JP5571031B2 - 細菌由来のインタクトなミニ細胞を介した哺乳動物細胞への標的化invitro及びinvivo薬物送達のための組成物及び方法 - Google Patents
細菌由来のインタクトなミニ細胞を介した哺乳動物細胞への標的化invitro及びinvivo薬物送達のための組成物及び方法 Download PDFInfo
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Description
現在のところ、癌を治療するのに使用されている多くの薬物は全身投与される。細胞傷害性抗癌剤の全身的な送達は癌治療において重要な役割を担っているが、そのような送達は重大な問題をも引き起こす。例えば、正常な組織/器官が投与された薬物に全身暴露されると、重い毒性が生じ得る(Sarosy及びReed、1993)。この毒性は、全身的に送達された癌化学療法剤が、しばしば、薬物の生物利用性の悪さを克服するため非常に多い投与量で送達されるという事実、並びに、患者の体内での大量分布により一層悪化する。また、全身薬物投与は、しばしば主要血管に安全なカテーテルを使用することが必要となるため、このような投与は侵襲性であり得る。全身薬物投与はしばしば末梢又は中枢のいずれかの静脈の使用を必要とするので、静脈炎などの局所合併症を引き起こし得る。また薬物の管外遊出は、ビンカアルカロイド及びアントラサイクリンの投与に一般にみられるような、投与の局部に発疱/組織損傷を起こし得る。
上記及び他のニーズを取り扱う本発明は、1つの態様において、癌化学治療剤などの薬物を含むインタクトなミニ細胞を本質的に含んでなる組成物を提供する。関連した態様において、本発明は、(i) 薬物を含む、細菌由来のインタクトなミニ細胞及び(ii)製薬上許容できる担体を含む組成物を提供する。
本発明者らは、細菌由来のインタクトなミニ細胞が、in vitro及びin vivoで哺乳動物細胞にターゲティングするための、薬物をパッケージングして送達するのに有効なビヒクルであることを見出した。より具体的には、本発明者らは、標的細胞がミニ細胞をインターナライズし該ミニ細胞を処理して標的細胞の細胞質に薬物ペイロードを放出する、そのような標的細胞に、該薬物ペイロードを保有するミニ細胞が指向することを見出した。驚くべきことに、薬物は分解されずにこの処理に対し生き残る。
ステップA: 細菌性細胞培養物を製造するミニ細胞の分画遠心。このステップは、約20分間2000gで行うことができ、ほとんどの細菌性親細胞を除去する一方、上清にミニ細胞を残す。
本実施例は、親水性薬物を細菌由来のインタクトなミニ細胞の細胞質にパッケージできることを示す。
この実施例は、疎水性薬物を細菌由来のインタクトなミニ細胞の細胞質にパッケージできることを示す。ミニ細胞の表面膜はリン脂質二重層から構成されているので、疎水性の高い薬物がこのバリアを通って拡散するとは予想されないだろう。
本実施例は細菌由来のインタクトなミニ細胞の薬物濃度を測定する方法を示す。より具体的には、本実施例はミニ細胞DOXに存在するドキソルビシンの濃度を測定する方法を説明し、搭載溶液におけるドキソルビシン濃度の効果を示す。薬物を搭載したミニ細胞を治療を目的として適用するには、パッケージされた薬物の量を測定することを含む、パッケージされた薬物の実体を特徴づけできることが求められる。しかしながら以前には、細菌由来のインタクトなミニ細胞または細菌性細胞を効率的に破壊し、パッケージされた薬物分子を抽出する方法はなかった。
本実施例は、ミニ細胞に薬物をパッケージすること及び薬物をパッケージしたミニ細胞の表面にリガンドが結合することによって、ミニ細胞が不安定になったり、薬物が漏出したり、又はミニ細胞膜に埋め込まれている構造物の損失を起こさないことを示す。その結果は驚くべきものであり、細胞質にある薬物、特に非常に有害な化学治療剤はミニ細胞の二重層膜を不安定にすると予想されていたからである。
本実施例は、細胞表面と結合した二重特異性リガンドを有するインタクトなミニ細胞にパッケージされた化学療法剤のドキソルビシンが、(a)標的非食作用性哺乳動物の細胞表面、即ちヒト脳腫瘍細胞にあるEGFレセプターと特異的に結合できること、及び(b)ドキソルビシンをパッケージしたミニ細胞のエンドサイトーシスと破壊の後、哺乳動物細胞内に薬物が細胞内送達できることを示す。
