JP2017508739A - アテローム動脈硬化映像化用組成物、及びそれを用いたアテローム動脈硬化の診断方法 - Google Patents
アテローム動脈硬化映像化用組成物、及びそれを用いたアテローム動脈硬化の診断方法 Download PDFInfo
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Abstract
Description
以下、望ましい実施例を参照して、本発明を当業者が容易に実施できるように詳しく説明する。しかし、本発明は、さまざまな異なる形態として具現され、ここで説明する実施例に限定されるものではない。
0.1M炭酸ナトリウム緩衝液(pH9.5)5mlに20mgのヒト血清アルブミンを溶かした後、5.5mgのα−L−マンノピラノシルフェニルイソチオシアネート(α−L−mannopyranosylphenyl isothiocyanate)を添加し、室温でよくかき混ぜながら、20時間反応させた。その後、反応液を−70℃に冷凍保管した。
段階1で製造した1mlマンノシルヒト血清アルブミン(13.6mg/ml)に10mgのp−SCN−Bz−NOTAを添加した後、室温で1時間反応させた。反応後、セファデックスG−25カラムを用いてベンジルNOTAとフェニルマンノースが結合したヒト血清アルブミンを分離精製した。
1mlベンジルNOTAとフェニルマンノースが結合したヒト血清アルブミン(13.6mg/ml)の1mlを、0.3ml酢酸ナトリウム緩衝溶液(0.5M、pH5.5)に添加した後、タンパク質1mgに相当する量ずつバイアルに分注し、それを凍結乾燥して−70℃で保管した。
実施例2のキットに、68Ge/68Ga−発生器(Cyclotron Co.,Russia)から製造された68GaClの0.1M塩酸溶液1mlをそれぞれ添加して、37℃で反応しながら、10分、30分、1時間、2時間後に標識効率をTLCで測定した。この際、固定相は、ITLC−SG(Gelman Co.,USA)を用い、展開溶媒は、0.1Mクエン酸溶液を用いた。ITLCプレート上の放射能分布は、TLC−スキャナー(Bioscan Co.)を用いて測定した。標識された68Gaは、原点に残っており、標識されていない68Gaは、頂点に移動した(図1)。また、pH4〜5にて、37℃で30分間反応すれば、標識がほとんど終了することが分かった(図2)。このように標識した68Ga−NOTA−MSAをヒト血清と混合して、37℃でインキュベートした時の放射化学的純度を測定して安定性を検証した。この結果は、下記の図3に示した。図3から見られるように、血清中で37℃でインキュベートした場合、2時間99%以上の純度を保持し、実際の核医学的映像を得る際には、標識後、1時間以内にほとんど注射するので、十分に実用的に安定であることを確認することができた。
まず、実施例1の段階1のような方法でMSAを製造した。MSA100mgと、0.1M炭酸ナトリウム緩衝液(pH9.5)13mLに溶かした16mg(0.03mmol)のローダミンBイソチオシアネート(RITC:rhodamine B isothiocyanate)とを、室温暗所で20時間反応させた。生成されたRITC−MSAは、PD−10カラムで生理食塩水を使って分離精製した後、凍結乾燥した。MSA当たり結合したRITCは、窒素レーザ(337nm)を装着したMALDI−TOF質量スペクトロメーターで分子量を測定して計算した。そのために、線形モードで500回のレーザを発射して測定した。あらゆるサンプルは、4回ずつ分析し、MSAとRITC−MSAの分子量は、その平均値を取った。
前記実施例のキットに、Mo−99/Tc−99m−ジェネレーター(三栄ユニテック)から製造された過テクネチウム酸塩(99mTcO4−)の生理食塩水溶液2mlまたは5mlをそれぞれ添加して、室温で1〜30分間反応した。テクネチウムの放射性同位元素標識効率は、ITLC(Instant Thin Layer Chromatography)に少量の反応物を撮った後、生理食塩水で展開し、TLC−スキャナーで放射能分布を測定することで、決定した。標識されたテクネチウムは、原点に残っており、他のテクネチウムは、いずれも溶媒の先端に沿って移動した。標識の結果、常に99%以上の効率を示した。標識した99mTc−MSAを室温にそのまま置いた時とヒト血清と混合して37℃でインキュベートした時との経時的な放射化学的純度(%)により安定性を測定した。その結果は、下記の表1に示した。
