JP4680185B2 - アテローム性動脈硬化症の診断法 - Google Patents
アテローム性動脈硬化症の診断法 Download PDFInfo
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- JP4680185B2 JP4680185B2 JP2006514981A JP2006514981A JP4680185B2 JP 4680185 B2 JP4680185 B2 JP 4680185B2 JP 2006514981 A JP2006514981 A JP 2006514981A JP 2006514981 A JP2006514981 A JP 2006514981A JP 4680185 B2 JP4680185 B2 JP 4680185B2
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Description
本出願は、2003年5月30日出願の米国特許仮出願第60/474,731号に対し米国特許法35条119(e)項により優先権を主張する。なお、この仮出願を参照することにより本出願に含める。
L−X
の結合体を含む組成物の有効量を投与する工程(上式において、基Lはリガンドを含み、基Xは指定の条件下で光を発することが可能な発色団を含む)と、十分な時間をかけて、リガンド結合体を、活性プラークに付着した活性化マクロファージに結合させる工程と、カテーテル導入装置を用いて血管壁を指定の条件下に置く工程、および、カテーテル導入装置を用いて発色団によって発せられた光を検出することによって活性プラークを特定する工程を含む。
L−X
の結合体を含む組成物の有効量を投与する工程(上式において、基Lはリガンドを含み、基Xは放射線を放出することが可能な化学基を含む)と、十分な時間をかけて、リガンド結合体を、活性プラークに付着した活性化マクロファージに結合させる工程、および、カテーテル導入装置を用いて化学基によって放出される放射線を検出することによって活性プラークを特定する工程を含む。
===動脈硬化症ウサギの臓器におけるEC20取り込みの分析===
ワタナベ・遺伝性高脂血症ウサギモデル(すなわち、動脈硬化症のモデル)を用いて、葉酸標的99mTcキレート化学基(EC20;米国特許出願第60/378,571号参照、この文書を引用により本明細書に含める)の結合が、動脈硬化症ウサギの動脈において検出できるかどうかを調べた。ワタナベウサギは、LDL受容体を欠損しており、従って、高コレステロール血症および動脈硬化症のモデルとなる。
===材料===
Fmoc保護アミノ酸誘導体、Fmoc-グリシン負荷Wang樹脂、2-(1H-ベンゾトリアゾル-1-イル)-1,1,3,3-テトラメチルウロニウム・ヘキサフルオロフォスフェート(HBTU)、および、N-ヒドロキシベンゾトリアゾールを、Novabiochem(サンディエゴ、カリフォルニア州)から購入した。以前に発表された報告書(Godwin 1972)に従って、葉酸(Sigma Chemical Company、セントルイス、ミズーリ州)からN10-トリフルオロアセチルプテロイン酸を合成した。ガンマカルボキシ結合葉酸−フルオレセイン(葉酸-FITC)の合成法は、以前の刊行物(Kennedy et al., 2003)に記載されている。L-グルタミンを含むが、葉酸を含まないRPMI1640培地は、Gibco-BRL(Grand Island、ニューヨーク州、米国)から、葉酸および、トリグリセリド試薬GPO-PAPは、DIALAB(ウィーン、オーストリア)、INFINITY CHOLESTEROL試薬および、その他の化学薬品は、Sigma Chemical Co.(セントルイス、ミズーリ州)からそれぞれ入手した。
===葉酸−テキサスレッド結合体の合成===
標準的Fmocペプチド化学を用いて、テキサスレッドに対して、葉酸のガンマカルボキシルを介して結合する、葉酸誘導ペプチドを合成した。Fmoc化学に基づき、HBTUおよびN-ヒドロキシベンゾトリアゾールを活性化剤として、それと共に、ジイソプロピルエチルアミンを塩基、および、DMFに溶解した20%ピペリジンをFmoc基の脱保護用として用いて、配列Gly-Lys-(γ)Glu-プテロイン酸を構築した。ε-アミンに4-メチルトリチル保護基を含むFmoc保護リシンを、Wang樹脂に付着させたFmoc-保護グリシンに結合させた。次に、このペプチドに、α-t-Boc保護N-α-Fmocグルタミン酸を結合させ、ペプチドにN10-トリフルオロアセチルプテロイン酸を付着させた後、葉酸に対するγ-結合結合体を得た。リシンのε-アミンにおけるメトキシトリチル保護基を、ジクロロメタンに溶解した1%トリフルオロ酢酸で除去し、テキサスレッドを付着可能にした。DMFに溶解したテキサスレッド・N-ヒドロキシスクシニミド(Molecular Probes, Eugene、オレゴン州)を、このペプチドと一晩反応させ、その後、このペプチド樹脂ビーズから十分に洗い落とした。