JP2009535348A - 膜貫通薬物送達システムに適用するためのプロサポシン由来の融合タンパク質又はポリペプチドを含む組成物 - Google Patents
膜貫通薬物送達システムに適用するためのプロサポシン由来の融合タンパク質又はポリペプチドを含む組成物 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
【選択図】 なし
Description
本願は、2006年4月28日に出願された米国特許仮出願第60/745,969号(その全体が参照により本明細書に援用される)の利益を主張する。
h−u−Cys−Glu−h−Cys−Glu−h−h−h−Lys−Glu−h−u−Lys−h−h−Asp−Asn−Asn−Lys−u−Glu−Lys−Glu−h−h−Asp−h−h−Asp−Lys−h−Cys−u−Lys−h−h(式中、h=疎水性アミノ酸(Val、Leu、Ile、Met、Pro、Phe、及びAlaを含む)、u=非荷電極性アミノ酸(Thr、Ser、Tyr、Gly、Gln、及びAsnを含む))。
「投与される」及び「投与」という用語は一般的に、例えば脂質及び/又は小胞組成物及びフラッシュ剤を含む生体適合性材料の患者への投与を表す。したがって、「投与される」及び「投与」は例えば、脂質及び/又は小胞組成物及び/又はフラッシュ剤の血管への注射を表す。「投与される」及び「投与」という用語は、脂質及び/又は小胞組成物及び/又はフラッシュ剤の対象の領域への送達も表すことができる。
14:0 PS 1,2−ジミリストイル−sn−グリセロ−3−[ホスホ−L−セリン](ナトリウム塩)(DMPS)、16:0 PS 1,2−ジパルミトイル−sn−グリセロ−3−[ホスホ−L−セリン](ナトリウム塩)(DPPS)、17:0 PS 1,2−ジヘプタデカノイル−sn−グリセロ−3−[ホスホ−L−セリン](ナトリウム塩)、18:0 PS 1,2−ジステアロイル−sn−グリセロ−3−[ホスホ−L−セリン](ナトリウム塩)(DSPS)、18:1 PS 1,2−ジオレオイル−sn−グリセロ−3−[ホスホ−L−セリン](ナトリウム塩)(DOPS)、18:2 PS 1,2−ジリノレオイル−sn−グリセロ−3−[ホスホ−L−セリン](ナトリウム塩)、20:4 PS 1,2−ジアラキドノイル−sn−グリセロ−3−[ホスホ−L−セリン](ナトリウム塩)、22:6 PS 1,2−ジドコサヘキサエノイル−sn−グリセロ−3−[ホスホ−L−セリン](ナトリウム塩)、16:0−18:1 PS 1−パルミトイル−2−オレオイル−sn−グリセロ−3−[ホスホ−L−セリン](ナトリウム塩)(POPS)、16:0−18:2 PS 1−パルミトイル−2−リノレオイル−sn−グリセロ−3−[ホスホ−L−セリン](ナトリウム塩)、16:0−22:6 PS 1−パルミトイル−2−ドコサヘキサエノイル−sn−グリセロ−3−[ホスホ−L−セリン](ナトリウム塩)、18:0−18:1 PS 1−ステアロイル−2−オレオイル−sn−グリセロ−3−[ホスホ−L−セリン](ナトリウム塩)、18:0−18:2 PS 1−ステアロイル−2−リノレオイル−sn−グリセロ−3−[ホスホ−L−セリン](ナトリウム塩)、18:0−20:4 PS 1−ステアロイル−2−アラキドノイル−sn−グリセロ−3−[ホスホ−L−セリン](ナトリウム塩)、18:0−22:6 PS 1−ステアロイル−2−ドコサヘキサエノイル−sn−グリセロ−3−[ホスホ−L−セリン](ナトリウム塩)、16:0 PC 1,2−ジパルミトイル−sn−グリセロ−3−ホスホコリン(DPPC)、17:0 PC 1,2−ジヘプタデカノイル−sn−グリセロ−3−ホスホコリン、18:0 PC 1,2−ジステアロイル−sn−グリセロ−3−ホスホコリン(DSPC)、16:1 PC(シス) 1,2−ジパルミトレオイル−sn−グリセロ−3−ホスホコリン、16:1 トランスPC 1,2−ジパルミテライドイル(Dipalmitelaidoyl)−sn−グリセロ−3−ホスホコリン、18:1 PC デルタ6(シス) 1,2−ジペトロセリノイル−sn−グリセロ−3−ホスホコリン、18:2 PC(シス) 1,2−ジリノレオイル−sn−グリセロ−3−ホスホコリン、18:3 PC(シス) 1,2−ジリノレノイル−sn−グリセロ−3−ホスホコリン、20:1 PC(シス) 1,2−ジエイコセノイル−sn−グリセロ−3−ホスホコリン、22:1 PC(シス) 1,2−ジエルコイル−sn−グリセロ−3−ホスホコリン、22:0 PC 1,2−ジベヘノイル−sn−グリセロ−3−ホスホコリン、24:1 PC(シス) 1,2−ジネルボノイル−sn−グリセロ−3−ホスホコリン、16:0−18:0 PC 1−パルミトイル−2−ステアロイル−sn−グリセロ−3−ホスホコリン、16:0−18:1 PC 1−パルミトイル−2−オレオイル−sn−グリセロ−3−ホスホコリン、16:0−18:2 PC 1−パルミトイル−2−リノレオイル−sn−グリセロ−3−ホスホコリン、18:0−18:1 PC 1−ステアロイル−2−オレオイル−sn−グリセロ−3−ホスホコリン、18:0−18:2 PC 1−ステアロイル−2−リノレオイル−sn−グリセロ−3−ホスホコリン、18:1−18:0 PC 1−オレオイル−2−ステアロイル−sn−グリセロ−3−ホスホコリン、18:1−16:0 PC 1−オレオイル−2−パルミトイル−sn−グリセロ−3−ホスホコリン、18:0−20:4 PC 1−ステアロイル−2−アラキドニル−sn−グリセロ−3−ホスホコリン、16:0−18:1 PG 1−パルミトイル−2−オレオイル−sn−グリセロ−3−[ホスホ−rac−(1−グリセロール)](ナトリウム塩)(POPG)、18:1 PG 1,2−ジオレオイル−sn−グリセロ−3−[ホスホ−rac−(1−グリセロール)](ナトリウム塩)(DOPG)、18:1 PA 1,2−ジオレオイル−sn−グリセロ−3−ホスフェート(モノナトリウム塩)(DOPA)、18:1 PI 1,2−ジオレオイル−sn−グリセロ−3−ホスホイノシトール(アンモニウム塩)、16:0(D31)−18:1 PI 1−パルミトイル(D31)−2−オレオイル−sn−グリセロ−3−ホスホイノシトール(アンモニウム塩)、18:1 PE 1,2−ジオレオイル−sn−グリセロ−3−ホスホエタノールアミン(DOPE)、18:2 PE 1,2−ジリノレオイル−sn−グリセロ−3−ホスホエタノールアミン。
