JP2021514941A - ビリルビン誘導体基盤の診断および治療用超音波造影剤 - Google Patents
ビリルビン誘導体基盤の診断および治療用超音波造影剤 Download PDFInfo
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- JP2021514941A JP2021514941A JP2020542067A JP2020542067A JP2021514941A JP 2021514941 A JP2021514941 A JP 2021514941A JP 2020542067 A JP2020542067 A JP 2020542067A JP 2020542067 A JP2020542067 A JP 2020542067A JP 2021514941 A JP2021514941 A JP 2021514941A
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Abstract
【選択図】図1
Description
(a)ビリルビンに親水性分子をコンジュゲーションさせたビリルビン誘導体を含むナノ粒子を水性溶媒に溶解させて、ビリルビン誘導体ナノ粒子溶液を製造する段階;および
(b)ビリルビン誘導体ナノ粒子溶液に、ガスが含まれた油相溶液を混合して超音波処理することによって、内部にガスが捕集されてコア部を形成し、前記コア部の表面をビリルビン誘導体ナノ粒子が取り囲んでシェル層を成す微細粒子を製造する段階。
本段階は、ビリルビンを親水性分子と結合した親水性〜両親媒性のビリルビン誘導体を製造し、これからビリルビン誘導体を含むナノ粒子溶媒を製造する段階である。
本段階は、前記ビリルビン誘導体ナノ粒子溶液に疎水性ガス(例えばペルフルオロカーボン)を混合し、疎水性ガスをビリルビン誘導体ナノ粒子の疎水性コアに封入させることによって、微細粒子を製造する段階である。
実施例1:本発明のペグ化ビリルビン基盤超音波造影剤の製造
1−1.ビリルビン誘導体(ペグ化ビリルビン、Pegylated bilirubin)の製造
本発明者は、ビリルビン基盤の超音波造影剤を製造するに先立って、ビリルビンに親水性分子を結合させたビリルビンの両親媒性誘導体を製造した。親水性分子としては、ポリエチレングリコール(polyethyleneglycol)を使用した。
本発明のビリルビン基盤のエコー源性微細粒子(echogenic nanoparticle,or microparticle)は、簡単な水中油(oil−in−water,O/W)エマルジョン化方法で製造された。前記実施例1−1であらかじめ製造したビリルビン誘導体(Pegylated bilirubin)を脱イオン水に溶解させて、ビリルビン微細粒子溶液(1.2mg/2ml)を製造し、プローブタイプの超音波粉砕機が備わったアイスバスに移した。バブルのコアを形成する疎水性ガスとしては、ペルフルオロペンタン(perfluoropentane,PFP)を使用した。油相(oil phase)の形態で存在するペルフルオロペンタンを多様な体積比(PFP 0、2.5、5、10% v/v)でビリルビン微細粒子溶液(水相、water phase)に点滴し、30%のパワーで90秒間超音波処理過程を行った。その結果、エマルジョン形態の疎水性気体(ペルフルオロペンタン)をコアとし、ビリルビン誘導体がシェルを成すナノ−またはマイクロ−バブルシステムを製造した(図1および図2)。
超音波ファントムイメージは、マウス用超音波装置プローブであるRMV 706プローブが備わったVevo770(High−Resolution Micro−Imaging System,Visualsonics,Toronto,Canada)を使用して取得した。本発明者らは、超音波イメージングのための体内条件を模写するために、3%(w/v)アガロースゲルに500μL単位のエペンドルプチューブを包埋して製造したアガ−ゲルファントムを使用した。
3−1.顕微鏡形態学
微細粒子の顕微鏡形態学は、酢酸ウラニウム(uranium acetate)のネガティブ染色(negative staining)と透過電子顕微鏡(Tecnai G2 F30,Eindhoven,Netherlands)(図6)およびカバースリップ下の光学顕微鏡(図7)で観察した。