次に、この葉酸−テキサスレッドペプチドを、95%トリフルオロ酢酸:2.5%水:2.5%トリイソプロピルシラン溶液によって樹脂から分離した。ジエチルエーテルを用いてこの産物を沈殿させ、この沈殿を遠心にて回収した。次に、この産物をジエチルエーテルにて2回洗浄し、減圧下に一晩乾燥した。次に、この産物を、質量分析によって確認した([M-]計算値:1423、観測値:1422)。N10-トリフルオロアセチル保護基を除去するために、この産物を、0.5 mlの10%水酸化アンモニウムを含む5 mlの水で、pHを9.5-10.0に調節させた液に溶解し、室温で30分攪拌した。次に、この産物をイソプロパノール/エーテルを用いて沈殿させ、遠心にて回収した。産物を、G-10セファデックスゲルろ過カラム(1.5 x 15 cm)に加え、水を溶出液として用いた。産物のピークを回収し、凍結乾燥した。
===動物モデル===
健康な雄性の、RAPマウスおよびゴールデンシリア・ハムスターを実験用に選んだ。動物を三つの実験グループに分けた。すなわち、(i)100 kg当たり0.1 gの葉酸を含む正常食餌(N)による飼育グループ、(ii)葉酸欠損食餌(D)による飼育グループ、および、(iii)葉酸欠損食餌と、3%コレステロールと15%バターを含む高脂血症食餌(H)とを共に、6ヶ月与えられた飼育グループである。市販の動物食餌は、葉酸の生理的濃度を超える量が添加されているので、これらの「正常」動物における血清葉酸レベルは、生得のレベルを40倍も超えることがよくある(Wang等)。葉酸の、このように高い血清含量は、FR発現の抑制をもたらす。
===高脂血症動物のマクロファージ上の葉酸受容体===
FITCに結合させた葉酸(FA-FITC)、または、テキサスレッドに結合させた葉酸(FA-TR)のどちらかを、腹腔内に注入し(10 μg/100 g体重)、4時間後、動物を失血させ(軽いエーテル麻酔下)、次に頚動脈切断によって屠殺した。マクロファージ濃縮懸濁液(若干のマスト細胞、PMN、および単球も含んでいる)を腹腔洗浄にて得た(Aviram、1989)。手短に言うと、腹腔に、10 mlの冷却リン酸バッファー生食液(PBS)、pH7.4を注入し、穏やかに2分マッサージした。腹腔細胞の懸濁液をナイロン布でろ過し、250 x g、4℃での10分間の遠心によりPBSで2回洗浄した。次に、この細胞ペレットを、冷却細胞溶解バッファー(1% NP-40、50 mM TRIS-HCl、2 mM EDTA、1 mM DTT、PMSF、プロテアーゼ阻害剤)にて可溶化し、遠心にて透明にし、蛍光を、RF-5001 PC分光光度蛍光測定器を用い、標準曲線に基づいて定量した。タンパク濃度はアミドブラックにて定量し、結果は、各動物ブループについて、ng FA/mgタンパク比として表した。同じ定量を、各動物から収集した血清サンプルについても行った(ng FA-FITC/血清タンパク)。対照実験では、動物に、100X過剰な遊離葉酸の存在下にFA-FITC結合体を注入した。6ヶ月の食餌飼育後における総コレステロールおよび血清トリグリセリド濃度を、特異的試薬キットを用いて測定した。
===組織切片の作製===
アテローム硬化病巣頻発区域(大動脈および弁)の組織断片を、各実験グループから採取し、蛍光顕微鏡観察のために処理した。大動脈を露出し、分枝動脈を切り離し、ゆるやかな外膜は生体内で除去した。次に、この血管を切開し、冷却無菌PBSにて十分に洗浄した。大動脈および心臓弁を丁寧に切り出し、全てのセグメントを、PBSに溶解した4% p-フォルムアルデヒドに室温で90分投入して固定した。次に、この組織を、OTC溶媒に浸し、液体窒素で瞬間凍結し、凍結切片を作製した。この凍結切片を、オイルレッドOにて染色し、ヘマトキシリンにて対比染色した(Mancini, 1995)。同様の半薄切凍結切片を、適当なフィルターを用い、位相差顕微鏡および蛍光顕微鏡の両方によって観察した。
===培養腹腔マクロファージにおけるFA-テキサスレッドの特異的取り込み===
ハムスターの腹腔マクロファージ(ハムスター1匹当たり10−20 x 10-6個)を、腹水から収集し、PBS中で1000 x gで10分の遠心によって3度洗浄した。細胞を、L-グルタミンを含むが葉酸を含まないRPMI1640培地の10 mlに懸濁した。なお、この培養液には、(56℃30分で加熱不活性化した)10%仔牛血清、100 U/mlのペニシリン、および100 μg/mlのストレプトマイシンが添加されていた。未修飾のRPMI中に存在する高い葉酸濃度の中で細胞を培養すると、通常細胞表面のFRの発現の低下が起こるが、この低下を阻止するために、葉酸は培養液から取り除かれた。次に、この腹腔マクロファージを、50 mmペトリ皿に撒き、加湿インキュベーター(5% CO2、95%空気)で培養した。2時間のインキュベーション後、細胞を洗浄して、非接着細胞を除去し、さらに18時間同様の条件下でインキュベートした。細胞を素早く洗浄し、「slow fade」でマウントし、テキサスレッドフィルターの下に蛍光顕微鏡(Nikon)を用いて調べた。