12週齢の一般ウサギ(New Zealand white rabbits)10匹を対象とした。それぞれ5匹をランダムに選定して2群に分け、1つのグループには正常の餌を食べさせ、残りの1つのグループには1%のコレステロールを含有した食餌を与えた。飼育は、標準化された条件(21℃、湿度41%〜62%)で行い、規則的な昼/夜(10/14時間)周期にて、水と飼料に自在に接近可能にした。3ヶ月の食餌療法後に、麻酔状態で68Ga−MSA 1mCiを静脈注射し、10分後から10分間全身を対象にして陽電子放出断層撮映を施行した(図5、図6)。翌日、ウサギに麻酔をかけた後、RITC標識−MSA(42μg/0.1mL)またはRITCを0.9%食塩水に混ぜてウサギの耳静脈から注射した。その10分後にウサギを安楽死させ、大動脈を剥離して、−20℃に保管した。大動脈切片は、常温で30分間4%(v/v)緩衝ホルマリン液で固定し、冷PBS(pH7.4)で洗浄後、optimum cutting temperature compound(OCT compound,Sakura,Tokyo)に包埋し、組織透過のために1日経過後、−80℃に保管した。10mmの厚さに切片化した組織薄片は、ポリ-D-リジンと共にスライドに置き、光を遮断して45℃で乾かし、使用時まで常温で保管した。スライド組織片は、PBS(pH7.4)で2回洗浄して、Fluoromount−GTM(SouthernBiotech,Birmingham,AL)を用いてマウントした。蛍光映像は、IX81−ZDC focus drift compensating microscope(Olympus,Tokyo,Japan)で励起波長と蛍光波長とをそれぞれ547nm及び572nmで観察した(図6)。
実施例と比較例との場合で、アテローム動脈硬化の診断映像の鮮明度を比較する実験を行った。実験の方法は、同じウサギに2日間隔で68Ga−MSAと18F−FDGとをそれぞれ注射して比較する方法で行い、その結果は、図7、図8、及び図9に示した。
実施例の場合、臨床において適用可能か否かを評価する実験を行った。その実験は、急性心筋梗塞患者群と正常対照群とを対象にして頸動脈部位のアテローム硬化部位の68Ga−MSA映像を比較するphase I臨床研究方法で行い、その結果は、下記の図11、図12、及び図13に示した。下記の図11は、急性心筋梗塞患者で超音波で確診された頸動脈部位のアテローム動脈硬化の病巣部位の68Ga−MSA映像を示した例であって、首部位の緑色のアテローム硬化部位がよく観察され、図12は、頸動脈にアテローム硬化の病巣のない対照群での68Ga−MSA映像を示した例であって、何の異常部位が観察されないことを確認することができた。また、図13から確認されるように、頸動脈にアテローム硬化のある心血管疾患者で正常対照群に比べて、68Ga−MSAのPET/CT映像で視覚的判断(PET_visual_grade)、SVU(PET_RCA_grade)及びtarget SUV/background SUV ratio(PET_RCA_TBR)を用いた重症度診断方法いずれもでアテローム動脈硬化の病巣の映像を用いてアテローム動脈硬化の病巣の有無の判別が容易に確認することができ、実施例の場合、臨床でも適用可能なアテローム動脈硬化映像化用組成物であることを確認した。
Claims (6)
- 二官能性キレート剤−マンノシルヒト血清アルブミン、二官能性キレート剤−マンノシルナノ粒子、二官能性キレート剤−マンノシルポリマーからなる群から選択される何れか1つに放射性同位元素を標識した放射性同位元素標識化合物を含むアテローム動脈硬化映像化用組成物。
- 前記放射性同位元素は、68Ga、99mTc、111In、18F、11C、123I、124I、及び131Iからなる群から選択される何れか1つ以上であることを特徴とする請求項1に記載のアテローム動脈硬化映像化用組成物。
- 前記放射性同位元素は、68Gaであることを特徴とする請求項1に記載のアテローム動脈硬化映像化用組成物。
- 前記二官能性キレート剤は、[1,4,7−トリアザシクロノナン−1,4,7−三酢酸(NOTA)]、[1,4,7,10−テトラアザシクロドデカン−1,4,7,10−四酢酸(DOTA)]、ジエチレントリアミン五酢酸(DTPA)、ヒドラジノニコチン酸(HYNIC)、N2S2、及びN3Sから選択される何れか1つ以上であることを特徴とする請求項1に記載のアテローム動脈硬化映像化用組成物。
- 前記二官能性キレート剤は、1,4,7−トリアザシクロノナン−1,4,7−三酢酸(NOTA)であることを特徴とする請求項1に記載のアテローム動脈硬化映像化用組成物。
- 請求項1ないし請求項5のうち何れか一項に記載のアテローム動脈硬化映像化用組成物を用いるアテローム動脈硬化の診断方法。
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