JP6043396B2 - 磁性ナノ粒子、磁性検出器アレイ、および生物学的分子の検出におけるそれらの使用方法 - Google Patents
磁性ナノ粒子、磁性検出器アレイ、および生物学的分子の検出におけるそれらの使用方法 Download PDFInfo
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- JP6043396B2 JP6043396B2 JP2015075418A JP2015075418A JP6043396B2 JP 6043396 B2 JP6043396 B2 JP 6043396B2 JP 2015075418 A JP2015075418 A JP 2015075418A JP 2015075418 A JP2015075418 A JP 2015075418A JP 6043396 B2 JP6043396 B2 JP 6043396B2
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Description
政府は、米国国防総省国防高等研究事業局(DARPA)による認可番号 N00014-02-1-0807にしたがい、本発明における権利を所有しうる。
本発明は、磁性ナノ粒子、磁性ナノ粒子検出器、および、生物学的物質を、天然または合成を問わず、および修飾または非修飾を問わず、検出する方法に関する。本発明はまた、生物学的物質の検出に使用するための磁性ナノ粒子材料、およびこれら材料の作成方法に関する。最後に、本発明は、磁性粒子検出器および関連装置、ならびに生物学的物質の検出のためのそのような装置の使用方法に関する。
高感度で定量的なDNA断片検出および同定システムの開発は、機能的ゲノム学、科学捜査、生物兵器防衛、バイオテロ対策、および他のバイオテクノロジー適用において重要性が増している。
磁性ナノ粒子および検出器アレイのシステムが記載される。このシステムは、DNAのような核酸分子の高感度検出に有用である。ナノ粒子は、超常磁性であるか、または少なくとも2つの反強磁性的に結合した高モーメント強磁性体の層を含む反強磁性的ナノ粒子である、高モーメント磁性ナノ粒子でありうる。
以下の図は、本明細書の一部を形成し、本発明のある局面をさらに説明するために含まれる。本発明は、これら図の1またはそれ以上を本明細書に示される具体的態様の詳しい説明と組み合わせて参照することにより、より良く理解できる。
以下の定義は、当業者が本発明の詳しい説明を理解するのを助けるために提供される。
検出システムは、典型的には、スピンバルブまたはMTJ検出器のアレイ、図1Aに示すようにアレイ中の個々の検出器に連結している対象とする標的に相補的なオリゴヌクレオチドプローブ、マクロ流体またはマイクロ流体サンプル送達システム、および図1Bに示すように標的DNA断片と結合している磁性ナノ粒子を含みうる。図1Cに示すように、タグ付加されたDNA断片は、選択的ハイブリダイゼーションのため流体チャンネルによって検出器アレイに送達される。ハイブリダイズしなかったDNA断片は、洗浄除去されるか、または傾斜磁場により取り除かれる。図2Aおよび2Bに示すように、検出器アレイは、DCバイアス場(DC bias field)およびACティックリング場(AC tickling field)の組み合わせにより調べられる。印加磁場により磁性ナノ粒子タグが正味の磁気モーメント(net magnetic moment)を示すようになり、それは続いてスピンバルブまたはMTJ検出器により検出することができる。面内検出モードにおいて、検出器シグナルは、ACティックリング場 Htと同じ周波数を有する。これに対して、図2Cに示すように、垂直モードにおいては検出器シグナルはACティックリング場の第二高調波(second harmonic)である。いずれの場合も、たとえシグナル対ノイズ比が小さくても、ロックイン検出を用いることができる。このようにして、標的DNA断片の存在をシグナルにて示す磁性ナノ粒子タグの存在を検出することができる。検出器電圧シグナルは、磁性ナノ粒子の数に、それゆえ標的DNA断片の数に比例する。
表1:スピンバルブシグナル電圧(最高最低振幅)と磁性タグの対照。垂直検出モードのデータ(図2B)のみをここに挙げる。電圧は、その中心がスピンバルブフリー層の中央平面から20 nm離れた単一のナノ粒子によるものである。センサーサイズは、3μm x 0.2μmで、その有効長は1μmである。センス方向の電流密度は108 A/cm2である。スピンバルブセンサー由来の漂遊磁界の効果が計算に含まれる。合成FeCoは30 Oeで飽和すると想定され、その粒子は印加磁場より物理的に回転する。超常磁性ナノ粒子の室温磁気モーメントは、Langevin関数により説明されるように減少するが、合成反強磁性的結合ナノ粒子の室温磁気モーメントは、超常磁性によりあまり変化しないことに注目。
