JP2006516539A - 物質を血液−脳関門を渡って輸送するための人工低密度リポタンパク質キャリア - Google Patents
物質を血液−脳関門を渡って輸送するための人工低密度リポタンパク質キャリア Download PDFInfo
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- JP2006516539A JP2006516539A JP2004556682A JP2004556682A JP2006516539A JP 2006516539 A JP2006516539 A JP 2006516539A JP 2004556682 A JP2004556682 A JP 2004556682A JP 2004556682 A JP2004556682 A JP 2004556682A JP 2006516539 A JP2006516539 A JP 2006516539A
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Abstract
Description
リポソームは、リン脂質を水溶液中で音波処理したときに自然に形成される小粒子であり、水性環境を取り囲む中空球として構成されるシンメトリー脂質二重層から成る。そのリン脂質は形質膜に吸収され、これによりリポソームの内容物が自動的にサイトゾルへ放出されるため、リポソームは、水溶性薬剤を細胞膜を通過させて輸送する手段として魅力を有する。この技術の成功したバリエーションには、陽イオン性脂質の使用が挙げられ、これは、膜にナノ孔を協同的に作り出すことができる。陽イオン性脂質は、細胞培養において広く使用され、DNA分子などの水溶性物質を実験のために培養細胞に導入する。
ポリソルベート80で被覆したポリ(ブチルシアノアクリレート)またはポリアクリルアミドなどの合成ポリマーも試験してみた。これらポリマーは、その粒子が充分親水性で水に可溶であり、更に長時間にわたってその構造形態を維持することができ、これにより、天然の解毒プロセスを受ける肝臓および腎臓への取込みから治療剤は保護されるため、魅力的である。いずれのケースにおいても、取込みは、細胞膜を渡る受動拡散により起こるか、あるいはクラスリン被覆小胞による防御的取込みとして起こると一般に想像される。その後、前者のケースにおいて治療剤は、以前ほどターゲットにさほど近くない内皮細胞にトラップされるが、後者のケースにおいて治療剤は、プロテアーゼや胃の内容物に類似した他の消化酵素を含有する細胞における高酸性コンパートメントであるリソソームに輸送される。よって後者のケースでは、治療剤は、より過酷な状況の間ずっと安定なまま留まらなければならない。いずれのケースも、薬剤は細胞を渡って運搬されず、所望の結果である脳実質組織への排出は起こらない。よって、これら二つの方法のいずれもが、さほど臨床上使用されていないことは驚くことではない。
BBBを渡って輸送可能な物質、たとえばインスリンと薬理学的作用物質の直接的コンジュゲーションも試みられている。インスリンおよびインスリン様増殖因子は、特殊な促進拡散システムにより血液脳関門を通過することが知られている(Reinhardt et al. (1994) Endocrinology 135(5): 1753-1761)。インスリンは、内皮インスリンレセプターにより媒介されるトランスサイトーシスにより吸収される(Pardridge et al. (1986) Ann. Intern. Med. 105(1): 82-95)。また、グルコースやトリプトファンなどの大きなアミノ酸のための特定のトランスポーターが存在する。しかし、インスリントランスポーターはその特異性が高いため、インスリンに共有結合した薬理学的作用物質を脳へ通過させることができないことが分かっている。同様の結果が、グルコースやアミノ酸コンジュゲートでも得られており、その取込みは、他の低分子量物質と同じ一般的原理に従うことが観察されており、700 Da以下の非電荷分子のみが脳への有意なアクセスを達成する。コンジュゲート形態の生体分子の化学合成を考え出す煩わしさ、予期しない毒性効果を引き起こすリスク、および完全に新規な化合物についてFDA認可を得なければならないかもしれない必要性が、このアプローチに対する熱意を失わせる。
