JP6176406B2 - 血中循環癌細胞捕獲方法 - Google Patents
血中循環癌細胞捕獲方法 Download PDFInfo
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- JP6176406B2 JP6176406B2 JP2016538433A JP2016538433A JP6176406B2 JP 6176406 B2 JP6176406 B2 JP 6176406B2 JP 2016538433 A JP2016538433 A JP 2016538433A JP 2016538433 A JP2016538433 A JP 2016538433A JP 6176406 B2 JP6176406 B2 JP 6176406B2
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- blood
- cancer cells
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- KRZKNIQKJHKHPL-UHFFFAOYSA-J tripotassium;gold(1+);disulfite Chemical compound [K+].[K+].[K+].[Au+].[O-]S([O-])=O.[O-]S([O-])=O KRZKNIQKJHKHPL-UHFFFAOYSA-J 0.000 description 1
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Description
また、図3(B)は銅板2’へのフォトレジスト3のラミネートする工程を示している。また、図3(C)はフォトマスク4を重ねてのフォトレジスト露光を示している。また、図3(D)は未露光部3bのフォトレジストの現像除去を示している。また、図3(E)はフォトレジストの露光部3aで覆われていない部分への電解めっきによりめっき層を形成する工程を示している。また、図3(F)は薬液による化学的溶解(ケミカルエッチング)によって銅板2’ を除去し、露光部3a及びめっき層5により形成される自立膜を取り出す工程を示している。また、図3(G)は自立膜内に残ったフォトレジストによる露光部3aを除去し、めっき層5に対して貫通孔6を形成する工程を示している。また、図3(H)は無電解金めっきを行い、フィルター表面に金めっき層7を形成する工程を示している。
感光性樹脂組成物(PHOTEC RD−1225:厚さ25μm、日立化成株式会社製)を250mm角の基板(MCL−E679F:MCLの表面にピーラブル銅箔を貼り合わせた基板、日立化成株式会社製)の片面にラミネートした。ラミネート条件はロール温度90℃、圧力0.3MPa、コンベア速度2.0m/分で行った。
非小細胞癌細胞株であるNCI−H358細胞を10%ウシ胎児血清(FBS)を含むRPMI−1640培地にて、37℃、5%CO2条件下にて静置培養した。トリプシン処理により培養皿から細胞を剥離させて回収し、リン酸緩衝液(Phosphate buffered saline、PBS)を用いて洗浄した後に、10μM Cell Tracker Red CMTPX(ライフテクノロジーズジャパン株式会社)にて37℃、30分間静置させることで、NCI−H358細胞を染色した。その後、PBSにて洗浄し、トリプシン処理にて37℃にて3分間静置させることで、細胞塊を解離させた。その後、培地にてトリプシン処理を停止させ、PBSにて洗浄後、2mM EDTA及び0.5%ウシ血清アルブミン(BSA)を含むPBS(以下2mM EDTA−0.5% BSA−PBSという。)中に懸濁して、調整用の懸濁液を得た。なお、PBSはリン酸緩衝生理食塩水であり和光純薬工業製製品コード166−23555を用いた。BSAはSIGMA−ALDRICH社製(Product Name:Albumin from bovine serum−Lyophilized powder, Bio Reagent for cell culture)のものを用いた。また、EDTAは2Na(エチレンジアミン−N,N,N’,,N’−4酢酸二ナトリウム塩二水和物)(和光純薬工業製製品コード345−01865)を用いた。
(実施例1)
7.5mlの血液サンプルとして、EDTA−2Na含有真空採血管に採血した健常者血液に、血液7.5mLあたり1000個の前出癌細胞を含有させたサンプルを用いた。サンプル中の白血球の数は470万個/ml即ち、3525万個/7.5mlであった。
100mlの血液サンプルとして、EDTA−2Na含有真空採血管に採血した健常者血液を用い、がん細胞をスパイクしなかった。サンプル中の白血球の数は530万個/ml即ち、5億3千万個/100mlであった。
前述の懸濁液を用い、白血球数が5万個となるように2mM EDTA−20.0% FBS(牛胎児血清)−PBS(Gibco製PBS、pH7.4)で10mlに調整した後、がん細胞を1000個スパイクしたサンプル3を用いた以外は実施例2と同様の方法で実施例3に係る測定を行った。