表2:スピンバルブシグナル電圧 (最高最低振幅)とフリー層幅の対照。電圧は直径11 nmの単一のCo ナノ粒子によるものであり、その端はスピンバルブフリー層中央平面から6 nm離れている。面内モードおよび垂直モードの両方を、適当なバイアス場およびティックリング場振幅とともに挙げる。
実施例1:マグネタイトナノ粒子の検出
本発明にしたがい、Co、Fe、およびそれらの合金に加えて、フェライト、例えばマグネタイトおよびMn-フェライトもまた生物学的タグとして機能しうることを示すため、一連の実験を行った。図3に示すように、0.3μm幅スピンバルブセンサー上の16-nm Fe3O4 ナノ粒子 (NP)の単層は、ポリエチレンイミン (PEI)仲介自己集合法を用いてコートした(S. Sun, et al., J. Am. Chem. Soc., 124, 2884 (2002)を参照)。図3Bに示すように、マグネタイトナノ粒子に覆われたスピンバルブからの電圧シグナルは、予想どおり、センサー上に印加されたバイアス電圧にほぼ比例するが、マグネタイトナノ粒子にまったく覆われていない参照スピンバルブからのシグナルはほぼゼロであることがわかった。電圧シグナルは、Wheatstoneブリッジ回路から、ロックイン増幅器を用いて様々なブリッジ回路バイアスにて測定した。さらに、測定されたシグナルは、例えばG. X. LiおよびS. X. WangのIEEE Trans. Magn., 39(5),3313-5, (2003)に記載されるような分析モデルにより適切に説明できることが示された。
4 nmの不動態化層の信頼性を、一連の受動的腐食(passive corrosion)研究を通して検討した。プロトタイプのMagArray(商標)チップを、標準的DNAマイクロアレイにおいて現在用いられている2種類のDNA溶液の1つに浸した。第1の溶液はハイブリダイゼーションバッファー (pH = 7.5)であり、0.6 M NaCl、0.06 M C6H5Na3O7 (クエン酸ナトリウム)、および0.1% SDS (ドデシル硫酸ナトリウム)の混合物からなる。その名称が示すように、この溶液は、マイクロアレイにおける実際のハイブリダイゼーション工程のための主要媒体である。もう1つの溶液、ブロッキング溶液 (pH = 7.9)は、Surmodics (Eden Prarie, MN)の特許品であり、主として試験領域の非特異的結合を除去するために使用される。このプロセスにより、標的分子がプローブと相互作用する可能性が上昇する。これら溶液に最後に添加するのは、濃度0.1 mg/mLのDNA(超音波分解したサケ精子DNA)である。
本発明者らはここに、化学的経路のかわりに物理的方法により作成され、MagArray(商標)において検出すべき標的生物分子の標識に適する、新規磁性ナノ粒子タグを開示する。このタグは、少なくとも2つの薄層強磁性層、好ましくはFexCo1-x、0.5≦x≦0.7、またはFexCo1-x基盤合金よりなる。FexCo1-xは、既知の強磁性物質の中で最高の飽和磁化 (約24.5 kGauss)を有することが知られている (Bozorth, R.M., Ferromagnetism, D. Van Nostrand Company, 1951)。これらの強磁性層は、非磁性スペーサー層、例えばRu、Cr、Auなど、またはそれらの合金、により隔てられる。図5に示すように、このスペーサー層は、得られる粒子の正味の残留磁気がゼロまたはほぼゼロとなるように、それら強磁性層が反強磁性的に結合するよう適宜加工される。ナノ粒子が生物分子と金-チオール結合または他の化学結合を介して結合するように、金キャップを反強磁性的スタックの上に付加する。ナノ粒子の端は、化学的安定性のため、Auその他の不活性薄層により不動態化することができる。当業者は、上記ナノ粒子を作成するための多くの物理的方法を想起しうる。
図6に、加法作成法を示す。ここに示すように、図の上部から下部へ矢印の方向に、この作成法は超平滑基体上への連続薄層 (後に粒子を放出するための層)の積層に始まり、次に該放出層へのマスク層の積層が続く。最終的に、マスク層に同じ穴がパターン化される。
MagArray(商標)の化学的感度を改善するため、DNAプローブおよび標的サンプルが磁性タグに感受性のある検出器表面にのみ連結するか、または向かうように、マイクロ流体回路 (Thorsen, T., et al., Science, Vol. 298, p. 580 (2002)) を検出器アレイ上に直接組み込み、それによりDNAプローブまたはDNA標的の浪費を最小限にした。このようなシステムの概略図を図7Aおよび7Bに示す。DNAプローブは、検出器表面に特異的に連結する。図7Aにおいて、検出器は、マイクロ流体チャンネルの幅である20μmよりも幾分長く作られている。長い検出器は、比較的大量のDNAサンプルに適している。図7Bにおいて、検出器は、マイクロ流体チャンネルの幅よりも短くつくられている。短い検出器は、比較的少量のDNAサンプルにより適する。後者の場合、印加電場または傾斜磁場、および流体力学集束スキームを用いて、DNAサンプルを検出器表面に向かわせることができる。図7Bのマイクロ流体チャンネルを検出器長と同じ長さとすることもまた考えられる。
