JP7464304B2 - 鉄イオンを含む自己組み立て複合体 - Google Patents
鉄イオンを含む自己組み立て複合体 Download PDFInfo
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- JP7464304B2 JP7464304B2 JP2022183802A JP2022183802A JP7464304B2 JP 7464304 B2 JP7464304 B2 JP 7464304B2 JP 2022183802 A JP2022183802 A JP 2022183802A JP 2022183802 A JP2022183802 A JP 2022183802A JP 7464304 B2 JP7464304 B2 JP 7464304B2
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- assembled complex
- iron ion
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- FYWLYWMEGHCZAX-MCDZGGTQSA-M sodium [(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl hydrogen phosphate Chemical compound [Na+].C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)([O-])=O)[C@@H](O)[C@H]1O FYWLYWMEGHCZAX-MCDZGGTQSA-M 0.000 description 1
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Images
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Description
1.実施例1(Fe-AMP)
Fe-AMP自己組み立て複合体を製造した。
Fe-ADP自己組み立て複合体を製造した。
大きさを調節できるFe-ATP自己組み立て体を合成した。
1.走査電子顕微鏡(SEM、Scanning electron microscopy)イメージング
自己組み立て複合体の形態的特性を確認するために、SEM(FEI、Quanta 250 FEG)イメージングを遂行した。製造された自己組み立て複合体を収集して室温の真空オーブンで乾燥させ、SEMイメージング前に90秒間白金めっきを遂行した。
自己組み立て複合体の磁気的特性を分析するために、室温で-19000Oeから19000Oeの間の磁場を印加してVSM(Tecnai 20、FEI、USA)測定を遂行した。サンプルの乾燥重量に対して正規化した後、生成された磁気モーメントが可逆ヒステリシスループ(reversible hysteresis loop)に表示された。
自己組み立て複合体の大きさおよび元素組成を確認するために、TEMイメージングおよびEDSマッピング(Tecnai 20、FEI、USA)を遂行した。
Fe-ATP自己組み立て複合体が自発的に自己組み立てまたは自己分解される様子を確認し、前記自己組み立て複合体に磁場を印加した時に移動する速度および方向を確認するために現場光学顕微鏡イメージング(Nikon Eclipse Ts2)を遂行した。
2D Fe-AMPプレート合成のために、500mM AMP溶液を含むDIウォーター20mL、500mM FeCl2溶液を含むDIウォーター20mLおよびローダミン(Rhodamine、Rhodamine 6G、CAS:989-38-8、Sigma-Aldrich)溶液を含むDIウォーター2mL(5mg/mL)を準備した。
2D Fe-AMPに細胞を培養する実験を遂行した。
ポリ(メチルメタクリレート)(PMMA、poly(methyl methacrylate))浸出方法を利用して3D Fe-AMP巨大多孔性骨支持体(macroporous bone scaffold)を合成した。
自己組み立て複合体の物質伝達性能を実験するためにドキソルビシン放出実験を遂行した。ドキソルビシン(doxorubicin、BORYUNG製薬、A.D.Mycin、品目基準コード:199001007)を含むFe-ATP、Fe-ADP、Fe-AMPまたはFe-(ATP+AMP、1:1)自己組み立て体を合成するために、FeCl2、ATP、ADPおよびAMP溶液を含むDIウォーター(濃度100mM、いずれも同じ濃度)をそれぞれ準備した。
前記実験で使用した物質は、下記のとおりである。
AMP:Adenosine-5’-monophosphate disodium salt(J61643、Alfa Aesar)
ADP:Adenosine 5’-diphosphate sodium salt(A2754、Sigma-Aldrich)
FeCl2:Iron(II) chloride(97%、Sigma-Aldrich、25g、cat.No.372870)
EDTA:Ethylenediaminetetraacetic acid(EDTA、99.5%、Junsei、500g、cat.No.17385S0401)
Rhodamine:Rhodamine 6G(CAS:989-38-8、Sigma-Aldrich)
PMMA:PMMA(125 to 150μm in diameter;Bangs Laboratories、BB05N)
Doxorubicin:BORYUNG製薬、A.D.Mycin(品目基準コード:199001007)
[実験例]
1.形態分析
図2乃至4は、Fe-AMP、Fe-ADPおよびFe-ATP自己組み立て体それぞれの形態および成分を分析した図である。EDSマッピングは、鉄(Fe)およびリン(P)元素に対して遂行した。
鉄イオンとリガンドが自己組み立ておよび自己分解されることを観察した。ここで、リガンドは、ATPを使用した。
