JP2016517506A - 線虫類におけるアッセイのための化合物‐担体システム - Google Patents
線虫類におけるアッセイのための化合物‐担体システム Download PDFInfo
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Abstract
Description
本発明は、線虫、本質的にしかし非限定的に線虫シノラブディス・エレガンス(C. elegans)による化合物の吸収を増大する方法に関する。特に、本発明は、前記虫による複合体「化合物‐担体システム」の摂取を促進させることを特徴とする、特異的な分子タグを発現するポリマーおよび/または脂質の送達システムの設計に関する。
シノラブディス・エレガンス(Caenorhabditis elegans;C. elegans)は、土壌環境に天然に存在する自由生活性の線虫である。これは、約3日で、胚から4つの幼虫期であるL1からL4を経て、長さ約1 mmおよび直径80 μmの成体に迅速に成長する。成体は、99.5%雌雄同体であり、たまに発育障害により雄個体が生じる。それぞれの自家受精した雌雄同体は、同時に300個の幼虫を産生することができる。成熟した個体は、上皮、筋肉、神経、小腸、有性生殖系を含めた大部分の主な組織を有する一定数の体細胞(成体の雌雄同体で959個、成体の雄性で1031個)を含む。注目すべきことに、シノラブディス・エレガンスのゲノムの全長配列解析により、線虫遺伝子の60〜80%がヒト対応物を有しており、大部分の主な生化学的経路が、ヒトとシノラブディス・エレガンスとの間で保存されていることが明らかになった。特に、線虫における生体異物解毒および酸化的ストレス応答に関与する経路は、哺乳類系のものと極めて類似している(Voorhies 2002; Lindblom and Dodd 2006)。虫ミトコンドリアおよびそれらのヒト対応物の間の構造および生体エネルギー学の高い保存性も報告されている(Tsang and Lemire 2003)。
本明細書において用いられる「タグ」(またはタグ物質)との用語は、線虫による担体の吸収を促進する分子的実体のことをいう。好ましくは、タグは、線虫に対して化学誘引性である。
上記した担体システムが診断および治療への応用において見せる長所を超えて、これらが、その表面に、線虫に対して化学誘引性の物質を提示し、それにより、細菌粒子と一定の類似性を共有するということを強調しなければならない。
本明細書に言及された大部分の担体について、細菌サイズの範囲は、球状の種については、0.5〜5 μm、桿状の細菌では、直径が0.2〜2 μmおよび長さが1〜10 μmの範囲である。直径において、最小の種は、100〜500 nmの範囲であるのに対して、最大の種は、500 μmに至る。さらには、細菌は、タンパク質および多糖類を含む多様な他の分子が埋め込まれているリン脂質二重層からほぼ排他的になる細胞膜で取り囲まれている。
上述したように、担体は、細菌よりも栄養価が低いので、経験上、線虫は、それを拒否し、より良質の細菌を好む可能性がある。
本発明は、さらに、上記した担体システムと虫に適した栄養素とを含有する線虫用の栄養組成物に関する。このような栄養素は、当技術分野において公知であり、特にStiernagleの文献(2006)に記載されている。特に、栄養組成物は、ステロールを含有する。
本発明の担体システムは、捕捉された関心対象の化合物の線虫による吸収を促進するのに特に有用である。これは、虫における前記関心対象の化合物の代謝を決定するいくつかのアッセイを設計可能にする。
シノラブディス・エレガンスなどの代替的なインビボモデルにおいて、生体異物の毒性評価および測定の一つの主な論題は、その毒性と直接比例する虫により吸収される化合物量の定量である。カプセル化した化合物の量が、全て線虫の臓器に到達するものではない。実際、化合物の一部の量が、シノラブディス・エレガンス培養培地への拡散により消失し、または虫の消化管などにおいて分解および/または除去される。
Northern Lipids Inc (Vancouver, BC, Canada)から水素添加大豆ホスファチジルコリン(HSPC)、1,2-ジステアロイル-sn-グリセロ-3-ホスホエタノールアミン-N-[PEG (2000)]結合体(DSPE-PEG)、およびDSPE-PEG(2000)アミン(DSPE-PEG-NH2)を入手した。Sigma (St Louis, MO)からコレステロールを入手した。
−虫の環境に存在するものの50%を超える濃度までシノラブディス・エレガンス内に容易に蓄積されることが知られたもの、および
−虫の防御を回避できず、該動物に全く浸透しないもの。
リポソームは、それぞれ65:30:5のモル比の、HSPC、コレステロール、およびDSPE-PEG-NH2から構成された。
タグ付リポソームの調製のために、AHL誘導体をリポソームのPEG鎖の遠位末端にカップリングさせた。このリガンドのカップリングを可能にするため、リポソーム製剤における一部(2 mol%)のDSPE-PEGをDSPE-PEG-NH2官能脂質に置き換えた。カップリング反応に用いたリポソーム分散液の総脂質濃度は、100 mMであった。AHLをpH 6.5の50 mM HEPES緩衝液に、2.7 μmol/mLの濃度(0.1 mL)で溶解し、PEG鎖の遠位末端にNH2官能基を有するリポソーム(4 mL)と、pH 6.5および1:30 (AHL)のモル比で室温(25℃)にて12時間反応させた。カップリング反応の略図を図3に示す。
リポソーム表面へのAHLの付着は、HPLCを用いて非カップリングAHL画分を判定することによって間接的に確認された。
リポソーム製剤中の全薬物および遊離薬物「x」は、HPLC分析を用いて判定された。