Claims (12)
- 以下の工程を含む、対象とする分子を検出する方法:
少なくとも1つの磁化可能ナノ粒子に連結している第1の分子を提供する工程;
基体上の磁性検出器アレイに連結している第2の分子を提供する工程であって、該磁性検出器アレイが複数の検出部位を含み、該複数の検出部位の各々が磁性検出器および10nmまたはそれより薄い不動態化層を含む、工程;
該第1の分子の該第2の分子への選択的結合に適する条件下において、該第1の分子を該第2の分子と接触させ、複合体を形成する工程;および
磁性検出器アレイで、該複合体からの磁性シグナルを検出する工程。 - 検出が、磁性シグナルを生じさせるのに十分なDCバイアス磁場およびACティックリング磁場を印加することを含む、請求項1に記載の方法。
- ACティックリング磁場がDCバイアス磁場に直角に印加される、請求項2に記載の方法。
- DCバイアス磁場が、基体と実質的に平行である、請求項2または3に記載の方法。
- 磁性検出器アレイが、スピンバルブ検出器アレイまたは磁気トンネルジャンクション検出器アレイを含む、請求項1〜4のいずれかに記載の方法。
- 第1の分子および第2の分子が、独立に、核酸分子、蛋白質分子、ペプチド分子、抗原または抗体を含む、請求項1〜5のいずれかに記載の方法。
- 第1の分子がDNAまたはRNAであり、第2の分子がDNAまたはRNAである、請求項6に記載の方法。
- 第1の分子が、金−チオール結合により、少なくとも1つの磁化可能ナノ粒子と連結している、請求項1〜7のいずれかに記載の方法。
- ナノ粒子が、磁場の非存在下では磁化されず、磁場の存在下では磁化される、請求項1〜8のいずれかに記載の方法。
- ナノ粒子が、常磁性粒子、超常磁性粒子または合成フェリ磁性粒子である、請求項1〜9のいずれかに記載の方法。
- ナノ粒子の平均直径が、5nmから250nmである、請求項1〜10のいずれかに記載の方法。
- 検出が、外部傾斜磁場を印加すること、および正味の磁気モーメントを検出することを含む、請求項1に記載の方法。
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JP4635166B2 (ja) * | 2000-11-28 | 2011-02-16 | 株式会社泉精器製作所 | 回転式電気かみそり |
GB0124341D0 (en) * | 2001-10-10 | 2001-11-28 | Randox Lab Ltd | Assay |
ATE403751T1 (de) * | 2001-11-09 | 2008-08-15 | Nanosphere Inc | Biokonjugat-nanopartikelsonden |
KR20040068968A (ko) * | 2001-12-21 | 2004-08-02 | 코닌클리케 필립스 일렉트로닉스 엔.브이. | 마이크로-어레이상의 자기 나노입자들의 면적 밀도를측정하는 센서 및 방법 |
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EP1687634A4 (en) | 2007-12-05 |
US20050100930A1 (en) | 2005-05-12 |
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US7906345B2 (en) | 2011-03-15 |
US8318093B2 (en) | 2012-11-27 |
WO2005047864A3 (en) | 2005-09-29 |
WO2005047864A2 (en) | 2005-05-26 |
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EP1687634A2 (en) | 2006-08-09 |
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US20120122732A1 (en) | 2012-05-17 |
JP5161459B2 (ja) | 2013-03-13 |
JP2015163882A (ja) | 2015-09-10 |
US20080255006A1 (en) | 2008-10-16 |
JP2013040951A (ja) | 2013-02-28 |
US7682838B2 (en) | 2010-03-23 |
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