JP6044920B2 - 酸化ldl受容体に作用するリポソーム - Google Patents
酸化ldl受容体に作用するリポソーム Download PDFInfo
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- JP6044920B2 JP6044920B2 JP2012072404A JP2012072404A JP6044920B2 JP 6044920 B2 JP6044920 B2 JP 6044920B2 JP 2012072404 A JP2012072404 A JP 2012072404A JP 2012072404 A JP2012072404 A JP 2012072404A JP 6044920 B2 JP6044920 B2 JP 6044920B2
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Landscapes
- Medicinal Preparation (AREA)
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Description
(A)DOPG溶液を容器上で薄膜化する工程;
(B)該薄膜化したDOPGを乾燥後水和させる工程
(C)(B)で水和したDOPG溶液を攪拌しつつ凍結させ、その後加熱して溶解し、必要に応じてこれを繰り返す工程;および
(D)該DOPG溶液をサイジングフィルターに通す工程
を包含する、方法を提供する。
以下に本明細書において特に使用される用語の定義を列挙する。
本明細書において使用される場合、用語「固相」とは、本明細書中において「基板」および「基材」と互換的に使用され、本発明のデバイスが構築される材料をいう。抗体のような分子が固定され得る平面状の支持体をいう。本発明において表面プラズモン共鳴の原理を用いて検出する場合、固相は、金、銀またはアルミニウムを含む金属薄膜を片面に持つガラス基板の基材であることが好ましい。本発明において水晶発振子マイクロバランスの原理を用いて検出する場合は、周波数変換素子(例えば水晶発振子、表面弾性波素子)を固相として用い、直接受容体を結合させる。水晶板の片面はシリコーンで被覆し、もう一方の面は金電極を施したものを固相として用いる。本発明において酵素結合イムノソルベント検定法(ELISA)のような機構を使用する場合、一般に、固相(基材)としては、マイクロタイタープレートが使用される。基板の材料としては、共有結合かまたは非共有結合のいずれかで、本発明において使用される生体分子に結合する特性を有するかまたはそのような特性を有するように誘導体化され得る、任意の固体材料が挙げられる。適切な基材としては、ビーズ、金粒子、プレート(例えば、マイクロタイタープレート)、試験管、チップ、磁性粒子、膜、繊維、スライドガラス、金属薄膜、フィルター、チューブ、ボール、ダイアモンド様炭素被膜ステンレスなどが挙げられるが、これらに限定されない。
以下に好ましい実施形態の説明を記載するが、この実施形態は本発明の例示であり、本発明の範囲はそのような好ましい実施形態に限定されないことが理解されるべきである。当業者はまた、以下のような好ましい実施例を参考にして、本発明の範囲内にある改変、変更などを容易に行うことができることが理解されるべきである。
1つの局面において、本発明は、実質的に1,2−ジオレオイル−sn−グリセロー3−[ホスホ−rac−(1−グリセロール)](DOPG)からなる、単層膜リポソーム、例えば、小単層膜リポソーム(SUV)または大単層膜リポソーム(LUV)(本明細書においてDOPG SUV、DOPG LUV、あるいはDOPG SUVまたはLUVともいう。)を提供する。好ましくは、本発明のリポソームは、粒径が70nm〜150nmである。
本発明は、1,2−ジオレオイル−sn−グリセロー3−[ホスホ−rac−(1−グリセロール)](DOPG)を含む単層膜リポソーム(小単層膜リポソーム(SUV)および/または大単層膜リポソーム(LUV)を含む)を含む、酸化LDL受容体に対して物質を特異的に送達するための媒体を提供する。DOPGがLOX−1等の酸化LDL受容体に対して特異的な相互作用を示すことは従来知られておらず、本発明において初めて見出された知見であり、本発明はこれを利用することによって、酸化LDL受容体に対して物質を特異的に送達することを達成した。
・LOX−1への極めて高い結合能
・LOX−1への特異的結合
・血管内皮細胞上で、LOX−1に特異的に認識され、取り込まれるが(他の変性LDL受容体による認識・取り込みは認められない)、変性LDLと異なり、細胞の機能不全を誘導することはない等
LOX−1を標的とした物質送達系等として使用可能なSUVが、簡単に得られたことが明らかになった。なお、DOPGおよびDOPCの構造は以下に示す。
