JP2012501681A - 生体分子の貯蔵および安定化のためのマトリックスおよび媒体 - Google Patents
生体分子の貯蔵および安定化のためのマトリックスおよび媒体 Download PDFInfo
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Abstract
Description
薬学および医学研究、法的処置、および軍人身分証明などの多くの適用例では、数多くの生体サンプルを貯蔵しかつそのサンプルを利用できることが、しばしば望ましい。従来のバイオレポジトリーまたはその他のサンプル貯蔵施設は、サンプル貯蔵のために、液体または低い温度の極低温システムを利用する。これらの液体および極低温システムは、製造および維持の両方に費用がかかり、したがって現行の技術は一般に、複雑で労働集約的な維持および管理上の責任をシステムオペレータにもたらす。さらに、これらのシステムは、多数のサンプルが同時に処理されるときに生ずる作業の流れの問題に対処していない。そのような条件下で、サンプルは、長時間にわたり周囲温度に曝され、その結果、サンプルが劣化する可能性がある。
本発明は、一部には、ある化合物、特に水溶性無機化合物と、一重項酸素クエンチャーとして機能する化合物とが、高温を含めた乾燥状態での生体分子の安定化および/または貯蔵に有用であるという発見に基づく。本発明は、一部には、化合物のある組合せが、水溶液中でRNAを含めた生体分子を安定化させるという発見にも基づく。
別の態様では、本発明は、本発明の組成物を含むサンプルキャリアを提供する。ある実施形態では、サンプルキャリアは、容器およびサンプルノードを含み、このサンプルノードは、本明細書に開示される組成物(例えば、本明細書に開示される固体状態のマトリックスまたは水性媒体)を含みまたはこの組成物からなる。ある実施形態では、サンプルノードは、容器に可逆的に取着される。ある実施形態では、容器は、サンプルノードを含有および/または支持する。容器は、そのような組成物を含有しまたは支持するのにかつ/または本発明の方法を実施するのに適した任意のサイズおよび形状にすることができる。例えば、ある実施形態では、容器がチューブ(例えば、試験管、サンプル管であって、容積が約0.1mlから約2.0mlのものなど)またはウェル(例えば、標準的なマルチウェルプレートなどの、プレートのウェル)である。
別の態様では、本発明は、本明細書に開示される組成物と、生体分子の貯蔵のためにこの組成物を使用する取扱説明書とを含むキットを提供する。ある実施形態では、組成物は、本明細書に開示される固体状態マトリックスである。他の実施形態では、組成物は、本明細書に開示される水性媒体である。ある実施形態では、取扱説明書は、本明細書に開示される生体分子を乾燥貯蔵するための方法について述べている。他の実施形態では、取扱説明書は、生体分子を安定化させるための方法(例えば、乾燥状態でまたは液体媒体中で)について記述した。さらに他の実施形態では、取扱説明書は、本明細書に記述される生体分子を輸送するための方法(例えば、乾燥状態で)について述べている。
ある態様では、本発明は、生体分子を貯蔵する方法を提供する。ある実施形態では、方法は、生体サンプルなどの生体分子を含有するサンプルと、本明細書に記述される組成物(例えば、本明細書に記述される固体状態マトリックスまたは水性媒体)とを混合して混合物を形成するステップと、この混合物を乾燥して、生体分子を含んだ乾燥状態マトリックスを形成するステップとを含む。サンプルは、本明細書に記述されるサンプルの、任意のタイプにすることができる。
ホウ酸乾燥状態マトリックス
水溶性無機化合物を含むマトリックスを、円錐底、ポリプロピレンの96ウェルマイクロタイタープレートに製作した。ホウ酸の4.0mg/ml水溶液からなる媒体の一定分量20μLを、個々のウェルに添加した。媒体を、引き続き、各ウェルの底面上で室温で空気乾燥して、個別の固体状態無機マトリックス(即ち、個別のサンプルノード)を形成した。乾燥プロセスは、典型的には、真空遠心分離器で2時間またはフード内で一晩要した。図1は、これらの手順により形成された代表的なマトリックスを示す。
ホウ酸およびヒスチジンの乾燥状態マトリックス