前述の懸濁液を用い、白血球数が1万個となるように2mM EDTA−20.0% FBS(牛胎児血清)−PBS(Gibco製PBS、pH7.4)で10mlに調整した後、がん細胞を1000個スパイクしたサンプル4を用いた以外は実施例2と同様の方法で実施例4に係る測定を行った。
前述の懸濁液を用い、白血球数が5千個となるように2mM EDTA−20.0% FBS(牛胎児血清)−PBS(Gibco製PBSpH7.4)で10mlに調整した後、がん細胞を1000個スパイクしたサンプル5を用いた以外は実施例2と同様の方法で実施例5に係る測定を行った。
前述の懸濁液を用い、白血球数が5万個となるよう2mM EDTA−20.0% 人血清−PBS(Gibco製PBS、pH7.4)で10mlに調整した後、がん細胞を1000個スパイクしたサンプル6を用いた以外は実施例2と同様の方法で実施例6に係る測定を行った。
前述の懸濁液を用い、白血球数が5万個となるよう2mM EDTA−20.0% ウマ血清−PBS(Gibco製PBS、pH7.4)で10mlに調整した後、がん細胞を1000個スパイクしたサンプル7を用いた以外は実施例2と同様の方法で実施例7に係る測定を行った。
前述の懸濁液を用い、白血球数が5万個となるよう2mM EDTA−20.0% ウシ血清−PBS(Gibco製PBS、pH7.4)で10mlに調整した後、がん細胞を1000個スパイクしたサンプル8を用いた以外は実施例2と同様の方法で実施例8に係る測定を行った。
前述の懸濁液を用い、白血球数が5万個となるよう2mM EDTA−0.5% ウシ血清アルブミン−PBS(Gibco製PBS、pH7.4)で10mlに調整した後、がん細胞を1000個スパイクしたサンプル9を用いた以外は実施例2と同様の方法で実施例9に係る測定を行った。
前述の懸濁液を用い、白血球数が5万個となるよう2mM EDTA−PBS(Gibco製PBS、pH7.4)で10mlに調整した後、がん細胞を1000個スパイクしたサンプル10を用いた以外は実施例2と同様の方法で実施例10に係る測定を行った。
前述の懸濁液を用い、白血球数が5万個となるよう2mM EDTA−50.0%FBS(牛胎児血清)−PBS(Gibco製PBS、pH7.4)で10mlに調整した後、がん細胞を1000個スパイクしたサンプル11を用いた以外は実施例2と同様の方法で実施例11に係る測定を行った。
前述の懸濁液を用い、白血球数が5万個となるよう100%FBS(牛胎児血清)で10mlに調整した後、がん細胞を1000個スパイクしたサンプル12を用いた以外は実施例2と同様の方法で実施例12に係る測定を行った。
前述の懸濁液を用い、白血球数が5万個となるよう2mM EDTA−1.0%FBS(牛胎児血清)−PBS(Gibco製PBS、pH7.4)で10mlに調整した後、がん細胞を1000個スパイクしたサンプル13を用いた以外は実施例2と同様の方法で実施例13に係る測定を行った。
前述の懸濁液を用い、白血球数が5万個となるよう20.0%FBS(牛胎児血清)−PBS(Gibco製PBSpH7.4)で10mlに調整した後、がん細胞を1000個スパイクしたサンプル14を用いた以外は実施例2と同様の方法で実施例14に係る測定を行った。
7.5mlの血液サンプルとして、EDTA−2Na含有真空採血管に採血した健常者血液に、血液7.5mLあたり1000個の前出癌細胞を含有させたサンプル15をそのまま用いた。サンプル中の白血球の数は470万個/ml、すなわち、3525万個/7.5mlであった。
測定の結果を表2に示す。実施例1により3525万個の白血球を磁気ビーズで減らした後にフィルターを行うことで、白血球の残渣をかなり減らすことができることがわかった。抗原抗体反応とフィルター法の組み合わせにより、従来に無い白血球除去率を実現している。実施例2〜5は抗原抗体反応で残った白血球にがん細胞をスパイクしたモデル実験である。50万個→45個、5万個→11個、1万個→6個、5千個→1個の結果が示すように、フィルトレーションを行う際の白血球を減らすことで、最終的に残るフィルター上の白血球の量を減らすことができる。
Claims (21)
- 血中循環癌細胞を血液中から取り出す血中循環癌細胞捕獲方法であって、前記血中循環癌細胞と白血球とを分離するためのフィルターによる血液フィルトレーションの前に、磁気ビーズを用いて前記血液から白血球を取り除く工程を有し、
前記白血球を取り除く工程において、又はその後に、細胞懸濁液を哺乳動物の血清或いは血漿を含む水溶液で希釈する工程を有し、
前記哺乳動物の血清或いは血漿が、ウシ、ウマ、ヒト由来であることを特徴とする血中循環癌細胞捕獲方法。 - 血中循環癌細胞を血液中から取り出す血中循環癌細胞捕獲方法であって、前記血中循環癌細胞と白血球とを分離するためのフィルターによる血液フィルトレーションの前に、磁気ビーズを用いて前記血液から白血球を取り除く工程を有し、
前記白血球を取り除く工程において、又はその後に、細胞懸濁液を哺乳動物の血清或いは血漿を含む水溶液で希釈する工程を有し、
