JP6861643B2 - テキサフィリン−リン脂質複合体及びその調製方法 - Google Patents
テキサフィリン−リン脂質複合体及びその調製方法 Download PDFInfo
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- JP6861643B2 JP6861643B2 JP2017554284A JP2017554284A JP6861643B2 JP 6861643 B2 JP6861643 B2 JP 6861643B2 JP 2017554284 A JP2017554284 A JP 2017554284A JP 2017554284 A JP2017554284 A JP 2017554284A JP 6861643 B2 JP6861643 B2 JP 6861643B2
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- texaphyllin
- phospholipid
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- texaphyrin
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- QAHREYKOYSIQPH-UHFFFAOYSA-L cobalt(II) acetate Chemical compound [Co+2].CC([O-])=O.CC([O-])=O QAHREYKOYSIQPH-UHFFFAOYSA-L 0.000 description 1
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- 150000002148 esters Chemical class 0.000 description 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 1
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- AFRWBGJRWRHQOV-UHFFFAOYSA-N ethyl 5-bromopentanoate Chemical compound CCOC(=O)CCCCBr AFRWBGJRWRHQOV-UHFFFAOYSA-N 0.000 description 1
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- 229910052740 iodine Inorganic materials 0.000 description 1
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- LNOZJRCUHSPCDZ-UHFFFAOYSA-L iron(ii) acetate Chemical compound [Fe+2].CC([O-])=O.CC([O-])=O LNOZJRCUHSPCDZ-UHFFFAOYSA-L 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
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- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- 229910052713 technetium Inorganic materials 0.000 description 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- PWWGCBMGIAPMHQ-UHFFFAOYSA-N thulium(3+) Chemical compound [Tm+3] PWWGCBMGIAPMHQ-UHFFFAOYSA-N 0.000 description 1
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- AWSFICBXMUKWSK-UHFFFAOYSA-N ytterbium(3+) Chemical compound [Yb+3] AWSFICBXMUKWSK-UHFFFAOYSA-N 0.000 description 1
- GRTBAGCGDOYUBE-UHFFFAOYSA-N yttrium(3+) Chemical compound [Y+3] GRTBAGCGDOYUBE-UHFFFAOYSA-N 0.000 description 1
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Description
上述のテキサフィリン−リン脂質複合体を集合させてナノ粒子とすることができる。更なる態様によれば、このテキサフィリン−リン脂質複合体を含むナノ粒子が提供される。そのようなナノ粒子は、少なくとも15、25、35、45、55、65、75、85、95または100モル%の複合体を含み得る。
更なる態様によれば、上述のテキサフィリン−リン脂質複合体を調製する方法であって、好適な反応条件下で、
更なる態様によれば、上述のテキサフィリン−リン脂質複合体またはナノ粒子の光音響画像化、光力学療法、光熱療法または蛍光画像化のための使用が提供される。