本明細書で使用される「人工LDL粒子」の用語は、球状のリン脂質単一層と固体の脂質コアを含む構造体を意味する。
本発明は、人工LDL粒子が、トランスサイトーシスとして公知の活性レセプター介在性プロセスにより、物質を効率的にターゲットにし血液−脳関門を渡ってデリバーするという発見に関する。トランスサイトーシスは、コレステロールおよび必須脂肪酸を脳へ輸送する手段として、脳の毛細血管内皮細胞に天然に存在する。従って、本発明の人工LDLキャリアシステムは、BBBの破壊またはその他の望ましくない副作用を最小限にして、薬剤を脳へ効率的に向けデリバーする手段を提供する。
好ましい態様において、本発明の人工LDL粒子は、卵黄ホスファチジルコリン(EYPC)、コレステロールオレアート、およびApoE3の混合物を含む。構成成分の脂質は、3つの層から成る固形粒子を形成する(Hevonoja et al.(2000) Biochim. Biophys. Acta 1488: 189-210):コレステロール、コレステロールエステル、およびコレステロールにコンジュゲートされていてもコンジュゲートされていなくてもよい薬理学的活性物質を含有する固体の脂質コア;ホスファチジルコリンの脂肪酸鎖の混合物を含有する中間の界面層;およびリン脂質の頭部の基およびApoE3を含有する表面層。
本発明のLDL粒子は、治療する脳疾患のタイプによって種々の方法で製剤化され得る。従って、本方法は、ヒトまたは動物薬に使用するために製剤化された少なくとも一の薬剤含有LDL粒子複合体を含む薬学的組成物をその範囲内に含む。かかる組成物は、薬学的に許容可能なキャリアまたは賦形剤、必要に応じて補助的薬剤と共に使用に供されてもよい。また慣用的なキャリアも本発明とともに使用することができる。許容可能なキャリアには、グルコース、生理食塩水、およびリン酸緩衝生理食塩水が含まれるがこれらに限定されない。
更なる態様において、人工LDL粒子を、治療を必要としている哺乳類宿主に投与して、作用物質をBBBを渡って脳へ効果的にデリバーすることができる。治療用としては、効果的な量の薬剤含有LDL粒子を、LDL粒子を毛細血管内皮細胞に取込むことが可能な任意の様式により対象に投与することができる。
コレステロールは、相対的に化学的に不活性な分子である。その結果、コレステロールをアミン含有治療剤と反応させる前に、コレステロールを活性化しなければならない。たとえば、コレステロールは、環状無水物、たとえばカルボキシル基を含有するフタル酸エステルまたはコハク酸エステルを産生する無水フタル酸または無水コハク酸と反応させることにより活性化することができる。カルボキシル基は、その後ペンタフルオロフェノールとの反応により活性化され、更にジイソプロピルカルボジイミドと反応して、アミン含有治療剤とアミド結合をつくる。得られた生成物は、治療剤がエステル結合を介してコレステロールにコンジュゲートしたコレステロール−治療剤コンジュゲートである。コレステロール−治療剤コンジュゲートは、充分親油性であるため本発明の人工LDL粒子に組込み可能である。また、好ましい結合がエステル結合であるため、治療剤は、ユビキタスな内在性エステラーゼの作用によりコレステロール部分から放出され得る。このように、コンジュゲートからの治療剤の放出は、過酷な状況やリソソームにみられる非特異的ペプチダーゼに依存しない。コレステロールと治療剤との間の好ましい結合はエステル結合であるが、本発明は、エーテル、アミドおよびペプチド結合を含むがこれらに限定されない他の結合を想定する。
以下の実施例は、本発明を更に説明するためのものであり、本発明の範囲を限定するものと解釈すべきでない。