DOPG:1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phospho-(1'-rac-glycerol) (sodium salt)
本発明は、別の局面において、本発明のDOPGを含むSUVを生産する方法を提供する。この方法は、たとえば、(A)DOPG溶液を容器上で薄膜化する工程;(B)該薄膜化したDOPGを乾燥後水和させる工程(C)(B)で水和したDOPG溶液を攪拌しつつ凍結させ、その後加熱して溶解し、必要に応じてこれを繰り返す工程;および(D)該DOPG溶液をサイジングフィルターに通す工程を包含する。
1.試験管に脂質DOPGクロロホルム溶液(Avanti)(50mg/ml)を100μLとる。
2.試験管を回しながら、窒素を緩やかに吹き付けてクロロホルムを乾かし、脂質を試験管に薄膜として付着する。
3.デシケーターに試験管を入れて真空ポンプで引き、一晩乾燥する。
4.ミリQを1mL加えて30分静置し、脂質DOPGを水和した。蛍光色素を入れる場合は、ここでDiIストック溶液(蛍光色素DiI(invitrogen)を濃度50mg/mlでDMSOに溶かしたもの)を32μl加える。
5.試験管をボルテックスで攪拌しながら液体窒素に潜らせ、試験管壁に溶液が張り付くように凍結させる。その後42℃の恒温槽に入れて溶解する。これを5回繰り返す。
100、50、30nmのサイジングフィルター(Avanti)に10回ずつ順に通し、リポソームのサイズを均一にする。
本発明は、1つの局面において、DOPGを含むSUVまたはLUVを含む、血管内皮の機能を調節しうる因子をスクリーニングまたは分析するための組成物を提供する。血管内皮の機能に悪影響がないことの特徴については、AcLDLの知見からは予想できなかった。本明細書において「血管内皮の機能を調節しうる因子」は、血管内皮の機能を調節しうる限りどのような因子でも用いることができる。例えば、血管内皮の機能を調節しうる因子は、血管内皮の機能不全を誘導する因子または誘導を抑制する因子であってもよい。「血管内皮の機能不全を誘導する因子」は、血管内皮の機能不全を誘導することができるものであればどのような因子を用いてもよい。「血管内皮の機能不全の誘導を抑制する因子」としては血管内皮の機能不全の誘導を抑制することができる限りどのような因子を用いてもよい。血管内皮の機能不全を誘導する因子は動物モデル等を作製するために用いることができる。血管内皮の機能不全の誘導を抑制する因子は、疾患の治療等に用いることができ、本明細書において「血管内皮機能不全に対する薬剤」とも称される。そのような因子としては、例えば、カルシウム拮抗薬、ACE阻害薬,アンジオテンシンII受容体拮抗薬(ARB)、チアジリン誘導体等、種々のアンタゴニスト等の医薬を挙げることができるがこれらに限定されない。このような実施形態の例としては、動脈硬化に抑制的に働く一酸化窒素(NO)の産生に関わる血管内皮型NO産生酵素(endothelial NO synthase:eNOS)の活性を上昇させる作用のあるジヒドロピリジン系Ca拮抗剤などを封入したDOPG 単層膜リポソームを内皮上に発現しているLOX−1を介して効率的に血管内皮に導入することができ、内皮細胞機能不全に伴い誘導される血管細胞接着分子−1(VCAM−1)、細胞間接着分子−1(ICAM−1),E−セレクチンなどの接着因子、単球走化性因子−1(MCP−1)などのサイトカインの発現を抑制するために、siRNAをDOPG 単層膜リポソームをキャリアとして内皮細胞内に導入する遺伝子サイレンシングによる治療を想定することができる。
別の局面において、本発明は、変性LDLのLOX−1への結合を阻害するための、DOPGを含むSUVまたはLUVを含む組成物を提供する。LOX−1への結合阻害を試薬(種々のアンタゴニスト)として利用することのほか、LOX−1の変性LDLへの結合に起因する状態(例えば、動脈硬化性疾患の初期過程)および/または当該分野で公知で本明細書に例示されるような血管内皮状態の悪化に起因する状態、障害または疾患等を抑制することができる。
本発明は、DOPG SUVまたはLUVのLOX−1への特異的結合および変性LDLとの競合阻害特性から、それ自体を治療剤として使用することのほか、これを特異的送達媒体として医薬組成物として使用することができる。
(リポソームの製造)
酸化LDL受容体(LOX−1)に高い親和性を有し、LOX−1を介して細胞内に取り込まれる1,2−Dioleoyl−sn−Glycero−3−[Phospho−rac−(1−glycerol)](DOPG)から構成される単層膜リポソーム(small unilamellar vesicles:SUVまたはlarge unilamellar vesicles:LUV)を作製した。単層膜リポソームは最終的に30nmのフィルターを通した粒径約100nmのサイズのものと、100nmのフィルターを通した粒径約150 nmのサイズのものを調製した(図1参照)。