一実施形態において、本発明は、1つ又は複数のリソソーム融合タンパク質又はポリペプチドを含むリン脂質膜を提供する。別の実施形態では、1つ又は複数のリソソーム融合タンパク質又はポリペプチドが、アニオン性リポソーム内に含有される。別の実施形態では、アニオン性リポソームは薬学的因子をさらに含む。
Ser−Asp−Val−Tyr−Cys−Glu−Val−Cys−Glu−Phe−Leu−Val−Lys−Glu−Val−Thr−Lys−Leu−Ile−Asp−Asn−Asn−Lys−Thr−Glu−Lys−Glu−Ile−Leu−Asp−Ala−Phe−Asp−Lys−Met−Cys−Ser−Lys−Leu−Pro(配列番号1)、
Val−Tyr−Cys−Glu−Val−Cys−Glu−Phe−Leu−Val−Lys−Glu−Val−Thr−Lys−Leu−Ile−Asp−Asn−Asn−Lys−Thr−Glu−Lys−Glu−Ile−Leu−Asp−Ala−Phe−Asp−Lys−Met−Cys−Ser−Lys−Leu−Pro(配列番号2)、並びにその誘導体、類似体、相同体、断片及び混合物が挙げられる。式:
h−u−Cys−Glu−h−Cys−Glu−h−h−h−Lys−Glu−h−u−Lys−h−h−Asp−Asn−Asn−Lys−u−Glu−Lys−Glu−h−h−Asp−h−h−Asp−Lys−h−Cys−u−Lys−h−h
(式中、h=疎水性アミノ酸(Val、Leu、Ile、Met、Pro、Phe、及びAlaを含む)、u=非荷電極性アミノ酸(Thr、Ser、Tyr、Gly、Gln、及びAsnを含む))のポリペプチドも含まれる。
本発明は、皮膚膜若しくは粘膜を通して、又は血液脳関門若しくは他の細胞膜を通して特定の薬学的因子又は画像化因子を送達するためのサポシン媒介性の膜融合に影響を与える、アニオン性リン脂質膜を利用する。これらのアニオン性リン脂質膜は一般的に、リポソームを調製するのに用いられる。リポソームは、同心円状の脂質二重層から成る微小小胞であり、本明細書で用いられるように球状の二重層で配置された両親媒性脂質から成る小さい小胞を表す。構造的にリポソームは、数百Å〜わずか1mmの寸法で、長いチューブから球体までとサイズ及び形状に幅がある。全体的な形状にかかわらず、二重層は一般的に、閉じた同心円状のラメラとして組織化され、水性層がそれぞれのラメラと隣接したラメラとを隔てている。通常、小胞のサイズは、直径約20nm〜約30000nmの範囲である。
本発明に従って、生体活性剤(例えば、薬学的因子)は、皮膚膜及び粘膜内の及び/又は下の、又は血管脳関門若しくは他の細胞膜を通る、サポシン媒介性輸送のために、アニオン性リン脂質膜又はリポソーム内に含有される。活性剤は、脂質、特にセラミド、ステロイド、脂肪酸、トリアシルグリセロール、遺伝子及びタンパク質、DNA、RNA、又はsiRNAを含む(が、これらに限定されない)大きな生体分子であり得る。活性剤は、小さな有機分子から成っていてもよい。本明細書で用いられるように、「薬学的因子」は、サポシンCリポソームによって送達する場合に美容的利点又は治療的利点を与える任意の材料又は材料の組合せを意味する。
薬学的因子の好ましい例としては、ジギタリス薬(例えばジゴキシン、ジギトキシン、ジゴキシゲニン、及びジギトキシゲニン)が挙げられる。これらの薬物は全て主に、強心剤として用いられる。
ステロイド化合物は別の好ましい群の薬学的因子を形成する。ステロイド系の薬学的因子の例は、主な雄ステロイドのテストステロン(17β−ヒドロキシアンドロスト−4−エン−3−オン)である。この主な治療的使用は、睾丸の内分泌機能の欠損の治療である。エストラジオール(エストラ−1,3,5(10)−トリエン−3,17β−ジオール)も好ましいステロイド系の薬学的因子である。エストラジオール及びそのエステル誘導体は、更年期症状及び内因性エストロゲン産生不足を引き起こす他の病態の治療に適応される。プロゲステロンも好ましいステロイド系の薬学的因子である。プロゲステロンは主に、発情期を抑制又は同調するのに、並びに習慣流産を制御し、生理不順を診断及び治療するのに用いられる。付加的な好ましいステロイド系の薬学的因子としては、3−ヒドロキシ−5α−プレグナン−20−オン、3−β−ヒドロキシ−プレグン−5−エン−20−オン及び関連化合物が挙げられる。
NSAIDの例としては、ピロキシカム(4−ヒドロキシ−2−メチル−N−2−ピリジニル−2H−1,2−ベンゾチアジン−3−カルボキサミド1,1−ジオキシド)、ジクロフェナク、イブプロフェン、ケトプロフェン、メペリジン、プロポキシフェン、ナルブフィン、ペンタゾシン、ブプレノルフィン、アスピリン、インドメタシン、ジフルニサル、アセトアミノフェン、ナプロキセン、フェノプロフェン、ピロキシカム、スリンダク、トルメチン、メクロフェナメート、ゾメピラク、ペニシラミン、フェニルブタゾン、オキシフェンブタゾン、クロロキン、ヒドロキシクロロキン、アザチアプリン、シクロホスファミド、レバミゾール、プレドニゾン、プレドニゾロン、ベタメタゾン、トリアムシノロン、及びメチルプレドニソロン、及びインドメタシン(1−(4−クロロベンゾイル)−5−メトキシ−2−メチル−1H−インドール−3−酢酸)が挙げられる。
タンパク質及びペプチドベースの薬物、並びに他のアミノ酸ベースの薬物は、本発明による薬学的因子として用いてもよい。タンパク質及びペプチド薬物に対する従来の送達戦略に関連した課題は広く理解されている。これらの薬物の経口投与は、胃腸管中での分解及び非吸収のために一般的には実用的ではない。したがって、未だに非経口経路が主な送達経路である。
一般的に核酸ベースの薬物は、一部その安定性及び送達に関する課題のために、治療的因子としての成功が制限されている。ヌクレオチドベースの薬学的因子は、ヌクレアーゼによる分解に感受性があるホスホジエステル結合を含有することが多い。このような分解は、その認識特異性のために配列の完全性によって変わる薬学的因子としてのオリゴヌクレオチド又は核酸の使用に対する重大な障害となる。したがって典型的に、天然オリゴヌクレオチド及び核酸を化学修飾し、in vivoで、又は適切な条件を選択するのに注意を払わなければ、さらにin vitroでこれらを分解するヌクレアーゼに対して耐性にさせなければいけない場合が多い。しかし、これは、必ずしも本発明の薬物送達システムを用いる必要はない。
複素環式薬物、特に少なくとも1つの窒素複素環を含有するものは、本明細書で記載される方法における薬学的因子として用いることができる。例えば、ヨヒンビンは、α−2−アドレナリン受容体を遮断するインドールアルカロイドである。ヨヒンビンの末梢効果は、アドレナリン活性を低減させるのと同時に、コリン活性を増大させることである。この組合せによって、或る特定の種類の雄の勃起性インポテンツの治療及び診断分類にヨヒンビンが使用されている。