水溶性無機化合物(ホウ酸)および小分子安定化剤(ヒスチジン)を含むマトリックスを、円錐底、ポリプロピレンの96ウェルマイクロタイタープレートに製作した。ホウ酸(4.0mg/ml)およびヒスチジン(0.5mg/mlから2.5mg/ml)の水溶液からなる媒体の一定分量20μLを、個々のウェルに添加した。媒体を、引き続き、各ウェルの底面上で室温で空気乾燥して、個別の固体状態無機マトリックス(即ち、個別のサンプルノード)を形成した。乾燥プロセスは、典型的には、真空遠心分離器で2時間またはフード内で一晩要した。
ホウ酸およびグリセロールの乾燥状態マトリックス
水溶性無機化合物(ホウ酸)および可塑剤(グリセロール)を含むマトリックスを、円錐底、ポリプロピレンの96ウェルマイクロタイタープレートに製作した。ホウ酸(4.0mg/ml)およびグリセロール(0.5mg/mlから4.0mg/ml)の水溶液からなる媒体の一定分量20μLを、個々のウェルに添加した。媒体を、引き続き、各ウェルの底面上で室温で空気乾燥して、個別の固体状態無機マトリックス(即ち、個別のサンプルノード)を形成した。乾燥プロセスは、典型的には、真空遠心分離器で2時間またはフード内で一晩要した。
ホウ酸およびヒスチジンを含む、またはホウ酸を含みヒスチジンを含まない乾燥状態マトリックスでのDNAの貯蔵
実施例1〜2に記述されるマトリックスに、ヒトDNA(Roche提供)をTE緩衝液に加えた一定分量20μLを、ウェル毎に添加した。各ウェルの固体状態マトリックスを、繰り返しピペット操作することによってDNA溶液に再懸濁しかつ可溶化した。次いで得られた溶液を空気乾燥して、生体分子を含む固体状態マトリックスを形成した。各ウェルに添加されたDNAの量は、約100ngから約5000ngに及んだ。DNAを含むマトリックスが形成された後、プレートを室温(即ち、約25℃)、37℃、55℃、または76℃で貯蔵した。
水の添加による乾燥状態マトリックスからのDNAの回収
実施例4の乾燥状態貯蔵からDNAを回収するために、水20μLを各ウェルに添加し、プレートを室温で約15分間インキュベートした。DNA含有溶液を、ピペット操作により回収し、次いで「そのまま」または必要に応じて水で希釈して、さらなる分析のために使用した。
乾燥状態マトリックスから回収されたDNAのゲル電気泳動
実施例4により貯蔵され、実施例5により回収されたDNAを、ゲル電気泳動によって分析した。回収されたDNA100ng(100%回収と仮定する。)に相当するDNA含有溶液の体積を、250ボルトで1時間、0.8%アガロースゲルに流し、臭化エチジウムで染色した。その結果を図2に示す。
乾燥状態マトリックスから回収されたヒトDNAのリアルタイムPCR分析
リアルタイムPCRを使用して、実施例4の乾燥状態マトリックスからのDNAの回収を比較し評価した。DNAは、実施例5で記述したように回収した。PCR分析は、ABI(カタログ#401846)から提供された、核染色体コード遺伝子、β−アクチンをベースにした。
乾燥状態マトリックスから回収されたDNAのマイクロアレイ分析
マイクロアレイ分析を、実施例6の乾燥状態マトリックスから回収されたDNAに関して行った。DNAを、実施例8に記述されるように回収した。Affymetrix 6.0およびIllumina 1MマイクロアレイSNP分析を、製造業者の推奨に従い、Expression Analysis,Inc.(Durham、NC)により行った。分析の結果を図4に示す。
ホウ砂を含む乾燥状態マトリックスでの口内スワブまたは血液スワブ溶解物の貯蔵
全血または頬細胞サンプルを、綿棒に収集し、空気乾燥する。これらのスワブを、後で、ホウ砂の100mM水溶液を添加することによって再水和し、その後、95℃で10分間加熱する。スワブ抽出物を、遠心分離によってまたはスワブから流体を手で絞り取ることによって、回収する。次いで得られた溶液を、ウェル当たり約200μLを超えない体積で、96ウェルマイクロタイタープレートの1つまたは複数のウェル内に分取する。プレートを室温で乾燥させ、したがって、生体分子を含む乾燥状態マトリックスが形成される。
ホウ砂およびヒスチジンを含む乾燥状態マトリックスでの口内スワブまたは血液スワブ溶解物の貯蔵