本実施例は、非食作用性哺乳動物細胞へのミニ細胞仲介薬物送達の効率を示す。比色分析細胞毒性アッセイ((Promega; CellTiter 96 Aqueous OneTM)を使用した。MDA−MB−468ヒト乳腺癌細胞をEGFRミニ細胞DOXまたは遊離ドキソルビシン及び非標的化ミニ細胞DOXを含む対照で処理した。MDA−MB 468細胞をT75フラスコに5×106個播種して、48時間インキュベーションし、約1×107個の細胞/フラスコを得た。培地を変えて、細胞を109個の非標的ミニ細胞DOX又はEGFRミニ細胞DOXで処理した。遊離ドキソルビシン(50ng/ml)も陽性対照として含めた。細胞を24時間インキュベーションし、PBSを3回交換して完全に洗浄し、トリプシン処理を行った。生存細胞をトリパンブルー排除法を用いて血球計数器でカウントした。1ウエルあたり1×104個の細胞/mlを24ウエルプレートにアリコートし(1処理あたり6ウエル)、3、4、5及び6日間、毎日培地を交換してインキュベーションした。MTSアッセイを製造者の指示書に従って、各時点で行った。簡単に言えば、MTS試薬100μlを各ウエルに加えて色の変化を2.5時間〜4時間にわたってモニターした。各ウエルから100μlを96ウエルプレートに移し、吸光度を490nmで測定した。
本実施例は、二重特異性リガンド標的化し、ドキソルビシンをパッケージしたインタクトなミニ細胞が、6週齢のメス無胸腺ヌードマウスに定着させたヒト乳癌細胞種移植片の縮退を起こすことを示す。
本実施例は、標的化され薬物をパッケージしたミニ細胞を介してヌードマウスにおけるヒト乳癌異種移植片への、疎水性化学療法剤のパクリタキセルの高効率な送達を示す。実施例7に示した実験を実験的治療としてEGFRミニ細胞パクリタキセルを用いて繰り返した。治療は、(i)G1−腫瘍のみ、(ii)G2−遊離パクリタキセル(400μg)を腫瘍内に与えた、(iii)G3−遊離パクリタキセル(400μg)を静脈内に与えた、(iv)G4−抗-O抗原/抗-EGFR BsAb及び遊離パクリタキセル(400μg)を静脈内に与えた、(v)G5−非標的化ミニ細胞Pacを静脈内に与えた、(vi)G6−非標的化ミニ細胞Pacを腫瘍内に与えた、(vii)G7−EGFRミニ細胞Pacを静脈内に与えた、(viii)G8−EGFRミニ細胞Pacを腫瘍内に与えた。様々な治療を15、21、26、29及び33日目に行った。1×108個のミニ細胞を各ミニ細胞治療で使用した。
本実施例は、以下:(i)標的化され、薬物をパッケージされたミニ細胞ベクターがある範囲の異なる非食作用性細胞において治療効果を達成する十分な多用途性があり、(ii)ターゲティングのメカニズムが、EGFレセプターに限定されず、病的細胞に存在する異なる細胞表面レセプターターゲットを使用することができる十分な多用途性があり、及び(iii)ミニ細胞ベクター自身が異なる細菌属由来のミニ細胞を使用できる十分な多用途性があること、を証明する。
本実施例は、薬物をパッケージしたミニ細胞について用量-効果の関係を示す。より具体的には、本実施例は、ヌードマウスにおけるヒト腫瘍異種移植片に対する最大の治療効果を達成するために必要とされる、標的化された薬物をパッケージしたミニ細胞の用量を示す。
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Claims (3)
- ミニ細胞を含む細胞外媒体とミニ細胞の細胞質との間にペプチド又はタンパク質の濃度勾配を作り、これによって、前記ペプチド又はタンパク質が前記濃度勾配に沿って前記ミニ細胞の細胞質に移動するステップを含む、細菌由来のインタクトなミニ細胞にペプチド又はタンパク質を搭載する方法。
- 前記ペプチド又はタンパク質を、治療有効量まで前記ミニ細胞に搭載する、請求項1に記載の方法。
- インタクトなミニ細胞に治療有効量のペプチド又はタンパク質を搭載する、請求項1又は2に記載の方法によって得ることができる細菌由来のインタクトなミニ細胞を含む組成物。
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