本発明の組成物は一般的に、融合サポシンタンパク質又はポリペプチドを含み、所望の効果のために安全で且つ効果的な量で薬学的因子又は画像化因子(全て適切なpHで薬学的に許容可能な担体に含有される)を含有する、少なくとも1つの中性長鎖脂質を有する又は有しない少なくとも1つのアニオン性長鎖脂質と、少なくとも1つの中性若しくはアニオン性短鎖脂質とのいずれかから成るアニオン性リポソームに関する。活性剤の安全で且つ効果的な量は、患者において所望の美容効果又は治療効果を引き起こす量として定義される。本発明に熟練した経験のある実践者は適切な用量比に関する知識を有する。
本明細書に記載の薬学的因子−化学修飾剤複合体は経皮投与することができる。経皮投与は典型的に、患者の体循環への薬物の経皮通過のために薬学的因子を送達することを伴う。皮膚部位は、薬物を経皮投与するための解剖学的領域を含み、前腕、腹部、胸部、背部、臀部、及び乳様突起域等が挙げられる。
様々な種類の経皮パッチが本明細書に記載の方法で用いられることが見出される。例えば、単一の接着パッチは、基材及びアクリル酸系接着剤から調製することができる。薬学的因子−化学修飾剤複合体及び任意の促進剤が接着剤を流し込んだ溶液に配合され、完全に混合された。溶液を基材上に直接流し込み、流延溶媒をオーブンでエバポレートし、接着フィルムをもたらす(leaving)。剥離(release)ライナーを接着し、このシステムを完了させることができる。
本発明の別の態様は、薬学的組成物の局所送達を提供する。この治療レジメンは、薬学的因子の全身投与、又は局所療法(すなわち病理組織又は疾患組織に直接)のいずれかに好適である。
本明細書におけるほとんどの記述は経皮送達に関する技法に集中しているが、本発明の方法は、粘膜(例えば胃腸膜、舌下膜、口腔膜、鼻膜、肺膜、膣膜、角膜及び眼球膜)を通る薬学的因子の輸送及び送達の増強にも適用可能である(Mackay他(1991) Adv. Drug Del. Rev, 7:313-338を参照されたい)。特に、皮膚膜と粘膜との間には多くの類似性が存在する。例えば、口腔膜は非角化である。しかし、口腔膜は皮膚に類似しており、これは両方とも、表面の扁平上皮細胞に至る基底膜において多角性細胞から成る口腔膜で層を成しているためである。
口腔膜又は舌下膜への送達に関しては典型的に、経口製剤(例えばロゼンジ、錠剤、又はカプセル)が用いられる。これらの製剤の製造方法は当該技術分野で既知であり、製造前錠剤への薬学的因子−化学修飾剤複合体の添加;不活性充填剤と、結合剤と、薬学的因子−化学修飾剤複合体又は複合体を含有する物質のいずれかとの冷間圧縮(米国特許第4,806,356号(参照により援用される)で記載される);及び封入が挙げられるが、これらに限定されない。
鼻膜及び/又は肺膜への送達に関しては典型的に、エアロゾル製剤が用いられる。「エアロゾル」という用語は、細気管支又は鼻腔に吸引することができる、任意の気体媒介性(gas-borne)懸濁相の薬学的因子−化学修飾剤複合体を含む。特にエアロゾルは、定量吸入器若しくはネブライザ、又は噴霧器で作製され得るような本発明の化合物の気体媒介性懸濁液滴を含む。エアロゾルは、空気又は他の担体気体中で懸濁された薬学的因子−化学修飾剤複合体の乾燥粉末組成物も含み、吸入器からの吸入によって送達され得る。
本発明を用いて、血液脳関門を通して薬学的因子又は画像化因子を輸送することもできる。サポシンC(又はその変異体若しくはそのペプチド)を含有するリポソーム、及びDOPS等の負に荷電した長鎖脂質は、当該技術分野で記載されたような方法を用いて、CNS(特に脳)への送達のために筋肉内投与、静脈内投与、眼球内投与又は経鼻投与することができる。例えば、鼻腔を通る投与によって、嗅覚器官のCSFへ、それから脳室内注入(ICV)と同様に末梢血液中へと侵入する。全て上記のように、当業者は、他の中性長鎖脂質及び/又は短鎖脂質(中性又は陰性)が、最終組成物の安定性又は有用性を改善するために上記されたリポソーム組成物に含まれ得ることを理解されたい。
さらに、サポシンCは、in vivoでのグルコシルセラミドのセラミドへの加水分解に必須である。表皮グルコセレブロシダーゼの欠乏によって、グルコシルセラミドとセラミドとの比が変わり、この比の変化がゴーシェ病の特徴である皮膚バリアの異常に関わる。サポシンCは、角質層において生理学的濃度のグルコシルセラミド及びセラミドを維持することによる表皮透過バリアの形成に必須であると考えられる。この様式によれば、グルコセレブロシダーゼを刺激する際のサポシンCの役割は、膜に対する脱安定化作用によって媒介される。このように、表皮グルコセレブロシダーゼが欠乏した患者では、薬学的に許容可能な担体に含有された混合物であるサポシンC−リポソーム複合体(リポソームは酸βグルコシダーゼを含有する)の局所適用を利用して、皮膚バリアの形成及び機能の調節の助けとなるように、グルコシルセラミドのセラミドへの加水分解を容易にするために、細胞膜と融合することができる。例えば、これらの組成物は、クリーム、ローション、溶液又はゲルとして作製することができる。例えば、担体としては、薬学的に許容可能な皮膚軟化剤、乳化剤、増粘剤、溶媒、防腐剤、着色剤及び香料が挙げられ得る。
本発明の別の実施形態において、サポシンC含有リポソームを用いて、1つ又は複数の異なる画像化特性を有する少なくとも1つの画像化因子を同時に送達することができる。これらの画像化因子は、核磁気画像化特性、蛍光特性、又はCT/PET検出特性を利用し得る。サポシンC含有リポソームの単一集団を用いて、薬学的因子を有する又は有しない複数の画像化因子が所望の組織に送達され得るように、1つ又は複数の画像化因子は、サポシンC含有リポソームに同時に統合又は封入され得る。