===U937細胞系統におけるFA-FITCの特異的取り込み===
生きた動物モデルの試験をさらに広げるために、U937細胞(Harris, 1985)を用いて細胞培養実験を行った。U937細胞は、瀰漫性組織球リンパ腫の患者の胸膜液に由来する細胞系統で、単球の多くの特性を示す。葉酸受容体の発現を促進するために、U937細胞を、5%FCSか、あるいは、高コレステロールおよび高グルコースレベル(コレステロール:295 mg/dl、グルコース:315 mg/dl)の患者由来の5%血清、のいずれかを添加した、葉酸欠損RPMI中で培養した。平行して行なわれた、U937細胞活性化のための比較的古典的な方法によるFR発現の評価を目的とした実験では、U937細胞を、0.5 g/mlの細菌性リポ多糖類(LPS)の存在下に、または、非存在下に、葉酸無添加であるが5%FCSを添加したRPMIにて培養した。患者の血清またはLPSのどちらかによって24時間活性化した後に、細胞を2.5 g/ml FA-FITCとインキュベートした。細胞を、PBSで洗浄し、細胞溶解バッファー(50 mM TRIS-HCl、1% NP-40、2 mM EDTA、および、1 mM DTTとプロテアーゼ阻害剤)にて可溶化し、FA-FITCの取り込みを蛍光分光法によって定量した。タンパク濃度は、BCA法によって定量し、結果は、各実験条件におけるng FA-FITC/mgタンパクの比として表した。
Claims (14)
- 血管壁に連結した活性アテローム硬化プラークであって、
ビタミンに対する接触可能な結合部位を持つ活性化マクロファージを含む
該プラークを、
特定/監視するための組成物の製造における、
一般式
L−X
の結合体の用法であって、
上式において、
基Lは葉酸塩を含み、
基Xは指定の条件下で光を発することが可能な発色団を含む
ことを特徴とする前記用法。 - 前記血管壁が、
カテーテル導入装置を用いて指定の条件下に置かれる
ことを特徴とする、請求項1の用法。 - 前記発せられた光は、
カテーテル導入装置を用いて検出される
ことを特徴とする、請求項1または2の用法。 - 前記発色団は、蛍光発色団である
ことを特徴とする、請求項1〜3のいずれかの用法。 - 前記蛍光発色団は、フルオレセインである
ことを特徴とする、請求項4の用法。 - 血管壁に連結した活性アテローム硬化プラークであって、
ビタミンに対する接触可能な結合部位を持つ活性化マクロファージを含む
該プラークを、
特定/監視するための組成物の製造における、
一般式
L−X
の結合体の用法であって、
上式において、
基Lは葉酸塩を含み、
基Xは放射線を発することが可能な化学基を含む
ことを特徴とする前記用法。 - 前記放射線は、
カテーテル導入装置を用いて検出される
ことを特徴とする、請求項6の用法。 - 前記化学基は、金属キレート基を含む
ことを特徴とする、請求項6または7の用法。 - 前記金属キレート基は、金属陽イオンをさらに含む
ことを特徴とする、請求項8の用法。 - 前記金属陽イオンは、放射性核種である
ことを特徴とする、請求項9の用法。 - 前記組成物が薬学的に受容可能な担体をさらに含むことを特徴とする、請求項1〜10のいずれかに記載の用法。
- 前記薬学的に受容可能な担体が液性担体であることを特徴とする、請求項11に記載の用法。
- 前記液性担体が、アルコール、グリコール、エステル、アミドおよびこれらの組み合わせ、からなる群から選択されることを特徴とする、請求項12に記載の用法。
- 前記組成物が等張生食液またはグルコース溶液を含有するように剤形化されることを特徴とする、請求項1〜13のいずれかに記載の用法。
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ES2317010T3 (es) | 2009-04-16 |
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US20050244336A1 (en) | 2005-11-03 |
JP2006526642A (ja) | 2006-11-24 |
EP1629281B1 (en) | 2008-10-29 |
WO2004110250A2 (en) | 2004-12-23 |
DE602004017452D1 (de) | 2008-12-11 |
ATE412897T1 (de) | 2008-11-15 |
US20110189086A1 (en) | 2011-08-04 |
US8808998B2 (en) | 2014-08-19 |
US8383354B2 (en) | 2013-02-26 |
WO2004110250A3 (en) | 2005-04-28 |
EP1629281A4 (en) | 2006-08-30 |
CA2527196A1 (en) | 2004-12-23 |
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