JP2014517913A - 酵素活性のインビボでの画像化 - Google Patents
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- A—HUMAN NECESSITIES
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
Description
本願は、2011年4月13日に出願された米国仮出願第61/517,090号の利益を主張する。米国仮出願第61/517,090号の開示は、その全体が本明細書に参考として援用される。
本開示は、生きている生物における酵素活性の評価において使用するための試薬の分野にある。特に、インビボでの酸化的ストレスに関連する酵素活性をモニターするための組成物および方法が本明細書に記載される。
生きている生物から酵素活性の指標となる光を検出することは、疾患経路の同定、作用機構の決定、薬物化合物の効力評価、および生きた動物における疾患進行に対するリード候補の影響をモニターすることを可能にする、診断、創薬および医療における強力なツールである。例えば、ミエロペルオキシダーゼ活性の画像化は、酸化的ストレスをモニターすることについて記載されてきた。例えば、非特許文献1;非特許文献2;および特許文献1を参照のこと。これら方法は、ストレスを受けた組織中に好中球および単球/マクロファージが浸潤することによって炎症プロセスの間に産生される侵襲性の反応性酸素種を検出するために、外から供給されたルミノールを使用する。
本発明は、酵素活性をモニターする化学発光性酵素反応を、近赤外(NIR)ナノ粒子に組み合わせ、それによって、化学発光性プローブ単独と比較して、上記酵素活性の検出の増強を提供することによって生きている生物(例えば、動物)における酵素活性をモニターするための組成物および方法を包含する。
本発明の実施は、別段示されなければ、当該分野の技術範囲内である、化学、生化学、および組換えDNA技術の従来法を使用する。このような技術は、文献中で十分に説明されている。例えば、A.L. Lehninger, Biochemistry(Worth Publishers, Inc., current addition);Sambrook, et al., Molecular Cloning:A Laboratory Manual(2nd Edition, 1989);Short Protocols in Molecular Biology, 4th ed.(Ausubel et al. eds., 1999, John Wiley & Sons);Molecular Biology Techniques: An Intensive Laboratory Course,(Ream et al., eds., 1998, Academic Press);PCR(Introduction to Biotechniques Series),2nd ed.(Newton & Graham eds., 1997, Springer Verlag);およびMethods In Enzymology(S. Colowick and N. Kaplan eds., Academic Press, Inc.)を参照のこと。
本発明を記載するにあたって、以下の用語が使用され、以下に示されるように定義されることが意図される。
上記組成物および方法を詳細に記載する前に、本開示は、特定の製剤にもプロセスパラメーターにも限定されず、よって、当然のことながら変動し得ることが理解されるべきである。本明細書で使用される用語法は、特定の実施形態を記載する目的のために過ぎず、限定することを意図していないこともまた、理解されるべきである。
本明細書に記載される組成物は、化学発光性プローブ(例えば、ルミノール)およびNIRナノ粒子の両方を含む。
本明細書で記載されるとおりにNACで処置される動物は、米国特許第5,650,135号および同第7,449,567号に記載されるように、ならびにIVISTM 画像化システムの製造業者(Caliper Life Sciences)によって提供される材料に記載されるように、便利に画像化される。
本発明はまた、本明細書で記載される試薬を含み、本明細書で記載される方法を実施するためのキットを提供する。特に、これらキットは、代表的には、予め作製したNAC試薬もしくは個々の要素(例えば、NIRナノ粒子、化学発光性酵素プローブなど)を含む。上記キットは、必要に応じて、緩衝液および容器、ならびに本明細書に記載される方法を実施するための書面による説明書を含む。予めパッケージされた試薬の場合に、上記キットは、必要に応じて、測定なしで上記方法へと組み込まれる準備ができている、予め測定されたもしくは予め調薬された試薬(例えば、予め測定された流体アリコート、または上記キットのエンドユーザーによって容易に再構成され得る、予め秤量されたかもしくは予め測定された固体試薬)を含む。
以下は、本開示を実施するための具体的実施形態の例である。上記例は、例示目的のみで提供され、本開示の範囲を限定することは決して意図していない。
肺組織における急性炎症応答を、マウスへのLPSの気管内送達によって誘導した。特に、LPSを、濃度10mg/mlになるように滅菌PBS中に溶解した。LPS(総体積50μlにおいて)を、22ゲージ挿管でマウスに気管内送達した。LPSの最終用量は、1mg/kgであった。LPSの送達後、ルミノールとナノ粒子(Quantum dot 800)との混合物を、動物に静脈内送達した。画像化を、注射の5分後に行った。
炎症は、腫瘍発生を含め、広い範囲の疾患プロセスに関与しているので、上記NAC組成物および方法の有用性をまた、腫瘍検出について試験した。MDA−MB−231−luc腫瘍の心臓内注射を介した全身転移モデルにおいて、肺および膝関節における転移性腫瘍発生をまた、NAC組成物を使用して評価した。簡潔には、Nu/Nuマウスに、100万個のMDA−MB−231−luc2腫瘍細胞を心臓内注射した。3週間において、上記マウスを、ルシフェリン(150mg/kg)の腹腔内注射の後に、IVISスペクトルで画像化した。生体発光性シグナルがベースラインレベルに戻っていた、ルシフェリン注射の24時間後に、このマウスに、ルミノールを静脈内注射した。膝関節における腫瘍転移が検出された。上記シグナルがバックグラウンドレベルに戻っていた、さらに24時間後に、ルミノールとQD800(PBS中のルミノール−R)との混合物を静脈内注射し、上記腫瘍を、注射の5分後に画像化した。
Claims (13)
- 化学発光性酵素プローブおよび近赤外(NIR)ナノ粒子を含む、組成物。
- 前記化学発光性酵素プローブは、ルミノールを含む、請求項1に記載の組成物。
- 前記NIRナノ粒子は、標的化部分をさらに含む、請求項1または請求項2に記載の組成物。
- 前記標的化部分は、抗体、抗体フラグメント、低分子、アパトマーおよびポリペプチドからなる群より選択される、請求項3に記載の組成物。
- 生きた動物における酵素活性をモニターする方法であって、該方法は、
請求項1〜4のいずれか1項に記載の組成物を投与する工程であって、ここで前記NIRナノ粒子は、前記化学発光性酵素プローブから放出された化学発光に曝されると光を放出する、工程;
該NIRナノ粒子から放出された光を検出し、それによって、該生きた動物における酵素活性をモニターする工程、
を包含する、方法。 - 前記化学発光性酵素プローブは、ルミノールを含む、請求項5に記載の方法。
- ROS活性がモニターされる、請求項5または6に記載の方法。
- がんが検出される、請求項6に記載の方法。
- 前記酵素活性は、炎症応答の指標である、請求項6に記載の方法。
- 前記炎症応答は、肺の中にある、請求項9に記載の方法。
- 前記酵素活性は、腫瘍もしくは腫瘍転移の存在の指標である、請求項6に記載の方法。
- 生きた動物におけるがんを検出する方法であって、該方法は、
化学発光性酵素プローブを該動物に投与する工程;
近赤外(NIR)ナノ粒子を該動物に投与する工程であって、ここで該ナノ粒子は、該化学発光性酵素プローブから放出された化学発光に曝されると光を放出する、工程;
該NIRナノ粒子から放出された光を検出し、それによって、該生きた動物におけるがんをモニターする工程、
を包含する、方法。 - 前記がんは、固形腫瘍もしくは転移部位である、請求項12に記載の方法。
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