本発明のペグ化ビリルビン基盤超音波造影剤は、天然抗酸化剤であるビリルビンを含んでいる。本発明者らは、本発明の超音波造影剤の活性酸素(reactive oxygen species,ROS)種に対する反応性を確認するために、Nanosizer ZS 90(Malvern Instruments,Ltd.,Malvern,UK)を用いて活性酸素種(ROS;H2O2)を処理する前/後の本発明の造影剤の微細バブルの水力学的サイズ分布(hydrodynamic size distribution)を測定した。結果は、図8に示した。図8に示されたように、本発明の超音波造影剤は、活性酸素種(H2O2)と反応してバブルの水力学的サイズが増加した。
酸化鉄ナノ粒子(iron oxide nanoparticle)のローディングは、上記した実施例1の製造方法を変形して行われた。水中油(oil−in−water,O/W)層を作るとき、ヘキサン(hexane)に分散させた酸化鉄ナノ粒子を油相(oil phase)で存在するペルフルオロペンタン(PFP)と同時に点滴した。次に、前述したように、超音波処理して得られたエマルジョンを薄明かり(dim light)の下で6時間撹拌してヘキサンを蒸発させた後、5000rpmで遠心分離して凝集体を除去した。上澄み液を分液し、希土類磁石(rare earth magnet)を用いて、酸化鉄ナノ粒子がローディングされたペグ化ビリルビン微細バブル(iron oxide nanoparticles−loaded PEGylated bilirubin microbubble)を抽出した(図9および図10)。
Claims (23)
- 内部にガスを含むコア(core)部と;
ビリルビン誘導体を含み、前記コア部の表面を囲むシェル(shell)層と;を含む微細粒子。 - 前記ガスは、空気、窒素、ヘリウム、アルゴン、二酸化炭素、サルファーヘキサフルオリド(sulfur hexafluoride,SF6)およびC1〜C10のペルフルオロカーボン(perfluorocarbon)よりなる群から選ばれることを特徴とする請求項1に記載の微細粒子。
- 前記ビリルビン誘導体は、ビリルビンに親水性分子が結合されたことを特徴とする請求項1に記載の微細粒子。
- 前記親水性分子は、デキストラン(dextran)、カルボデキストラン(carbodextran)、ポリサッカライド(polysaccharide)、サイクロデキストラン(cyclodextran)、プルロニック(pluronic)(登録商標)、セルロース(cellulose)、デンプン(starch)、グリコーゲン(glycogen)、カルボハイドレート(carbohydrate)、単糖類(monosaccharide)、二糖類(disaccharide)およびオリゴ糖類(oligosaccharide)、ポリペプチド(polypeptide)、ポリホスファゼン(polyphosphagen)、ポリラクチド(polylactide)、ポリ(乳酸−コ−グリコール酸)(poly(lactic−co−glycolic acid))、ポリカプロラクトン(polycaprolactone)、ポリアンヒドリド(polyanhydride)、ポリマレイン酸(polymaleic acid)およびポリマレイン酸の誘導体、ポリアルキルシアノアクリレート(polyalkylcyanoacrylate)、ポリヒドロキシブチレート(polyhydroxybutylate)、ポリカーボネート(polycarbonate)、ポリオルソエステル(polyorthoester)、ポリエチレングリコール(polyethyleneglycol,PEG)、メトキシポリエチレングリコール(methoxy polyethyleneglycol,mPEG)、ポリプロピレングリコール、ポリエチレンイミン(polyethylenimine)、ポリ−L−リジン(poly−L−lysine)、ポリグリコライド(polyglycolide)、ポリメチルメタクリレート(polymetacrylate)、ポリビニルピロリドン(polyvinylpyrrolidone)、ポリ(アクリレート)(poly[acrylate])、ポリ(アクリルアミド)(poly[acrylamide])、ポリ(ビニルエステル)(poly[vinylester])、ポリ(ビニルアルコール)(poly[vinyl alcohol])、ポリスチレン(polystryene)、ポリオキシド(polyoxide)、ポリエレクトロライト(polyelectrolyte)、ポリ(1−ニトロプロピレン)(poly[1−nitropropylene])、ポリ(N−ビニルピロリドン)(poly[N−vinyl pyrrolidone])、ポリビニルアミン(poly[vinyl amine])、ポリ(ベータ−ヒドロキシエチルメタアクリレート)(Poly[beta−hydroxyethylmethacrylate])、ポリエチレンオキシド(Polyethyleneoxide)、ポリ(エチレンオキシド−b−プロピレンオキシド(Poly[ethylene oxide−bpropyleneoxide])およびポリリジン(Polylysine)よりなる群から選ばれることを特徴とする請求項3に記載の微細粒子。