本発明の組成物は任意に、1つ又は複数の標識(例えば蛍光標識又は発光標識等の光学的に検出可能な標識、及び/又は磁性標識等の非光学的に検出可能な標識)を含む。多くの蛍光標識は当該技術分野で既知であり、量子ドット、疎水性フルオロフォア(例えばクマリン、ローダミン及びフルオレセイン)及び緑色蛍光タンパク質(GFP)並びにそれらの変異型(例えばシアン蛍光タンパク質及び黄色蛍光タンパク質)が挙げられるが、これらに限定されない。例えば、Haughland(2002)著「蛍光プローブ及び研究成果のハンドブック(Handbook of Fluorescent Probes and Research Products)」(第9版又は最新のウェブ版、両方ともMolecular Probes, Incから利用可能である)を参照されたい。同様に、例えば蛍光共鳴エネルギー移動(FRET)ベースの蛍光消失(quenching)、非FRETベースの蛍光消失、又は波長シフト回収(harvester)分子を利用した多様なドナー/アクセプタ及びフルオロフォア/クエンチャの組合せが既知である。組合せの例としては、シアン蛍光タンパク質及び黄色蛍光タンパク質、テルビウムキレート及びTRITC(テトラローダミンイソチオシアネート)、ランタニド(例えば、ユーロピウム又はテルビウム)キレート及びアロフィコシアニン(APC)又はCy5、ユーロピウムクリプテート及びアロフィコシアニン、フルオレセイン及びテトラメチルローダミン、IAEDANS及びフルオレセイン、EDANS及びDABCYL、フルオレセイン及びDABCYL、フルオレセイン及びフルオレセイン、BODIPY FL及びBODIPY FL、並びにフルオレセイン及びQSY7色素が挙げられる。DABCYL等の非蛍光アクセプタとQSY7及びQSY33色素とは、直接(すなわち非感作)アクセプタ励起に起因するバックグランド蛍光を取り除くという特定の利点がある。例えば、FRET色素の記載に関しては、Mathies他への米国特許第5,668,648号、同第5,707,804号、同第5,728,528号、同第5,853,992号、及び同第5,869,255号を参照されたい。
a)
i)十分量の画像化因子と、
ii)二重層、融合タンパク質若しくはポリペプチド、及び内部容積を含むリポソームであって、当該リポソームは当該リポソームを組織に送達させるのに十分な量であり、且つ画像化因子を保有する、リポソームと、
を含む組成物を、それを必要とする哺乳動物に投与すること、並びに
b)哺乳動物の組織を画像化すること、
を含む画像化する方法を提供する。
a)
i)常磁性イオンを有する常磁性キレートであって、当該常磁性キレートはNMR画像化を高めるのに十分な量である、常磁性キレートと、
ii)二重層、融合タンパク質若しくはポリペプチド、及び内部容積を含むリポソームであって、当該リポソームは当該リポソームを組織に送達させるのに十分な量であり、且つ当該常磁性キレートを保有する、リポソームと、
を含む組成物を、それを必要とする哺乳動物に投与すること、並びに
b)上記哺乳動物の組織をMNR画像化すること、
を含むことができる。
また、上記の生体適合性脂質及びポリマーに加えて、合成物(compositions of matter)を用いてミクロスフェアを調製することは、このように調製されたミクロスフェアが本明細書に記載の安定性及び他の基準を満たしていれば、本発明の一部であることが予測される。
材料 − 以下の材料は、商業的供給源からのものである:マウスラミニン、P/S、ウシ胎仔血清、及びDMEM(Gibco BRL, Gaithersborg, MD);B27を補充したNeurobasal培地(Life Technologies);制限エンドヌクレアーゼ(New England Biolabs, Beverly, MA);pET21a(+)DNAベクター、大腸菌宿主株[BL21(DE3)]、及びHis・Bind樹脂(Novagen, Medison, WI);Alexa Fluor488と結合した抗Hisモノクローナル抗体(QIAGEN, Valencia, CA);フルオレセイン結合ヤギ抗ウサギ抗体及びローダミン結合ヒツジ抗マウス抗体(ICN/CAPPEL, Aurora, OH);アンチフェード(antifade)試薬(Ventana Medical Systems, Tucson, AZ);C4逆相HPLCカラム(Alltech Association Inc.、イリノイ州ディアフィールド);クロロホルムストック溶液としてDOPS及び1,2−ジオレオイル−sn−グリセロ−3−ホスホ−L−セリン−N−(7−ニトロ−2−1,3−ベンゾキサジアゾール−4−イル)(NBD−DOPS)(Avanti Polar Lipids、アラバマ州アラバスター);ポリエチレンイミン及びパパイン(Sigma、ミズーリ州セントルイス)。アニオン性脂質はナトリウム塩である。全ての他の化学物質は試薬等級又はそれより上級のものである。
本発明者等の研究所で、大腸菌細胞におけるIPTG誘導性pETシステムを用いて、組み換えサポシンCを通常通り作製する11。全ての発現タンパク質は、Hisタグを含有しており、ニッケルカラム上で、0.1%トリフルオロ酢酸中のアセトニトリルの線形(0%〜100%)勾配を用いて、C4逆相HPLCクロマトグラフィによって精製する。主要なタンパク質ピークを回収し、凍結乾燥する。Qi他11によって以前に記載されたように、タンパク質濃度を求める。
カバーガラス(Lab−Tek II, Nalge Nunc International)を備える8ウェルチャンバスライドで48時間、DMEM培地中で細胞(105個)を培養する。培地中のサポシンC−DOPS複合体を細胞培養物に添加する。37℃で48時間インキュベート後、PBSで2回、細胞を洗浄し、免疫蛍光アッセイのために2%パラホルムアルデヒドで固定する。in vivo研究では、PBS中のプロテオリポソームをマウスの尾静脈に注射する。免疫蛍光アッセイのために、タンパク質−脂質複合体の投与の48時間後にマウスの脳組織を回収する。
マウスの脳組織を固定し、処理する前に10%ホルマリンで急速凍結する。パラフィン切片をヘマトキシリン及びエオシン(H&E)で染色し、光学顕微鏡で分析する。
材料及び方法
DOPS、DPPC及びDHPCの全てのリン脂質を粉末状でAvanti polar lipidsから購入し、さらに精製せずに用いる。動的光散乱(DLS)測定に関して、混合物中のDOPSとDPPCとのモル比は約10:約1の範囲であり、全てのサンプルで([DPPC]+[DOPS])/DHPC=約4である。ボルテックスと温度サイクル(50℃〜4℃)との組合せを利用して、脂質混合物を全脂質濃度10重量%で濾過した超純粋H2O(Millipore EASYpure UV)で溶解する。それから、濾過したH2Oで5、2、1、0.5及び0.1重量%に均質化した10重量%溶液を段階的に希釈する。