全血または頬細胞サンプルを、綿棒に収集し、空気乾燥する。100mMホウ砂および2mM〜100mMヒスチジンを水に溶かした溶液を添加することによって、スワブを再水和し、その後、95℃に10分間加熱する。スワブ抽出物を、遠心分離によってまたはスワブから流体を手で絞り取ることによって、スワブから回収する。次いで得られた溶液を、ウェル当たり約200μLを超えない体積で、96ウェルマイクロタイタープレートの1つまたは複数のウェルに分取する。プレートを室温で乾燥させ、したがって無機貯蔵マトリックスが形成される。
高温での乾燥状態貯蔵中のRNA安定性
精製された全RNAの1マイクログラムサンプルを、本発明の様々な組成物(以下に記述される。)と混合し、次いで(A)25℃または(B)76℃の乾燥状態で7日間貯蔵した。その時点で、サンプルを再懸濁し、Agilent Bioanalyzerで分析した。乾燥状態マトリックスは、下記の通りであった:
1)ボレート、シトレート、EDTA、ピルベート、およびデキストラン(図5に示される結果);
2)Tris、ボレート、マンニトール、およびEDTA(図6に示される結果);
3)ボレート、シトレート、マンニトール、およびデキストラン(図7に示される結果);
4)ボレート、シトレート、マンニトール、およびピルベート(図8に示される結果);
5)ボレート、シトレート、ピルベート、およびデキストラン(図9に示される結果);
6)ボレート、シトレート、EDTA、およびデキストラン(図10に示される結果);
7)ボレート、EDTA、およびピルベート(図11に示される結果);
8)ボレート、シトレート、およびピルベート(図12に示される結果);
9)ボレート、シトレート、およびマンニトール(図13に示される結果);
10)ボレート、シトレート、およびEDTA(図14に示される結果);
11)マトリックスなしの対照(図15に示される結果)。
Claims (45)
- 無機化合物と、
安定化剤、可塑剤、またはこれらの組合せと
を含む、乾燥状態マトリックスであって、
前記安定化剤は、一重項酸素クエンチャー、ヒドロキシルラジカルスカベンジャー、ヒドロペルオキシド除去剤、還元剤、金属キレート剤、洗浄剤、カオトロープ、またはこれらの任意の組合せからなる群より選択され、
前記無機化合物は水溶性であり、前記マトリックスは固体状態にある、乾燥状態マトリックス。 - 前記無機化合物が、金属キレート剤もしくは殺菌剤であり、または生体分子に対して不活性である、請求項1に記載のマトリックス。
- 前記無機化合物が、元素の周期表の第IIIA族、第VA族、または第VB族の元素を含む、請求項1に記載のマトリックス。
- 前記無機化合物が、ホウ素、リン、バナジウム、およびアルミニウムからなる群より選択される元素を含む、請求項1に記載のマトリックス。
- 前記無機化合物が、ホウ酸、対応するホウ酸の塩、リン酸、対応するリン酸の塩、バナデートを含む塩、カリウムミョウバン、ソーダミョウバン、アンモニウムミョウバン、またはこれらの任意の組合せを含む、請求項1に記載のマトリックス。
- 前記マトリックスが安定化剤を含み、前記安定化剤が、アルキルイミダゾール、インドール、硫黄含有アミノ酸、フェノール化合物、芳香族の酸、アジド、トコフェロール、ビタミンE誘導体、カロチン、ビタミンA誘導体、およびこれらの任意の組合せからなる群より選択される一重項酸素クエンチャーを含む、請求項1に記載のマトリックス。
- 前記マトリックスが安定化剤を含み、前記安定化剤が、EDTA、EGTA、o−フェナントロリン、シトレート、およびこれらの任意の組合せからなる群より選択される金属キレート剤を含む、請求項1に記載のマトリックス。
- 前記マトリックスが安定化剤を含み、前記安定化剤が、アジド、ジメチルスルホキシド、ヒスチジン、マンニトール、およびこれらの任意の組合せからなる群より選択されるヒドロキシルラジカルスカベンジャーを含む、請求項1に記載のマトリックス
- 前記マトリックスが安定化剤を含み、前記安定化剤が、カタラーゼ、ピルベート、グルタチオン、グルタチオンペルオキシダーゼ、およびこれらの任意の組合せからなる群より選択されるヒドロペルオキシド除去剤を含む、請求項1に記載のマトリックス。
- 前記マトリックスが、単糖類、二糖類、複合糖類、および直鎖状短鎖多価アルコールまたは分枝状短鎖多価アルコールからなる群より選択される可塑剤を含む、請求項1に記載のマトリックス。
- 前記マトリックスが、核酸増幅、核酸消化、および/またはタンパク質消化の方法に対して不活性である、請求項1に記載のマトリックス。
