JP7055906B2 - 細胞膜透過性を増加させるための交流電界の使用 - Google Patents
細胞膜透過性を増加させるための交流電界の使用 Download PDFInfo
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Description
本出願は、米国特許仮出願第62/693,811号(2018年7月3日に出願される)、第62/728,255号(2018年9月7日に出願される)及び第62/795,136号(2019年1月22日に出願される)の権益を主張し、それぞれは参照により本明細書に完全に組み込まれる。
TTフィールドの誘導は、ルシフェラーゼを発現する神経膠芽腫における生物発光(BLI)を増加させる。
U87-MG/eGFP-fLuc細胞をThermanoxカバーガラスの上に播種し、沈殿及び増殖させ、その後TTフィールド下又は無TTフィールド下に置いた。この実験では、TTフィールド(4V/cm、200kHz、0.5~24時間)の使用は、非曝露条件と比較してU87-MG/eGFP-fLuc細胞の生物発光強度(BLI)を有意に増加させた。BLIのこの増加は、TTフィールドの開始の30分後という早い時期に起こり、24時間のTTフィールド曝露まで継続した。ROI定量化を実行したとき、TTフィールド曝露試料のBLI強度の時間経過は、TTフィールド非曝露試料と比較して有意に上昇した(p<0.0001、二元配置ANOVA、TTフィールド対無TTフィールド)。これらの実験のBLI結果の時間的定量化を表すデータを、図2Aに要約する。この理論によって縛られるとは限らないが、生物発光の上昇はホタルルシフェラーゼ活性に対するTTフィールドの直接効果によるものではなかったと考えられ、その理由は、200kHzのTTフィールドへの精製ホタルルシフェラーゼの曝露がTTフィールドの開始の60分後に酵素活性の1000倍を超える減少につながったからである。
TTフィールドの賦課が細胞膜特性に、したがって膜透過性に影響を及ぼすかどうか試験するために、細胞膜に結合する蛍光タグ付きの試薬の挙動に対するTTフィールドの効果を判定した。最初に、アネキシン-V-APCのU87-MG/eGFP-fLuc細胞の膜への結合に及ぼすTTフィールドの影響を測定した。アネキシン-V-APCの結合は、膜の波打ち運動によって特徴付けられる初期アポトーシスのサインである。U87-MG/eGFP-fLuc細胞へのアネキシン-V-APC結合の可視性を調査するために、アポトーシスのための陽性対照(U87-MG/eGFP-fLuc細胞への21μM Withaferin Aの添加)を使用し、そのような結合はTTフィールド非曝露試料での蛍光顕微鏡検査法を通して可視化できることを示した。しかし、TTフィールドをU87-MG/eGFP-fLuc細胞に印加されたとき、アネキシン-V-APC結合はTTフィールドへの曝露のいかなる時点でも観察されなかった。したがって、TTフィールドはU87-MG細胞においていかなる有意な程度のアポトーシスも誘導しなかったようである。
神経膠芽腫細胞における5-ALAの取り込みに対するTTフィールドの効果(PpIX蓄積及びその結果として生じた蛍光によって測定した)を判定するために、実験を実行した。本5-ALAバイオアッセイを使用して腫瘍と正常細胞の間の限界を識別することが困難であるので、この問題に対処するためにPpIX蛍光の測定を使用した。細胞膜を通した、及び神経膠芽腫細胞への5-ALAの透過をTTフィールド曝露によって増加させることができるか判定するために、調査を実行した。U87-MG細胞を各々6~24時間TTフィールドに曝露させたか曝露させなかった。図4Aに要約される結果は、以下の通りだった:TTフィールド曝露は、6時間のTTフィールド曝露という早い時期に5-ALAのU87-MG/eGFP-fLuc細胞への取り込みの有意な増加をもたらし(p=0.047、スチューデントのt検定、TTフィールド対無TTフィールド)、この増加は、24時間の長期TTフィールド曝露によって維持された(p=0.011)。