Avanti Polar Lipids, Inc.から入手したDMPC (1,2-ジミリストイル-sn-グリセロ-3-ホスホコリン) を、ガラス管内でベンゼン中に100 mg/mlの濃度で懸濁し、ベンチトップソニケーターを用いて音波処理する。DMPC懸濁液をシェル凍結し、一晩凍結乾燥した後、30 ml 標準バッファー (10 mM Tris-HCl. pH 7.6. 0.15 M NaCI, 1 mM EDTA. 0.0005% NaN3) 中に再懸濁し、10-20 mg/ml DMPCを作成し、プラスチック製50 ml円錐管に移す。円錐管を水浴に置き、マイクロチップを備えたソニケーターを用いて、4回の10分間隔で、2-3 分の冷却を散在させて音波処理する。音波処理は、溶液がほぼ透明になるまで繰り返す。その後、音波処理されたDMPCを2000 rpmで20分間遠心分離し、音波処理の間に分離した(slough off)かもしれないチタンを除去する。
1.脂質ケーキの調製: 卵黄ホスファチジルコリン(25 mg)およびコレステリルオレアート(2 mg)を、メタノール/クロロホルム(2:3)に溶解する(比25:1)。溶媒を4℃で窒素下において蒸発させる。
約1 mgの脂質を含有する14C-LDLのPBS懸濁液を、Sprague-Dawleyラット(150 g)の尾部静脈に注射した。種々の間隔で、EGTAを含有するシリンジを用いた心臓穿刺により血液サンプルを得た。血漿、RBC、および組織を、水中でホモジナイズし、14Cをシンチレーションカウンターで測定した。
コレステロール−フタレートエステルの調製: コレステロール(1 mg)を、窒素を用いて蒸発させ、凍結乾燥させてエタノールを除去する。その固体を最少体積のTHFに溶解し、ガラス反応バイアルに移す。固体の無水フタル酸(1-2 mg, >4当量)を添加し、その後50 Et3Nを添加する。その混合物を100℃で5分間加熱し、〜20μlピリジンを添加して、懸濁液を透明にする。その混合物を100℃で30分間、溶液が赤くなるまで加熱し、TLC(Silica/UV254プレート)でEtOH/トルエン(2:1)を用いて精製する。最も濃いUVバンド(RF=0.74)をプレートからスクラップし、生成物をTHFで溶出する(収率:98=100%)。
THF中の活性化されたコレステロール−フタレート−PFPを10μlまで蒸発させる。DMF中に溶解した2当量のアドリアマイシンを添加する。DMFによる副反応は、過剰のアミンを用いることにより低減することができる。メタノールまたはエタノールなどのアルコールの添加は、その収率を大きく低下させる。3マイクロリットルのDIICを添加し、溶液をRTで一晩反応させ、TLC(CHCl3/CH3OH 30:5)により精製する(収率 95%)。このバンドは、アドリアマイシン−DIICコンジュゲートと生成物を含有する。コレステロール−アドリアマイシンコンジュゲートは、100% CH3OH中でC18−逆相HPLCにより単離することができる(流速=0.5 ml/分、検出=A471)。生成物は、コレステロールとアドリアマイシンのおよそ中間の4.7分で溶出する。全収率:95%。アドリアマイシン−コレステロールコンジュゲート(I)の構造を図5に示す。
N-[p-マレイミドフェニル]イソシアネート (PMPI) (5 mg) を、200μl DMSO中で1当量のヒドロキシ含有化合物と混合し、室温で30分間反応させる。チオコレステロール (6.4 mg) を添加する。その混合物を室温で120分間インキュベートし、生成物を、0.1 M EDTA pH 8.0で下塗りしたSilica Gel G UV 254プレートを用いて、EtOH/H2O 1:1を溶媒として用いた薄層クロマトグラフィーにより単離する。
テトラサイクリンを凍結乾燥させて溶媒を除去し、200μl DMSO中の2.2 mgテトラサイクリンを5 mg PMPIと混合し、室温で30分間反応させる。チオコレステロール(6.4 mg)を添加する。その混合物を室温で120分間インキュベートし、生成物を、0.1 M EDTA pH 8.0で下塗りしたSilica Gel G UV 254プレートを用いて、EtOH/H2O 1:1を溶媒として用いた薄層クロマトグラフィーにより単離する。テトラサクリン−コレステロールコンジュゲート(II)の構造を図6に示す。
下記参照文献のそれぞれは、その全体を参照により本明細書の開示内容の一部とする。
Claims (41)
- 外側のリン脂質単一層と固体の脂質コアとを含む人工LDL粒子であって、前記外側のリン脂質単一層が少なくとも一のアポリポタンパク質を含み、前記固体の脂質コアが少なくとも一の治療剤を含有する人工LDL粒子。