USPIO等のMR検出用標識を含有するリポソームを調製するために、以下の方法を用いる。DOPSを含む水溶液中でのデキストランで覆われたUSPIO粒子の超音波処理では、リポソーム内で十分な封入が得られない。リポソーム内のUSPIO含有量を増大させるために、Bogdanov他著「アミノリン脂質との一時的な結合によるリポソームにおけるデキストランで覆われたコロイドの封入(Trapping of dextran-coated colloids in liposomes by transient binding to aminophospholipid: preparation of ferrosomes)」 Biochim Biophys Acta, 1994. 1193(1): p. 212-8によって記載されたような化学カップリング法が若干変更して用いられる。要するに、USPIO粒子上を覆うデキストランを酸化して、アルデヒド基を発生させる。アルデヒドは、DOPSのアミンによって高pHでシッフ共有結合を形成する。N4+粒子サイズ分析器(Beckman Coulter、カリフォルニア州)の分析によって確認されたように、得られるリポソームの平均サイズは150nmである。リポソーム溶液が低pH溶液に対して透析され、リポソームの外層と結合したUSPIOを分離させる。Con−Aセファロース4Bカラム(Amersham Biosciences Corp.、ニュージャージ州)を用いたアフィニティクロマトグラフィによって、封入していないUSPIOを除去する。従来の電子顕微鏡法によって、USPIO−DOPSリポソーム構造を確認する。既知の量の遊離USPIO及びDOPSリポソーム混合物を用いて作製した標準R2緩和能曲線を用いて、DOPSリポソームにおける鉄濃度を予測する。1mMのDOPS濃度を用いると、Fe最大含有量が32μg/mlに達する。1つの群当たり約10000個の細胞を用いて、4つの神経芽種細胞のサンプルを調製する。それぞれの培養培地中の100μM及び300μMのUSPIO−DOPSリポソーム調製物を用いて、第1のサンプル及び第2のサンプルをインキュベートする。第3のサンプルは、USPIO又はリポソームを有しない細胞を含有していた。インキュベートの36時間後、細胞を4回洗浄し、4ml容のガラスバイアル中で0.5%アガロース溶液と、培養培地との混合物(1:1)でトリプシン化し、固定する。
SapCのプロトン付加を用いて、SapCとDOPS膜との結合を促進する。最初に、一定量の酸性緩衝液(pH5、20μl)で溶解してから、PBS又は中性緩衝液(pH7)で最終容量1mlに希釈することによって、SapCにプロトン付加する。代替的に、ブロンステッド酸(例えばTFE、クロロホルム、メタノール(methonal)等)を用いて、DOPS脂質でSapCを溶解することができる。これらのブロンステッド酸は、良好なH結合ドナーであり、タンパク質に対するプロトン付加効果があることが報告されている(1)。これらの溶媒をエバポレートし、N2ガス又は真空系下で乾燥させることができる。好適な緩衝液(plecable)(例えばPBS)を添加し、SapC−DOPSプロテオリポソームを形成する。この手法は、酸性pHでSapCによって誘導されたDOPSリポソーム融合を避けることである。このアプローチによって調製されたプロテオリポソームは、平均サイズが200nmの単分散形態である。
リポソームに封入した内容物が漏出する温度に感受性があるように、様々な脂質組成物でSapC−DOPSプロテオリポソームを設計する。
サポシンと、リポソーム膜との一時的な空間的相互作用を明らかにするために、本発明者は、内因性(Trp)及び/又は外因性(NBD、ピレン等)の蛍光測定法の開発に努力している。これらのアプローチには、最大発光スペクトルシフト、蛍光共鳴エネルギー移動、蛍光ストップフロー解析、蛍光ビーズ−サポシン−リポソーム複合体のフロー分析、及び蛍光顕微鏡法が含まれる。さらに、円偏光二色性(CD)を利用して、脂質無含有サポシンから脂質結合サポシンへの相対的な二次構造変化を評価する。最初の結果の解析が仮説の提示に発展した。
a)原核細胞系由来のサポシンの発現
天然サポシンを単離し、特徴付けているが、提示された研究のために、大量の通常のサポシン、突然変異したサポシン及びTrp標識したサポシンのアクセス可能な供給源を提供する組み換え発現系を確立することが重要である。以下に基づいて、原核生物系を開発する:1)サポシンは、少なくとも1つの占有的なN−グリコシル化部位を有するが、サポシンB及びサポシンCに関して、機能するのにはこれらの部位の占有は必要ではない。2)真核生物系におけるタンパク質の発現が労働集約型で且つ資源集約型であり、緩やかである。これに比べて、原核生物系は迅速であり、高収率の野生型タンパク質及び組み換えタンパク質が与えられる。また、3)野生型であるサポシンAが天然Trp(37W)を含有する唯一のサポシンであるので、内因性蛍光プローブとしてTrp残基でタンパク質を標識することができる。
pET21aシリーズのベクターを用いて、機能的なサポシンをBL21(DE3)で過剰発現した。37℃又は30℃でのIPTG誘導の後に、大量のHisタグを含有するサポシンが破壊細胞の可溶性画分で見出された。これらを電気泳動的に均質になるまでニッケル充填カラム上で好都合に精製した。代替的に、タンパク質コード領域の後に停止コドンを導入することによってHisタグを有しないサポシンを生成し、それからT7−taqモノクローナル抗体を有する免疫親和性カラムを用いて精製した。精製された組み換えサポシンCは、酸β−グリコシダーゼの優れた活性化及び他の生物学的な特性を示す。円偏光二色性スペクトル、光散乱、及びES−MS解析を用いて、精製したサポシンの物理的特性(例えば凝集状態及び分子量)を評価した。必要となる対照実験のために、Hisタグを有しないTrp−サポシンも生成した。リポソーム再構築システム及び神経突起生成アッセイにおいて、脱脂された同種の酸β−グリコシダーゼを用いて、組み換えサポシンCの機能的完全性を求める。スルファチド結合アッセイを用いて、組み換えサポシンBの機能を求める。組み換えサポシンB及びサポシンCのin vitro機能は、天然サポシン又は脱グリコシル化サポシンに類似している。
サポシンC−リン脂質相互作用の特異性を求めるために、CD、蛍光発光シフト、及び蛍光消失法を用いて、リポソームシステムを開発する。個々のTrp(W)を含有するように産生された突然変異サポシンCは、サポシンC(0W)、(S37W)、及び(81W)と呼ばれる。これらのTrp標識サポシンCは以下の通りである:サポシンC(0W)は、成熟サポシンCの最初のNH2末端のアミノ酸の前にTrpを有し、サポシンC(S37W)は、37番目の残基で(すなわち、中央で)Trpを有し、サポシンC(81W)は、最後のCOOH末端のアミノ酸の後ろにTrpを有する。これらの置換には、サポシンCの活性化特性又はCDスペクトルに影響を与えなかった。