1.試験管に脂質DOPGクロロホルム溶液(Avanti)(50mg/ml)を100μLとった。
2.試験管を回しながら、窒素を緩やかに吹き付けてクロロホルムを乾かし、脂質を試験管に薄膜として付着した。
3.デシケーターに試験管を入れて真空ポンプで引き、一晩乾燥した。
4.ミリQを1mL加えて30分静置し、脂質DOPGを水和した。蛍光色素を入れる場合は、ここでDiIストック溶液(蛍光色素DiI(invitrogen)を濃度50mg/mlでDMSOに溶かしたもの)を32μl加えた。
5.試験管をボルテックスで攪拌しながら液体窒素に潜らせ、試験管壁に溶液が張り付くように凍結させた。その後42℃の恒温槽に入れて溶解した。これを5回繰り返した。
6.100、50、30nmのサイジングフィルター(Avanti)に10回ずつ順に通し、リポソームのサイズを均一にした。
得られた単層膜リポソームの粒子サイズは、製造後60日以上を経ても室温で安定であった(図2)。
表面電位も60日以内であれば室温で変化がないことを確認した。表面電位は、DOPG SUV(濃度 2.5mg/ml)の表面電位を25℃でゼータサイザーナノ(マルバルーン社)により測定した。
次に、表面プラズモン共鳴によるLOX−1集積単相チップとAcLDLの相互作用解析を行った。以下にそのプロトコルを示す。
複数の粒子サイズのDOPG単層膜リポソームについて、LOX−1への親和性を分析した。本実施例では、実施例3と基本的に同様の手順で行った。ただし、AcLDLの代わりに、DOPG SUV,DOPG LUVそれぞれについて同様のことを行った。
DOPG SUVに蛍光色素DiIを導入し、細胞上におけるDOPG単層膜リポソームのLOX−1への結合と取り込みを蛍光顕微鏡により観察した。
本実施例では、DOPG単層膜リポソームとAcLDLの結合の競合を解析した。以下にプロトコルを示す。
本実施例では、DOPG SUVのヒト大動脈内皮細胞(HAEC)への結合と取り込みの観察を行った。以下にプロトコルを示す。
本実施例では、HAECへのAcLDLとDOPG SUVの結合の競合を解析した。以下にプロトコルを示す。
本実施例9ではDOPG SUVのHAECへの結合と取り込みの定量解析を行った。
本実施例では、のDOPG SUVの血管内皮機能不全の誘導がないことを実証した。以下にプロトコールを示す。
実際の治療剤の例としては以下が考えられる。
MRIなどリポソーム製剤の診断での例として以下のような利用法が例示されうる。
配列番号2:PR−LOX−1またはLOX−1のアミノ酸配列
Claims (13)
- 実質的に1,2−ジオレオイル−sn−グリセロー3−[ホスホ−rac−(1−グリセロール)](DOPG)から構成される小単層膜リポソーム(SUV)および/または大単層膜リポソーム(LUV)を含む、血管内皮の機能不全を誘導せずに酸化LDL受容体に対して物質を特異的に送達するための媒体。
- 前記酸化LDL受容体は細胞に含まれるものである、請求項1に記載の媒体。
- 前記細胞は、血管内皮細胞である、請求項2に記載の媒体。
- 前記細胞は、微小血管内皮、静脈内皮または動脈内皮細胞である、請求項3に記載の媒体。
- 前記送達は、前記酸化LDL受容体のうちLOX−1にのみ特異的である、請求項1〜4のいずれか1項に記載の媒体。
- 前記SUVおよび/またはLUVの粒径は70nm〜150nmである、請求項1〜5のいずれか1項に記載の媒体。
- 前記SUVおよび/またはLUVはLOX−1に対する解離定数KDが5.0×10−12以下である、請求項1〜6のいずれか1項に記載の媒体。
- 実質的にDOPGから構成されるSUVまたはLUVを含む、血管内皮の機能不全を調節しうる因子を、該因子を必要とする被験体に送達するための組成物。
- 前記因子は、カルシウム拮抗薬、ACE阻害薬,アンジオテンシンII受容体拮抗薬(ARB)、チアジリン誘導体、ならびに血管細胞接着分子−1(VCAM−1)、血管内皮機能不全に関連するsiRNAからなる群より選択される、請求項8に記載の組成物。
- 変性LDLのLOX−1への結合を阻害するための、実質的にDOPGから構成されるSUVまたはLUVを含む組成物であって、該SUVまたはLUVはLOX−1に対する解離定数KDが5.0×10−12以下である、組成物。
- 血管内皮機能不全を抑制するための、実質的にDOPGから構成されるSUVまたはLUVを含む組成物。
- 前記組成物は、血管内皮機能不全に対する薬剤を含む、請求項11に記載の組成物。
- 前記組成物は、血管内皮機能不全に関連するsiRNA、遺伝子導入キャリアまたはシグナル伝達調節剤を含む、請求項11に記載の組成物。
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