JP6174603B2 - T2*強調磁気共鳴イメージング(mri)のための造影剤 - Google Patents
T2*強調磁気共鳴イメージング(mri)のための造影剤 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
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Description
マグネタイト(磁鉄鉱)ナノ粒子(Fe3O4)は、pHが10までのアンモニア溶液(29.6%)でFe3+イオンとFe2+イオン0.3M(モル比 2:1)の共沈によって、25°Cの不活性雰囲気中で調整され、次いで30分間80℃で水熱処理される。磁性ナノ粒子は脱イオン水とエタノールで数回洗浄され、次の処理のため乾燥機中にて70℃で乾燥される。ポリアクリル酸(PAA)を結合させるため、100mgのFe3O4ナノ粒子はまず2mLの緩衝液A(0.003Mリン酸塩、pH6)及び0.5mLのカルボジイミド溶液(緩衝液A中0.025g・mL−1)と混合される。10分間超音波処理された後、2.5mLのPAA溶液(緩衝液A中60mg・mL−1)が加えられ、この混合液はさらに30分間超音波処理される。最後に、PAAによりコートされたFe3O4ナノ粒子は磁力的に回収され、水で2回洗浄され、緩衝生理食塩水溶液に対して透析される(図1及び図2A)。以下においてこのナノ粒子はNanotex(ナノテックス)と称される。
実施例1において合成されたナノ粒子から開発された本発明によるNanotexの磁気的緩和特性(T1,T2及びT2*)の評価は、磁気共鳴スペクトロメータ Bruker Minispec[ブルカーバイオスピン社(Bruker Biospin)、エットリンゲン、ドイツ]を使用して、臨床上の磁場強度1.5テスラで、またPharmascan Bruker scanner[ブルカーバイオスピン社(Bruker Biospin)、エットリンゲン、ドイツ]を使用して7テスラで行われた。
C6グリオーマ細胞(神経膠腫細胞)を使用したNanotexのイン−ビトロ毒性は、細胞膜の完全性を測定する手順である乳酸デヒドロゲナーゼ(LDH)の放出を試験することにより、研究をおこなった。細胞死は培養培地への酵素の放出を測定することにより検出された。このような条件下では、LDH放出は細胞膜の透過性の劇的な改変又は破壊と関連しており、そのためLDH放出の増大は細胞死の増加と細胞生存可能性(バイアビリティ)の低下を示す。
脾臓におけるNanotexのイン−ビボでの蓄積は、Nanotexの静脈内投与(体重1kg当たり15マイクロモルのFe)の1時間後に屠殺されたマウスの単離された脾臓におけるT2*の値の測定によって測定される。この投与量は商業的製造者により推奨されているナノ粒子の臨床投与量に対応しており、ここでは基準用量(reference dose)として使用されている。脾臓は頚部脱臼により屠殺されたマウスから単離され、6個のプレキシガラスの皿に置いて対応するT2*マップを再構成させた。図6は、Nanotexを投与された6匹の動物の単離された脾臓を有する皿上の、このアプローチの代表的な結果を示す。この方法を使用して達成される解像度と感度は、イン−ビボでの脾臓では達成できない生体外(ex vivo)での脾臓におけるT2*の非常に正確な測定を可能とする。
MRI用Nanotexナノ粒子のイン−ビボでの薬物動態の研究のために、T2*強調画像と、CD1スイスマウスの胸郭及び腹部を通過する冠状断面におけるT2*強調画像に対応するマップが得られた。画像はNanotexの静脈内投与前と、投与後の時間増加時(1,3,6,24,48,168h)において取得した。Nanotexナノ粒子は、体重1kg当たり15マイクロモル量のFeを静脈内に投与した。この投与量は商業的ナノ粒子の製造者により推奨されているナノ粒子の臨床投与量に対応しており、ここでは基準用量として使用されている。
微小血管灌流の評価手続は、「ボーラス(bolus)」タイプ造影の通過動態のモニタリングに基づく。つまり、急速注入が行われ、造影剤が脈管系をグループ化したボーラス(大型丸剤)として通過し、それぞれの通過組織において(少なくとも最初の組織を通過中に)、注入溶液の当初の濃度を維持する。ボーラスが、得られるMRI画像平面(plane)の断面(section)に到達する時、注入される溶質の濃度に比例した画像強度の低下が磁気共鳴イメージング(MRI)によって測定され得る。
Claims (1)
- ヒトを含む動物の健康な組織について、及び、血管障害、組織阻血、神経変性、炎症、浮腫又は癌に冒された組織について、灌流測定を行うために適したT2*強調磁気共鳴イメージング(MRI)のために動物の体重1kg当たりFeとして30マイクロモル相当量を投与するための造影剤であって、
直径15nm未満のコアを有して表面に正味の電荷を持ち、7テスラで測定された119s−1mM−1の血清緩和値r2*を有する1以上のナノ粒子を含んでなり、ナノ粒子は1)無機のコアと2)肝臓または脾臓に蓄積しない水溶性ポリマーコーティングとを含み、
i)無機のコアが磁鉄鉱−Fe304−からなり、
ii)水溶性ポリマーコーティングがポリアクリル酸であることを特徴とするT2*強調磁気共鳴イメージングのための造影剤。
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