CD分光法を用いて、組み換えサポシンの相対的な二次構造の変化が膜結合によって誘導される。酸性の不飽和ホスファチジルセリン(PS)/サポシンC複合体、及び中性のホスファチジルコリン(PC)/サポシンB複合体から得られたサポシンの相対的な二次構造の変化は類似しており、β鎖が減少し、αへリックス含有量が増大する(表4)。
トリプトファン環境が極性を変化させる場合、タンパク質の発光スペクトルがシフトする。脳ホスファチジルセリン(PBS)リポソームの添加の際に得られたサポシンA(0W)、A(37W)、A(81W)、C(0W)、及びC(81W)の蛍光スペクトルは、青色シフトを示していた(表5)。
サポシンとリポソーム膜との一時的な空間的相互作用を研究するために、サポシンの内因性蛍光プローブとしてTrpを用いて、蛍光ストップフローアプローチ及び蛍光消失アプローチを利用する。これらの実験によって、サポシンと脂質二重層との間の局所的相互作用、及びこれらの結合速度が同定される。
酸性pHで合成ホスファチジルセリン[PS(18:1、1)]小胞とのサポシンC(0W)の結合の際に、蛍光強度が有意に増大した。この結合は、脂質濃度依存的な変化を誘導し、少なくとも1つの不飽和脂肪酸鎖が必要である。この相互作用の速度を評価するために、ストップフロー実験を行い、サポシンC/リポソーム複合体形成中の蛍光の変化をモニタリングする。サポシンC(0W)をPS(18:1、1)又はBPS小胞を混合すると、Trpの蛍光は増大するが、機械性能に限界があるため、この変化の経時的変化は検出不可能である。明らかに、サポシンCと、不飽和PS含有膜との相互作用は少なくとも10ms以内で起こる。
BPSリポソームへのサポシンの挿入深度を求めるために、モルパーセントを増大しながら(0%〜50%)、スピン標識ホスファチジルコリン(SLPC)をBPSリポソームに組み込む。疎水性蛍光消失剤であるSLPCは、アシル鎖の異なる炭素(n)に位置するドキシル基を含有する:SLPC5(n=5)、SLPC10(n=10)、及びSLPC16(n=16)。Trp−サポシンの添加後、タンパク質−リポソーム混合物(タンパク質:脂質=1:20)を室温で30分間インキュベートし、それから蛍光強度の変化を記録する。表2で青色シフトを示すTrp−サポシンに関して、BPS/SLPC5リポソームで有意な消光効果(30%〜60%)が見られる。消光効率は、SLPC上のドキシル基のアシル鎖における位置に依存する。ドキシル基が膜中で深くにあれば、消光効率が低くなる。BPS/SLPC10では、サポシンC(0W)のトリプトファン蛍光は30%消失する。
サポシンCは、リポソーム酵素活性及び神経突起生成活性を有する多官能性分子である。サポシンCの詳細な機能/組織構造を図3に示す。
蛍光プローブは、膜融合(例えば蛍光発光(dequenching)及び蛍光共鳴エネルギー移動(FET))を求めるのに広く使われており、定量分析及び速度分析に用いることができる。発光アプローチを用いて、サポシンCの融合活性を研究する。オクタデシルローダミンB(R18)が蛍光プローブとして選択され、BPS又はPS(18:1、1)による同時超音波処理によって、リポソーム小胞の内部水性区画に封入される。R18は高濃度で自己消光を示す。
融合小胞のサイズが非融合のものよりも大きいため、小胞融合分析には、電子顕微鏡法(EM)を用いる。N4+サブミクロン粒子サイズを用いて、3nm〜3μmの範囲の粒子サイズを予測する。これは、ほとんどのリポソームがこの範囲に適合するためである。カップ音波処理器による音波処理条件は、サイズが約200nmの単分散BPS−リポソームを与える。サポシンCの添加の際に、これらの小胞は最大2μm〜3μmのより大きいサイズに変化する。上記の発光実験によって示されるように、サイズ増大は小胞融合に関連する。サポシンCは、pH4.7で10分間にわたって小胞サイズが大きくなるが、pH7.4では大きくならない(図4を参照されたい)。
タンパク質の構造変化は、タンパク質媒介性膜融合に関与すると考えられる。サポシンC依存性膜融合を用いて、この融合機構を評価する。最初に、サポシンC−PS(18:1、1)リポソーム複合体が形成される。このサポシンC固定膜で、タンパク質構造が変化する。この複合体はpH3〜10で安定であり、低濃度のSDS溶液中に存在する。これは、PS小胞からのサポシンCの解離速度が非常に緩やかであることを示していた。
サポシンCのDNA配列は、mRNAの二次構造、及び後でサブクローニングに用いられる制限部位の脱離を考慮して、大腸菌における発現に対してコドンを最適化する。制限部位NdeI及びSalIをそれぞれその遺伝子の5’末端及び3’末端に付加し、二重終止コドンをサポシンCコード配列の末端に付加し、確実に発現タンパク質を適切に末端化させる。遺伝子合成は、DNA2.0が請け負っており、シーケンシングによって最適化された遺伝子を確認し、クローニングベクター「pJ2」におけるVTIに供給する。このベクター構築物はpJ2−SapCgと称され、制限部位NdeI及びSalIで分けられた最適化サポシンC遺伝子カセットはSapCgと称される。
SapCgのpET24aへのクローニングは以下のように行う。制限部位NdeI及びSalIを用いて、pJ2−SapCgからSapCgを切断し、またこれらと同じ部位で切断されている発現ベクターpET24a(Novagen)にライゲートする。このライゲートした構築物を大腸菌クローニング株TOP10(Invitrogen)に形質転換する。カナマイシン(50mg/L)によって選択を行う。コロニーPCRを行い、どの形質転換コロニーが、SapCgが挿入されたベクターを保有していたかを求める。さらなる研究のために、陽性と試験されたコロニーから1つのコロニーを選択する。プラスミドミニプレップキット(Qiagen)によって、このクローンからプラスミドDNAを調製し、制限及び配列分析によって、SapCg挿入DNAの存在を確認する。このプラスミド構築物はpET24a−SapCgと呼ばれる。
発現構築物pET24a−SapCgをコンピテント大腸菌発現株BL21(DE3)(Novagen)に形質転換する。3つのコロニー(クローン)を選択し、最初の試験でサポシンCの発現を試験する。BL21(DE3)クローンに関して、カナマイシン(50mg/L)を有するLB培地を用いて、125ml容の振盪フラスコでこの小規模な発現を行う。細胞のOD600が約0.6に達する場合、1mMの最終濃度までIPTGを添加することによって、誘導が達成される。誘導の直前、又は誘導の4時間後、サンプルを採取する。正しいサイズのタンパク質の発現は、3つのBL21(DE3)クローン全てと類似している。3つのクローン全てに対して、研究用の(Working)グリセロール種(seed stocks)を調製する。さらなる開発のために、1つのクローンをランダムに選択する。