大型MLVは、押出しプロセスの前に、光学顕微鏡(Olympus, CKX41, Tokyo, Japan)を用いて可視化した。最終のリポソームを逆染色法により電子顕微鏡の下で可視化した。希釈したリポソームサンプルを、フォルムバールコーティングおよび炭素コーティング銅グリッド上に吸着させ、2%酢酸ウラニル(pH 7.0)で染色し、JEM1200EX電子顕微鏡(JEOL, Tokyo, Japan)により倍率50 000倍で観察した。リポソームのサイズおよびサイズ分布プロファイルを、Malvern Zetasizer (Nano ZS, Malvern Instruments, Worcestershire, UK)を用いて動的光散乱法によりモニタリングした。
コンブレタスタチンA4のリポソーム封入安定性を、37℃で維持された700体積の逆浸透水に対してサンプルを48時間透析することにより、インビトロでモニタリングした。
虫培養(Culture worms)は、確立されたプロトコル[Lewis and Fleming, 1995; Stiernagle, 1999]にしたがって行われた。HTS実験はBurnsら[2010 and 2006]にしたがって行われた。NA22大腸菌にて45時間25℃で同期化されたふ化個体から成長させた後期第4幼虫期の虫を、蓄積アッセイに用いた。虫を回収し、少なくとも2回洗浄し、1 μlあたり虫およそ10匹の終濃度を得るために充分なM9緩衝液1に再懸濁した。この虫懸濁液500マイクロリットルをPall AcropPrep 96ウェルフィルタープレート(0.45 μmのGHP膜, 1 mlのウェル容量)の各ウェルに加えた。
シノラブディス・エレガンスは、ヒト薬物のスクリーニング、薬物標的の特定および検証、薬物の作用機序、ヒット医薬およびリード医薬ならびに生態毒性および環境毒性のための生体異物のADMEパラメータ (吸着、分布、代謝および排泄/排出)および毒性パラメータのスクリーニング、化粧品学、アポトーシス、炎症、酸化的ストレス、呼吸、細胞エネルギーなどの主要な細胞シグナル伝達経路の研究、化学物質および細菌毒素による水(血液透析、飲用水、非経口投与用)の汚染の管理など、広範囲の用途に向けた多目的のインビボ・プラットフォームである[Jones et al, 2005; Artal-Sanz, 2006]。
表1は、虫において測定されうる毒性エンドポイントを要約している。これらのエンドポイントは、製薬業界または化粧品学のいずれか、例えばそれぞれそのリード治療用化合物およびリード化粧用化合物に関係する。
代謝産物を虫溶解物からHPLC精製し、Savant DNA120 SpeedVacを用いて乾燥させた(酸はHPLC溶媒に加えられなかった)。
シノラブディス・エレガンスのいくつかの野生型(WT)株が利用可能であり(詳細にはhttps://www.cbs.umn.edu/cgc/strains (College of Biological Sciences, University of Minnesotaを参照のこと)、最も一般的にはN2株である。
Claims (15)
- 関心対象の化合物を含有できる小胞を含む、線虫による関心対象の化合物の取り込みを誘導する担体システムであって、該小胞が、その表面上に該線虫に対して化学誘引性であるタグ物質を提示する、担体システム。
- タグ物質が前記小胞の表面に共有結合で連結されている、請求項1記載の担体システム。
- タグ物質が、細菌オートインデューサー、特にAI-2またはアシル化ホモセリンラクトンからなる群より選択される、請求項1記載のシステム。
- タグ物質が、細菌オートインデューサーに対する受容体、特にAI-2またはアシル化ホモセリンラクトンに対する受容体からなる群より選択される、請求項1記載のシステム。
- タグ物質が、アミノ酸、ヌクレオチドおよびビタミンからなる群より選択される、請求項1記載のシステム。
- タグ物質が、リンカー物質によって担体システムに連結された細菌全体である、請求項1記載のシステム。
- リンカー物質がマルトースベースの多糖類を含み、該マルトースベースの多糖類が、線状ポリマー、環状ポリマー、分岐状ポリマーおよびこれらの混合物からなる群において選択される共有結合で連結されたマルトースの繰返し単位のポリマーである、請求項6記載のシステム。
- リンカー物質が、2000 g/mol以下の分子量を有するマルトデキストリンまたはマルトデキストリン類似体である、請求項7記載のシステム。
- 前記小胞にカプセル化された蛍光マーカーをさらに含む、請求項1〜8のいずれか一項記載のシステム。
- 請求項1〜9のいずれか一項記載の担体システムを含む、線虫用の栄養組成物。
- タグ物質がビオチンである、およびビオチンと少なくとも2つのビオチン結合部位を含むビオチン結合タンパク質とをさらに含む、請求項10記載の栄養組成物。
- 線虫による関心対象の化合物の取り込みを促進させるための請求項1〜9のいずれか一項記載の担体システムの使用。
- 請求項1〜9のいずれか一項記載の担体システムを得るなどのために関心対象の化合物を小胞中に捕捉する段階、前記担体を含む栄養組成物を線虫に供給する段階、および取り込み後に線虫における関心対象の化合物の生理学的特性を評価する段階を含む、関心対象の化合物の生理学的特性を評価するための方法。
- 担体システムが、前記小胞にカプセル化された蛍光マーカーをさらに含む、請求項13記載の方法であって、一緒に吸収された蛍光マーカーの蛍光強度を測定し、それによって吸収された関心対象の化合物の定量化を可能にする、方法。
- 変異/多型が存在する線虫に、関心対象の化合物を含有する請求項1〜9のいずれか一項記載の担体システムを供給する段階、ならびに前記関心対象の化合物の取り込みおよび分解を、前記変異/多型が存在しない線虫に供給された前記関心対象の化合物の取り込みおよび分解と比較する段階を含む、遺伝子における変異/多型の影響を評価/決定するための方法。
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