患者における神経膠芽腫切除の間、神経外科医が腫瘍と周囲の正常な脳組織の間を正確に示すのを助けるために、5-ALAが使用される。同様に、神経膠芽腫と正常細胞の間の5-ALA取り込みの差を識別するために、U87-MG細胞をPCS -201線維芽細胞の床の中央に播種し、TTフィールドに曝露させるか又はTTフィールドに曝露させない共培養を開発した。共培養セットアップにおいて、蛍光及び明視野顕微鏡写真は、個別の神経膠芽腫対線維芽細胞領域の存在を確認した。共培養をヘマトキシリン-エオジン(H&E)で染色したとき、顕微鏡写真は、TTフィールド曝露試料について線維芽細胞周辺に浸潤するGBM細胞の数の低減を明らかにした。
TTフィールドに3日間曝露させなかったかTTフィールドに曝露させた低密度(5,000細胞/カバーグラス)U87-MG/eGFP-fLuc細胞のSEM画像を、2000×、20,000×及び60,000×の倍率で得た。これらのSEM像を精査することによって得られたデータを、図5に要約する。TTフィールド非曝露細胞(23.9±11.0)と比較してTTフィールド曝露細胞(53.5±19.1)のROIの中に、サイズが51.8nm2(60,000×倍率で9ピクセル2と同等)より大きな孔の有意に増加した数があった(p=0.0002、一変量マン-ホイットニー検定法)。TTフィールド非曝露細胞(129.8±31.9nm2)と比較してTTフィールド曝露細胞(240.6±91.7nm2)において、ROIの中の孔の平均サイズも有意により大きかった(p=0.0005(一変量マン-ホイットニー検定法))。図5に表すデータ得るために、500nm半径の目的の円形領域の範囲内で、TTフィールド非曝露及び曝露細胞の間の、孔の数及びサイズの定量化及び比較を行った。最小の孔サイズカットオフは、20kDa及び50kDaデキストラン-FITCのそれぞれ3.3及び5.0nmストークス半径に基づいた。各条件につき3件の実験からのカバーグラスを使用し、各カバーグラスにつき少なくとも5細胞を、二重盲検方式で孔の数及びサイズについて分析した。
がん細胞に対するTTフィールドの効果の可逆性を調査するために、U87-MG/eGFP-fLuc細胞を3つの条件に付した:(1)無TTフィールド曝露、標準の細胞培養条件(37℃、95%O2、5%CO2)、(2) 24時間のTTフィールド曝露及び(3) 24時間のTTフィールド曝露、及び続く24時間の無TTフィールド曝露。BLI、PpIX蛍光(5-ALA生成物)及びデキストラン-FITC(4kDa)蛍光の読み出しを取得した。全ての実験条件は、3反復で実行した。図7Aは、BLIのデータを要約する:24時間のTTフィールド(中間バー)の存在は、無TTフィールド曝露(左のバー)と比較してBLIフラックスを有意に増加させた(p<0.0005、二元配置ANOVA、TTフィールド対無TTフィールド)が、この増加は、細胞を無TTフィールド条件に24時間再導入したとき(右のバー)、有意に減弱された(二元配置ANOVA、p<0.005、24時間のTTフィールド対24時間のTTフィールドと続く24時間の無TTフィールド)。図7Bは、可逆的読み出しの類似パターンがPpIX蛍光で起こったことを示す(p<0.0005、二元配置ANOVA、TTフィールド(中間バー)対無TTフィールド(左のバー)、及びp<0.0004、TTフィールド対TTフィールドと続く無TTフィールド(右のバー))。図7Cは、可逆的読み出しの類似パターンが4kDaデキストラン-FITC蛍光で起こったことを示す(p<0.05、二元配置ANOVA、TTフィールド(中間バー)対無TTフィールド(左のバー);及びp<0.05、TTフィールド対TTフィールドと続く無TTフィールド(右のバー))。各実験セットで、eGFP蛍光は有意に変化しなかった。SEM調査は、孔数(p=0.007、二元配置ANOVA、TTフィールド対無TTフィールド)及び孔のサイズ(p=0.0007、二元配置ANOVA、TTフィールド対無TTフィールド)の両方におけるTTフィールドによる有意な増加も、24時間の曝露無しの後に可逆的であることを明らかにした。ここで、NS=非有意;BLI=生物発光画像化;eGFP=増強された緑色蛍光タンパク質;fLuc=ホタルルシフェラーゼ;5-ALA=5アミノレブリン酸;FITC=フルオレセインイソチオシアネート;PpIX=プロトポルフィリンIX;及びFL=蛍光。