- 生体分子を含むサンプルをさらに含む、請求項1に記載のマトリックス。
- 無機化合物と、
生体分子を含むサンプルと
を含む、乾燥状態マトリックスであって、
前記無機化合物が水溶性であり、前記マトリックスが固体状態にある、乾燥状態マトリックス。 - 前記無機化合物が、ホウ酸、対応するホウ酸の塩、リン酸、対応するリン酸の塩、バナデートを含む塩、カリウムミョウバン、ソーダミョウバン、アンモニウムミョウバン、またはこれらの組合せを含む、請求項13に記載のマトリックス。
- 一重項酸素クエンチャー、ヒドロキシルラジカルスカベンジャー、ヒドロペルオキシド除去剤、還元剤、キレート剤、洗浄剤、カオトロープ、またはこれらの任意の組合せを含む安定化剤と、
無機塩、可塑剤、またはこれらの任意の組合せと
を含み、固体状態にある、乾燥状態マトリックス。 - 前記安定化剤が一重項酸素クエンチャーを含み、前記一重項酸素クエンチャーが、アルキルイミダゾール、インドール、硫黄含有アミノ酸、フェノール化合物、芳香族の酸、アジド塩、トコフェロール、ビタミンE誘導体、カロチン、ビタミンA誘導体、およびこれらの組合せからなる群より選択される、請求項15に記載のマトリックス。
- 前記マトリックスが、単糖類、二糖類、複合糖類、および直鎖状短鎖多価アルコールまたは分枝状短鎖多価アルコールからなる群より選択される可塑剤を含む、請求項15に記載のマトリックス。
- 生体分子を含むサンプルをさらに含む、請求項15に記載のマトリックス。
- 無機化合物、一重項酸素クエンチャー、ヒドロキシルラジカルスカベンジャー、ヒドロペルオキシド除去剤、還元剤、金属キレート剤、洗浄剤、および可塑剤からなるリストから選択される、少なくとも3種の成分
を含む、乾燥状態マトリックスであって、
前記無機化合物が水溶性であり、前記マトリックスが固体状態にある、乾燥状態マトリックス。 - 前記マトリックスが、無機化合物、ヒドロキシルラジカルスカベンジャー、およびヒドロペルオキシド除去剤を含む、請求項19に記載のマトリックス。
- 可塑剤、金属キレート剤、RNase阻害剤、またはこれらの任意の組合せをさらに含む、請求項20に記載のマトリックス。
- 生体分子を含むサンプルをさらに含む、請求項19に記載のマトリックス。
- 無機化合物と、
安定化剤、可塑剤、またはこれらの組合せと、
任意選択で、RNase阻害剤と
を含む、水性媒体であって、
前記安定化剤が、一重項酸素クエンチャー、ヒドロキシルラジカルスカベンジャー、ヒドロペルオキシド除去剤、およびこれらの任意の組合せからなる群より選択され、
前記無機化合物が水溶性である、
水性媒体。 - 前記無機化合物が、ホウ酸、対応するホウ酸の塩、リン酸、対応するリン酸の塩、バナデートを含む塩、カリウムミョウバン、ソーダミョウバン、アンモニウムミョウバン、またはこれらの組合せを含む、請求項23に記載の媒体。
- 2’−シチジンモノホスフェート遊離酸(2’−CMP)、アルミノン、アデノシン5’−ピロリン酸、5’−ジホスホアデノシン3’−リン酸(ppA−3’−p)、5’−ジホスホアデノシン2’−リン酸(ppA−2’−p)、ロイシン、ポリ−L−アスパラギン酸、チロシン−グルタミン酸ポリマー、オリゴビニスルホン酸、アデノシン3’−リン酸との、5’−ホスホ(phopho)−2’−デオキシウリジン3’−ピロリン酸P’→5’エステル(pdUppAp)からなる群より選択される、RNase阻害剤を含む、請求項23に記載の媒体。
- 還元剤、キレート剤、洗浄剤、カオトロープ、またはこれらの任意の組合せをさらに含む、請求項23に記載の媒体。
- 生体分子を含むサンプルをさらに含む、請求項23に記載の媒体。
- 1種または複数のヒドロキシルラジカルスカベンジャーと、
無機塩、可塑剤、またはこれらの任意の組合せと、
任意選択で、RNase阻害剤と
を含む、水性媒体。 - 一重項酸素クエンチャー、還元剤、キレート剤、洗浄剤、カオトロープ、またはこれらの任意の組合せをさらに含む、請求項28に記載の媒体。
- 生体分子を含むサンプルをさらに含む、請求項28に記載の媒体。
- 容器と、
サンプルノードと
を含む、サンプルキャリアであって、
前記サンプルノードが、前記容器によって支持され、かつ請求項1、13、15、もしくは19に記載の乾燥状態マトリックス、または請求項23もしくは28に記載の水性媒体を含む、