- 前記少なくとも一のアポリポタンパク質がApoEである、請求項1に記載の人工LDL粒子。
- 前記少なくとも一のアポリポタンパク質がApoE3である、請求項2に記載の人工LDL粒子。
- 前記外側のリン脂質単一層が、一以上のオキシステロールおよび/またはApoBおよびApoE4から成る群より選択される追加のアポリポタンパク質を更に含む、請求項3に記載の人工LDL粒子。
- 前記少なくとも一の治療剤が、アミノ酸、ペプチド、タンパク質、炭水化物および脂質から成る群より選択される、請求項1に記載の人工LDL粒子。
- 前記少なくとも一の治療剤が、アミノ酸、ペプチド、タンパク質、核酸、炭水化物および脂質から成る群より選択される作用物質とコレステロールとの間で形成されたコンジュゲートである、請求項1に記載の人工LDL粒子。
- 前記治療剤が、向神経性因子、成長因子、酵素、抗体、神経伝達物質、神経調節物質、抗生物質、抗ウイルス剤、抗真菌剤および化学療法剤から成る群より選択される、請求項5に記載の人工LDL粒子。
- 前記治療剤が、向神経性因子、成長因子、酵素、神経伝達物質、神経調節物質、抗生物質、抗ウイルス剤、抗真菌剤および化学療法剤から成る群より選択される、請求項6に記載の人工LDL粒子。
- 前記外側のリン脂質単一層が、ホスファチジルコリンおよび少なくとも一のアポリポタンパク質を含む、請求項1に記載の人工LDL粒子。
- 前記少なくとも一のアポリポタンパク質がApoEである、請求項9に記載の人工LDL粒子。
- 前記粒子が直径約15〜50 nmである、請求項1に記載の人工LDL粒子。
- 前記粒子が直径約20〜30 nmである、請求項1に記載の人工LDL粒子。
- 前記粒子が密度約1.00〜1.07 g/mLである、請求項1に記載の人工LDL粒子。
- 前記粒子が密度約1.02〜1.06 g/mLである、請求項1に記載の人工LDL粒子。
- 前記粒子が少なくとも2時間の血清安定性を有する、請求項1に記載の人工LDL粒子。
- 前記粒子が、トランスサイトーシスにより血液−脳関門(BBB)を渡って輸送される、請求項1に記載の人工LDL粒子。
- 前記粒子の脳に対する取込み特異性が、肝臓に比べて少なくとも3倍高い、請求項1に記載の人工LDL粒子。
- 前記少なくとも一の治療剤が、コレステロールとアドリアマイシンとの間で形成されたコンジュゲートである、請求項1に記載の人工LDL粒子。
- 前記少なくとも一の治療剤が、コレステロールとテトラサイクリンとの間で形成されたコンジュゲートである、請求項1に記載の人工LDL粒子。
- 前記コンジュゲートのコレステロールとアドリアマイシンが、エステル結合により連結される、請求項18に記載の人工LDL粒子。
- 前記コンジュゲートのコレステロールとテトラサイクリンが、エステル結合により連結される、請求項19に記載の人工LDL粒子。
- 外側のホスファチジルコリン単一層、脂肪酸アシル−コレステロールエステルを含む固体の脂質コア、および前記外側単一層におけるApoEを含む、作用物質を血液−脳関門を渡ってデリバーするための人工LDL粒子。
- 前記固体の脂質コアが、コレステロールを更に含む、請求項22に記載の人工LDL粒子。
- 前記外側単一層におけるApoEが、ApoE3である、請求項22に記載の人工LDL粒子。
- 請求項1に記載の人工LDL粒子と薬学的に許容可能なキャリアを含む、作用物質を血液−脳関門を渡ってデリバーするための組成物。
- 請求項4に記載の人工LDL粒子と薬学的に許容可能なキャリアを含む、作用物質を血液−脳関門を渡ってデリバーするための組成物。
- 請求項5に記載の人工LDL粒子と薬学的に許容可能なキャリアを含む、作用物質を血液−脳関門を渡ってデリバーするための組成物。
- アミノ酸、ペプチド、タンパク質、核酸、炭水化物および脂質から成る群より選択される治療剤に連結されたコレステロールを含むコンジュゲート。
- 前記治療剤が、向神経性因子、成長因子、酵素、抗体、神経伝達物質、神経調節物質、抗生物質、抗ウイルス剤、抗真菌剤および化学療法剤から成る群より選択される、請求項28に記載のコンジュゲート。
- 前記治療剤がアドリアマイシンである、請求項29に記載のコンジュゲート。