- 前記微細粒子は、Cu、Ga、Rb、Zr、Y、Tc、In、Ti、Gd、Mn、Fe、Au、Pt、Zn、Na、K、Mg、Ca、Sr、およびランタン族金属よりなる群から選ばれる金属のイオンまたは金属化合物をさらに含むことを特徴とする請求項1に記載の微細粒子。
- 前記微細粒子は、シスプラチン(cisplatin)、カルボプラチン(carboplatin)、オキサリプラチン(oxaliplatin)、ネダプラチン(nedaplatin)、およびヘプタプラチン(heptaplatin)よりなる群から選ばれるプラチナ系抗癌剤をさらに含むことを特徴とする請求項1に記載の微細粒子。
- 前記微細粒子は、アントラサイクリン系抗癌剤、タキサン(taxane)系抗癌剤またはカンプトテシン(camptothecin)系抗癌剤をさらに含むことを特徴とする請求項1に記載の微細粒子。
- 前記アントラサイクリン系抗癌剤は、ダウノルビシン、ドキソルビシン、エピルビシン、イダルビシン、ゲムシタビン、ミトサントロン、ピラルビシンおよびバルルビシンよりなる群から選ばれることを特徴とすることを特徴とする請求項7に記載の微細粒子。
- 前記タキサン系抗癌剤は、パクリタキセル(paclitaxel)、ドセタキセル(docetaxel)およびカバジタキセル(cabazitaxel)よりなる群から選ばれることを特徴とする請求項7に記載の微細粒子。
- 前記微細粒子は、超常磁性酸化鉄ナノ粒子(SPION:superparamagnetic iron oxide nanoparticle)をさらに含むことを特徴とする請求項1に記載の微細粒子。
- 請求項1〜10のいずれかに記載の微細粒子を含む超音波造影剤。
- 前記超音波造影剤は、磁気共鳴(magnetic resonance,MR)による映像診断兼用であることを特徴とする請求項11に記載の超音波造影剤。
- 前記超音波造影剤は、磁気共鳴ガイド下集束超音波(MR−guided focused ultrasound,MRgFUS)用であることを特徴とする請求項12に記載の超音波造影剤。
- 前記超音波造影剤は、薬物伝達体兼用であることを特徴とする請求項11に記載の超音波造影剤。
- 下記の段階を含む微細粒子の製造方法:
(a)ビリルビンに親水性分子が結合されたビリルビン誘導体を含むナノ粒子を水性溶媒に溶解させて、ビリルビン誘導体ナノ粒子溶液を製造する段階;および
(b)ビリルビン誘導体ナノ粒子溶液に、ガスが含まれた油相溶液を混合し、超音波を処理することによって、内部にガスが捕集されてコア部を形成し、前記コア部の表面をビリルビン誘導体ナノ粒子が取り囲んでシェル層を成す微細粒子を製造する段階。 - 前記ガスは、空気、窒素、ヘリウム、アルゴン、二酸化炭素、サルファーヘキサフルオリド(sulfur hexafluoride,SF6)およびC1〜C10のペルフルオロカーボン(perfluorocarbon)よりなる群から選ばれることを特徴とする請求項15に記載の微細粒子の製造方法。
- 前記親水性分子は、デキストラン(dextran)、カルボデキストラン(carbodextran)、ポリサッカライド(polysaccharide)、サイクロデキストラン(cyclodextran)、プルロニック(pluronic)(登録商標)、セルロース(cellulose)、デンプン(starch)、グリコーゲン(glycogen)、カルボハイドレート(carbohydrate)、単糖類(monosaccharide)、二糖類(disaccharide)およびオリゴ糖類(oligosaccharide)、ポリペプチド(polypeptide)、ポリホスファゼン(polyphosphazen)、ポリラクチド(polylactide)、ポリ(乳酸-コ-グリコール酸)(poly(lactic−co−glycolic acid))、ポリカプロラクトン(polycaprolactone)、ポリアンヒドリド(polyanhydride)、ポリマレイン酸(polymaleic