本明細書に記載される方法は、神経膠芽腫の場面に限定されない。反対に、それらは、他のタイプのがん細胞に適用可能である。より具体的には、(a) ある時間期間の間、交流電界を細胞に印加する工程であって、交流電界の印加は細胞膜の透過性を増加させる工程;及び(b)物質を細胞の付近に導入する工程によって、細胞の細胞膜を越えて物質を送達することができる。細胞膜の透過性の増加は、物質が細胞膜を通過することを可能にする。注目すべきことに、本明細書に記載される方法は、他のタイプのがん細胞(例えば、MDA-MB-435及びMCF-7細胞)を限定されずに含む、異なるタイプの細胞(すなわち、神経膠芽腫以外の細胞)の細胞膜を通して(通常、関連する細胞膜を通過しないだろう)大きな分子を送達するために使用することができる。
以前の研究は、核(例えば、微小管)、セプチン、ミトコンドリア及び自己貪食に対するTTフィールドの効果に重点を置いた。しかし、本明細書に記載される実験は、がん細胞膜の完全性に対するTTフィールドの効果を報告する最初であると考えられ、様々な評価技術(例えば、生物発光画像化、蛍光画像化及び走査電子顕微鏡法)を使用して、TTフィールドの存在下でがん細胞(例えば、複数のヒトGBM細胞系)のための増加した細胞膜透過性を実証する。
より具体的には、図11Aは、U-87 MG細胞に最高レベルの細胞傷害性を提供する周波数を判定するための第1の実験の結果を表し;図11Bは、U-87 MG細胞の細胞膜の透過性の最大の増加を提供する周波数を判定するための第2の実験の結果を表す。
細胞培養研究:2名の患者由来のGBM系(GBM2、GBM39)、市販のヒトGBM細胞系(ATCC、Manassas、VA、USAからのU87-MG)、並びにマウス星状細胞腫細胞系(KR158B;University of Florida School of MedicineのDepartment of NeurosurgeryのDuane Mitchell博士からの寄贈)を使用した。ヒトU87-MG、ヒトPCS-201及びマウスKR158B神経膠芽腫細胞系は、DMEM(Invitrogen/Life Technologies、Carlsbad、CA、USA)/10% FBS/及び1×抗生物質-抗真菌剤(Invitrogen/Life Technologies、Carlsbad、CA)で増殖させた。GBM2及びGBM39は、その組成物は以前に記載されている、規定の無血清培地で増殖させた。
42 コントローラー
44 AC電圧ジェネレーター
Claims (1)
- 対象の体内の腫瘍を処置し、対象の体内の細胞膜を越えた物質の送達を促進するための装置であって、
50~500kHzの細胞透過性を誘導するための第1の周波数及び50~500kHzの細胞傷害性を誘導するための第2の周波数で作動できるAC電圧ジェネレーター(44)であって、前記第2の周波数は前記第1の周波数と異なり、前記AC電圧ジェネレーター(44)は制御入力を有し、制御入力が第1の状態にあるとき前記第1の周波数を出力し、制御入力が第2の状態にあるとき前記第2の周波数を出力するように構成される前記AC電圧ジェネレーター(44);及び
(a) 前記AC電圧ジェネレーター(44)が前記第2の周波数を出力するように制御入力を前記第2の状態に置き、(b) 前記AC電圧ジェネレーター(44)を前記第1の周波数を出力するように切り替える要求を受け取り、(c)要求を受け取り次第、前記AC電圧ジェネレーター(44)がある時間区間の間、前記第1の周波数を出力するように、制御入力を前記第1の状態に置き、及び(d)前記時間区間が経過した後、前記AC電圧ジェネレーター(44)が前記第2の周波数を出力するように、制御入力を前記第2の状態に置くようにプログラムされた、コントローラー(42)、を含み、前記時間区間が12~72時間である、装置。
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