図7において、鉄イオンとATPの濃度を異なるようにして自己組み立て体の大きさを調節しながら自己組み立て体を製造し、特性を分析した。多様な大きさのFe-ATP自己組み立て体は、互いに異なる磁気特性を示し、磁場印加時、移動速度で異なるように現れた。図8は、Fe-ADPでの可逆的磁気特性(常磁性)が現れることを示す。
Fe-ATP自己組み立て体のMRI造影剤としての性能を確認する実験を進行し、その結果を図13に示した。実験は、Fe-ATPおよびFe-ATP+EDTAの条件で遂行し、対照群として水を利用した。
生体内に自己組み立て体を注入した後、生体外部で磁場を印加して自己組み立て体の磁気的特性を確認し、図14に示した。ここで、リガンドは、ATPを使用し、全身蛍光顕微鏡(whole-body fluorescence)を利用して撮影した。赤色部分が自己組み立て体のある部分であり、自己組み立て体が永久磁石のある方向にますます移動して拡散することを確認できる。これにより生体外部で磁場を印加して生体内に自己組み立て体が適用される部位を調節できる。
図15および16は、生体内で自己組み立て体が自己分解されることを実験したものである。Cy5カプセル化されたFe-ATP自己組み立て体を利用してEDTAがある条件とない条件で遂行した。EDTAを注入した場合にのみFe-ATPが自己分解されて広がることを確認できる(図15)。また、マウスに注入して生物発光イメージを撮影した図16においては、EDTAの存在の有無と関係なく蛍光が観察されたが、EDTAを注入した場合にはFe-ATP自己組み立て体が分散されてさらに広い範囲で観察された。
自己組み立て体に薬物を担持した後、放出する実験を遂行し、図18および21に示した。
Claims (19)
- 鉄イオン、および
1種以上のリガンドを含み、
前記リガンドと鉄イオンが可逆的に自己組み立てまたは自己分解され、
前記リガンドと鉄イオンが自己組み立てされて少なくとも一部がラウンド形態である組み立て体を形成する、
鉄イオンを含む自己組み立て複合体であって、ここで、
前記リガンドは、ATP、ADP、AMP及びこれらの混合物からなる群から選択される少なくとも1以上である、自己組み立て複合体。 - 有効成分をさらに含み、
前記有効成分は、前記自己組み立て複合体に担持される、
請求項1に記載の鉄イオンを含む自己組み立て複合体であって、ここで、
前記有効成分は、Cy5、ローダミン、ドキソルビシン及びトリアムシノロンアセトニドからなる群から選択される少なくとも1以上である、自己組み立て複合体。 - 前記有効成分は、前記自己組み立て複合体が自己分解されることで排出され、
前記有効成分は、放出時間の間持続的に放出される、
請求項2に記載の鉄イオンを含む自己組み立て複合体。 - 前記放出時間は、1日~90日である、
請求項3に記載の鉄イオンを含む自己組み立て複合体。 - 前記リガンドは、AMPおよびATPが混合されたものであり、
前記AMPおよびATPが2:1~1:2のモル濃度比率で含まれる、
請求項1に記載の鉄イオンを含む自己組み立て複合体。 - 前記リガンドがADPおよびATPのうち少なくともいずれか一つを含む場合、前記自
己組み立て複合体は親水性を有し、
前記リガンドがAMPを含む場合、前記自己組み立て複合体は疎水性を有する、
請求項1に記載の鉄イオンを含む自己組み立て複合体。 - 前記リガンドは、AMP、ADP、ADPとATPの混合リガンド、およびAMPとATPの混合リガンドのうち少なくともいずれか一つであり、
前記自己組み立て複合体が球形に備えられ、
複数の前記自己組み立て複合体が互いに付着されて2次元的プレート形状または3次元的集合体を形成する、
請求項1に記載の鉄イオンを含む自己組み立て複合体。 - 前記2次元的プレート形状は、磁場の印加時に回転する、
請求項7に記載の鉄イオンを含む自己組み立て複合体。 - 前記3次元的集合体は、集合体の内部に気孔を含む、
請求項7に記載の鉄イオンを含む自己組み立て複合体。 - 前記2次元的プレート形状および3次元的集合体のうち少なくともいずれか一つは、内
部に細胞を担持して生体内に細胞を伝達する、
請求項7に記載の鉄イオンを含む自己組み立て複合体。 - 隣り合う前記リガンドの間のπ-π相互作用、および水素結合のうち少なくともいずれ
か一つ、または
鉄イオンと前記リガンドとの間の配位結合によって自己組み立て複合体を形成する、
請求項1に記載の鉄イオンを含む自己組み立て複合体。 - 前記鉄イオンおよび前記リガンドは、5:1~1:1のモル濃度比率で含まれる、
請求項1に記載の鉄イオンを含む自己組み立て複合体。 - 前記リガンドの種類によって自己分解速度が変わる、
請求項1に記載の鉄イオンを含む自己組み立て複合体。 - 1日~90日間自己分解される、
請求項1に記載の鉄イオンを含む自己組み立て複合体。 - キレート化剤を含む条件、強酸条件および強塩基条件のうち少なくともいずれか一つの条件で自己分解が促進され、
前記強酸条件のpHは2~5であり、前記強塩基条件のpHは9~12である、
請求項1に記載の鉄イオンを含む自己組み立て複合体。 - 自己分解が促進されて0.5秒~1分間自己分解される、
請求項12に記載の鉄イオンを含む自己組み立て複合体。 - 前記自己組み立て複合体は、常磁性を有し、
前記自己組み立て複合体が大きく形成されるほど磁気モーメントが大きく形成される、
請求項1に記載の鉄イオンを含む自己組み立て複合体。 - 生体内または生体外で前記自己組み立て複合体に磁場印加する場合、前記自己組み立て複合体が大きく形成されるほどさらに速く拡散される、
請求項1に記載の鉄イオンを含む自己組み立て複合体。 - 物質伝達キャリア、細胞培養培地、T2造影剤および人工骨の材料のうち少なくともいずれか一つとして使用される、
請求項1に記載の鉄イオンを含む自己組み立て複合体。
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