前記哺乳動物の血清或いは血漿が、ウシ胎児由来であることを特徴とする血中循環癌細胞捕獲方法。 - 血中循環癌細胞を血液中から取り出す血中循環癌細胞捕獲方法であって、前記血中循環癌細胞と白血球とを分離するためのフィルターによる血液フィルトレーションの前に、磁気ビーズを用いて前記血液から白血球を取り除く工程を有し、
前記白血球を取り除く工程において、又はその後に、細胞懸濁液を哺乳動物の血清或いは血漿を含む水溶液で希釈する工程を有し、
前記哺乳動物の血清或いは血漿の水溶液濃度が1%〜50%の範囲であることを特徴とする血中循環癌細胞捕獲方法。 - 血中循環癌細胞を血液中から取り出す血中循環癌細胞捕獲方法であって、前記血中循環癌細胞と白血球とを分離するためのフィルターによる血液フィルトレーションの前に、磁気ビーズを用いて前記血液から白血球を取り除く工程を有し、
前記白血球を取り除く工程において、又はその後に、細胞懸濁液を哺乳動物の血清或いは血漿を含む水溶液で希釈する工程を有し、
前記血清或いは血漿の水溶液がリン酸緩衝液を主成分とすることを特徴とする血中循環癌細胞捕獲方法。 - 血中循環癌細胞を血液中から取り出す血中循環癌細胞捕獲方法であって、前記血中循環癌細胞と白血球とを分離するためのフィルターによる血液フィルトレーションの前に、磁気ビーズを用いて前記血液から白血球を取り除く工程を有し、
前記白血球を取り除く工程において、又はその後に、細胞懸濁液を哺乳動物の血清或いは血漿を含む水溶液で希釈する工程を有し、
前記血清或いは血漿の水溶液が抗凝固剤を含むことを特徴とする血中循環癌細胞捕獲方法。 - 前記抗凝固剤がEDTA、ヘパリン、クエン酸ナトリウム、フッ化ナトリウムのいずれかであることを特徴とする請求項5に記載の血中循環癌細胞捕獲方法。
- 血中循環癌細胞を血液中から取り出す血中循環癌細胞捕獲方法であって、前記血中循環癌細胞と白血球とを分離するためのフィルターによる血液フィルトレーションの前に、磁気ビーズを用いて前記血液から白血球を取り除く工程を有し、
前記血液フィルトレーションの前に哺乳動物の血清或いは血漿を含む水溶液にフィルターを浸漬する工程を含むことを特徴とする血中循環癌細胞捕獲方法。 - 血中循環癌細胞を血液中から取り出す血中循環癌細胞捕獲方法であって、前記血中循環癌細胞と白血球とを分離するためのフィルターによる血液フィルトレーションの前に、磁気ビーズを用いて前記血液から白血球を取り除く工程を有し、
前記血液フィルトレーションの後に哺乳動物の血清或いは血漿を含む水溶液で血球細胞を洗浄する工程を含むことを特徴とする血中循環癌細胞捕獲方法。 - 前記哺乳動物の血清或いは血漿が、ウシ、ウマ、ヒト由来であることを特徴とする請求項7又は8に記載の血中循環癌細胞捕獲方法。
- 前記哺乳動物の血清がウシ胎児血清或いは血漿であることを特徴とする請求項7又は8に記載の血中循環癌細胞捕獲方法。
- 前記白血球を取り除く工程が白血球を磁性ビーズにより取り除く工程であることを特徴とする請求項1〜10のいずれか一項に記載の血中循環癌細胞捕獲方法。
- 前記白血球を取り除く工程の後であって前記血液フィルトレーションの前の前記血液の白血球数が50個以下であることを特徴とする請求項1〜11のいずれか一項に記載の血中循環癌細胞捕獲方法。
- 前記フィルターの表面が金又は白金又はパラジウム、或いはそれらの合金であることを特徴とする請求項1〜12のいずれか一項に記載の血中循環癌細胞捕獲方法。
- 前記フィルターがニッケルを主成分とし、その表面に金又は白金又はパラジウム、或いはそれらの合金がめっきされていることを特徴とする請求項13に記載の血中循環癌細胞捕獲方法。
- 前記フィルターが銅を主成分とし、その表面に金又は白金又はパラジウム、或いはそれらの合金がめっきされていることを特徴とする請求項13に記載の血中循環癌細胞捕獲方法。
- 前記フィルターがパラジウムを主成分とし、その表面に金又は白金、或いはそれらの合金がめっきされていることを特徴とする請求項13に記載の血中循環癌細胞捕獲方法。
- 前記フィルターの最外層が金めっきであることを特徴とする請求項14〜16のいずれか一項に記載の血中循環癌細胞捕獲方法。
- 前記フィルターの最外層が0.05μm〜1μmの貴金属めっきあることを特徴とする請求項14〜16のいずれか一項に記載の血中循環癌細胞捕獲方法。
- 前記フィルターの貫通孔の開口形状が円、楕円、角丸長方形、長方形、正方形のいずれかである請求項1〜18のいずれか一項に記載の血中循環癌細胞捕獲方法。
- 前記フィルターの貫通孔の開口形状が長方形及び角丸長方形のいずれか一つ以上の形状を含み、その短辺の長さが5μm〜15μmであることを特徴とする請求項1〜19のいずれか一項に記載の血中循環癌細胞捕獲方法。
- 前記フィルターの膜厚が3μm〜50μmであることを特徴とする請求項1〜20のいずれか一項に記載の血中循環癌細胞捕獲方法。
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