発酵に用いられるクローンは、大腸菌発現株BL21(DE3)で形質転換したpET24a−SapCg(上記)である。発酵は、8L容のNBSC BioFlow3000発酵槽を用いて行い、DO−Stat供給方式によるフェドバッチ発酵から成る。最初の培養容量は5Lである。バッチ培地及び供給培地の組成は表1及び表2に示す。誘導前の発酵温度は30℃である。37℃への温度変化を伴って、後期の対数期で1mMの最終濃度までIPTGを添加することによって、誘導が達成される。全発酵は22時間続き、10時間誘導される。
上記の発酵由来のペーストを用いて、封入体調製を行う。ペースト約20gを全量200mlの溶解緩衝液(50mMのトリス(pH8)、1mMのEDTA、100mMのNaCl)で再懸濁する。再懸濁及び完全な均質化の後、微小流動化を用いて開細胞を破壊する。4℃、16000×gで60分間、遠心分離によって、細胞溶解物の不溶性部分を沈澱させる。全量800mlの溶解緩衝液+1%トリトンX−100中で、ペレットを均質化し、室温で45分間混合する。4℃、16000×gで60分間、遠心分離を行う。1%トリトンX−100を有する溶解緩衝液を用いて2回以上、及びトリトンX−100を有しない溶解緩衝液を用いて1回、洗浄を行う。それから、全量600mlの6Mの尿素(pH8.5)(20mMのトリスで緩衝化する)でペレットを再懸濁し、室温で3時間撹拌する。4℃、16000×gで60分間、遠心分離を行い、サンプルを透明にする。サポシンC特異的な抗体を用いて、サポシンCの存在を確認した後、得られた上清を用いて、さらに精製する。
エンドトキシン無含有条件下で、以下のクロマトグラフィ工程、リフォールディング工程及び濃縮工程を全て行う。Qセファロース高速流樹脂(GE Amersham)を用いたイオン交換クロマトグラフィによって、封入体由来のサポシンCの精製を行う。平衡緩衝液(緩衝液A)は、6Mの尿素/0.02Mのトリス(pH8.5)である。溶離緩衝液(緩衝液B)は、6Mの尿素/1MのNaCl/0.02Mのトリス(pH8.5)である。最初に10カラム容量に対して5%緩衝液B/95%緩衝液A、それから10カラム容量に対して10%緩衝液B/90%緩衝液Aの段階勾配、その後10カラム容量で10%〜100%緩衝液Bの線形勾配で溶離を行う。全ての画分を回収及び維持する。サポシンCの存在に関する画分の分析をSDS−PAGEによって行い、大部分のサポシンCを含有する画分をリフォールディングのために選択する。
Claims (52)
- a)長鎖リン脂質、短鎖脂質及びこれらの混合物から成る群から選択される1つ又は複数のリン脂質と、
b)安全で且つ効果的な量の作用因子と、
c)プロサポシン由来の融合タンパク質又はポリペプチドと、
d)薬学的に許容可能な担体と、
を含む組成物を前記膜に適用させることを含み、前記融合タンパク質又はポリペプチドの濃度が該膜を通して前記作用因子を送達するのに十分な量であり、該組成物が前記標的生体膜と融合可能なリポソームを形成する、標的生体膜を通して作用因子を送達する方法。 - 前記リン脂質がアニオン性長鎖脂質と中性長鎖脂質との混合物である、請求項1に記載の方法。
- 前記リン脂質が、アニオン性長鎖脂質と、中性長鎖脂質と、中性短鎖脂質との混合物である、請求項1に記載の方法。
- 前記リポソームがカチオン性リン脂質を含有する、請求項3に記載の方法。
- アニオン性長鎖脂質、中性長鎖脂質及び短鎖脂質の量が、([中性長鎖脂質]+[アニオン性長鎖脂質])/(短鎖脂質)=約4である式によって支配される、請求項3に記載の方法。
- 前記標的生体膜が、皮膚膜、粘膜、血液脳関門及び細胞膜から成る群から選択される、請求項3に記載の方法。
- 前記リポソームが、ジオレオイルホスファチジルセリン、ジパルミトイルホスファチジルコリン及びヘキサノイルホスファチジルコリンから成り、アニオン性長鎖脂質、中性長鎖脂質及び中性短鎖脂質の量が、([中性長鎖脂質]+[アニオン性長鎖脂質])/(中性短鎖脂質)=約4である式によって支配される、請求項1に記載の方法。
- リン脂質の濃度が、前記融合タンパク質又はポリペプチドの濃度に対してモル比で約1倍〜10倍過剰である、請求項1〜7のいずれか一項に記載の方法。
- ジオレオイルホスファチジルセリンと、ジパルミトイルホスファチジルコリンとのモル比が約10:1である、請求項7に記載の方法。
- 前記組成物のpHが約6.8〜2である、請求項1に記載の方法。
- 前記組成物のpHが約5.5〜約2である、請求項10に記載の方法。
- pHを中和緩衝液で中性にするさらなる工程を含む、請求項11に記載の方法。
- 平均直径が50nm〜350nmのリポソームを形成するように前記組成物のpHが調整される、請求項12に記載の方法。
- 平均直径が約200nmのリポソームを形成するように前記組成物のpHが調整される、請求項12に記載の方法。
- 前記組成物が乾燥粉末状で提供される、請求項1に記載の方法。
- 前記組成物が酸で処理される、請求項15に記載の方法。
- 前記酸が酸性緩衝液又は有機酸である、請求項16に記載の方法。
- 前記タンパク質の少なくとも一部分にプロトンを付加するのに十分なレベルで前記酸が添加される、請求項17に記載の方法。
- 前記組成物の最終pHが約5.5〜約2である、請求項18に記載の方法。
- 前記タンパク質に実質的にプロトンを付加するのに十分なレベルで前記酸が添加され、前記組成物のpHが約5.5〜約2である、請求項18に記載の方法。
- 酸で処理した前記組成物のpHをその後実質的に中性にする、請求項18に記載の方法。
- pHを中性pH緩衝液で中性にする、請求項21に記載の方法。
- 前記得られるリポソームのサイズを制御するのに十分、pHを中性pH緩衝液で中性にする、請求項21に記載の方法。
- 前記得られるリポソームのサイズを制御して、平均直径が50nm〜350nmのリポソームを提供するのに十分、pHを中性pH緩衝液で中性にする、請求項21に記載の方法。
- 前記得られるリポソームのサイズを制御して、平均直径が約200nmのリポソームを提供するのに十分、pHを中性pH緩衝液で中性にする、請求項21に記載の方法。
- pHが約7〜約10の最終組成物を提供するように、前記緩衝液が前記組成物に添加される、請求項25に記載の方法。
- 前記膜が粘膜である、請求項1に記載の方法。
