPPORTS FOR ASSAYING ANALYTES AND METHODS OF MAKING AND USING THEREOF」という発明の名称の米国特許公報第2007−0154348号に開示されている。
Claims (5)
- ポリマを有する基板を含むバイオセンサ製品であって、
前記ポリマは前記基板の表面に関連付けられており、前記ポリマは、[化1]に示され
た化学式(I)のポリマを含み、
Rは、存在しないか、水素、1から6までの炭素原子を有する置換若しくは未置換の直鎖若しくは分枝の一価のヒドロカルビル残基であり、
R’は、1から18までの炭素原子を有する不飽和のモノマの共重合から生じる置換若しくは未置換の直鎖若しくは分枝の2価のヒドロカルビル残基であり、
R’’は、1から20までの炭素原子を有する置換若しくは未置換の直鎖若しくは分枝の2価のヒドロカルビル残基であり、
Sは、基板に対する付着に関する少なくとも1つのポイントを含み、
Wは、少なくとも1つの金属イオンキレート剤残基を含み、
Xは、−NH−、−NR−、又はOであり、
x基:(y+z)基のモル比は、約2:8から約8:2までである、ことを特徴とするバイオセンサ製品。 - Wと錯体化された少なくとも1つの金属−イオンを有する前記ポリマをさらに含み、
前記少なくとも1つの金属−イオンは、Ni、Cu、Zn、Co、Fe又はこれらの組み合わせから選択された少なくとも一つの金属イオンを含むことを特徴とする請求項1に記載の製品。 - Wと錯体化された前記少なくとも1つの金属イオンに関連付けられたHisタグ付きエンティティをさらに含む請求項2に記載の製品。
- 前記基板表面のポリマは、約20nmから約1000nmの膜厚を有する連続層又は半連続層を含むことを特徴とする請求項1に記載の製品。
- 請求項1に記載のバイオセンサ製品を製造する方法であって、前記方法は、パスA又はパスBを含み、
前記パスAは、
第1のアクリルアミドモノマと第2のアクリルアミドモノマとの混合物から構成され且つ付着されたポリマを有する基板表面と活性化剤とを接触して活性化ポリマを形成するステップと、
当該形成された活性化ポリマをキレート基フォーマに接触させて、化学式(I)のポリマを形成するステップと、を含み、
前記パスBは、
少なくとも1つの金属‐イオンキレート剤残基を有する少なくとも1つのアクリルアミドモノマと、不飽和有機シラン修飾表面とを重合化して、化学式(I)のポリマを形成するステップを含むことを特徴とする方法。
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