両親媒性分子は、疎水性表面の互いの相互作用、及び水面に対する親水性部分との相互作用に起因する所定の条件下での自己組織化を受けることが実証されている。テキサフィリン−脂質複合体の構造は、本質的に、大きな親水性マクロサイクル頭部、及び長い疎水性脂肪酸鎖を有する両親媒性の双性イオン性分子である。自己組織化の原理の知識を考慮し、これをテキサフィリン−脂質複合体の特徴に適用すると、理想的な条件下で、遊離塩基のテキサフィリン−脂質及び金属−テキサフィリン脂質複合体が自己組織化を受けて繰り返し単位のナノ構造を形成するであろうということが予測された。遊離塩基のテキサフィリン−脂質及び金属−テキサフィリン脂質複合体の両方が適切な条件で容易に自己組織化することができ、100〜120nmの範囲の直径を有するナノ粒子を生成すると共に、単分散性を示すことが実証された(図6参照)。
Mn−ナノテキサフィリンのワンポット形成(図8参照):10mLの無水MeOH中の遊離塩基のテキサフィリン−リン脂質複合体(60mg、55.18μmol)及びMn(OAc)2・(H2O)4(13.52mg、55.18μmol)を反応容器に添加し、0℃に冷却する。次に、トリエチルアミン(76.71μL、551.75μmol)を添加することにより、明るい赤から濃緑への即時の色変化によってMnの即座のキレート化が観察される。コレステロール(14.83mg、40mol%)及び1,2−ジステアロイル−sn−グリセロ−3−ホスホエタノールアミン−N−[アミノ(ポリエチレングリコール)−2000](DSPE−2KPEG、13.46mg、5mol%)を導入し、溶媒を高真空下で溶媒を除去すると、フィルムが形成される。フィルムをPBS(30mL)で再水和化し、凍結融解サイクル(8)に付し、75℃で100nmのポリカーボネート膜で押し出した。Mn−ナノテキサフィリンのサイズは、Nanosizer ZS90(Malvern Instruments)を用いて特性化された。TEM画像は、200kVの加速電圧(及び150000倍の倍率)を有するFEI Technai 20顕微鏡を使用して収集した。試料をカーボン被覆銅グリッド上に沈着させ、2%酢酸ウラニル染色剤と共にインキュベートして画像造影を誘導した。Fluoromax蛍光光度計(Horiba Jobin Yvon)を使用して、Mn−ナノテキサフィリンの蛍光消光を特性化した。PBS(完全粒子)及び0.5%Triton−X100(ナノ構造破壊試料)を有するPBS中のMn−ナノテキサフィリン溶液をそれぞれ460nmで励起し、蛍光発光スペクトルを600〜800nmで収集した。発光ピーク下の面積を積分し、完全な及び解離したナノ粒子からの値を比較した。
メタロ−テキサフィリンライブラリのナノアセンブリは、マンガン(Mn)−テキサフィリン−リン脂質構築ブロックの合成から開始した。常磁性のMnは、組織のT1及びT2両方の緩和時間定数の大幅な低下を引き起こす強力な磁気共鳴画像化(MRI)造影剤である。(i)インビボ安定性;(ii)安全性;及び(iii)造影向上についてMn送達を改善するための多くのキレート化方策が開発されてきた。ポルフィリンは、Mn用の有望なキレート化マクロサイクルとして使用されており[10]、主にT1の観点から、有効な造影向上を有する一方で、インビボで極めて安定な錯体を提供する[11]。従来のポルフィリン(4−配位状態)と比較して、テキサフィリンのより大きな構築及びより強い配位(5−配位状態)により、安定性及び緩和性の改善などの新しい特性を有するより安定なMnベースのキレート化を導き得る。
Mn−ナノテキサフィリンを7Tの磁場強度で評価した。縦緩和(r1)及び横緩和(r2)は、Mn−テキサフィリン−リン脂質濃度に対して緩和時間の逆数をプロットすることによって決定した(図9)。完全Mn−ナノテキサフィリンは、T1及びT2強調画像の両方において用量依存的増加を示し、ポジティブ(T1)及びネガティブ(T2)の造影向上の際立った増大が観察された。完全Mn−ナノテキサフィリンについて、計算された0.81mM−1s−1のr1が決定された(図9a)。ホスファチジルコリンヘッドグループから構成される直径100nmのベシクルについての幾何学的計算は、ナノテキサフィリン当たりおおよそ8×104のテキサフィリン複合体があることを示している。我々のMn−ナノテキサフィリン中の各々のテキサフィリンは安定な1:1キレート化から構成されているので、これはおよそ8×104のMn(II)イオンを有する各々のMn−ナノテキサフィリンと同等である(ナノ粒子当たり6.48×104mM−1s−1のr1)。0.5%のTriton X−100を含有するPBSにおいてMn−ナノテキサフィリンを個々のモノマーに解離させた後、計算された0.99mM−1s−1のr1が確立され、自己組織化構築物と比較して22%の向上を示した。各々の個々のナノ粒子へのMn(II)の高装填は、透過性及び保持効果の向上による新生物組織への送達及び選択性の向上に結びつき[12]、個々のモノマーの使用によって達成できない利点をもたらし得る。
キレート化安定性:PBS中のMn−テキサフィリン−リン脂質をFBSと1:1で混合し、37℃でインキュベートした。0、24及び48時間で、少量のアリコートを使用してキレート安定性を評価した。Mn−キレート化の割合は、uPLC−MS分析による遊離塩基のテキサフィリンリン脂質及びMn−テキサフィリン−リン脂質のピークの積分によって計算した。
[1] J.L.Sessler,G.Hemmi,T.D.Mody,T.Murai,A.Burrell,S.W.Young,Accounts of Chemical Research 1994,27,43−50.