acid)およびポリマレイン酸の誘導体、ポリアルキルシアノアクリレート(polyalkylcyanoacrylate)、ポリヒドロキシブチレート(polyhydroxybutylate)、ポリカーボネート(polycarbonate)、ポリオルソエステル(polyorthoester)、ポリエチレングリコール(polyethyleneglycol,PEG)、メトキシポリエチレングリコール(methoxy polyethyleneglycol,mPEG)、ポリプロピレングリコール、ポリエチレンイミン(polyethylenimine)、ポリ−L−リジン(poly−L−lysine)、ポリグリコライド(polyglycolide)、ポリメチルメタクリレート(polymetacrylate)、ポリビニルピロリドン(polyvinylpyrrolidone)、ポリ(アクリレート)(poly[acrylate])、ポリ(アクリルアミド)(poly[acrylamide])、ポリ(ビニルエステル)(poly[vinylester])、ポリ(ビニルアルコール)(poly[vinyl alcohol])、ポリスチレン(polystryene)、ポリオキシド(polyoxide)、ポリエレクトロライト(polyelectrolyte)、ポリ(1−ニトロプロピレン)(poly[1−nitropropylene])、ポリ(N−ビニルピロリドン)(poly[N−vinyl pyrrolidone])、ポリビニルアミン(poly[vinyl amine])、ポリ(ベータ−ヒドロキシエチルメタアクリレート)(Poly[beta−hydroxyethylmethacrylate])、ポリエチレンオキシド(Polyethyleneoxide)、ポリ(エチレンオキシド−b−プロピレンオキシド(Poly[ethylene oxide−bpropyleneoxide])およびポリリジン(Polylysine)よりなる群から選ばれることを特徴とする請求項15に記載の微細粒子の製造方法。
- 前記段階(b)は、ビリルビン誘導体ナノ粒子溶液に、ガス;およびCu、Ga、Rb、Zr、Y、Tc、In、Ti、Gd、Mn、Fe、Au、Pt、Zn、Na、K、Mg、Ca、Sr、およびランタン族金属よりなる群から選ばれる金属のイオンまたは金属化合物が含まれた油相溶液を混合して超音波処理することを特徴とする請求項15に記載の微細粒子の製造方法。
- 前記段階(b)は、ビリルビン誘導体ナノ粒子溶液に、ガス;およびシスプラチン(cisplatin)、カルボプラチン(carboplatin)、オキサリプラチン(oxaliplatin)、ネダプラチン(nedaplatin)、およびヘプタプラチン(heptaplatin)よりなる群から選ばれるプラチナ系抗癌剤が含まれた油相溶液を混合して超音波処理することを特徴とする請求項15に記載の微細粒子の製造方法。
- 前記段階(b)は、ビリルビン誘導体ナノ粒子溶液に、ガス;およびアントラサイクリン系抗癌剤、タキサン(taxane)系抗癌剤またはカンプトテシン(camptothecin)系抗癌剤が含まれた油相溶液を混合して超音波処理する特徴とする請求項15に記載の微細粒子の製造方法。
- 前記アントラサイクリン系抗癌剤は、ダウノルビシン(daunorubicin)、ドキソルビシン(doxorubicin)、エピルビシン(epirubicin)、イダルビシン(idarubicin)、ピクサントゥロン(pixantrone)、ミトクサントゥロン(mitoxantrone)およびバルルビシン(valrubicin)よりなる群から選ばれることを特徴とすることを特徴とする請求項20に記載の微細粒子の製造方法。
- 前記タキサン系抗癌剤は、パクリタキセル(paclitaxel)、ドセタキセル(docetaxel)およびカバジタキセル(cabazitaxel)よりなる群から選ばれることを特徴とする請求項20に記載の微細粒子の製造方法。
- 前記段階(b)は、ビリルビン誘導体ナノ粒子溶液に、ガス;および超常磁性酸化鉄ナノ粒子(SPION:superparamagnetic iron oxide nanoparticle)が含まれた油相溶液を混合して超音波処理することを特徴とする請求項15に記載の微細粒子の製造方法。
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WO2019151827A1 (ko) | 2019-08-08 |
CN111757758A (zh) | 2020-10-09 |
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