- 前記リポソーム複合体が前記血液脳関門に浸透することを目的とする、請求項1に記載の方法。
- 前記融合タンパク質又はポリペプチドが、サポシンA、サポシンC、配列番号1、配列番号2、配列番号3、及びそれらの混合物から成る群から選択される、請求項1に記載の方法。
- 前記組成物の投与が、経皮パッチ、経腸、経鼻、静脈内、筋肉内又は局所から選択される、請求項1に記載の方法。
- 前記作用因子が生体活性剤である、請求項1に記載の方法。
- 前記生体活性剤が、診断剤、調合薬、薬物、合成有機分子、タンパク質、ペプチド、ビタミン、ステロイド及び遺伝物質から成る群から選択される、請求項31に記載の方法。
- 前記作用因子が画像化因子である、請求項1に記載の方法。
- 前記画像化因子が、磁気共鳴、蛍光、又はCT/PET検出用標識から成る群から選択される1つ又は複数の作用因子である、請求項33に記載の方法。
- 前記画像化因子が2つ以上の画像化特性を有する、請求項33に記載の方法。
- 前記画像化因子が磁気共鳴画像法(MRI)又は共焦点蛍光顕微鏡法によって検出することができるフルオロフォア及びGd(III)部の両方を含有するPTIR色素である、請求項33に記載の方法。
- 前記血液脳関門の膜を通して薬学的因子又は画像化因子を送達する方法であって、
a)アニオン性長鎖リン脂質、中性長鎖脂質、中性短鎖脂質、アニオン性短鎖脂質及びこれらの混合物から成る群から選択されるリン脂質と、
b)安全で且つ効果的な量の前記薬学的因子又は画像化因子と、
c)プロサポシン由来の融合タンパク質又はポリペプチドと、
d)薬学的に許容可能な担体と、
を含む組成物の前記膜への投与を含み、リポソームの濃度が前記膜を通して安全で且つ効果的な量の前記薬学的因子を送達するのに十分な量であり、前記リン脂質が全体的に負に荷電したリポソームを形成する、前記血液脳関門の膜を通して薬学的因子又は画像化因子を送達する方法。 - 前記リン脂質がアニオン性長鎖脂質と中性長鎖脂質との混合物である、請求項37に記載の方法。
- 前記リン脂質が、アニオン性長鎖脂質と、中性長鎖脂質と、中性短鎖脂質との混合物である、請求項37に記載の方法。
- 前記リポソームがカチオン性リン脂質を含有する、請求項39に記載の方法。
- アニオン性長鎖脂質、中性長鎖脂質及び短鎖脂質の量が、([中性長鎖脂質]+[アニオン性長鎖脂質])/(短鎖脂質)=約4である式によって支配される、請求項38に記載の方法。
- 前記リポソームが、ジオレオイルホスファチジルセリン、ジパルミトイルホスファチジルコリン及びヘキサノイルホスファチジルコリンから成り、アニオン性長鎖脂質、中性長鎖脂質及び中性短鎖脂質の量が、([中性長鎖脂質]+[アニオン性長鎖脂質])/(中性短鎖脂質)=約4である式によって支配される、請求項37に記載の方法。
- 前記組成物のpHが約5.5〜約2である、請求項37に記載の方法。
- 前記融合タンパク質又はポリペプチドがサポシンCである、請求項37に記載の方法。
- 前記リポソームの濃度が、プロサポシン由来の前記融合タンパク質又はポリペプチドの濃度に対してモル比で少なくとも約1倍〜約10倍過剰である、請求項37に記載の方法。
- ジオレオイルホスファチジルセリンと、ジパルミトイルホスファチジルコリンとのモル比が約10:1である、請求項42に記載の方法。
- q値が1〜10である、請求項38に記載の方法。
- 前記画像化因子が、磁気共鳴、蛍光、又はCT/PET検出用標識から成る群から選択される1つ又は複数の作用因子である、請求項38に記載の方法。
- 前記画像化因子が2つ以上の画像化特性を有する、請求項38に記載の方法。
- 前記画像化因子が磁気共鳴画像法(MRI)又は共焦点蛍光顕微鏡法によって検出することができるフルオロフォア及びGd(III)部の両方を含有するPTIR色素である、請求項49に記載の方法。
- ゴーシェ病を治療する方法であって、このような治療が必要な被験者に、
アニオン性長鎖リン脂質、中性長鎖リン脂質、中性短鎖リン脂質、アニオン性短鎖リン脂質及びこれらの混合物から成る群から選択される1つ又は複数のリン脂質を含有するアニオン性リポソーム(アニオン性長鎖脂質、中性長鎖脂質及び中性短鎖脂質の量が、([中性長鎖脂質]+[アニオン性長鎖脂質])/(中性短鎖脂質)=約4である式によって支配される)と、
安全で且つ効果的な量の酸β−グルコシダーゼと、
プロサポシン由来の融合タンパク質又はポリペプチドと、
薬学的に許容可能な担体と、
を含む組成物の投与を含み、該組成物のpHが約5.5〜約2であり、前記融合タンパク質又はポリペプチドの濃度が前記膜を通して前記薬学的因子を送達するのに十分な量であり、このサポシンCが静電気的な疎水性相互作用によって前記リポソームの表面と結び付く、ゴーシェ病を治療する方法。 - 前記リポソームの濃度が、融合タンパク質又はポリペプチドの濃度に対してモル比で少なくとも約1倍〜約10倍過剰である、請求項51に記載の方法。
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BRPI0710945A2 (pt) | 2012-03-13 |
US9271932B2 (en) | 2016-03-01 |
JP2014111600A (ja) | 2014-06-19 |
JP5437790B2 (ja) | 2014-03-12 |
ES2641272T3 (es) | 2017-11-08 |
CN101583346B (zh) | 2015-08-19 |
US20180230190A1 (en) | 2018-08-16 |
JP5873858B2 (ja) | 2016-03-01 |
CA2650691C (en) | 2015-10-06 |
EP2020988B1 (en) | 2017-08-16 |
EP2020988A2 (en) | 2009-02-11 |
US20090142267A1 (en) | 2009-06-04 |
WO2007127439A2 (en) | 2007-11-08 |
CN101583346A (zh) | 2009-11-18 |
WO2007127439A3 (en) | 2008-07-31 |
EP3357490A1 (en) | 2018-08-08 |
JP2016121165A (ja) | 2016-07-07 |
CA2650691A1 (en) | 2007-11-08 |
US20160200784A1 (en) | 2016-07-14 |
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