サンプルキャリア。 - 前記サンプルノードが、前記マトリックスを約10から約1000マイクログラム、または前記水性媒体を約10から約1000マイクロリットル含む、請求項31に記載のサンプルキャリア。
- 識別表示をさらに含む、請求項31に記載のサンプルキャリア。
- 前記サンプルノードが識別表示を含む、請求項31に記載のサンプルキャリア。
- 複数の前記容器と、
複数の前記サンプルノードと
をさらに含み、
複数の前記サンプルノードのそれぞれが、複数の前記容器の1つによって支持される、請求項31に記載のサンプルキャリア。 - 請求項1、13、15、もしくは19に記載の乾燥状態マトリックスまたは請求項23もしくは28に記載の水性媒体を含有する容器、または請求項31に記載のサンプルキャリアと、
生体分子を貯蔵するために前記乾燥状態マトリックス、前記水性媒体、または前記サンプルキャリアを使用するための取扱説明書と
を含むキット。 - 生体分子を含むサンプルと、請求項1、13、15、もしくは19に記載の乾燥状態マトリックスまたは請求項23もしくは28に記載の水性媒体とを混合して、混合物を形成するステップと、
前記混合物を乾燥して、前記生体分子を乾燥状態で貯蔵するステップと
を含む、乾燥状態で生体分子を貯蔵する方法。 - 前記サンプルが液体サンプルであり、前記液体サンプルが前記乾燥状態マトリックスと混合される、請求項37に記載の方法。
- 前記サンプルが固体支持体によって保持され、前記混合するステップが、前記固体支持体を前記水性媒体で濯ぐステップを含む、請求項37に記載の方法。
- 前記生体分子が、約25℃から約72℃で貯蔵される、請求項37に記載の方法。
- 生体分子を含むサンプルと、請求項23または28に記載の水性媒体とを混合して、混合物を形成するステップ
を含む、水溶液中で生体分子を安定化させる方法。 - 前記サンプルが固体支持体によって保持される、請求項41に記載の方法。
- 前記サンプルが固体組織サンプルである、請求項41に記載の方法。
- 前記方法によって安定化された生体分子がRNAを含む、請求項41に記載の方法。
- 前記混合物が、約4℃から約37℃で維持される、請求項41に記載の方法。
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WO2007075253A2 (en) * | 2005-12-01 | 2007-07-05 | Biomatrica, Inc. | Integration of sample storage and sample management for life science |
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JP2016527897A (ja) * | 2013-08-16 | 2016-09-15 | ゼネラル・エレクトリック・カンパニイ | 核酸の抽出及び保存のための方法及び組成物 |
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CN102177237B (zh) | 2013-10-30 |
US8951719B2 (en) | 2015-02-10 |
US20150158902A1 (en) | 2015-06-11 |
EP2334792B1 (en) | 2020-09-09 |
WO2010031007A3 (en) | 2010-07-29 |
EP2334792A2 (en) | 2011-06-22 |
US20100248363A1 (en) | 2010-09-30 |
US10160997B2 (en) | 2018-12-25 |
US8283165B2 (en) | 2012-10-09 |
HK1159684A1 (en) | 2012-08-03 |
US20120308987A1 (en) | 2012-12-06 |
US9637513B2 (en) | 2017-05-02 |
WO2010031007A2 (en) | 2010-03-18 |
EP2334792A4 (en) | 2014-09-03 |
CN102177237A (zh) | 2011-09-07 |
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