[2] L.Sessler,T.D.Mody,G.W.Hemmi,V.Lynch,Inorganic Chemistry 1993,32,3175−3187.
[3] D.I.Rosenthal,P.Nurenberg,C.R.Becerra,E.P.Frenkel,D.P.Carbone,B.L.Lum,R.Miller,J.Engel,S.Young,D.Miles,Clinical Cancer Research 1999,5,739−745.
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Claims (18)
- テキサフィリン−リン脂質複合体を調製する方法であって、
前記テキサフィリン−リン脂質複合体が、リン脂質の脂質側鎖に共有結合している、テキサフィリン、テキサフィリン誘導体又はテキサフィリン類似体を含み、
前記テキサフィリン誘導体又は前記テキサフィリン類似体が下記式Iで表されるコア部分を有し、
塩酸存在下及び少なくとも50℃の加熱下で、
(上記式中、R7〜R10のうちの1つは、下記式(C)で表されるリン脂質基であり、
R7〜R10の残りは、独立して、H、アルキル基、ヘテロアルキル基、シクロアルキル基、アルケニル基、ヘテロアルケニル基、アルキニル基、ヘテロアルキニル基、アリール基、ヘテロアリール基、複素環基、及びアシル基から選択される。nは1〜20の整数である。)
を、
と反応させて、
を生成することを含む、方法。 - 前記化合物5が、N,N−ジイソプロピルエチルアミン、4−ジメチルアミノピリジン及びN−(3−ジメチルアミノプロピル)−N’−エチルカルボジイミド塩酸塩存在下で、a)下記化合物4と、b)下記式(B)で表されるリン脂質とを反応させることによって調製される、請求項2に記載の方法。
(上記式中、nは1〜20の整数である。)
- 前記複合体から前記テキサフィリン、テキサフィリン誘導体又はテキサフィリン類似体を開裂することを含むテキサフィリン、テキサフィリン誘導体又はテキサフィリン類似体を合成することを更に含む、請求項1に記載の方法。
- 前記開裂が、酵素を使用して実施される、請求項4に記載の方法。
- 前記リン脂質が分岐又は不飽和である、請求項1に記載の方法。
- 前記テキサフィリン、テキサフィリン誘導体またはテキサフィリン類似体が、sn−1またはsn−2位で前記脂質側鎖に結合している、請求項1に記載の方法。
- 前記テキサフィリン、テキサフィリン誘導体またはテキサフィリン類似体が、テキサフィリンである、請求項1に記載の方法。
- 前記ポルフィリン−リン脂質複合体をMn、Fe、Co、Zn、Y、Cd、In、La、Hg、Pb、Bi、Ce、Pr、Nd、Sm、Eu、Gd、Tb、Dy、Ho、Er、Tm、Yb、及びLuよりなる群から選択される金属と錯体形成することを更に含む、請求項1に記載の方法。
- 前記テキサフィリン−リン脂質複合体を含むナノ粒子を形成することを更に含み、
前記ナノ粒子が少なくとも15、25、35、45、55、65、75、85、95または100モル%のテキサフィリン−リン脂質複合体を含む、請求項1に記載の方法。 - 前記ナノ粒子が、PEG、PEG−脂質及びPEG−DSPEよりなる群から選択されるPEG化物を更に含む、請求項12に記載の方法。
- 前記PEG化物が、約5モル%の量で存在する、請求項13に記載の方法。
- 二重層ベシクル又は単層ベシクルである、請求項12に記載の方法。
- 前記ナノ粒子が、実質的に球状であり、直径が約3nm〜約200nmである、請求項12に記載の方法。
- 活性剤を中に封入することを更に含む、請求項12に記載の方法。
- 前記ナノ粒子が、標的分子を更に含む、請求項12に記載の方法。
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