- 前記アドリアマイシンとコレステロールがエステル結合により連結される、請求項30に記載のコンジュゲート。
- 前記治療剤がテトラサイクリンである、請求項29に記載のコンジュゲート。
- 前記テトラサイクリンとコレステロールがエステル結合により連結される、請求項32に記載のコンジュゲート。
- 1)コンジュゲートまたは非コンジュゲート治療剤を含有するリン脂質を緩衝液中に懸濁する工程;
2)前記溶液を音波処理し、外側のリン脂質単一層と固体の脂質コアを形成する工程;および
3)少なくとも一のアポリポタンパク質を含む溶液を添加し、前記アポリポタンパク質が前記外側のリン脂質単一層に取り込まれる工程
を含む、請求項1に記載の人工LDL粒子を製造する方法。 - 製造される前記人工LDL粒子が、直径10〜50 nmである、請求項34に記載の方法。
- 効果的な量の請求項25に記載の組成物を、それを必要とする哺乳類に投与することを含む、物質を血液−脳関門を渡ってデリバーするための方法。
- 効果的な量の請求項26に記載の組成物を、それを必要とする哺乳類に投与することを含む、物質を血液−脳関門を渡ってデリバーするための方法。
- 効果的な量の請求項27に記載の組成物を、それを必要とする哺乳類に投与することを含む、物質を血液−脳関門を渡ってデリバーするための方法。
- 請求項25に記載の組成物を含有する容器と使用説明書を含む、物質を血液−脳関門を渡ってデリバーするためのキット。
- 請求項26に記載の組成物を含有する容器と使用説明書を含む、物質を血液−脳関門を渡ってデリバーするためのキット。
- 請求項27に記載の組成物を含有する容器と使用説明書を含む、物質を血液−脳関門を渡ってデリバーするためのキット。
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JP4995423B2 (ja) | 2012-08-08 |
JP5587352B2 (ja) | 2014-09-10 |
KR20110086775A (ko) | 2011-07-29 |
WO2004050062A3 (en) | 2004-12-29 |
US20040204354A1 (en) | 2004-10-14 |
AU2003302676A1 (en) | 2004-06-23 |
CN100386068C (zh) | 2008-05-07 |
JP2012131799A (ja) | 2012-07-12 |
WO2004050062A2 (en) | 2004-06-17 |
US7220833B2 (en) | 2007-05-22 |
CA2791165A1 (en) | 2004-06-17 |
TWI347196B (en) | 2011-08-21 |
US7576055B2 (en) | 2009-08-18 |
AU2003302676A8 (en) | 2004-06-23 |
EP1581186A2 (en) | 2005-10-05 |
KR101111477B1 (ko) | 2012-02-23 |
CN101284136A (zh) | 2008-10-15 |
US7514402B2 (en) | 2009-04-07 |
CA2791165C (en) | 2015-02-24 |
CN1717223A (zh) | 2006-01-04 |
KR20050084163A (ko) | 2005-08-26 |
CA2507762A1 (en) | 2004-06-17 |
KR101186210B1 (ko) | 2012-10-08 |
US7682627B2 (en) | 2010-03-23 |
US20070134313A1 (en) | 2007-06-14 |
US20070292413A1 (en) | 2007-12-20 |
TW200501999A (en) | 2005-01-16 |
US20070264351A1 (en) | 2007-11-15 |
CA2507762C (en) | 2013-02-05 |
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